VOLUME 39
N U M B E R 3 PA RT I
MARCH 2013
ISSN 1076-0512
IN THIS ISSUE Incidence, Risk Factors, and Preventative Management of Skin Cancers in Organ Transplant Recipients: A Review of Single- and Multicenter Retrospective Studies from 2006 to 2010 Importance of Vertical Pathology of Debulking Specimens During Mohs Micrographic Surgery for Lentigo Maligna and Melanoma in Situ Supplementing Fat Grafts with Adipose Stromal Cells for Cosmetic Facial Contouring
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DERMATOLOGIC
SURGERY
EDITOR-IN-CHIEF William P. Coleman III, MD CO-EDITOR Desiree Ratner, MD MANAGING EDITOR Barbara Tregre ASSISTANT EDITORS Joel Cook, MD Jonathan Cook, MD Lisa Donofrio, MD Hayes Gladstone, MD Mitchel Goldman, MD George Hruza, MD Naomi Lawrence, MD
Gary Monheit, MD Rhoda Narins, MD Henry Randle, MD Randall Roenigk, MD Robert Weiss, MD
CONTRIBUTING EDITORS Macrene Alexiades-Armenakas, MD Mathew Avram, MD Ritu Sonia Batra, MD Kenneth Beer, MD Vince Bertucci, MD Fredric Brandt, MD Harold Brody, MD Marc Brown, MD Kimberly Butterwick, MD Henry H.L. Chan, MD Mary Christian, MD Joel Cohen, MD Kyle Coleman, MD Sue Ellen Cox, MD Jeffrey Dover, MD Zoe Diana Draelos, MD David Duffy, MD Lawrence Field, MD Richard Fitzpatrick, MD Timothy Flynn, MD Roy Geronemus, MD Richard Glogau, MD Michael Gold, MD
David Goldberg, MD Greg J. Goodman, MD Jean-Je´roˆme Guex, MD Eckart Haneke, MD Marwali Harahap, MD Christopher Harmon, MD Alysa Herman, MD Tatyana Humphreys, MD Laurie Jacobson, MD Francisco Jimenez, MD Derek Jones, MD Baruch Kaplan, MD Bruce Katz, MD Andrew Kaufman, MD Arielle Kauvar, MD Jeffrey Klein, MD Robert Koppel, MD Pearson Lang, MD Gary Lask, MD Jennifer MacGregor, MD Mary Maloney, MD Andrew C. Markey, MD Seth Matarasso, MD David McDaniel, MD Stanley Miller, MD Gregg Menaker, MD Andrei Metelitsa, MD Tri Nguyen, MD Joe Niamtu, III
Keyvan Nouri, MD Darrell Rigel, MD Gary Rogers, MD Nicole Rogers, MD E. Victor Ross, MD Adam M. Rotunda, MD Mark Rubin, MD Javier Ruiz-Esparza, MD Gerhard Sattler, MD Robert Schwartz, MD Roberta Sengelmann, MD Daniel Siegel, MD Stephen Snow, MD Nowell Solish, MD James Spencer, MD Dow Stough, MD Elizabeth Tanzi, MD Emily Tierney, MD Whitney Tope, MD Mario Trelles, MD Ada Trindade de Almeida, MD Ren-Yeu Tsai, MD Walter Unger, MD Richard Wagner, MD Margaret Weiss, MD Ronald Wheeland, MD David Wrone, MD Cyndi Yag-Howard John Zitelli, MD
Perry Robins, MD, and Founder (1975–1977) Morris Leider, MD (1978–1981)
George L. Popkin, MD (1982–1985) C. William Hanke, MD (1986–1990) Leonard M. Dzubow, MD (1991–1996)
Murad Alam, MD John Albertini, MD Tina Alster, MD Marc Avram, MD Alastair Carruthers, MD Jean Carruthers, MD David Clark, MD FEATURE EDITORS Reconstructive Conundrums: David Brodland, MD Wound Healing: Robert Kirsner, MD
EDITORS EMERITI Ronald Moy, MD (1997–2001)
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PROCEDURAL DERMATOLOGIST Ochsner Health System New Orleans is seeking a Board Certified/Board Eligible Procedural Dermatologist. Candidates must be trained in Mohs Micrographic Surgery and interested in building a cosmetic dermatology practice. Our department is an affiliate training site with the Dermatology Residency Programs at both Tulane University and Louisiana State University.
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Save $100 when you register by April 8–call (800) 766-4955 or visit PlasticSurgery.org/tips Program panel topics include* ADMs Biofilms Digital Applications in Plastic Surgery Fillers and Volumizers Large Volume Fat Grafting Neuromodulation: Chemicals, Currents and Extreme Temperatures Non-Invasive Body Contouring Negative Pressure Wound Therapy and Instillation Therapy (NPWT)
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DERMATOLOGIC
SURGERY
CONTENTS
Volume 39, Number 3 Part I, March 2013
REVIEW ARTICLE 345
Incidence, Risk Factors, and Preventative Management of Skin Cancers in Organ Transplant Recipients: A Review of Single- and Multicenter Retrospective Studies from 2006 to 2010 Tejaswi Mudigonda, BS, Michelle M. Levender, MD, Jenna L. O’Neill, MD, Cameron E. West, MD, Daniel J. Pearce, MD, and Steven R. Feldman, MD, PhD
ORIGINAL ARTICLES 365
372 374 381
387 393 398
406 412 414 422 426 435
443 449
457
Importance of Vertical Pathology of Debulking Specimens During Mohs Micrographic Surgery for Lentigo Maligna and Melanoma in Situ Luciano J. Iorizzo, III, MD, Isaac Chocron, BSc, Wilfred Lumbang, MD, and Thomas Stasko, MD Commentary: Complete Melanoma Microstaging Stanley J. Miller, MD Incidence of Residual Nonmelanoma Skin Cancer in Excisions After Shave Biopsy Kurt Grelck, DO, Sean Sukal, MD, PhD, Les Rosen, MD, and Gabriel P. Suciu, MSPH, PhD Positive KI67 and Periodic Acid-Schiff Mandates Wider Range of Excision in Scrotal Extramammary Paget’s Disease Chen-chen Feng, MD, Lu-jia Wang, MD, Zhong-wen Zhou, MD, Qiang Ding, MD, Zu-jun Fang, MD, Guo-wei Xia, MD, Hao-wen Jiang, MD, Gang Xu, MD, and Hui Wen, MD Tangential Shave Removal of Basal Cell Carcinoma Amanda K. Abramson, MD, Mark J. Krasny, MD, and Glenn D. Goldman, MD Operative Technique with Rapid Recovery for Ingrown Nails with Granulation Tissue Formation in Childhood Claudio I. Perez, MD, Ximena A. Maul, MD, M. Catalina Heusser, MD, and Alejandro Zavala, MD A Simple Therapeutic Approach to Pincer Nail Deformity Using a Memory Alloy: Measurement of Response Jonathan Te-Peng Tseng, MD, Wen-Tsao Ho, MD, Chun-Hung Hsu, MD, Ming-Hsiu Lin, MD, Chien-Nien Li, MD, and Woan-Ruoh Lee, MD, PhD Repigmentation of Poliosis After Epithelial Grafting for Vitiligo Sherif S. Awad, MD, PhD Commentary on Repigmentation of Poliosis After Epithelial Grafting for Vitiligo Nicole E. Rogers, MD Superficial Hemangioma: Pulsed Dye Laser Versus Wait-and-See Janneke P.H.M. Kessels, MD, Ellen T. Hamers, BSc, and Judith U. Ostertag, MD, PhD Inhibition of Fibroblast Proliferation In Vitro Using Low-Level Infrared Light-Emitting Diodes Hadar Lev-Tov, MD, Neil Brody, MD, PhD, Daniel Siegel, MD, MS, and Jared Jagdeo, MD, MS Nonablative Fractional Laser Resurfacing for the Treatment of Hypertrophic Scars: A Randomized Controlled Trial Evelien Verhaeghe, MD, Katia Ongenae, MD, PhD, Jessica Bostoen, MD, and Jo Lambert, MD, PhD Oral Tranexamic Acid Enhances the Efficacy of Low-Fluence 1064-Nm Quality-Switched Neodymium-Doped Yttrium Aluminum Garnet Laser Treatment for Melasma in Koreans: A Randomized, Prospective Trial Jung U. Shin, MD, Jihun Park, MD, Sang Ho Oh, MD, PhD, and Ju Hee Lee, MD, PhD Safety and Efficacy of Intradermal Injection of Botulinum Toxin for the Treatment of Oily Skin Amy E. Rose, MD, and David J. Goldberg, MD Supplementing Fat Grafts with Adipose Stromal Cells for Cosmetic Facial Contouring Jie Li, MD, PhD, Jianhua Gao, MD, PhD, Pengfei Cha, MD, PhD, Qiang Chang, MD, Yunjun Liao, MD, PhD, Chao Liu, MD, Kecheng Li, MD, and Feng Lu, MD, PhD Polycaprolactone for the Correction of Nasolabial Folds: A 24-Month, Prospective, Randomized, Controlled Clinical Trial Marion Michaela Moers-Carpi, MD, and Sally Sherwood, MA
HOW WE DO IT 464
Excessive Columellar Show: Causes, Presentations and a New Therapeutic Approach with Onabotulinum Toxin A Mohammed G. Turkmani, MD, and Koenraad De Boulle, MD
RECONSTRUCTIVE CONUNDRUM 468
Modified Three-Point Rotation-Advancement Flap for the Repair of the Melolabial Groove and a Peri-Alar C-Shaped Defect Byung Cheol Park, MD, Ji Won Gye, MD, Seung Pil Hong, MD, and Myung Hwa Kim, MD
LETTERS 472 474
477 480 483 487 490 490 491
OnabotulinumtoxinA Unmasking Myasthenia Gravis Zoey R. Glick, MD, Michael S. Vaphiades, DO, and Marian E. Northington, MD Superficial Frostbite Masquerading as Ecchymosis from Improper Cryotherapy Use After Q-Switched Laser Tattoo Treatment William Kirby, DO, FAOCD, Madeline Tarrillion, MSIV, and Alpesh Desai, DO, FAOCD Refractory Pyoderma Gangrenosum Effectively Treated Using a 10,600-nm Carbon Dioxide Fractional Laser Jihun Park, MD, Min Ju Choi, MD, Boncheol Goo, MD, PhD, and Sung Bin Cho, MD, PhD Laser Hair Removal Put in the Wrong Hands Mahrukh S. Nisar, BA, MPA, Jenifer R. Lloyd, DO, and Tanweer Khan, MD Challenging the Dogma of “Watchful Waiting” for Desmoplastic Trichoepithelioma Selina Singh, BA, Ronald Rapini, MD, Mary Schwartz, MD, Robin Friedman-Musicante, MD, and Paul M. Friedman, MD Evaluation of Residual Tumor from Mohs Micrographic Specimens of Clinically Resolved Preoperative Biopsy Sites Soonyou Kwon, MD, Tonja Godsey, HT, and Hugh M. Gloster Jr., MD Adamantinoid Basal Cell Carcinoma: A Predictor of More Aggressive Clinical Behavior Hina Ahmad, MD, and Richard G. Bennett, MD Judicious Discontinuation of Antithrombotic Medications in Skin Surgery Porntawee P. Aphivantrakul, BS, Mary Alice Mina, MD, M. Dale Sarradet, MD, and Ryan Wells, MD Cell Phone-Assisted Identification of Surgery Site Michael K. Lichtman, MD, and Nicholas B. Countryman, MD, MBA
Simulated Simulated image image based based on locally on locally advanced advanced BCCBCC patient patient at Week at Week 24.24. • Advise • Advise patients patients to contact to contact theirtheir healthcare healthcare provider provider immediately immediately if they if they suspect suspect they they (or, (or, for males, for males, Erivedge Erivedge (vismodegib) (vismodegib) capsule capsule is indicated is indicated for the for the female female partner) partner) maymay be pregnant be pregnant treatment treatment of adults of adults withwith metastatic metastatic basalbasal cell carcinoma, cell carcinoma, theirtheir • Immediately • Immediately report report exposure exposure to Erivedge to Erivedge during during or with or with locally locally advanced advanced basal basal cell cell carcinoma carcinoma thatthat pregnancy pregnancy and and encourage encourage women women who who may may have have has recurred has recurred following following surgery surgery or who or who are not are candidates not candidates exposed exposed to Erivedge to Erivedge during during pregnancy, pregnancy, either either for surgery, for surgery, and and whowho are not are candidates not candidates for radiation. for radiation. beenbeen directly directly or through or through seminal seminal fluid, fluid, to participate to participate in in Boxed Boxed Warning Warning andand Additional Additional the Erivedge the Erivedge pregnancy pregnancy pharmacovigilance pharmacovigilance program program by contacting by contacting the the Genentech Genentech Adverse Adverse Event Event LineLine Important Important Safety Safety Information Information at (888) at (888) 835-2555 835-2555 • Erivedge • Erivedge capsule capsule can can cause cause fetalfetal harm harm when when Blood Blood Donation Donation administered administered to ato pregnant a pregnant woman woman based based on on its mechanism its mechanism of action of action • Advise • Advise patients patients not to notdonate to donate blood blood or blood or blood products products while while receiving receiving Erivedge Erivedge and and for at forleast at least 7 months 7 months • Verify • Verify pregnancy pregnancy status status priorprior to the to the initiation initiation of of the the last last dosedose of Erivedge of Erivedge Erivedge. Erivedge. Advise Advise malemale and and female female patients patients of these of these afterafter risks. risks. Advise Advise female female patients patients of the of the needneed for for Nursing Nursing Mothers Mothers contraception contraception during during and and afterafter treatment treatment and and advise advise • Inform • Inform female female patients patients of the of the potential potential for serious for serious malemale patients patients of the of the potential potential risk risk of Erivedge of Erivedge adverse adverse reactions reactions in nursing in nursing infants infants fromfrom Erivedge, Erivedge, exposure exposure through through semen semen taking taking intointo account account the the importance importance of the of the drugdrug to the to the mother mother
Indication Indication ®
®
1 1 ORAL, ORAL, ONCE-DAILY ONCE-DAILY THERAPY THERAPY
TRANSFORM TRANSFORM THE THE TREATMENT TREATMENT OFOF ADVANCED ADVANCED BCC BCC Erivedge— Erivedge— a unique a unique treatment treatment option option • Systemic • Systemic therapy therapy thatthat targets targets dysregulated dysregulated Hedgehog Hedgehog 1,2 1,2 pathway pathway signaling, signaling, a known a known driver driver of BCC of BCC • One • One 150-mg 150-mg capsule capsule a day a day untiluntil disease disease progression progression 1 1 or unacceptable or unacceptable toxicity toxicity 1,3 1,3 • Erivedge • Erivedge reduced reduced lesions lesions in patients in patients withwith advanced advanced BCCBCC
1,3* 1,3* Objective Objective response response ratesrates (ORR) (ORR) by IRF by IRF fromfrom ERIVANCE ERIVANCE
laBCC laBCC (n=63) (n=63)mBCC mBCC (n=33) (n=33) 43%43% (n=27) (n=27) 30%30% ORRORR (n=10) (n=10) (30.5-56.0) (30.5-56.0) (15.6-48.2) (95% (95% CI) CI) (15.6-48.2) (n=13) (n=13) 0% 0% Complete Complete response response 21%21% Partial Partial response response Median Median response response duration duration (months) (months) (95% (95% CI) CI)
22%22% (n=14) (n=14) 30%30% (n=10) (n=10) 7.6 7.6 (5.7-9.7) (5.7-9.7)
7.6 7.6 (5.6-NE) (5.6-NE)
*Patients *Patients received received at least at 1least dose1 of dose Erivedge of Erivedge with independent with independent pathologist-confi pathologist-confi rmed rmed diagnosis diagnosis of BCC. of BCC. Response Response in laBCC: in laBCC: absence absence of disease of disease progression progression and either and either ≥30%≥30% reduction reduction in lesion in lesion size (sum size of (sum theof longest the longest diameter) diameter) from baseline from baseline in target in target lesionslesions by by radiography radiography or in externally or in externally visiblevisible dimension dimension (including (including scar tissue); scar tissue); or complete or complete resolution resolution of ulceration of ulceration in all target in all target lesions. lesions. Complete Complete responders responders also had alsonohad residual no residual BCC on BCC sampling on sampling biopsybiopsy and partial and partial responders responders had residual had residual BCC on BCC sampling on sampling biopsy.biopsy. Response Response in mBCC: in mBCC: assessed assessed by theby Response the Response Evaluation Evaluation Criteria Criteria in Solid in Solid Tumors Tumors (RECIST) (RECIST) version version 1.0. 1.0. IRF=Independent IRF=Independent Review Review Facility. Facility. laBCC=locally laBCC=locally advanced advanced BCC. BCC. mBCC=metastatic mBCC=metastatic BCC. BCC. CI=confi CI=confi dencedence interval. interval. NE=not NE=not estimable. estimable.
Adverse Adverse Reactions Reactions
• The • The mostmost common common adverse adverse reactions reactions (≥10%) (≥10%) werewere muscle muscle spasms, spasms, alopecia, alopecia, dysgeusia, dysgeusia, weight weight loss,loss, fatigue, fatigue, nausea, nausea, diarrhea, diarrhea, decreased decreased appetite, appetite, constipation, constipation, arthralgias, arthralgias, vomiting, vomiting, andand ageusia ageusia • In •clinical In clinical trials, trials, a total a total of 3ofof310 of premenopausal 10 premenopausal women women developed developed amenorrhea amenorrhea whilewhile receiving receiving Erivedge Erivedge • Treatment-emergent • Treatment-emergent grade grade 3 laboratory 3 laboratory abnormalities abnormalities observed observed in clinical in clinical trials trials werewere hyponatremia hyponatremia in 6in 6 patients patients (4%), (4%), hypokalemia hypokalemia in 2in patients 2 patients (1%), (1%), and and azotemia azotemia in 3inpatients 3 patients (2%) (2%) Please Please see see BriefBrief Summary Summary of Prescribing of Prescribing Information Information on following on following page. page.
© 2012 © Genentech 2012 Genentech USA, Inc. USA, AllInc. rights All reserved. rights reserved. HED0001473000 HED0001473000 PrintedPrinted in USA. in USA.
SeeSee what what youyou cancan offer offer youryour patients patients withwith advanced advanced BCC BCC at www.Erivedge.com at www.Erivedge.com ® ® References: References: 1. Erivedge 1. Erivedge (vismodegib) (vismodegib) capsule capsule Prescribing Prescribing Information. Information. Genentech, Genentech, Inc. January Inc. January 2012.2012. 2. Epstein 2. Epstein EH. Nat EH.Rev NatCancer. Rev Cancer. 2008;2008; 8:743-754. 8:743-754. 3. Sekulic 3. Sekulic A, Migden A, Migden MR, Oro MR,AE, OroetAE, al.et N al. Engl N JEngl Med. J Med. 2012;366:2171-2179. 2012;366:2171-2179.
T:8” S:7”
Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)
MedDRA Preferred Term
Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia
ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].
All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss
All Grades 3 (%)
Grade 3 (%)
Grade 4 (%)
42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)
1 (0.7%) 1 (0.7%) -
-
55 (39.9%)
7 (5.1%)
1 (0.7%)
62 (44.9%)
10 (7.2%)
-
All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)
35 (25.4%)
3 (2.2%)
-
99 (71.7%) 22 (15.9%)
5 (3.6%) 1 (0.7%)
-
76 (55.1%) 15 (10.9%)
-
-
88 (63.8%)
-
-
aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1
7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because
Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t"EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t*OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t*OTUSVDUBMMNBMFQBUJFOUT FWFOUIPTFXJUIQSJPSWBTFDUPNZ UPVTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t*OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t*OTUSVDUQBUJFOUTUPJNNFEJBUFMZSFQPSUBOZQSFHOBODZFYQPTVSFUP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t*OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t"EWJTFQBUJFOUTOPUUPEPOBUFCMPPEPSCMPPEQSPEVDUTXIJMFUBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t"EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.
ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301
S:9.75”
1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients
2
of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]
Clinical Assistant Professor of Mohs Surgery Position A full-time position in Mohs surgery at the rank of Clinical Assistant Professor is available in the Division of Dermatology, The University of Texas Health Science Center at San Antonio (UTHSCSA). UTHSCSA, the largest medical institute in South Texas, serves San Antonio and the 50,000 square-mile area of South Texas with a population of more than 4.2 million. The applicant should have a M.D. or D.O., be board certified in Dermatology, and be fellowship trained in Mohs surgery. The applicant should be motivated, organized and able to fulfill the surgical support needed for the division and our GME Dermatology residency program. The Mohs position will allow complete care of skin cancers particularly of the head and neck for non-melanoma (Squamous cell carcinoma/Basal cell carcinoma) and melanoma skin cancers. Clinical Dermatology, Laser and Cosmetic experience is preferred. The city of San Antonio, the seventh-most populated in the U.S., has a vibrant art community that reflects the rich history and culture of the area with affordable housing, excellent schools, and a low crime rate. This unique city offers some of the best cultural institutions, events, restaurants, and friendly people in South Texas. Interested candidates should email:
[email protected] The University of Texas Health Science Center at San Antonio is an Equal Employment Opportunity/Affirmative Action Employer. All faculty appointments are designated as security sensitive positions.
2013 Mohs College Annual Meeting Join us in the Nation's Capital for the highest caliber educational sessions in Mohs surgery, cutaneous oncology, reconstruction, and more!
• Attend multiple morning mini-sessions • Earn valuable continuing medical education credit hours, Thursday through Sunday • Settle in at a first-rate hotel, which has played host to presidents, world leaders and inaugural balls, making it a true historic Washington, D.C. landmark • Reconnect with colleagues • Earn up to 24.5 continuing medical education credit hours, Thursday through Sunday
WASHINGTON, TON, D.C. Omni Shoreham • May 2 ~ May 5, 2013
Take advantage of advanced meeting and hotel registration rates starting January 10, 2013. More information is available at: Website: http://www.mohscollege.org/annualmeeting Email:
[email protected] Tel: 414-347-1103 or 800-500-7224
ACMS-0113-829
REVIEW ARTICLE
Incidence, Risk Factors, and Preventative Management of Skin Cancers in Organ Transplant Recipients: A Review of Singleand Multicenter Retrospective Studies from 2006 to 2010 TEJASWI MUDIGONDA, BS,* MICHELLE M. LEVENDER, MD,* JENNA L. O’NEILL, MD,* CAMERON E. WEST, MD,* DANIEL J. PEARCE, MD,* AND STEVEN R. FELDMAN, MD, PHD*†‡
BACKGROUND Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. OBJECTIVES OTRs.
To characterize the most common skin cancers arising from chronic immunosuppression in
METHODS A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study’s immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. RESULTS Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi’s sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). CONCLUSION Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function. The Center for Dermatology Research is supported by an educational grant from Galderma Laboratories, L.P. Dr. Feldman has received research, speaking and/or consulting support from Galderma, Abbott Labs, Warner Chilcott, Aventis Pharmaceuticals, 3M, Connetics, Roche, Amgen, Astellas, Centocor, National Biological Corporation, Biogen, Leo, GSK/Steifel and Genentech. The remaining authors indicate no significant interest with commercial supporters.
I
n the United States, approximately 100,000 individuals receive long-term immunosuppressive therapy to preserve life-sustaining solid organ allografts.1 Chronic immunosuppression places these organ transplants recipients (OTRs), especially lung, heart, and double OTRs, at high risk of developing cancer. Skin cancers are the most frequent malignancies associated with post-transplantation immu-
nosuppression, with nearly 44% of OTRs developing multiple skin cancers. The lesions found in this population are often much larger and more aggressive than those typically found in immunocompetent patients.2–4 Dermatologic management of immunosuppressed OTRs presents a daunting therapeutic challenge that
*Department of Dermatology, Center for Dermatology Research, School of Medicine, Wake Forest University, Winston-Salem, North Carolina; †Department of Pathology, Center for Dermatology Research, School of Medicine, Wake Forest University, Winston-Salem, North Carolina; ‡Department of Public Health Sciences, Center for Dermatology Research, School of Medicine, Wake Forest University, Winston-Salem, North Carolina © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:345–364 DOI: 10.1111/dsu.12028 345
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has led to the development of specialized care in integrated OTR dermatology clinics within transplant centers. Many of the basic management principles and techniques for immunocompetent patients apply equally to OTRs but with the additional measure of monitoring various immunosuppressive regimens. The objective of this review is to characterize the incidence, risk factors, and management of skin cancers in OTRs. We also highlight the importance of preventative care, the role of integrated OTR clinics, and modifications of immunosuppressive regimens as integral to the preventative management of OTRs.
Methods A PubMed search was performed using the search terms “transplant [title/abstract] cancer [title/ abstract] skin,” which yielded 664 entries (Figure 1). To narrow the search, we focused on studies that met the following inclusion criteria: retrospective studies with a cohort of 50 or more OTRs, studies published from 2006 to 2010, studies indicating that patients were on a maintenance immunosuppressive regimen after transplantation and specifying immunosuppressant medications, and English language only.
For information regarding the management of posttransplantation management of skin cancers, we sought studies that discussed the role of preventative care and integrated OTR dermatology clinics. We also briefly evaluated reviews, surveys, case series, and prospective studies that discussed immunosuppressant drug reduction as an effective therapeutic strategy in the management of skin cancer in OTRs. Prospective studies and randomized controlled studies were excluded because they tended to focus more specifically on the treatment parameters of immunosuppression such as the mechanism of immunosuppressants or comparisons in the efficacy of different immunosuppressive agents. Case reports and foreign studies were also excluded, as were studies reporting only on premalignant benign or atypical nevi. Thus our review focused on singleand multicenter retrospective studies published from 2006 to 2010. Thirty-six articles that met our inclusion criteria were examined for further review. Information on the types of immunosuppressive regimens, maintenance immunosuppressants used, mean time of posttransplantation cancer diagnosis, number of skin
Figure 1. Flow chart showing the selection of single and multicenter retrospective studies that reported skin cancers in organ transplant recipients.
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cancer lesions, and percentage of transplanted recipients with skin cancer was extracted from these studies. In addition, we sought information regarding any statistically significant risk factor correlations for skin cancer in the OTR cohort of each study.
Results Role of Immunosuppression in Transplantation The different types and incidence of skin cancers, infections, and drug side effects often depend on the specific immunosuppressive regimen used. Current protocols use a combination of agents with different modes of action and toxicities directed at specific sites of the T-cell activation cascade, allowing lower doses of each drug.5,6 In transplantation, immunosuppressive therapy consists of two phases: induction and maintenance. The induction phase occurs perioperatively and immediately after transplantation. Maintenance therapy then proceeds for the life of the allograft. Both phases use different medicines at specific dose regimens, and it is the aim of the maintenance phase to chronically immunosuppress the patient to prevent rejections throughout the life of the graft. The pharmacology and toxicities of the most common immunosuppressive agents used in transplantation are outlined in Table 1. Incidence and Risk Factors of Skin Cancers in OTRs Nonmelanoma Skin Cancer Nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most common cutaneous malignancy in OTRs, accounting for nearly 90% of all skin cancers in transplant recipients.7–9 The incidence of BCC and SCC is 10 and 100 times as great, respectively, as in the general population.10 SCC in particular appears to be more aggressive in transplant recipients than in nonimmunosuppressed individuals.11–14 Furthermore, NMSC has been shown to be associated with mortality of 5% to 8% in OTRs.15
Twenty-eight of 36 of the reviewed studies reported incidences of NMSC (Table 2). Contrary to the situation in the general population, numerous studies have reported that cutaneous SCC is more frequent than BCC in transplant patients.16–21 With regard to incidence and ratios of NMSC, a reversal of the high BCC:SCC ratio seen in the general population was observed in four notable studies, which reported 7:122, 3:122, and 2:123,24 SCC:BCC ratios. Reversal of this ratio appears to be organ specific according to most of the published studies. In other retrospective studies, three recent reviews reported a greater percentage of OTRs with BCC than SCC, with BCC:SCC ratios of 16:125, 6:126, and 4:110. The reasons for the higher BCC:SCC ratio have not been well elucidated, although two of the studies indicate that the small sample size may be a cause of for the ratio discrepancy.10,26 Two studies reported an approximately 1:127,28 BCC:SCC ratio for diagnosed NMSC cancers, possibly because of short follow-up.28 The mean age of diagnosis of a first NMSC since transplantation has varied between studies, with reports of between 4 and 9 years after kidney transplantation.19,29,30 The primary anatomic NMSC location reported is the head and neck10,22,23,31; other common areas include the upper limbs, trunk, and other sun-exposed areas. Numerous risk factors have been associated with the development of NMSC in OTRs in the reviewed studies (Table 3). Sex plays a strong role, with men having greater risk of developing NMSC than women.23,24,27,32 Age at transplantation is also important, with older age correlating with greater risk of NMSC.22–24,27,32,33 Longer post-transplantation follow-up time is also correlated with NMSC development.27 Fitzpatrick skin phototypes play an important role, with patients with fair skin having far more SCCs than dark-skinned individuals.34 Sunlight exposure32 ( 2,500 hours annually) and geography23 (northern climate) were also correlated with greater risk of developing NMSC.
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TABLE 1. Pharmacology of the Most Commonly Used Transplantation Immunosuppressants Class
Mode of Action
Azathioprine
Antimetabolite; purine analog
Corticosteroids
Calcineurin inhibitor
Cyclosporine
Calcineurin inhibitor
Inhibits purine and DNA synthesis Inhibit production of T cell cytokines such as IL-2, IL-6 Inhibits phosphatase activity of calcineurin
Fingolimod
Synthetic analog
Reduces circulation of lymphocytes
Leflunomide
Pyrimidine analog
Inhibits pyrimidine synthesis
Rifampin, tolbutamide
Muromonab-CD3 (OKT3)
Monoclonal antibody
Cyclosporine, basiliximab, azathioprine
Mycophenolate mofetil
Antimetabolite, acid prolog
Causes depletion and receptor modulation in T cells Inhibits purine and DNA synthesis
Sirolimus (rapamycin)
Rapamycin inhibitor
Tacrolimus
Calcineurin inhibitor, macrolide antibiotic
Inhibits IL-2- and IL-15-driven proliferation of B, T, and vascular smooth muscle cells Inhibits phosphatase activity of calcineurin
Characteristics of the immunosuppressive regimen itself—duration, type, induction therapy—are important risk factors. Longer duration of immunosuppression correlates with greater number of SCCs.34 Azathioprine and tacrolimus were associated with greater risk of developing skin cancer.32,35 Two studies found that induction therapy with
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Major Potential Drug Interactions
Agent
DERMATOLOGIC SURGERY
Major Toxicity
Allopurinol, warfarin
Lymphoma, pancreatitis
Antacids, cyclosporine A
Cushing disease, bone disease
Diltiazem, verapamil, nicardipine, erythromycin, azithromycin, clarithromycin Ketoconazole
Nephrotoxicity, neurotoxicity, hypertension
Acyclovir, ganciclovir, probenecid, salicylates, sirolimus, aluminum or magnesium, cholestyramine, iron, metronidazole, norfloxacin, rifampin Erythromycin, fluconazole, protease inhibitors
Erythromycin, azithromycin, fluconazole, diltiazem, verapamil, nelfinavir
Fatigue, melanocytic nevus, lymphopenia Hypertension, gastrointestinal effects (diarrhea, dyspepsia), skin rash, allergic reactions, alopecia Nephrotoxicity, encephalopathy, neurotoxicity Gastrointestinal toxicity, anemia, neutropenia
Thrombocytopenia, leukopenia, anemia, hyperlipidemia
Nephrotoxicity, neurotoxicity, diabetes mellitus
OKT3 and anti-thymocyte globulin therapy increased the incidence of NMSC.24,32 The presence of premalignant infections such as human papillomavirus (HPV) and post-transplant viral warts23 are risk factors for NMSC in the setting of chronic immunosuppression.36 One factor for the
Retrospective single-center study (France) Retrospective single-center study (Canada)
Retrospective single-center study (Taiwan) Retrospective single-center study (Wisgerhof)
Kessler et al.117
Feng et al.128
Wisgerhof et al.35
Comeau et al.23
Retrospective multicenter study (Spain)
Retrospective single-center study (Switzerland) Retrospective single-center study (England) Retrospective single-center study (Croatia)
Crespo-Leiro et al.24
Basic-Jukic et al.25
Perera et al.26
Keller et al.34
Authors
Study Design (Location)
208 SPKTR, 1,111 RTR
283 RTR
608 RTR
488 RTR
3,393 HTR
Monotherapy to triple therapies
Dual or triple therapies
N/A
Double or triple therapy
N/A
Monotherapy
Monotherapy to triple therapies
100 LTR
1,232 RTR
Monotherapy to quadruple therapies
Types of Immunosuppressive Regimens
243 RTR
Recipient Cohort
TABLE 2. Skin Cancers Arising in Organ Transplant Recipients
Cyclosporine, prednisolone, azathioprine Azathioprine in any combination, MMF in any combination, cyclosporine A-alone, tacrolimus-alone
Cyclosporine, azathioprine, MMF, prednisone, tacrolimus, sirolimus, everolimus, OKT3, ATG, basiliximab, daclizumab Cyclosporine, prednisone, azathioprine Prednisone, MMF, cyclosporine, azathioprine,
Prednisone, cyclosporine, azathioprine, MMF, sirolimus, tacrolimus Cyclosporine A, azathioprine, prednisolone, tacrolimus, MMF CNI, sirolimus
Maintenance Immunosuppressants
N/A
3.71
5.4 (women), 6.4 (men) N/A
N/A
4.7
N/A
N/A
Mean Time of PostTransplantation Cancer Diagnosis, Years
73 SCC, 36 BCC in 26 SPKTR; 102 SCC, 121 BCC in 68 RTR
2 KS
376 SCC, 157 BCC
16 BCC, 1 MCC, 1 SCC, 6 basocellular skin cancer in 21 RTR 639 total tumors in 490 HTR; 327 skin cancers: 216 SCC, 92 BCC, 10 KS, 9 M N/A
541 AK, 138 SCC, 20 BCC, 2 M in 243 RTR 1 SCC, 6 BCC in 4 LTR
Number of Skin Cancer Lesions*
N/A
KS, 0.8% 12.5% of SPKTR and 6.1% of RTR developed at least one NMSC skin cancer
N/A
NMSC, 10.4%
Primary NMSC skin cancers: head and neck (67.8%) N/A
N/A
N/A
SCC, 8.7% BCC, 6.6%
All cancers: head and neck (100%)
N/A
SCC, 1% BCC, 3% AK, 11% N/A
N/A
Location of Lesion‡
N/A
Transplant Recipients Affected†
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Retrospective registry analysis (Ireland)
Retrospective single-center study (Israel)
Retrospective single-center study (Czech Republic) Retrospective single-center study (France)
Moloney et al.22
Amital et al.59
Kalinova et al.30
Popov et al.131
Aseni et al.130
Koukourgianni et al.48
Retrospective single-center study (Italy) Retrospective single-center study (Macedonia)
Retrospective multicenter study (Tunisia) Retrospective single-center study (Hungary)
Harzallah et al.61
Fekecs et al.10
Retrospective single-center study (Japan)
Arichi et al.129
Authors
Study Design (Location)
TABLE 2. Continued
185 RTR
502 LTR
240 RTR
603 RTR
121 lung and heart/lung transplant recipients
Monotherapy or double therapies
Quadruple therapies
N/A
Triple therapies
Triple therapies
Triple therapies
Monotherapy
116 RTR and P/RTR
1,556 RTR
N/A
Monotherapy or double therapies
Types of Immunosuppressive Regimens
514 RTR
429 RTR
Recipient Cohort
Cyclosporine A, azathioprine, prednisone, ATG MMF, prednisone
Cyclosporine, azathioprine, prednisone, MMF, tacrolimus ATG, prednisolone, azathioprine, cyclosporine A, basiliximab, MMF
Prednisone, tacrolimus, MMF
Cyclosporine, zathioprine, steroids
Azathioprine, prednisone, cyclosporine, tacrolimus CNI, cyclosporine A, tacrolimus, azathioprine, MMF, corticosteroids Cyclosporine, MMF
Maintenance Immunosuppressants
N/A
N/A
10.6
NMSC, 5.2; M, 4.83; MCC, 3.83
4.3
N/A
4.1
8 SCC, 2 BCC, 3 KS in 13 RTR
N/A
2 SCC, 4 BCC, 1 BD in 3 RTR
76 BCC, 48 SCC, 2 M, 1 MCC
449 SCC, 168 BCC, 2 nonspecific, 3 other in 257 RTR N/A
13 BCC, 3 SCC in 11 RTR and P/RTR
N/A
N/A
16.75
KS: 2.59
Number of Skin Cancer Lesions*
Mean Time of PostTransplantation Cancer Diagnosis, Years
NMSC, 5.4% KS, 1.62%
NMSC, 1.94% KS, 1.08%
SCC, 0.41% BCC, 0.83% BD, 0.41%
SCC, 4.1% basosquamous skin cancer, 0.8% BCC, 1.7% KS, 2.5% NMSC, 8.6% M, 0.3% MCC, 1.6%
64.8% NMSC
SCC, 0.97% BCC, 0.19% KS, N/A 9.5% of RTR andP/RTR developed skin cancer
15% of RTR developed skin cancer
Transplant Recipients Affected†
SCC and BCC on eyelid, BCC only on scalp, BD on hand Sun-exposed areas for NMSC N/A
MCC on right buttock
SCC and BCC: head and neck (81.25%), upper limbs (12.5%), trunk (6.25%) All NMSC cancers: scalp and neck, upper limb, right arm N/A
N/A
N/A
Location of Lesion‡
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Double to quadruple therapies N/A
66 HTR
Retrospective single-center study (Taiwan)
Retrospective single-center study (Hungary)
Retrospective multicenter study (Italy)
Chen et al.132
Vegso et al.33
Tessari et al.31 1,476 RTR and 458 HTR
2535 RTR
Monotherapy to combinatorial therapies
Double to quadruple therapies
N/A
1017 RTR
4,089 HTR
Retrospective single-center study (Spain)
Molina et al.32
Navarro et al.27
Double or triple therapies
Types of Immunosuppressive Regimens
Retrospective multicenter study (Italy) Retrospective registry analysis (Spain)
417 LTR
Recipient Cohort
Baccarani et al.60
Authors
Study Design (Location)
TABLE 2. Continued
Cyclosporine, steroids, azathioprine, MMF Cyclosporine, azathioprine, prednisone, MMF, tacrolimus, sirolimus, everolimus, OKT3, ATG, basiliximab, daclizumab Prednisolone, cyclosporine, tacrolimus, azathioprine, MMF ATG, prednisolone, cyclosporine, azathioprine, MMF, tacrolimus Prednisone, azathioprine, cyclosporine, MMF, tacrolimus Azathioprine, cyclosporine, methylprednisolone, tacrolimus, MMF, sirolimus, everolimus, OKT3, ATG
Maintenance Immunosuppressants
1st NMSC, 8.4; 2nd NMSC, 2.2
159 SCC, 132 BCC in 146 RTR and 54 HTR
Of 8 HTR diagnosed with malignancy, 1 HTR had SCC 51 skin tumors in 51 RTR
N/A
4.59
26 SCC, 24 BCC, 2 KS
7.5
169 SCC, 104 BCC, 9 M, 4 KS, 35 other, 3 unknown in 204 HTR
6 KS, 2 M
N/A
N/A
Number of Skin Cancer Lesions*
Mean Time of PostTransplantation Cancer Diagnosis, Years
9.9% RTR and 11.8% HTR developed at least one NMSC
Head and neck (58.5% vs 54.9%), trunk (22% vs 17.6%), upper arms (17% vs 15.4%), lower legs (2.5% vs 12.1%) for primary and secondary NMSC, respectively
SCC on left cheek and anterior chest N/A
SCC, 1.5%
2.0% RTR developed skin cancer
N/A
N/A
SCC, 4.1% BCC, 2.5%
SCC, 2.6% BCC, 2.4% KS, 0.2%
N/A
Location of Lesion‡
KS, 1.4% M, 0.5%
Transplant Recipients Affected†
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352
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Double to triple therapies
2,211 RTR
273 RTR
Retrospective single-center study (Iran)
Retrospective single-center study (Iraq)
Retrospective single-center study (Spain) Retrospective multicenter study (Iran)
Retrospective single-center study (Spain)
Altaee et al.133
Marques Medina et al.28 Einollahi et al.62
RomeroVargas134 N/A
Double therapy to combination therapies
7939 RTR
515 LTR
N/A
528 LTR
Monotherapy or double therapies
Abbaszadeh and Taheri58
1,874 RTR
Retrospective single-center study (England)
Le Mire et al.76
N/A
Types of Immunosuppressive Regimens
Retrospective single-center study (Italy)
382 RTR and 202 LTR
Recipient Cohort
Baccarani et al.100
Authors
Study Design (Location)
TABLE 2. Continued
Cyclosporine, azathioprine, prednisone, tacrolimus, MMF
Cyclosporine A, azathioprine, steroids Prednisone, azathioprine, cyclosporine, MMF, ATG/ALG
Azathioprine, cyclosporine, prednisolone, mycophenolate Azathioprine, cyclosporine, prednisolone
Azathioprine, prednisolone, and cyclosporine
Tacrolimus, cyclosporine, MMF, steroids
Maintenance Immunosuppressants
N/A
KS: 2.25
In 32 LTR, 59 total tumors were found: 9 BCC, 6 SCC
14 BCC, 11 SCC, 1 M, 1 KS In 23 LTR 17 SCC, 9 BCC, 2 M, 55 KS in 83 RTR
N/A
N/A
N/A
8 KS in 10 RTR
6 SCC, 2 BCC, 2 M, 2 KS in 12 RTR; 1 SCC, 1 BCC, 1 M, 1 MCC in 4 LTR 12 M in 10 RTR
Number of Skin Cancer Lesions*
N/A
11
N/A
Mean Time of PostTransplantation Cancer Diagnosis, Years
N/A
4.3% of LTR developed skin cancer SCC, 0.21% BCC, 0.11% KS, 0.7% M, 0.02%
SCC, 1.5% BCC, 0.7% KS, 1.8%
KS, 0.36%
M, 0.5%
3.14% RTR and 2.0% LTR developed skin cancer
Transplant Recipients Affected†
For KS, skin involvement was universal as legs were 2x affected than arms N/A
BCC and SCC appeared on sunexposed areas; individuals with KS presented on upper and lower limbs N/A
Trunk (58%), upper limbs (25%), lower limbs (17%) N/A
N/A
Location of Lesion‡
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Retrospective multicenter study (Italy)
Retrospective registry analysis (Australia) Retrospective registry analysis (Finland)
Tessari et al.65
Vajdic et al.75 Combination therapy
Combination therapy
4,200 RTR
Combinatorial therapy
8,152 RTR
1,356 RTR, 268 HTR, 97 LTR
Cyclosporine A, methylprednisolone, azathioprine
Azathioprine-based, cyclosporine-based, MMF, tacrolimus, sirolimus Azathioprine, cyclosporine A, prednisolone, tacrolimus, MMF Calcineurin inhibitors, antiproliferative agents, ATG, OKT3
Azathioprine, cyclosporine, MMF, tacrolimus, sirolimus, prednisone, ATG, methylprednisolone, basiliximab
Cyclosporine, prednisolone, azathioprine, MMF
Maintenance Immunosuppressants
82 M in 82 RTR
N/A
MCC, 11
MCC, 0.07%
M, 1%
KS- 2.3%
55 KS in 55 OTR
N/A
KS, 1.5% SCC, 0.05% BCC, 0.32%
14.2% of RTR developed skin cancer N/A
Transplant Recipients Affected†
N/A
34 M in 31 OTR
M: 4.7
KS. 2.84; other skin cancers. 7.13 KS: 1.5
20 AK, 7 SCC, 5 BCC, 1 KS in 33 RTR
Number of Skin Cancer Lesions*
N/A
Mean Time of PostTransplantation Cancer Diagnosis, Years
All MCC occurred in the skin of the head: two in a cheek, one in an earlobe
N/A
N/A
Most commonly diagnosed areas were abdomen, back, arms, and shoulders N/A
N/A
Location of Lesion‡
HTR, heart transplant recipients; LTR, liver transplant recipients; OTR, organ transplant recipients; P/RTR, pancreas and renal transplant recipients; RTR, renal transplant recipients; SPKTR, simultaneous pancreas and kidney transplant recipients; ALG, antilymphocyte globulin; ATG, antithymocyte globulin; CNI, calcineurin inhibitor; MMF, mycophenolate mofetil; OKT3, muromonab-CD; AK, actinic keratosis; BD, Bowen’s disease; BCC, basal cell carcinoma; M, melanoma; MCC, Merkel cell carcinoma; SCC, squamous cell carcinoma; NMSC, nonmelanoma skin cancer. *Reports of Kaposi’s sarcoma (KS) incidence consisted of only those with cutaneous involvement. † Number of affected recipients/total number of reported transplant recipients. If study reported only recipients with skin cancer, percentage breakdown with respect to specific type of skin cancer is provided. Percentage also accounts for patients with single or multiple tumors. ‡ Location site and frequency are with respect to all skin cancers or a specific skin cancer.
Koljonen et al.99
Retrospective single-center study (Egypt)
Donia et al.64 Combinatorial therapy
N/A
N/A
Retrospective multicenter study (United States)
Dapprich et al.77
1,866 RTR
Double or triple therapies
233 RTR
Types of Immunosuppressive Regimens
Retrospective single-center study (Iran)
Recipient Cohort
Zamanian et al.42
Authors
Study Design (Location)
TABLE 2. Continued
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TABLE 3. Major Skin Cancer Risk Factors in Organ Transplant Recipients (OTR) Taking Immunosuppressants Risk Factor Category
Authors
Study Characteristic 34
Sex
Keller et al. Molina et al.32 Navarro et al.27 Comeau et al.23 Crespo-Leiro et al.24
Age at transplantation
Keller et al.34 Tessari et al.65 Abbaszadeh and Taheri58 Vajdic et al.75 Wisgerhof et al.35 Vegso et al.33 Moloney et al.22 Molina et al.32 Navarro et al.27 Comeau et al.23 Arichi et al.128 Crespo-Leiro et al.24
Duration of immunosuppression
Keller et al.34 Moloney et al.22
Type of immunosuppressant
Keller et al.34 Tessari et al.65
Wisgerhof et al.35
Molina et al.32 Navarro et al.27 Crespo-Leiro et al.24
354
Induction therapy
Crespo-Leiro et al.24
Skin type
Molina et al.32 Keller et al.34
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Men had AK and SCC more frequently than women Men had a higher risk of SCC but not BCC Men had higher risk of developing NMSC Men had higher risk of developing NMSC Incidence per 1,000 person-years was higher in men than women Older patients had AK more frequently than younger patients Higher risk for older OTR ( 30) Incidence of KS was significantly associated with older age at transplantation Melanoma risk was positively associated with older age Older age at transplantation was risk factor for SCC and BCC Risk of developing malignancy greater with age in RTR Higher risk for older RTR ( 50) Older age (>45) associated with higher risk of SCC and BCC Older recipient age associated with higher risk of NMSC Individuals aged >45 had higher risk of developing NMSC Older age at transplantation was significant risk factor for development of malignancy Incidence per 1,000 person-years increased from 4.6 in younger patients (<45) to 26.5 in older patients ( 65 ) Longer duration of immunosuppression correlated with greater number of AK and SCC Higher risk of NMSC was associated with longer duration of immunosuppression Prednisone was found to be correlated with higher risk of developing AK Combined immunosuppressive therapy with MMF, prednisolone, and cyclosporine A was associated with higher risk of KS, especially during first 2 years after transplantation Azathioprine was associated with higher risk of SCC in RTR than cyclosporine A and MMF; azathioprine was associated with higher risk of SCC in simultaneous pancreas and kidney transplant recipients than MMF Azathioprine was associated with higher risk of SCC; MMF and Tac were associated with lower risk of NMSC Therapy with Tac was associated with higher risk of developing skin cancer Use of MMF and of tacrolimus (3 months after heart transplantation) was associated with lower incidence of skin cancer Induction therapy with muromonab-CD and antithymocyte globulin was risk factor for skin cancer Induction therapy increased risk of SCC and BCC Patients with fair skin had more AK and SCC than dark-skinned patients
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TABLE 3. Continued Risk Factor Category Post-transplantation time
Authors
Study Characteristic 27
Navarro et al.
Zamanian et al.42 Warts
Comeau et al.23
Sunlight exposure
Molina et al.32
Dapprich et al.77 Dysplastic nevi
Dapprich et al.77
Organ donor medical history Family history
Dapprich et al.77
History of NMSC
Dapprich et al.77
Geography
Comeau et al.23
Dapprich et al.77
Longer post-transplant time was associated with higher risk of developing NMSC Risk of skin malignancy increased with increasing post-transplantation duration Individuals with a history of post-transplantation warts were at higher risk of developing NMSC Patients who were transplanted in a high sunshine zone (>2,500 h/y) were at higher risk of developing SCC and BCC History of blistering sun exposure or sunburns was correlative with higher risk of melanoma History of histologically dysplastic nevi was a risk factor for melanoma Organ donors with a history of melanoma present significant risk of melanoma transmission to OTR Family history of melanoma was risk factor for development of melanoma in OTR Recipients with a history of NMSC were at higher risk of development of melanoma Individuals who had a longer duration of residence in a northern climate (Northern Alberta) were at higher risk of developing NMSC
RTR, renal transplant recipients; MMF, mycophenolate mofetil; AK, actinic keratosis; BCC, basal cell carcinoma; SCC, squamous cell carcinoma; NMSC, nonmelanoma skin cancer.
pathogenesis of post-transplantation viral warts is believed to be HPV, which infect the squamous epithelia of the skin and are increasingly active in the immunosuppressed host.37,38 HPV, particularly oncogenic HPV 5 and 8 strains, have been associated with greater incidence in SCCs of OTRs.4,39,40 One study by Meyer and Arndt41 reported that HPV DNA was diagnosed more frequently in SCCs of OTRs (75%) than the same lesion was in nonimmunosuppressed patients (47%). Actinic keratoses (AKs) are often the earliest identifiable premalignant lesions that can develop into invasive SCCs. Three of 36 studies reported incidence of AKs (Table 2).26,34,42 AKs are found in approximately 50% of OTRs,18,43,44 and one study34 identified 541 AKs, more than any other skin cancer diagnosed at the center. Older age and male sex are correlated with AK diagnosis in these patients (Table 3).34
There is a 3% to 5% risk that Bowen’s disease (BD), also known as squamous cell carcinom in situ,45 will develop into invasive SCC, and progression may occur at a higher rate in immunosuppressed patients.46,47 Although most of the reviewed reports studying the presentation of NMSC in immunosuppressed OTRs have focused on invasive SCC, one study48 reported a single case of BD of the hand, but only limited data were available (Table 2). An earlier (pre-2006) retrospective study by Drake and colleagues47 reviewed 299 patients with 407 BD tumors, 57 (17%) of patients were immunocompromised, categorized as OTRs, acute and chronic leukemia, immunosuppressing infections, or autoimmune disease. Immunocompromised patients were significantly more likely (33%) than the nonimmunocompromised cohort (15%) to have multiple BD tumors and present with BD tumors on the trunk, extremities, and neck.47 Although there
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were no available studies elucidating the risk factors for BD tumors, factors associated with the development of invasive SCC are similar for BD.47,49,50 Kaposi’s Sarcoma Kaposi’s sarcoma (KS) is a rare vascular tumor that affects the skin and visceral organs and is associated with human herpes virus 8.51,52 KS is more common in immunosuppressed patients, and is the most common neoplasm in patients with AIDS.53–55 Although it accounts for fewer than 5% of posttransplantation skin cancers, KS has an incidence in OTR approximately 20 times that in the nonimmunosuppressed population.4,56,57 Sixteen of our reviewed studies identified incidences of KS in OTRs (Table 2). Reports of KS ranged from 0.36%58 to 2.5%59 of OTRs. One study60 reported that KS was the third most common de novo tumor in this patient population. Cutaneous KS appears to be more common than visceral KS.61 Several reports58,62 from Middle Eastern organ transplant centers indicated high incidences of KS—an observation consistent with reports that the incidence of KS is much higher in Middle Eastern OTRs (5.3%) than in those from Western countries (including the United States) (0.5%).36,63 With regard to time to diagnosis of KS after transplantation, four studies reported a range of 1.5 to 2.8 years,62,64,65 which is slightly less than the range for time to NMSC diagnosis. KS of the skin was diagnosed much earlier than visceral KS (2.6 vs 9.1 years).61 Areas of cutaneous diagnosis mostly included the upper and lower limbs, with legs being affected nearly twice as often as arms. 62 Survival rates for individuals with KS appear to be significantly higher than for those with solid tumors or post-transplant lymphoproliferative diseases.60 One, 3, and 5 years after diagnosis, survival rates were reported as 100%, 100%, and 83%, respectively.60 Similar risk factors and correlations associated with NMSC are also found in OTRs with KS (Table 3). Of
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40 patients diagnosed with KS, older age at transplantation ( 30)58,65 and an immunosuppressive regimen consisting of cyclosporine, azathioprine, and prednisolone65 were associated with KS. With regard to sex, one previously published report66 found a quantified high risk of KS particularly in women after the first year after transplantation. Melanoma The incidence of malignant melanoma is increasing worldwide, and its outcomes have been well documented in the general population, but data regarding the incidence and characteristics of and prognosis for melanoma in the immunosuppressed OTR population are limited.67,68 Given the strong influence of the immune system on the tumor’s pathogenesis and progression, melanoma incidence in OTRs would be expected to be high,69–72 but incidence rates have been far lower than that of SCC —approximately 0 to 17.2 times as high as in the general population.4,56,67,73,74 Eight of the reviews identified incidences of melanoma in OTRs (Table 2). Reports of melanoma ranged from 0.02%62 to 1%75 of OTRs. Three studies30,34,60 reported only two cases of melanoma (<1% recipients) within their respective OTR cohorts. Higher incidences of 1276 and 8275 cutaneous melanomas in large OTR cohorts have also been reported.75,76 One study76 reported that 12 melanoma tumors developed in 10 patients out of 1,874 renal transplant recipients (RTRs), representing an eight times greater incidence of melanoma than in the general population. The mean time to diagnosis of melanoma after transplantation varied, with reports of 4.777 and 1176 years. Most commonly diagnosed areas included the abdomen, back, arms, and shoulders.76,77 Although data are limited, mortality from melanoma in OTRs appears to be high and soon after transplantation. In one study, one of 12 OTRs had a recurrence of melanoma at a mean of 3.7 years of follow-up and eventually died from metastasis.76 In another study, eight of 31 OTRs
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died of any cause ranging from 0.1 to 12 years after transplantation.77 Numerous risk factors have been associated with the development of melanoma (Table 3). One study reported that melanoma risk was positively correlated with older age at transplantation.75 In a second study,76 30% of individuals with melanoma had a history of dysplastic nevi; 60% had a history of other skin tumors; and 50% had a history of viral warts, seborrheic dermatitis, or solar keratoses. Six of 10 individuals with melanoma had a documented history of excessive sun exposure. One unique variable that a third study evaluated was OTRs who acquired their melanoma because of transmission from organ donors with a history of the cancer.77 Reports of the development of donorderived melanomas date back to the late 1960s.78,79 Provided the required immunosuppression associated with receiving a heterotopic solid organ transplant, one would expect the consequences of a transplanted melanoma to be grave.80 Melanoma is known to exhibit late (>10 years) and ultra-late (>15 years) disease recurrence.81–84 Early screening of donor-derived origin of malignancy may be beneficial. Screening techniques include PCR-based microsatellite markers, immunohistochemistry, DNA typing, or FISH.85–87 With regard to donor-related transmission from the reviewed studies, the sole transplant recipient who received a kidney from a donor died from metastasis to the brain.77 This finding corroborated the findings from the Israel Penn International Transplant Registry, the largest and most comprehensive registry in the world, which reported 124 cases of confirmed donor cancer transmission from 296 donors with known or incidentally discovered malignancies that were recorded in the registry from 1965 to 2003.88 Reports of management and outcomes are often incomplete, but several strategies have been recommended. Current recommendations for donor-derived melanoma in OTRs involve cessation of immunosuppression to allow rejection of melanoma cells, with subsequent
donor organ removal.86,89-91 Perhaps further documentation of prognostic factors such as Clark level, Breslow depth, lymph node status, and time since diagnosis might be helpful in classifying individuals with melanoma who could be organ donors.80 Merkel Cell Carcinoma Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin that originates from Merkel cells located in the basal layer of the epidermis. MCC predominantly affects elderly Caucasian men ( 50) on sun-exposed areas of the skin.92 The percentage of OTRs with MCC is surprisingly large (7–8%), a higher incidence than in the general population.93–95 Although the causative factors remain largely unknown,96 numerous articles have linked immunosuppressed individuals with MCC to a newly found virus named the polyoma virus, which was detected in approximately 80% of individuals with MCC.97,98 Four of the studies identified incidences of MCC in OTRs (Table 2). Reports of MCC ranged from 0.07%99 to 1.6%30 of OTRs. Three studies25,30,100 identified a single case of MCC, and the fourth study99 identified three cases of MCC. Mean time to post-transplantation diagnosis of MCC differed drastically, from 3.830 years for one patient to 11.099 years for three patients. Locations of the MCC lesions included the head and the gluteal region.30,99 Previous case reports have also reported the appearance of MCC on the parotid glands,101 axilla,101 forearm,101–103 and shin.104 One notable observation in the reviewed reports was the high mortality associated with post-transplantation development of MCC. In one study,30 one individual with MCC of 603 RTRs died from tumor generalization 7 months after diagnosis. In a second study,100 reviewing 582 RTRs and liver transplant recipients (LTRs), the affected individual with Merkel Cell Carcinoma (MCC) died of liver and lymph node metastatic disease 19 months after diagnosis. In a third study,99 the three individuals with MCC of 4,200 RTRs died from progressive
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MCC, with a survival time after diagnosis ranging from 0.5 to 2.1 years. No significant risk factors are mentioned in the reviewed studies because there is a dearth of large series studies on MCC in the literature.99 Several early reports93,101 suggest that sun exposure and general immunosuppression, without regard to any particular drug type, are strong risk factors for developing MCC after transplantation. Although the majority of individuals with MCC in the general population are aged 50 and older, a recent review105 noted that nearly 50% of OTRs with MCC were younger than 50 at diagnosis. With regard to sex, in contrast to the approximately 1:1 proportion of men to women with MCC in the general population, men outnumbered women 2.4 to 1 in the OTR population,105 although this difference may be insignificant and merely reflect the 2:1 ratio of men to women who undergo renal and cardiac transplantation worldwide.93,95
Preventative Management of Post-Transplantation Skin Cancers Preventative Care and the Role of Integrated OTR Dermatology Clinics Preventative post-transplantation dermatologic management is essential to reduce morbidity and improve the recipient’s quality of life (QOL). One survey reported that QOL was poor at baseline in 80 transplant patients and that the number of NMSCs after transplant approached significance of being indicative of higher anxiety levels.106 Another questionnaire-based study in which high Dermatology Life Quality Index scores reflected a significant effect of skin disease on QOL, found that patients undergoing extensive post-transplantation immunosuppressive therapy had high scores, indicating that the dermatologic complications of immunosuppressive therapy significantly impair QOL in certain patients.107 As a response to these concerns, multidisciplinary approaches to the care of OTR have integrated dermatology and dermatologic surgery clinics within transplant units.108
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The existence of dermatologic care within the transplant center significantly facilitates the prevention of skin disease and surveillance in the post-transplantation period. Patients taking chronic immunosuppressants can be evaluated and assessed on risk of development of skin disease in the immediate postoperative period, if not before transplantation, as part of the standard of care.109 The most important elements of preventative management of skin disease in transplant recipients are rigorous sun protection and early detection. Sun prevention programs in OTR clinics can help promote awareness of occupational and recreational ultraviolet light exposure.110 Protective behaviors may include restriction of outdoor activities, sunscreen usage, wearing photoprotective clothing, and cessation of tanning. Monthly full-body examinations may help detect cancerous and noncancerous cutaneous disorders.111 Several follow-up studies have highlighted the benefits of sun protection awareness programs. One survey found that skin cancer awareness and adherence to photoprotective measures were significantly better in OTRs treated in a specialist OTR dermatology clinic than in those who had not attended the clinic.112 Part of this has to do with the educational nature of the dermatologic consultation, with one study reporting that patients who received intensive educational intervention were more adherent to recommendations for sun-protective behavior than those who received standard education.113 One interventional study found that RTRs receiving education approximately 1 year after transplantation performed self-skin examination as much as those receiving education 3 to 7 years after transplantation.101 The RTRs were receptive to performing self-skin examination and acted on the recommendation made in the workbook to make an appointment with a dermatologist when a troubling lesion was discovered.101 Although photoprotective measures for OTRs are strongly advised, the tradeoff and severe health risk of vitamin D deficiency poses a risk for OTRs
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undergoing a regimen of strict sun protection. Previous studies have reported lower levels of serum 25-hydroxyvitamin D (25(OH)D) levels in transplant patients undergoing sun protection than in control groups.114,115 Nearly 90% of all requisite vitamin D is formed within the skin through the action of the sun. This poses a serious problem, because a correlation between vitamin D deficiency and the incidence of various cancers (colon, prostate, breast) has been reported.115–119 Although optimal vitamin D levels for general health are being debated, careful monitoring of vitamin D status and oral substitution in case of vitamin D deficiency is consequential for the immunosuppressed such as OTRs. It is therefore important in post-transplantation management to strike a balance in protecting patients against the serious health problems of 25 (OH)D deficiency while avoiding the risk of developing ultraviolet light–induced cancers. Overall, the intervention of OTR dermatologic clinics in the early prevention of immunosuppressant-associated skin disorders continues to be an important specialized approach. At the same time, as preventative measures fail and skin disease manifests, OTR clinic dermatologists can effectively manage cancers as they arise. The treatment of aggressive (high risk) and less-common tumors such as KS and MCC frequently involves a multidisciplinary approach incorporating surgical and medical oncology. Modifications in Immunosuppressive Regimens Perhaps the most important adjuvant therapeutic strategy for managing immunosuppressionassociated skin diseases, particularly skin cancer, is adjusting the immunosuppressive regimen itself. The clinical factors contributing to post-transplantation complications are complex but are believed to correlate with the duration, amount, and types of immunosuppression.102 Because of the remarkably high incidence of skin malignancies in immunosuppressed OTRs, multiple lines of evidence support titration of immunosuppression to minimize the incidence of skin cancer.1
One recent survey by the Immunosuppression Task Force of the International Transplant Skin Cancer Collaborative (ITSCC) found that, when confronted with cases of extensive skin malignancies, transplant physicians were generally willing to reduce immunosuppression and accept a greater risk of allograft rejection.1 In a recent expert consensus survey by the ITSCC involving hypothetical OTR scenarios, expert opinions about appropriate level of reduction of systemic immunosuppression (mild, moderate, severe) were created.120 It was concluded that mild reduction of transplant-associated immunosuppression was acceptable once multiple skin cancers developed per year or with single instances of highrisk skin cancers. Moderate reduction was considered appropriate when patients experienced more than 25 skin cancers per year or for skin cancers with a 10% 3-year risk of mortality. Severe reduction was considered warranted only for potentially fatal skin cancers. Most of the data supporting a strategy of reduction are in the form of a small case series or indirect evidence.121 One randomized controlled study of 231 renal allograft recipients found that the reduction of cyclosporine (from 150–250 ng/mL to 75–125 ng/mL) did not adversely affect graft function and patient survival 1 year after transplantation.122 In subsequent years of low-dose cyclosporine treatment, skin diseases, particularly viral-associated cancers, were less common in the low-dose group (75–125 ng/mL) than in the highdose group (150–250ng/mL) (p = .05).122 Additional studies112,123–127 of individuals with NMSC describe much indirect evidence of the efficacy of immunosuppression reduction and all reach a similar conclusion; because NMSC incidence is related to level of immunosuppression, lowering the level of immunosuppression may result in lower NMSC incidence. Although there is no consensus on a singular protocol, further studies should continue to assess the timing, mechanism, and efficacy of reduced immunosuppression regimens to allow for the best graft function while preventing skin cancers in OTRs.
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Recent studies have also supported regimen changes from calcineurin inhibitors (CNIs) such as tacrolimus to rapamycin agents such as sirolimus, which inhibits the mammalian target of rapamycin113 (mTOR) pathway. Conversion to sirolimus after initial CNI-based immunosuppression has been documented to be safe as early as 3 months after transplantation and is warranted in all patients with a history of skin cancer. Two studies found that conversion from CNIs to sirolimus resulted in regression of KS in RTRs.114,115 In five RTRs who had switched from CNI to sirolimus-based regimens because of recurrent multiple NMSC, the incidence of skin cancer significantly decreased from 71.9% per person before to 23.8% after the switch to sirolimus.116 The continuing evidence that conversion to sirolimus may reduce the morbidity and mortality of skin cancer, particularly NMSC in RTRs, ought to be considered in the management of multiple or aggressive skin cancers. The thiopurine immunosuppressant class in particular has drawn much attention in recent years. After preparation of this manuscript, several studies have highlighted the role of thiopurines in the development of skin cancer in OTR and non-OTRs. Immunosuppression with azathioprine in combination with prednisone was associated with significantly greater risk of subsequent or secondary SCCs in RTRs.126 In individuals with inflammatory bowel disease (IBD), the use of thiopurines increases the risk of developing NMSC.127,128 Thus, physicians ought to be concerned about the long-term use of thiopurines in OTRs and non-OTRs with IBD.
Conclusion Skin cancers pose a significant problem for OTRs undergoing long-term immunosuppression. Immunosuppressants have made successful organ transplantation possible, albeit at the cost of greater risk of infection and neoplasms in the post-transplantation setting. NMSCs account for the majority of skin cancers in transplant recipients, but cases of the less common KS, melanoma, and MCC continue to arise
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as well. Although for many patients can manage the cutaneous malignancies that manifest easily, some experience significant morbidity and mortality. Sex, age, and most importantly, sunlight exposure are important risk factors for malignancy development. Education programs about photoprotective behavior and frequent screenings in dermatologic OTR clinics have been valuable management tools for preventing skin cancer in OTRs, but additional insight into the immunosuppressive regimen parameters suggest that different factors, such as the type, duration, and dosage of immunosuppressive agents, are equally important risk factors for skin cancer development in OTR. Therefore, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further longterm, randomized controlled studies should continue to assess the effect of using lower immunosuppressant medication while preserving graft function. References 1. Otley CC, Griffin MD, Charlton MR, Edwards BS, et al. Reduction of immunosuppression for transplant-associated skin cancer: thresholds and risks. Br J Dermatol 2007;157 (6):1183–8. 2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47(1):1–17;quiz 18–20. 3. Penn I. Cancers in renal transplant recipients. Adv Ren Replace Ther 2000;7(2):147–56. 4. Kovach BT, Stasko T. Skin cancer after transplantation. Transplant Rev (Orlando) 2009;23(3):178–89. 5. Mukherjee S, Mukherjee U. A comprehensive review of immunosuppression used for liver transplantation. J Transplant 2009;2009:701464. 6. Sharma VK, Li B, Khanna A, Sehajpal PK, et al. Which way for drug-mediated immunosuppression? Curr Opin Immunol 1994;6(5):784–90. 7. Sheil AG, May J, Mahoney JF, Horvath JS, et al. Incidence of cancer in renal transplant recipients. Proc Eur Dial Transplant Assoc 1980;17:502–6. 8. Edwards NM, Rajasinghe HA, John R, Chen JM, et al. Cardiac transplantation in over 1000 patients: a single institution experience from Columbia University. Clin Transpl 1999;??:249–61. 9. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000;23(2):101–13.
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10. Fekecs T, Kadar Z, Battyani Z, Kalma´r-Nagy K, et al. Incidence of nonmelanoma skin cancer after human organ transplantation: single-center experience in Hungary. Transplant Proc 2010;42(6):2333–5. 11. Euvrard S, Kanitakis J, Pouteil-Noble C, Disant F, et al. Aggressive squamous cell carcinomas in organ transplant recipients. Transplant Proc 1995;27(2):1767–8. 12. Adamson R, Obispo E, Dychter S, Dembitsky W, et al. High incidence and clinical course of aggressive skin cancer in heart transplant patients: a single-center study. Transplant Proc 1998;30(4):1124–6. 13. Pollard JD, Hanasono MM, Mikulec AA, Le QT, et al. Head and neck cancer in cardiothoracic transplant recipients. Laryngoscope 2000;110(8):1257–61. 14. Veness MJ. Aggressive skin cancers in a cardiac transplant recipient. Australas Radiol 1997;41(4):363–6. 15. Stockfleth E, Ulrich C, Meyer T, Christophers E. Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment. Recent Results Cancer Res 2002;160:251–8. 16. Caforio AL, Fortina AB, Piaserico S, Alaibac M, et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000;19 (Suppl 3):III222–7. 17. Barr BB, Benton EC, McLaren K, Bunney MH, et al. Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1989;1(8630):124–9. 18. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol 1995;1:222–9. 19. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990;49(3):506–9. 20. Ong CS, Keogh AM, Kossard S, Macdonald PS, et al. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol 1999;40(1):27–34. 21. Lampros TD, Cobanoglu A, Parker F, Ratkovec R, et al. Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant 1998;17(6):586–91. 22. Moloney FJ, Comber H, O’Lorcain P, O’Kelly P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006;154(3):498–504. 23. Comeau S, Jensen L, Cockfield SM, Sapijaszko M, et al. Nonmelanoma skin cancer incidence and risk factors after kidney transplantation: a Canadian experience. Transplantation 2008;86(4):535–41. 24. Crespo-Leiro MG, Alonso-Pulpon LA, Villa-Arranz A, Brossa-Loidi V, et al. The prognosis of noncutaneous, nonlymphomatous malignancy after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry. Transplant Proc 2010;42(8):3011–3. 25. Basic-Jukic N, Bubic-Filipi L, Prgomet D, Djanić Hadzibegović A, et al. Head and neck malignancies in Croatian renal transplant recipients. Bosn J Basic Med Sci 2010;10(Suppl 1): S37–9.
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77. Dapprich DC, Weenig RH, Rohlinger AL, Weaver AL, et al. Outcomes of melanoma in recipients of solid organ transplant. J Am Acad Dermatol 2008;59(3):405–17. 78. Wilson RE, Hager EB, Hampers CL, Corson JM, et al. Immunologic rejection of human cancer transplanted with a renal allograft. N Engl J Med 1968;278(9):479–83. 79. Jeremy D, Farnsworth RH, Robertson MR, Annetts DL, et al. Transplantation of malignant melanoma with cadaver kidney. Transplantation 1972;13(6):619–20. 80. Cotter MA, Tristani-Firouzi P. Unsuitability of organ donation from a patient with a history of melanoma? J Am Acad Dermatol 2006;54(6):1096–8. 81. Crowley NJ, Seigler HF. Late recurrence of malignant melanoma. Analysis of 168 patients. Ann Surg 1990;212 (2):173–7. 82. Ozsoy Z, Ozyigit MT, Turkaslan T, Gulluoglu MG. Ultralate metastasis of cutaneous melanoma. Dermatol Surg 2006;32 (10):1287–9. 83. Tsao H, Cosimi AB, Sober AJ. Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 1997;79 (12):2361–70. 84. Schmid-Wendtner MH, Baumert J, Schmidt M, Konz B, et al. Late metastases of cutaneous melanoma: an analysis of 31 patients. J Am Acad Dermatol 2000;43(4):605–9. 85. Schmitt C, Cire K, Schattenkirchner S, Pollok M, et al. Highly sensitive DNA typing for detecting tumors transmitted by transplantation. Transpl Int 1998;11(5):382–6. 86. Morris-Stiff G, Steel A, Savage P, Devlin J, et al. Transmission of donor melanoma to multiple organ transplant recipients. Am J Transplant 2004;4(3):444–6. 87. Cankovic M, Linden MD, Zarbo RJ. Use of microsatellite analysis in detection of tumor lineage as a cause of death in a liver transplant patient. Arch Pathol Lab Med 2006;130(4):529–32. 88. Buell JF, Beebe TM, Trofe J, Gross TG, et al. Donor transmitted malignancies. Ann Transplant 2004;9(1):53–6. 89. Elder GJ, Hersey P, Branley P. Remission of transplanted melanoma—clinical course and tumour cell characterisation. Clin Transplant 1997;11(6):565–8. 90. Suranyi MG, Hogan PG, Falk MC, Axelsen RA, et al. Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation. Transplantation 1998;66(5):655–61. 91. Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2(4):7–12. 92. Krejci K, Zadrazil J, Tichy T, Hora´k P, et al. [Merkel cell skin carcinoma]. Klin Onkol 2010;23(4):210–7. 93. Buell JF, Trofe J, Hanaway MJ, Beebe TM, et al. Immunosuppression and Merkel cell cancer. Transplant Proc 2002;34(5):1780–1. 94. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999;8(2):153–8. 95. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999;68(11):1717–21.
96. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002;20(2):588–98. 97. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319(5866):1096–100. 98. Rollison DE, Giuliano AR, Becker JC. New virus associated with merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8(8):874–80. 99. Koljonen V, Kukko H, Tukiainen E, Bo¨hling T, et al. Incidence of Merkel cell carcinoma in renal transplant recipients. Nephrol Dial Transplant 2009;24(10):3231–5. 100. Baccarani U, Adani GL, Montanaro D, Risaliti A, et al. De novo malignancies after kidney and liver transplantations: experience on 582 consecutive cases. Transplant Proc 2006;38(4):1135–7. 101. Urbatsch A, Sams WM Jr, Urist MM, Sturdivant R. Merkel cell carcinoma occurring in renal transplant patients. J Am Acad Dermatol 1999;2:289–91. 102. Stempfle HU, Mudra H, Angermann CE, Weiss M, et al. Rapid growth of cutaneous neuroendocrine (Merkel cell) carcinoma during treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. J Heart Lung Transplant 1993;12 (3):501–3. 103. Traest K, De Vos R, van den Oord JJ. Pagetoid Merkel cell carcinoma: speculations on its origin and the mechanism of epidermal spread. J Cutan Pathol 1999;26(7):362–5. 104. Gooptu C, Woollons A, Ross J, Price M, et al. Merkel cell carcinoma arising after therapeutic immunosuppression. Br J Dermatol 1997;137(4):637–41. 105. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49 (5):832–41. 106. O’Reilly F, Traywick C, Pennie ML, Foster JK, et al. Baseline quality of life and anxiety in solid organ transplant recipients: a pilot study. Dermatol Surg 2006;32(12):1480–5. 107. Moloney FJ, Keane S, O’Kelly P, Conlon PJ, et al. The impact of skin disease following renal transplantation on quality of life. Br J Dermatol 2005;153(3):574–8. 108. Reichrath J, Nurnberg B. Solar UV-radiation, vitamin D and skin cancer surveillance in organ transplant recipients (OTRs). Adv Exp Med Biol 2008;624:203–14. 109. Traywick C, O’Reilly FM. Management of skin cancer in solid organ transplant recipients. Dermatol Ther 2005;18(1):12–8. 110. Terhorst D, Drecoll U, Stockfleth E, Ulrich C. Organ transplant recipients and skin cancer: assessment of risk factors with focus on sun exposure. Br J Dermatol 2009;161(Suppl 3):85–9. 111. Otley CC, Cherikh WS, Salasche SJ, McBride MA, et al. Skin cancer in organ transplant recipients: effect of pretransplant end-organ disease. J Am Acad Dermatol 2005;53(5):783–90. 112. Ismail F, Mitchell L, Casabonne D, Gulati A, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol 2006;155(5):916–25. 113. Clowers-Webb HE, Christenson LJ, Phillips PK, Roenigk RK, et al. Educational outcomes regarding skin cancer in organ
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Address correspondence and reprint requests to: Cameron West, MD, Department of Dermatology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, or e-mail:
[email protected]
ORIGINAL ARTICLE
Importance of Vertical Pathology of Debulking Specimens During Mohs Micrographic Surgery for Lentigo Maligna and Melanoma in Situ LUCIANO J. IORIZZO, III, MD,* ISSAC CHOCRON, BSC,† WILFRED LUMBANG, MD,† THOMAS STASKO, MD†
AND
BACKGROUND Recent Recovery Audit Contractor audits have targeted Mohs micrographic surgery (MMS) if permanent-section pathology codes have been used on the same day. In lentigo maligna (LM) or melanoma in situ (MIS) cases, this is done to further evaluate the tumor for staging. OBJECTIVE To determine the percentage of LM, MIS, and thin invasive melanomas upstaged when a central debulking specimen from MMS is sent for permanent vertical sections. METHODS A single-center retrospective study examining LM, MIS, and thin melanomas treated with MMS between January 1, 2004, and September 30, 2011, at Vanderbilt University was performed. The elements needed for staging, sex, age, tumor location, size, and previous skin cancer history were obtained. RESULTS Fourteen of 173 cases (8.1%; 95% confidence interval = 4.9–13.1%) were identified in which the tumor was upstaged; 13 of the cases initially diagnosed as LM or MIS were invasive (average Breslow depth 0.69 mm). One melanoma at 0.6 mm depth on initial biopsy increased to 1.2 mm after the debulking specimen from Mohs surgery was examined histologically. Debulking in four cases revealed a depth of 1 mm or greater. No differences existed in characteristics between upstaged and nonupstaged cases. CONCLUSION When performing MMS for LM or MIS, it is appropriate and necessary to send the central debulking specimen for permanent histology for accurate tumor staging. The authors have indicated no significant interest with commercial supporters.
I
n the United States, it is estimated that, in 2012, more than 75,000 people will be diagnosed with melanoma.1 The incidence rate of melanoma has been increasing in both sexes and all age groups over the last decade, including the incidence of thin melanomas.2 Although melanoma can have a grave prognosis, if diagnosed and treated while thin (0.01to 1.00-mm Breslow depth), 1-, 5-, and 10-year melanoma-specific survival rates are 99.6%, 97.4%, and 95.2% respectively.3 Survival rates are even higher for lentigo maligna (LM) and melanoma in situ (MIS). Many treatments have been used for LM and MIS with varying cure rates, including wide local excision, staged surgical excision; topical
therapy with imiquimod, primary radiation therapy, cryotherapy, multiple lasers (e.g., carbon dioxide, argon, quality-switched (QS) ruby, QS neodymiumdoped yttrium aluminum garnet, and alexandrite lasers), and Mohs micrographic surgery (MMS).4,5 MMS has become a popular surgical option for treating LM because the clinical margins may be ill defined, and margins greater than the commonly recommended 0.5 cm may be necessary to clear the tumor.4 There is ongoing controversy over what margins should be recommended for standard excision of LM, although recent data suggest that margins as wide as 0.9 cm may be required to obtain acceptable clearance rates.6
*Department of Internal Medicine, Albany Medical Center, Albany, New York; †Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:365–371 DOI: 10.1111/dsu.12078 365
IMPORTANCE OF VERTICAL PATHOLOGY OF DEBULKING SPECIMENS
When performing MMS on a LM, MIS, or thin melanoma, many Mohs surgeons send the central portion for permanent pathology. A 2009 survey of Mohs surgeons found that 119 of 151 responders sent the central debulking specimen for permanent pathology (A. Levy and T. Stasko, unpublished data) to determine whether there is any invasion of the tumor for staging purposes. MMS examines only the base of the central portion of the tumor to determine whether the margin is clear. This, combined with the horizontal nature of frozen-section examination of the base of the tumor prepared for margin examination (most of the periphery of the layer is examined using vertical sectioning), precludes additional determination of the Breslow depth of tumor invasion for staging purposes. The examination of Breslow depth at definitive treatment is important because previous analyses have found discrepancies between Breslow depth on biopsy specimens and the depth seen at surgical excision. In a review article, Dawn and colleagues7 reported that, after complete surgical removal of lesions found to be MIS on initial biopsy, the rate of invasive melanoma was found to vary from 5% to 67%. Recently, Medicare recovery audit contractors, misinterpreting the November 2006 issue of the Current Procedural Terminology assistant, have asserted that MMS was not being performed if permanent-section pathology codes were being used on the same day as MMS. The American College of Mohs Surgery has advocated submission of the central debulking specimen for permanent pathology to Medicare and insurance payers as an important adjuvant to MMS in the treatment of LM and MIS.8 The purpose of this study was to examine LM and MIS cases and thin melanomas that were treated with MMS to ascertain the number and circumstances of cases upstaged using TNM and American Joint Committee on Cancer (AJCC) classifications9 on the basis of examination of vertical sections from a full-thickness debulking taken at MMS and to determine whether patient and tumor characteristics may correlate with upstaging. We hypothesized that
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DERMATOLOGIC SURGERY
sending this central specimen for permanent histology would be critical because the original biopsy would not always provide accurate staging reflective of the entire specimen.
Methods Settings and Patients Before performing this study, exempt status was received from the Vanderbilt University Institutional Review Board. A single-center retrospective study was performed examining all cases of LM, MIS, and thin melanomas (Breslow depth <1 mm) treated with MMS from January 1, 2004, to September 30, 2011, for which a permanent pathology report on the central debulking specimen was available. Only patients aged 18 and older were included. Study Design From the medical record, the elements needed for staging (Breslow depth, ulceration, mitoses) were obtained for the biopsy and the permanent tissue vertical sections of the central MMS debulking specimen to determine the number and percentage of cases in which the staging was altered because the debulking specimen was examined, using the AJCC staging9 and TNM criteria.10 Data on sex, age, tumor location, preoperative tumor size, postoperative defect size, history of nonmelanoma skin cancer (NMSC), and history of melanoma were also extracted to examine possible differences in these characteristics between cases that were upstaged and those that were not. The five categories analyzed for location included face and ears, scalp, neck, trunk, and upper and lower extremities. If a patient had been treated with MMS for two separate LMs, MISs, or thin melanomas, the individual lesions were analyzed separately. Statistical Analysis A Wilson two-sided 95% confidence interval was calculated when analyzing the percentage of cases that were upstaged. When comparing age and
IORIZZO ET AL
preoperative and postoperative tumor size between tumors that were upstaged and tumors that were not upstaged for significance, we used a Wilcoxon test. A Pearson test was used when examining significance in differences between the two groups for sex, location, and history of NMSC or melanoma.
Results One hundred ninety-seven cases of LM, MIS, or thin melanomas treated with MMS were identified in 192 patients during the specified period; 173 had permanent-section pathology reports available for the central debulking specimen: 16 thin, invasive melanomas and 157 LM or MIS. The average age was 66.7. The median preoperative tumor size was 1.40 by 1.30 cm, and the median postoperative tumor size was 2.55 by 2.55 cm. Eighty percent of tumors were located on the face and ears, 6% on the scalp, 3% on the neck, 3% on the trunk, and 8% on the extremities. In 19% of cases, there was a history of a previous melanoma, and in 44% there was a history of a previous NMSC (Table 1). TABLE 1. Patient and Tumor Characteristics (N = 173) Characteristic Age, average Sex, n (%) Male Female Location, n (%) Face and ears Scalp Neck Trunk Extremities Preoperative tumor width, cm, median (N = 159) Preoperative tumor length, cm, median (N = 159) Postoperative defect width, cm, median (N = 158) Postoperative defect length, cm, median (N = 158) Previous melanoma, n (%) (N = 167) Previous nonmelanoma skin cancer, n (%) (N = 169)
Value 66.7 130 (75.1) 43 (24.9) 139 (80.3) 10 (5.8) 6 (3.5) 5 (2.9) 13 (7.5) 1.40 cm 1.30 cm 2.55 cm 2.55 cm 31 (19) 74 (44)
Fourteen cases (8.1%, 95% confidence interval = 4.9 –13.1%) were found in which the tumor was upstaged, indicating a more-aggressive melanoma, based on TNM and AJCC criteria (Table 2). All of the cases were upstaged based on an increase in Breslow depth rather than mitotic rate or ulceration. Thirteen of the cases initially diagnosed as LM or MIS were now diagnosed as invasive melanoma, with an average Breslow depth of 0.69 mm. One initially thin melanoma (0.6 mm) was deeper than 1 mm (1.2 mm). Eleven cases were upstaged from TNM stage TIS to T1A, two from TIS to T2A, and one from T1A to T2A. Using AJCC staging, 11 cases were upstaged from stage 0 to 1A, two from 0 to 1B, and one from 1A to 1B. The debulking in four cases revealed a Breslow depth of 1 mm or greater. There were no significant differences in the age (69.2 upstaged vs 66.5 not upstaged, p = .64), sex (79% male upstaged vs 75% male not upstaged, p = .76), tumor location (p = .12), preoperative tumor width (p = .27), preoperative tumor length (p = .70), postoperative defect width (p = .35), postoperative defect length (p = .58), history of NMSC (p = .24), and history of melanoma (p = .53) between tumors that were upstaged and those that were not (Table 3).
Discussion In clinical practice, a practitioner may often perform a partial biopsy of a pigmented lesion to attempt to minimize the size of a scar if the lesion is large or if it is not practical to take the entire lesion. Partial removal may also be unintentional because of poorly defined borders. In this situation, the original biopsy specimen may not provide an accurate representation of Breslow depth. In our cases, 8.1% of MIS, LM, or thin invasive melanomas were upstaged when the MMS debulking specimen was examined on permanent histologic sections. In a review article, Dawn and colleagues reported the percentage of cases of LM and MIS that have an invasive component to be from 5% to 67%, with wide variation between studies.7 When further examining the studies included in this range, we believe that this range is too wide and that the larger percentages are
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368
Age
64
78
88
62
68
66
62
56
69
69
59
Case
1
2
3
4
DERMATOLOGIC SURGERY
5
6
7
8
9
10
11
Male
Male
Male
Female
Male
Female
Male
Male
Male
Male
Male
Sex
0.35 mm
proliferation,
for MIS
melanoma 1.4 mm
melanocytic
proliferation,
note)
0.6 mm
depth
1.2 mm
Breslow
T2A
1A
1B
1A
1A
1B
1A
1A
1A
NA
0.7
NA
0.6
2.5
2.0
1.7
NA
0.7
NA
0.5
1.7
1.8
1.7
1.4
NA
2.1
NA
2.0
4.8
3.0
2.1
3.3
NA
2.3
NA
1.5
3.9
2.5
2.3
3.9
10.0
2.7
1.8
N
Y
Y
Y
N
N
N
N
Y
N
N
Y
Y
N
Y
N
N
N
N
N
N
Y
Left
scalp
parietal
Left
lobule
Right
Location
Left
forearm
Left
cheek
buccal
Left
cheek
malar
Right
scalp
Parietal
of nose
Dorsum
forehead
Right
helix
inferior
Left
mandible
LMM
T1A
0
0
0
0
0
0
1.5
6.0
2.3
2.1
*
Skin Cancer
0.8 mm
T1A
T1A
T2A
T1A
T1A
T1A
1A
6.0
1.3
0.7
*
Melanoma
anterior
TIS
TIS
TIS
TIS
TIS
TIS
0
2.5
1.7
1.4
cm
Nonmelanoma
History of
melanoma
Melanoma,
MIS
Malignant
0.75 mm
(based on
consultation
LMM
MIS
vs MIS
nevus
dysplastic
severely
includes
diagnosis
differential
Malignant
Atypical
LM
LMM 1 mm
melanoma
suspicious
Malignant
melanocytic
0.6 mm
LMM
0.5 mm
invasion
possible
T1A
1A
1A
1A
New
History of
arm
LM with TIS
0
0
0
Original
Length
Postoperative
0.8 mm
T1A
T1A
T1A
New
Width
Postoperative
flexor
TIS
TIS
TIS
Original
Length
Preoperative
melanoma
Malignant
0.2 mm
LMM
0.5 mm
LMM
Results
Specimen
Width
Atypical
LM
LM
MIS
LM
LM
Diagnosis
Original
Preoperative AJCC Stage
Debulking
TNM Stage
Mohs
TABLE 2. Individual Characteristics of Upstaged Tumors
NA
NA
NA
NA
0
<1
NA
NA
NA
NA
NA
mm2
Rate/
Mitotic
NA
None
NA
None
None
None
NA
NA
NA
NA
NA
Ulceration
IMPORTANCE OF VERTICAL PATHOLOGY OF DEBULKING SPECIMENS
evaluate cheek
upper
Right N 4.0 5.0 2.4 2.7 1B 0 T2A TIS
1.4 mm
Melanoma note)
MIS 66 14
Female
0.45 mm type
consultation
melanoma spreading
(based on
spreading superficial
*The medical record said previous skin cancer so it was assumed to be nonmelanoma skin cancer. LM, lentigo maligna; LMM, lentigo maligna melanoma; MIS, melanoma in situ; NA, not addressed or not available from medical records.
N
arm
3.1 3.7 1.8 1.2 1A 0 T1A TIS Superficial MIS, Male 79 13
0.3 mm
not comparable with the clinical situations we commonly encounter.
2
0 upper
N
Y
Right
chin
2.8 1.2 2.2 1A 0 T1A TIS LMM Possible LM 83 12
Male
cm New Original New Original Results Diagnosis Sex Age
Specimen Original
Cannot
NA
NA NA Right N 2.5
N
Rate/
mm2 Skin Cancer Melanoma
Nonmelanoma
Length TNM Stage Debulking
Mohs
TABLE 2. Continued
Case
Postoperative
Width Length
Preoperative
AJCC Stage
Preoperative
Width
Postoperative
History of
History of
Location
Mitotic
Ulceration
IORIZZO ET AL
In a study by Huilgol and colleagues11 in which the upstaged rate was said to be 67%, the rate of cases upstaged comparable with those in our study appears to be 16%. They examined 161 LM or lentigo maligna melanoma (LMM) cases treated using mapped serial excision to assess the margins required for excision of LM and LMM. They found that 24 cases referred by outside dermatologists with a diagnosis of LM were invasive. When adding this number to the number of LM and MIS cases of 125, the number of cases originally diagnosed as LM or MIS was 149, meaning that 16% (24/149) of these tumors were upstaged. In another study that reported an upstaged rate of 29%, the rate was based on cases that were re-evaluated using additional stains, not cases that were upstaged from an initial biopsy to definitive surgical management of the tumor.12 In 1968, Wayte and Helwig13 published that, in 85 cases diagnosed as “melanotic freckle of Hutchinson” that were re-examined, there was invasive melanoma in 45 of them, a rate of invasive melanoma of 53%. This rate of invasion is also not comparable because it was based on a re-examination of existing, not reexcision, specimens. More similar to our study, Cohen and colleagues14 examined 29 patients with an original diagnosis of LM or MIS and 16 with LMM who had MMS. The primary goal of the study was to report cure rate, which was 97%. They also reported that three (10.3%) of the 29 LM or MIS patients had an invasive component to the melanoma after the entire tumor had been removed. Somach and colleagues15 examined partial biopsy specimens and noticed that nine of 46, (20%) cases originally diagnosed as MIS had an invasive component in the full re-excision specimen. Zalla and colleagues16 examined their experience with MIS and melanoma using MMS. They found that invasion was found in three of 46 (6.5%) patients with MIS when the MMS debulking section was examined. Shumaker and colleagues17 reported on their experience with periocular
39:3:MARCH 2013
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IMPORTANCE OF VERTICAL PATHOLOGY OF DEBULKING SPECIMENS
TABLE 3. Upstaged Versus Nonupstaged Tumors (N = 173) Characteristic
Upstaged, n = 14
Age, median 67.0 Sex Male 11 (78.6) Female 3 (21.4) Preoperative measurements, cm, median (N = 159) Width 1.70 Length 1.55 Postoperative measurements, cm, median (N = 158) Width 2.90 Length 2.60 Location, n (%) Face and ears 9 (64.3) Scalp 2 (14.3) Neck 0 (0) Trunk 0 (0) Extremities 3 (21.4) Previous melanoma (N = 167) 4 (28.6) Previous nonmelanoma skin cancer (N = 169) 5 (35.7)
Nonupstaged, n = 159 67.0
p-Value .63*
119 (74.8) 40 (25.2)
.76†
1.30 1.30
.27* .70*
2.50 2.55
.35* .58*
130 8 6 5 10 27 69
(81.7) (5.0) (3.8) (3.1) (6.3) (17.6) (44.5)
.12†
.24† .52†
*Wilcoxon test. † Pearson test.
melanoma and MIS using MMS. They found that one out of 18 patients with MIS had an invasive melanoma. Bub and colleagues18 used staged excision to treat LM and found that three out of 58 (5.2%) cases originally read as LM were diagnosed as invasive melanoma at the time of definitive excision. Osborne and Hutchinson19 found that three of 59 (5%) biopsies that originally showed MIS showed invasive melanoma after complete excision. AgarwalAntal and colleagues20 found that 16% of their 92 cases originally diagnosed as LM had an invasive component. Mahoney and colleagues21 reported their staged perimeter technique as an alternative to MMS for LM and found invasive melanoma in two of 11 (18%) patients. In these studies, upstaging was typically an incidental finding. A more-accurate representation from the literature is that 5% to 20% of cases are upstaged from the biopsy when the entire specimen is examined.11,14–21 This study was designed primarily to determine the frequency of upstaging based on examination of the debulking specimen. Our rates, in a series that was significantly larger than previously reported series, are consistent with rates previously reported.
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We found no differences in clinical characteristics or patient history or demographics when comparing patients in whom tumors were upstaged with those in whom they were not. This precludes the sending of selective debulking specimens for permanent sections based on clinical characteristics or demographics. In four of the cases, the final depth of tumor invasion was noted to be 1 mm or greater. In such circumstances, upstaging might result in alterations in evaluation and therapy, including consideration of sentinel lymph node biopsy. Partial biopsy techniques can not only misrepresent LM and MIS, but can also misrepresent the depth of invasive melanomas. In a study examining partial biopsy techniques of melanomas, Karimipour and colleagues22 found that the average Breslow depth of a partial biopsy was 0.66 mm, whereas upon complete removal of the lesion, the average Breslow depth was 1.07 mm. Upstaging occurred in 21% of cases. The study also found that, as the percentage of the melanoma biopsied decreased, the lesion was slightly more likely to be upstaged.
IORIZZO ET AL
Egnatios and colleagues23 examined 609 patients who underwent sentinel lymph node biopsy for invasive melanoma and found that 10% of all patients had their T-category upstaged and that 25% with residual disease on wide local excision had an upstaged T-category, some of which would have changed the treatment algorithm. They also found that some patients with no residual disease on initial biopsy had residual disease when the tumor was re-excised. During typical MMS, only the peripheral and deep margins are examined. When MMS is performed for LM or MIS, the sectioning does not typically extend to the more-superficial central portion of the specimen where residual tumor may reside. In addition, if invasive melanoma is encountered on MMS sections, the nature of the MMS technique may preclude accurate measurement of Breslow depth. In this study, 8.1% of patients had a more-aggressive melanoma diagnosed after the central debulking specimen was sent for permanent vertical sections. We propose that, when MMS is performed for LM, MIS, or melanoma, it is appropriate and necessary that the central debulking specimen be sent for permanent paraffin histologic section to allow for accurate tumor staging. References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 2. Jemal A, Saraiya M, Patel P, Cherala SS, et al. Recent trends in cutaneous melanoma incidence and death rates in the united states, 1992–2006. J Am Acad Dermatol 2011;65(5 Suppl 1):S17– 25. e1–3. 3. Pollack LA, Li J, Berkowitz Z, Weir HK, et al. Melanoma survival in the United States, 1992–2005. J Am Acad Dermatol 2011;65:S78–86. 4. Bichakjian CK, Halpern AC, Johnson TM, Foote Hood A, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol 2011;65:1032–47. 5. McLeod M, Choudhary S, Giannakakis G, Nouri K. Surgical treatments for lentigo maligna: a review. Dermatol Surg 2011;37:1210–8. 6. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol 2012;66:438–44. 7. Dawn ME, Dawn AG, Miller SJ. Mohs surgery for the treatment of melanoma in situ: a review. Dermatol Surg 2007;33:395–402.
8. Zitelli JA. American college of Mohs surgery letter regarding proper pathology services. Available from: http://www. mohscollege.org/acms/RACAuditInfo/3Zitelli_CPT_Letter.pdf Accessed May 21, 2012. 9. Edge SB, Byrd RD, Compton CC, Fritz AG, et al. eds. AJCC Cancer Staging Manual, (7th ed). New York: Springer, 2009. 10. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206. 11. Huilgol SC, Selva D, Chen C, Hill DC, et al. Surgical margins for lentigo maligna and lentigo maligna melanoma: the technique of mapped serial excision. Arch Dermatol 2004;140:1087–92. 12. Megahed M, Schon M, Selimovic D, Schon MP. Reliability of diagnosis of melanoma in situ. Lancet 2002;359:1921–2. 13. Wayte DM, Helwig EB. Melanotic freckle of hutchinson. Cancer 1968;21:893–911. 14. Cohen LM, McCall MW, Zax RH. Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma a follow-up study. Dermatol Surg 1998;24:673–7. 15. Somach SC, Taira JW, Pitha JV, Everett MA. Pigmented lesions in actinically damaged skin. histopathologic comparison of biopsy and excisional specimens. Arch Dermatol 1996;132:1297–302. 16. Zalla MJ, Lim KK, Dicaudo DJ, Gagnot MM. Mohs micrographic excision of melanoma using immunostains. Dermatol Surg 2000;26:771–84. 17. Shumaker PR, Kelley B, Swann MH, Greenway HT Jr. Modified mohs micrographic surgery for periocular melanoma and melanoma in situ: long-term experience at scripps clinic. Dermatol Surg 2009;35:1263–70. 18. Bub JL, Berg D, Slee A, Odland PB. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol 2004;140:552–8. 19. Osborne JE, Hutchinson PE. A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision. Br J Plast Surg 2002;55:611–5. 20. Agarwal-Antal N, Bowen GM, Gerwels JW. Histologic evaluation of lentigo maligna with permanent sections: implications regarding current guidelines. J Am Acad Dermatol 2002;47:743–8. 21. Mahoney MH, Joseph M, Temple CL. The perimeter technique for lentigo maligna: an alternative to mohs micrographic surgery. J Surg Oncol 2005;91:120–5. 22. Karimipour DJ, Schwartz JL, Wang TS, Bichakjian CK, et al. Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma. J Am Acad Dermatol 2005;52:798–802. 23. Egnatios GL, Dueck AC, Macdonald JB, Laman SD, et al. The impact of biopsy technique on upstaging, residual disease, and outcome in cutaneous melanoma. Am J Surg 2011;202:771–7. discussion 777–8.
Address correspondence and reprint requests to: Luciano J. Iorizzo III, MD, Mohs Micrographic Surgery, Dermatologic Surgery, Cutaneous Oncology, 2 Corporate Plaza, Suite 201, Albany, NY 12203, or e-mail:
[email protected]
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COMMENTARY
Complete Melanoma Microstaging STANLEY J. MILLER, MD*
The author has indicated no significant interest with commercial supporters.
I
n 2005, Karimipour and colleagues1 published the results of a prospective, single-institution study that examined microstaging accuracy of an incisional biopsy of primary cutaneous melanoma of any thickness in which a significant portion of the clinical lesion ( 50%) remained after the biopsy. Two hundred fifty of 1,783 patients (14%) presenting to the institution with primary cutaneous melanoma met these criteria. After complete excision of the residual lesion, upstaging occurred in 21% of patients, and 10% became candidates for sentinel lymph node biopsy. In this issue of Dermatologic Surgery, Iorizzo and colleagues2 extend these findings to another subset of patients with primary cutaneous melanoma: individuals with lentigo maligna/melanoma in situ or thin melanoma treated using Mohs micrographic surgery. In this retrospective, single-institution study, 173 of 196 cases had permanent section pathology reports available for the central debulking specimen. After permanent pathology assessment of this “residual tumor,” upstaging occurred in 8.1% of patients, and 2.3% became candidates for sentinel lymph node biopsy. The “practice gap” that this study addresses concerns how Mohs surgeons who treat patients with melanoma can ensure that the highest level of
diagnostic accuracy—and with it, the most accurate prognosis and most correct therapy—is provided to patients with this disease. As both of these studies illustrate, partial biopsies, especially when they represent only a small portion of the entire lesion, do not always reflect the true extent of tumor invasion. The upstaging that occurs after residual lesional tissue is examined can affect prognosis, even if therapy is unchanged, as well as therapy itself. In addition, specifically with melanoma in situ, complete examination of a Mohs debulking specimen can diagnose undetected, underlying desmoplastic melanoma—a rare and subtle tumor, but one that occurs in 80% to 85% of cases in association with an overlying melanoma in situ.3 This “complete melanoma microstaging” practice gap exists in large part, I think, because the valuable data presented in this month’s study by Iorizzo and colleagues have simply not existed. This work should inform all Mohs surgeons who provide care to patients with melanoma of the importance of sending debulking specimens for postoperative permanent section assessment to ensure that accurate microstaging of the entire lesion is performed. Only by doing this can we provide the highest quality medical care to our patients with melanoma.
*Department of Dermatology, Johns Hopkins Hospital, Towson, Maryland © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:372–373 DOI: 10.1111/dsu.12041 372
MILLER
References 1. Karimipour DJ, Schwartz JL, Wang TS, Bichakjian CK, et al. Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma. J Am Acad Dermatol 2005;52:798–802. 2. Iorizzo LJ, Chocron I, Lumbang W, Stasko T. The importance of vertical pathology of the debulking specimen during Mohs micrographic surgery for lentigo maligna/melanoma in situ. Dermatol Surg 2013;39:365–71.
3. Busam KJ. Desmoplastic melanoma. Clin Lab Med 2011;31: 321–30.
Address correspondence and reprint requests to: Stanley J. Miller, MD, Department of Dermatology, Johns Hopkins Hospital, 1104 Kenilworth Drive, Suite 201, Towson, MD 21204, or e-mail:
[email protected]
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Incidence of Residual Nonmelanoma Skin Cancer in Excisions After Shave Biopsy KURT GRELCK, DO,* SEAN SUKAL, MD, PHD,† LES ROSEN, MD,‡ AND GABRIEL P. SUCIU, MSPH, PHD§
BACKGROUND Nonmelanoma skin cancer is an increasingly common disease that is typically treated surgically. After histopathologic confirmation by biopsy, the carcinoma is typically removed by excision, but not all excisional specimens contain residual carcinoma. OBJECTIVES To define the rate of residual basal and squamous cell carcinomas within excisional specimens after shave biopsy in a general dermatology office. METHODS We retrospectively reviewed 439 consecutive cases sent to a single dermatopathology lab from a practitioner’s general dermatology office who also performs Mohs micrographic surgery. One hundred cases had a histopathologically proven carcinoma on biopsy with subsequent excision. Histopathologic type, location, age, sex, and time from biopsy to excision were all analyzed for statistical association. RESULTS Of 57 cases of basal cell carcinoma, 34 (59.6%) had positive residuals. Of 43 cases of squamous cell carcinoma, 12 (27.9%) had positive residuals. Histologic type was significantly associated (p = .002) with residual carcinoma in excisional specimens, with basal cells 2.13 times as likely to have residual carcinoma present. CONCLUSION The rate of residual nonmelanoma carcinoma in excision specimens after shave biopsy was found to be different from previously reported in the literature. These data may have therapeutic ramifications if further substantiated. The authors have indicated no significant interest with commercial supporters.
T
he evaluation of possible nonmelanoma skin cancer (NMSC) often begins with a shave biopsy for histopathologic confirmation of a clinical suspicion of carcinoma. Upon finding histopathologic evidence of a basal cell carcinoma (BCC) or a squamous cell carcinoma (SCC), the clinician will typically perform an excision at the biopsy site to remove residual carcinoma. Patients frequently question this practice because they often do not understand the motivations behind excision of residual, sometimes clinically unapparent carcinoma1 and are often unaware of the dangers of leaving residual carcinoma behind.2–14 Other
investigators have evaluated the likelihood of having residual disease in Mohs micrographic surgery (MMS) excisions after a positive biopsy in patients in whom no apparent clinical disease remained and found that approximately 68% of excisional MMS specimens contained residual BCC.2 Another larger study conducted out of a Veteran’s Affairs Health Care System (VAHCS) found similar data, with 80% of excision specimens containing residual BCC and 60% of SCC excisional specimens containing residual carcinoma after punch or shave biopsy.15 Because the cases that Holmkvist and colleagues examined were limited to the typical sites and
*Dermatology Associates of Wisconsin, Stevens Point, Wisconsin; †Sukal Skin Institute, Boca Raton, Florida; ‡ Dermpath Diagnostics, Pompano Beach, Florida; §Department of Biostatistics, Nova Southeastern University, Fort Lauderdale, Florida © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:374–380 DOI: 10.1111/dsu.12056 374
GRELCK ET AL
situations appropriate to Mohs therapy and BCCtype malignancies, and the cases examined in the series out of the VAHCS were not taken from a private general dermatology practice that uses MMS, the applicability of these results may be limited. Additionally, as overall patient age and degree of concomitant illness continue to increase, patients may wish to know the chances of treatmentrelated morbidity versus the chances of possible “cure” after shave biopsy. Based on anecdotal levels of residual NMSC in excisions, we suspected that the rates of residual tumor presence in our patient population were probably lower than what had been reported in the literature. We therefore conducted a retrospective analysis of BCC and SCC excisions that had been initially evaluated with shave biopsy in a single practitioner’s office where MMS was performed. We examined the relationship between patient age and sex, location of skin cancer, type of skin cancer (BCC vs SCC), and the interval from biopsy to excision and the rate of residual neoplasm within excision specimens.
Methods This was a cross-sectional study nested within a case series based on patient charts and histopathology reviewed from a single practitioner’s office between June 1, 2009, and February 25, 2011. The patients reviewed had biopsy-proven NMSC that was excised and sent to the same dermatopathology laboratory. Patients whose biopsy locations or histopathologic characteristics were indications for MMS were excluded from final analysis. Indications for MMS were the same as put forth by the Centers for Medicare and Medicaid Services (www.medicare. gov). Patients with punch biopsies, those with lesions larger than 1 cm in diameter, and those with clinical diagnoses other than NMSC were also excluded. All biopsy locations were documented and digitally photographed before shave biopsy, and excision sites were verified using documentation and biopsy site photographs. Shave biopsy was performed using a curved razor blade to make a small superficial saucerization of the lesion in
question for diagnostic purposes without intent to remove additional nonlesional tissue or to completely remove the lesion. Each excision was performed with a 4-mm margin, and no curettage was performed before excision. Histopathologic analysis was performed with the tissue block sectioned at 2-mm intervals and cut 3 lm thick, with multiple sections placed on each slide. Each specimen was sectioned into six or more sections depending on the excision size, and additional step sections were performed if there was evidence of possible residual carcinoma. NMSC histopathologic type and subtype were determined when possible. Statistical analyses using the frequency of biopsies according to NMSC histopathologic type, histopathologic subtype, lesional location site, patient age and sex, and time from biopsy to excision were performed to determine percentages and relationships. The cases with a documented biopsy interpreted and processed at the same laboratory to which the subsequent excision was sent were particularly analyzed for positive or negative residuals. Chi-square tests, risk ratios (RRs), and 95% confidence intervals (CIs) were assessed for the amount of association.
Results There were 439 consecutive cases fitting the inclusion criteria taken from a general dermatology practice that also practiced MMS; 372 had documented biopsies. Two hundred seventy-two cases had no documented excisions (73.1%) for that laboratory. This was largely because cases were sent for subsequent MMS, although some specimens were sent to other laboratories and were therefore excluded. There were 100 cases with documented biopsies and documented subsequent excisions (positive or negative), 46 of which were positive and 54 negative. According to histopathologic type, for BCC, 34 of the 57 cases of documented biopsies (59.6%) had positive residuals, and 23 (40.3%) were negative.
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The average age of a patient with BCC was 63. For SCC, 12 of the 43 cases of documented biopsies (27.9%) had positive residuals, and 31 (72.1%) were negative. The average age of patients with SCC was 69.6. NMSC histopathologic type (BCC vs SCC) and the presence of residual carcinoma were significantly associated (p = .002), and the RR indicated a higher risk of positive residuals for BCC than for SCC (RR=2.13, 95% CI = 1.26–3.61. Patients who had biopsies with BCC were 2.13 times as likely to have positive residuals as those with SCC. When we analyzed the above association according to sex, there was a significant association (RR = 2.19, 95% CI = 1.17–4.09) for male sex, of which 59% of our patient population was composed. The male patients who had BCC histology were 2.19 times as likely to have positive residuals as those with SCC. There was no statistically significant association between location and the other variables: presence of residual carcinoma, histologic type (BCC vs SCC), age, sex, or time from biopsy to excision. (See Tables 1 and 2 for locational frequencies.) The same lack of statistically significant association was found between patient age and the other variables. The relative frequencies of NMSC subtypes (e.g., superficial BCC, Bowens) and other variables were also not found to be statistically related (Table 3).
The last set of variables analyzed were time between shave biopsy and excision and the presence of residual carcinoma. One patient had to be excluded because of an aberrantly long period between procedures, which was a result of referral difficulties. Although statistical significance was not present (p < .05) in either case according to the Spearman nonparametric correlation, a weak positive correlation between time and residual BCC was observed (rho = 0.041, p = .76) and a weak negative correlation between time and residual SCC (rho = 0.056, p = .72). A linear regression approach was also used for the time interval between shave biopsy and excision and the presence of residual carcinoma
TABLE 2. Frequency of Anatomic Locale Among Those Cases Fitting Inclusion Criteria Anatomic Location
n (%)
Abdomen Back Chest Lower extremity Upper extremity Shoulder Total
5 24 22 5 35 9 100
TABLE 3. Biopsy Nonmelanoma Skin Cancer (NMSC) Histopathologic Subtype and Excisional Residual Carcinoma
NMSC Subtype TABLE 1. Anatomic Location of Biopsy Specimens
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Anatomic Location
n (%)
Abdomen Back Chest Ear Lower extremity Upper extremity Face Genitals Neck Scalp Shoulder
11 53 59 5 66 82 112 1 16 11 23
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(2.5) (12.1) (13.4) (1.1) (15.0) (18.7) (25.5) (0.2) (3.6) (2.5) (5.2)
(5) (24) (22) (5) (35) (9) (100)
n
Basal cell carcinoma Superficial 17 Nodular 19 Keratinizing 4 17 Unspecified* Squamous cell carcinoma Bowen’s disease 33 Well differentiated 1 Moderately 2 differentiated Keratoacanthoma 3 Unspecified* 4
Frequency/Percentage of Excisional Specimens with Residual Carcinoma, n (%) 12 8 2 11
(70.6) (42.1) (50.0) (64.7)
11 (33.3 0 (0.0) 0 (0.0) 2 (66.6 1 (25.0)
*Unspecified because of biopsy specimen size or quality.
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according to subtype, but there was no linear statistically significant relationship between time and the presence of residual NMSC.
Discussion This investigation was instigated because of the seemingly high anecdotal rate of excisions that occurred in a private practice that were negative for residual skin cancer. There has not been an analysis published that examines the rate of residual carcinoma in standard excision specimens that were initially diagnosed by shave biopsy in this setting. Because shave biopsy represents one of the most frequent methods of histologic confirmation of disease, the results of this study are pertinent to patients and clinicians alike. More than half (59.6%) of excised BCCs in our study contained residual tumor. This percentage is similar to that reported in the series of Holmkvist and colleagues, which evaluated patients with biopsy-diagnosed BCC with no evidence of clinical disease, and the prevalence of residual BCC in MMS excision specimens (66%). In the aforementioned study, 88% of biopsies were by shave, and removal of residual tumor was via MMS excision, with the histopathologic subtype limited to BCC.2 The sole use of MMS for BCC confined to the head and neck, a location that Swetter and colleagues found to be more likely to contain residual carcinoma, may have increased the likelihood of residual carcinoma being found.15 In a different study by Alcalay and colleagus, investigators performed a preoperative biopsy for nodular BCC, using a 15 blade at the clinical borders of the lesion immediately before MMS and found that 78.4% of excisional specimens contained residual tumor.16 Again, it is likely that the specific use of MMS biased the locations sampled. Additionally, the procedural technique of biopsy (immediately preoperative) followed by MMS excision would have excluded any temporal effects on the presence of residual tumor, such as inflammationinduced regression. There was a median interval of 16 days for BCC and 14 for SCC in our series. Although the relationship between residual
carcinoma and time interval was not found to be statistically significant with our data, there was a trend toward longer time and positive BCC residual and between longer time and less SCC residual. An earlier study by Acalay and colleagues in which a temporally distant preoperative biopsy was performed and NMSC excised using MMS, the overall rate of residual of tumor was 74.7%.17 This study utilized data from MMS cases alone, which may reflect the greater rate of residual carcinoma identified, perhaps because MMS lesions were more likely to be in cosmetically or functionally sensitive areas in which the initial shave biopsy was more conservative. Also in this investigation, the type of preoperative biopsy performed was not noted, and the results yielded were a combined measure of BCC and SCC, which are biologically distinct in behavior. In the larger series conducted out of the VAHCS, investigators measured the rate of NMSC after biopsy and found a positive rate of residual BCC in excision specimens of 80%.15 This rate of BCC tumor residual in non-MMS excisions is considerably higher than the rate of 59.6% we found in our cases. This may reflect the overall higher rate of male patients seen (97% of the VAHCS population was male) with an average age of 71, versus our mean age of 65.8. In our study’s patient population, 33% of cases evaluated were from women. It is likely that the predominant male patient constituency seen influenced the high rate of residual tumor, because others have shown a statistically significantly greater rate of BCC invasion in men,18 as well as the more advanced degree of disease see at presentation at Veterans Affairs Medical Centers in general.19 Although mean time from biopsy to excision in the VAHCS study (46 days for BCC, 52 days for SCC) was longer than our temporal interval (27 days for BCC, 31 days for SCC), there was no statistically significant association between time and the presence of residual in either study.15 The rate of residual SCC in excision specimens initially evaluated using shave biopsy in our study was striking at less than 27.9%. This differs markedly from the rate of residual SCC seen in the
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series collected from the VAHCS (60%). Again, it is likely that a factor contributing to this higher rate of residual in the VAHCS series was the predominance of men, which has been shown to be associated with greater likelihood of larger SCC lesions at presentation,20 as well as the acuity of the veteran’s population itself.19 Additionally, it is likely that morefrequent follow-up in the private setting would result in smaller size at NMSC presentation, as well as bias toward MMS for lesions that are clinically large, histologically invasive, or located in places that would make them difficult to remove (more often located on the head and neck, areas that were largely sent for MMS in our series), possibly leading to a lower rate of residual in the excisions from our study. The scope of this investigation limited the results of our analysis, which was performed in a retrospective fashion out of a single practitioner’s office. Our data are subject to many confounding factors. First, the overall prebiopsy size of the suspected neoplasm plays a large role in whether a shave biopsy can functionally remove the lesion. Higher rates of residual tumor are more likely to be found in practices in which the patient population is underserved or in an individual patient in whom rapidly growing or neglected tumors are being biopsied. There is also always the possibility of the incorrect clinical correlation between biopsy and excision site, a factor we believe we minimized with meticulous documentation and photography, a methodology that the literature supports.21,22 Time from biopsy to excision was not statistically associated with residual in our series, although this factor could play a role in the degree of success that the body’s inflammatory processes would have in eradicating residual neoplastic cells after biopsy. Alcalay and colleagues’ work would seem to temper this possible bias, because they performed a shave biopsy immediately before MMS and found 25.3% of patients to be clear of residual tumor.16,17 Holmkvist and colleagues also found no correlation between extent of inflammation in MMS sections and the presence of residual BCC.2 A trial by Spencer and colleagues substantiated this finding, after examining the
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influence of inflammation on histologically residual BBC after electrodesiccation and curettage (EDC) and not finding a positive association.23 Nouri and colleagues found that after ED&C of BCC and then eventual excision, there was an association between decreased residual BCC and increased time to excision, but this trend did not meet statistical significance.24 That something that seems intuitive (longer time interval allows for inflammation to decrease excisional residual frequency) has not been shown to be statistically significant in this or other series remains surprising. The sole use of shave biopsy in our study also may have contributed to our lower yield of residual tumors. The series from the VAHCS found evidence of statistically significant reduction of residual with the method of biopsy (shave) (p < .001).15 Depth and scope of shave biopsy also were not controlled for because smaller neoplasms could have been inadvertently removed during shave, whereas obviously larger neoplasms could have been only partially sampled because tumor bulk would prohibit more-aggressive biopsy technique, although only one practitioner was performing the biopsies, which would somewhat internally standardize the procedure. The inclusion criteria for clinical size smaller than 1 cm in diameter would also mitigate this variable, although in the larger investigation by Swetter and colleagues, the prebiopsy size of NMSC with residual neoplasm after excision was essentially the same as NMSC without residual in excisional specimens, with the stipulation that lesions measuring larger than 1.5–2.0 cm in diameter or exhibiting aggressive growth patterns were sent for MMS, similar to the methodology in our study.15 The socioeconomic status of the patient population served, frequency of full skin examinations, degree of compliance, and the age and ethnicity of the patients may also have influenced our results. The patient population in this investigation was nonindigent and from an urban setting. Furthermore, the study was conducted in a MMS practice in which tumors fulfilling the criteria for subsequent inter-
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vention with MMS were excluded from our data, and this reduced or eliminated cases with aggressive histopathology or in functionally or cosmetically sensitive locations. This trial was underpowered (n = 100) to determine the relationship between tumor subtype (Table 3) and residual carcinoma within excisional specimens, although in the larger (n = 910) VAHCS investigation, there was no influence on tumor subtype (e.g., superficial, nodular) according to regression analysis.
unfounded. Further studies to answer these questions should include a comparison of microscopic features of lesions that were clear with biopsy alone with features of those that were not to attempt to risk-stratify patients based on microscopic features found in shave biopsies other than simple positive or negative residual margins, as well as integration of prebiopsy clinical size and location.
Conclusion A single pathology laboratory performed histologic processing and interpretation of specimens, with several dermatopathologists interpreting our cases. It is possible that variances in training and microscopic interpretation of cancer subtypes or regression may have varied between individual dermatopathologists and affected our results as well. It is also possible that, with 3-lm sections taken 2 mm apart, microscopic remnants of tumor cells may have been missed and falsely increased our rate of excisions without residual. Previous industrysponsored trials investigating the efficacy of imiquimod used 0.5- to 3-mm step sections through excisional specimens to check for residual BCC.25–30 This methodology might have increased our residual rate of carcinoma within excisional specimens, but our study was an attempt to quantify the rate of clearance of NMSC after shave biopsy given the limitations of a retrospective data set and the specified inclusion criteria, which mirror the conditions of clinical practice. Analyses such as ours are necessary if we are to save the specialty of dermatology in a U.S. health care system in which reimbursements for procedures are bound to be cut and treatment necessity will become a sure requirement for reimbursed treatments. Studies such as this one are a beginning to perhaps address the question of which tumors truly require more costly procedures such as excision or MMS and those that can be treated more conservatively. Additionally, the somewhat frequent lack of residual carcinoma may protect dermatologic surgeons from accusations of wrong site surgery that may be
In this study, conducted out of a general dermatologist’s office that practices MMS, we found a higher rate of residual BCCs than SCCs in excision specimens that had first been evaluated using shave biopsy. The rate of residual BCC within excisional tissue was similar to rates in previous reports (59.6%). The rate of residual SCC was significantly lower (27.9%), a finding that is markedly less than has previously been reported in the literature. This finding has several possible sources of bias, although it may have clinical and therapeutic ramifications if further substantiated with additional larger prospective studies.
References 1. Vujevich JJ, Kimyai-Asadi A, Goldberg LH. Where was that biopsy taken? Dermatol Surg 2007;33:1534–1536. 2. Holmkvist KA, Rogers GS, Dahl P. Incidence of residual basal cell carcinoma in patients who appear tumor free after biopsy. J Am Acad Dermatol 1999;41:600–605. 3. Boulinguez S, Grison-Tabone C, Lamant L, Valmary S, et al. Histological evolution of recurrent basal cell carcinoma and therapeutic implications for incompletely excised lesions. Br J Dermatol 2004;151(3):623–6. 4. Roenigk RK, Ratz JL, Bailin PL, Wheeland RG. Trends in the presentation and treatment of basal cell carcinoma. J Dermatol Surg Oncol 1986;12:860–5. 5. Hauben DJ, Zirkin H, Mahler D, Sacks M. The biologic behavior of basal cell carcinoma: analysis of recurrence in excised basal cell carcinoma: part II. Plast Reconstr Surg 1982;69:110–6. 6. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975–983. 7. Richmond JM, Davie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg 1987;40:63–7.
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8. Sussman LAE. Liggins DR incompletely excised basal cell carcinoma: a management dilemma? Aust NZ J Surg 1996;66:276–8. 9. Park A J, Strick M, Watson JD. Basal cell carcinomas: do they need to be followed up? J R Coll Surg Edinb 1994;39:109–11. 10. Liu FF, Maki E, Warde P, Payne D, et al. A management approach to incompletely excised basal cell carcinomas of skin. Int J Radiat Oncol Biol Phys 1991;20:423–8. 11. De Silva SP, Dellon AL. Recurrence rate of positive margin basal cell carcinoma: results of a five-year prospective study. J Surg Oncol 1985;28:72–4. 12. Gooding CA, White G, Yatsuhashi M. Significance of marginal extension in excised basal-cell carcinoma. N Engl J Med 1965;273:923–4. 13. Pascal RR, Hobby LW, Lattes R, Crikelair GF. Prognosis of “incompletely excised” versus “completely excised” basal cell carcinoma. Plast Reconstr Surg 1968;41:328–32.
23. Spencer JM, Tannenbaum A, Sloan L, Amonette PA. Does inflammation contribute to the eradication of basal cell carcinoma following curettage and electrodesiccation? Dermatol Surg 1997;23:625–31. 24. Nouri K, Spencer JM, Taylor JR, Hayag M, et al. Does wound healing contribute to the eradication of basal cell carcinoma following curettage and electrodessication? Dermatol Surg 1999;25(3):183–7; discusion 187–8. 25. Beutner KR, Geisse JK, Helman D, Fox TL, et al. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 1999;41 (6):1002–7.
14. Taylor GA, Barisoni B. Ten years experience in the surgical treatment of basal cell carcinoma. Br J Surg 1973;60:522–5.
26. Marks R, Gebauer K, Shumack S, Amies M, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 2001;44(5):807–13.
15. Swetter SM, Boldrick JC, Pierre P, Wong P, et al. Effects of biopsy-induced wound healing on residual basal cell and squamous cell carcinomas: rate of tumor regression in excisional specimens. J Cutan Pathol 2003;30(2):139–46.
27. Geisse JK, Rich P, Pandya A, Gross K, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol 2002;47(3):390–8.
16. Alcalay J, Alkalay R. Histological evaluation of residual basal cell carcinoma after shave biopsy prior to Mohs micrographic surgery. J Eur Acad Dermatol Venereol 2011;25(7):839–41.
28. Shumack S, Robinson J, Kossard S, Golitz L, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma. Arch Dermatol 2002;138(9):1165–71.
17. Alcalay J, Alkalay R, Hazaz B. Residual skin cancer after preoperative biopsy: evaluation by Mohs micrographic surgery. Int J Dermatol 2004;43:456–458.
29. Sterry W, Ruzicka T, Herrera E, Takwale A, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol 2002;147 (6):1227–36.
18. Takenouchi T, Nomoto S, Ito M. Factors influencing the linear depth of invasion of primary basal cell carcinoma. Dermatol Surg 2001;27(4):393–6. 19. Agha Z, Lofgren R, Van Ruiswyk J, Layde P. Are patients at veterans affairs medical centers sicker? Arch Intern Med 2000;160:3252–3257. 20. Renzi C, Mastroeni S, Passarelli F, Mannooranparampil TJ, et al. Factors associated with large cutaneous squamous cell carcinomas. J Am Acad Dermatol 2010;63(3):404–11. 21. Ke M, Moul D, Camouse M, Avram M, et al. Where is it? The utility of biopsy site photograph. Dermatol Surg 2010;36:198– 202.
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22. McGinness JL, Goldstein G. The value of preoperative biopsy-site photography for identifying cutaneous lesions. Dermatol Surg 2010;36(2):194–7.
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30. Geisse J, Caro I, Lindholm J, Takwale A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004;50(5):722–33.
Address correspondence and reprint requests to: Kurt Grelck, DO, 5501A Vern Holmes Blvd., Stevens Point, WI 54482, or e-mail:
[email protected]
Positive KI67 and Periodic Acid-Schiff Mandates Wider Range of Excision in Scrotal Extramammary Paget’s Disease CHEN-CHEN FENG, MD,*a LU-JIA WANG, MD,*a ZHONG-WEN ZHOU, MD,† QIANG DING, MD,* ZU-JUN FANG, MD,* GUO-WEI XIA, MD,* HAO-WEN JIANG, MD,* GANG XU, MD,* AND HUI WEN, MD*
BACKGROUND Extramammary Paget’s disease (EMPD) of the scrotum is a rare disease that requires surgical excision. A positive margin is related to recurrence and poorer prognosis. We aimed to investigate the expression of Ki67 and periodic acid-Schiff (PAS) in a biopsy sample and to evaluate their predictive value in true margin status. METHODS Sixty-four patients with noninvasive scrotal EMPD were included. Immunohistochemical staining of Ki67 and PAS was reviewed and compared statistically with the margin status of intraoperative frozen section examination (FSE). RESULTS Seventeen of 64 patients had a positive margin discovered at the first FSE. Expression of Ki67 was not significantly different between positive and negative margin status (p = .16). Expression of PAS was higher in samples with positive margins (p = .05). The incidence of positive margins was significantly higher in the double-positive group than in the double-negative group (p = .03). CONCLUSION Positive expression of both factors in a biopsy sample requires wider excision to ensure negative margins. The authors have indicated no significant interest with commercial supporters.
E
xtramammary Paget’s disease (EMPD) is a rare malignancy and is even less commonly seen on genitalia.1 In men, the scrotum is more often involved than the penis, and the disease is usually misdiagnosed as eczema. The lesion originates from the skin-bearing apocrine glands and presents in a variety of forms, such as pruritic, well demarcated, erythematous, and white scaly plaques. The disease can be classified as primary or secondary EMPD. Primary EMPD originates from the intra-epidermal cells of the apocrine gland ducts or from pluripotent keratinocyte stem cells.2 Secondary EMPD is less commonly seen and originates from an underlying neoplasm of the dermal adnexal gland or
organs that have continuous epithelium, such as the colorectum.3–5 Unlike Paget’s disease of the breast, most EMPD is located entirely in the intra-epithelium (in situ) and develops slowly.3,7 Even with minimal invasion less than 1 mm deep, the prognosis of EMPD is similar to that of the noninvasive entity.3 The microscopic diagnosis of EMPD is not difficult in most cases because Paget’s cells can be identified. Paget’s cells are large and abundant in basophilic or amphophilic, finely granular cytoplasm, and have a large, centrally situated nucleus.8 Surgical excision is the mainstream of treatment of scrotal EMPD. Intraoperative frozen section examination (FSE) is mandatory to ensure clear surgical margins.9 More
*Department of Urology, Huashan Hospital, Fudan University, Shanghai, China; †Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China a
These authors contributed equally.
© 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:381–386 DOI: 10.1111/dsu.12080 381
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recently, Mohs micrographic surgery (MMS) has been recommended because of its low recurrence rate and tissue-sparing capability in critical regions such as the anogenital region, but it has not been widely accepted because of its complexity.10 The goal of all surgical modalities it to ensure clear margins. Therefore, we intended to assess the value of routine enzyme labels in indicating margin status. A number of enzyme labels have been accepted globally in pathological diagnosis of EMPD, including cytokeratin (CK)7, CK20, carcinoembryonic antigen (CEA), vimentin, Ki67, and p53.11 Contributions of some factors have been established (e.g., CEA indicating potential metastasis and CD20 indicating secondary EMPD).12,13 In the current study, we intended to evaluate the roles of Ki67 and periodic acid-Schiff (PAS), two enzyme-labels routinely used in our institute, in indicating margin status in the process of standard lesion excision.
Materials and Methods Sixty-four patients with a mean age of 65.8 (range 54– 81) with nonmetastatic scrotal EMPD were included in this study. Patients were surgically treated between January 2009 and May 2012. All patients were primarily diagnosed. Complete physical examination, ultrasonogram, and pelvic computed tomography (CT) were performed to exclude potential local or distal lymph node involvement. All patients adhered to complete protocols for diagnosis and treatment of our institute: outpatient biopsy, surgical excision with intraoperative FSE for margin status, and final pathology diagnosis of excised specimen. One patient had recurrent disease, and four had local invasion. Those cases were excluded because the population is not large enough for accurate statistical analysis. Surgical excision was performed initially approximately 1 to 2 cm from the visualized margin of the lesion. The excisions generally included all appendages. In patients with suspected local invasion, the deepest cut reached deep fascia. FSE was performed immediately after the lesion was completely
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removed. FSE was performed using the bread-loafing method, and only hematoxylin and eosin (H&E) staining was used. Excision was widened for another 1 cm on the margin-positive side (including base) if FSE was positive until a negative margin was acquired. Closure was customized to the size of lesion and included scrotal skin release angioplasty, pedicle flap repair, and skin grafting. The pathologic profiles of all samples were retrospectively studied. Routine enzyme-labelled study for EMPD in our institute for biopsy and final pathology included CKs, CEA, S100, vimentin, Ki67, leukocyte common antigen, HMB45, p53, and special stains of PAS, all performed on permanent paraffin-embedded sections. Ki67 and PAS expression were studied. Expression of Ki67 was seen in all sections and was graded using a labelling index from 0 to 100 according to the percentage of tumor cells stained.11 Regarding the intensity and extensity of staining in the majority of the sections in this study, sections with more than 10% of Ki67 expression were defined as positive. Criteria for positive PAS stain in Paget cells were well established.14 All sections were confirmed using H&E staining and were reviewed by two independent pathologists. The expressions of all factors stained in biopsy were concordant with those in gross pathology. Positive margins were defined as margins with Paget’s cells discovered intraoperatively using FSE. The Huashan Institutional Review Board approved the study, and informed consent was obtained from all patients. Expressions of Ki67 and PAS were compared with margin status revealed by the first FSE. The chisquare test was used to analyze the relationship of expressions between two or more groups. The Fisher exact test was used to analyze data between two groups. The p < .05 was accepted as statistically significant.
Results Seventeen of 64 patients had a positive margin discovered at the first FSE and had a 3-cm excision
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edge in total (true margin) on the involved side. Four patients had positive margins at the second excision with 5 cm of true margin, and 1 patient underwent closure after five extended excisions with 7 cm of true margin on the involved side. We reviewed the expressions of the aforementioned factors in patients with different margin status and found that expression of Ki67 and PAS varied between groups, whereas the others remained consistent. Immunopositive Ki67 and PAS sections are respectively demonstrated in Figures 1 and 2. Subjects were first grouped according to Ki67 and PAS. There were 29 cases with negative Ki67
Figure 1. Immunohistochemical Ki67 staining in extramammary Paget’s disease of the scrotum (9200).
Figure 2. Immunohistochemical periodic acid-Schiff staining in extramammary Paget’s disease of the scrotum (9200).
expression and 35 cases with positive Ki67 expression. Ki67 expression was not significantly different according to margin status (p = .16), but PAS expression was negative in 36 patients and positive in 28 patients. Incidence of positive PAS was higher in patients with positive margin status (p = .05). Nonetheless, when cases were grouped further according to co-expression of both factors, as demonstrated in Table 1, significant differences were found between the double-negative and double-positive groups and between all four groups (Table 1).
Discussion Wide excision of the skin lesion is currently recommended for scrotal EMPD because of the high local recurrence rate.12,15 One critical reason is that the visualized lesion border is usually inadequate microscopically although it seems clear in most cases.10 Excision 1.0 to 1.5 cm from the lesion can entail a recurrence rate up to 25.3%,16 so an excision greater than 3 cm from lesion border is recommend.17 Nonetheless, larger excision entails complexity of reconstruction and more complications. The importance of intraoperative FSE is thus warranted and is currently a routine practice in most centers.18,19 In comparison, depth is not significantly associated with recurrence, and only extension deeper than 5 mm may substantially compromise survival.3,11 Unlike earlier studies that found a weak association between marginal status and recurrence,16,20,21 recent investigations indicate that recurrence and prognosis are strongly related to positive margin and lymphovascular permeation.11,22 FSE and MMS, which are currently the mainstays, also have insufficiencies. With FSE, there is a risk of false-negative reports, although we did not experience any in this study. For MMS, as mentioned above, the complexity of the procedure makes it difficult to practice in low-volume centers. We thus focus on the value of routine immunoprofiles in predicting margin status in biopsy samples, which may subsequently guide the extent of the excision. Patients with a double-positive Ki67 and
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TABLE 1. Relationship Between Marginal Status and Expression of Ki67 and Periodic Acid-Schiff (PAS) Defined According to Immunohistochemistry Ki67 /PAS Margin
n
Negative Positive
14 3
Ki67 /PAS+
Ki67 + /PAS
Ki67 + /PAS+
10 2
16 3
7 9
Ki67 = <10% Paget cells stained using immunohistochemistry. p = .02 calculated between all four groups. p = .03 alculated between Ki67 /PAS and Ki67 + /PAS+.
PAS stain should undergo wider excision than standard procedure, whereas the lesion base can be excised at normal depth. A second FSE was negative in most margin-positive subjects in our cohort, so we think that 3 cm is suitable in those patients. Expression of Ki67 in EMPD was not recognized until 2002,23 so reports on its role in Paget’s disease of the breast are limited as well. Because Ki67 is a protein expressed in all active parts of the cell cycle, expression is often quantified according to the percentage of immunopositive cells rather than grading category. Ki67 is highly expressed in Paget’s disease and is therefore often used for differential diagnosis.24, 25 Investigation of vulval EMPD reveals that Ki67 is not an indicator of prognosis and is not related to the invasiveness of vulval EMPD.23 Expression of Ki67 is also not associated with recurrence.11 Our study find that Ki67 alone is not associated with margin status, supporting that Ki67 is not related to recurrence. We assume that the expression of Ki67 in EMPD has more qualitative than quantitative value, and its sensitivity and specificity for EMPD should be further studied. Therefore, we assume that the labelling index of Ki67 may be subjective, and we thus applied a categorical stratification for Ki67 in this study. In contrast, there are even fewer studies on special stains of PAS in EMPD. PAS is mainly used for staining structures containing a high proportion of carbohydrate macromolecules, including glycogen, mucin, mucoprotein, and glycoprotein, as well as fungi. It is sensitive, but specificity depends upon interpretation. Application of PAS is well estab-
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lished in Paget’s disease of the breast. Focal expression of PAS in EMPD is also used in differential diagnosis in ambiguous cases.26 We find that PAS alone may probably indicate margin status. Like Ki67, PAS-positive Paget cells can always been seen in all sections. Negative expression is defined as sporadic PAS-stained cells. In our study, the indicative value of double-positive PAS and Ki67 may be because Paget cells expressing both factors are actively proliferative and small clusters of cells may have extended over the visible boundary. We thus postulate that the co-expression of both factors may indicate wider tumor boundary due to several factors. Energy preparation for proliferation: the glycogen detected using PAS staining is critical for cell proliferation as an intracellular energy source. With the presence of Ki67, a protein that consistently promotes cell proliferation in all active phases, positive PAS staining may indicate mitosis of tumor cells in the early stage when there are not enough cells to provide visible change of the skin lesion. In addition, the expression of either factor is individual, indicating, however, a more-aggressive nature of the tumor. Because Ki67 expression is measured using a labelling index that is correlated with higher grade and stage and worse prognosis in most malignancies, the PAS-positive cases in this category may be a more-aggressive subtype that extends microscopically outside the visible borders. MMS, also known as chemosurgery, has nowadays been widely practiced in western countries. It guarantees clean margins, reserves healthy tissue, and has a high cure rate. Such advantages have made it the criterion standard for a variety of skin
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cancers.10 Despite its obvious advantages, the use of MMS for scrotal EMPD in China is limited. The MMS requires multidivisional cooperation that sharply increases the total expense. Given that scrotal EMPD grows slowly, is not aggressive, and occurs mostly in elderly adults, most patients would choose traditional excision as their first choice. Besides margin control, MMS maximally reserves healthy skin for better aesthetic outcomes but also lengthens the operation time. Indifference regarding the cosmetic effects in the scrotal area together with the fact that many scrotal EMPD should be managed under epidural anesthesia makes many patients reluctant to choose this modality. Most patients with scrotal EMPD presenting to our institute have a disease course ofl onger than 2 years, generally because it has been mistaken for eczema in lowvolume centers. The lesion is usually larger than 25 cm2 and requires flap reconstruction. This makes the reservation of 1 or 2 mm of skin not so critical for wound closure. In all, we assume that the practice of MMS would not suit most patients with scrotal EMPD we met,whereas a wider and deeper excision that guarantees a clear margin with one cut may be more practical in China, although MMS can be used in younger patients with suspected local invasion and patients with aesthetic demands.
find that positive co-expression of both factors requires wider excision than standard to ensure negative margins.
Our study has limitations. First, cases with local invasion were not included, which limits the indicative value of basal involvement. Second, lymphovascular invasion is not reviewed in the pathologic sections. To better interpret our results, this is an imperative supplement in future research. Third, data on recurrence is not involved in our study. Long-term outcomes should be investigated to determine the predictive values of Ki67 and PAS.
10. Li B, Ding Q. Extramammary Paget’s disease involving the penis, scrotum and the axilla. Australas J Dermatol 2011;52: e18–20.
Conclusion Scrotal EMPD is an indolent malignancy that can recur in cases of incomplete excision. We investigated Ki67 and PAS expression in biopsy sample and evaluated their predictive value in margin status. We
References 1. Park S, Grossfeld GD, McAnich JW, Santucci R. Extramammary Paget’s disease of the penis and scrotum: excision, reconstruction and evaluation of occult malignancy. J Urol 2001;166:2112. 2. Lloyd J, Flanagan AM. Mammary and extramammary Paget’s disease. J Clin Pathol 2000;53:742. 3. Song Y, Wang Z, Xu H, Yue Z, Xing C, et al. Paget’s disease is associated with eleven cancerous regions: a case report and therapeutic strategy. J Huazhong Univ Sci Technolog Med Sci 2009;29:677–8. 4. Ohnishi T, Watanabe S. The use of cytokeratin 7 and 20 in the diagnosis of primary and secondary extramammary Paget’s disease. Br J Dermatol 2000;142:243. 5. Lerner LB, Andrews SJ, Gonzalez JL, Heaney JA, Currie JL. Vulvar metastases secondary to transitional cell carcinoma of the bladder. A case report. J Reprod Med 1999;44:729. 6. Jones RE Jr, Austin C, Ackerman AB. Extramammary Paget’s disease. A critical reexamination.. Am J Dermatopathol 1979;1:101. 7. Hart WR, Millman JB. Progression of intraepithelial Paget’s disease of the vulva to invasive carcinoma. Cancer 1977;40:2333. 8. Sitakalin C, Ackerman AB. Mammary and extramammary Paget’s disease. Am J Dermatopathol 1985;7:335. 9. Xu K, Fang Z, Zheng J, Lu Y, et al. Intraoperative frozen biopsy in wide surgical excision of Paget’s disease of the scrotum. Urol Oncol 2009;27:483–5.
11. Choi YD, Cho NH, Park YS, Cho SH, et al. Lymphovascular and marginal invasion as useful prognostic indicators and the role of c-erbB-2 in patients with male extramammary Paget’s disease: a study of 31 patients. J Urol 2005;174:561–5. 12. Zhu Y, Ye DW, Yao XD, Zhang SL, et al. Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget’s disease. Br J Dermatol 2009;161:577–82. 13. Bagby CM, MacLennan GT. Extramammary Paget’s disease of the penis and scrotum. J Urol 2009;182:2908–9. 14. Fishman A, Lew S, Altaras M, Beyth Y, Bernheim J. A 30s PAS stain for frozen section analysis of surgical margins of vulvectomy in Paget’s disease. Eur J Gynaecol Oncol 1998;19:482–3. 15. Yang WJ, Kim DS, Im YJ, choks, et al. Extramammary Paget’s disease of penis and scrotum. Urology 2005;65:972. 16. Chanda JJ. Extramammary Paget’s disease: prognosis and relation-ship to internal malignancy. J Am Acad Dermatol 1985;13:1009.
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17. Lai CS, Lin SD, Yang CC, Chou CK, et al. Surgical treatment of the penoscrotal Paget’s disease. Ann Plast Surg 1989;23: 141–6.
23. Ellis PE, Fong LF, Rolfe KJ, Crow JC, et al. The role of p53 and Ki67 in Paget’s disease of the vulva and the breast. Gynecol Oncol 2002;86:150–6.
18. Zhu Y, Ye DW, Chen ZW, Zhang SL, Qin XJ. Frozen sectionguided wide local excision in the treatment of penoscrotal extramammary Paget’s dis-ease. BJU Int 2007;100:1282–7.
24. B€ oer-Auer A, August C, Falk TM, Jung JE, et al. Benign mucinous metaplasia of the genital mucosa: histomorphological and immunohistochemical features and criteria for differentiation from extramammary Paget disease. Br J Dermatol 2011;165:1263–72.
19. Wang Z, Lu M, Dong GQ, et al. Penile and scrotal Paget’s disease: 130 Chinese patients with long-term follow-up. BJU Int 2008;102:485–8. 20. Kodama S, Kaneko T, Saito M, Yoshiya N, et al. A clinicopathologic study of 30 patients with Paget’s disease of the vulva. Gynecol Oncol 1995;56:63. 21. Crawford D, Nimmo M, Clement PB, Thomson T, et al. Prognostic factors in Paget’s disease of the vulva: a study of 21 cases. Int J Gynecol Pathol 1999;18:351. 22. Hegarty PK, Suh J, Fisher MB, Taylor J, et al. Penoscrotal extramammary Paget’s disease: the University of Texas M. D. Anderson Cancer Center contemporary experience. J Urol 2011;186:97–102.
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25. Noel JC, Fayt I, Buxant F. Proliferating activity in paget disease of the nipple. Pathol Oncol Res 2010;16:7–10. 26. Du X, Yin X, Zhou N, Zhang G, et al. Extramammary Paget’s disease mimicking acantholytic squamous cell carcinoma in situ: a case report. J Cutan Pathol 2010;37:683–6.
Address correspondence and reprint requests to: Hui Wen, MD, Department of Urology, Huashan Hospital, Fudan University, 12 Central Urumqi Rd., Shanghai 200040, PR China, or email:
[email protected]
Tangential Shave Removal of Basal Cell Carcinoma AMANDA K. ABRAMSON, MD, MARK J. KRASNY, MD,
AND
GLENN D. GOLDMAN, MD*
OBJECTIVE To determine the outcome of tangential shave removal (TS) of basal cell carcinoma (BCC) on the trunk and extremities. DESIGN Cohort study of patients with multiple truncal BCC treated using TS in an academic dermatologic surgery practice. SETTING PATIENTS lesions.
Academic institution referral practice. Individuals with BCC referred to the dermatologic surgery unit for ongoing therapy of multiple
INTERVENTIONS TS of amenable superficial and nodular BCCs with twice-annual follow-up. Lesions were removed using a scalpel as a uniform-depth mid-to-upper dermal shave and sent for routine pathology. Basic wound care was applied. PRIMARY OUTCOME MEASURES
Apparent cure rate and outcome of scars.
RESULTS One hundred eighty-two BCCs were treated in 19 individuals. Patients were followed for an average of 5.2 years. One lesion recurred. Three specimens had positive margins requiring further surgery. Scarring was acceptable and similar to what is observed with curettage and electrocoagulation. CONCLUSIONS extremities.
TS is a reasonable treatment for primary superficial and nodular BCC on the trunk and
The authors have indicated no significant interest with commercial supporters.
P
atients with fair skin and extensive sun exposure often present with multiple small truncal basal cell carcinomas (BCCs). For the last several decades, most dermatologists have treated such lesions with curettage with or without electrodesiccation (CE). Surgeons tend to excise BCCs regardless of size, morphology, or depth. A minority of providers use cryosurgery. Recently, imiquimod has emerged as a suitable option for smaller biopsy-proven superficial BCCs. Where available, photodynamic therapy can treat many lesions simultaneously, but the technique is subject to operator experience with multiple variables. All of the above methods are suitable but have limitations.
Electrodesiccation has a strong basis in the literature justifying its use.1 Published cure rates for CE are high, but cure rates in practice may be lower because of lesion selection and procedural shortfalls often related to operator inexperience.2 Scarring is usually acceptable but not as minimal as is often reported. Several studies have demonstrated residual BCC in a surprisingly high percentage of curetted lesions after seemingly definitive curettage.3 It is our experience in following up with patients who have been treated with multiple lesion curettage that many have irregular, depressed, or elevated scars and a high rate of recurrence (Figure 1).
*All the authors are affiliated with the Fletcher Allen Health Care, College of Medicine, University of Vermont, Burlington, Vermont © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:387–392 DOI: 10.1111/dsu.12106 387
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effect a uniform mid- to upper dermal shave in well-defined, apparently superficial BCCs 1.5 cm or less in diameter. This was a longitudinal follow-up over nearly 10 years with visits at 4- to 60 month intervals to assess apparent cure rate and cosmesis.
Study Design
Figure 1. This patient has had multiple lesions removed by curettage. Note numerous depressed, white, irregular scars and three recurrent, now-infiltrative basal cell carcinomas (arrows).
Excision and closure is an excellent treatment modality for well-defined, deep nodular and infiltrative lesions, but formal excision of superficial BCCs on the trunk and proximal extremities is often unnecessary. In our experience, the results of cryosurgery may be suboptimal. Imiquimod may be successful in the treatment of small, superficial BCCs, but the treatment course is protracted, requiring application five times a week for 6 weeks to effect a cure rate of 85%. In practice, many dermatologists remove superficial BCCs by tangential shave (TS) with a half razor blade. The technique has been well described in the plastic surgery literature, albeit with a scalpel blade rather than a half razor blade.4 In addition, the use of a half blade can lead to an irregular specimen and is challenging with broader lesions. Over the years TS has been widely employed in practice. A written survey of dermatologists attending the annual meeting of the Massachusetts Academy of Dermatology in 2011 provides anecdotal evidence. Of 80 responding dermatologists, 50% noted that they sometimes remove BCC by shave without doing a prior biopsy. We report 9 years of experience with a standardized form of TS using a disposable #15 scalpel blade to
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This was a retrospective study of 20 patients with a total of 182 BCCs of the trunk and proximal extremities treated with TS. Only patients who were to be seen regularly in follow-up were included in this evaluation. Lesion Selection All lesions treated using TS were located on the back, upper chest, shoulder, upper arm, or leg. Lesions were 1.5 cm or less in diameter and were clinically superficial or superficial and nodular BCCs. Method of TS The area to be removed is prepped with alcohol, Povidine, or chlorhexidine. The lesion is evaluated in good light and delineated with a marking pen. A 2- to 3-mm margin is delineated around the apparent BCC. Local anesthesia is provided. Using a #15 blade on a scalpel handle, the skin is incised around the lateral margin to the superficial reticular dermis. With a sweeping motion, blade pointed against the deeper dermis, the lesion is shaved from the underlying tissue. A cleavage plane is identified in the upper reticular dermis. Slowly and with care, a uniform wafer of tissue is shaved, leaving behind a flat wound of residual mid- and deep dermis and deep adnexal structures (Figure 2). Neither the undersurface of the specimen nor the base should be serrated, and removing a uniform wafer of tissue is the most challenging aspect of the procedure. The specimen may then be oriented as needed with a 6.0 suture and sent for routine histology with standard margin analysis (Figure 3). The wound is cared for daily with petrolatum and nonstick gauze until
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healed. Multiple lesions may be treated in a single session (Figure 4). Follow-up Our patients are reexamined and have full skin checks at 4- to 6-month intervals. Surgery sites are assessed for recurrence, symptoms, and cosmetic outcome. The treatment sites are graded for cosmesis as flat white, depressed white, mildly hypertrophic, or hypertrophic.
Results Figure 2. Patient with several basal cell carcinomas on the back undergoing tangential shave removal (TS). Two small adjacent lesions are being removed. The lesion at the upper left is marked for removal. A healed TS site is visible on the right.
Figure 3. Pathology from a tangential shave showing a standard central vertical section with negative margins.
(A)
One hundred eighty-four lesions were removed using TS. None had prior biopsies. One lesion was a lichen planus–like keratosis, and one was a dermal nevus. The remaining 182 lesions were BCCs. Forty lesions were classified on pathology as having a component of nodular BCC, and three lesions were infiltrative BCC. The remaining 177 lesions were superficial BCC. The average BCC measured 0.98 0.39 cm in maximal diameter. The majority of the lesions (64%) were on the back. Patients were followed up for an average of 5.2 2.3 years. One lesion recurred (0.5%) (Figure 5), and three specimens had positive margins on pathology (1.6%). Two of these were infiltrative BCC with positive deep margins, and the third was a superficial BCC at the shave edge. The three positive margins were re-excised and closed linearly without incident. The recurrent lesion was a small superficial recurrence and was removed by shave with no further recurrence at 4 years.
(B)
Figure 4. Multiple basal cell carcinomas (BCCs) removed at once using tangential shave removal (TS). (A) Seven lesions marked for TS. A well-healed scar is noted from a prior TS. (B) Immediate result after TS of seven BCCs.
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(A)
(B)
Figure 5. Recurrence after tangential shave removal (TS). (A) A small superficial recurrence is noted at the upper left of the scar. (B) One year after second shave removal.
Healing was generally favorable and similar to that seen with CE. At the time of observation, 78.5% of lesions had healed with smooth, oval, flat, white scars (Figure 6). Only 3% of scars were judged to be substantially hypertrophic (Figure 7), and these responded to intralesional triamcinolone acetonide 10%. One patient who had four somewhat larger lesions removed on the back complained about the healing course and did not like this modality. On average, sites took 3 to 4 weeks to heal.
Comment The use of TS for the removal of truncal BCC is not new, but the literature supporting its use has been sparse. In the mid-1980s, several dermatologists reported the use of curettage followed by shave excision for relatively large facial lesions,5 but such lesions now are generally handled surgically, with better cosmesis and a demonstrated high cure rate. Harrison reported a series of facial BCC shave excisions with a #10 scalpel blade, with an initial tumor clearance of 61% and no recurrence data.6 Nevi on the trunk and proximal extremities are frequently and successfully removed using shave.7 The results can be satisfactory, and this method is often preferred to full-thickness excision for such lesions. CE and excision are suitable methods of removal for nonmelanoma skin cancers, but TS has a place in the management of such lesions and appears to be in reasonably widespread use without an evidence-based approach. To our knowledge, no one has previously detailed the outcome of a series
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of tangential shaves for the definitive removal of BCCs on the trunk or extremities. The virtues and failures of CE have been emphasized previously, often with hyperbole. What we have attempted to do is to show that, in certain cases, TS is a suitable modality when performed with care and with margin analysis. Our apparent cure rate is in line with other frequently employed methods. Given that BCCs can recur up to 2 decades after definitive treatment, some of our lesions will likely recur, but our followup time frame is as long or longer than most prior study publications for CE and excision. TS is cost conscious, because the only charges are for shave removal and standard histopathology. Multiple lesions can be treated in a single setting at a rapid clip. TS provides a pathology reading with negative or positive margins similar to standard excision. Unlike CE, when infiltrative BCC is present, this is identified on histology, allowing for further treatment, but more than 98% of lesions were superficial and nodular BCC, demonstrating that dermatologists generally can predict the type of tumor removed by careful preoperative examination. The authors also feel that a curette is not needed to delineate the extent of modest-sized BCC, a the low frequency of positive margins noted in our examinations indicates. Margin control with standard breadloaf sections is not as good as that done with Mohs micrographic surgery, but for the purposes of truncal BCC, we feel that it is adequate, as the high cure rate that we have observed seems to support.
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(A)
(B)
(C)
(D)
Figure 6. Typical outcomes after tangential shave removal (TS) of multiple basal cell carcinomas (BCCs). (A) Patient has had 48 TS of BCC, the majority on his back. Well-healed scars are seen across the entire back. Freshly healing sites are seen on the right mid-back. A larger excision site is seen lateral to the right scapula. (B) Patient has had 10 TS on the back. These are well healed, with a fresher TS site on the left upper back. A new BCC is seen at right near the brassiere. (C) Fifteen healed TS sites and one new BCC marked for removal. This patient has substantial hypopigmentation from his removals. (D) Outcome after removal of seven lesions using TS and excision of one infiltrative lesion.
Although we have not done so, it would be reasonable to perform this technique using frozen sections, which might avoid the need for further surgery in the event of positive margins. Healing from TS is similar to that we observe after CE. We recommend the application of petrolatum
Figure 7. Early healing at approximately 4 weeks demonstrating mild to moderate hypertrophic scars.
and a bandage. As with CE, scars are frequently mildly hypertrophic and pruritic early on, but after 1 year, the majority are flat and white. Symptomatically hypertrophic scars respond predictably and in rapid fashion to a single injection of 10 mg/mL of triamcinolone acetonide suspension. Regarding the healing from curettage or CE, many authors claim essentially no scar formation, but we have not had that experience or noted an absence of scars after CE in those who have been treated elsewhere. The benefits of TS include low cost, expediency, no need for activity limitation, and an apparent high cure rate. Negatives associated with TS include the need for care of an open wound with the attendant need for prolonged wound care and the formation of a scar, but we believe the scars to be in line with other effective forms of therapy, and we do not employ this method in areas where we feel that cosmesis is clearly better with excisional surgery,
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such as on the face, scalp, neck, abdomen, distal upper extremities, and thighs. Similarly, patients with a single lesion who do not wish to have an open wound may prefer excision and closure. A less-invasive procedure may be preferable in patients with multiple lesions, in whom repeated full-thickness excisions are problematic. TS is not always an easy procedure to perform, and there is a learning curve. The disc of tissue is best removed at a flat, level plane without maceration or serration of the tissue. As such, it is similar to the harvesting of an initial Mohs layer for a shallow, flat lesion. Individuals we have trained often start by creating a wound that is deeper than necessary, and although these heal well in the long run, they take longer to granulate and re-epithelialize. We do not expect that TS will supplant CE or standard excision, but feel that it is a reasonable choice for the treatment of BCC on the trunk and extremities and that it has an adequate cure rate and acceptable outcomes. TS may be added to the list of evidence-based treatments for BCC.
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References 1. Sheridan AT, Dawber RPR. Curettage, electrosurgery, and skin cancer. Australas J Dermatol 2000;41:19–30. 2. Silverman MK, Kopf AW, Grin CM. Recurrence rates of treated basal cell carcinomas. Part 2: curettage-electrodesiccation. J Dermatol Surg Oncol 1991;17:720–6. 3. Suhge d’Aubermont PC, Bennett RG. Failure of curettage and electrodesiccation for removal of basal cell carcinoma. Arch Dermatol 1984;120:1456–60. 4. Emmett AJJ, Broadbent GD. Shave excision of superficial solar skin lesions. Plast Reconstr Surg 1987;80:47–54. 5. Brooks NA. Curettage and shave excision. A tissue-saving technic for primary cutaneous carcinoma worthy of inclusion in graduate training programs. J Am Acad Dermatol 1984;10:279–84. 6. Harrison PV. Therapy of basal cell carcinoma—treatment in 1980– 81 compared with 1985–86 and advantages of shave excision for smaller tumors. Br J Dermatol 1987;117:349–57. 7. Harrison PV. Good results after shave excision of benign moles. J Dermatol Surg Oncol 1985;11:668–86.
Address correspondence and reprint requests to: Glenn D. Goldman, MD Fletcher Allen Health Care— University of Vermont College of Medicine, 111 Colchester Avenue, Burlington, VT 05401, or e-mail:
[email protected]
Operative Technique with Rapid Recovery for Ingrown Nails with Granulation Tissue Formation in Childhood CLAUDIO I. PEREZ, MD,* XIMENA A. MAUL, MD,* M. CATALINA HEUSSER, MD,* ALEJANDRO ZAVALA, MD†
AND
BACKGROUND Ingrown toenail is a common disease that causes pain and discomfort. There are conservative and surgical treatments, but many have the drawbacks of recurrence and long recovery time. OBJECTIVE To analyze for the first time the results of a technique called nail splinting using a flexible tube secured using a suture (FTSS) performed on a series of patients with ingrown toenails. METHODS AND MATERIALS A retrospective descriptive study of 71 pediatric patients operated on using the FTSS technique between 2001 and 2009 was performed. The data were collected using medical record review or telephone survey. The main outcomes were high percentage of success and shorter recovery time than with partial matrix excision. RESULTS Sixty-two patients (87.3%) were cured using a single procedure, with an average follow-up of 13.1 months. Recurrence occurred in nine patients (12.6%); three required the classic technique with resection of the matrix and nail bed plastic surgery, and in 6, FTSS was repeated with good results. CONCLUSION Flexible tube secured using a suture has a lower recurrence rate than matricectomy. Additional advantages are the speed with which complaints can be monitored and quick return to school because recovery may be as short as 48 hours. The authors have indicated no significant interest with commercial supporters.
nychocryptosis, or ingrown toenail, is a common pediatric condition that causes pain and discomfort and may affect daily activities such as participation in hobbies and sports. It occurs most frequently at two stages of growth, in children younger than 2 years old and in adolescence.1 The onychocryptosis population constitutes 20% of those who seek consultation for foot problems.2
O
It is postulated that several factors, both anatomical and behavioral, contribute to onychocryptosis. These factors include hallux valgus, improper nail cutting, repetitive trauma, genetic predisposition, hyperhidrosis, and poor hygiene.3,4 There is no agreement on the best treatment for onychocryptosis.5 There are various treatments described for this condition, both conservative and surgical, with a recurrence rate of 2%–73%.5–27
Onychocryptosis usually involves the hallux. It results from a wound in the nail wall at the site of penetration by the spicule of the nail. A cascade of reaction to a foreign body ensues, with secondary inflammation, infection, and tissue regeneration with formation of a granuloma.3
Nail splinting using a flexible tube secured using a suture (FTSS) is a modification of the gutter treatment technique described by Wallace.11 The FTSS technique has been reported only once as a case report.28 The main difference between the gutter technique and FTSS is that the tube is secured with a
*Faculty of Medicine, Pontificia Universidad Cat olica de Chile, Santiago, Chile; †Department of Surgery, Pontificia Universidad Catolica de Chile, Santiago, Chile © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:393–397 DOI: 10.1111/dsu.12048 393
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suture. A series of patients operated on with the novel FTSS technique is presented. Our results in terms of success of treatment, recovery time, and complications are discussed below.
Material and Methods A retrospective descriptive study of patients under 18 years old with an ingrown toenail who were operated on using the nail splinting technique (FTSS) between July 2001 and July 2009 was performed. Data were collected by medical record review or telephone survey. All patients included in the study had granulation tissue, which is stage 3 of the Mozena Classification.29 Patients who presented with an infection in the ingrown toenail were treated with antibiotics before surgery. Patients with an active infection were not treated using FTSS. According to patient age, FTSS was performed under local anesthesia in a procedure room or under general anesthesia in and operating room. Surgical Technique FTSS procedure (Figure 1): (1) Informed consent is obtained.
Figure 1. Nail splinting using a flexible tube secured using a suture (FTSS).
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(2) Oral antibiotics are given 48 hours before surgery. Flucloxacillin is generally used, but in case of allergy, the best alternative is chosen. (3) The foot is washed with soap and water before the procedure. (4) A fasting regimen is indicated 4 hours before the procedure if local anesthesia is used and 6 hours before general anesthesia. (5) The side of the toe to be operated on is marked with an arrow. (6) Cleaning with chlorhexidine or povidoneiodine is done. A sterile field is created. (7) Local anesthesia is applied around the base of the hallux with lidocaine 2%. (8) The use of a tourniquet is optional. (9) The granuloma is scraped off using an anatomical forceps or spoon; its resection with a scalpel or other procedures are usually not necessary. (10) The extreme end of the nail plate is freed with a stylus on its anterior and posterior surfaces up to the extreme outer edge of the matrix. It is important that the instrument be thin. We recommend the thin branch of a thin clip, otherwise it will traumatize the matrix, and the nail could be lost. (11) A tube is channeled to the outer edge of the nail. A number 19 butterfly needle protective tube, which is cut on one side, is used. When the tube is placed, the ingrown edge must be incorporated in the channel. This often has the appearance of a lateral spike several millimeters below the edge of the nail plate. If the spike is within the proximal two-thirds of the nail edge, it is better to cut the spike and then funnel. (12) A tube is inserted as deeply as possible, moving 1 to 2 mm below the eponychium and proximal nail fold. (13) The tube is fixed as proximally as possible with one or two stitches of silk or 4–0 nylon thread to gather the tube and the nail plate (Figure 2). The nail is held with the contralateral thumb so as not to detach it as the stitch perforates the nail. This stitch should not include the nail fold. (14) The nail edge and tube are covered with a layer of antibiotic ointment, and a follow-up
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Figure 2. The tube is fixed as proximally as possible with one or two stitches of silk or 4–0 nylon thread to gather the tube and the nail plate.
(15)
(16)
(17) (18)
appointment is scheduled for 2 days later. Antibiotics are continued for 7–14 days and analgesia with a nonsteroidal antiinflammatory drug for 48 hours. If the patient has no discomfort, she or he is allowed to walk in 24 hours’ time. After 2 days, the hallux can be uncovered, and daily showering and swimming can be resumed, with application of antibiotic ointment 2 times a day for the first 3 weeks and as needed after that. A second follow-up visit is arranged for 3–4 weeks after surgery. No contact sports are permitted in the first 4 weeks. Instructions are given to be careful when putting on and removing socks because the tube can become hooked on them. The tubes are removed following nail growth at 8–12 weeks. After removal of the tube, the proper way to trim the nail is taught. The child is monitored monthly for 3 months before final discharge.
Results Seventy-one children were treated with FTSS in this study. The average age was 12 years (range 2–16 years), and 46 (64.7%) were male. All patients who underwent surgery had an ingrown toenail without infection but at stage 3, with granulation tissue present. The mean postoperative follow-up
period was 13.1 months (range 3–72 months). Sixty two patients (87.3%) underwent a single procedure with success. Relapse was observed in nine patients (12.6%), all within the first 3 months after surgery. Three of these nine patients required resection of the matrix and nail bed plasty surgery16 for eradication of their problem. In the remaining six, FTSS was repeated with good results. The procedure was repeated twice in one patient; after the second relapse, the classic wedge excision procedure was performed. These nine patients who experienced recurrence had a follow-up period of 3 months after the second surgery. The time of tube permanence had a range of 1 to 20 weeks. All patients returned to school approximately 48 hours after the surgery. Complications of FTSS are shown in Table 1. One patient had cellulitis requiring hospitalization and intravenous antibiotics. This patient had been managed improperly without antibiotics pre- and postoperatively. In patients who had recurrence, the average length of time that the tube remained in place was 4.4 weeks, versus 4.8 weeks in those without. Discussion There is no agreement on the best method to manage children with onychocryptosis. Wedge resection of the offending nail edge, the affected nail wall, and the adjacent matrix bed with phenolization has been shown to be the technique with the lowest recurrence rate (2–5%),5–27 but a systematic review14 suggests that, although there are significantly fewer symptomatic recurrences than with other surgical techniques without the use of phenolization, there are more postoperative infections. Also, the TABLE 1. Complications of Nail Splinting Using a Flexible Tube Secured Using a Suture (N = 71) Complication
n
Treated infection Infection, withdrawal of the tubes Loss of the nail Classic nail plastic surgery Loss of the tube
2* 2 3 3 4
*One patient required hospitalization.
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conventional matricectomy method with wedge resection often results in deformities and narrowing of the nail plate.5,21 Aggressive surgical intervention may also endanger the hallux, with rare complications of ischemia and necrosis of the hallux or osteomyelitis.30,31 In these cases, it is advisable to perform a classical nail plastic surgery such as a fish mouth or lateral foldplasty.32 The senior author therefore elected to try FTSS, a less-invasive treatment option for this common condition. FTSS is an adaptation of the technique described by Wallace.11 This study is the first to report on a series of patients operated on using this technique. We have found FTSS easy to perform. In 71 children, the recurrence rate was 12.6%, which is lower than with other techniques described in the literature.5–27 Other advantages of FTSS are speed of recovery after the procedure, with most children returning to school after 48 hours.33 Because there is no damage to the matrix, an excellent cosmetic result can be ensured, as was seen is all our patients. Recurrences and complications in our patients were mostly due to lack of experience with the technique at the beginning of the learning curve. The most serious complication was one case of cellulitis due to a failure to order appropriate perioperative antibiotic treatment. In our opinion, FTSS is a good alternative for the treatment of children with ingrown toenail in Mozena classification stage 3, because it is less traumatic than conventional matricectomy and allows rapid recovery. This technique is particularly indicated in initial onychocryptosis and when the ingrown edge is more than halfway from the edge of the proximal nail fold. Because there is no consensus on the best surgical technique for ingrown nails5, new randomized controlled trials should be performed to compare this technique with others described in the literature.
Acknowledgments The authors thank Dr. Albert Shun, from the Royal Alexandre Hospital for
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Children, Weatmead, Australia, for his help in preparing and reviewing this manuscript.
References 1. Berker D. Childhood Nail Diseases. Dermatol Clin 2006;24: 355–63. 2. Reyzelman AM, Trombello KA, Vayser DJ, Armstrong DG, et al. Are antibiotics necessary in the treatment of locally infected ingrown toenails? Arch Fam Med 2000;9(9):930–2. 3. Heidelbaugh J, Lee H. Managment of the ingrown toenail. Am Fam Physician 2009;79(4):303–8. 4. Langford DT, Burke C, Robertson K. Risk factors in onychocryptosis. Br J Surg 1989;67:45–8. 5. No€el B. Surgical treatment of ingrown toenail without matricectomy. Dermatol Surg 2008;34:79–83. 6. Pettine KA, Cofield RH, Johnson KA, Bussey RM. Results of surgical treatment. Foot Ankle 1988;9(3):130–4. 7. Young MRA, Rutherford WH. Reoperation rate for ingrowing toenail treated by phenolisation 3 year follow up. Br J Surg 1987;74:202–3. 8. Morkane AJ, Robertson RW, Inglis GS. Segmental phenolization of ingrowing toenails: a randomized controlled study. Br J Surg 1984;71:526–7. 9. Murray WR, Bedi BS. The surgical management of ingrowing toenail. Br J Surg 1975;62:409–12. 10. Palmer BV, Jones A. Ingrowing toenails: the results of treatment. Br J Surg 1979;66:575–6. 11. Wallace WA, Milne DD, Andrew T. Gutter treatment for ingrowing toenails. Br Med J 1979;2:168–71. 12. Bos AMC, Tilburg vanMWA, Sorge van AA, Klinkenbijl JHG. Randomised clinical trial of surgical technique and local antibiotics for ingrowing toenail. BJOS 2007;94:292–6. 13. Buckley D. Segmental phenolic ablation for ingrown toenails in general practice. Ir Med J 2000;93(8):242–4. 14. Rounding C, Bloomfield S. Surgical treatments for ingrowing toenails. Cochrane Database Syst Rev 2005;2:CD001541. 15. Lazar L, Erez I, Katz S. A conservative treatment for ingrown toenails in children. Pediatr Surg Int 1999;15(2):121–2. 16. Gerritsma-Bleeker CLE, Klaase JM, Geelkerken RH, Hermans J, et al. Partial matrix excision or segmental phenolization for ingrowing toenails. Arch Surg 2002;137:320–5. 17. Ikard RW. Onychocryptosis. J Am Coll Surg 1998;187:96–102. 18. Issa MM, Tanner WA. Approach to ingrowing toenails: the wedge resection/segmental phenolization combination treatment. J Surg 1988;75:181–3. 19. Kim SH, Ko HC, Oh CK, Kwon KS, et al. Trichloroacetic acid matricectomy in the treatment of ingrowing toenails. Dermatol Surg 2009;35(6):973–9. 20. Ross WR. Treatment of the ingrown toenail and a new anesthetic method. Surg Clin North Am 1969;49:1499–504.
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21. Van der Ham AC, Hackeng CA, Yo TI. The treatment of ingrowing toenails. A randomised comparison of wedge excision and phenol cauterisation. J Bone Joint Surg Br 1990;72:507–9.
29. Mozena JD. The Mozena Classification System and treatment algorithm for ingrown hallux nails. J Am Podiatr Med Assoc 2002;92:131–5.
22. Antrum RM. Radical excision of the nailfold for ingrowing toenail. J Bone Joint Surg Br 1984;66:63–5.
30. Rueff N, Gapany C. A rare ischemic complication of ingrowing toenail surgery in a child. Dermatol Surg 2010 Feb;36(2):250–2.
23. Burzotta JL, Turri RM, Tsouris J. Phenol and alcohol chemical matrixectomy. Clin Podiatr Med Surg 1989;6:453–67.
31. Majcen ME, Wilfinger CC, Pilhatsch A. Interpretation of radiologic abnormalities in patients with chronically infected ingrown toenails with regard to a possible exogenic osteomyelitis. J Pediatr Surg 2009 Nov;44(11):2179–83.
24. Cameron PF. Ingrowing toenails: an evaluation of two treatments. Br Med J 1981;283:821–2. 25. Ozdemir E, Bostanci S, Ekmekci P, Gurgey E. Chemical matricectomy with 10% sodium hydroxide for the treatment of ingrowing toenails. Dermatol Surg 2004;30:26–31. 26. Grieg JD, Anderson JH, Ireland AJ, Anderson JR. The surgical treatment of ingrowing toenails. J Bone Joint Surg Br 1991;73 (1):131–3. 27. Vaccari S, Dika E, Balestri R, Rech G, et al. Partial excision of matrix and phenolic ablation for the treatment of ingrowing toenail: a 36-month follow-up of 197 treated patients. Dermatol Surg 2010;36(8):1288–93. 28. Weyandt GH, Gesierich A, Hamm H. Unguis incarnatus: nail splinting by flexible tube secured by suture. J Dtsch Dermatol Ges 2009;7(2):169–71.
32. Aksoy B, Aksoy HM, Civas E, Oc B, et al. Lateral foldplasty with or without partial matricectomy for the management of ingrown toenails. Dermatol Surg 2009 Mar;35(3):462–8. 33. Salasche SJ, Schulte KW, Neumann NJ, Ruzicka T. Surgical Pearl: Nail splinting by flexible tube—A new noninvasive treatment for ingrown toenails. J Am Acad Dermatol 1998;39:629–30.
Address correspondence and reprint requests to: Alejandro Zavala, MD, Department of Surgery, Pontificia Universidad Cat olica de Chile, Diagonal Paraguay 415 Of. 22, Santiago, Chile, or e-mail:
[email protected]
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A Simple Therapeutic Approach to Pincer Nail Deformity Using a Memory Alloy: Measurement of Response JONATHAN TE-PENG TSENG, MD,* WEN-TSAO HO, MD,* CHUN-HUNG HSU, MD,* MING-HSIU LIN, MD,*† CHIEN-NIEN LI, MD,* AND WOAN-RUOH LEE, MD, PHD*†‡
BACKGROUND Pincer nail deformity (PND) is a dystrophy characterized by transverse overcurvature of the nail plate that may cause intractable pain and decrease the quality of life of patients. OBJECTIVES To evaluated the efficacy of a superelastic nickel–titanium (SE NiTi) wire for the treatment of PND using transverse curvature improvement and subjective assessment of pain relief during and after the treatment. METHODS SE NiTi wire was implanted over the distal tip of the nail for the treatment of PND in 43 patients (28 female, 15 male), with a total of 73 digits receiving treatment. Evaluations of improvement included measuring changes in transverse curvature of the nail and subjective assessment of pain relief throughout the follow-up period. RESULTS In all patients, treatment of the pincer nail with implantation of SE NiTi wire achieved satisfactory results. Significant improvement (p < .05) of the transverse overcurvature of the nail was seen in all patients at 2 months, and relief of pain was determined in 100% of cases throughout our follow-up period. CONCLUSION This simple SE NiTi wire insertion method is noninvasive and inexpensive, leaves no cosmetic disfigurement, and leads to excellent therapeutic results. Patients achieved great satisfaction. Thus, this technique should be considered the first line of treatment in the correction of mild to moderate PND. The authors have indicated no significant interest with commercial supporters.
P
incer nail deformity (PND) is characterized by excessive transverse curvature of the nail plate that increases along the longitudinal axis of the nail. The curvature commonly increases proximally to distally, giving the nail a trumpet-like appearance.1–5 This results in impingement of the distal nail bed between the free lateral edges of the nail plate, leading to a narrow or even obliterated nail bed. PND may cause excruciating pain and possibly secondary infection, hindering normal walking and markedly decreasing quality of life.1,2,6 Other names for this condition include incurved nail, unguis constringens, transverse overcurvature, trumpet nail,
convoluted nail, and omega nail.5 PND most frequently affects the large toes but can occur in all toenails and even fingernails. The pathogenesis of PND has not been defined, although numerous factors can contribute to this deformity.3 PND may arise as a result of mechanical deformation of the nail unit because of exostoses, implantation cysts, or epidermoid cysts.4,7 Deformity in the foot deviation of phalanges, probably caused by high-heeled or narrow-toed shoes, has also been proposed as a frequent cause of PND.4,8 PND has been reported in association with infection (tinea unguium), arteriovenous fistula, gastrointestinal malignancies,
*Department of Dermatology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; †Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; ‡Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:398–405 DOI: 10.1111/dsu.12094 398
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beta-blocker use, and Kawasaki disease.9–13 In cases associated with the latter two conditions, spontaneous recovery of PND was observed after discontinuation of beta-blockers and recovery from Kawasaki disease. Epidermolysis bullosa simplex (Dowling-Meara type) is also reported to have a possible association with pincer nail abnormality, with a slight thickening of finger- and toenails.14 Since publication of the first case, a large number of successful conservative and surgical treatment modalities have been described for the correction of PND, but no consensus exists as to the most common and accepted form of treatment. Some surgical therapies have been reported.1,2,4,6,15–18 Although recurrence is less common after surgical treatment, there are some disadvantages during and after the procedure. These include complexity of the surgery, pain, time consumption, secondary infection, and need for local anesthesia. Moreover, some of the methods may induce cosmetic deformity, resulting in disfigurement. The aim of the study was to demonstrate an excellent conservative treatment modality for pincer nail. This study evaluated the efficacy of a superelastic nickel–titanium (SE NiTi) wire, originally designed for orthodontic practice, in the treatment of PND by measuring transverse curvature improvement and subjective assessment of pain relief during and after treatment. SE NiTi wire is composed of shape-memory NiTi alloy and has strong elasticity. Machida and colleagues first introduced the material and methodology in the treatment of ingrown and curved nails in 1999, with promising results.19 Thereafter, Moriue and colleagues20 applied a similar therapeutic strategy for treating ingrown nails with successful outcomes. This research presents a case series study describing the clinical benefits of SE NiTi wire for the treatment of pincer nails.
Methods This case series study was performed on patients with PND who received SE NiTi wire treatment. We assessed the therapeutic effects of this modality in monthly follow-up visits measuring transverse
curvature of the nail and improvement in quality of life, such as relief of pain and discomfort. This study was performed in the Department of Dermatology at Taipei Medical University, Shuang-Ho Hospital. The trial was conducted according to the ethical guidelines of the Declaration of Helsinki. The Ethical Committee of the university reviewed the protocol and granted approval for the study. Patients This technique was used to treat 43 patients with symptomatic PND, with a total of 73 affected digits. All patients (28 female, 15 male, mean age 43, range 20–101) complained of pain while wearing closedtoe shoes or even at the slightest touch. Each patient provided written informed consent. Patients with severe deformity of the nail bed, concurrent ingrown nail with infection, and concurrent granulation tissue around the periungual region were not treated. Preoperative evaluation included presence of onychomycosis, history of ingrown nail, prior trauma to the affected digits, prior treatment of the nail, and family history of similar deformity. Patients were instructed to return monthly to take the clinical outcome assessment. Intervention The wire used was the SE NiTi wire (Highland Metals Inc., San Jose, CA), which was originally designed for the orthodontic practice of teeth straightening. The wire is available in several different diameters (0.12–0.20 inches), with an ovalshaped cut surface. This study primarily used 0.16and 0.18-inch wires for treatment. The technique was based on the description provided by Moriue and colleagues20 and Machida and colleages,19,21 with minor modification. The SE NiTi wire method is indicated for clinically diagnosed PND when the width of the free border of the affected nail is greater than 2 mm and the angle of the nail plate is within 90º.20
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Two holes are made using 18-G needles at the distal free edge of the nail plate in the white portion, which does not have sensation (Figure 1A and B). When drilling, the needle should be held obliquely so that the wire can be easily bent and inserted into another hole from the outside of the nail (full insertion of the needle is unnecessary). Care should be taken not to puncture soft tissue. The wire is then pushed with pliers downward into one of the holes (Figure 1C), and the other end of the wire is bent forward and inserted into another hole (Figure 1D and E). Finally, the excess wire is cut with clippers to prevent it from protruding from the nail end. Medical adhesive tape (elastic adhesive tape, 3M Company, Maplewood, MN) is cut into small pieces and attached to the wire implantation site. This final step protects the nail plate and prevents the wire from detaching (Figure 1F). A cotton cap may be added to the end of the SE NiTi wire below the nail plate to protect the nail bed from wire-induced injury. Patients should avoid strenuous exercise, which may damage the nail plate. The procedure takes 10 to 15 min, and the wire typically remains in place for 2 to 3 months. After treatment, the nail plate becomes sufficiently flat, and the wire can be pulled out with pliers.20
Clinical Assessment Improvement of the transverse curvature of the nail was evaluated based on the following two systems: For statistical comparison, nail height (A) and nail width (B) at the distal end of the nail were measured directly using a caliper, and the ratio of A to B was calculated (Figure 2). As the ratio approaches 0, it indicates a flatter nail plate, whereas higher values are indicative of a nail displaying marked dorsal protrusion. The patients provided subjective data. They were asked to rate pain relief along a scale with three options: no relief, partial relief, and total relief. (Clinical photographs of the nail were also taken to assist in the evaluation). Statistical Analysis SPSS 13.0 (SPSS, Inc., Chicago, IL) was used to perform statistical analysis. A two-sample t-test was used to determine the correlation of the severity of transverse overcurvature of the nail in PND patients with the presence of onychomycosis or a history of ingrown nail at the baseline. A paired t-test was also performed to compare transverse overcurvature of the nail before and after treatment. p < .05 was considered statistically significant.
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(B)
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Figure 1. (A) Pincer nail deformity. (B) Holes are made using needles. (C–E) The wire is inserted into the holes. (F) Medical adhesive tape is attached to the wire implantation site.
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TABLE 1. Baseline Demographic Data and Disease Characteristics of All Patients with Pincer Nail Deformity Characteristic
Figure 2. Pincer nail deformity. Nail height (A) and nail width (B) at the distal end of the nail were measured. The ratio of A to B was calculated.
Results The demographic and clinical characteristics of all patients at baseline are presented in Table 1. Three patients had the hereditary type of PND in that they had a positive family history revealing the same deformity in parents or siblings. Twenty-five patients had bilateral toenail involvement. In three patients, several lesser toes were also involved to varying extents. Although PND patients with onychomycosis outnumbered those without onychomycosis, no significant difference in the severity of PND at baseline was detected between the two groups. A statistically significant difference in the severity of PND at baseline was detected between PND patients with and without a medical history of ingrown nail. The degree of transverse overcurvature seen in PND patients with a medical history of ingrown nail was more severe than in those without. The transverse curvature of the nail was measured in all 43 patients with clinically confirmed PND for at least 2 consecutive months. The improvement in quality of life regarding relief of pain and discomfort was evaluated continuously according to clinical follow-up or telephone interview for at least 6 months. Difficulties in coming to the outpatient clinic and other personal reasons caused discrepancies in the length of the outpatient clinic follow-up periods.
Value
Patients (digits), n 43 (73) Age, mean (range) 43 (20–101) Sex, patient; digit, n (%) Male 15 (35); 26 (36) Female 28 (65); 47 (64) Duration of disease, years, range 0.4–20 Onychomycosis, patient; digit, n (%) Yes 34 (79); 52 (71) No 9 (21); 21 (29) Medical history of ingrown nail, patient; digit, n (%) Yes 23 (53); 39 (53) No 20 (47); 34 (47)
In all patients, treatment of the pincer nail achieved satisfactory results, and all clinical symptoms were relieved during or after therapy. Photographs demonstrating the treatment response of some PND patients are shown in Figure 3. The SE NiTi wire implantation method was found to be well tolerated and safe. None of the enrolled patients reported any adverse events from the treatment. No ingrown nail or infection occurred during the treatment period. The progress of nail flattening over a 2-month period is shown in Figure 4. All patients showed significant therapeutic response to the SE NiTi wire. In two with thick nail plates, minimal response of the PND was observed at the 1-month mark, so a second wire was implanted. Flattening of the nails was seen at their next visits (Figure 5). Total relief of pain was achieved in all 43 patients by the third month. In some patients, immediate relief of pain was observed right after implantation of the wire. The average recurrence rate of this method remains under investigation, but of the three patients with hereditary PND, two experienced recurrence by the sixth month. Patients with recurring PND preferred having the wire reinserted because of the immediate satisfactory outcome that the procedure offered, along with the lack of associated discomfort during and after therapy.
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(A)
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Figure 3. Pincer nail deformity. Photographs demonstrating the treatment response of some patients with pincer nail deformity. (A) Pretreatment condition. (B) Post-treatment condition at 2 months. The curvature of the nail plate has been improved.
Discussion Pincer nail deformity is a nail pathology that develops with accompanying pain and discomfort, affecting quality of life. It is characterized by an increase of transverse curvature along the longitudinal axis of the nail.2,3 Despite several causative
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factors having been identified, the pathogenesis of PND remains unclear. Controversy exists as to whether osteophytes are a cause or a result of nail deformity. A recent investigation5 supported the latter hypothesis. First, the nail begins to incurve
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(A)
(D)
(B)
(E)
(C)
(F)
Figure 4. Transverse curvature of the pincer nail deformity: The ratio of A to B at 0, 1, and 2 months were compared. As the ratio approaches 0, it indicates a flatter nail plate, whereas higher values are indicative of a nail with marked dorsal protrusion. (A) Demonstrating the average of the A to B ratio of all 43 patients (73 digits) at different time marks. (B–F) Results of every patient (in digits).
because of an underlying pathogenesis. Then, as the distal end of the nail becomes elevated, continuous traction is subsequently exerted on the distal dorsal tuft. This phenomenon can be considered a secondary deformity consequent to the primary nail deformity. Thus, an osteophyte of the distal phalanx may be the result of an overcurving deformity, rather than a cause.5 Essentially, the etiology of PND can be divided into hereditary and acquired forms. Hereditary PND is almost always symmetrical, and similar nail changes may be seen in other family members. Acquired PND is not symmetrical, although in some cases, involvement may be extensive and appear to be fairly
symmetrical.4 Treating PND has always been challenging, whether managed surgically or conservatively. No common and widely accepted classical method has been presented in the literature, although different therapeutic strategies have been proposed. Dermatologists in Taiwan commonly perform total or partial excision of the nail bed and phenol matricectomy, but these methods may leave disfigurement and are considered overly aggressive for mild to moderate PND. In our opinion, surgical interventions are more suitable in cases involving severe deformity of the nail or in patients who have received unsuccessful conservative treatments previously.
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Figure 5. (A) view from anterior aspect. (B) view from dorsum aspect. Pincer nail deformity. Pincer nail deformity patient with thick nail plates (0 months). Minimal response was observed at the 1-month mark, so a second wire was implanted. One month after implantation of two wires the curvature of the nail plate had improved (2 months). One wire was later removed as the nail grew longer (4 months).
Patients are commonly encouraged to undergo thinning of the nail plate as a conservative treatment. Although some benefit may be seen, this procedure seemingly has low patient adherence and a long treatment period, and in cases of severe deformity, it does not produce satisfactory results easily. This study used a shape-memory alloy therapeutic procedure that has numerous advantages over other methods. The alloy used was an SE NiTi wire, originally designed for orthodontic practice. This alloy has two unique properties. One is its shape-memory effect, and the other is its outstanding elasticity” The
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elasticity of the wire helps returning the overcurvature of the PND to its original state. Even if the wire is bent, the shape-memory effect is sustained for several months. Comparable with previous research using similar material,19,21 these results show that treatment with SE NiTi wire is effective at relieving pain and discomfort. Most patients confirm cosmetic improvement. Patients with slight curvature of the toenail achieve relief from pain immediately after treatment. Machida recommends using an adhesive to attach the wire to the nail plate tightly.20 In this study, we used medical adhesive tape, which not only prevents detachment of the wire, but also protects the nail plate. According to this study, no major risk is associated with this therapeutic strategy, with the exception that extra care should be taken not to puncture soft tissue during the implantation process. The risk of contact allergy from the SE NiTi wire is believed to be low because the wire used was originally designed for the orthodontic practice of teeth straightening. Other than the excellent therapeutic results shown in this study, this strategy has several other advantages. It is particularly useful for patients who cannot miss work and those with diabetes, peripheral vascular disease, or any disease that might affect wound healing.20 This method can be performed easily in an outpatient clinic with only 10 to 15 min of therapeutic time, and local anesthesia is not required during the process. Moreover, the cost of the wire is low, and the wire is easy to acquire. In some patients with thick nail plates, insertion of two wires simultaneously or repeated treatment may be indicated. A high prevalence of onychomycosis was observed in the patients in this study. Although no statistically significant difference was detected between patients with and without onychomycosis in severity of PND at baseline, severity of onychomycosis may be a determining factor for therapeutic response because of the thickness or fragility of the nail plate. According to the research data, the degree of transverse overcurvature seen in patients with PND with a medical history of ingrown nail is more
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severe than in those without. That is, ingrown nail may play an important role in the pathogenesis of PND. Further studies may be required to determine the above hypotheses. Many patients seen in the clinic had multiple toes with nails cut too short for the procedure to be performed immediately. Patients should be instructed on proper nail cutting and footwear. In a nail with improper cutting, the cut lateral nail edge often regrows in a notched manner over the nail bed, creating spicules and serrated nail edges. These irregular nail edges pierce the surrounding soft tissue and cause pain, inflammation, and granulation tissue, which ill-fitting footwear further compounds.22 Therefore, patient education plays an important role in successful treatment. The average elapsed time between SE NiTi wire removal and recurrence of PND was not measured because it was not the objective of the current study, but this could be an interesting parameter to help increase understanding of the pathogenesis of PND and the characteristics of the SE NiTi wire. Further study may be warranted. Conclusion This clinical study presented a simple strategy to treat PND using SE NiTi wire. This technique has several distinct advantages over other methods. It is noninvasive, inexpensive, and easy to perform; leaves no cosmetic disfigurement; and has excellent therapeutic results. Patients achieved great satisfaction. It is particularly useful for patients with diabetes, peripheral vascular disease, or any disease that might affect wound healing. This method is currently our first choice of treatment for mild to moderate PND. Surgery was indicated only in severe cases or in cases in which use of SE NiTi wire failed. References 1. Mutaf M, Sunay M, Isk D. A new surgical technique for the correction of pincer nail deformity. Ann Plast Surg 2007;58:496–500. 2. Aksakal AB, Akar A, Erbil H, Onder M. A new surgical therapeutic approach to pincer nail deformity. Dermatol Surg 2001;27:55–57. 3. Kim KD, Sim WY. Surgical pearl: nail plate separation and splint fixation—a new noninvasive treatment for pincer nails. J Am Acad Dermatol 2003;48:791–792.
4. Baran R, Haneke E, Richert B. Pincer nails: definition and surgical treatment. Dermatol Surg 2001;27:261–266. 5. Kosaka M, Kusuhara H, Mochizuki Y, Mori H, et al. Morphologic study of normal, ingrown, and pincer nails. Dermatol Surg 2010;36:31–38. 6. Plusje LG. Pincer nails: a new surgical treatment. Dermatol Surg 2001;27:41–43. 7. Baran R, Broutart JC. Epidermoid cyst of the thumb presenting as pincer nail. J Am Acad Dermatol 1988;19:143–144. 8. Baran R, Dawber RPR, Tosti A, Haneke E. A text atlas of nail disorders. London: Martin Dunitz; 1996. 9. Higashi N. Pincer nail due to tinea unguium. Hifu 1990;32:40–44. 10. Hwang SM, Lee SH, Ahn SK. Pincer nail deformity and pseudoKaposi’s sarcoma: complications of an artificial arteriovenous fistula for haemodialysis. Br J Dermatol 1999;141:1129–1132. 11. Jemec GB, Thomsen K. Pincer nails and alopecia as markers of gastrointestinal malignancy. J Dermatol 1997;24:479–481. 12. Greiner D, Schofer H, Milbradt R. Reversible transverse overcurvature of the nails (pincer nails) after treatment with a b-blocker. J Am Acad Dermatol 1998;39:486–487. 13. Vanderhooft SL, Vanderhooft JE. Pincer nail deformity after Kawasaki’s disease. J Am Acad Dermatol 1999;41:341–342. 14. Kitajima Y, Jokura Y, Yaoita H. Epidermolysis bullosa simplex, Dowling-Meara type. A report of two cases with different types of tonofilament clumping. Br J Dermatol 1993;128:79–85. 15. Ozawa T, Yabe T, Ohashi N, Harada T, et al. A splint for pincer nail surgery: a convenient splinting device made of an aspiration tube. Dermatol Surg 2005;31:94–98. 16. Kosaka M, Kamiishi H. New strategy for the treatment and assessment of pincer nail. Plast Reconstr Surg 2003;111: 2014–2019. 17. Brown RE, Zook EG, Williams J. Correction of pincer-nail deformity using dermal grafting. Plast Reconstr Surg 2000;105:1658–1661. 18. Hatoko M, Iioka H, Tanaka A, Kuwahara M, et al. Hard-palate mucosal graft in the management of severe pincer-nail deformity. Plast Reconstr Surg 2003;112:835–839. 19. Machida E, Maruyama K, Sano S. The correction of ingrown, curved nails with super elastic wire. J Jpn Soc Surg Foot 1999;20:S87. 20. Moriue T, Yoneda K, Moriue J, Matsuoka Y, et al. A simple therapeutic strategy with super elastic wire for ingrown toenails. Dermatol Surg 2008;34:1729–1732. 21. Machida E. Treatment of pincer nail using Machiwire and Machiplate. MB Derma 2007;128:42–48. 22. Arai H, Arai T, Nakajima H, Haneke E. Formable acrylic treatment for ingrowing nail with gutter splint and sculptured nail. Int J Dermatol 2004;43:759–765.
Address correspondence and reprint requests to: WoanRuoh Lee, MD, PhD, 291 Jhongjheng Rd., Jhonghe District, New Taipei City, 23561, Taiwan (R.O.C.), or e-mail:
[email protected]
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Repigmentation of Poliosis After Epithelial Grafting for Vitiligo SHERIF S. AWAD, MD, PHD*
BACKGROUND Vitiligo is a disease of color loss from skin and possibly also from hair. The presence of white hair follicles is known to be a bad prognostic sign. OBJECTIVES
To evaluate the possibility of repigmentation of white hair follicles after epithelial grafting.
METHODS Patients with recalcitrant vitiligo with loss of hair pigment were treated using Chinese cupping blisters or ultrathin Thiersch grafting after de-epithelialization of vitiliginous patches by dermabrasion. Phototherapy was used afterward to enhance success. RESULTS Repigmentation of the skin surface was obtained with as little as 1 to 2 months of phototherapy, as expected, and further follow-up of cases revealed the re-coloring of hair follicles after 4 to 11 months. CONCLUSION Re-coloring of poliosis with vitiligo is possible but was unexpected because of the difference in mechanism and signaling required between hair bulb melanization and the surface skin. One likely mechanism to explain this change is that melanocyte stem cells are stimulated and migrate to supply hair bulbs with new mature melanocytes. Epithelial grafting of vitiligo with poliosis in hairy areas should be a treatment of choice when white hair tufts cause cosmetic disfigurement. The author has indicated no significant interest with commercial supporters.
V
itiligo is an acquired idiopathic pigmentary disorder that affects the melanocytes of the skin and hair follicles, leading to the development of leukoderma and poliosis, respectively.1 Whereas active melanocytes in the epidermis are responsible for skin melanization, active melanocytes in the hair bulb are responsible for hair color by transferring melanin to the cortical keratinocytes of the shaft.2 Hair bulb melanocytes are targeted first only in acute alopecia areata, whereas poliosis develops later in vitiliginous patches because of the loss of melanocytes from hair bulbs after the primary immunologic destruction of epidermal melanocytes.3 Vitiligo duration was reported to be inversely correlated with melanocyte presence within hair
follicles, and maturing melanocytes were absent in all examined depigmented follicles in vitiligo.4 The presence of poliosis in vitiligo used to be a sign of recalcitrance and expected treatment failures,5 and surgery is usually required. Surgical methods aim to repopulate the recalcitrant depigmented skin with new generations of melanocytes harvested from normal skin of the same patient. Epithelial grafting using ultra-thin Thiersch grafts6 or Chinese cupping blisters7 have been used successfully to repigment skin in difficult-to-treat cases.
Aim of Work This study aimed to investigate the possibility of hair repigmentation after epithelial grafting for vitiligo with poliosis.
*Department of Dermatology and Venereology, Faculty of Medicine, Minia University, Minia, Egypt © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:406–411 DOI: 10.1111/dsu.12082 406
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Patients and Methods Seven patients with recalcitrant vitiligo (5 female, 2 male; aged 6–30 years old) with poliosis who were nonresponders to previous phototherapy were treated using epithelial grafting after dermabrasion. The duration of the disease before phototherapy ranged from 3 to 15 years. The seven treated sites were face and eye brow, forehead and scalp, back, scalp, and leg (n = 3). The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki and was approved by our institutional review board. Informed consent was obtained from the patients.
and the recipient site. A pressure bandage using petroleum gauze dressings was applied to the grafted area to allow for good apposition between the two raw surfaces. A routine dressing with an ample amount of topical antibiotic ointment (fusidic acid) was applied to the donor site. After 2 weeks, the dressings were discarded, and phototherapy was initiated twice weekly, as advised previously.6 Results Clinical photos before and after the procedures can be seen in Figures 1–8. After dressing removal,
Chinese cupping blisters were used in three cases with small patches. Briefly, the suction cups were applied to the inner aspect of the thigh over normal-looking skin. Manual induction of negative pressure was performed until mild erythema appeared underneath the cup; the attachment was then released, leaving the cup with skin sucked into it. Approximately 3 hours was needed for a blister to be formed, then a small pair of scissors was used to de-roof the blister, which was moved to a recipient glass slide. In the other four patients with larger areas of depigmentatoin, a freehand surgical knife was used to harvest a split-thickness graft (Thiersch graft) from the anesthetized area on the buttocks with the knife adjusted to harvest an ultrathin partial-thickness skin graft. The graft harvested from the donor site was approximately 0.15 mm thick and consisted of epidermis and thin parts of the papillary dermis. Harvested grafts were kept in saline. The anesthetized vitiliginous area was dermabraded using appropriate diamond fraises attached to a rapidly revolving abrading device. Dermabrasion was performed superficially on the depigmented patch to a depth that produced pinpoint bleeding, suggesting complete removal of the epidermis. Good hemostasis was ensured on the recipient dermabraded areas, and the grafts were applied smoothly with direct contact between the graft’s raw surface
Figure 1. Vitiligo on the eye brow for 4 years with poliosis. The patient epilated white hairs but some short stumps can be seen.
Figure 2. Roof of induced blister is gently spread over the dermabraded vitiliginous skin before applying dressings.
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grafted islands were noted in the treatment areas, with some sloughed regions. Then depigmentation began encroaching mainly at the periphery and toward the center of the treated patches. The percentage of depigmentary encroachment varied between patients (Figures 3 and 6).
islands for a maximum of 6 months duration, but follow-up was maintained for another 12 months. At the beginning of this period, hair color was still absent despite repigmentation of the surface skin
The twice weekly phototherapy sessions successfully halted this depigmenting effect. By the second week of phototherapy, gradual repigmentation was observed, and by 1 to 2 months, acceptable repigmentation resulted but with persistence of poliosis (Figure 6). Phototherapy was maintained twice weekly to help further repigmentation of remaining depigmented
Figure 5. A 6-year-old child with a depigmented patch on the forehead and scalp of 3 years’ duration. The hair is dyed to camouflage the color difference.
Figure 3. Dressings were removed after 2 weeks; graft islands and sloughed parts can be seen with regrowth of white hair follicles.
Figure 4. After 4 months of phototherapy, complete repigmentation of skin and recolorization of hair follicles.
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Figure 6. After 1 month of Thiersch grafting and phototherapy, gradual skin pigmentation with persistence of poliosis can be seen.
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(Figure 7). New pigmented follicles gradually started to appear. The majority of follicular repigmentation was attained 4 to 11 months after the grafting procedure (mean 7.7 2.8 months) (Figures 4 and 8). These pigmented follicles persisted for another 6 months, and the patients were satisfied.
Discussion Repigmentation failure in vitiligo is frustrating to patients and physicians as well.8 Although black hair follicles in vitiligo are able, under certain circumstances, to repigment the vitiliginous areas, the presence of white hairs in vitiligo is a negative prognostic sign.5 Epithelial grafts followed by phototherapy led to repigmentation of the skin surface, as expected and previously reported.6,7 Repigmentation of hair follicles was not an expected consequence after the procedures because epithelial grafts are merely epidermal cells (when blister roofs are used) or mainly epidermis with tiny islands of dermis (when thin Thiersch is used).6 Prior dermabrasion removed only nonmelanized epidermis and did not target the removal of deeper depigmented follicles. In both procedures, mature melanocytes in the epidermis from donor areas were the expected element to start repigmenting amelanotic skin.
Figure 7. After 4 months, good skin pigmentation with persistent poliosis.
These mature melanocytes are known to be differentiating and functioning and have a limited proliferative power that UV therapy may enhanced, but they are not known to have migratory power,9 so their repopulation of deep follicles was not expected. Nevertheless, hair repigmentation was attained in all cases, which is a potentially revolutionary finding. Mature hair follicles contain melanotic dopa-positive melanocytes in the basal layer of the infundibulum and around the upper dermal papilla in normal individuals, but are lacking these dopa-positive melanocytes in poliosis in patients with vitiligo. Instead, amelanotic dopa-negative melanocytes are present in the mid to lower outer root sheath.10
Figure 8. After 11 months, hair coloring was obtained in a majority of follicles.
Although maturing melanocytes were not found in all examined white hair follicles of vitiligo cases in a previous report,4 it is thought that melanocyte stem cells (MSCs) exist in the bulge region in a hibernating state. The lower permanent portion of hair
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follicles contains a reservoir for MSCs, and these cells can repopulate the epidermis and hair follicles when stimulated.9 The bulge areas of the hair follicles harbor MSCs, which may be transferred using Thiersch grafts when considerable thickness of dermis is obtained. If they are being transferred, they may then proliferate and migrate to the inferior portion of the hair follicle and supply mature melanocytes for repigmentation, although the roofs of blisters are composed solely of epithelial layers with no dermal components.7 The availability of bulge cells is negligible, yet similar repigmentation of hair follicles was attained in all cases. It was previously reported that patients with graying hair unexpectedly regained their hair color after radiation therapy for head cancer11 or after certain inflammatory events (e.g., erythrodermic eczema and erosive candidiasis of the scalp).12 The return to original hair color in these individuals may reflect repopulation of the hair bulb melanogenic zone in response to these stimuli.9 The effect of ultraviolet light in inducing amelanotic melanocytes in the outer root sheath to become mature functioning melanocytes has also been reported previously.13,14 Repigmentation of hair follicles in this report can not be attributed to the effects of phototherapy alone, because all cases received phototherapy without any success before grafting procedures. This may raise the question as to whether there was a depletion of bulge stem cells in these cases in spite of the assumption that vitiligo destroys only mature melanocytes.15 The hair repigmentation here may suggest the existence of hibernating MSCs that the treatment stimulated. Dermabrasion, which was used to de-epithelialize vitiliginous patches before application of epithelial grafts, is well known to stimulate those immature bulge cells to proliferate and migrate, as stated earlier.16
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Migration of MSCs depends on C-kit signaling when cells are migrating toward the hair follicles3 and C-kit protein is expected to be expressed in considerable amount during the pigmentation process of hairs in these cases.
Conclusions When faced with recalcitrant vitiliginous patches, patients and doctors generally seek repigmentation of the skin surface, because white hair has proved resistant. This study demonstrated unexpected repigmentation of hair, which is an exceptionally promising result. This suggests that epithelial grafts should be considered in the treatment of patients with poliosis and vitiligo affecting the scalp, eyebrows, or similar locations with cosmetically significant areas of depigmented hairs. Many factors acted together to initiate hair recoloring, including effects of dermabrasion and phototherapy, yet other internal aspects including expression of stem cell factors and duration of anagen phase in each site may affect the time required for repigmentation of the hair follicles in vitiligo. This process depends on the availability of melanocyte precursors and a raft of signal transduction pathways that have been described as highly complex and commonly redundant.3
References 1. Passeron T, Ortonne JP. Physiopathology and genetics of vitiligo. J Autoimmun 2005;25:63–8. 2. Tobin DJ, Bystryn JC. Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Res 1996;9:304–10. 3. Tobin DJ. Human hair pigmentation—biological aspects. Int J Cosmet Sci 2008;30:233–57. 4. Anbar TS, Abdel-Raouf H, Awad SS, Ragaie MH, Abdel-Rahman AT. The hair follicle melanocytes in vitiligo in relation to disease duration. J Eur Acad Dermatol Venereol 2009;23:934–9. 5. Seghal VN. A clinical evaluation of 202 cases of vitiligo. Cutis 1974;14:439–46. 6. Awad SS, Abdel-Raof H, Hosam El-Din W, El-Domyati M. Epithelial grafting for vitiligo requires ultraviolet A phototherapy to increase success rate. J Cosmet Dermatol 2007;6:119–24.
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7. Awad SS. Chinese cupping: a simple method to obtain epithelial grafts for the management of resistant localized vitiligo. Dermatol Surg 2008;34:1186–92.
14. Ortonne JP, Schmitt D, Thivolet J. PUVA-induced repigmentation of vitiligo: scanning electron microscopy of hair follicles. J Invest Dermatol 1980;74:40–2.
8. Arrunategui A, Arroyo C, Garcia L. Melanocyte reservoir in vitiligo. Int J Dermatol 1994;33:484–7.
15. Cui J, Shen LY, Wang GC. Role of hair follicles in the repigmentation of vitiligo. J Invest Dermatol 1991;97: 410–6.
9. Nishimura EK, Jordan SA, Oshima H, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 2002;416:854–60. 10. Slominski A, Wortsman J, Plonka PM, et al. Hair Follicle Pigmentation. J Invest Dermatol 2005;124:13–21. 11. Shetty M. Radiation therapy activates melanocytes in hair. BMJ 1995;311:1582. 12. Verbov J. Erosive candidiasis of the scalp, followed by the reappearance of black hair after 40 years. Br J Dermatol 1981;105:595–8.
16. Starrico R. Mechanism of migration of the melanocytes of the hair follicle into the epidermis following dermabrasion. J Invest Dermatol 1961;36:99–104.
Address correspondence and reprint requests to: Sherif S. Awad, MD, PhD, 8, AbdelMenam Garby Sq., Minia, Egypt, or e-mail:
[email protected]
13. Staricco R, Miller-Milinska A. Activation of amelanotic melanocytes in the outer root sheath of he hair follicle following ultraviolet rays exposure. J Invest Dermatol 1962;39:163–4.
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Commentary on Repigmentation of Poliosis After Epithelial Grafting for Vitiligo NICOLE E. ROGERS, MD*
The author has indicated no significant interest with commercial supporters.
T
he crossover between vitiligo and alopecia areata is interesting. Patients with alopecia areata are frequently observed to have white hair regrowth (poliosis, or leukotrichia) upon resolution of their condition, which appears to be related to an ongoing autoimmune attack of the melanocytes even after hair regrowth. The pigment loss usually resolves upon subsequent growth cycles. These white hairs can also appear in patches of vitiligo and are also believed to be due to a similar attack of the melanocytes within the hair bulb. It has been suggested that such hair whitening occurs in more-recalcitrant cases of vitiligo. This article is valuable because it demonstrates how stem cells responsible for pigmentation can migrate from epithelial donor skin cells to adjacent hair follicles.1 Similar results have been demonstrated previously in the setting of piebaldism.2 When suction blister epidermal grafting was performed, the pigment spread not only horizontally into the affected skin areas of depigmentation, but also vertically into neighboring white hairs. Within 1 year after grafting, white hairs became pigmented, and immunofluorescence studies using a melanocyte-
specific antibody (NKI/beteb) revealed the presence of melanocytes in the newly pigmented hair follicles. It has been suggested that a number of other modalities correct vitiligo in non-hair-bearing areas, including phototherapy, topical immune modulators, punch grafts, and suction blisters.3,4 In some cases, hair transplantation can help treat vitiligo. An area of pubic vitiligo was corrected with hair transplantation and subsequent phototherapy in a 27-year-old woman.5 Repigmentation was observed around the transplanted follicles between 4 and 6 weeks after surgery. Many of the hairs that had lost their color regained their pigment in this study as well. The mechanisms involved in melanocyte migration are complex and still unclear. Stem cells in the outer root sheath of the hair follicle presumably can migrate vertically and laterally to the surrounding skin. As the authors showed in this article, melanocytes can also migrate from the surrounding skin down into the hair follicles. These observations will hopefully offer new ideas for research going forward.
*Tulane School Medicine, New Orleans, Louisiana © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:412–413 DOI: 10.1111/dsu.12090 412
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References 1. Awad SS. Repigmentation of poliosis after epithelial grafting for vitiligo. Dermatol Surg 2013;39:406–11. 2. Horikawa T, Mishima Y, Nishino K, Ichihashi M. Horizontal and vertical pigment spread into surrounding piebald epidermis and hair follicles after suction blister epidermal grafting. Pigment Cell Res 1999;12:175–80. 3. Patel NS, Paghdal KV, Cohen GF. Advanced treatment modalities for vitiligo. Dermatol Surg 2012;38:381–91.
5. Park BC, Kim MH, Hong SP. Correction of pubic vitiligo with hair transplantation plus narrow-band ultraviolet B light therapy. Dermatol Surg 2012;38:807–8.
Address correspondence and reprint requests to: Nicole E. Rogers, MD, Tulane School Medicine, New Orleans, LA, 70118; and Private Practice, 701 Metairie Road, Suite 24205, Metairie, LA 70005 or e-mail:
[email protected]
4. Feetham HJ, Chan JL, Pandya AG. Characterization of clinical response in patients with vitiligo undergoing autologous epidermal punch grafting. Dermatol Surg 2012;38:14–9.
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Superficial Hemangioma: Pulsed Dye Laser Versus Wait-and-See JANNEKE P.H.M. KESSELS, MD,* ELLEN T. HAMERS, BSC,*†
AND
JUDITH U. OSTERTAG, MD, PHD*
BACKGROUND AND OBJECTIVES Childhood hemangioma is the most common soft tissue tumor of infancy, occurring in 10% of children younger than 1 year old. Ten percent of these infantile hemangiomas involute yearly without intervention. Treatment with the pulsed dye laser (PDL) is the criterion standard for treating vascular lesions. It is well established as the most effective, safest treatment for port-wine stains. Previous studies of the use of PDL treatment in superficial hemangioma showed inconsistent results. Main objectives were to compare the efficacy and adverse effects of PDL treatment with those of observation in the treatment of superficial hemangiomas. Parental quality of life was also assessed. MATERIALS AND METHODS This was a prospective, randomized, controlled trial in which we enrolled 22 infants aged 1.5 to 5 months old with early hemangiomas with a maximum diameter of 5 cm. We assigned the infants to PDL treatment (n = 11) or observation (n = 11), and followed up until the age of 1 year. Patients in the intervention group were treated using a 595-nm PDL (VBEAM, Candela Corp., Wayland, MA) with a 7-mm spot diameter, 30/10 to 40/10-ms epidermal cooling, a 7- to 15-J/cm2 fluence range, and a pulse duration of 0.45 to 40.0 ms. During follow-up, color measurements were made (Colori meter; Minolta, Tokyo, Japan), and surface area and echo depth of the hemangioma were determined. RESULTS No significant differences were seen between the groups at time of inclusion or at the age of 1 year in echo depth (p = .66) or surface area (p = .62). Results were significant for color difference (p = .03) between PDL treatment and observation. Cosmetic outcome judged by an independent panel consisting of a dermatologist, physician assistant, dermatology resident, dermatology nurse, and plastic surgery resident was significantly better in the PDL treatment group (46%) than in the observation group (18%) (p = .006). CONCLUSIONS Pulsed dye laser is only to be considered as an alternative treatment up to the age of 6 months, at which time parents and physicians consider cosmetic outcome to be a relevant factor, but laser therapy plays a major role in the treatment of residual lesions at older ages. The authors have indicated no significant interest with commercial supporters.
C
hildhood hemangioma is the most common soft tissue tumor of infancy, occurring in 10% of Caucasian children younger than 1 year old. Fewer than 10% are present at birth, with 90% appearing within the first 4 weeks of life.1,2 The hallmark of hemangioma is a rapid proliferative phase and a slower involution phase. During the proliferative phase, 80% of all hemangiomas will double their original size.3 They usually reach their maximum size by the age of 6 to 9 months. Each year, 10% of all hemangiomas undergo complete resolution, with 50% of hemangiomas resolving spontaneously by the age of 5 years and more than 90% by the age of 10 years.4,5 During the prolifer-
ate phase, complications such as bleeding, infection, functional impairment due to obstruction of vital structures, and disfigurement can arise.6–8 Hemangiomas located on the face are more likely to have complications that need treatment.9 Regression results in normal skin texture in most patients, but residual skin changes such as telangiectasia, atrophy, fibrofatty tissue residuum, and scarring will remain in up to 50% of patients. The most important prognostic factors for the permanent damage left by involutive hemangiomas are size, involvement of subcutaneous structures, and associated complications.4,10,11 Hemangiomas,
*Department of Dermatology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands; †Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:414–421 DOI: 10.1111/dsu.12081 414
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especially on the face, often cause great psychosocial morbidity that affect parents and children, so it may be desirable to have the hemangioma removed before the child enters school.12 The search for a therapy that eliminates hemangiomas before development of complications and without systemic or cutaneous adverse effects has been difficult.10,11,13–18 Several recent publications concerning the treatment of hemangiomas show promising results with beta-blockers such as propanolol.19,20 Treatment using the pulsed dye laser (PDL) is the criterion standard for treating vascular lesions. It is established as the mosteffective, safest treatment for port-wine stains in children.21 PDL can reach a depth of approximately 1 to 2 mm, so it is mostly indicated in the treatment of superficial skin lesions. Previous studies of PDL in superficial hemangiomas had inconsistent results. Several nonrandomized controlled trials have suggested that PDL is better than observation.22–28 It was hypothesized that using a 595-nm PDL and pulse widths of up to 40 ms with epidermal cooling would result in fewer side effects, better cosmetic outcome, and earlier remission than observation. We monitored the quality of life in parents and their opinions regarding the cosmetic outcome of the hemangioma. We expected PDL treatment to have a better psychosocial outcome. Our aim with this study was to perform a prospective randomized controlled trial to ascertain whether treatment of superficial hemangioma results in earlier remission and better cosmetic outcome than observation. Materials and Methods Participants Participants were recruited in the Eindhoven region by distribution of information leaflets to general practitioners, pediatricians, dermatologists, infant centers, and websites. All infants were assessed and treated in the dermatology outpatient department at the Catharina Hospital in Eindhoven, the Netherlands, between May 2009 and December 2011.
Patients aged 0 to 6 months were included and, after parents signed informed consent, were randomized using a computer program to two groups: a PDL treatment group and an observation group. Twentytwo infants were included. We did not include patients aged 6 months and older, and treatment was not performed on those aged 8 months and older because of the growth phase that occurs between 0 and 6 to 9 months and the expectation that treatment would be most efficient in that period of time. Treating older children was considered not to be ethical because of the increasing awareness of the child and the possible development of fear. Inclusion criteria were nontreated superficial and cutaneous hemangioma with a maximum diameter of 5 cm, a maximum depth to the papillary dermis, and a maximum of one hemangioma per patient. Exclusion criteria were subcutaneous or compound hemangioma, hemangioma with a diameter >5 cm, hemangioma associated with neurocutaneous syndromes, ulcerating hemangioma, hemangioma at great risk for auditory or visual compromise, and previous treatment. Study Design and Measurements After randomization, the infants were assigned to the PDL treatment group or the control group. Before treatment, the size of the hemangioma was measured using a tape measure and the Visitrak Digital (Smith & Nephew, Tuttlingen, Germany), which calculates total surface area of the hemangioma. Frontal and side-view photographs were taken with a ruler included. A color duplex sonograph was used to assess depth. Color of the hemangioma was measured suing a hand-held microprocessor-controlled, operator-independent reflectance photometer with a digital readout (CR-3000 Colori meter, Minolta) to determine color changes. The perceived color of the skin is quantified based on the proportions of red, green, and blue present in the spectral skin reflectance. The difference in color of the hemangioma between time of inclusion and the age of 12 months was calculated using a standardized formula (DE*).
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using a dynamic cooling device (DCD spray/delay) for a duration of 30/10 to 40/10 ms. Fluence ranged from 7 to 15 J/cm2 and pulse duration from 0.45 to 40 ms. Treatment duration was always <1 minute. Statistics
Figure 1. Color measurement: pulsed dye laser versus observation.
Patients assigned to the treatment group were treated every 2 to 6 weeks until complete remission, stop of proliferation, or no response of the hemangioma, meaning no change or a stable situation of the hemangioma within a maximum of 10 treatments. In the treatment and control groups, followup visits were scheduled at the ages of 3, 6, 9, and 12 months. All measurements described above were made at these visits. All parents were asked to fill in a standardized quality-of-life questionnaire at inclusion and at the age of 1 year in which they were asked to define the cosmetic outcome, psychosocial influence of the hemangioma, and their opinion regarding the PDL treatment.
Results
The same group of dermatologists and dermatology residents at the Catharina Hospital in Eindhoven assessed and treated all of the infants.
Twenty-two patients were randomized into the study and followed until the age of 12 months. (11 PDL treatment group, 11 observation group). Baseline characteristics are shown in Table 1. Table 2 shows patient characteristics and laser settings for the PDL treatment group. All patients were Caucasian, and the majority were female (15 vs 7 male). The median age of inclusion was 3 months (range 1.5–5 months). Most hemangiomas were located on the face (13 vs 9 on the back, trunk, or arm). Three infants were lost to follow-up during the study (1 PDL treatment group, 2 observation group) for reasons such as long travel distance between hospital and home and dissatisfaction with final group randomization, leaving data from 19 patients to be analyzed.
Laser
PDL Versus Observation
Laser treatments were performed using a 595-nm PDL (VBEAM, Candela Corp., Wayland, MA). We used a 7-mm spot diameter and epidermal cooling
Echo On average, five treatments were performed in the PDL treatment group. To assess whether PDL causes
At the end of the study, we asked a panel consisting of a dermatologist, physician assistant, dermatology resident, dermatology nurse, and plastic surgery resident to score improvement on a scale from 1 to 3 (1 = no improvement, 2 = moderate improvement, 3 = significant improvement) based on color photographs taken at inclusion and at the age of 1 year (Figure 1). The panel was blinded to treatment group and when the photographs were taken.
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A power analysis done before the start of the study calculated that a sample size of 70 infants (35 PDL treatment group, 35 observation group) was needed with 80% power and 5% significance. We conducted a statistical analysis on a per-protocol analysis. All data were processed in a SPSS database (version 19.0 for Windows, SPSS, Inc., Chicago, IL). Because of the small number of subjects, a nonparametric statistical test was used to compare medians and interquartile ranges (IQRs) of the quantitative variables. An independent Mann–Whitney U-test was used for group comparisons. A Pearson chi-square test was used to assess interobserver reliability concerning cosmetic outcome judged by the panel. p .05 was considered significant in all analyses.
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TABLE 1. Baseline Characteristics at Time of Inclusion Characteristic
Pulsed dye laser treatment group, n = 11
Sex, n (%) Male Female Age, months, median (range) Location, n (%) Face Trunk Arm Back Size, cm2, median (range) Echo, mm, median (range)
Observation group, n = 11
5 (45%) 6 (55) 3 (1.7–5.0) 6 3 1 1 1.71 2.54
2 (18%) 9 (82) 3 (1.5–4.5)
(55) (27) (9) (9) (0.20–6.60) (0.50–5.30)
7 3 1 0 1.24 2.35
(64) (27 (9) (0) (0.10–7.00) (0.0–5.0)
TABLE 2. Individual Patient Characteristics of the Pulsed Dye Laser Group Patient
Age, months
Location
Size at inclusion (mm)
1 2 3 4 5 6 7 8 9 10 11
4.0 1.7 3.5 2.5 3.0 5.0 2.5 3.5 2.0 2.2 2.0
Back Trunk Face Face Arm Trunk Face Face Face Trunk Face
18 8 5 18 34 5 13 8 11 4 14
9 9 9 9 9 9 9 9 9 9 9
18 7 5 15 30 3 16 8 9 9 8
Treatment Pulse intervals, weeks duration (ms)
Fluence (J/cm2)
Treatments, n
4 4–5 4 3–4 – 3 3–4 4–5 4–5 3–4 3–4
11–12 10–14 8–12 10–11 8 10–13 8–14 8–11 10–14 8–12 7–12
2 9 6 4 1 3 6 3 7 4 5
20 10–40 3–40 6–20 3 3–10 6–40 0.45–6 3–40 3–6 6–20
Spot size for all was 7 mm.
earlier involution of hemangiomas than observation, echo thickness at time of inclusion was compared with that at the age of 12 months. Median change in echo thickness was 1.18 (IQR 1.95 to 1.18) in the PDL treatment group and 1.00 (IQR 2.00 to 1.50) in the observation group (p = .66). Absolute echo depth difference was 1.21 mm (IQR 1.75 to 0.15 mm) in the PDL treatment group and 1.10 mm (IQR 2.00 to 0.96 mm) in the observation group (p = .69). Results are shown in Table 3. Surface Area Median variation in surface area at time of inclusion and at the age of 1 year was 0.20 (IQR 0.10 to 0.58) in the PDL treatment group and 0.00 (IQR 0.10 to 0.4) in the observation group (p = .62). The absolute difference in surface area was 0.40 cm2 (IQR 0.10–0.80 cm2) in the PDL treatment group
and 0.00 cm2 (IQR control group.
0.08 to 0.40 cm2) in the
Color Measurement Color changes were measured during follow-up visits. The color measurement was missing for one patient, so the analysis was done with 18 patients. The color of the hemangioma at inclusion was compared with the color at the age of 12 months. Median DE* was 10.16 (IQR 5.50–15.41) in the PDL treatment group and 4.23 (IQR 0.84–5.28) in the observation group (p = .03) (Figure 2). Photographs The independent panel observed all photographs at inclusion time and at the age of 1 year. They scored a higher percentage of significant improvement in the PDL treatment group (46%) than in observation
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TABLE 3. Comparisons (Inclusion Time—Age of 12 Months) Between Both Groups PDL treatment group Measurement Echo 12 months, mm Difference in echo depth, mm Δ echo, absolute, mm Δ echo, relative, % Surface 12 months, cm2 Difference in surface, cm2 Δ surface absolute, cm2 Δ surface relative, % Color, Δ E*
Observation group
Median (interquartile range)
p-Value
1.30 1.18 1.21 67.61
(0.19 to 8.80) ( 1.95 to 1.18) ( 1.75 to 0.15) ( 87.45 to 5.95)
2.00 1.00 1.10 41.66
(0.51 to 4.50) ( 2.00 to 1.50) ( 2.00 to 0.96) ( 96.81 to 29.58)
.57 .66 .69 .66
1.50 0.20 0.40 36.36 10.16
(0.50 to 2.90) ( 0.10 to 0.58) (0.10 to 0.80) (6.06 to 100.00) (5.50 to 15.41)
0.70 0.00 0.00 0.00 4.23
(0.25 to 1.05) ( 0.10 to 0.4) ( 0.08 to 0.40) ( 8.33 to 107.70) (0.84 to 5.28)
.11 .62 .08 .23 .03
not assess the severity of skin problems as more severe than parents in treatment group at time of inclusion or at the age of 12 months. In the PDL treatment group, 62.5% of parents thought that the hemangioma had a better cosmetic outcome or looked better than at inclusion, compared with 33% in the observation group. Seventyfive percent of parents in the PDL treatment group would recommend PDL treatment to others. Side Effects
Figure 2. Color photographs at time of inclusion and age 12 months old.
group (18%) (p = .006). Sixteen percent judged the hemangioma not to be improved after PDL treatment, compared with 38% in the observation group.
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After laser treatments, patients experienced mild to moderate purpura that resolved within 4 to 7 days. The only side effect was minimal crusting, occurring in two patients. Definite textural changes or scarring were not reported. In the PDL treatment group, 12.5% of all parents judged the laser treatment to be very painful.
Quality of Life
Discussion
All parents completed the hemangioma-specific quality-of-life questionnaire. We received 22 questionnaires at time of inclusion and 19 questionnaires at the end of the study in which parents answered questions about the quality of life of their child and cosmetic outcome of the hemangioma. Three questionnaires were missing because of attrition at the age of 12 months. Parents in the control group did
The aim of this study was to detect earlier remission, prevention of further proliferation, and better cosmetic outcome with PDL treatment than with observation. Our results indicate no significant difference regarding echo depth and surface area, but there was a significant difference in color change between inclusion and the age of 12 months. The PDL treatment group had a significantly greater
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reduction in redness than the observation group. There was a significant difference between the cosmetic improvement of the hemangioma in the PDL treatment group and the observation group as judged by an independent panel, and more parents in the PDL treatment group felt that a better cosmetic outcome was achieved. Pulsed dye laser has been extensively used in the treatment of vascular lesions and is established as the most-effective and safest treatment for port-wine stains in children. Previous studies regarding the use of PDL in superficial hemangiomas had inconsistent results. Several nonrandomized controlled trials have found that PDL is better than observation.15–18,21–28 Batta and colleagues published their work in 2002 and stated that treatment using a 585-nm-wavelength PDL without epidermal cooling did not achieve significantly better results in the treatment of superficial hemangiomas and resulted in a higher incidence of skin atrophy and hypopigmentation.29 Kono and colleagues showed that longpulsed dye laser (595-nm LPDL with epidermal cooling) was more effective and significantly safer than PDL.30 Our study is the first randomized controlled study comparing 595-nm PDL with 30/10 epidermal cooling in this context. Additional cooling could result in fewer side effects of laser treatment, and the longer pulse widths can reach deeper and thereby have a better effect. Even though prior studies reported a greater incidence of skin atrophy and hypopigmentation after PDL treatment for childhood hemangioma, this was not seen in our study, probably because of the epidermal cooling and longer pulse duration used. Because of the small number of patients followed-up until 1 year (n = 22), a nonparametric test was used in which we compared the medians and IQRs of both groups. Results were not significant for decrease in echo depth or surface area. Both groups show an increase since inclusion. It may be that this was because hemangiomas grow rapidly during the first year of life. This measurement therefore is not an adequate endpoint to define earlier regression.
The small number of subjects could explain the nonsignificant difference in decrease in echo depth between the groups. There could also be interobserver variance. Infants tend not to sit still during echo color duplex examination, so measurements might vary widely and not be adequate. Even though the above-mentioned data do not tend to recommend the use of PDL, there was a significant decrease in redness between inclusion and the age of 12 months after PDL treatment. This was not seen in the observation group. Improvement in color could indicate a better cosmetic outcome and be an indicator of earlier remission of the hemangioma when treated with PDL than with observation. The independent panel that judged the clinical cosmetic improvement in hemangiomas using standardized photographs found a higher percentage of improvement in the PDL treatment group than in the observation group. This could also indicate a better clinical and cosmetic outcome after PDL treatment. Mild to moderate purpura and edema was reported, which are common reactions after treatment. Duration of side effects was short (4–7 days). Hemangiomas, especially located on the face, often cause great psychosocial morbidity affecting parents and children. Therefore, it could be desirable to have the hemangioma removed before the child enters school.12 It appeared that parents in both groups thought that the hemangioma was cosmetically improved 1 year after inclusion. The recent promising findings regarding betablockers such as propranolol as therapeutic intervention for hemangiomas might overshadow the importance of this study, although propranolol is known as a therapy for deep hemangiomas.20,21 Because of possible risks of treatment, it is generally not used for superficial hemangiomas. As seen in this study, laser treatment results in cosmetic improvement. The PDL plays a significant role in the proliferation phase and can have a positive effect on reducing proliferation, sometimes even beyond the
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age of 6 months. Hunzeker and colleagues studied the effect of 595-nm PDL on superficial eyelid hemangiomas in a retrospective analysis and concluded that it is a safe and effective treatment that effectively diminishes proliferative growth of the hemangioma. Rizzo and colleagues also performed a retrospective study and reported excellent clearance rates and only few adverse events in the early treatment of superficial hemangiomas using the 595-nm PDL.31,32 Overall, this indicates that early PDL treatment of superficial hemangiomas is a satisfactory treatment when cosmetic outcome is relevant. Lasers also have therapeutic relevance for residual lesions of hemangioma at older ages to reduce fibrofatty tissue and residual telangiectasias.
Conclusion There were only a small number of subjects in our study, which resulted in poor power of evidence. The results indicate that PDL leads to higher parent satisfaction and a higher improvement score. There also was a significantly better color outcome in the PDL group, which indicates better cosmetic outcome. Evidence from recent studies indicates that betablockers are successful for the treatment of deep hemangiomas. Pulsed dye laser is a relevant treatment in superficial childhood hemangiomas, especially when in the proliferation phase and when parents and physicians perceived cosmetic outcome to be a relevant factor.
References 1. Jacobs AH. Strawberry haemangiomas. The natural history of the untreated lesion. Ca Med J 1957;86:8. 2. Halmdahl K. Cutaneous haemangiomas in premature and mature infants. Acta Paediatr 1955;44:370–9. 3. Leaute-Labreze C, Prey S, Ezzedine K. Infantile haemangioma: part 1. Pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities. JEADV 2011;25:1245–53.
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4. Fitzpatrick E, Cote D. Hemangiomas of the head and neck. J La State Med Soc 1995;147:291–5. 5. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol 1060;82:667–80. 6. Drolet BA, Esterly NB, Friedon IJ. Hemangioma in children. N Engl J Med 1999;341:173–81. 7. Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol 2001;44:962–72. 8. Ceisler EJ, Santos L, Blei F. Periocular hemangiomas: what every physician should know. Ped Dermatol 2004;21:1–9. 9. Haggstrom AN, Drolet ZBA, Baselga E. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 2006;118(3):882–7. 10. Enjolras O, Mulliken JB. The current management of vascular birthmarks. Pediatr Dermatol 1993;10:311–33. 11. Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming haemangiomas in infancy: a review of 25 cases. Peadiatrics 1990;85:491–8. 12. Tanner J, Dechert MP, Frieden IJ. Growing up with facial haemangioma in infancy. A overview of 25 cases. Paediatrics 1990;85:491–8. 13. Goldman MP, Fitzpatrick RE, Ruiz-Esparza J. Treatment of port wine stains (capillairy malformations) with the flashlamp pumped dye laser. J Pediatr 1993;122:71–7. 14. Anderson RR, Parisch JA. Selective photthermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220:524–7. 15. Hohenleutner S, Badur-Ganter E, Landthaler M, Hohenleutner U. Long-term results in the treatment of childhood hemangioma with the flashlamp-pumped pulsed dye laser: an evaluation of 617 cases. Lasers Surg Med 2001;28(3):273–7. 16. Waner M, Suen JY, Dinehart S, Mallory SB. Laser photocoagulation of superficial proliferating hemangiomas. J Dermatol Surg Oncol 1994;20(1):43–6. 17. Waner M, Suen JY, Dinhart S. Treatment of haemangiomas of the head and neck. Laryngoscope 1992;102:1123–32. 18. Garden JM, Bakus AD, Paller AS. Treatment of cutaneous haemangioma by the flash-lamp-oumped pulsed dye laser: prospective analysis. J Pediatr 1992;120:555–60. 19. Starkey E, Shahidullah H. Propanolol for infantile haemangiomas: a review. Arch Dis Child 2011;96:890–3. 20. Leaute-Labreze C, Dumas de la Roque E, Hubiche T. Propanolol for severe hemangiomas of infancy. N Engl J Med 2008;358: 2650–1. 21. Landthaler M, Hohenleutner U, el-Raheem TA. Laser therapy of childhood haemangiomas. Br J Dermatol 1995;133(2): 275–81. 22. Barlow RJ, Walker NP, Markey AC. Treatment of proliferative haemangiomas with the 585 nm pulsed dye laser. Br J Dermatol 1996;134(4):700–4. 23. Maier H, Neumann R. Treatment of strawberry marks with flaschlamp pumped pulsed dye laser in infancy. Lancet 1996;347:131–2.
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24. Achauer BM, Chang CJ, Vander Kam VM. Management of hemangioma of infancy: review of 245 patients. Plast Reconstr Surg 1997;99(5):1301–8. 25. Ricci RM, Finley EM, Grimwood RE. Treatment of cutaneous haemangiomas in preterm neonatal twins with flashlamp-pumped pulsed dye laser. Laser Surg Med 1998;22:10–3. 26. Ashinoff R, Geronemus RG. Capillary hemangiomas and treatment with the flash lamp-pumped pulsed dye laser. Arch Dermatol 1991;127(2):202–5. 27. Michel S, Wlotzke U, Hohenleutner U, Landthaler M. Laser and cryotherapy of hemangioma in infants in a direct comparison. Hautarzt 1998;49(3):192–6. 28. Poetke M, Philipp C, Berlien HP. Flashlamp-pumped pulsed dye laser for hemangiomas in infancy: treatment of superficial vs mixed hemangiomas. Arch Dermatol 2000;136 (5):628–32. 29. Batta K, Goodyear HM, Moss C, Williams HC, et al. Randomised controlled study of early pulsed dye laser treatment
of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet 2002;360(9332):521–7. 30. Kono T, Sakurai H, Groff WF, Chan HH, et al. Comparison study of a traditional pulsed dye laser versus a long-pulsed dye laser in the treatment of early childhood hemangiomas. Lasers Surg Med 2006;38(2):112–5. 31. Hunzeker CM, Geronemus NG. Treatment of superficial infantile hemangiomas of the eyelid using the 595-nm pulsed dye laser. Dermatol Surg 2010;36(5):590–7. 32. Rizzo C, Brightman L, Chapas AM, Hale EK, et al. Outcomes of childhood hemangiomas treated with the pulsed-dye laser with dynamic cooling: a retrospective chart analysis. Dermatol Surg 2009;35(12):1947–54.
Address correspondence and reprint requests to: Janneke Kessels, MD, Department of Dermatology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands, or e-mail:
[email protected]
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Inhibition of Fibroblast Proliferation In Vitro Using Low-Level Infrared Light-Emitting Diodes HADAR LEV-TOV, MD,*† NEIL BRODY, MD, PHD,‡ DANIEL SIEGEL, MD, MS,‡ JARED JAGDEO, MD, MS*†‡
AND
BACKGROUND Scars, including hypertrophic and keloidal-type scars, may occur after burns, trauma, or surgery. Despite several treatment options available for scars, few effective, noninvasive modalities exist. Recently, a few small clinical studies revealed the possible benefit of red and infrared (IR) low-level light therapy (LLLT) in scar treatment. One of the important features of scars is proliferation of dermal fibroblasts, but in vitro data regarding the effects of light-emitting diode (LED)-generated IR light on human skin fibroblasts is lacking. OBJECTIVE vitro.
To evaluate the effect of IR LLLT generated using LEDs on fibroblast proliferation and viability in
METHODS AND MATERIALS Irradiation of normal human skin fibroblasts using IR LED panels was performed in vitro, and modulation of proliferation and viability was quantified using Trypan blue dye exclusion assay. RESULTS Fluences of 80, 160 and 320 J/cm2 resulted in statistically significantly less fibroblast proliferation than in controls, without statistically significantly less cellular viability. CONCLUSION IR LLLT can effectively inhibit fibroblast proliferation in vitro without altering viability and holds promise for the treatment of scars. Photomedex loaned the device used in the paper to the authors. Dr. Siegel is on the Photomedex Scientific Advisory Board.
S
cars, hypertrophic scars, and keloids are of significant concern to patients and physicians. Scars can arise after trauma, burns, or surgery. Scarring is a significant international problem, with estimates each year that more than 100 million people worldwide develop scars.1 Many of these scars are cosmetically and psychosocially disfiguring and may result in patients seeking a variety of treatments to address the aesthetic and functional concerns attributed to scarring. Scarring is the end result of normal wound healing, but abnormal healing often occurs, resulting in hypertrophic or keloidal scars. The alterations in
normal scarring biologic mechanisms that result in abnormal hypertrophic and keloid scars are not fully understood. Modulation of fibroblast function, proliferation, and other cellular properties hold considerable promise for the treatment of scars. Noninvasive treatment of scars is also of significant interest. The current available treatments for scars, such as intralesional triamcinolone injection, 5-fluorouracil injections, topical agents, silicon dressings, revision surgery, fractionated ablative and nonablative laser treatments, nonfractional ablative laser treatments, and other modalities each have associated benefits,
*Department of Dermatology, University of California at Davis, Sacramento, California; †Dermatology Service, Sacramento Veterans Affairs Medical Center, Mather, California; ‡Department of Dermatology, State University of New York Downstate, Brooklyn, New York © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:422–425 DOI: 10.1111/dsu.12087 422
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range of financial and time costs, and side effects. Injectable treatments are time consuming for the patient and physician and usually require repeated office visits and procedures. Silicon dressings are typically not as effective for voluminous hypertrophic or keloidal scars compared to smaller scars. Scar revision surgery always carries the risk of a resultant hypertrophic or keloidal scar after surgery. Laser treatments are expensive for patients and dermatologic surgeons and may require multiple office visits. Light-emitting diode (LED)-generated LLLT confers many clinical advantages over alternative scar therapeutics; it can cover larger areas of tissue at a time, is less expensive, safer, usually painless, and has superior portability, allowing for patient home use.2 Recently, a few clinical observations and small studies have revealed the possible benefit of red and infrared (IR) low-level light therapy (LLLT), with and without adjunctive agents, to improve scars.3–6 There is a lack of basic scientific data in dermatology that demonstrate inhibition of fibroblast proliferation and modulation of other cellular characteristics of keloid scars induced by LEDs. LLLT is based on the principle that heme-copper photoacceptors within the cytochrome C component of the electron transport chain can be photo-stimulated or photo-inhibited, leading to modulation of cellular properties. We conducted this study to evaluate the ability of LED-generated IR light to modulate normal human skin fibroblast proliferation in vitro. To achieve this aim, we assessed the effect of IR LED light on normal human skin fibroblast proliferation and viability in vitro.
Methods Briefly, monolayers of normal human skin fibroblasts (AG13145 strain; Coriell Institute for Medical Research, Camden, NJ) were cultured in Dulbecco’s modified Eagle medium (Gibco/Invitrogen, Carlsbad, CA) with 15% bovine calf serum (Atlanta Bio, Lawrenceville, GA) and 1% penicillin, streptomycin,
and neomycin antibiotic mixture (Gibco). The cell cultures were incubated at 37°C with 5% carbon dioxide. Fibroblasts seeded at 2 9 104 cells per 35mm dish were irradiated 24 hours after passaging, using an 830-nm LED array (Omnilux new-U Photo Therapeutics, Carlsbad, CA) at a power density of 360.2 W/m2 at room temperature. Media temperatures measured throughout irradiations remained less than 37°C. By remaining within physiologic temperatures, heat stress was not induced. Immediately after irradiation, cells were qualitatively assessed to exclude instant cell death. After 48 hours of additional incubation, the cells were harvested, counted, and assessed for viability as determined using a Trypan blue exclusion assay. All experiments were repeated at least in triplicate to verify data reproducibility and accuracy. Each experimental plate receiving LED treatment was randomly matched with a bench control plate (BCP) to ensure that the measured effect was a result of LED treatment and not incandescent light. BCPs were derived from the same stock of cell suspension and were taken out of the incubator at the same time as their matched treatment pairs. They were then left on the bench for the same amount of time and in the same ambient environment as the treatment plates. BCPs were protected from the LED light source, and media temperatures measured throughout duration on bench remained under 37°C. Treatment plates and BCPs were then returned to the incubator and processed according to the same protocol. Cell counts included all cells in the sample, including media change, trypsinization products, and washes. Mean percentage proliferation and viability (live cells/total (live + dead) cells) relative to nonirradiated controls are reported as mean values standard errors of the mean (SEMs). Statistical analysis was performed using analysis of variance (ANOVA) to compare treatment arms and Student t-test to compare each treatment arm with the paired control arm.
Results Our findings demonstrate that the use of near-IR (830 nm) LEDs at these fluences inhibit normal
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human skin fibroblast proliferation without significant alteration in viability (Figures 1 and 2). LEDdelivered IR irradiation resulted in statistically significantly less cellular proliferation at the following fluences (time): 80 J/cm2 (37 minutes, 1 second),
160 J/cm2 (1 hour, 14 minutes, 2 seconds), and 320 J/cm2 (2 hours, 28 minutes, 4 seconds) (Figure 1). Relative viability for the aforementioned fluences ranged from 97.5 2.0% to 99.8 2.0% without statistically significant differences from the nonirradiated controls (Figure 2). BCPs demonstrated less proliferation. Treatment plates demonstrated 9.0% less proliferation than their matched BCPs for the lowest dose (80 J/cm2, 37 minutes, 1 second; p = .05) and, for the higher doses, statistically significantly less proliferation than their corresponding BCP (24.7%: 160 J/cm2, 1 hour, 14 minutes, 2 seconds, p < .001; 9.5%: 320 J/cm2, 2 hours, 28 minutes, 4 seconds, p = .04) (Figure 1). BCPs demonstrated no statistically significant difference in viability from controls.
Discussion Figure 1. Light-emitting-diode (LED)-generated infrared (IR) light (830 nm) induces statistically significantly less proliferation of normal human skin fibroblasts at fluences of 80 J/ cm2 (82.9 2.1%), 160 J/cm2 (63.1 2.0%), and 320 J/cm2 (58.6 1.7%). Assessed using Trypan blue assay. Proliferation is presented as percentage of control. Error bars represent standard error of the mean. (*p < .01).
Figure 2. Cellular viability is maintained in normal human skin fibroblasts treated using light-emitting-diode (LED)generated infrared (IR) light (830 nm) (viability range (97.5 2.0% to 99.8 2.0%). Assessed using Trypan blue assay. Relative viability is presented as percentage of control. Error bars represent standard error of the mean. No statistically significant differences found.
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Our findings demonstrate that certain doses of LED-generated IR LLLT decreases proliferation of normal human skin fibroblasts in vitro. Irradiation with fluences of 80, 160 and 320 J/cm2 resulted in significant decrease in cell number without significant effect on viability. This effect is dose dependent (Figure 1). To our knowledge, this bioinhibitory effect of IR LED photobiomodulation in fibroblasts in vitro has not been previously reported. These findings provide a basic science in vitro correlate to clinical observations and therefore may hold promise for translation into therapeutic strategies for scars and other hyperproliferative skin diseases. Demonstrating light-induced effects in human skin fibroblasts requires attention to bias because the effects can be attributed to environmental factors other than the light energy generated by the LED device as well as plate-to-plate variations in proliferation patterns. We controlled for environmental conditions by using bench controls, monitored to confirm that no supraphysiologic temperatures were induced, and performed all experiments in triplicate to account for any variation in baseline cellular proliferation patterns.
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The use of LEDs for LLLT of scars is attractive to dermatologic surgeons, dermatologists, and other medical practitioners because of the established safety profile of LEDs, low cost, portability of LEDs, and potential for home use. There are also minimal side effects associated with LED LLLT, the most common being temporary generation of heat in tissues during treatment. Data that demonstrate no significant effect of LED LLLT on cellular viability at fluences that are effective in inhibiting fibroblast proliferation support the safety of LEDs for LLLT (Figure 2). We anticipate that elucidating the cellular and mechanistic effects of LLLT on fibroblasts will contribute to the development of optimal light-based technologies that can be applied to improving the lives of patients with cosmetically and functionally impairing scars and other proliferative skin conditions. We acknowledge the need for further basic science and translational data to make this an accepted clinical option.
References 1. Bayat A, McGrouther DA, Ferguson MW. Skin scarring. BMJ 2003;326:88–92. 2. Barolet D, Roberge CJ, Auger FA, Boucher A, et al. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol 2009;129:2751–9. 3. Sakamoto FH, Izikson L, Tannous Z, Zurakowski D, et al. Surgical scar remodelling after photodynamic therapy using aminolaevulinic acid or its methylester: a retrospective, blinded study of patients with field cancerization. Br J Dermatol 2012;166:413–6. 4. Bruscino N, Lotti T, Rossi R. Photodynamic therapy for a hypertrophic scarring: a promising choice. Photodermatol Photo, 2011;27:334–5. 5. Barolet D, Boucher A. Prophylactic low-level light therapy for the treatment of hypertrophic scars and keloids: a case series. Lasers Surg Med 2010;42:597–601. 6. Sebastian A, Allan E, Allan D, Colthurst J, et al. Addition of novel degenerate electrical waveform stimulation with photodynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy. J Dermatol Sci 2011;64:174–84. Epub 2011 Sep 17.
Address correspondence and reprint requests to: Jared Jagdeo, MD, MS, 3301 C Street, Suite 1400, Sacramento, CA 95816, or e-mail:
[email protected]
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Nonablative Fractional Laser Resurfacing for the Treatment of Hypertrophic Scars: A Randomized Controlled Trial EVELIEN VERHAEGHE, MD, KATIA ONGENAE, MD, PHD, JESSICA BOSTOEN, MD, JO LAMBERT, MD, PHD*
AND
BACKGROUND Nonablative fractional laser (NAFL) therapy is a noninvasive procedure that has been suggested as a treatment option for hypertrophic scars. OBJECTIVES scars.
To evaluate the efficacy and safety of 1540-nm NAFL therapy in the treatment of hypertrophic
MATERIALS AND METHODS An intraindividual randomized controlled trial (RCT) with split lesion design and single-blinded outcome evaluations. Patients received four NAFL treatments at monthly intervals. Primary endpoint was a blinded on-site visual and palpable Physician Global Assessment (PhGA). Adverse event registration and pain evaluation were used to evaluate safety. Patient global assessment (PGA) was a secondary endpoint to additionally evaluate efficacy. RESULTS The PhGA did not find a statistically significant difference between the treated and untreated control side of 18 patients, although there was significant difference on the PGA 1 (p = .006) and 3 (p = .02) months after last treatment (Wilcoxon signed rank test). Patients experienced moderate pain during treatment and mild adverse events. CONCLUSION In this trial, blinded PhGA could not confirm the clinical efficacy of 1540-nm nonablative fractional laser in the treatment of hypertrophic scars, but the treatment is safe, and patients judged that the treated part had a better global appearance. The authors have indicated no significant interest with commercial supporters.
W
hen skin is violated, wound healing, including scar formation, is crucial to restoring the 1 barrier. In some individuals, the wound healing process leads to abnormal extracellular matrix accumulation and cellular activity, resulting in hypertrophic scars (HTSs).2 These scars are pink or red and raised above the skin level and do not exceed the margins of the original wound. Hypertrophic scars can cause significant functional and cosmetic impairment, pruritus, and pain, which are all responsible for a decrease in quality of life.3 They can be clinically distinguished from keloids, which extend beyond the boundaries of the skin injury and rarely regress.
The exact pathogenesis of HTSs remains unclear, although early onset of a failed immunologic response after wounding seems to be an important factor.1 Histopathologically, they contain primarily type III collagen oriented parallel to the epidermal surface with abundant nodules containing myofibroblasts, large extracellular collagen filaments, and acid mucopolysaccharides.4 Studies report incidences varying from 40% to 94% after surgery and from 30% to 91% after burns.3 These data reflect the burden of hypertrophic scarring, with approximately 100 million people developing a scar from surgical procedures,
*Department of Dermatology, Ghent University Hospital, Ghent, Belgium © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:426–434 DOI: 10.1111/dsu.12059 426
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burns, or trauma each year in the developed world. Hypertrophic scars are a therapeutic challenge. All existing treatments have their limitations, and a universally accepted treatment modality resulting in complete HTS amelioration is lacking.5 Intralesional corticosteroid injections are the common standard treatment. There is broad consensus that they are efficacious if other easier treatments fail,4,6 but they are associated with side effects including atrophy, color changes, pain caused by injection, and granuloma formation.2,6,7 Pressure garment therapy is a generally accepted procedure for the prevention and treatment of HTSs, but beneficial effects remain to be proven, and additional research is required to study the effectiveness, risks, and costs.8 Silicone gel sheeting is widely used, but trials evaluating its efficacy are of poor quality and highly susceptible to bias.4 Surgery, cryotherapy, radiotherapy, interferon, bleomycin, and fluorouracil have also been used, with varying success rate.5,7 These limitations brought lasers into the field as a new treatment modality for HTSs. Although the initial devices (carbon dioxide, argon, and neodymium-doped yttrium aluminum garnet lasers) did not have an advantage over scalpel excision, in 1994, Alster and colleagues described improvement in HTSs using the 585-nm pulsed dye laser (PDL).9 Multiple studies on hypertrophic scar treatment with PDLs followed this initial report.10–12 Until now, there has been no consensus on how PDL achieves its effect, but a possible explanation could be that PDL induces reduction in transforming growth factor beta expression, fibroblast proliferation, and collagen type III deposition.13 Later, intense pulsed light (IPL) and other moreselective laser systems were introduced.12,14 More recently, fractional lasers were introduced as a promising treatment for hypertrophic burn scars.15
A recent systematic review on the use of lasers and IPL for the treatment of HTSs demonstrated little evidence of the efficacy of laser therapy for the treatment of HTSs older than 6 months. Because of a lack of controlled studies, only 13 studies could be included in the review. Most evidence was found for PDL, although further research was recommended.16 Only one trial on nonablative fractional laser treatment was retained. There was not enough evidence to draw any conclusions. Despite the lack of clear efficacy data, nonablative fractional laser therapy (NAFL) has been suggested as a possible treatment option for nonhypertrophic surgical scars17–21 and hypertrophic burn scars15 and in the prevention of scars.22 Two noncontrolled studies23,24 and one recent RCT25 suggested a positive effect on HTS. The main principle of NAFL treatment is the coagulation of small columns of skin, leaving the surrounding tissue intact.26 This pattern of microscopic thermal damage stimulates a wound healing response. This wound healing response has been confirmed by increase in collagen III; heat shock proteins 70, 72, and 47; and alpha smooth muscle cell actin 1–7 days after NAFL.27,28 The pattern of microscopic treatment zones enhances the healing of the treated skin and minimizes the risk of unwanted side effects. The noninvasive character of this technique and minimal risk of unwanted side effects make this treatment attractive for treating HTSs. The objective of this study was to evaluate the clinical efficacy and safety of 1540-nm NAFL in the treatment of HTSs in a RCT. Material and Methods Study Design We conducted a prospective, single-center intraindividual RCT with split-lesion design. The local ethical committee approved the study (registration number B 67020097471), which was registered on http://clinicaltrials.gov (NCT01056211).
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Patients The study was conducted in the Outpatient Clinic of the Department of Dermatology, Ghent University Hospital. All outpatients with a HTS were asked to participate in the trial by flyers and announcements in the waiting room. Recruitment occurred from January 2010 to January 2011, and the study finished in July 2011. Inclusion criteria were aged 18 and older, skin type I–IV, a HTS that could be defined as two areas of similar sizes and appearance within the same anatomic region, and willingness and ability to adhere to the requirements of the protocol.
Scar split : 2 similar areas
Untreated control
Treated area Laserdevice : 1540 nm NAFL 10 mmHP – 15 ms Treatment 1 : 45 - 55 mJ/mB 3 - 4 passes every 4 weeks
No treatment
Treatment 2 - 3 - 4 : ↑ 5 - 10 mJ/mB/session 3 - 4 passes
Figure 1. Laser treatment plan.
Exclusion criteria were a history of keloid formation, history of adverse outcome related to NAFL therapy, pregnancy or lactation, or oral retinoid drugs within the past 6 months. Use of anticoagulative medication and a history of photodermatosis were not retained as exclusion criteria as mentioned in the original protocol. We found no evidence of important side effects after NAFL in the literature in patients taking anticoagulative medication and having a history of photodermatosis. Intervention Medical history, medication, scar history, and previous treatments were recorded. Patients underwent a clinical assessment, and two areas of similar size and appearance were defined in the lesion and marked as L (left) or R (right). The areas were randomized to treatment or no treatment. The randomization procedure involved computergenerated randomization lists in which allocation was indicated. The random allocation sequence was created using a digital randomization program. The randomization was performed immediately before the first treatment. The allocated treatment was concealed from the assessor throughout the study and revealed only to the treating physician. This physician was not included in the preliminary or post-treatment assessment of the patients. Patients were instructed not to tell the evaluating physician which area was treated. Patient and treating physi-
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cian were not blinded because this was not feasible from a practical perspective. The area randomized for treatment received four treatments at monthly intervals with the 1540-nm NAFL (Starlux 300 with Lux 1540-nm fractional hand piece, Palomar Medical Technologies, Burlington, MA). We used a 10-mm hand piece (100 microbeams/cm2), 15-ms pulse duration, and energies from 45 to 85 mJ/microbeam (mB) in three to four passes. The energy level was 45–55 mJ/mB during the first treatment and was increased 5– 10 mJ/mB every subsequent session depending on side effects. The maximum delivered energy was 85 mJ/mB. Passes were applied by covering the entire treatment area three to four successive times (Figure 1). Patients were treated without topical or infiltrative anesthesia. A single physician performed all treatments. Blinded on-site response evaluations were performed 1 and 3 months after the final treatment. Measurements The primary endpoint to evaluate clinical efficacy of the treatment was the physician global assessment (PhGA). Adverse events and pain were the primary endpoints to evaluate safety. PhGA was measured for the treated and untreated control side on a visual analogue scale (VAS) ranging from 0 to 100 mm
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(0 = normal skin and 100 = worst possible scar) at baseline and 1 and 3 months after the last treatment. The physician performing the evaluations was blinded to the treatment. Acute adverse events were registered on a standard form after an interview of the patient over the telephone 4 days after the treatment. Long-term adverse events were registered 3 months after the last treatment. The patient assessed treatmentrelated pain after each treatment on a VAS from 0 to 100 mm (0 = no pain and 100 = worst possible pain). Secondary endpoints were patient global assessment (PGA), Patient and Observer Scar Assessment Scale (POSAS), and skin reflectance measurements. At baseline and 1 and 3 months after the last treatment, the PGA was measured for the treated and untreated control side on a VAS ranging from 0 to 100 mm (0 = as normal skin and 100 = worst possible scar). The POSAS is a recent scar assessment scale validated for the evaluation of burn scars and linear surgical scars. The combination of a patient and an observer scale allows for a more-complete evaluation of the scar.29 The observer scale contains six parameters: vascularization, pigmentation, thickness, relief, pliability, and surface area. The patient scale also contains six items: pain, itching, color, stiffness, thickness, and relief. Each of the six items has a 10-step score, with 10 indicating the worst imaginable scar or sensation. The total score of both scales is calculated by adding the scores of each of the six items (range 6–60). The lowest score 6 reflects normal skin, and the highest score (60) reflects the worst imaginable scar. Skin reflectance measurements quantified skin redness and pigmentation before and 1 and 3 months after the last treatment (DSM II Color meter, Cortex Technology, Hadsund, Denmark). The erythema (E) and melanin (M) index was measured three times for the treated side, the untreated control side, and the
healthy surrounding skin at each time point. An average of the E and M index of the treated and untreated control area was calculated and subtracted from the average of the E and M index of the surrounding normal skin to adjust for fluctuations in the vascular bed and pigmentation (DE and DM). The location of the measurement was marked on plastic templates at baseline, and measurements were taken at 1- and 3-month follow-up at the same location. Digital photographs were taken for documentation in JPEG format using a digital camera. Statistical Analysis Aiming for a significance level of .05, a power of 0.8, and the assumption that the smallest clinically important minimum relevant difference was 20 (scale 0–100) on the PhGA, we calculated that at least 16 patients should be included in the trial. SPSS 19 (SPSS, Inc., Chicago, IL) was used for statistical analysis. We used the Wilcoxon matched paired test for two-paired comparison and the Friedman test for more than two-paired comparison p < .05 was considered significant.
Results Participants Flow and Demographics The trial profile is shown in Figure 2. Twenty-two patients were randomized to the treatments. One patient withdrew during the study for personal, non-treatment-related reasons and did not complete allocated treatments. Two patients were lost to follow-up for personal non-treatment-related reasons, and one patient was excluded from statistical analysis because the blinded assessor judged that both parts of the scar were not identical at baseline. Eighteen patients were included in the statistical analyses. Most of the participating patients were women (sex ratio F/M: 5/1) with hypertrophic scars on the trunk (n = 5), upper limbs (n = 4), joints (n = 4), head and neck region (n = 3), and lower limbs (n = 2). The median age of the patients was 45 years (interquartile range (IQR) 23–57 years), and the median age of the lesions was
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Figure 2. Trial profile.
14 months (IQR 4.7–63.2 months). Fifteen scars were postsurgical, and three were post-trauma. No scars were a result of burns. Further patient characteristics are summarized in Table 1. Primary endpoints At 1-month follow-up, the blinded assessor scored 11 patients better on the PhGA scale on the treated side and seven on the untreated control side. At 3-month follow-up, PhGA scores were better in 10 patients on the treated and in five on the untreated side; in three patients, both sides were scored identically. There was not a statistically significant difference on the PhGA between the treated side and the untreated control side 1 (p = .46) and 3 (p = .19) months after treatment. Patients experienced moderate pain during the treatments. Median pain score (IQR) measured on a VAS was 37.0 (26.0–53.5) for the first treatment session, 41.0 (26.7–60.7) for the second, 53.0 (22.5
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–71.0) for the third, and 48.0 (23.5–78.5) for the fourth. The intensity of the pain was similar for the four treatments (p = .71). Four days after treatment, patients reported erythema (70%), edema (20%), burning sensation (18%), crusts (15%), purpura (7%), and vesicles (3%). Three months after the last laser treatment, mild hyperpigmentation and scar formation were reported in one patient each on the treated part of the scar as longterm side effects. Secondary endpoints Statistical analysis of the PGA indicated a significant difference 1 (p = .006) and 3 months (p = .02) after the last treatment. One and 3 months after the last treatment, 10 patients scored the treated side of the scar better, seven scored both sides identically, and one scored the control side better. Statistical analysis using the Wilcoxon signed rank test shows a significant difference in the total POSAS
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TABLE 1. Patient Characteristics
Patient
Sex
Race
Skin Type
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Female Female Female Male Female Male Female Female Female Female Female Female Female Female Female Female Male Female
Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Asian Asian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian Caucasian
III III II I II III III III IV IV II II II IV III II I II
Age
Lesion Age, Months
Scar Length, cm
Scar Location
Scar Source
Other Treatment
23 46 60 62 17 19 44 57 29 29 41 21 60 23 56 46 56 57
79 9 3 11 8 58 223 3 92 34 28 4 7 1 88 27 5 17
3 2,4 6 15 5,5 2 4 8 8,2 9,1 4,2 10 4 2,3 3,5 6,5 3,7 11
Trunk Joints Joints Trunk Upper limb Upper limb Upper limb Head and neck Upper limb Lower limb Trunk Joints Lower limb Trunk Trunk Head and neck Head and neck Joints
Surgery Trauma Surgery Surgery Surgery Surgery Surgery Surgery Trauma Surgery Surgery Surgery Surgery Surgery Surgery Surgery Trauma Surgery
S C S, C S, M S, C, M, P, L no C M C M S, M S, M S M M M M S
S, silicone dressing; C, local corticosteroids; M, moisturizer; P, pressure therapy; L, pulsed dye laser treatment.
scale between the treated and untreated control sides for the patient part of the scale 1 (p = .02) and 3 (p = .047) months after treatment, but no significant difference was found on the observer part of the scale. One month after the treatment, patients evaluated color (p = .02), stiffness (p = .01), thickness (p = .005), and irregularity (p = .007) of the treated part of the scar as being significantly closer to normal skin, but 3 months after the last treatment, patients evaluated only thickness (p = .04) and irregularity (p = .04) a being significantly closer to normal skin. Skin reflectance measurements were not significantly different between the treated and untreated control side for DE and DM 1 and 3 months after the last treatment. Subanalysis of Scars Younger Than Six months Different studies suggest that interventions on scars should start early after the injury.9,30,31 Although this study was not powered to examine differences between older and younger scars, we found that the PhGA of four of five scars younger than 6 months had greater improvement of the treated side than of the untreated control side at 3-month follow up.
Baseline demographics and characteristics of the five scars younger than 6 months included in the trial are presented in Table 1.
Discussion Using the chosen settings, 1540-nm NAFL was not found to be effective for the treatment of HTSs. Moreover, one patient each developed hyperpigmentation and laser-induced scar formation. Nevertheless, patients judged that the treated part of their scars had a significantly better appearance. Analysis of the observer and patient part of the POSAS scale showed a better score for thickness and irregularity on the patient part of the scale. There was no significant improvement in color measurements. Subanalysis of five scars younger than 6 months showed a better PhGA in four of five treated parts of the scars. Two studies have reported using 1540-nm NAFL in the treatment of scars with positive results.15,32 In a RCT, Haedersdal and colleagues reported better
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skin texture on the treated side of thermal burn scars than on the untreated control side in 15 of 17 patients 12 weeks after last treatment measured using blinded on-site evaluation,15 although patients with a tendency to produce HTSs or keloids were excluded from this trial. Positive results have also been reported in a noncontrolled trial on 33 scars 1 month after six to seven treatment sessions.32 Three studies have reported the use of a 1550-nm NAFL (Fraxel Re:Store, Solta Medical, Hayward, CA) in HTSs with positive treatment outcomes. Lin and colleagues reported greater improvement in treated than untreated HTS sides in a RCT with intraindividual study design in 20 patients. Patients were divided into high-density (26% coverage) and low-density (14% coverage) groups (10 patients in each group) and treated every 2 weeks for four sessions. Blinded observers evaluated photographs. The ratings for the treated sides were significantly better 1 and 3 months after treatment for the low-density group and significantly better only at 1 month in the high-density group. There was no statistically significant difference in erythema, pigmentation, or skin texture. Niwa and colleagues treated eight hypertrophic scars in an uncontrolled prospective study with two to three treatments at 4-week intervals with positive results. In a report of cases, Kunishige and colleagues reported greater than 50% improvement in five HTSs at 2-month follow-up after up to eight treatments scored by an independent observer on a quartile grading scale. Several limitations of our study need to be addressed: laser device and settings, small patient number, and subjective evaluation scores. Because of a lack of comparative studies, it is difficult to compare the performance of different NAFL devices and settings. The maximum penetration achieved with the device used could be shallower than with other NAFL, but there are no data investigating the clinical effect of depth in the treatment of scars that could explain our negative results.33,34
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We used lower semifixed energy settings than Haedersdal and colleagues in their trial of burn scars, with similar coverage. Choosing settings individualized for each patient and scar or less coverage (as suggested by the data of Lin and colleagues) might result in better outcomes. Another limitation was the patient number. Although the sample size was limited to draw firm conclusions, the study design made the total patient number sufficient for statistical analysis, but the small patient number makes it impossible to determine whether scar improvement could be related to scar location on the body. Subjective evaluation methods always have drawbacks, but to counter this, the primary endpoint of the study (PhGA) evaluating clinical efficacy was performed on site using side-by-side assessments through a blinded physician. Patients were selected before inclusion with scars that allowed two similar scar areas to be determined, and the randomized trial design compensated for minor discrepancies in global appearance of both scar parts.15 The downside of this experimental set-up is that we cannot exclude local effects of NAFL treatment surpassing the border of the treated scar region. Because results of POSAS were consistent with those of PhGA, they confirm the findings of the primary endpoints. We are cautious with the interpretation of the PGA. Although patient evaluation is important, it was not blinded because of pain and immediate side effects. We believe that these side effects form a bias and could explain the inconsistency between patient and observer assessment. Hyperpigmentation and scar formation are mentioned as side effects, and in a small group of patients, the treated part improved less than the untreated part. This last finding can be interpreted as a worsening of the treated part. Haedersdal and colleagues (minor atrophic scarring in 1 patient) and Lin and colleagues (3/10 cases in the highdensity treatment group group may have worsened) reported side effects of NAFL laser treatment.
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Further study is needed to optimize treatment parameters related to scar characteristics to improve treatment results and avoid side effects. There was high variability in age of the HTSs in this study. Scars less than 6 months old improved in 80% of the cases after treatment. In two other studies, similar findings have been reported. Lin and colleagues reported that scars that were less than 2 years old trended toward a more-significant response than those more than 6 years old, although the results did not reach statistical significance. Niwa and colleagues reported that HTSs less than 1 year old had better improvement scores. In the past, different laser systems have been used in the preventive treatment of scars. Different studies with nonablative lasers such as PDL30,35,36 and laserassisted skin healing37 have achieved good results. In these trials, treatment was started immediately to 2– 3 weeks after surgery. In one comparative trial, 1550-nm NAFL seemed to be superior to PDL.18 Although our patient group was small, combined with findings of prior studies, further research on NAFL treatment of young HTSs seems worthwhile to investigate. In conclusion, at the chosen settings, 1540-nm NAFL treatment of HTSs does not result in greater improvement of scars than a control part evaluated by an independent blinded observer, although in a subgroup of HTSs less than 6 months old, the treatment could be more effective. This may be a clue for further research because HTS resistance to therapy remains a challenge. Acknowledgments This work was supported by a grant of the Klinisch Onderzoeksfonds of Ghent University Hospital. References 1. van der Veer WM, Bloemen MC, Ulrich MM, Molema G, et al. Potential cellular and molecular causes of hypertrophic scar formation. Burns 2009;35:15–29. 2. Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. Arch Facial Plast Surg 2006;8:362–8.
3. Bloemen MC, van der Veer WM, Ulrich MM, van Zuijlen PP, et al. Prevention and curative management of hypertrophic scar formation. Burns 2009;35:463–75. 4. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med 2011;17:113–25. 5. Alster TS, Tanzi EL. Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol 2003;4:235–43. 6. Alster TS, West TB. Treatment of scars: a review. Ann Plast Surg 1997;39:418–32. 7. Sharma PK. Scar revision treatment and management. In. Available from: http://emedicine.medscape.com/article/1129913treatment; 2011, Accessed August 1, 2012. 8. Anzarut A, Olson J, Singh P, Rowe BH, et al. The effectiveness of pressure garment therapy for the prevention of abnormal scarring after burn injury: a meta-analysis. J Plast Reconstr Aesthet Surg 2009;62:77–84. 9. Alster TS. Improvement of erythematous and hypertrophic scars by the 585-nm flashlamp-pumped pulsed dye laser. Ann Plast Surg 1994;32:186–90. 10. Alster TS, Williams CM. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye laser. Lancet 1995;345:1198–200. 11. Alster TS, Nanni CA. Pulsed dye laser treatment of hypertrophic burn scars. Plast Reconstr Surg 1998;102:2190–5. 12. Bouzari N, Davis SC, Nouri K. Laser treatment of keloids and hypertrophic scars. Int J Dermatol 2007;46:80–8. 13. Alster T, Zaulyanov L. Laser scar revision: a review. Dermatol Surg 2007;33:131–40. 14. Nouri K. Laser revision of scars. In. Available from: http:// emedicine.medscape.com/article/1120673-overview; 2010, Accessed June 15, 2012. 15. Haedersdal M, Moreau KE, Beyer DM, Nymann P, et al. Fractional nonablative 1540 nm laser resurfacing for thermal burn scars: a randomized controlled trial. Lasers Surg Med 2009;41:189–95. 16. Vrijman C, van Drooge AM, Limpens CE, Bos JD, et al. Laser and intense pulsed light therapy for the treatment of hypertrophic scars: a systematic review. Br J Dermatol 2011;165:934–42. 17. Kunishige JH, Katz TM, Goldberg LH, Friedman PM. Fractional photothermolysis for the treatment of surgical scars. Dermatol Surg 2010;36:538–41. 18. Tierney E, Mahmoud BH, Srivastava D, Ozog D, et al. Treatment of surgical scars with nonablative fractional laser versus pulsed dye laser: a randomized controlled trial. Dermatol Surg 2009;35: 1172–80. 19. Rogge FJ, Cambier B. Safe and effective treatment of problem scars with the purely thermal non-ablative Er:YAG laser scar mode. J Cosmet Laser Ther 2008;10:143–7. 20. Behroozan DS, Goldberg LH, Dai T, Geronemus RG, et al. Fractional photothermolysis for the treatment of surgical scars: a case report. J Cosmet Laser Ther 2006;8:35–8.
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21. Pham AM, Greene RM, Woolery-Lloyd H, Kaufman J, et al. 1550-nm Nonablative Laser Resurfacing for Facial Surgical Scars. Arch Facial Plast Surg 2011;13:203–10. 22. Choe JH, Park YL, Kim BJ, Kim MN, et al. Prevention of thyroidectomy scar using a new 1,550-nm fractional erbium-glass laser. Dermatol Surg 2009;35:1199–205. 23. Babilas P, Schreml S, Eames T, Hohenleutner U, et al. Experience with non-ablative fractional photothermolysis with a dual-mode laser device (1,440/1,320 nm): no considerable clinical effect on hypertrophic/acne scars and facial wrinkles. Lasers Med Sci 2011;26:473–9. 24. Niwa AB, Mello AP, Torezan LA, Osorio N. Fractional photothermolysis for the treatment of hypertrophic scars: clinical experience of eight cases. Dermatol Surg 2009;35:773–7; discussion 77–8. 25. Lin JY, Warger WC, Izikson L, Anderson RR, et al. A prospective, randomized controlled trial on the efficacy of fractional photothermolysis on scar remodeling. Lasers Surg Med 2011;43:265–72. 26. Manstein D, Herron GS, Sink RK, Tanner H, et al. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med 2004;34:426–38. 27. Laubach HJ, Tannous Z, Anderson RR, Manstein D. Skin responses to fractional photothermolysis. Lasers Surg Med 2006;38:142–9. 28. Hantash BM, Bedi VP, Struck SK, Chan KF. Immunohistochemical evaluation of the heat shock response to nonablative fractional resurfacing. J Biomed Opt 2010;15:068002. 29. van de Kar AL, Corion LU, Smeulders MJ, Draaijers LJ, et al. Reliable and feasible evaluation of linear scars by the Patient and Observer Scar Assessment Scale. Plast Reconstr Surg 2005;116:514–22.
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30. Nouri K, Rivas MP, Stevens M, Ballard CJ, et al. Comparison of the effectiveness of the pulsed dye laser 585 nm versus 595 nm in the treatment of new surgical scars. Lasers Med Sci 2009;24:801– 10. 31. Leclere FM, Mordon SR. Twenty-five years of active laser prevention of scars: what have we learned? J Cosmet Laser Ther 2010;12:227–34. 32. Vasily DB, Cerino ME, Ziselman EM, Zeina ST. Non-ablative fractional resurfacing of surgical and post-traumatic scars. J Drugs Dermatol 2009;8:998–1005. 33. Farkas JP, Richardson JA, Hoopman J, Brown SA, et al. Microisland damage with a nonablative 1540-nm Er:glass fractional laser device in human skin. J Cosmet Dermatol 2009;8:119–26. 34. Thongsima S, Zurakowski D, Manstein D. Histological comparison of two different fractional photothermolysis devices operating at 1,550 nm. Lasers Surg Med 2010;42:32–7. 35. Nouri K, Elsaie ML, Vejjabhinanta V, Stevens M, et al. Comparison of the effects of short- and long-pulse durations when using a 585-nm pulsed dye laser in the treatment of new surgical scars. Lasers Med Sci 2010;25:121–6. 36. Alam M, Pon K, Van Laborde S, Kaminer MJ, et al. Clinical effect of a single pulsed dye laser treatment of fresh surgical scars: randomized controlled trial. Dermatol Surg 2006;32:21–5. 37. Capon A, Iarmarcovai G, Gonnelli D, Degardin N, et al. Scar Prevention Using Laser-Assisted Skin Healing (LASH) in Plastic Surgery. Aesthetic Plast Surg 2010;34:438–46.
Address correspondence and reprint requests to: Evelien Verhaeghe, MD, Ghent University Hospital, Department of Dermatology, De Pintelaan 185, B-9000 Ghent, Belgium, or e-mail:
[email protected]
Oral Tranexamic Acid Enhances the Efficacy of Low-Fluence 1064-Nm Quality-Switched Neodymium-Doped Yttrium Aluminum Garnet Laser Treatment for Melasma in Koreans: A Randomized, Prospective Trial JUNG U SHIN, MD,† JIHUN PARK, MD,† SANG HO OH, MD, PHD,
BACKGROUND disorders.
AND
JU HEE LEE, MD, PHD*
Tranexamic acid (TA) has recently gained in popularity in the treatment of pigmentary
OBJECTIVE To evaluate the clinical efficacy and safety of oral TA combined with low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser for the treatment of melasma. MATERIALS AND METHODS Forty-eight patients with melasma were enrolled in the study and subsequently divided into two groups: a combination group and a laser treatment group. All patients were treated with two sessions of low-fluence QSNY laser, and patients in the combination group took 8 weeks of oral TA. Two blinded dermatologists evaluated patients using the Modified Melasma Area and Severity Index (mMASI) and a clinical improvement scale. RESULTS Mean mMASI score 4 weeks after the second treatment decreased significantly in both groups from base line. Based on overall clinical improvement, a greater number of patients scored as grade 3 and more in the combination group; no patients were scored as grade 4 in the laser-alone group. CONCLUSIONS Oral TA may prove a safe and efficient treatment option for melasma in combination with low-fluence QSNY laser therapy. The authors have indicated no significant interest with commercial supporters.
M
elasma is a common acquired disorder of hyperpigmentation in Asians that typically presents as symmetric hyperpigmented patches in sun-exposed areas, including the face, cheeks, forehead, upper lip, nose, and chin.1 Although many etiologic factors have been associated with melasma, including genetics, pregnancy, hormone therapy, thyroid disease, and cosmetics, exposure to ultraviolet (UV) light is the single most important factor.1–3 Although there are a multitude of therapeutic options for melasma, no single modality has ever been proven superior, given associated side-effect
profiles and high rates of recurrence. For this reason, various combinations of conventional treatments are often employed (e.g., bleaching or whitening agents, chemical peels, and laser- or light-based treatments).4,5 Trans-4-aminomethylcyclohexanecarboxylicacid (tranexamic acid [TA]), which has been introduced recently, has been shown to disrupt interactions between melanocytes and keratinocytes and has thus gained public attention for its lightening effects in cosmetic fields. Several forms of TA have been tried in the treatment of hyperpigmentation, including topical creams,6 localized microin-
*All the authors are affiliated with the Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, College of Medicine, Yonsei University, Seoul, Korea †
The first two authors contributed equally to this work and should be considered as first authors.
© 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:435–442 DOI: 10.1111/dsu.12060 435
COMBINATION OF ORAL TRANEXAMIC ACID AND LASER TREATMENT
jections,7 and most recently systemic pills.8 Nonetheless, it remains unclear whether TA enhances the effect of other conventional melasma treatments. Accordingly, this prospective study was proposed to evaluate the effect and safety of oral TA combined with a low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet (QSNY) laser in the treatment of melasma.
Materials and Methods This randomized prospective trial combined an oral TA-based medication (125 mg TA, 53 mg coated ascorbic acid, 40 mg L-cysteine, 4 mg calcium pantothenate, and 1 mg pyridoxine hydrochloric acid) with a low-fluence QSNY laser for the treatment of melasma, and was approved by the Institutional Review Board at Yonsei University Severance Hospital. Investigators complied with national and international Good Clinical Practice guidelines and the Declaration of Helsinki. Patients and study design Forty-eight healthy Korean women with melasma (Fitzpatrick skin types III and IV) aged 18–55 were enrolled in this study. Before enrollment, the procedures used in this study were explained to all patients, and written informed consent was
obtained. Exclusion criteria included any previous treatments with laser- or light-based devices for melasma, pregnancy, nursing, current or past treatment with oral contraceptives or anticoagulants, a history of any photosensitive dermatosis or photosensitivity syndrome, or a history of any bleeding disorders. Once enrolled, patients were randomly assigned to the combination treatment group or the laser treatment group, with the trial flow diagram depicted in Figure 1. Forty-four of the 48 enrolled patients (aged 28–56, median 48) completed this study. In all cases, study withdrawal occurred secondary to difficulties with attending follow-up visits and in no cases was associated with adverse effects of the medication or laser treatment. Treatment procedure As described above, patients were randomly assigned to one of two groups upon enrollment: oral TA combined with low-fluence QSNY laser or lowfluence QSNY alone. Patients in the combination group were treated with oral TA at a dose of 750 mg per day for 8 weeks, at which time they also underwent two rounds of treatment with lowfluence QSNY laser therapy (VRM IV Spectra, Lutronic Corporation, Goyang, Korea) at 4-week intervals. This interval was used to reduce any confounding effect of the low-fluence QSNY laser
Figure 1. Flow diagram of the randomized clinical trial algorithm.
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and allow better evaluation of the efficacy of oral TA. In the laser group, patients also underwent low-fluence QSNY laser treatments at the same time intervals (Figure 2). In all cases, a topical mixture of 2.5% lidocaine hydrochloric acid and 2.5% prilocaine (AstraZeneca AB, S€ odert€ alje, Sweden) was applied under occlusion for 1 hour before the laser treatment. Treatment parameters included a fluence of 2.0 J/cm2 and a spot size of 7 mm. All patients were advised to use sunscreen with a sun protection factor greater than 30, and no other topical therapies such as hydroquinone or Kligman’s formula were used. Treatment Assessment Photographs were obtained using a high-resolution digital camera at baseline and again 2 months after treatment. Two rubrics were used to assess patient improvement: the modified Melasma Area and Severity Index (mMASI), and a clinical improvement– based quartile grading scale that two blinded dermatologists evaluated using photographs. Specifically, mMASI scores were derived according to the protocol that Pandya and colleagues validated.9 Melanin indices was measured twice using a Mexameter MX 18 connected to a Multiprobe Adapter System (Courage Khazaka electronic GmbH, K€ oln, Germany)—before treatment and 2 months after the initial treatment. Two blinded dermatologists performed objective clinical assessments, comparing baseline and 2-month-visit photographs using the following classification system: grade 0 (worsening or stable disease), grade 1 (minimal (0–25%) improve-
ment), grade 2 (moderate (26–50%) improvement), grade 3 (marked (51–75%) improvement), and grade 4 (near total ( 75%) improvement). At every visit, adverse effects associated with the medication (nausea, vomiting, heartburn, or thrombosis-related conditions) and the laser therapy (persisting erythema, postinflammatory hyper- and hypopigmentation) were assessed. Statistical Analysis All measured values were expressed in the form of means and standard deviations. The efficacies of the treatment groups were analyzed using a paired t-test to compare the change in mMASI between the baseline and final follow-up visits. An independent t-test was used to compare the mean reduction in mMASI between the combination group and laser group. Clinical improvement scores between the two groups were compared using the chi-square test, with a complete-case analysis (n = 40) and intention-to-treat analysis (n = 44) performed separately. All statistical analyses were performed out using SPSS version 18.0 (SPSS Inc., Chicago, IL), with p < .05 considered statistically significant in all cases.
Results Demographic Data Forty-four patients completed this study, although four were later excluded from the complete-case analysis because of poor medication adherence. Four other patients who quit the study because of
Figure 2. Outline of treatment schedule and evaluation.
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difficulty with follow-up visit attendance were also not included in the intention-to-treat analysis, because no follow-up data were available. Of the 44 patients who completed the study course, 23 had been randomized to the combination group (mean age 44.4 7.9, mMASI 7.9 3.7) and 21 to the laser group (mean age 43.2 6.91, nMASI 7.9 3.9). No statistically significant differences were observed between the two groups in age or baseline mMASI score.
Treatment Efficacy The efficacy of the treatment groups was assessed according to mMASI scoring, with the completecase analysis showing that the mMASI score decreased significantly in both groups after treatment (combination group 7.9 3.7–5.0 3.4, p < .001; laser group: 7.9 3.9–6.0 3.2, p < .001). The intention-to-treat analysis also revealed a significant decline in mMASI score in both treatment groups (combination group 8.0 4.3–5.1 3.3, p < .001; laser group 7.9 3.9–6.0 3.2, p < .001; Figure 3). Furthermore, the mean reduction in mMASI score 4 weeks after the second treatment session was significantly higher in the combination group than in the laser group in the complete-case analysis (37.8 23.9% vs 21.9 18.5%, p = .02) and in the intention-totreat analysis (38.1 22.1% vs 21.9 18.5%, p = .01; Figure 4). A statistically significant decrease in melanin index was not observed either the combination group (166.5 49.6– 157.5 56.9, p = .23) or the laser group (163.1 44.6–158.1 28.7, p = .65) in the intention-to-treat analysis. Similarly, the change in melanin index did not differ significantly (p = .65) between the combination group (10.6) and the laser group (5.0). A clinical improvement score was also determined according to the evaluations of two blinded dermatologists who compared patients’ appearances on the first visit with those 4 weeks after the final treatment session (Figures 5 and 6). Of those in the combination
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Figure 3. Change in modified Melasma Area and Severity Index score in each group 4 weeks after the final treatment session. All histograms demonstrate means standard deviations (*p < .001).
group, five (22%) were graded as having greater than 50% clinical improvement (grade 3) 4 weeks after the last treatment session, and two (9%) achieved greater than 75% (grade 4) at this time point. In the laser group, only two (11%) were graded as having improved more than 50%, with no patients graded as having experienced grade 4 improvement. The number of patients who did not respond to treatment (grade 0) was significantly higher in the laser group than the combination group (combination group 42.9% vs laser-alone group 10.5%, p = .02, complete-case analysis; combination group 47.7% vs laser-alone group 8.7%, p = .009, intention-to-treat analysis, Figure 7). Safety Assessments Two individuals randomized to the combination group reported medication-associated heartburn, and one complained of nausea. Otherwise, the medication was well tolerated during the study
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(A)
(B)
Figure 6. Clinical photographs of a 43-year old woman in the laser group who achieved grade 3 improvement at baseline (A) and after 2 months (B).
Discussion
Figure 4. Mean modified Melasma Area and Severity Index reduction in both groups. All histograms demonstrate meansstandard deviations (*p = .01).
(A)
(B)
Figure 5. Clinical photographs of a 39-year-old woman in the combination group who achieved grade 4 improvement at baseline (A) and after 2 months (B).
period. All patients experienced transient erythema after the laser treatment, but there were no reports of severe adverse events (crusting, infection, hyperpigmentation, or bulla) in either group.
Melasma is a challenging cosmetic disorder of hyperpigmentation, despite a variety of treatment options. Until now, topical hydroquinone and tretinoin have been viewed as the most effective treatment options for melasma,5,10 but such topical medications require long durations of treatment to achieve noticeable skin lightening and are associated with several undesirable side effects, including skin irritation and paradoxical postinflammatory hyperpigmentation, especially in Asian patients. Accordingly, new safe and effective treatment modalities are much needed. Based on the notion of the subcellular selective photothermolysis theory, the long wavelength of the 1064-nm QSNY allows the laser to penetrate the dermis and target melanin, with the absorbed energy selectively destroying melanin without damaging surrounding tissue. As such, the 1064-nm QSNY laser has been used in the treatment of a wide range of benign pigmented lesions in the dermis, including Ota nevus and acquired bilateral nevus of Ota-like macules. Recently, the low-fluence QSNY laser has been suggested as a novel treatment modality for melasma11,12 or partial unilateral lentiginosis.13 Although the exact mechanism by which the lowfluence QSNY laser improved melasma is not clearly
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Figure 7. Clinical improvement scores assessed by two blinded dermatologists (*p = .009, 0 = no improvement, 1 = 0–25%, 2 = 26–50%, 3 = 51–75%, 4 = 76–100% improvement).
understood, decreased melanocyte melanin synthesis and enhanced melanin excretion have been suggested as possibilities.12 The long treatment duration, risk of postinflammatory hyperpigmentation, and high recurrence rate are all notable drawbacks associated with the treatment of melasma using a low-fluence QNSY laser. As such, attempts are being made to identify new agents to enhance its efficacy. TA has recently become more widely used in the treatment of disorders of pigmentation, especially in Japan. TA has traditionally been used in the treatment or control of bleeding disorders because of the selective antifibrinolytic effect achieved by inhibiting plasminogen lysine receptors.14 More recently, TA has also been employed in the treatment of hyperpigmentation. Although still unclear, one possible mechanism for this pharmacologic effect is the inhibition of UV-induced keratinocyte plasmin activity. Specifically, it has been theorized that TA prevents plasminogen from binding to keratinocytes, reducing the amount of free arachidonic acid, decreasing prostaglandin production, and ultimately down-egulating tyrosinase activity in melanocytes.2,6–8,15 Other research suggests that plasmin not only stimulates the release of arachidonic acid, but also promotes increases in alpha-melanocyte
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stimulating hormone, another major mediator of melaninogenesis.15,16 Various routes of administration have been described for the use of TA in the treatment of hyperpigmentation, including a topical liposomal formulation and intradermal microinjections.6,7 Although there are only limited data regarding the use of oral TA,8,17 several reports have suggested that oral TA is a potent and convenient modality for treating melasma. Accordingly, we hypothesized that, when combined with low-fluence QSNY, oral TA medication might enhance the efficacy of laser treatments and reduce the risk of postinflammatory hyperpigmentation. The MASI, calculated as the subjective assessment of three separate factors (total area of involvement, darkness, and homogeneity), is recognized as a reliable, semiobjective tool in the analysis of melasma, although Pandya and colleagues9 recently proposed the modified MASI score (mMASI), which eliminates homogeneity as a criterion because it had the lowest interrater agreement. Because the mMASI score has been proven to be a more accurate measurement of melasma severity, it was used as the primary endpoint for the study described here. Using this scoring system, mMASI scores from both treatment groups were assessed 4 weeks after the
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final treatment session and compared with baseline. The resulting data showed that a treatment regimen combining low-fluence QSNY laser with oral TA led to a significantly greater mean reduction in mMASI score than low-fluence QSNY laser treatment alone. Moreover, the number of patients graded as achieving improvements of greater than 50% and greater than 75% was significantly higher in the combination group, with no patients graded as having improved more than 75% in the laser-alone group. These results also suggest that combining oral TA with low-fluence QSNY laser may boost the efficacy of this type of laser treatment in Korean patients. Most data studies shown that five treatment sessions, with intervals of 1–2 weeks, are the minimum necessary (range 5–12) for low-fluence QSNY laser to treat melasma in Asian patients effectively.11,12,18 In contrast, some patients in our cohort achieved clinical improvement of greater than 75% after only two laser treatment sessions spaced at 4-weeks intervals. Moreover, significantly fewer patients did not respond to treatment in the combination group. In this way, our results suggest that oral TA may enhance the efficacy of lowfluence QSNY laser in the treatment of melasma in Asian patients. Regarding associated complications, low-fluence QSNY laser has generally been proven safe and tolerable in treating melasma in Koreans. With the exception of immediate post-treatment erythema and edema, no other associated side effects— including postinflammatory hyperpigmentation, punctate leukoderma, and atrophic scars—were observed in either treatment group. Moreover, no cases of secondary postinflammatory hyperpigmentation have ever been reported with the QSNY laser dose (2.0 J/cm2) used here. Furthermore, as per the previous reports regarding oral TA administration, no significant medication-related adverse reaction occurred during our 8-week study, with only a small number of participants reporting mild gastrointestinal discomfort.8,19 As such, we believe that oral TA
(750 mg/d) can be used safely for an 8-week period, although further research regarding ideal TA dosing and administration is needed. Although our data suggest that the combination of low-fluence QSNY laser and oral TA medication may be an effective treatment for melasma, the major limitation of this study was the mixed composition of the oral medication used. Specifically, other ingredients in the formulation—including ascorbic acid20 and L-cysteine21—have been reported to influence melanogenesis, although the quantities of these agents in the oral medication are much lower than in other reports, so the additive effect of TA-based oral medication in this study might be from the TA. Another major limitation is the short follow-up period. Because patients were followed for only 4 weeks after the final treatment session, our results do not address recurrence rates, and longer studies are needed. In conclusion, oral TA may enhance the clinical efficacy of low-fluence QSNY in the treatment of melasma. Combining these two treatment modalities resulted in greater improvement in mMASI scores and physician-assessed clinical analyses than laser alone. As such, we contend that cases of melasma refractory to conventional treatments may benefit from the addition of oral TA. A larger-scale study with a longer follow-up period should be conducted to confirm these findings and further evaluate the recurrence rates associated with this combination treatment.
Acknowledgments This study was supported by Hyundai Pharmacy, Seoul, Korea. J.H. Lee has received fees as a consultant and investigator in a clinical trial by Hyundai Pharmacy.
References 1. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol 1995;131:1453–7. 2. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohex anecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol, B 1998;47:136–41.
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3. Morelli JG, Norris DA. Influence of inflammatory mediators and cytokines on human melanocyte function. J Invest Dermatol 1993;100:191S–5S. 4. Prignano F, Ortonne JP, Bugglani G, Lotti T. Therapeutical approaches in melasma. Dermatol Clin 2007;25:337–42.
15. Li D, Shi Y, Li MY, Liu J, et al. Tranexamic acid can treat ultraviolet radiation-induced pigmentation in guinea pigs. Eur J Dermatol 2010;20:289–92.
5. Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of melasma: a review of clinical trials. J Am Acad Dermatol 2006;55:1048–65.
16. Wang N, Zhang L, Miles L, Hoover-Plow J. Plasminogen regulates pro-opiomelanocortin processing. J Thromb Haemost 2004;2: 785–96.
6. Manosroi A, Podjanasoonthon K, Manosroi J. Development of novel topical tranexamic acid liposome formulations. Int J Pharm 2002;235:61–70.
17. Konishi N, Kawada A, Morimoto Y, Watake A, et al. New approach to the evaluation of skin color of pigmentary lesions using Skin Tone Color Scale. J Dermatol 2007;34:441–6.
7. Lee JH, Park JG, Lim SH, Kim JY, et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in asian patients: a preliminary clinical trial. Dermatol Surg 2006;32:626–31.
18. Brown AS, Hussain M, Goldberg DJ. Treatment of melasma with low fluence, large spot size, 1064-nm Q-switched neodymiumdoped yttrium aluminum garnet (Nd:YAG) laser for the treatment of melasma in Fitzpatrick skin types II-IV. J Cosmet Laser Ther 2011;13:280–2.
8. Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd:YAG laser. J Dermatolog Treat 2011 epub, doi:10.3109/09546634. 2011.643220. 9. Pandya AG, Hynan LS, Bhore R, Riley FC, et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol 2011;64:78–83. 10. Rendon M, Berneburg M, Arellano I, Picardo M, et al. Treatment of melasma. J Am Acad Dermatol 2006;54:S272–81. 11. Suh KS, Sung JY, Roh HJ, Jeon YS, et al. Efficacy of the 1064-nm Q-switched Nd:YAG laser in melasma. J Dermatolog Treat 2011;22:233–8. 12. Zhou X, Gold MH, Lu Z, Li Y. Efficacy and safety of Q-switched 1,064-nm neodymium-doped yttrium aluminum garnet laser treatment of melasma. Dermatol Surg 2011;37: 962–70. 13. Lee Y, Choi EH, Lee SW. Low-fluence Q-switched 1,064-nm neodymium-doped yttrium Aluminum garnet laser for the treatment of facial partial unilateral lentiginosis in Koreans. Dermatol Surg 2012;38:31–7.
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14. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999;57:1005–32.
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19. Kato H, Araki J, Eto H, Doi K, et al. A prospective randomized controlled study of oral tranexamic acid for preventing postinflammatory hyperpigmentation after q-switched ruby laser. Dermatol Surg 2011;37:605–10. 20. Sehgal VN, Verma P, Srivastava G, Aggarwal AK, et al. Melasma: treatment strategy. J Cosmet Laser Ther 2011;13:265– 79. 21. Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatolog Treat 2012;23:97–102.
Address correspondence and reprint requests to: Ju Hee Lee, MD, PhD, Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, Korea, or e-mail:
[email protected]
Safety and Efficacy of Intradermal Injection of Botulinum Toxin for the Treatment of Oily Skin AMY E. ROSE, MD,*
AND
DAVID J. GOLDBERG, MD†‡
OBJECTIVE To evaluate the safety and efficacy of intradermal injection of abobotulinumtoxinA for the treatment of oily skin. METHODS AND MATERIALS Twenty-five patients with oily skin were treated in the forehead region with intradermal injections of botulinum toxin. Baseline and post-treatment sebum production was measured using a sebometer. Photographs were taken. Patients were also asked to rate their satisfaction with the treatment in terms of improvement in their oily skin. RESULTS Treatment with botulinum toxin resulted in significantly lower sebum production at 1 week and 1, 2, and 3 months after injection (p < .001, t-test). Twenty-three patients (91%) reported that they were satisfied (50–75% improvement) with intradermal botulinum toxin as a treatment for oily skin. CONCLUSION Intradermal injection of botulinum toxin significantly reduced sebum production in the forehead region, with a high degree of patient satisfaction. Intradermal botulinum toxin may be an effective treatment to reduce sebum production in patients with oily skin. Larger, randomized, blinded, placebocontrolled studies are warranted. Medicis provided research funding and botulinum toxin used in this study.
O
ily skin is a common chief complaint of patients presenting for dermatologic evaluation, but the available treatments are overall unsatisfactory. Sebum production is physiologic and serves to lubricate and hydrate the stratum corneum but becomes pathologic when produced in excess in acne vulgaris. Excess sebum production is also an aesthetic concern for many patients without acne because it is associated with enlargement of facial pores and shiny, greasy skin. Lasers, isotretinoin, chemical peels, retinoids, and other topical therapies have all been used to treat oily skin and enlarged pores, with varying degrees of efficacy. Several factors contribute to pore size and sebum production, including the activity of the arrector pili muscle and the activation of local
muscarinic receptors in the pilosebaceous unit by acetylcholine. These observations and anecdotal reports of patients noting tighter, smoother skin after botulinum toxin injection have prompted speculation that botulinum toxin may be an effective treatment for oily skin and enlarged pores. In previous studies of botulinum toxin for the treatment of rhytides, acne occurred at a lower rate in treated patients than in those who received placebo.1 There is also evidence to suggest that the action of acetylcholine at the muscarinic receptor is an important regulator of sebum production.2 Shah and colleagues3 recently described a novel technique of intradermal, as opposed to intramuscular, injection of botulinum toxin as a possible new strategy for the treatment of oily skin and enlarged
*Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York; † Department of Dermatology, Mount Sinai School of Medicine, New York, New York; ‡Skin Laser and Surgery Specialists of New York and New Jersey, New York, New York © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:443–448 DOI: 10.1111/dsu.12097 443
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facial pores. In this retrospective study, 20 subjects with a history of oily skin and enlarged pores were treated using intradermal onabotulinumtoxinA to the T-zone and evaluated photographically at 1 month. Seventeen of 20 subjects reported improvement in oiliness after only one treatment, but the authors recognized that the study’s retrospective design and the lack of an objective measurement of post-treatment sebum production were limitations. The purpose of this study was to prospectively evaluate the safety and efficacy of intradermal botulinum toxin for the treatment of oily skin in the forehead region. Post-treatment sebum production was evaluated using sebometer readings at four follow-up points and pre- and post-treatment photographs. Subjects were asked to rate their degree of satisfaction with the treatment in terms of improvement in their oily skin.
Methods Five male and 20 female subjects with mild to moderate oiliness in the forehead region were enrolled in the study. Inclusion criteria were aged 35 to 50, no smoking for at least 2 years before the study, and Fitzpatrick skin type I to IV. Exclusion criteria included infection in the target area, previous treatment with botulinum toxin in the target area, history of deep chemical peeling, treatment with isotretinoin within the previous 24 months, Fitzpatrick skin type V or VI, history of poor wound healing or keloid formation, human immunodeficiency virus, hepatitis, immunocompromise, pregnant or lactating, hypersensitivity to botulinum toxin or any of its components, and allergy to cow’s milk protein. All subjects signed informed consent, and an independent institutional review board approved the study. Each 300-U vial of abobotulinumtoxinA (Dysport, Medicis, Scottsdale, AZ) was diluted using 3 mL of bacteriostatic saline. The face was cleansed with isopropyl alcohol, and the forehead area (above the
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eyebrows and between the right and left temples) was injected intradermally with 30 to 45 U of botulinum toxin using a 30-G needle. Ten injection sites were chosen, and 3 to 5 U of botulinum toxin were injected at each point (Figure 1). Ice packs were applied after treatment, and subjects were advised to use gentle cleansers on the day of treatment. Subjects returned for follow-up visits 1 week and 1, 2, and 3 months after the initial injection. Photographs were taken of the treatment area at baseline and at each follow-up visit. Measurements of sebum production were obtained using a sebometer at baseline and at each follow-up visit. The sebometer works according to the principal of photometry, using a plastic strip that becomes more transparent with the absorption of lipids. The variation of light transmitted through the strip is proportional to the amount of lipid absorbed, which is then translated to a numeric value. The sebometer was placed at the midway point of the 10 injection sites of each subject. Location of sebometer placement was confirmed at each visit by comparison with initial photographic documentation. At the conclusion of the study, patients were asked to rate their satisfaction with the treatment with regard to improvement in their oily skin (0– 25% = not satisfied, 25–50% = somewhat satisfied, 50–75% = satisfied, and 75–100% very satisfied).
Figure 1. Sites of intradermal botulinum toxin injection (9). Three to 5 U of toxin was injected at each of the 10 points across the forehead.
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Change in oiliness was evaluated by comparing average sebum production at each follow-up visit with the baseline value using a Student t-test (twotailed, two-sample equal variance) with p < .05. Although not a primary endpoint of the study, subjects were evaluated for any evidence of decreased muscle tone or paralysis in the treated areas.
patients (91%) reported that they were satisfied (50– 75% improvement) with the treatment, one patient was very satisfied (>75% improvement), and one was somewhat satisfied (25–50% improvement). Two subjects had decreased frontalis muscle tone 2 months after treatment. No other adverse events were noted.
Discussion Results Twenty-five subjects were enrolled. One was lost to follow-up after the initial treatment and another after the initial follow-up visit at week 7, leaving 23 patients with at least two post-treatment sebometer readings. Treatment with intradermal botulinum toxin resulted in significantly lower sebum production as measured using the sebometer at all follow-up time points assessed (Figure 2) (p < .001, t-test). Sebometer readings demonstrated an average percentage decrease in sebum production of 75% at 1 week (N = 22), 80% at 1 month (N = 19), 73% at 2 months (N = 23), and 59% at 3 months (N = 22). All patients except for one demonstrated at least a 50% decrease in sebum production from baseline at the 1-week follow-up visit. Subjective differences in pore size could also be seen photographically (Figures 3–4). Twenty-three
Figure 2. Intradermal injection with botulinum toxin significantly reduced sebum production in the forehead region relative to baseline at all follow-up time points evaluated (*p < .001, t-test).
Our results suggest that intradermal injection of botulinum toxin reduces sebum production in patients with oily skin, with a high degree of patient satisfaction. Although we did not specifically assess pore size, prior studies have shown that reducing sebum production results in smaller pores.4 Thus, intradermal botulinum toxin injection may represent
Figure 3. Before intradermal injection of botulinum toxin, sebometer reading 21 units. Note the visible pores in the central forehead (delineated by arrows).
Figure 4. Same subject shown in Figure 3 after intradermal injection of botulinum toxin, sebometer reading 11 units. Note the reduction in visible pores in the central forehead (delineated by arrows).
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a promising new treatment for both of these notoriously difficult-to-treat conditions. The mechanism by which intradermal botulinum toxin results in decreased sebum production is not entirely clear. Intradermal injection of botulinum toxin can reduce hyperhidrosis by blocking the release of acetylcholine from cholinergic neurons that innervate sweat glands.5 In contrast to the eccrine sweat glands, which are regulated primarily by the sympathetic nervous system, androgens are the major influence controlling the development of the sebaceous glands and the production of sebum. Many topical treatments, including green tea extracts and other novel topical anti-androgens, have been shown to reduce sebum production through inhibition of 5-alpha-reductase.6 The role of the nervous system and acetylcholine in sebum production is not well defined. It is possible that the decrease in oiliness and shininess noted subjectively in the pilot study of intradermal botulinum toxin of Shah and colleagues merely represented a decrease in sweating. In our study, the sebometer used photometry and lipid absorption from the lipid-rich secretions of the sebaceous gland to measure sebum production, making this possibility unlikely. Intradermal botulinum toxin may reduce sebum production through its neuromodulatory effects on the arrector pili muscles and the local muscarinic receptors in the sebaceous gland. Endogenously produced acetylcholine alters sebocyte differentiation and sebum production, with the highest concentration of acetylcholine receptors at the infundibulum of the pilosebaceous unit.7 Thus, it is plausible that blockade of local acetylcholine receptors in the pilosebaceous unit with botulinum toxin could result in altered rates of sebum production. The most effective treatment for reducing sebum production is isotretinoin, but many patients cannot tolerate isotretinoin, are unwilling to accept the side effects, or do not have severe enough disease to warrant its use. Intradermal botulinum toxin may be a viable alternative for patients who have oily skin
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and enlarged pores but not cystic acne. Another limitation of currently available treatments for oily skin is that the treatment target, the sebaceous glands, are deeper in the dermis than many of the laser or resurfacing devices can reach. One study of a 1,450-nm-diode laser in patients with oily skin reported a maximum reduction in sebum output of only 18% after three treatments.8 Another study using the same laser found no significant change in sebum excretion rate after three treatments.9 Treatment using intradermal botulinum toxin in our study resulted in an average decrease in sebum production of 80% at 1-month follow-up. This is comparable with the reported reduction of sebum in patients taking isotretinoin (60–90%).8 Many patients with oily skin and enlarged pores are young and do not necessarily have other manifestations of extensive photodamage or aging. Thus, this patient population is particularly well suited for a treatment option that can be performed quickly in a single office visit, has no downtime and few side effects, and is relatively inexpensive. Intradermal injection of botulinum toxin allows for targeted treatment of the pilosebaceous unit without affecting the underlying skeletal muscle. Few reports in the literature describe the use of intradermal botulinum toxin for aesthetic indications. It has been reported that intradermal injections of toxin can reduce pain associated with conditions such as migraines and other types of neuralgia not necessarily related to muscle contraction.10 Such findings have prompted speculation that botulinum toxin may work not only by blocking acetylcholine, but also by inhibiting the release of other neurotransmitters.11 One split-face study of 10 subjects who received intradermal botulinum toxin or saline demonstrated no difference between the two sides with regard to skin rejuvenation, which included parameters such as skin texture, tightness, pore size, and sebum production,12 although there was subjective improvement noted in skin texture and tightness on both sides of the face. This finding prompted the authors to speculate that perhaps the
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microinjury from the needle sticks, rather than the botulinum toxin, was responsible for any observed effect. Lack of objective measurements and an untreated control limited the study. When targeting intradermal structures such as the sebaceous gland with toxin, the injection technique is critical because placement of the toxin too superficially will not be effective, and too deep an injection may lead to inadvertent paralysis of underlying skeletal muscle. Proper placement becomes even more important if treating oily skin on the cheeks or the perioral region because inadvertent paralysis in these areas can significantly affect function. The potential for intramuscular injection and subsequent paralysis also becomes relevant in the design of future studies of intradermal botulinum toxin because it has the potential to unblind the treated subject and the investigator. Previous studies of intradermal botulinum toxin have suggested that inserting the needle at a 75° angle facilitates placement into the dermis and that extrusion of toxin from adjacent pores may be an indication that the injection is at the appropriate level.3 We used a similar injection technique and also looked for pore extrusion as an end point. Intradermal botulinum toxin may also be useful as a primary or adjunctive treatment for enlarged pores. The pilot study of botulinum toxin and sebum production of Shah and colleagues3 also demonstrated a reduction in pore size using a subjective photographic assessment. We recognize that the ability to accurately assess pore size using photography is limited and that there may be confounding variables such as changes in frontalis tone that contribute to differences noted in the pre- and posttreatment photographs. Although we did not objectively evaluate pore size, we found a statistically significant reduction in sebum production. Previous studies examining various factors that contribute to pore size demonstrated that, in a multivariate model, sebum output level was the factor that correlated most significantly with pore size.4 Subsequent studies have validated the correlation between sebum
production and pore size.13 Thus, it is possible that a reduction in pore size would also accompany the significant reduction in sebum production after treatment with intradermal botulinum toxin seen in our study. Further studies that include objective measurements of pore size would be needed to prove this correlation. The results of our study are promising and provide an objective measurement of reduced sebum production that was lacking in the pilot study by Shah,3 although the lack of a control group and the openlabel nature of the study design limit the results. A larger, randomized, blinded, placebo-controlled dose-response trial is necessary to substantiate our findings that intradermal botulinum toxin is an effective treatment for oily skin.
Conclusions Intradermal injection of botulinum toxin significantly reduced sebum production in the forehead region and provided a high degree of patient satisfaction. Intradermal botulinum toxin may be an effective treatment for oily skin and may also play a role in the treatment of enlarged pores. Further study is needed to determine the optimal number of units and the duration of action of intradermal botulinum toxin when used for this novel indication.
References 1. Brin MF, Boodhoo TI, Pogoda JM, James LM, et al. Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol 2009;61(6):961–70. e961–911. 2. Kurzen H, Schallreuter KU. Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors. Exp Dermatol 2004;13(Suppl 4):27–30. 3. Shah AR. Use of intradermal botulinum toxin to reduce sebum production and facial pore size. J Drugs Dermatol 2008;7(9): 847–50. 4. Roh M, Han M, Kim D, Chung K. Sebum output as a factor contributing to the size of facial pores. Br J Dermatol 2006;155 (5):890–4.
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5. Lowe NJ, Glaser DA, Eadie N, Daggett S, et al. Botulinum toxin type A in the treatment of primary axillary hyperhidrosis: a 52week multicenter double-blind, randomized, placebo-controlled study of efficacy and safety. J Am Acad Dermatol 2007;56(4): 604–11. 6. Mahmood T, Akhtar N, Khan BA, Khan HM, et al. Outcomes of 3% green tea emulsion on skin sebum production in male volunteers. Bosn J Basic Med Sci 2010;10(3):260–4. 7. Zouboulis CC, Baron JM, Bohm M, Kippenberger S, et al. Frontiers in sebaceous gland biology and pathology. Exp Dermatol 2008;17(6):542–51. 8. Perez-Maldonado A, Runger TM, Krejci-Papa N. The 1,450-nm diode laser reduces sebum production in facial skin: a possible mode of action of its effectiveness for the treatment of acne vulgaris. Lasers Surg Med 2007;39(2):189–92. 9. Laubach HJ, Astner S, Watanabe K, Clifford J, et al. Effects of a 1,450 nm diode laser on facial sebum excretion. Lasers Surg Med 2009;41(2):110–15. 10. Kumada A, Matsuka Y, Spigelman I, Maruhama K, et al. Intradermal injection of Botulinum toxin type A alleviates
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infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay. J Oral Rehabil 2012;39(1):63–72. 11. Cho HR, Lew BL, Lew H, Sim WY. Treatment effects of intradermal botulinum toxin type A injection on alopecia areata. Dermatol Surg 2010;36(Suppl 4):2175–81. 12. Kapoor R, Shome D, Jain V, Dikshit R. Facial rejuvenation after intradermal botulinum toxin: is it really the botulinum toxin or is it the pricks? Dermatol Surg 2010;36(Suppl 4):2098–105. 13. Kim B, Choi J, Park K, Youn S. Sebum, acne, skin elasticity, and gender difference—which is the major influencing factor for facial pores? Skin Res Technol. 2011 Dec 28. doi: 10.1111/j.1600-0846. 2011.00605.x. [Epub ahead of print].
Address correspondence and reprint requests to: David J. Goldberg, MD, 115 East 57th Street, Suite 710, New York, NY 10022, or e-mail:
[email protected]
Supplementing Fat Grafts with Adipose Stromal Cells for Cosmetic Facial Contouring JIE LI, MD, PHD, JIANHUA GAO, MD, PHD, PENGFEI CHA, MD, PHD, QIANG CHANG, MD, YUNJUN LIAO, MD, PHD, CHAO LIU, MD, KECHENG LI, MD, AND FENG LU, MD, PHD*
BACKGROUND Numerous methods have been proposed to enhance the survival of fat grafts, but no definitive treatment is available. Stromal vascular fraction (SVF)-assisted cell therapy offers new perspectives for improving fat graft survival. OBJECTIVES To determine whether SVF supplementation could improve graft retention in patients undergoing autologous fat grafting for cosmetic improvement of facial contour. METHODS We retrospectively analyzed data from 38 women who underwent fat transplantation with SVF (n = 26) or fat grafting alone (n = 12) between October 2010 and January 2012. Each patient underwent computed tomography, and photographs were taken before and 6 months after surgery. The Philips Extended Brilliance Workspace was used for analysis of volume augmentation. RESULTS All patients showed cosmetic improvements, but the degree varied. No complications were evidenced during follow-up. Fat survival was higher with SVF (64.8 10.2%) than fat grafting alone (46.4 9.3%) (p < .01). SVF supplementation resulted in better clinical improvement than fat grafting alone. CONCLUSION Supplementing fat grafts with SVF for cosmetic facial contouring can improve the survival of fat grafts over fat grafting alone and provides satisfactory outcomes without major complications. Autologous fat grafting has been used for various cosmetic treatments and difficult reconstructive indications such as temporal depression, wrinkles of nasolabial folds, and hemifacial atrophy, with no incisional scar or complications associated with foreign materials, although problems such as a low rate of graft survival because of early resorption remain. (Aesthet Plast Surg, 14, 1990 and 127) Despite many innovations to overcome these problems, (Dermatol Surg, 26, 2000 and 1159); (Ann Plast Surg, 60, 2008 and 594); (Dermatol Surg, 27, 2001 and 819); (Dermatol Surg, 28, 2002 and 987) we lack a definitive method of fat processing that ensures maximal graft take and viability. (Plast Reconstr Surg, 115, 2005 and 197); (Dermatol Surg, 37, 2011 and 619) The authors have indicated no significant interest with commercial supporters.
T
he exact mechanisms that mediate fat graft survival and resorption remain unclear. One potential mechanism for graft loss is lack of adequate neovascularization within the transplanted fat. If timely neovascularization does not occur after transplantation, cells within the graft can die of ischemia, leading to tissue necrosis and graft loss.8,9 For autologous transplantation, Yoshimura and colleagues10 proposed cell-assisted lipotransfer to decrease resorption rates by adding stromal vascular
fraction (SVF) to the fat graft. The SVF of adipose tissue contains a group of heterogeneous cells consisting of adipose tissue–derived stem cells (ASCs), endothelial progenitor cells, hematopoietic progenitors, Tcells, and antiinflammatory cells.11 The SVF would differentiate into mature adipocytes, stimulate in vivo regeneration by triggering migration of host stem cells to the recipient site, and promote vascularization, which is essential for fat graft take.12,13 SVF acts as the main player in
*All the authors are affiliated with the Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:449–456 DOI: 10.1111/dsu.12058 449
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adipogenesis and angiogenesis in the adipose repair process by not only differentiating into adipocytes or vascular endothelial cells, but also releasing angiogenic growth factors.12,14 In this study, we aimed to determine whether SVF supplementation could improve the survival rate of grafts in patients undergoing autologous fat grafting for cosmetic improvement of facial contour.
Materials and Methods Patients The experimental design was a controlled clinical trial. Patients were divided into experimental and control groups according to the voluntary principle. Data were analyzed for 38 women who underwent transplantation with fat mixed with SVF (n = 26) or fat grafting alone (n = 12) between October 2010 and January 2012. The indications were temporal, cheek, and facial asymmetry. The mean age was 29.5 6.8 for the SVF group and 29.1 6.0 for the group that underwent fat grafting alone (range 18–45). Each patient underwent computed tomography (CT) and had photographs taken before and 6 months after surgery. The follow-up time for each patient was 6 months. Informed consent was obtained from all patients. The study protocol conformed to the guidelines of the 1975 Declaration of Helsinki and was approved by individual institutional review boards.
appropriate amount of fat was gently aspirated with finger pressure on the plunger of the syringe without using a suction machine so as to minimize trauma to the fat grafts. The fat grafts were then centrifuged at low speed (1,000 rpm, g force 178) for 3 minutes. The control group fat was centrifuged as well. After centrifugation, the middle layer, primarily consisting of usable fat parcels, was used for fat injection. In the SVF group, approximately half of the collected liposuction aspirate was used for isolation of the SVF. This cell-processing procedure required approximately 60 minutes. During the processing period, the other half of the lipoaspirate was harvested as graft material. The suctioned fat was digested with 0.25% collagenase (Sigma, St. Louis, MO) in phosphate buffered saline (PBS) for 30 minutes on a shaker at 37°C. Enzyme activity was neutralized with PBS containing 10% autologous patient serum. The cell suspension was filtrated through a 100-lm filter, then mature adipocytes were separated from the cell pellet. The pellets were resuspended in erythrocyte lysis buffer (155 mM ammonium chloride, 10 mM potassium bicarbonate, 0.1 mM ethylenediaminetetraacetic acid) and incubated for 5 minutes at room temperature and then collected by centrifugation (1,200 g, 5 minutes) and filtered through 100lm nylon mesh to remove cellular debris. To eliminate any remaining collagenase, the pellets were washed three times in PBS using repeated suspension and centrifugation. The harvested pellet was SVF. Each SVF sample underwent bacterial culture and susceptibility testing.
Fat Harvesting and Treatment The lower abdomen or thigh in each patient was the donor site for harvesting fat. A tumescent solution of 0.08% lidocaine and 1:500,000 epinephrine was infiltrated into the donor site. Harvesting involved use of a 2.5-mm suction cannula with two holes in the tip attached to a 20-mL syringe with the plunger held back with 7.5 mL of air or saline before aspiration. An
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Surgery The surgery was performed in a sterile operating room, and cell isolation was performed in a super clean bench. For SVF treatment, fresh SVF isolated from adipose was added to the graft material, and after gentle mixing and waiting for 10– 15 minutes for cell adherence to the aspirated fat, the SVF-supplemented fat was put into injection syringes.
LI ET AL
Fat supplemented with SVF(experimental group) or fat alone (control group) was injected into multiple tissue areas (within subcutaneous tissue and under superficial musculoaponeurotic system) in multiple tissue planes, tunnels, and areas with use of a syringe connected to a blunt needle with an external diameter of 1.5 or 3 mm. Grafts were injected in small quantities in one place each time, radially, from distal to proximal. In the buccal area, the needle was parallel to the facial nerve to avoid direct injury to the nerve. The syringe was drawn back before each injection to check blood return to avoid hematoma or injecting fat grafts into blood vessels and thus possibly causing fat emboli. The quantity of transplanted adipose tissue was overcorrected by approximately 20–30% because of possible later absorption after facial recontouring.
Figure 1. Computed tomography (CT) was performed on all patients before and 6 months after surgery. The Philips Extended Brilliance Workspace was used for analysis of volume augmentation. CT slice thickness 1 mm, the sum of the green area of each CT slice is equal to the fat volume.
TABLE 1. Number of Cases According to Injection Location and Group
Clinical and Radiological Evaluation and Postoperative Follow-Up The grafted site was immobilized using a compression dressing for a week. Patients were instructed to reduce or avoid movements of facial muscles if possible because these movements might traumatize the newly formed blood vessels around the injected fat grafts. All patients were seen at postoperative day 7 and at 6-month intervals. Patients underwent CT, and photographs were taken preoperatively and 6 months postoperatively. For analysis of volume augmentation, we used the Philips Extended Brilliance Workspace, which can provide objective data for various facial plastic and reconstructive surgeries (Figure 1), but this measurement has potential for error in positioning of the skull and delineation of subcutaneous tissue. Statistical Analysis All data are reported as means standard deviations. Differences in fat graft volume between the two groups were analyzed using independentsamples t-tests. p < .05 was considered statistically significant. Statistical analyses were performed using SPSS 16.0 (SPSS, Inc., Chicago, IL).
Stromal Vascular Fraction Group Location
n
Temporal area Cheek area Frontal area Zygomatic area Mandibular area
13 11 2 2 3
Control Group
6 5 1 1 1
Results The transplantation of fat supplemented with SVF or fat alone was successful in all cases (Table 1). Bacterial culture of each SVF sample was negative. Patients showed slight bruising and swelling during the first week after surgery but no scars during followup and no obvious contour irregularity. No further complications were evidenced during follow-up. Mean fat transplanted was 17.5 7.3 mL in the SVF group and 16.2 6.3 mL in the fat alone group. Six months later, mean final fat volume was 11.5 5.3 mL in the SVF group and 7.6 3.3 mL in the fat alone group. The final fat volume was calculated using CT imaging. The difference in fat take between the two groups was statistically significant (p < .01; Table 2, Figures 1–3).
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TABLE 2. Fat Volume and Survival Rate Change in the Two Groups (Mean SD) Mean Standard Deviation Group
Injected Volume, mL
Final Volume, mL
Survival Rate, %
Experimental group (stromal vascular fraction + fat) n = 26 Control group (fat alone) n = 12
17.5 7.3
11.5 5.3
64.8 10.2
16.2 6.3
7.6 3.3
46.4 9.3
All patients showed cosmetic improvements but to varying degrees. The SVF group had better clinical improvement than the fat grafting alone group (Figures 4 and 5).
Discussion
Figure 2. Fat volume changes before and after surgery in two groups.
Figure 3. The difference in fat take between the two groups was statistically significant (p < .01).
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Numerous methods have been proposed to enhance the survival of fat grafts, but no definitive treatment protocol is available. Because SVF-assisted cell therapy offers new perspectives for improving fat graft survival, we aimed to determine whether SVF supplementation could improve the survival rate of grafts in patients who underwent autologous fat grafting for cosmetic improvement of facial contour. We retrospectively analyzed data for 38 women who underwent fat transplantation with SVF or fat grafting alone. All patients showed cosmetic improvements but to varying degrees. No complications were evidenced during follow-up. Fat survival was greater with SVF than fat grafting alone. The SVF group showed better clinical improvement than the fat grafting alone group. Supplementing fat grafts with SVF for cosmetic facial contouring can improve the survival rate of fat transplantation over fat grafting alone and provides satisfactory outcomes without any major complications. Autologous fat transplantation is useful for filling soft tissue and contour defects, and the transplant material is relatively cheap, easy to harvest, available in large quantities, and autogenic, which eliminates the potential risks associated with allogenic fillers and implants, but problems such as a low rate of graft survival because of early resorption remain. The mechanism of fat tissue survival and absorption is not fully understood. Histologic studies have
LI ET AL
(A)
(B)
Figure 4. A 26-year-old woman with bilateral temporal depression had stromal vascular fraction–supplemented autologous fat transplantations. (A) Preoperative and (B) 6-month postoperative views.
suggested that revascularization of autologous fat transplants occurs after 48 hours.15 This delay appears to critically impair the survival of the fat cells, which undergo degenerative changes, including destruction of their nuclei and cell membranes. After this cell destruction, fatty cysts develop, and the fat gradually becomes absorbed.16 Many theories have been put forth to explain this phenomenon, and early and abundant neovascularization seems to be important to survival of free fat transplants, which in turn leads to good transplant outcomes.17–19 Concerning autologous transplantation, Yoshimura and colleagues10 proposed cell-assisted lipotransfer to decrease resorption rates by adding SVF to the fat graft. SVF contains several types of stem and regen-
erative cells, including ASCs; vessel-forming cells, such as endothelial and smooth muscle cells and their progenitors; and preadipocytes. ASCs can differentiate into multiple cell lineages, including adipocytes, osteocytes, chondrocytes, endothelial cells, and other types of cells.20–23 In addition, ASCs can secrete vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1,14,24 which have proangiogenic, antiapoptotic, and proadipogenic effects. After transplantation, ASCs may interact with other cells such as vascular endothelial cells, and supplementation with SVF may be superior to supplementation with ASCs alone. Most studies evaluating the survival of transplanted fat are based on subjective analysis of photographs
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(A)
(B)
Figure 5. A 21-year-old woman with bilateral temporal and cheek area depression had stromal vascular fraction– supplemented autologous fat transplantations. (A) Preoperative and (B) 6-month postoperative views.
or anecdotal assessment by physicians.25–28 Photography is limited in its ability to document volume changes because these changes in facial shape and contour are often reflected as changes in shadowing. Even with standardized lighting techniques, determination of volume changes with photography is inherently variable. In this research, we used the novel method of Philips Extended Brilliance Workspace to analyze volume augmentation, which can provide objective data for various facial plastic and reconstructive surgery applications. The clinical results appeared to be better with SVF than fat grafting alone. The surviving fat volume was greater with SVF than with fat grafting alone. Slight bruising and swelling was seen during the first week after surgery but no scars or obvious contour irregularity. No further complications were evidenced during follow-up. A major challenge that SVF therapy poses is the need to ensure efficacy and safety. Bacterial culture of each of our SVF samples was negative. All cell products for human clinical applications are free of bacterial contamination. Fetal bovine serum added to the recipient immune system may produce antibodybased responses with the risk of serum sickness.29,30 A number of laboratories have found that human
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serum can serve as an alternative.31 In this research, collagenase activity was neutralized with PBS containing 10% autologous patient serum, although tissue processing with multiple steps and the use of serum products increases the potential for bacterial infections and blood-borne diseases. Adipose-derived cell immunomodulatory and immunosuppressive properties present additional concerns. Recent reports document the ability of ASCs to promote the proliferation of active breast cancer cells in vitro and in vivo through paracrine mechanisms.32–36 Consequently, plastic surgeons and related clinical practitioners remain cautious concerning the use of SVF cells in individuals with cancer.37 The SVF field is at a critical juncture as it transitions from basic science to clinical therapy. We anticipate that comprehensive reports documenting that SVF cell safety testing will appear in the literature and that such evidence will accelerate the clinical translation process.
Conclusions We demonstrated that supplementation of fat grafts with SVF for cosmetic facial contouring can improve the survival of fat grafts over fat grafting alone.
LI ET AL
Transplanting SVF-supplemented fat tissue has provided satisfactory outcomes without any major complications. Larger studies and longer follow-up times are needed to establish the overall safety and efficacy of the treatment.
References 1. Chajchir A, Benzaquen I, Wexler E. Fat injection. Aesthet Plast Surg 1990;14:127–36. 2. Sommer B, Sattler G. Current concepts of fat graft survival: histology of aspirated adipose tissue and review of the literature. Dermatol Surg 2000;26:1159–66. 3. Ferguson RE, Cui X, Fink BF, Vasconez HC, et al. The viability of autologous fat grafts harvested with the LipiVage system: a comparative study. Ann Plast Surg 2008;60:594–7. 4. Shiffman MA, Mirrafati S. Fat transfer techniques: the effect of harvest and transfer methods on adipocyte viability and review of the literature. Dermatol Surg 2001;27:819–26. 5. Butterwick KJ. Lipoaugmentation for aging hands: a comparison of the longevity and aesthetic results of centrifuged versus noncentrifuged fat. Dermatol Surg 2002;28:987–91. 6. Ramon Y, Shoshani O, Peled IJ, Gilhar A, et al. Enhancing the take of injected adipose tissue by a simple method for concentrating fat cells. Plast Reconstr Surg 2005;115:197–201. 7. Oh DS, Cheon YW, Jeon YR, Lew DH. Activated platelet-rich plasma improves fat graft survival in nude mice: a pilot study. Dermatol Surg 2011;37:619–25. 8. Nguyen A, Pasyk KA, Bouvier TN, Hassett CA, et al. Comparative study of survival of autologous adipose tissue taken and transplanted by different techniques. Plast Reconstr Surg 1990;85:378–86. 9. Billings E Jr, May JW Jr. Historical review and present status of free fat graft autotransplantation in plastic and reconstructive surgery. Plast Reconstr Surg 1989;83:368–81. 10. Yoshimura K, Sato K, Aoi N, Kurita M, et al. Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. Dermatol Surg 2008;34:1178–85. 11. Zimmerlin L, Donnenberg VS, Pfeifer ME, Meyer EM, et al. Stromal vascular progenitors in adult human adipose tissue. Cytometry A 2010;77:22–30. 12. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res 2007;100:1249–60. 13. Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, et al. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 2007;25:220–7.
16. Ogawa R. The importance of adipose-derived stem cells and vascularized tissue regeneration in the field of tissue transplantation. Curr Stem Cell Res Ther 2006;1:13–20. 17. Yamaguchi M, Matsumoto F, Bujo H, Shibasaki M, et al. Revascularization determines volume retention and gene expression by fat grafts in mice. Exp Biol Med (Maywood) 2005;230:742–8. 18. Ogawa R, Oki K, Hyakusoku H. Vascular tissue engineering and vascularized 3D tissue regeneration. Regen Med 2007;2:831– 7. 19. Lu F, Li J, Gao JH, Ogawa R, et al. Improvement of the survival of human autologous fat transplantation by using VEGFtransfected adipose-derived stem cells. Plast Reconstr Surg 2009;124:1437–46. 20. Zuk PA, Zhu M, Mizuno H, Huang J, et al. Multilineage cells from human adipose tissue: implications for cell- based therapies. Tissue Eng 2001;7:211–28. 21. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279–95. 22. Planat-Benard V, Silvestre JS, Cousin B, Andre M, et al. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 2004;109:656–63. 23. Schenke-Layland K, Strem BM, Jordan MC, Deemedio MT, et al. Adipose tissue-derived cells improve cardiac function following myocardial infarction. J Surg Res 2009;153:217–23. 24. Sadat S, Gehmert S, Song YH, Yen Y, et al. The cardioprotective effect of mesenchymal stem cells is mediated by IGF-I and VEGF. Biochem Biophys Res Commun 2007;363:674–9. 25. Ersek RA. Transplantation of purified autologous fat: a three year follow-up is disappointing. Plast Reconstr Surg 1991;87:219– 27. 26. Fulton JE, Suarez M, Silverton K, Barnes T, et al. Small volume fat transfer. Dermatol Surg 1998;24:857–65. 27. Fournier PF. Fat grafting: my technique. Dermatol Surg 2000;26:1117–28. 28. Coleman SR. Long-term survival of fat transplants: controlled demonstrations. Aesthetic Plast Surg 1995;19:421–5. 29. McIntosh KR, Lopez MJ, Borneman JN, Spencer ND, et al. Immunogenicity of allogeneic adipose-derived stem cells in a rat spinal fusion model. Tissue Eng Part A 2009;15:2677–86. 30. Lindroos B, Aho KL, Kuokkanen H, R€ aty S, et al. Differential gene expression in adipose stem cells cultured in allogeneic human serum versus fetal bovine serum. Tissue Eng Part A 2010;16:2281–94. 31. Mesimaki K, Lindroos B, Tornwall J, Mauno J, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg 2009;38:201–9.
14. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004;109:1292–8.
32. Donnenberg VS, Zimmerlin L, Rubin JP, Donnenberg AD, et al. Regenerative therapy after cancer: what are the risks? Tissue Eng Part B Rev 2010;16:567–75.
15. Atik B, Ozt€ urk G, Erdogan E, Tan O, et al. Comparison of techniques for long-term storage of fat grafts: an experimental study. Plast Reconstr Surg 2006;118:1533–7.
33. Zimmerlin L, Donnenberg AD, Rubin JP, Basse P, et al. Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast
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cancer cells from clinical isolates. Tissue Eng Part A 2011;17:93– 106. 34. Muehlberg FL, Song YH, Krohn A, Pinilla SP, et al. Tissueresident stem cells promote breast cancer growth and metastasis. Carcinogenesis 2009;30:589–97. 35. Jotzu C, Alt E, Welte G, Li J, et al. Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors. Anal Cell Pathol (Amst) 2010;33:61–79. 36. Zhao M, Dumur CI, Holt SE, Beckman MJ, et al. Multipotent adipose stromal cells and breast cancer development: think globally, act locally. Mol Carcinog 2010;49:923–7.
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37. Brown SA, Levi B, Lequex C, Wong VW, et al. Basic science review on adipose tissue for clinicians. Plast Reconstr Surg 2010;126:1936–46.
Address correspondence and reprint requests to: Feng Lu, MD, PhD, or Jianhua Gao, MD, PhD, Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China, or e-mail:
[email protected] or
[email protected]
Polycaprolactone for the Correction of Nasolabial Folds: A 24-Month, Prospective, Randomized, Controlled Clinical Trial MARION MICHAELA MOERS-CARPI, MD,*
AND
SALLY SHERWOOD, MA†
BACKGROUND In this study, we examined two polycaprolactone (PCL)-based dermal filler formulas (PCL-1; PCL-2) for safety, patient satisfaction, likelihood to return, efficacy, and duration of correction. OBJECTIVE This 40-patient, 24-month, prospective, randomized, controlled study evaluated the efficacy, safety, longevity, and volume of two PCL formulas for correction of nasolabial folds. METHODS Patients enrolled in a medical clinic in Europe received two injections 1 month apart and returned at 3, 6, 9, 12, 15, 18, and 24 months for blinded patient evaluation using accepted aesthetic rating scales. RESULTS At 12 months, the efficacy outcomes on Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale (GAIS) of PCL-1 and PCL-2 were consistently maintained, with sustained improvement in 90% and 91.4% of patients, respectively. At 24 months, PCL-2 was found to be more effective than PCL-1 with respect to GAIS and WSRS, showing sustained improvement for the entire 2-year study period (linear p = .52; quadratic p > .99). Patient satisfaction at 24 months was 72.4% for PCL-1 and 81.7% for PCL-2. Both products were found to be safe and well tolerated. CONCLUSIONS PCL-1 and PCL-2 are safe and have sustained efficacy and high patient satisfaction, with PCL-2 demonstrating longer-lasting results than PCL-1. AQTIS Medical BV (Utrecht, The Netherlands) provided support and funding for this study. Dr. Moers-Carpi received compensation for presentations to the medical community. Sally Sherwood is an independent professional medical writer.
I
njectable fillers have become an increasingly popular option in the treatment for aesthetic facial enhancements and appeal to the growing population wanting to reverse the signs of aging. With recent technologic advances, newer types of dermal fillers have been approved, providing practitioners the option of administering soft tissue fillers–such as hyaluronic acid and calcium hydroxylapatite (CaHA)–with minimal inconvenience to the patient, although some shortcomings remain unaddressed. Over the last decades, the safety and efficacy of dermal fillers have improved continuously, with
an ongoing quest for safe but longer-lasting although not permanent results.1 Moreover, in the growing market of noninvasive treatments for soft tissue augmentation, which are replacing surgical interventions, the search for improved therapies for correction of wrinkles and folds, contouring, sculpting, and volumizing is steadily improving.
Polycaprolactone This article details a clinical study in which two polycaprolactone (PCL)-based, biocompatible, longlasting, bioresorbable soft tissue filler formulas
*Private Clinic, Hautok, Munich, Germany; †Sally Sherwood Communications, New York, New York © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:457–463 DOI: 10.1111/dsu.12054 457
PCL FOR THE CORRECTION OF NASOLABIAL FOLDS
(Ellanse-S [PCL-1] and Ellanse-M [PCL-2], AQTIS Medical BV, Utrecht, The Netherlands) were administered in a 24-month, prospective, randomized, controlled clinical trial. These two formulas are part of a novel dermal filler family that incorporates sustained performance (continuous and stable improvement over time), tunable longevity (duration of clinical performance can be modified by adjusting the initial PCL formula), and total bioresorbability (complete and controlled bioresorption process) (STAT). This dermal filler family is composed of smooth, soft, non-cross-linked bioresorbable PCL microspheres (25–50 lm) homogeneously suspended in an aqueous carboxymethylcellulose (CMC) gel carrier. All formulas are available in sterile ready-to-use, prefilled 1.0-mL syringes. PCL and CMC have been used successfully for decades in numerous Conformite Europeene (CE)-marked and Food and Drug Adminstration–approved bioresorbable device applications in the medical, cosmetic, and pharmaceutical industries (e.g., oral and maxillofacial surgery, wound dressing, bioresorbable sutures, and controlled drug delivery).2–7 CMC is a well-known carrier for dermal fillers.7,8 The biocompatibility and in vivo behavior of PCL as a bioresorbable medical polymer have been well documented since the 1980s.3–5,9–12 Its bioresorption characteristics are attractive because of its controlled and safe bioresorption by the hydrolysis of the polymer ester-linkages, resulting in nontoxic bioresorption products that are resorbed through the normal metabolic pathways and readily excreted.9–12 The controlled bioresorption of PCL has been proven in3H- and C14-labeled PCL implantation studies.9,10 Dermal filler characteristics such as a particle size, particle size distribution, particle concentration, particle surface, shape, gel viscosity and elasticity, gel homogeneity, and injectability are the same throughout the family. Furthermore, the smooth, sphere shape of the microparticles and their size and
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concentration stimulate the formation of new highquality collagen (neocollagenesis).13–17 The only distinguishing characteristic within the dermal filler family is the initial average length of the individual polymer chains within the microspheres, which is the basis for the different duration options within the dermal filler family as a result of their difference in bioresorption time. Of the two formulas used in this study, PCL-2 has a higher average initial polymer chain length than PCL-1 and as such a longer bioresorption time. Upon injection, wrinkles and folds are immediately corrected because of the viscosity of the gel carrier and the presence of the microspheres. Macrophages gradually resorb the gel carrier over a period of several weeks, which patients’ own new collagen replaces, creating a three-dimensional scaffold anchoring the microspheres. In early 2009, the PCL-based dermal family received CE marking for deep dermal and subdermal implantation for the correction of wrinkles and folds. This is the first and currently only dermal filler that uses bioresorbable PCL microspheres for soft tissue augmentation. Methods Study Objective The objective of this study was to evaluate the safety and effectiveness of two PCL formulas, PCL-1 and PCL-2, for the correction of nasolabial folds (NLFs). Patient Population The study enrolled 40 subjects (38 women (95%) and two men (5%)) aged 36–69; 30 were treated with PCL-2 and 10 with PCL-1. Subjects were enrolled if they had a rating of 3 or 4 on the Wrinkle Severity Rating Scale (WSRS; moderate to severe NLFs).
MOERS AND SHERWOOD
Design In this two-arm study, subjects were randomized to receive the PCL-1 or PCL-2 formula for the correction of both NLFs. Both formulas were supplied in sterile ready-to-use, prefilled 1.0-mL syringes. All subjects were intended to receive an initial treatment and were eligible for a touch-up treatment at 1 month to provide optimal correction. Because this was a first-in-human study, subjects were initially given a suboptimal dose, and the investigators were allowed to provide a touch-up at the 1-month follow-up visit. Injected volumes for initial and touch-up treatments were recorded for all subjects. Subjects then returned for physician and subject evaluation at 3, 6, 9, 12, 15, 18, and 24 months. The study was conducted in accordance with International Standards Organization 14155 and the International Conference on Harmonisation Good Clinical Practice E6, and the study protocol conformed to the guidelines of the 1975 Declaration of Helsinki. Ethics committee approval was obtained before study initiation. Subjects had to be aged 18 and older with moderate to severe NLFs as determined according to a WSRS score of 3 or 4 in both folds at the pretreatment evaluation and be willing to abstain from other facial cosmetic procedures that could interfere with treatment outcomes through the 24-month followup visit (e.g., laser or chemical resurfacing, dermabrasion, botulinum toxin injections in or near the nasolabial area, aesthetic facial surgery, facial wrinkle treatments of the nasolabial area, lip enhancements), be willing and able to adhere to study follow-up procedures and schedule, and provide written informed consent for participation in the study Subjects who had received previous permanent implants in the nasolabial area at any time or undergone any aesthetic facial procedure in the nasolabial area within 6 months before enrollment that could interfere with study results; who had been
treated with chemotherapy agents or systemic corticosteroids within 3 months before enrollment; who had received antiplatelets, anticoagulants, thrombolytics, vitamin E, or anti-inflammatories 1 week before to 1 month after treatment; with a history of autoimmune disorder; with known allergies to topical or injectable anesthetics; with severe allergies manifested by a history of anaphylaxis or with severe, chronic allergies; with acute, chronic, or recurrent skin disease near the nasolabial area; with a known bleeding disorder; with an active infection of any kind at the time of enrollment; with known connective tissue disease; who were pregnant or lactating; and who were enrolled in another investigational clinical trial were excluded. Pretreatment Before participation in the study, subjects received patient information and signed and dated the study consent form, which the Ethics Committee had approved. Before treatment, subjects received a brief general examination including medical history and survey of current medications. Pretreatment photographs of the NLFs were taken for each subject and used throughout the course of the study to assist the subject and investigator in completion of the Global Aesthetic Improvement Scale (GAIS) at the followup visits. The investigator assessed and recorded initial wrinkle severity of both NLFs using the WSRS. Treatment Before the treatment, randomization of the PCL-1 or PCL-2 formula was determined and the applicable PCL formula administered to eligible subjects in both NLFs in accordance with the instructions for use. The PCL product formulas do not contain an anesthetic. The use of topical or local anesthesia was permitted at the discretion of the investigator. Approximately half of all subjects (55%) requested anesthesia. The PCL-1 or PCL-2 injection was administered into the deep dermis using a 27-G needle parallel to the length of the wrinkle or fold using a retrograde injection technique. Subjects were
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initially given a suboptimal dose, and the investigators were allowed to provide a touch-up at the 1-month follow-up visit. After administration, the injection site was gently massaged. Subjects were asked to return to the study site 1, 3, 6, 9, 12, 15, 18, and 24 months after the initial treatment. Safety and efficacy were assessed during these visits using GAIS and WSRS ratings. At each visit, subjects completed a visual analog scale (VAS) questionnaire to record their level of satisfaction and likelihood to return (probability of returning for repeat treatment with the same product after completion of the study).
Results Effectiveness The WSRS and GAIS assessments were used to determine effectiveness. Subject-evaluated GAIS and VAS assessments were used to support these findings. WSRS Ratings A repeated analysis of variance (R-ANOVA) model on the WSRS using SAS Proc Mixed (SAS Institute, Inc., Cary, NC) was applied to the data to account for within-subject correlation. The data were summarized for the total NLFs rather than according to face side because there were no statistical differences found when testing WSRS between the left and right side of the face. Month 6, 9, 12, 15, 18, and 24 data were pooled to a similar R-ANOVA model to investigate the WSRS effect trending with time after 3 months. After month 3, linear and quadratic time effects in the PCL-2 R-ANOVA model were tested and found not to be statistically significant. In the PCL-2 data, there were no detectable statistically significant differences in subjects over time, showing sustained performance for PCL-2 for 24 months (linear p = .52; quadratic p > .99). Running the same model for PCL-1 using data after month 3 up to 12 months showed no statistically significant differences for PCL-1, showing sustained performance for PCL-1 for 12 months (linear p = .24; quadratic p = .16).
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WSRS improvement >1 through 12 and 24 months indicated sustained performance over time in PLC-1 and PCL-2, respectively, in at least 50% of the population, with no statistically significant difference over time for PCL-2 (linear p = .21; quadratic p = .19) and PCL-1 (linear p = .12; quadratic p = .12). GAIS Ratings On the investigator-evaluated GAIS assessments, for PCL-2, 100% of subjects reported improvement at 24 months. For PCL-1, 90% of subjects reported improvement at 12 months, after which the GAIS evaluation for the PCL-1 arm decreased to 78% at 24 months. On GAIS, a R-ANOVA model using SAS Proc Mixed was applied to the data to account for within-subject correlation. Month 6, 9, 12, 15, 18, and 24 data were pooled to a similar R-ANOVA model to investigate the GAIS effect trending with time after 3 months. After month 3, linear and quadratic time effects in this R-ANOVA model were tested and found to be statistically significant in the PCL-2 group (linear p = .04; quadratic p = .02), but results in Table 1 suggest that, on average, total improvement for PCL-2 was maintained up to 24 months after injection. After 3 months, linear and quadratic time effects in the PCL-1 R-ANOVA model were tested using data from 6 to 12 months and were found not to be statistically significantly different for PCL-1 (linear p = .24; quadratic p = .20). Subject evaluations of GAIS ratings for PCL-1 (linear p = .41; quadratic p = .29) and PCL-2 (linear p = .68; quadratic p = .94) were also found to support sustained performance findings. Representative photographs of the treated NLFs are shown in Figures 1 and 2. Patient Satisfaction Patient satisfaction was recorded using a VAS questionnaire. Patients were asked about their overall satisfaction with treatment results and the
MOERS AND SHERWOOD
TABLE 1. Investigator-Evaluated Global Aesthetic Improvement Scale (GAIS) Product PCL-1
PCL-2
GAIS Score Change n Very much improved, % Much improved, % Improved, % No change, % worse, % Total improved, % n Very much improved, % Much improved, % Improved, % No change, % Worse, % Total improved, %
3 Months 6 Months 9 Months 12 Months 15 Months 18 Months 24 Months 18 0.0
20 20.0
20 10.0
20 20.0
20 0.0
18 11.1
18 0.0
55.0 35.0 10.0 0.0 90.0 58 3.5
45.0 15.0 20.0 0.0 80.0 58 13.8
45.0 35.0 10.0 0.0 90.0 58 5.2
60.0 10.0 10.0 0.0 90.0 58 6.9
10.0 40.0 50.0 0.0 50.0 54 3.7
11.1 44.4 33.3 0.0 50.0 54 5.6
0.0 77.8 22.2 0.0 77.8 56 0.0
51.7 41.4 3.5 0.0 96.6
50.0 25.9 10.3 0.0 89.7
63.8 27.6 3.5 0.0 96.6
70.7 13.8 8.6 0.0 91.4
51.9 37.0 7.4 0.0 92.6
50.0 44.4 0.0 0.0 100.0
23.2 76.8 0.0 0.0 100.0
(A)
(A)
(B)
(B)
Figure 2. A 57-year-old woman who received 1.3 mL of PCL-2 in the left and 1.4 mL of PCL-2 in the right nasolabial fold: (A) Baseline and (B) 24 months after initial injection. Global Aesthetic Improvement Scale ratings at 24 months were much improved. Figure 1. A 49-year-old man who received 1.5 mL of PCL-1 in the left and 1.0 mL of PCL-1 in the right nasolabial fold: (A) Baseline and (B) 12 months after initial injection. Global Aesthetic Improvement Scale ratings at 12 months were much improved.
likelihood of returning for regular treatment with the product injected into their NLFs.
Subjects rated their satisfaction at 24 months as 81.7% for PCL-2 and 72.4% for PCL-1. At 24 months, subjects treated with PCL-2 were 78.0% likely to return for additional treatments on average, and subjects treated with PCL-1 were
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TABLE 2. Total Average Volumes per Patient (Including Touch-Up) Total Initial Touch-Up Average Treatment Treatment Volume Product
mL
Polycaprolactone-1 1.36 Polycaprolactone-2 1.20
0.70 0.76
2.06 1.96
75.3% likely to return at 24 months (Figures 1 and 2). Injected Volumes Volumes at the initial suboptimal injection and at the 1-month touch-up are shown in Table 2. All nine patients in the PCL-1 group and 27 of 30 patients in the PCL-2 group (90.0%) received a touch-up, as expected because of the initial conservative treatment. No injections were offered after the 1-month touchup. Total mean injected volumes used for the initial and touch-up injections were 1.96 mL for PCL-2 and 2.06 mL for PCL-1 (Table 2). Safety No serious adverse events were reported at any of time points. Reported injection-related adverse events, such as edema (12 mild [30%] and 1 moderate [4%]) and ecchymosis (2 mild [5%]), all resolved without intervention. No nodules, granulomas, or other complications were reported. PCL-1 and PCL-2 are both considered to be safe and well tolerated.
Discussion Satisfaction Subject ratings demonstrated high and consistent satisfaction for both product formulations throughout the duration of the 24-month study. Investigation of likelihood to return for an additional treatment at 24 months also showed consistently high ratings for both formulations, suggesting high
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satisfaction and readiness for repeat treatments for both product formulations. Duration Sustained performance (consistent and continued improvement over time) was demonstrated using the WSRS results. Longer-lasting sustained performance was found for PCL-2 than PCL-1. Investigator GAIS results confirmed these results, with patient GAIS results supporting the investigator findings. At each point during the study, consistent and continued within-subject performance was statistically demonstrated for PCL-1 to 12 months and for PCL-2 to 24 months. GAIS assessments found 100% of subjects showing improvement in wrinkle severity at 24 months for PCL-2 and 90% of subjects showing improvement at 12 months for PCL-1. Subject and investigator GAIS assessments indicate sustained within-subject improvement and performance for PCL-1 12 months and PCL-2 for 24 months. Volume Average total volume used for two NLFs for both formulations for initial treatment and maintenance of improvement was 2.06 mL for PCL-2 and 1.96 mL for PCL-1, confirming a consistent formulation of both products and an effective filling capacity for immediate and sustained improvement for their respective durations. Cost Cost-minded physicians and subjects may appreciate the demonstrated feature of sustained performance providing continued and cost-effective improvement over time, with regard to currently available dermal fillers. Conclusions PCL-1 and PCL-2 had comparable safety profiles and are safe and well tolerated. PCL-2 outperforms PCL-1 in duration of sustained performance as a result of the developed STAT technology.
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Different PCL formulations provide a choice to physicians and subjects for desired and optimal duration of effect and associated sustained performance for physician, subject, and application requirements. We hypothesize that, because of an induced neocollagenesis process, in combination with the specific bioresorption time of the selected PCL-formulation, this PCL-based filler leads to longer-lasting results than current, conventional dermal fillers provide.
7. Falcone SJ, Doerfler AM, Berg RA. Novel synthetic dermal fillers based on sodium carboxymethylcellulose: comparison with crosslinked hyaluronic acid–based dermal fillers. Dermatol Surg 2007;33:S136–43. 8. Jansen -DH, Graivier -MH. Evaluation of a calcium hydroxylapatite-based implant (Radiesse) for facial soft-tissue augmentation. Plast Reconstr Surg, 2006;118(3 Suppl):22S–30S. 9. Pitt CG , Chasalow FI, Hibonada YM, Klimas DM, et al. Aliphatic polyesters I. The degradation of polycaprolactone in vivo. J Appl Polym Sci 1981;26(11):3779–87. 10. Pitt CG. Poly-e-caprolactone and its copolymers. In: Chasin M, Langer R, editors. Biodegradable polymers as drug delivery systems. New York, NY: Marcel Dekker; 1990. pp. 71–120. 11. Ma G, Song C, Sun H, Yang J, et al. A biodegradable levorgestrel-releasing implant made of PCL/F68 compound as tested in rats an dogs. Contraception, 2006;74:141–7.
We believe that this new dermal filler family will provide a unique option for patients seeking longerlasting but nonpermanent results.
12. Sun H, Mei L, Song C, Cui X, et al. The in vivo degradation, absorption and excretion of PCL based implant. Biomaterials 2006;27:1735–40.
References
14. Nicolau PJ. Long-lasting and permanent fillers: biomaterials influence over host response. Plast Reconstr Surg 2007;119:2271–86.
1. Kurkjian TJ, Kenkel JM, Sykes JM, Duffy SC. Impact of the current economy on facial aesthetic surgery. Aesthet Surg J 2011;31: 770–4. 2. Middleton JC, Tipton AJ. Synthetic biodegradable polymers as orthopedic devices. Biomaterials 2000;21:2335–46. 3. Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cells Mater 2003;5:1–16. 4. Hutmacher D, H^ urzeler MB, Schliephake H. A review of material properties of biodegradable and bioresorbable polymers and devices for GTR and GBR applications. Int J Oral Maxillofac Implants 1996;11:667–78. 5. Shina VR, Bansal K, Kaushik R, Kumria R, et al. Polycaprolactone microspheres and nanospheres: an overview, Intern. Int J Pharm, 2004;278:1–23. 6. Turaev AS. Dependence of the biodegradability of carboxymethylcellulose on its supermolecular structure and molecular parameters. Chem Nat Compd 1995;31: 254–9.
13. Laeschke K. Biocompatibility of microparticles into soft tissue fillers. Sem Cut Med Surg 2004;23:214–17.
15. Anderson JM. Mechanism of inflammation and infection with implanted devices. Cardiovasc Pathol 1993;2:33S–41S. 16. Morhenn VB, Lemperle G, Gallo RL. Phagocytosis of different particulate dermal filler substances by human macrophages and skin cells. Dermatol Surg 2002;28:484–90. 17. Evaluation of the local tolerance and neocollagenesis of AQTIS Medical Dermal Filler Ellanse-S and AQTIS Medical dermal filler Ellanse-M. Nine and 21 months after subdermal and intradermal injection in the rabbit. Dept. Pathobiology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands, 2011.
Address correspondence and reprint requests to: Marion Michaela Moers-Carpi, MD, Private Clinic, Hautok, Residenzstrasse 7, 80333 Munich, Germany, or e-mail:
[email protected]
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HOW WE DO IT
Excessive Columellar Show: Causes, Presentations and a New Therapeutic Approach with Onabotulinum Toxin A MOHAMMED G. TURKMANI, MD,*
AND
KOENRAAD DE BOULLE, MD†
The authors have indicated no significant interest with commercial supporters.
T
he columella is the bridge of skin directly between the nostrils. Columellar show is an assessment of how much of the inner nostril lining is visible when viewing the nose in profile. From an aesthetic point of view, the ideal amount of columellar show is 2–4 mm. Excessive columellar show refers to an imbalance between the alar rim and the columellar border, resulting in a distressing aesthetic nasal deformity (Figure 1). An unattractive appearance can be due to a retracted alar rim (excessively arched) or a columella that is pulled downward too strongly (hanging columella). Nine alar–columella relationships exist because there are three possible configurations for the columella (normal, hanging, retracted) and another three possible configurations for the alar rim (normal, hanging, retracted). Excessive columellar show describes the situation when 4 mm or more of the inner lining of the nostrils is visible when the nose is observed laterally in active condition (pushing the nose up and down). It is mainly brought about by the overcontraction of one or two muscles (levator labii superioris ala nasi
and depressor septi nasi). There are a variety of causes for excessive columellar show, including trauma, former rhinoplasty techniques, or an inherited tendency. Depending on the relationship between the alar rim and the columella, three forms of excessive columellar show can be observed: upper, lower, and combined (Figure 2). Upper show occurs when the medial alar portion of the levator labii superioris ala nasi, also called the levator ala nasi, elevates the wing of the nose and dilates the nostrils, resulting in a retracted alar rim, which makes it more arched. Lower show is caused by the downward pull of the depressor septi nasi on the nasal septum, making it more pronounced. Combined show is the combination of upper and lower show and is due to the hyperfunction of both muscles. Overuse of the muscles under physical or emotional stress or their unconscious and repeated contraction leads to more-pronounced columellar show. The most common presentation is upper show, whereas lower and combined show are rarely seen. Because excessive columellar show is not a true anatomic deformity but is linked to the hyperfunc-
*Derma Clinic, Riyadh, Saudi Arabia; †Aalst Dermatology Clinic, Aalst, Belgium © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:464–467 DOI: 10.1111/dsu.12118 464
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tion of the levator labii superioris ala nasi or depressor septi nasi, we hypothesized that it may benefit from onabotulinum toxin A (BoNTA) treatment. Experience in our patients has shown that
BoNTA can accurately correct upper columellar show, although this procedure is only partially effective for treating combined show and is not recommended for treating lower show because the effect of BoNTA when injected into the depressor septi nasi is minimal. In the case reports that follow, three patients with upper columellar show were treated with BoNTA. Figure 3 shows the muscles of interest (levator labii superioris ala nasi, depressor septi nasi and nasalis). Case Reports Three women aged 40–52 presented for the treatment of facial wrinkles. During clinical assessment, upper columellar show was noted in these patients. The excessive columellar show was primarily due to unnecessary activity of the levator labii superioris ala nasi. After global treatment for facial wrinkles, 4 U of BoNTA was injected into each side of the levator ala nasi (medial portion of levator ala nasi). Patients were followed up 10 days after treatment. In all three cases, a remarkable reduction in upper columellar show was observed in active and resting states (Figure 4).
Figure 1. Excessive columellar show in at-rest and active positions.
The effect of BoNTA was noticeable after 3 months of observation in all patients, with variable
Figure 2. Classification of columellar show. (A) Combined show: the visible amount of the inside of nostrils is equal above and below an imaginary line drawn from the tip of the nose to the lower point of the alar rim. (B) Upper show: the visible portion is more pronounced above the imaginary line than beneath it. (C) Lower show: the observable area of the nostril is more pronounced below the imaginary line.
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Figure 3. Muscles of interest.
Figure 4. Reduction in excessive columellar show during activity and at rest, before and after treatment with onabotulinum toxin A.
responses, but at 4-month follow-up, the effect had almost vanished.
Discussion When BoNTA is injected into hyperfunctional muscles, it decreases their activity by blocking the release of acetylcholine at the neuromuscular junction.1 This action effectively weakens the muscles for a period of 3–4 months. Nasal flare2 and nasal
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tip ptosis3,4 have already been described as indications for BoNTA injection. Excessive columella show is different from nasal flare. The latter occurs when individuals flare their nostrils and widen their nasal aperture repeatedly as they inhale. This can be a natural phenomenon or can be caused by emotional or physical stress. Nasal flare is the result of an involuntary contraction of the lower portion of nasalis (dilator nares). In contrast,
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excessive columellar show is due to the over contraction of the levator alae nasi, which pulls the lateral cartilaginous crus of the nose superiorly, dilating the nostrils and raising the alar rim. Nasal flare can be corrected by injecting the dilator nares muscle with BoNTA subcutaneously into the center of each ala toward the alar rim. Excessive columellar show is corrected by injecting the BoNTA midway along the levator alae nasi (Figure 3). As far as we are aware, this is the first report of the use of BoNTA for the successful treatment of excessive columellar show.
patients with excessive upper columellar show were treated with BoNTA and showed significant improvement. These results suggest that BoNTA could be a useful new treatment option for this condition.
References 1. Carruthers A, Carruthers J. The treatment of glabellar furrows with botulinum A exotoxin. J Dermatol Surg Oncol 1990;16:83. 2. LeLouran C. Botulinum toxin A and facial lines: the variable concentration. Aesthet Plast Surg 2001;25:73–84. 3. In: Hexel D, Almeida AT, eds. Cosmetic Use of Botulinum Toxin. Porto Alegre, Brazil: AGE Editora; 2002: pp. 155–7. 4. Redaelli A. Medical rhinoplasty with hyaluronic acid and botulinum toxin A: a very simple and quite effective technique. J Cosmet Dermatol 2008;7:210–20.
Conclusions BoNTA is the most commonly used noninvasive procedure for the management of facial wrinkles. Over the last 2 decades, its use has expanded into many new indications in aesthetic medicine. Three
Address correspondence and reprint requests to: Mohammed Ghias Turkmani, MD, Derma Clinic, Riyadh 11465, PO Box 20632, Saudi Arabia, or e-mail:
[email protected]
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RECONSTRUCTIVE CONUNDRUM
Modified Three-Point Rotation-Advancement Flap for the Repair of the Melolabial Groove and a Peri-Alar C-Shaped Defect BYUNG CHEOL PARK, MD, JI WON GYE, MD, SEUNG PIL HONG, MD,
AND
MYUNG HWA KIM, MD*
The authors have indicated no significant interest with commercial supporters.
A
60-year-old woman was referred to our dermatologic clinic for the treatment of a pigmented, ulcerative mass in the melolabial sulcus. Histopathologic examination later confirmed basal cell carcinoma (BCC).
The lesion was removed using two-stage Mohs micrographic surgery, which left a defect measuring 2.0 by 1.2 cm that involved the melolabial groove and peri-alar region (Figure 1). We were then faced with a challenge regarding
Figure 1. The 2.0- by 1.2-cm surgical defect remaining after Mohs microscopic surgery.
*All authors are affiliated with the Department of Dermatology, Dankook Medical College, Chungcheongnam-do, South Korea © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:468–471 DOI: 10.1111/dsu.12007 468
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the optimal way of reconstructing this surgical defect.
Resolution Reconstructing the superomedial aspect of the melolabial fold requires particular skill. It is a region of converging anatomic boundaries where lines of relaxed skin tension are arrayed in multiple directions around three-dimensional anatomic landmarks.1 Finally, the region attracts visual attention and invites comparisons of symmetry that place the surgeon’s skill under particular scrutiny. Linear side-to-side closure, second-intention healing, skin grafting, or a skin flap could be used for reconstruction after Mohs surgery, but each of these methods has its advantages and disadvantages. Local skin flaps are preferred for repairs in the melolabial fold and the peri-alar regions, but classic local skin flaps and skin grafts often fail to achieve acceptable aesthetic outcomes. For this reason, new skin flap designs and modifications of existing designs have been developed for the reconstruction of defects in these areas, such as the shark island flap, a combination of a transposition flap, and Burow’s triangle removal.1,2 In addition, Schmidt and Mellette introduced a novel dog-ear rotation flap for the repair of the large defects on the cheek and temple, and Josepth and colleagues reported the result of the lenticular island pedicle flap, which is a variation of the island pedicle flap.3,4 In the case described herein, we used a modified three-point advancement flap with a rotation component to repair the defect (Figure 2). An incision was initially placed in the natural nasolabial sulcus, and a rotated advancement flap was placed along the melolabial fold. The flap was undermined at the subcutaneous fat level, and its tip was placed at the center of the circular skin defect. The movement of the flap was part rotational, part advancement. This movement resulted in recovery of approximately two-thirds of the defect without exerting upward tension on the upper lip. The suture line was located within the
Figure 2. The modified three-point rotation-advancement flap was designed.
natural melolabial fold. An advancement flap was then used to cover the remaining defect with minimal wound-closure tension and no nasal alar deformity by removing the small Burow’s triangle on the nasal sidewall and along the C-shaped peri-alar area. Three radiating flaps were then made to provide full coverage of the initial defect and to meet at the center of the defect and were anchored with half-buried mattress sutures. All suture lines were placed parallel to natural skin creases or cosmetic boundaries or under the C-shaped shadow developed from the perpendicular junction of the nasal ala and upper lip. Finally, we placed trifurcated suture lines similar to those of the triple advancement flap–otherwise known as the Mercedes flap. We refer to this procedure as a modified three-point rotation-advancement flap (Figure 3). Six months after surgery, the patient expressed great satisfaction with the cosmetic outcome and experienced no functional problems (Figure 4). The triple advancement flap could be used to reconstruct round or ovoid defects, such as those caused by Mohs microscopic surgery, and can achieve good cosmetic outcomes. This method can also be used to close defects in areas of trifurcation or bifurcation of contour and skin tension lines. Accordingly, the classic triple advancement flap may be suitable for treating defects on the lateral neck,
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Figure 3. Immediate postoperative photographs showing the three radiating suture line resembling the Mercedes emblem.
three-point rotation-advancement flap. This flap was placed with mild rotation in the nasofacial sulcus to relieve massive wound-closure tension, and suture lines were placed in the natural alar facial groove. In addition, another two radiating nasal side wall and C-shaped peri-alar areas were reconstructed using side-to-side advancement flaps similar to classic triple advancement flaps, and every effort was made to place all incision and closure lines within natural skin creases. The three point rotation-advancement method has some shortcomings, including slight lateral displacement of the right ala and lowering of the melolabial fold on the right, although the overall outcome is acceptable. In terms of the practical application of skin flaps, we tend to modify classic skin flaps as described in the literature, because the individual characteristics of skin defects must be considered for optimal results. Moreover, the same considerations apply for the reconstruction of combined defects in the C-shaped peri-alar and melolabial fold regions. Therefore, several creative skin flaps (multiple combination flaps or skin grafts) have been recently described for the closure of defects of the nasal ala, lateral nasal sidewall, and nasofacial sulcus. We have also modified the traditional triple advancement flap, creating a three-point rotationadvancement flap, to good effect.
Figure 4. Six months after surgery.
the sternal notch, the upper lip, and the temple adjacent to the lateral canthus. The flap is also useful for treating larger defects, because it minimizes loss of normal tissue and has shorter closure lines than primary side-to-side wound closure.5 We have also tried to use the classic triple advancement flap to reconstruct skin defects in the upper lip, peri-alar, and melolabial fold regions, as described for the present case, but side-to-side movement of the triple advancement flap caused severe woundclosure tension and the upper lip to move upward, distortion of the nasal ala, and bluntness of the natural melolabial fold. Therefore, we modified the classic triple advancement flap to create the modified
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Conundrum Keys Several factors, such as the cosmetic units involved and distortions of aesthetic borders, should be considered to achieve a well-healed flap for the reconstruction of nasolabial fold and peri-alar defects. The classic triple advancement flap might be useful in regions of trifurcation of skin and tension lines. The modified triple rotation-advancement flap could be suitable for regions of bi- or trifurcation, such as nasolabial and peri-alar defects. Scars are best camouflaged by placing all incision and closure lines within natural skin folds or along cosmetic unit boundaries.
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References 1. Cvancara JL, Wentzell JM. Shark island pedicle flap for repair of combined nasal ala-peri-alar defects. Dermatol Surg 2006;325:726–729. 2. Brodland D. Repair of the left nasal sidewall, nasofacial sulcus, and medial cheek. Dermatol Surg 2001;27:505–507. 3. Schmidt DK, Mellette JR Jr. The dog-ear rotation flap for the repair of large surgical defects on the head and neck. Dermatol Surg 2001;27:908–910.
5. Glaich AS, Behroozan DS. Goldberg LH Triple advancement flap to repair an upper lip defect. Dermatol Surg 2006;32: 415–417.
Address correspondence and reprint requests to: Byung Cheol Park, MD, Department of Dermatology, Dankook University Hospital, San 16–5, Anseo-dong, Dongnam-gu, Cheonan-si, Chungcheongnam-do, Republic of Korea, or e-mail:
[email protected]
4. Cvancara JL, Jones MS, Wentzell JM. Lenticular island pedicle flap. Dermatol Surg 2005;31:195–200.
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OnabotulinumtoxinA Unmasking Myasthenia Gravis ZOEY R. GLICK, MD,* MICHAEL S. VAPHIADES, DO,†‡
AND
MARIAN E. NORTHINGTON, MD*
The authors have indicated no significant interest with commercial supporters.
M
yasthenia gravis (MG) and onabotulinumtoxinA (BTX-A) act at the neuromuscular junction to induce muscle fatigue. We present a case in which we hypothesize that immunosuppression with methotrexate kept a patient’s MG at a subclinical level for many years. Her MG was revealed only after an increased dose of BTX-A was combined with nonablative fractional resurfacing (NFR).
Case Report Our patient was a 64-year-old woman with a history of psoriasis and psoriatic arthritis (treated with methotrexate since 2008), melanoma, hypothyroidism, thymus irradiation as a child (due to enlarged thymus), and fatigue (attributed to fibromyalgia). She had been a long-term dermatology patient and had been treated for many years with neurotoxins and soft tissue fillers at our institution and outside providers. When she was seen in October 2009, her glabellar rhytides were treated with BTX-A (25 U) without complications. During a different visit in October 2009 and in December 2009 and February 2010, her face and neck were treated for photodamage and scars with NFR without complications. She returned to clinic in May 2010 for her fourth treatment with NFR to the face as neck and BTX-A to the glabella, forehead, and crow’s feet (58 U). Within 1 week of this treatment, she started to complain of binocular horizontal diplopia. We were
concerned that this was a side effect of BTX-A. Neuro-ophthalmology evaluated her and noted the absence of ptosis, normal acuity, pupillary function, and normal ductions but comitant 12-diopter esotropia. MG was a consideration, and a MG panel was ordered, in addition to a thyroid function panel and contrasted cranial and orbital magnetic resonance imaging (MRI). A 12-diopter-base-out Fresnel prism was prescribed for the left lens with good results. The MRI and thyroid panel were negative, but the acetylcholine receptor and modulating antibodies were positive, supporting a diagnosis of MG.
Discussion MG and BTX-A act at the neuromuscular junction, and the combination can overwhelm the function of the neuromuscular junction. MG is an autoimmune (antibody driven) disease targeting acetylcholine (Ach) receptors located at the postsynaptic junction. These antibodies block or destroy Ach receptors, effectively decreasing the number of sites for Ach binding. The lids and extraocular muscles are often the first muscles affected, resulting in diplopia and ptosis. Other cranial muscles often become involved, manifesting with eating and speech difficulties. A majority of the time (85%), muscle weakness becomes generalized.1 BTX-A acts in the neuromuscular junction as well by cleaving the SNAP-25 protein in the SNARE complex in the presynaptic
*Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama; †Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama; ‡Department of Neurology and Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:472–473 DOI: 10.1111/dsu.12022 472
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neuron, preventing release of acetylcholine to the junction and resulting in temporary muscle paralysis. Borodic first reported BTX-A unmasking a diagnosis of MG in 1998. Tarsy and colleagues also reported this case in 2000. These authors reported a patient diagnosed with MG after being treated with BTX-A for blepharospasm and oromandibular dyskinesia (Meige syndrome). Their patient was treated with 120 U of BTX-A (previously tolerating 30–120 U injected 18 times over 13 years) to the periocular and lower facial muscles. The patient subsequently developed dysphagia and systemic weakness, tested positive for acetylcholine receptor antibodies, and was diagnosed with MG. This patient initially had a falsely negative Tensilon (edrophonium chloride) test (repeat Tensilon was positive). Borodic hypothesized that the false-negative Tensilon test was due to BTX-A.2,3 Another previous report by Iwase and colleagues discussed MG being diagnosed after treatment with BTX-A for spasmodic torticollis and blepharospasm. After their patient was treated with 40 U for blepharospasm (previously tolerating 60 and 80 U for spasmodic torticollis), she developed dysphagia and systemic weakness. This patient had positive acetylcholine receptor antibodies and was diagnosed with MG.4 We hypothesize that our patient’s previous immunosuppression with methotrexate kept her symptoms of MG at a subclinical level, allowing her to tolerate BTX-A without unmasking her MG. Only when the dose of BTX-A was increased did the disease manifest. In contrast to the patient that
Borodic, Tarsy and colleagues, and Iwase and colleagues reported, our patient had not previously had higher doses of BTX-A. Because the tiny muscles fatigue first, did the fractional resurfacing cause more diffusion of the neurotoxin to these muscles, resulting in diplopia? Or was the dose of neurotoxin on its own sufficient to affect the neuromuscular junction and result in diplopia? Our patient was started on pyridostigmine and glycopyrrolate, which has dramatically helped her diplopia. Her neurologist also feels that the methotrexate may be benefiting her MG and has encouraged her to continue to take this medication.
Acknowledgments Support for this article was provided by Research to Prevent Blindness.
References 1. Drachman DB. Myasthenia gravis and other diseases of the neuromuscular junction. In: Longo DL, Kasper DL, Hauser SL, Jameson JL, et al. editors. Harrison’s Principles of Internal Medicine (18th ed.). New York: Mc-Graw Hill; 2012. 2. Borodic G. Myasthenic crisis after botulinum toxin. Lancet 1998;352:1832. 3. Tarsy D, Bhattacharyya N, Borodic G. Myasthenia gravis after botulinum toxin A for Meige syndrome. Mov Disord 2000;15: 736–8. 4. Iwase T, Iwase C. Systemic effect of local and small-dose botulinum toxin injection to unmask subclinical myasthenia gravis. Graefes Arch Clin Exp Ophthalmol 2006;244:415–6.
Address correspondence and reprint requests to: Marian E. Northington, MD, Department of Dermatology, University of Alabama at Birmingham, EFH 414 1530 3rd Ave. South Birmingham, AL 35294, or e-mail:
[email protected]
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Superficial Frostbite Masquerading as Ecchymosis from Improper Cryotherapy Use After Q-Switched Laser Tattoo Treatment WILLIAM KIRBY, DO, FAOCD,*† MADELINE TARRILLION, MSIV,‡
AND
ALPESH DESAI, DO, FAOCD§
The authors have indicated no significant interest with commercial supporters.
W
ith the development of quality-switched (QS) laser tattoo removal treatment, along with the increasing popularity of tattooing, the number of requests for tattoo removal has increased significantly. Tattoo removal using QS lasers is well established in the medical literature as safe and effective. Cryotherapy using ice packs is widely accepted as a common means by which to diminish postprocedural discomfort and edema from a large variety of medical procedures, including QS laser tattoo removal. In the following case report and discussion, the authors describe what they believe are the first cases of superficial frostbite from improper use of ice packs after laser tattoo removal treatment using QS lasers.
Case Reports In 2011 and 2012, three patients presented with a complaint of “bruising” in areas adjacent to tattoos that had recently been treated using a QS laser (Figures 1–3). The patients noted mild itching, pain, and numbness. Physical examination revealed what appeared to be confluent areas of well-demarcated angular ecchymosis outside the borders of the ink tattoo. The patients denied any
physical trauma to these areas. With subsequent questioning, each of the patients admitted to prolonged exposure of ice packs in direct contact with the treated area and surrounding skin. More specifically, two of the three patients placed an ice pack on the skin and secured it in place with an elastic wrapping.
Discussion With the development of QS laser technology, tattoo removal can be achieved with minimal side effects. QS laser tattoo removal uses photothermolysis, which is the technique of choosing a specific wavelength and pulse width to limit the thermal damage to a specific area while sparing the adjacent tissue.1 It is common to use cryotherapy after a QS laser tattoo removal treatment session to decrease pain, swelling, and edema. These effects are secondary to the vasoconstriction and decreased sensory nerve conduction from cryotherapy.2 Despite the benefits of cryotherapy, the induction of cutaneous anesthesia creates the risk of frostbite. There have been several reports of injuries due to improper use of ice packs. Most commonly, they
*Department of Dermatology, Western University Health Science Center, Los Angeles, California; †Division of Dermatology, NOVA Southeastern University, Los Angeles, California; ‡Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas; §South Texas Dermatology Residency, University of North Texas Health Science Center, Houston, Texas © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:474–476 DOI: 10.1111/dsu.12026 474
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Figure 1. Right inner arm with evidence of well-demarcated superficial frostbite surrounding and distal to a tattoo.
Figure 3. Right inner forearm showing superficial frostbite surrounding a recently treated tattoo.
Figure 2. Left inner arm evidence of superficial frostbite located medial to a recently treated tattoo.
were the result of direct application on the skin for an extended duration (hours to overnight) due to improper instruction, lack of instruction, or patient misuse.2–4 Unlike the cases reported in this article, all of these injuries were viewed to be the direct result of cryotherapy and not an unwarranted side effect. The authors contend that the three cases presented in this article represent the first reports of frostbite from improper cryotherapy use after QS laser tattoo removal treatment. Frostbite can occur once the skin reaches a certain temperature ( 2°C). At this temperature, cellular metabolism arrests, destruction of cellular proteins
and enzymes occurs, and ice crystals form in the extracellular space. These crystals draw water from the cells, leading to cell dehydration, tissue death, and necrosis.5 Clinically, patients may present with or develop the following symptoms: erythematous, dusky, blanched, painful, or blistered skin and possibly full-thickness skin necrosis. Depending on the severity of the injury, treatment ranges from conservative treatment with tissue debridement and application of petrolatum and dressing, to skin grafting.2–4 With frostbite due to cryotherapy, subsequent refreezing must be avoided to avoid further injury.5 Proper education is essential to prevent these injuries from happening in the future. Clinicians should always supply patients with oral and written instructions for proper cryotherapy use. As a standard rule, to avoid tissue damage, patients should not apply ice packs continuously for an extended period of time.3 The authors recommend a conservative regimen of 5-minute applications with frequent inspections of the area for signs of injury, such as dusky, blanched, or blistered skin. Direct application of the ice pack to the skin should also be avoided. It is recommended that ice or other
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cold packs be wrapped in a damp towel or dry paper towels.3
References
QS lasers are considered to be the criterion standard for tattoo removal treatment, and their safety and efficacy are well established, but postprocedural care of laser tattoo removal depends patient adherence. Nonadherence to aftercare recommendations may lead to adverse events, which can be mistaken for side effects. In these three cases, improper use of ice packs resulted in superficial frostbite. Fortunately, there were no lasting consequences, and the areas healed well with no long-term sequelae. It is imperative that practitioners provide patients with oral and written instructions on the proper use of cryotherapy, and nonadherence should be suspected if a patient presents with bruising after QS laser treatment.
2. Mailler-Savage E, Mutasim D. Cold injury of the knee and lower aspect of the leg after knee surgery and use of a cold therapy system. J Am Acad Dermatol 2008;58(5 Suppl 1):S106–8.
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1. Fitzpatrick R, Goldman M. Tattoo removal using the alexandrite laser. Arch Dermatol 1994;130:1508–14.
3. Keskin M, Tosun Z, Duymaz A, Savac N. Frostbite injury due to improper usage of an ice pack. Ann Plast Surg 2005;55:437–8. 4. Nishikawa M, Tanioka M, Araki E, Matsumura S, et al. Extensive skin necrosis of the arm in a patient with complex regional pain syndrome. Clin Exp Dermatol 2008;33:733–5. 5. Basler R. Skin injuries in sports medicine. J Am Acad Dermatol 1989;21:1257–62.
Address correspondence and reprint requests to: Madeline Tarrillion, MSIV, 4704 Libbey Lane, Houston, TX 77092, or e-mail:
[email protected]
Refractory Pyoderma Gangrenosum Effectively Treated Using a 10,600-nm Carbon Dioxide Fractional Laser JIHUN PARK, MD,* MIN JU CHOI, MD,* BONCHEOL GOO, MD, PHD,† AND SUNG BIN CHO, MD, PHD*
The authors have indicated no significant interest with commercial supporters.
P
yoderma gangrenosum (PG) is a chronic neutrophilic skin disease that appears as enlarging painful skin ulcers with an undermined border.1 In the absence of consistently effective therapy for PG, various immunosuppressive regimens are used, notably oral or intravenous corticosteroids and other immunomodulatory drugs.1 Biologically based modulators of immunity and inflammatory response have recently shown effectiveness as well.1 Herein, we present a patient with refractory PG who responded well to 10,600-nm carbon dioxide fractional laser (CO2 FS) therapy. Case Report A 71-year-old Korean woman visited our department with a painful ulcerative lesion on the right shin that had progressed significantly in the past month. She had been treated unsuccessfully for this lesion with systemic steroids, cyclosporine, colchicine, aspirin, and antibiotics, as well as weekly intralesional injections of triamcinolone acetonide over the preceding year. On her initial visit, physical examination showed an ulcerative and granulomatous lesion with an undermined border and a diameter of approximately 7 cm on the right shin (Figure 1A and B). Laboratory tests were performed for complete blood cell and platelet counts, blood glucose, erythrocyte sedimentation rate (ESR), C-reactive protein, lactate
dehydrogenase (LDH), renal and liver function, antinuclear antibodies, and venereal disease. Gastrointestinal tract studies and chest X-ray were also performed. Results were unremarkable, except for an ESR of 54 mm/h (normal range 20 mm/h) and LDH of 401 (normal range 247 IU/L). Pathologically, dense infiltrations of neutrophils and lymphocytes extending to the subcutis were found, with negative results for Grocott, periodic acid-Schiff, and Ziehl-Neelsen stains. No microorganisms or fungi were detected by tissue culture. Based on these findings, a diagnosis of PG was made. Having obtained written informed consent from the patient, we discontinued the systemic medications, including steroids, cyclosporine, and colchicine, and administered four sessions of CO2 FS treatment (Mosaic eCO2 laser; Lutronic Corp., Goyang, Korea) and four intralesional injections of triamcinolone acetonide (10 mg/mL) at 2-week intervals. After local anesthesia with 1% lidocaine, laser energy of 80 mJ was delivered in two passes to the skin lesion at a density of 150 spots/cm2 with a spot diameter of 120 lm. The expected maximal ablation depth was 1,168 lm, and coverage with single pass was 12.5% in the static mode. Immediately after treatment, an antibiotic ointment containing mupirocin and a foam dressing were applied. The skin lesion showed marked improvement from the
*Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; †Clinic L, Goyang, Korea © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:477–479 DOI: 10.1111/dsu.12020 477
CO2 FS FOR PYODERMA GANGRENOSUM
(A)
(C)
(B)
(D)
Figure 1. Seventy-one-year-old Korean woman with pyoderma gangrenosum (A and B) before treatment, (C) 1 week after the second session of ablative 10,600-nm carbon dioxide fractional laser treatment and (D) 5 months after the final treatment. All treatments were delivered in two passes at 80 mJ and a density of 150 spots/cm2 to the skin lesion.
second laser treatment session (Figure 1C) and had almost healed at the last combination treatment. For 5 months thereafter, the therapeutic effects were maintained without further treatment (Figure 1D). The patient did not present any major side effects, except for scarring of the treated area, and expressed satisfaction with the outcome of treatment.
Discussion Local therapies for mild PG include topical corticosteroids, benzoyl peroxide, disodium cromoglycate and tacrolimus, intralesional injection of triamcinolone acetonide or cyclosporine, and wound dressings,1 but it is widely accepted that the invasive surgical debridement of PG lesions should be avoided, because the trauma may induce new
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lesions.1 In the present case, although concomitant treatment of triamcinolone acetonide injection was performed, repeated ablative CO2 FS treatment did not make active PG lesions worse but instead induced a healing effect. Several investigations have provided evidence that laser and other phototherapies, including fractionated microneedle radiofrequency therapy and CO2 FS, exert beneficial effects on cutaneous inflammatory disorders.2–4 In addition to the benefits of laser treatment for inflammatory acne lesions, our group has reported the effectiveness of CO2 FS in axillary hidradenitis suppurativa.3 We found that this treatment not only reduced the number and severity of lesions, but also improved the associated granulation tissues and contracture scars.3 The CO2 laser resurfacing activity induces thermal coagulation and immediate contraction of the irradiated tissues5 and an influx of phagocytic cells that degrade dead tissues followed by new synthesis of collagen and other structural proteins to restore the skin.5 Despite the ablative nature of CO2 lasers, the fractionation may minimize the side effects seen with laser therapies, which may prevent worsening of present lesions and triggering of new ones. The CO2 FS treatment may be easily and safely performed with scant oozing or bleeding, and the thermocoagulative effects diminish the risk of secondary wound infection. Based on the clinical response observed in the present case, we suggest that CO2 FS alone or in combination with conventional treatments may effectively treat certain forms of PG lesions, but ablative laser treatment for PG awaits optimization and confirmation of its safety and efficacy through prospective studies.
References 1. Ruocco E, Sangiuliano S, Gravina AG, Miranda A, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009;23:1008–17.
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2. Ruiz-Esparza J, Gomez JB. Nonablative radiofrequency for active acne vulgaris: the use of deep dermal heat in the treatment of moderate to severe active acne vulgaris (thermotherapy): a report of 22 patients. Dermatol Surg 2003;29:333–9. 3. Cho SB, Jung JY, Ryu DJ, Lee SJ, et al. Effects of ablative 10,600-nm carbon dioxide fractional laser therapy on suppurative diseases of the skin: a case series of 12 patients. Lasers Surg Med 2009;41: 550–4. 4. Lee SJ, Goo JW, Shin J, Chung WS, et al. Use of fractionated microneedle radiofrequency for the treatment of inflammatory acne vulgaris in 18 Korean patients. Dermatol Surg 2012; 38:400–5.
5. Rahman Z, MacFalls H, Jiang K, Chan KF, et al. Fractional deep dermal ablation induces tissue tightening. Lasers Surg Med 2009;41:78–86.
Address correspondence and reprint requests to: Sung Bin Cho, MD, PhD, Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea, or e-mail:
[email protected]
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Laser Hair Removal Put in the Wrong Hands MAHRUKH S. NISAR, BA, MPA,* JENIFER R. LLOYD, DO,†‡
AND
TANWEER KHAN, MD§
The authors have indicated no significant interest with commercial supporters.
L
aser-assisted hair removal is a common procedure performed throughout many medical (med) spas in the United States. Laser hair removal is currently the most efficient method of long-term hair removal, using several systems, including the ruby laser (694 nm), alexandrite laser (755 nm), diode laser (800 nm), intense pulsed light source (590–1200 nm), and neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (1064 nm).1 The mechanism for its effectiveness is selective photothermolysis targeting the melanin in the hair follicle, which serves as the chromophore.1 Considerations including proper patient selection and customizing fluence to the patient’s skin type are important for effectiveness and tolerance to treatment.1 In the United States, the Food and Drug Administration requires that all laser machines be marketed as prescription devices, which are subject to state controls for appropriate use by or under a supervising licensed practioner.2 According to the American Society of Dermatologic Surgery, most states do not allow electrologists, cosmetologists, estheticians, or other nonmedical personnel to perform laser hair removal without an on-site medical supervisor.3
Case We report a case of a 33-year-old woman with Fitzpatrick skin type V who underwent laser hair
removal to assist with keratosis pilaris on the upper arms and acne related to the hair follicles on the back and face. The patient purchased a package of four laser hair removal treatments from a med spa in the state of Pennsylvania. She admitted that a physician did not evaluate her and that she did not see an on-site physician (as the company website promised). Laser technicians administered all treatments. She denied sun exposure or tanning for the past year. The first two treatments were spaced 8 weeks apart during the winter months using a diode laser with a cool tip at a frequency of 22 Hz. These treatments showed moderate improvement in hair reduction and pigmentation. The third treatment was performed midsummer with the same laser at a frequency of 24 Hz. During this treatment, the patient experienced extreme burning and pain on the upper arms, back, shoulder, and face. She was told this was a normal reaction. Immediately after treatment, several hyperpigmented macules appeared on the face, upper arms, and back in a distinct pattern of the diode tip. The laser technician again told the patient that this was a normal reaction that would resolve after a couple days. Two to 3 hours after treatment, she developed fluid-filled blisters at the sites of the hyperpigmented lesions (Figure 1). Dermatologic examination 10 days later showed multiple second-degree burns on the upper arms, back, shoulder, and left temple, exposing the dermis, with lesions marked in the
*Northeast Ohio Medical University, Rootstown, Ohio; †Residency Program, University Hospitals Health System – Richmond Heights Hospital; ‡Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio; §St. Matthew’s University School of Medicine, Atlanta, Georgia © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:480–482 DOI: 10.1111/dsu.12086 480
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treatments to reverse scars and hyperpigmentation after the skin healed. There has been no follow-up treatment.
Discussion
Figure 1. Fluid-filled blisters hours after laser hair removal with characteristic diode laser tip markings. (Patient’s photograph after treatment.)
Figure 2. Burns 1 week after laser hair removal showing the pink exposed dermis.
characteristic diode tip pattern (Figure 2). Dermatologic evaluation determined that these burns would require a series of chemical peels or laser
Laser hair removal is a technical procedure that requires a skilled healthcare professional. There is a low incidence of adverse effects from laser hair removal, but they are more common when untrained personnel perform them.4 Although laws dictate the presence of a licensed practitioner on site, many med spas illegally perform procedures without the supervision of physicians or licensed providers, including nurse practitioners and physician assistants.2,5 This case shows that, when lasers are put in the wrong hands, severe burns, scarring, and hyperpigmentation may occur. The advancing technology in lasers for hair removal has added features for patient comfort. The cool tip feature during this patient’s treatment ironically allowed for some relief while the patient received second-degree burns. In June 2012, Governor Jerry Brown of California signed a bill (AB 1548) into law to increase penalties for illegally owning and operating a medical spa. Before the bill, penalties included a mild $200 to $1200 fine, 60 to 180 days imprisonment, or both. The new law increases fines up to $50,000 and jail time up to 5 years if the cost of the services was greater than $950. With the rising number of med spas throughout the United States, tighter regulations are necessary to prevent laser burns, as well as adverse effects from other dermatologic procedures requiring expertise (e.g., Botox, chemical peels, injectable fillers). California’s new legislation represents a positive step toward tighter regulation of med spas with heavy penalties for improper med spa operations. As the number of med spa facilities rises, dermatologists may see an increase in the number of patients with laser burns and will need to treat the damage caused by unsupervised laser procedures.
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References
5. Handley RT. The medi-spa: a current cosmetic dermatology public safety concern. Int J Acad Phys Assist 2009. doi: 10.5580/1171
1. Liew SH. Laser hair removal: guidelines for management. Am J Clin Dermatol 2002;3:107–15. 2. Kelsall D. Laser hair removal: no training required? CMAJ 2010;182:743. 3. Galt V. Laser hair removal a risky business in need of regulation, experts say. CMAJ 2010;182:755–6. 4. Vano-Galvan S, Jaen P. Complications of nonphysician-supervised hair removal: case report and literature review. Can Fam Physician 2009;55:50–2.
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Address correspondence and reprint requests to: Jenifer R. Lloyd, DO, Lloyd Dermatology & Laser Center, 8060 Market Street, Youngstown, OH 44512, or e-mail:
[email protected]
Challenging the Dogma of “Watchful Waiting” for Desmoplastic Trichoepithelioma SELINA SINGH, BA,* RONALD RAPINI, MD,† MARY SCHWARTZ, MD,‡ ROBIN FRIEDMAN-MUSICANTE, MD,# AND PAUL M. FRIEDMAN, MD†§¶
The authors have indicated no significant interest with commercial supporters.
D
esmoplastic trichoepithelioma (DTE) is a benign adnexal tumor that typically presents as an asymptomatic, slow-growing plaque on the face. Clinical examination reveals an annular, skin-colored, firm plaque or nodule with a depressed center and raised border. Microscopically, DTEs are characterized by a triad of narrow strands of basaloid tumor cells, keratinous (horn) cysts, and desmoplastic stroma.
Clinically, the differential diagnosis includes basal cell carcinoma (BCC), sebaceous hyperplasia, conventional trichoepithelioma, granuloma annulare, and scleroderma. Histologically, DTEs may resemble morpheaform BCC, trichoepithelioma, syringoma, microcystic adnexal carcinoma, and trichoadenoma.1 Because DTEs can be clinically and histologically misdiagnosed as a malignancy, there is debate surrounding the treatment of choice. Current treatment options include watchful waiting, dermabrasion, laser surgery, excision, and Mohs micrographic surgery (MMS).1
Case 1 A 47-year-old Caucasian woman with Fitzpatrick skin type III presented with an asymptomatic lesion on her left nasal sidewall. She confirmed that the
lesion was slow growing and had been present for approximately 15 years. She denied any personal or family history of skin cancer or radiation therapy. On examination, a shiny, 1.0- by 0.6-cm skincolored plaque was noted on her left nasal sidewall. Fifteen years earlier, a shave biopsy had been interpreted as trichoepithelioma at an outside institution. The biopsy reportedly showed bland nests of keratinizing epithelium within the dermis with focal follicular differentiation. The lesion persisted. A punch biopsy was performed 8 years later and interpreted as DTE. A dermatopathologist originally read the punch biopsy as a well-circumscribed neoplasm with cords of basaloid cells rimmed by fibroblastic stroma and keratinous cysts (Figure 1). Based on the punch biopsy pathology report and our clinical impression, the patient elected to undergo MMS for definitive removal of the nasal DTE. Stage 2 revealed focal perineural invasion, and microcystic adnexal carcinoma (MAC) was diagnosed intraoperatively (Figures 2 and 3). The tumor was excised with MMS and cleared in three stages. The patient required referral for a paramedian forehead flap closure of the resulting full-thickness 2- by 2-cm
*University of Texas Medical School—Houston, Houston, Texas; †Department of Dermatology, University of Texas Medical School—Houston, Houston, Texas; ‡Department of Pathology, Methodist Hospital, Houston, Texas; #Memphis Dermatology Clinic, Memphis, Tennessee; §Dermatology and Laser Surgery Center, Houston, Texas; ¶Department of Dermatology, Weill Cornell Medical College, The Methodist Hospital, Houston, Texas © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:483–486 DOI: 10.1111/dsu.12051 483
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Figure 1. Punch biopsy read by dermatopathologist as wellcircumscribed neoplasm with cords of basaloid cells rimmed by fibroblastic stroma and keratinous cysts.
Figure 3. Focal perineural invasion and microcystic adnexal carcinoma (MAC) was diagnosed intraoperatively.
within some of the basaloid aggregates and focal perineural invasion was identified (Figure 2). Based on these additional findings, two dermatopathologists confirmed MAC.
Case 2
Figure 2. Focal perineural invasion and microcystic adnexal carcinoma (MAC) was diagnosed intraoperatively.
defect. The surgical site had healed without complication or recurrence at the 14-month follow-up. The punch biopsy was reviewed alongside the MMS site specimen. Revisiting the punch biopsy confirmed infiltrating basaloid cells, fibrous stroma, and horn cysts in a focus of calcification consistent with the original diagnosis of trichoepithelioma. The punch biopsy also revealed an infiltrating tumor with extension to the adipose tissue and margins of the specimen. The MMS site specimen showed the same infiltrating basaloid tumor with surrounding purplish metachromatic staining. Sweat ductal change
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A 36-year-old Caucasian woman with Fitzpatrick skin type II presented with a lesion on her right nasolabial fold. She confirmed that the lesion had been present since childhood. Seventeen years before, the lesion had been treated with cryotherapy. She denied any personal or family history of skin cancer or radiation therapy. The lesion had been clinically diagnosed at an outside institution as a changing nevus and biopsied. The shave biopsy was interpreted as combining features of an intradermal nevus and a desmoplastic trichoepithelioma (Figure 4). The patient was referred for MMS and definitive removal of the DTE. She presented with a 0.4- by 0.7-cm scar on her right nasolabial fold consistent with the recent biopsy. The tumor was excised with MMS and was cleared in two stages, leaving a 1.5- by 2.0-cm defect. The excision involved full-thickness dermis and extension into the subcutaneous fat.
SINGH ET AL
In addition, misinterpretation secondary to inadequate tissue sampling limits quantification of the subset of DTEs with aggressive behavior. To the best of our knowledge, this is the first reported case documenting the potential malignant degeneration of a DTE into a MAC. MACs are commonly misdiagnosed. There are numerous reports of MACs that were initially misdiagnosed histologically as benign tumors or less-aggressive malignancies.
Figure 4. Shave biopsy showing combined features of an intradermal nevus and a desmoplastic trichoepithelioma
Figure 5. Frozen section examination showing deep infiltration, perineural extension, and lymphoid aggregates
Frozen section examination revealed deep infiltration, perineural extension, and lymphoid aggregates, and MAC was diagnosed intraoperatively (Figure 5). The surgical site had healed without complication or recurrence at 2-month follow-up.
Discussion Desmoplastic trichoepitheliomas are uncommon benign tumors with an estimated incidence of two per 10,000.2 Correlation of histopathologic and clinical findings is required for accurate diagnosis. The low incidence of these tumors makes it difficult to assess their potential for malignant degeneration.
Microcystic adnexal carcinoma is an uncommon malignant adnexal tumor associated with high morbidity because of locally aggressive behavior, infiltrative growth pattern, and high recurrence rate. MACs may demonstrate local extension into the subcutis, muscle, and bone. The lesions typically present as an asymptomatic, indurated nodules or plaques. Numbness, tenderness, burning, or paresthesias may occur in patients with perineural invasion.3 MACs often have microscopic extension of the tumor beyond clinically apparent tumor. In one study including 26 MACs, mean clinical size at presentation was 3.0 cm, and mean postoperative size was 18.0 cm.4 Historically, treatment options for MAC have included wide local excision, MMS, irradiation, and chemotherapy.3 MMS is the treatment of choice because of the high likelihood of clear margins with the fewest procedures.3 Recurrence rates after wide local excision range from 40% to 60%, compared with recurrence rates of 0% to 12% after MMS.3,4 The timeline of these cases highlights the diagnostic uncertainty and potential malignant degeneration of DTEs. It is possible that the original biopsies were misinterpreted; it is unlikely for a MAC to behave indolently for 15 years.5 Understanding the longterm behavior of DTE and MAC is difficult in the absence of a prospective randomized clinical trial comparing treatment with watchful waiting. In addition, the limited number of review articles and case series makes it difficult to draw conclusions and apply them to the general population. These cases confirm that watchful waiting is insufficient for
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WATCHFUL WAITING FOR DESMOPLASTIC TRICHOEPITHELIOMA
DTEs. The subtle clinical findings, subclinical growth, propensity for misdiagnosis, occurrence in cosmetic and functionally sensitive areas, and potential malignant degeneration support MMS as the treatment of choice for DTEs.
3. Friedman PM, Friedman RH, Jiang SB, et al. Microcystic adnexal carcinoma: collaborative series reivew and update. J Am Acad Dermatol 1999; 41 (2 Pt 1):225–31. 4. Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg 2007;33:333–9. 5. Lupton GP, McMarlin SL. Microcystic adnexal carcinoma. Report of a case with 30-year follow-up. Arch Dermatol 1986;122(3):286–9.
References 1. Mamelak AJ, Goldberg LH, Katz TM, Graves JJ, et al. Desmoplastic trichoepithelioma. J Am Acad Dermatol 2010;62:102–6. 2. Koay JL, Ledbetter LS, Page RN, Hsu S. Asymptomatic annular plaque of the shin. Arch Dermatol 2002;138: 1091–6.
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Address correspondence and reprint requests to: Paul M. Friedman, MD, Dermatology & Laser Surgery Center, 6400 Fannin Street, Suite 2720, Houston, TX 77030, or e-mail:
[email protected]
Evaluation of Residual Tumor from Mohs Micrographic Specimens of Clinically Resolved Preoperative Biopsy Sites SOONYOU KWON, MD,* TONJA GODSEY, HT,†
AND
HUGH M. GLOSTER, JR., MD*
The authors have indicated no significant interest with commercial supporters.
O
n occasion, patients will present to a Mohs micrographic surgeon with only a faint scar at the biopsy site and no clinically apparent residual tumor (Figure 1). We hypothesized that clinically apparent resolution may translate to microscopic resolution of tumor in the majority of cases.
Methods The purpose of this study was to examine Mohs specimens for microscopic evidence of residual tumor in clinically resolved preoperative biopsy sites. Over a period of 12 months, we conducted a
single-center prospective case series on 28 patients who presented for a Mohs micrographic surgical procedure with a faint smooth biopsy scar between February 2011 and July 2012. The biopsy scar was excised with 1–2-mm margins using the Mohs technique. Six-lm sections were cut through the whole specimen to determine whether any residual tumor was present in the preoperative biopsy site.
Results There were 25 squamous cell carcinomas (SCCs) and three basal cell carcinomas (BCCs) (Table 1). All three BCCs were reported as nodular on the preoperative biopsy report. The specific diagnoses on the preoperative biopsy reports for the SCCs were SCC in situ (n = 16), SCC (n = 6), and superficial SCC (n = 3). Complete sectioning through the tissue block revealed no residual tumor in 26 of the 28 specimens. Residual BCC was found in two Mohs specimens. Microscopic resolution was confirmed on all 25 clinically resolved SCCs and one BCC.
Discussion
Figure 1. Preoperative photograph of a patient with clinically apparent resolution after biopsy of squamous cell carcinoma in situ on right cheek.
Practices that decrease cost without compromising outcomes are valuable given the rising incidence of skin cancer. Determining clinical resolution of tumor after biopsy is subjective, and there may be
*Department of Dermatology, University of Cincinnati; †University of Cincinnati Health, Cincinnati, Ohio © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:487–489 DOI: 10.1111/dsu.12088 487
EVALUATION FOR RESIDUAL TUMOR
TABLE 1. Patient Age, Tumor Type, Location, Specimen Size, and Presence of Residual Tumor Patient Age
Tumor Reported on Biopsy
Biopsy Site
Mohs Specimen Size, cm
65 56 82 42 52 56 85 80 55 75 69 60 83 85 82 62 27 83 38 74 80 53 84 66 65 58 69 55
SCCIS SCCIS SCC SCC SCCIS SCCIS SCCIS SCC SCC, superficial SCCIS SCC, superficial SCCIS SCCIS SCC SCC SCC BCC SCCIS SCC SCC BCC BCC SCC SCC, superficial SCCIS SCCIS SCC SCCIS
Sole of left foot Left lower eyelid Right nasal tip Left alar groove Left temple Right lower eyelid Right nasal sidewall Left dorsal hand Nasal dorsum Helix of left ear Right neck Right nasal tip Left lateral forehead Right dorsal hand Left dorsal hand Left nasal tip Right lower eyelid Left cheek Mid philtrum Left lateral eyebrow Left forehead Right lower eyelid Right upper lip Right lower lip Right cheek Left helix Right dorsal hand Right cheek
1 1 0.4 1 1.5 1 1.5 0.5 1 0.7 0.5 0.3 0.7 0.7 0.7 1 0.4 0.4 0.6 1.5 1.4 0.7 0.5 0.5 1.4 0.5 0.8 2
9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9
0.7 0.2 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.3 0.5 0.7 0.5 0.3 0.5 0.6 0.3 0.6 0.6 0.6 0.4 0.5 0.4 0.6 0.4 0.5
Tumor Found on Step Frozen Section N N N N N N N N N N N N N N N N N N N N Y Y N N N N N N
SCCIS, squamous cell carcinoma in situ; SCC, squamous cell carcinoma; BCC, basal cell carcinoma.
variation among physicians. Alcalay and colleagues1,2 suggest that another difficulty is determining whether there is true resolution or false resolution due to the potential of having the wrong site. We were successful in predicting microscopic resolution by clinical examination for patients with SCC, but we found that determining whether a BCC was clinically resolved was more difficult. Future studies evaluating the mechanism of resolution after preoperative biopsy are needed (e.g., clean margins after preoperative shave biopsy vs local immune response leading to resolution3–5). Alcalay and colleagues1 evaluated the surrounding tissue immediately after they performed a shave biopsy for diagnostic purposes and found that 25% were free of residual tumor.
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Again, this percentage would be widely variable among different physicians and their shave biopsy techniques. In conclusion, when only a small scar remains at the biopsy site without clinical evidence of residual tumor, re-evaluation using a shave biopsy should be considered instead of an excision or Mohs surgery, especially when the preoperative biopsy reveals SCC. The clinician may elect simply to follow the patient instead of performing a second biopsy on cosmetically sensitive areas such as the face. This conservative approach will decrease the cost of health care by preventing unnecessary excision of small tumors that may have resolved after the initial biopsy.
KWON ET AL
References 1. Alcalay J, Alkalay R, Hazaz B. Residual skin cancer after preoperative biopsy: evaluation by Mohs micrographic surgery. Intl J Dermatol 2004;43:456–8. 2. Alcalay J, Alkalay R. Histological evaluation of residual basal cell carcinoma after shave biopsy prior to Mohs micrographic surgery. J Eur Acad Dermatol Venereol 2011;25:839–41. 3. Batinac T, Zamolo G, Hadzisejdic I, Zaudar G. A comparative study of granzyme B expression in keratoacanthoma and squamous cell carcinoma. J Dermatol Sci 2006;44:109–12.
4. Jackaman C, Lew AM, Zhan Y, Allan JE, et al. Deliberately provoking local inflammation drives tumors to become their own protective vaccine site. Int Immunology 2008;20:1467–79. 5. Kuraishy A, Karin M, Grivennikov SI. Tumor promotion via injuryand death-induced inflammation. Immunity 2011;35:467–77.
Address correspondence and reprint requests to: Hugh M. Gloster, Jr., MD, Department of Dermatology, University of Cincinnati, 4460 Red Bank Road, Suite 130, Cincinnati, OH 45227, or e-mail:
[email protected]
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Adamantinoid Basal Cell Carcinoma: A Predictor of More Aggressive Clinical Behavior Letter to the Editor: We were pleased to see the article by Berk and colleagues1 on adamantinoid basal cell carcinoma (BCC). We agree with their main points that this subtype of BCC has been overlooked in the literature and that it usually requires a larger excision for clearance by Mohs micrographic surgery (MMS) than is appreciated clinically, but we felt that the method of their study was fraught with error. In their methods section, the authors compare a group of 44 adamantinoid BCCs with a control group of 445 BCCs, all of which presented sequentially for MMS. Thus, the control group must have consisted not only of nodular BCCs, but also of infiltrative and morphealike BCCs. The latter two subtypes, as the authors acknowledge,2,3 are aggressive BCC subtypes. Furthermore, in our Mohs practice, not only are these aggressive BCC subtypes common, 24% of the time the first stage of MMS shows no tumor. Thus, in the control group, the subtypes of the “unseen” BCCs were not known, nor were the percentage of aggressive subtypes stated. Perhaps the authors were only controlling against nodular BCCs, but this is not mentioned in the article and would be improbable anyway because the control group was a sequential
cohort. Furthermore, any subtyping of the control group would have needed to have been done at the time of MMS, as was the case in the adamantinoid BCC group. If there was no well-defined control group of non-aggressive or aggressive BCCs, we believe it is difficult to draw meaningful conclusions from their data shown in Table 1.
References 1. Berk DR, Ball Arefiev KL, Gladstone HB. Adamantinoid Basal cell carcinoma: a predictor of more-aggressive clinical behavior. Dermatol Surg 2012;38:1346–50. 2. Batra RS, Kelley LC. Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with Mohs micrographic surgery. Arch Dermatol 2002;138:1043–51. 3. Batra RS, Kelley LC. A risk scale for predicting extensive subclinical spread of nonmelanoma skin cancer. Dermatol Surg 2002;28:107–12.
HINA AHMAD, MD Bennett Surgery Center Santa Monica, California RICHARD G. BENNETT, MD University of Southern California, and University of California Los Angeles Los Angeles, California
Judicious Discontinuation of Antithrombotic Medications in Skin Surgery Letter to the Editor: We read with great interest the recent manuscript by Callahan and colleagues, “The management of antithrombotic medication in skin surgery.” This well-written and thorough review does an excellent job of detailing the most common antithrombotic medications routinely encountered in patients undergoing skin surgery and their mechanisms of action.1 It also highlights the dearth of wellpowered studies assessing complication rates in
patients taking antithrombotics, especially multiple and newer agents.1 Fortunately, although complications after skin surgery in patients taking antithrombotics rarely affect mortality, they are not inconsequential and without morbidity.2 Risk stratification for patients taking anticoagulants to determine the true risks and benefits of continuing versus discontinuing antithrombotic medication on a case-by-case basis is advised. In addition to the suggestions that Callahan and colleagues outline, we would like to add the following:
© 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:490–492 490
LETTERS TO THE EDITOR
1. Consider checking an international normalized ratio (INR) within 1 week of cutaneous surgery in patients taking warfarin and consider withholding warfarin and postponing surgery for a supratherapeutic INR (>3.5). 2. Obtain a thorough review of all supplements being taken and discontinue any with anticoagulant properties such as vitamin E, fish oil, garlic, gingko biloba, ginger, and ginseng.2 3. Consider discontinuing antithrombotics in patients with periocular lesions, in whom the defect may violate the orbital septum during skin surgery because this may lead to retrobulbar hemorrhage, optic nerve compression, and ultimately blindness if left untreated.3 Given the rare but documented catastrophic effects of discontinuing antithrombotic medications, it may seem prudent to continue all patients on these agents, but we would advocate the judicious discontinuation of these medications in the above circumstances. The dermatologist can play an important role in this discussion with the patient and the prescribing
physician regarding use of antithrombotic medications perioperatively.
References 1. Callahan S, Goldsberry A, Kim G, et al. The management of antithrombotic medication in skin surgery. Dermatol Surg 2012;38:1417–26. 2. Pomerantz RG, Lee DA, Siegel DM. Risk assessment in surgical patients: balancing iatrogenic risks and benefits. Clin Dermatol 2011;29:669–77. 3. Mejia JD, Egro FM, Nahai F. Visual loss after blepharoplasty: incidence, management, and preventive measures. Aesthet Surg J 2011;31:21–9.
PORNTAWEE P. APHIVANTRAKUL, BS MARY ALICE MINA, MD M. DALE SARRADET, MD Department of Dermatology Emory University Atlanta, Georgia RYAN WELLS, MD Ventura County Dermatology Camarillo, California
Cell Phone-Assisted Identification of Surgery Site Letter to the Editor: It has recently been reported that 9% of patients presenting for Mohs micrographic surgery (MMS) were unable to identify the site of a prior biopsy on the day of MMS.1 Based on survey data, this is a problem that plagues dermatologic surgeons nationwide.2 Many factors may play a role, including location, comorbidity, and lag time between biopsy and surgery. To ameliorate this problem, it has been suggested that patient cell phone cameras be used to identify biopsy sites.3 Below, we describe a recent case that highlights the utility and application of this suggestion:
A 77-year-old man presented for MMS in August 2012 for a recurrent, infiltrative basal cell carcinoma (BCC) on the posterior neck. Over the course of 4 years, the lesion had been excised on four occasions. The patient had last had an incisional biopsy 2 months prior. At the time of MMS, the patient presented with multiple well-healed incisions on the posterior neck, and no mass was identified (Figure 1). It was not clear according to physical examination where the recent biopsy had been, nor could the patient point to the exact location of the biopsy. However, he presented a cell phone picture that his medical dermatologist had taken at the time of biopsy (Figure 2). Using this image, we were able to correctly identify the site of
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LETTERS TO THE EDITOR
Together, these data suggest that cell phone cameras are ubiquitous and can be readily used to aid in correctly identifying the site of prior biopsy.
Figure 1. On exam, no obvious tumor was visualized or palpated. Proposed first Mohs layer circled in gentian violet.
Although cell phone cameras may be helpful, there are more-effective ways of photographing biopsy sites. As electronic medical records become more widely implemented, digital pictures could be obtained, stored, and transmitted directly between physicians. However, many Mohs surgeons practice at institutions different from those of the referring dermatologists, making secure passage of digital information difficult. Cell phone cameras may be more subject to operator errors, patients may be unable to find the pictures on their telephones, and images may be of variable quality, but until a more-reliable system is implemented, we believe this offers an easy-to-use solution to an important problem.
References 1. Rossy KM, Lawrence N. Difficulty with surgical site identification: what role does it play in dermatology? J Am Acad Dermatol, 2012;67:257–61. 2. Nemeth SA, Lawrence N. Site identification challenges in dermatologic surgery: a physician survey. J Am Acad Dermatol, 2012;67:262–8.
Figure 2. Cell phone picture of incisional biopsy. Confirmation that the first Mohs layer would include prior biopsy site.
biopsy, as evidenced by infiltrating BCC seen on the first Mohs layer. The tumor was ultimately cleared on the third MMS stage, leaving a 3.2- by 4.1-cm defect. According to a 2011 Pew survey, 83% of Americans have cell phones.4 It is estimated that, since 2001, nearly all cell phones have cameras.5
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3. Hussain W. Avoiding wrong site surgery—how language and technology can help. Br J Dermatol 2012;167:1186. 4. http://pewinternet.org/Reports/2011/Smartphones.aspx 5. http://www.eetasia.com/articleLogin.do? artId=8800353398&fromWhere=/ART_88003 3398_499488_NT_85fffae0.HTM&catId=499488 &newsType=NT&pageNo=null&encode=85fffae0).
MICHAEL K. LICHTMAN, MD NICHOLAS B. COUNTRYMAN, MD, MBA Laser and Skin Center of Indiana Carmel, Indiana, USA
Edited by
Keyvan Nouri, MD, Department of Dermatology & Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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Imported Skin Diseases 2ND EDITION By William R. Faber, Roderick J. Hay, Bernard Naafs
Global movement of people leads to the global movement of disease International travel enables skin diseases to move around the world with increasing ease. Skin diseases transmitted through casual contact with people, animal vectors and a foreign environment are particularly prone to transport. Dermatologists need to recognize the signs and symptoms of disease not native to their environment to enable proper diagnosis and care. Imported Skin Diseases provides a clinical guide to the foreign diseases increasingly seen in ‘Western’ clinics. With a focus on accurate diagnosis and effective therapy, the book covers: • Differences between pigmented and non-pigmented skin • Viral, bacterial and fungal Infections • Parasitic infestations
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