Distinctive clinical and histologic features in cutaneous melanoma with copy number gains in 8q24.

Cutaneous melanoma may be quite heterogeneous in its clinical, histologic, and molecular features. Yet, the current classification of melanoma is limited to 4 main subtypes on the basis of clinical and histopathologic features and has shown limited impact on clinical management including prognostication and treatment. Advances in our understanding of the driving molecular pathways in melanoma and the importance of the mitogen-activated protein kinase pathway have shown that specific activating mutations in oncogenes may correlate with characteristic clinical and histologic features. We evaluated 40 melanoma cases with gains in MYC at 8q24, and we show that their characteristic features include aggressive clinical course, occurrence in nonchronically sun-damaged skin, amelanotic clinical and histopathologic appearance, a nodular or primary dermal growth pattern by histology, frequent epidermal consumption, and infrequent association with a precursor nevus. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutation status was also determined. The presence of these mutations was comparable to frequencies previously reported from nonchronically sun-damaged skin. However, the BRAF mutant cases did not show histopathologic features considered characteristic of BRAF mutant melanoma. Considering these distinct clinical and histopathologic features and the possible role as a theragnostic tool, it may be of value to consider 8q24 status in cutaneous melanoma in addition to the mutation status of BRAF in future studies integrating molecular findings into the classification system for cutaneous melanoma.

Melanocytic nevi with an atypical epithelioid cell component: clinical, histopathologic, and fluorescence in situ hybridization findings.

Combined melanocytic nevi can contain a phenotypically distinct population of large atypical epithelioid cells in a background of smaller banal-appearing melanocytes. On the basis of the pattern of proliferation and degree of pigmentation, nevi with this pattern have been referred to as nevi with an atypical epithelioid cell component (N-AECC). When N-AECC display sheet-like or an expansile nodular growth pattern, notable cytologic atypia, and any level of mitotic activity, they can be difficult to distinguish from melanoma. The clinical history and appearance of these lesions may similarly raise concern for melanoma. In view of this diagnostic problem, we present 28 cases of N-AECC from our dermatopathology consultation and in-house practice. All 28 cases were found to be negative on the basis of fluorescence in situ hybridization (FISH) for imbalanced chromosomal aberrations commonly found in melanoma. The clinical outcomes showed a benign clinical course for all cases for which the outcome information was available. FISH analysis also revealed that, in 4 of 28 cases (14%), the AECC of the lesion demonstrated polyploidy localized to the large epithelioid cell component. This is likely more common among cases of N-AECC that have an atypical spitzoid epithelioid cell component, particularly those with obvious senescent nuclear changes. Care must be taken to avoid the pitfall of misinterpreting these FISH findings as changes consistent with melanoma. The use of ancillary testing methods including FISH may be beneficial in improving the diagnostic accuracy involved in making the distinction of N-AECC from melanoma. Further, we report a novel finding of polyploidy seen in certain cases of benign N-AECC.

Superficial melanocytic neoplasms with pagetoid melanocytosis: a study of interobserver concordance and correlation with FISH.

Pagetoid proliferation of single melanocytic cells or small nests of melanocytes may be seen in a variety of melanocytic neoplasms including pagetoid spitz nevi, de novo epithelioid melanocytic dysplasia, and melanoma. Distinction of these entities may be difficult as there is considerable clinical and histologic overlap in these entities. Patient outcome and management may be significantly influenced by the pathologists' impression. In this study, we collected 24 cases of superficial melanocytic neoplasms with prominent pagetoid melanocytosis. We allowed 3 experienced consultant dermatopathologists to independently evaluate these entities and score them from 1 to 4, with 1 being totally benign and 4 being melanoma. In addition, we performed fluorescence in-situ hybridization (FISH) using a new melanoma FISH assay targeting 6p25, 6q23, Cep6, and 11q13. We found strong interobserver reliability in the diagnosis in 71% of cases, whereas 29% showed considerable discordance. We found that FISH accurately identified as malignant 5 of 7 cases which had a consensus diagnosis of melanoma. None of the cases with a consensus diagnosis of benign were FISH positive. Two of 11 cases considered indeterminate by the judges were positive by FISH. One of these 2 cases showed definitive histologic changes of melanoma on later complete re-excision. There is considerable discordance in superficial melanocytic neoplasm with prominent pagetoid melanocytosis even among expert consultants. There is likely a subset of such cases where FISH can play a significant role as a diagnostic aid.