A diagnostic dilemma: Atypical melanocytic lesions arising in the setting of treatment with the BRAF inhibitor, vemurafenib

Abstract

IntroductionIn 2011, the Food and Drug Administration approved vemurafenib, a class 1 RAF inhibitor that is selective for BRAF, for use in unresectable or metastatic malignant melanoma. The BRAF V600E mutation is found in roughly 80%-90% of BRAF-mutated melanomas, and in about 50% of overall melanomas.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar, 2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar, 3Perier-Muzet M. Thomas L. Poulalhon N. et al.Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.J Invest Dermatol. 2014; 134: 1351-1358https://doi.org/10.1038/jid.2013.462Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Vemurafenib treatment achieved a response rate of about 50%, a stark improvement from the previous gold standard of dacarbazine chemotherapy (with a response rate around 5%).2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar,4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar Vemurafenib is also highly effective in patients with relapsed or refractory BRAF-mutated hairy cell leukemia, with overall response rates of 96%-100% in a restrictedstudy.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google ScholarThe use of BRAF inhibitors has come with a wide range of cutaneous side effects, from dermatitides and photosensitivity to atypical squamous proliferations and, more rarely, concerning melanocytic lesions.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,6Chu E.Y. Wanat K.A. Miller C.J. et al.Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.J Am Acad Dermatol. 2012; 67: 1265-1272https://doi.org/10.1016/j.jaad.2012.04.008Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Eruptive melanocytic lesions usually develop within 3 months of treatment with BRAF inhibitors and can also include darkening of preexisting nevi.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar Here, we present an interesting case of numerous eruptive atypical melanocytic lesions arising in a patient treated with vemurafenib for BRAF-mutated hairy cell leukemia. We suggest that new and evolving melanocytic lesions that are histologically concerning for melanoma should, in the context of vemurafenib treatment, be considered “atypical treatment-related melanocytic proliferations” as opposed to outright melanomas.Case reportA 62 year-old man with a history of recurrent hairy cell leukemia (BRAF V600E-mutated) presented 6 weeks after initiating vemurafenib (960 mg twice daily) with multiple new 1-3–mm dark-brown macules and papules on his scalp, trunk, and extremities (Fig 1). An initial biopsy from the posterior aspect of the left shoulder showed an atypical melanocytic lesion concerning for invasive melanoma, demonstrating full-thickness pagetoid migration overlying intradermal epithelioid melanocytic nests with rare mitoses (Fig 2). Molecular testing showed wild-type BRAF. Due to the concerning histologic changes in the initial lesion, 12 additional biopsies of new pigmented lesions were performed. Seven out of 12 subsequent biopsies showed atypical melanocytic lesions with concerning histologic features of early or evolving melanoma, including full-thickness pagetoid migration of atypical melanocytes. All lesions were symmetric at low power and the pagetoid spread did not extend beyond the nested dermal component. After outside consultation and discussion among multiple dermatopathologists, the consensus was that these lesions should be classified as “atypical treatment-related melanocytic proliferations” The remaining lesions sampled showed compound nevi with mild or moderate atypia. Vemurafenib was discontinued after 10 total weeks of treatment, due to the development of these concerning melanocytic lesions. The most atypical lesions were treated with conservative re-excision. At follow-up 5 months and 12 months after stopping vemurafenib, the patient had resolution of many of the remaining eruptive melanocytic lesions clinically.Fig 2Shave biopsy of the posterior aspect of the left shoulder showing an atypical melanocytic proliferation with histologic features concerning for malignant melanoma in situ with possible invasion. A, Compound melanocytic proliferation with relative symmetry at low power (hematoxylin-eosin stain; magnification ×40). B, Atypical junctional melanocytes with significant pagetoid spread (hematoxylin-eosin stain; magnification ×200). C, Prominent full-thickness pagetoid spread of melanocytes (Sox10 immunohistochemical stain, magnification ×100). D, Dermal nests of epithelioid melanocytes with rare deep dermal mitotic figure (black arrow) (hematoxylin-eosin stain; magnification ×400).View Large Image Figure ViewerDownload Hi-res image Download (PPT)DiscussionCutaneous adverse events occur in roughly 50% of patients treated with BRAF inhibitors for metastatic melanoma.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar These side effects include benign entities, such as acneiform facial eruptions, other dermatitidis, follicular eruptions, Grover disease, hair changes with alopecia, palmoplantar erythrodysesthesia, panniculitis, keratotic or verrucous papules, and photosensitivity. They also commonly include squamous cell carcinoma (keratoacanthoma-type commonly), as well as changing or atypical nevi and even melanoma.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar Eruptive melanocytic nevi have been described in about 10% of patients receiving vemurafenib.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar New primary melanomas as a result of vemurafenib treatment have been reported in approximately 2% of patients treated for metastatic melanoma and are invariably BRAF wild-type.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar While eruptive melanocytic lesions in patients treated for metastatic melanoma are well documented, there are only few reports of new melanomas developing during the treatment of non-melanoma malignancies.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar A single case of cutaneous melanoma was reported by Tiacci et al in a study of patients treated with vemurafenib for hairy cell leukemia.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar The changes seen in new or evolving melanocytic lesions are thought to arise not from direct tumor promotion but from a paradoxical activation of the MAPK pathway in RAS-mutated or BRAF wild-type cells.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar Combination therapies with BRAF and MEK inhibitors may help limit the development of secondary tumors caused by this paradoxical activation.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar,9Giurcaneanu C. Nitipir C. Popa L.G. Forsea A.M. Popescu I. Bumbacea R.S. Evolution of melanocytic nevi under vemurafenib, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.Acta Dermatovenerol Croat. 2015; 23: 114-121PubMed Google ScholarWhat has not been sufficiently studied is the criteria for diagnosing melanoma in patients treated with these drugs. Studying the natural progression is difficult, as standard of care indicates excision of worrisome lesions. However, in order to prevent unnecessary wide excisions, pathologists should be aware that, in the context of vemurafenib treatment, some microscopic features otherwise associated with melanoma, such as pagetoid spread or a mitotic figure, may not be sufficient, unless additional evidence (eg, marked asymmetry, nuclear pleomorphism, positive ancillary test results) support the diagnosis of melanoma. If there is uncertainty as to whether a lesion represents true melanoma, we recommend reporting it as an “atypical treatment-related melanocytic proliferation.” While larger studies are needed to create usable guidelines for diagnosing and treating these emerging lesions, with borderline cases, a conservative re-excision may be preferable to the standard wide local excision.Clinicians using BRAF inhibitors should be aware of these melanocytic side effects and the diagnostic and treatment challenges that might arise. Documentation of skin appearance prior to treatment and appropriate sequential follow-up over the course of treatment continues to be crucial for management. IntroductionIn 2011, the Food and Drug Administration approved vemurafenib, a class 1 RAF inhibitor that is selective for BRAF, for use in unresectable or metastatic malignant melanoma. The BRAF V600E mutation is found in roughly 80%-90% of BRAF-mutated melanomas, and in about 50% of overall melanomas.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar, 2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar, 3Perier-Muzet M. Thomas L. Poulalhon N. et al.Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.J Invest Dermatol. 2014; 134: 1351-1358https://doi.org/10.1038/jid.2013.462Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Vemurafenib treatment achieved a response rate of about 50%, a stark improvement from the previous gold standard of dacarbazine chemotherapy (with a response rate around 5%).2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar,4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar Vemurafenib is also highly effective in patients with relapsed or refractory BRAF-mutated hairy cell leukemia, with overall response rates of 96%-100% in a restrictedstudy.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google ScholarThe use of BRAF inhibitors has come with a wide range of cutaneous side effects, from dermatitides and photosensitivity to atypical squamous proliferations and, more rarely, concerning melanocytic lesions.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,6Chu E.Y. Wanat K.A. Miller C.J. et al.Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.J Am Acad Dermatol. 2012; 67: 1265-1272https://doi.org/10.1016/j.jaad.2012.04.008Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Eruptive melanocytic lesions usually develop within 3 months of treatment with BRAF inhibitors and can also include darkening of preexisting nevi.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar Here, we present an interesting case of numerous eruptive atypical melanocytic lesions arising in a patient treated with vemurafenib for BRAF-mutated hairy cell leukemia. We suggest that new and evolving melanocytic lesions that are histologically concerning for melanoma should, in the context of vemurafenib treatment, be considered “atypical treatment-related melanocytic proliferations” as opposed to outright melanomas. In 2011, the Food and Drug Administration approved vemurafenib, a class 1 RAF inhibitor that is selective for BRAF, for use in unresectable or metastatic malignant melanoma. The BRAF V600E mutation is found in roughly 80%-90% of BRAF-mutated melanomas, and in about 50% of overall melanomas.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar, 2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar, 3Perier-Muzet M. Thomas L. Poulalhon N. et al.Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.J Invest Dermatol. 2014; 134: 1351-1358https://doi.org/10.1038/jid.2013.462Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Vemurafenib treatment achieved a response rate of about 50%, a stark improvement from the previous gold standard of dacarbazine chemotherapy (with a response rate around 5%).2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar,4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar Vemurafenib is also highly effective in patients with relapsed or refractory BRAF-mutated hairy cell leukemia, with overall response rates of 96%-100% in a restrictedstudy.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar The use of BRAF inhibitors has come with a wide range of cutaneous side effects, from dermatitides and photosensitivity to atypical squamous proliferations and, more rarely, concerning melanocytic lesions.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,6Chu E.Y. Wanat K.A. Miller C.J. et al.Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.J Am Acad Dermatol. 2012; 67: 1265-1272https://doi.org/10.1016/j.jaad.2012.04.008Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Eruptive melanocytic lesions usually develop within 3 months of treatment with BRAF inhibitors and can also include darkening of preexisting nevi.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar Here, we present an interesting case of numerous eruptive atypical melanocytic lesions arising in a patient treated with vemurafenib for BRAF-mutated hairy cell leukemia. We suggest that new and evolving melanocytic lesions that are histologically concerning for melanoma should, in the context of vemurafenib treatment, be considered “atypical treatment-related melanocytic proliferations” as opposed to outright melanomas. Case reportA 62 year-old man with a history of recurrent hairy cell leukemia (BRAF V600E-mutated) presented 6 weeks after initiating vemurafenib (960 mg twice daily) with multiple new 1-3–mm dark-brown macules and papules on his scalp, trunk, and extremities (Fig 1). An initial biopsy from the posterior aspect of the left shoulder showed an atypical melanocytic lesion concerning for invasive melanoma, demonstrating full-thickness pagetoid migration overlying intradermal epithelioid melanocytic nests with rare mitoses (Fig 2). Molecular testing showed wild-type BRAF. Due to the concerning histologic changes in the initial lesion, 12 additional biopsies of new pigmented lesions were performed. Seven out of 12 subsequent biopsies showed atypical melanocytic lesions with concerning histologic features of early or evolving melanoma, including full-thickness pagetoid migration of atypical melanocytes. All lesions were symmetric at low power and the pagetoid spread did not extend beyond the nested dermal component. After outside consultation and discussion among multiple dermatopathologists, the consensus was that these lesions should be classified as “atypical treatment-related melanocytic proliferations” The remaining lesions sampled showed compound nevi with mild or moderate atypia. Vemurafenib was discontinued after 10 total weeks of treatment, due to the development of these concerning melanocytic lesions. The most atypical lesions were treated with conservative re-excision. At follow-up 5 months and 12 months after stopping vemurafenib, the patient had resolution of many of the remaining eruptive melanocytic lesions clinically. A 62 year-old man with a history of recurrent hairy cell leukemia (BRAF V600E-mutated) presented 6 weeks after initiating vemurafenib (960 mg twice daily) with multiple new 1-3–mm dark-brown macules and papules on his scalp, trunk, and extremities (Fig 1). An initial biopsy from the posterior aspect of the left shoulder showed an atypical melanocytic lesion concerning for invasive melanoma, demonstrating full-thickness pagetoid migration overlying intradermal epithelioid melanocytic nests with rare mitoses (Fig 2). Molecular testing showed wild-type BRAF. Due to the concerning histologic changes in the initial lesion, 12 additional biopsies of new pigmented lesions were performed. Seven out of 12 subsequent biopsies showed atypical melanocytic lesions with concerning histologic features of early or evolving melanoma, including full-thickness pagetoid migration of atypical melanocytes. All lesions were symmetric at low power and the pagetoid spread did not extend beyond the nested dermal component. After outside consultation and discussion among multiple dermatopathologists, the consensus was that these lesions should be classified as “atypical treatment-related melanocytic proliferations” The remaining lesions sampled showed compound nevi with mild or moderate atypia. Vemurafenib was discontinued after 10 total weeks of treatment, due to the development of these concerning melanocytic lesions. The most atypical lesions were treated with conservative re-excision. At follow-up 5 months and 12 months after stopping vemurafenib, the patient had resolution of many of the remaining eruptive melanocytic lesions clinically. DiscussionCutaneous adverse events occur in roughly 50% of patients treated with BRAF inhibitors for metastatic melanoma.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar These side effects include benign entities, such as acneiform facial eruptions, other dermatitidis, follicular eruptions, Grover disease, hair changes with alopecia, palmoplantar erythrodysesthesia, panniculitis, keratotic or verrucous papules, and photosensitivity. They also commonly include squamous cell carcinoma (keratoacanthoma-type commonly), as well as changing or atypical nevi and even melanoma.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar Eruptive melanocytic nevi have been described in about 10% of patients receiving vemurafenib.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar New primary melanomas as a result of vemurafenib treatment have been reported in approximately 2% of patients treated for metastatic melanoma and are invariably BRAF wild-type.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar While eruptive melanocytic lesions in patients treated for metastatic melanoma are well documented, there are only few reports of new melanomas developing during the treatment of non-melanoma malignancies.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar A single case of cutaneous melanoma was reported by Tiacci et al in a study of patients treated with vemurafenib for hairy cell leukemia.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar The changes seen in new or evolving melanocytic lesions are thought to arise not from direct tumor promotion but from a paradoxical activation of the MAPK pathway in RAS-mutated or BRAF wild-type cells.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar Combination therapies with BRAF and MEK inhibitors may help limit the development of secondary tumors caused by this paradoxical activation.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar,9Giurcaneanu C. Nitipir C. Popa L.G. Forsea A.M. Popescu I. Bumbacea R.S. Evolution of melanocytic nevi under vemurafenib, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.Acta Dermatovenerol Croat. 2015; 23: 114-121PubMed Google ScholarWhat has not been sufficiently studied is the criteria for diagnosing melanoma in patients treated with these drugs. Studying the natural progression is difficult, as standard of care indicates excision of worrisome lesions. However, in order to prevent unnecessary wide excisions, pathologists should be aware that, in the context of vemurafenib treatment, some microscopic features otherwise associated with melanoma, such as pagetoid spread or a mitotic figure, may not be sufficient, unless additional evidence (eg, marked asymmetry, nuclear pleomorphism, positive ancillary test results) support the diagnosis of melanoma. If there is uncertainty as to whether a lesion represents true melanoma, we recommend reporting it as an “atypical treatment-related melanocytic proliferation.” While larger studies are needed to create usable guidelines for diagnosing and treating these emerging lesions, with borderline cases, a conservative re-excision may be preferable to the standard wide local excision.Clinicians using BRAF inhibitors should be aware of these melanocytic side effects and the diagnostic and treatment challenges that might arise. Documentation of skin appearance prior to treatment and appropriate sequential follow-up over the course of treatment continues to be crucial for management. Cutaneous adverse events occur in roughly 50% of patients treated with BRAF inhibitors for metastatic melanoma.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar These side effects include benign entities, such as acneiform facial eruptions, other dermatitidis, follicular eruptions, Grover disease, hair changes with alopecia, palmoplantar erythrodysesthesia, panniculitis, keratotic or verrucous papules, and photosensitivity. They also commonly include squamous cell carcinoma (keratoacanthoma-type commonly), as well as changing or atypical nevi and even melanoma.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar Eruptive melanocytic nevi have been described in about 10% of patients receiving vemurafenib.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar New primary melanomas as a result of vemurafenib treatment have been reported in approximately 2% of patients treated for metastatic melanoma and are invariably BRAF wild-type.4Carrera C. Puig-Butillè J.A. Tell-Marti G. et al.Multiple BRAF wild-type melanomas during dabrafenib treatment for metastatic BRAF-mutant melanoma.JAMA Dermatol. 2015; 151: 544-548https://doi.org/10.1001/jamadermatol.2014.4115Crossref PubMed Scopus (16) Google Scholar While eruptive melanocytic lesions in patients treated for metastatic melanoma are well documented, there are only few reports of new melanomas developing during the treatment of non-melanoma malignancies.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar,8Cohen P.R. Bedikian A.Y. Kim K.B. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib.J Clin Aesthet Dermatol. 2013; 6: 27-37PubMed Google Scholar A single case of cutaneous melanoma was reported by Tiacci et al in a study of patients treated with vemurafenib for hairy cell leukemia.5Tiacci E. Park J.H. De Carolis L. et al.Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia.N Engl J Med. 2015; 373: 1733-1747https://doi.org/10.1056/NEJMoa1506583Crossref PubMed Scopus (218) Google Scholar The changes seen in new or evolving melanocytic lesions are thought to arise not from direct tumor promotion but from a paradoxical activation of the MAPK pathway in RAS-mutated or BRAF wild-type cells.1Zimmer 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; 30: 2375-2383https://doi.org/10.1200/JCO.2011.41.1660Crossref PubMed Scopus (192) Google Scholar,2Göppner D. Müller J. Krüger S. Franke I. Gollnick H. Quist S.R. High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.Acta Derm Venereol. 2014; 94: 517-520https://doi.org/10.2340/00015555-1813Crossref PubMed Scopus (19) Google Scholar Combination therapies with BRAF and MEK inhibitors may help limit the development of secondary tumors caused by this paradoxical activation.7Chen F.W. Tseng D. Reddy S. Daud A.I. Swetter S.M. Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.JAMA Dermatol. 2014; 150: 1209-1212https://doi.org/10.1001/jamadermatol.2014.838Crossref PubMed Scopus (23) Google Scholar,9Giurcaneanu C. Nitipir C. Popa L.G. Forsea A.M. Popescu I. Bumbacea R.S. Evolution of melanocytic nevi under vemurafenib, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.Acta Dermatovenerol Croat. 2015; 23: 114-121PubMed Google Scholar What has not been sufficiently studied is the criteria for diagnosing melanoma in patients treated with these drugs. Studying the natural progression is difficult, as standard of care indicates excision of worrisome lesions. However, in order to prevent unnecessary wide excisions, pathologists should be aware that, in the context of vemurafenib treatment, some microscopic features otherwise associated with melanoma, such as pagetoid spread or a mitotic figure, may not be sufficient, unless additional evidence (eg, marked asymmetry, nuclear pleomorphism, positive ancillary test results) support the diagnosis of melanoma. If there is uncertainty as to whether a lesion represents true melanoma, we recommend reporting it as an “atypical treatment-related melanocytic proliferation.” While larger studies are needed to create usable guidelines for diagnosing and treating these emerging lesions, with borderline cases, a conservative re-excision may be preferable to the standard wide local excision. Clinicians using BRAF inhibitors should be aware of these melanocytic side effects and the diagnostic and treatment challenges that might arise. Documentation of skin appearance prior to treatment and appropriate sequential follow-up over the course of treatment continues to be crucial for management. None disclosed.