Letters is typically a chronic condition that negatively influences qual- OBSERVATION ity of life and in which full remission may take years. Although Extensive Pigment Incontinence Mimicking this is the largest reported cohort of patients with CADM to date, Persistent Melanoma After Talimogene our study is limited by small sample size, lack of an available skin Laherparepvec Therapy severity measure given its retrospective nature, and potential in- Talimogene laherparepvec (TVEC) is a genetically modified, creased disease severity among patients in tertiary care centers. live oncolytic herpes simplex virus 1 therapy containing the Further studies are warranted to better characterize therapeutic granulocyte macrophage colony stimulating factor gene response in CADM. (GM-CSF). Approved by the US Food and Drug Administra- Joanie Pinard, MD, FRCPC tion in 2015 for treatment of unresectable melanoma in the skin Alisa N. Femia, MD and lymph nodes, this injectable immunotherapy delivers an Michael Roman, BS antitumor effect through improved antigen presentation, Abeer Alsarheed, MD 1 T-cell priming, and by direct lysis of tumor cells. Response to Cara Joyce, PhD therapy is generally assessed clinically through lesion regres- Janice Lin, MD, MPH sion. However, assessment may be confounded by pigment re- Ruth Ann Vleugels, MD, MPH tention in the absence of persistent melanoma. Author Affiliations: Department of Dermatology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts (Pinard, Report of a Case | A 48-year-old man was diagnosed with a non- Alsarheed, Lin, Vleugels); Department of Dermatology, New York University ulcerated, 0.87-mm, Clark level IV superficial spreading mela- Ronald O. Perelman School of Medicine, New York (Femia, Roman); Department noma on the scalp with 2 mitoses\/mm and lymphovascular in- of Public Health Sciences, Loyola University, Chicago, Illinois (Joyce); Division of Immunology & Rheumatology, Department of Medicine, Stanford University vasion. After a wide local excision and skin graft, extensive School of Medicine, Palo Alto, California (Lin). pigmented plaques and nodules grew within months around the Accepted for Publication: November 17, 2018. graft site. A positron-emission tomography\/computed tomogra- Corresponding Author: Ruth Ann Vleugels, MD, MPH, Department of phy scan revealed a focus of avidity in the colon, found to be a Dermatology, Brigham and Women\u2019s Hospital and Harvard Medical School, 221 polyp on colonoscopy. Findings of brain magnetic resonance Longwood Ave, Boston, MA 02115 (email@example.com). Published Online: January 23, 2019. doi:10.1001\/jamadermatol.2018.5215 imaging were negative. The patient began treatment with pem- Author Contributions: Drs Pinard and Vleugels had full access to all of the data brolizumab for unresectable melanoma, but owing to tumor pro- in the study and take responsibility for the integrity of the data and the accuracy gression after 3 cycles of therapy, TVEC was added. After 2 TVEC of the data analysis. Drs Pinard and Femia are co\u2013first authors. Drs Lin and Vleugels are co\u2013last authors. Concept and design: Pinard, Femia, Lin, Vleugels. Figure 1. Response to Talimogene Laherparepvec Therapy for Melanoma Acquisition, analysis, or interpretation of data: Pinard, Femia, Roman, Alsarheed, of the Scalp Joyce, Lin, Vleugels. Drafting of the manuscript: Pinard, Femia, Lin, Vleugels. Critical revision of the manuscript for important intellectual content: Femia, Roman, Alsarheed, Joyce, Vleugels. Statistical analysis: Joyce, Lin. Administrative, technical, or material support: Pinard, Vleugels. Supervision: Femia. Conflict of Interest Disclosures: Dr Pinard reported serving as consultant\/ advisor for Celgene, Actelion, Janssen, Eli Lilly, and Novartis Canada. No other disclosures were reported. 1. Bendewald MJ, Wetter DA, Li X, Davis MD. Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota. Arch Dermatol. 2010;146(1):26-30. doi:10.1001\/archdermatol. 2009.328 2. Gerami P, Schope JM, McDonald L, Walling HW, Sontheimer RD. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis sin\u00e9 myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol. 2006;54(4):597-613. doi:10.1016\/j.jaad.2005. 10.041 3. Callander J, Robson Y, Ingram J, Piguet V. Treatment of clinically amyopathic dermatomyositis in adults: a systematic review. [published online May 11, 2016]. Br J Dermatol. 2018;179(6):1248-1255. doi:10.1111\/bjd.14726 4. Galimberti F, Li Y, Fernandez AP. Clinically amyopathic dermatomyositis: clinical features, response to medications and malignancy-associated risk factors in a specific tertiary-care-centre cohort. Br J Dermatol. 2016;174(1):158-164. doi:10.1111\/ bjd.14227 5. Pelle MT, Callen JP. Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol. 2002;138(9):1231-1233. doi:10.1001\/ archderm.138.9.1231 6. Femia AN, Eastham AB, Lam C, Merola JF, Qureshi AA, Vleugels RA. Intravenous immunoglobulin for refractory cutaneous dermatomyositis: After 5 talimogene laherparepvec treatments, physical examination revealed a retrospective analysis from an academic medical center. J Am Acad Dermatol. extensive black macules and patches within and outside of the graft. 2013;69(4):654-657. doi:10.1016\/j.jaad.2013.06.007 496 JAMA Dermatology April 2019 Volume 155, Number 4 (Reprinted) jamadermatology.com \u00a9 2019 American Medical Association. All rights reserved. Letters Figure 2. Histological Examination of Lesional Scalp Specimens Following Talimogene Laherparepvec Therapy (Original Magnification \u00d710) A Hematoxylin-eosin B Melan-A stain A, Hematoxylin-eosin staining reveals dense, bandlike melanin pigment incontinence in the upper dermis with an overlying Grenz zone; numerous melanophages but no melanoma cells were identified. B, Melan-A staining confirms the absence of melanoma in the epidermis and dermis. treatments,thescalptumorscrustedandflattened.Afterthefifth tified in an area not injected with TVEC, suggesting a localized treatment, the patient reported malaise, and treatment was held. inflammatory response and melanoma cell death beyond the di- Each TVEC treatment was 3 to 4 mL of total volume; 3 of the larg- rect sites of injection. Identifying the exact perimeter of dis- est areas were injected on the first cycle, and 6 were injected on ease response to TVEC injections would require further study. the next 4 cycles. While further studies are needed to establish the preva- Physical examination revealed numerous black smooth lence, significance, and long-term outcomes with pigment in- macules and patches within and outside the graft (Figure 1). continence after TVEC therapy, the present case suggests that Dermoscopy revealed diffuse black structureless pigment spar- skin biopsies may be critical for determining disease response ing follicular and eccrine units. Given the possibility of per- and future management. Failure to recognize pigment inconti- sistent melanoma, 3 biopsies of the involved scalp were taken: nence may result in unnecessary continuation of treatment, 2 in areas of previous TVEC injection and 1 in an area not pre- higher costs, and patient distress. viously injected. All biopsy specimens showed prominent up- Melissa Danesh, MD per dermal melanophages associated with a lymphoplasma- Beverly Faulkner-Jones, MD, PhD cytic infiltrate (Figure 2A). No melanoma was identified on Anupam Desai, MD Melan-A immunostaining (Figure 2B). As no melanoma was Caroline C. Kim, MD found in the skin or on imaging, therapy was held and obser- vation recommended. Author Affiliations: Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Corresponding Author: Caroline C. Kim, MD, Department of Dermatology, Discussion | A new injectable immunotherapy, TVEC is available Pigmented Lesion Clinic, Cutaneous Oncology Program, Harvard Medical for patients with unresectable melanoma, and dermatologists School, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA need to be familiar with this treatment. Despite its local admin- 02215 (firstname.lastname@example.org). Published Online: February 13, 2019. doi:10.1001\/jamadermatol.2018.5347 istration to tumors, TVEC has been shown to initiate a systemic Conflict of Interest Disclosures: None reported. response in a phase 3 study of unresectable stage IIIB or IV mela- Additional Contributions: We thank the patient for granting permission to noma,demonstratingadurableresponserate(lasting\u22656months) publish this information. of 16.3% compared with 2.1% with GM-CSF. In an analysis of 1. Ott PA, Hodi FS. Talimogene Laherparepvec for the Treatment of Advanced patients with stage IIIB-IVM1 disease, 10.8% of patients treated Melanoma. Clin Cancer Res. 2016;22(13):3127-3131. doi:10.1158\/1078-0432.CCR-15- with TVEC showed a complete response compared with no pa- tients treated with GM-CSF. The most common adverse ef- 2. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. fects reported with TVEC are fatigue, chills, pyrexia, nausea, flu- 2 2015;33(25):2780-2788. doi:10.1200\/JCO.2014.58.3377 like symptoms, and pain at the injection site. 3. Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene One effect of TVEC that has not been well documented is pig- laherparepvec versus granulocyte-macrophage colony-stimulating factor in ment incontinence. Early phase 2 trials of TVEC alluded to pig- patients with stage IIIB\/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial. Onco Targets Ther. 2016;9:7081-7093. doi:10.2147\/OTT.S115245 ment incontinence in 1 of 50 patients treated. A recent case se- 4. Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a ries of 5 patients with melanoma treated with TVEC showed granulocyte-macrophage colony-stimulating factor-encoding, second-generation granulomatous dermatitis at sites of injection, with granuloma oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. formation and pigment incontinence on histopathologic 2009;27(34):5763-5771. doi:10.1200\/JCO.2009.24.3675 analysis. The present case is an example of extensive pigment 5. Everett AS, Pavlidakey PG, Contreras CM, et al. Chronic granulomatous incontinence after TVEC therapy with no evidence of granulo- dermatitis induced by talimogene laherparepvec therapy of melanoma matousdermatitis.Interestingly,pigmentincontinencewasiden- metastases. J Cutan Pathol. 2018;45(1):48-53. doi:10.1111\/cup.13048 jamadermatology.com (Reprinted) JAMA Dermatology April 2019 Volume 155, Number 4 497 \u00a9 2019 American Medical Association. All rights reserved.