OBSERVATION

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Dynamic Changes in Nevi of a Patient With Melanoma Treated With Vemurafenib Importance of Sequential Dermoscopy Holger A. Haenssle, MD; Sophie L. Kraus, MD; Franziska Brehmer, MD; Lutz Kretschmer, MD; Bernward Vo¨lker, MD; Hiba Asper, MD; Alexander Kapp, MD; Ralf Gutzmer, MD

Background: Therapy with vemurafenib, an inhibitor

of mutated BRAF, yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation. As an adverse effect of vemurafenib, proliferative disorders of keratinocytes, including squamous cell carcinoma, have been described. Low concentration of vemurafenib as present in the epidermis were found to activate wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. Observation: We present the case of a patient with dynamic changes of melanocytic nevi well documented by sequential digital dermoscopy during vemurafenib

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Author Affiliations: Department of Dermatology, Venereology, and Allergology, Georg-August-University Go¨ttingen, Go¨ttingen, Germany (Drs Haenssle, Kraus, Brehmer, and Kretschmer); Department of Pathology Krankenhaus Nordstadt Klinikum Region Hannover, Hannover, Germany (Dr Vo¨lker); and Department of Dermatology and Allergy, Skin Cancer Center Hannover, Medizinische Hochschule, Hannover (Drs Asper, Kapp, and Gutzmer).

therapy. A variety of dermoscopic changes were observed. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. Second, preexisting nevi increased in size, and pigmentation that rendered them atypical. Such lesions were flat and showed a predominant reticular pattern at baseline. Third, multiple new nevi occurred. One example of each of the latter 2 categories was excised and showed wild-type BRAF. Conclusion: Our findings of changing nevi in a patient

treated with vemurafenib highlight the need for sequential skin examinations, including dermoscopy. Arch Dermatol. 2012;148(10):1183-1185. Published online August 20, 2012. doi:10.1001/archdermatol.2012.2649

NHIBITORS OF ONCOGENIC BRAF,

such as vemurafenib and dabrafenib, termed type I BRAF inhibitors, block the active conformation of the BRAF kinase. Their clinical application has led to a high rate of objective tumor responses and improvement in overall survival in patients with metastatic melanoma harboring a BRAF V600E mutation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. Herein, we report dynamic changes of nevi in a patient treated with vemurafenib that were detected by sequential digital dermoscopy. REPORT OF A CASE

A 56-year-old woman with atypical mole syndrome, Fitzpatrick skin type II, and metastasizing melanoma harboring a BRAF V600E mutation showed stable melanocytic lesions by sequential digital dermoscopy before starting treatment with the

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BRAF inhibitor vemurafenib (960 mg orally twice a day). After 3 months of treatment and a partial response of metastatic melanoma lesions, dynamic changes within preexisting melanocytic nevi were noticed in comparison with baseline images. Most compound nevi with a papillomatous center and a globular or mixed globular and homogeneous dermoscopic pattern showed a homogeneous decrease in pigmentation, thickness, and number of visible blood vessels consistent with a rapid involution or senescence without clear signs of an immunologic regression (ie, small gray dots, white areas) ( Figure 1 A-F, FotoFinder dermoscope). No signs of halo nevus formation or vitiligo were found. On the contrary, 2 flat lesions with a more reticular dermoscopic pattern showed an increase in pigmentation. One of these developed an unusual central dark-purple color and also increased in size (Figure 1G-I). Moreover, in comparison with baseline overview images, at least 3 new melanocytic lesions with dermoscopic signs of activation, (eg, dark brownish-purple pigmen-

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Author Affil Department Venereology, Georg-Augu Go¨ttingen, G (Drs Haenssl and Kretschm of Pathology Nordstadt K Hannover, H (Dr Vo¨lker); Dermatology Cancer Cent Medizinisch Hannover (D and Gutzme

tation, dots, and globules) were documented (Figure 1J and K). The remaining lesions were unchanged. The histopathologic analyses of the 2 most atypical lesions (Figure 1G-K) revealed melanocytic nevi with cytologic dysplasia, melanophages, and lymphohistiocytic inflammation in the dermis but sharply demarcated with only minimal asymmetry and without mitoses in the dermal compartment. The lesion from the right A

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buttock showed a suprabasal spreading in the central part as well as fibroplasia in the papillary dermis and was therefore difficult to distinguish from initial melanoma (Figure 2). Immunohistochemical stainings for phosphohistone H3 (PH3) and Ki-67 antigen (MIB-1 antibody) showed no evidence for an increased mitotic activity in both lesions. For molecular analyses of both tumor specimens, DNA was extracted (QIAamp DNA FFPE-kit, Qiagen) and submitted to amplification by sequence-specific primers for codons 600 and 466-469 of the BRAF gene followed by pyrosequencing using the Pyromark Q24 BRAF kit following the instructions of the manufacturer (Qiagen). Both specimens revealed a BRAF wild-type mutational status. COMMENT

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Figure 1. Clinical and dermoscopic analysis of representative melanocytic lesions at baseline and after 3 months of vemurafenib treatment. A-F, Centrally papillomatous nevi with a mixed globular and homogeneous dermoscopic pattern show a uniformly decrease in pigmentation and thickness. G-I, Flat reticular lesion with increasing size and pigmentation. Newly developed irregular dark-brown-purple pigmentation in the center of the lesion led to the decision to excise (I). J and K, Newly developed lesion. The lesion was excised (K) owing to a central irregular dark brownish-purple pigmentation.

Therapy with vemurafenib yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation.1-3 However, as an adverse effect of vemurafenib, proliferative disorders of keratinocytes have been described in approximately 30% of patients. Clinicohistologically these lesions can resemble squamous cell carcinoma, often of the keratoakanthoma subtype) or seborrhoic, verrucalike, or follicular hyperkeratoses that develop within a few weeks after initiation of treatment.1,3 Extensive research has been performed to understand the pathogenetic mechanisms, and it has been shown that a low concentration of vemurafenib (as present in the epidermis) can lead to activation of wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation.4,5 While activating BRAF mutations occur in approximately 50% of melanomas, they are also frequently observed in melanocytic nevi.6,7 However, to our knowledge there are only 2 reports8,9 thus far that described the formation of atypical melanocytic proliferations and new primary melanomas in patients undergoing selective BRAF

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Figure 2. Histologic analysis of newly developed lesion. The newly developed lesion from the right buttock shows cytologic dysplasia, melanophages, and lymphohistiocytic inflammation in the dermis suprabasal spreading in the central part as well as fibroplasia in the papillary dermis made it difficult to distinguish from initial melanoma. Hematoxylin-eosin, original magnification ⫻4 (A) and ⫻10 (B).

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inhibition. All melanocytic lesions reported were BRAF wild-type. However, the authors provided no information about dermoscopic patterns of changing lesions or details about observed changes. We present a case with well-documented dynamic changes of melanocytic nevi during vemurafenib therapy. In our patient, we observed a variety of changes in melanocytic nevi. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. It is tempting to speculate that they carry an activating BRAF mutation and are therefore also targeted by vemurafenib. Our hypothesis is in line with that of a previous study that found BRAF mutations to be highly frequent in nevi classified as globular by dermoscopy and as dermal or compound nevi by histopathologic analysis. 7 Second, preexisting nevi increased in size and pigmentation that rendered them atypical. Such lesions were flat with a predominant reticular pattern at baseline. The study by Zalaudek et al7 and our analysis of 1 excised lesion showed that in most reticular pattern nevi, no BRAF-mutated clones could be found. Third, multiple new nevi occurred, which is quite unusual at the age of our patient. One example of each of the latter 2 categories was excised and showed wild-type BRAF. Our hypothesis of a paradoxical activation of the a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway, a signaling cascade to regulate cellular proliferation and survival, in BRAF-wild-type melanocytic lesions is supported by 2 earlier investigations8,9 that reported a BRAF-wild-type mutational status for all progressive melanomas and atypical nevi excised during vemurafenib treatment. Our findings of changing nevi in a patient treated with vemurafenib highlight the need for sequential skin examinations including dermoscopy. With regard to the rate of change and the severity of atypia in some of the observed melanocytic lesions, screening intervals of at least 3 months seem most reasonable. Accepted for Publication: June 9, 2012. Published Online: August 20, 2012. doi:10.1001 /archdermatol.2012.2649 Correspondence: Holger A. Haenssle, MD, Department of Dermatology, Venereology, and Allergology, Georg August University Go¨ttingen, Robert-Koch-Strasse 40, 37075 Go¨ ttingen, Germany (h.haenssle@med .uni-goettingen.de).

Author Contributions: Dr Haenssle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haenssle, Kretschmer, Kapp, and Gutzmer. Acquisition of data: Haenssle, Kraus, Brehmer, Vo¨lker, Asper, and Gutzmer. Analysis and interpretation of data: Haenssle, Kretschmer, Vo¨lker, and Gutzmer. Drafting of the manuscript: Haenssle and Gutzmer. Critical revision of the manuscript for important intellectual content: Haenssle, Kraus, Brehmer, Kretschmer, Vo¨lker, Asper, Kapp, and Gutzmer. Administrative, technical, and material support: Haenssle, Asper, Kapp, and Gutzmer. Study supervision: Haenssle, Kretschmer, and Kapp. Financial Disclosure: Dr Asper has received travel and meeting support from Roche Pharma. Dr Gutzmer has received honoraria, project support, and travel and meeting support from Roche Pharma. Funding/Support: This work was partially supported by a grant from the Niedersa¨chsische Krebsgesellschaft e.V., Hannover, Germany. Drs Haenssle, Kraus, and Brehmer were supported by a grant from the German Federal Ministry of Research and Technology (ZIM-KOOP program, grant No. KF2111209FR1). The FotoFinder dermoscope used in this study is a donation of FotoFinder Systems GmbH (Bad Birnbach, Germany) to the University Medical Center of Go¨ttingen. REFERENCES 1. Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. 2. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819. 3. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714. 4. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30(3):316-321. 5. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3): 207-215. 6. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19-20. 7. Zalaudek I, Guelly C, Pellacani G, et al. The dermoscopical and histopathological patterns of nevi correlate with the frequency of BRAF mutations. J Invest Dermatol. 2011;131(2):542-545. 8. Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;365(15):1448-1449. 9. Zimmer L, Hillen U, Livingstone E, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012;22(11):33-44.

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