Background: Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. Objectives: We describe 5 cases of sarcoidosis in patients treated with vemurafenib. Methods: Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. Results: Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. Conclusion: BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.

1.
Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 2007;357:2153-2165.
2.
Valeyre D, Prasse A: Sarcoidosis. Lancet 2014;383:1155-1167.
3.
Brincker H: Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986;13:147-156.
4.
Massaguer S, Sánchez M, Castel T: Mediastinal sarcoidosis induced by high-dose alpha-2-interferon therapy in a patient with malignant melanoma. Eur Radiol 2004;14:1716-1717.
5.
Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199-6206.
6.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T,Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516.
7.
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707-714.
8.
Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK: Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist 2013;18:314-322.
9.
Zhen Y, Thomas-Schoemann A, Sakji L, Boudou-Rouquette P, Dupin N, Mortier L, Vidal M, Goldwasser F, Blanchet B: An HPLC-UV method for the simultaneous quantification of vemurafenib and erlotinib in plasma from cancer patients. J Chromatogr B Analyt Technol Biomed Life Sci 2013;928:93-97.
10.
Herbort CP, Rao NA, Mochizuki M: International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm 2009;17:160-169.
11.
Seve P, Schott AM, Pavic M, Broussolle C, Gilis L, Thomas L: Sarcoidosis and melanoma: a referral center study of 1,199 cases. Dermatology 2009;219:25-31.
12.
Suárez-García C, Pérez-Gil A, Pereira-Gallardo S, Codes-Villena M, García-Escudero A, Miguel Camacho F: Interferon-induced cutaneous sarcoidosis in melanoma. Melanoma Res 2009;19:391-394.
13.
North J, Mully T: Alpha-interferon-induced sarcoidosis mimicking metastatic melanoma. J Cutan Pathol 2011;38:585-589.
14.
Berthod G, Lazor R, Letovanec I, Romano E, Noirez L, Mazza Stalder J, Speiser DE, Peters S, Michielin O: Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol 2012;30:156-159.
15.
Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU: Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol 2012;30:7-10.
16.
Green JS, Norris DA, Wisell J: Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases. Br J Dermatol 2013;169:172-176.
17.
Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC: Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol 2014;150:307-311.
18.
Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kamsu-Kom N, Thomas M, Vagner S, Favre M, Tomasic G, Wechsler T, Lacroix L, Robert C: Cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2012;24:1691-1697.
19.
Mössner R, Zimmer L, Berking C, Hoeller C, Loquai C, Richtig E, Kähler KC, Hassel JC, Gutzmer R, Ugurel S: Erythema nodosum-like lesions during BRAF inhibitor therapy: report on 16 new cases and review of the literature. J Eur Acad Dermatol Venereol 2015;29:1797-1806.
20.
Sinha R, Edmonds K, Newton-Bishop JA, Gore ME, Larkin J, Fearfield L: Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol 2012;167:987-994.
21.
Kim GH, Levy A, Compoginis G: Neutrophilic panniculitis developing after treatment of metastatic melanoma with vemurafenib. J Cutan Pathol 2013;40:667-669.
22.
Choy B, Chou S, Anforth R, Fernández-Peñas P: Panniculitis in patients treated with BRAF inhibitors: a case series. Am J Dermatopathol 2014;36:493-497.
23.
Wilmott JS, Haydu LE, Menzies AM, Lum T, Hyman J, Thompson JF, Hersy P, Kefford RF, Scolver RA, Long GV: Dynamics of chemokine, cytokine and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. J Immunol 2014;192:2505-2513.
24.
Guedj M, Quéant A, Funck-Brentano E, Kramkimel N, Lellouch J, Monnet D, Longvert C, Gantzer A, Brézin AP: Uveitis in patients with late-stage cutaneous melanoma treated with vemurafenib. JAMA Ophthalmol 2014;132:1421-1425.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.