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Melanoma accounts for ~ 1% of all skin cancers, and in the U.S., represents the fifth most common cancer in men of all age groups.1 The survival rate in patients with melanoma is related to the type and stage of the primary tumor, and metastasis confers poor survival.2, 3 Metastases can occur via lymphatics or hematogenously, and therefore, can involve different organs, such as lymph nodes, GI, liver, lungs, bone, CNS, among others. Metastases can be detected during the treatment of the primary disease, many years after the original diagnosis or even in the absence of a primary cutaneous disease.2-4
Histologically, melanoma is known to exhibit a diversity of morphologic appearances, and different histologic variants of primary melanoma have been described, such as spindle cell melanoma, desmoplastic melanoma, balloon cell melanoma, nevoid melanoma, signet-ring cell melanoma and myxoid melanoma, amongst others.5,6
Fine needle aspiration (FNA) biopsy has been reported as a rapid and fast diagnostic technique for the diagnosis of metastatic melanoma (MM).2,7 On smears preparation, the classical cytological features of melanoma includes: highly cellular smear with single cells or loosely cohesive aggregates, round to polygonal cells with moderate amount of cytoplasm, eccentrically located large nuclei, prominent nucleoli, intranuclear vacuole and brown melanin pigment.2,7-8 Unfortunately, not all cases of melanoma present with the classical cytologic features,8 and metastatic melanomas can also exhibit a diverse cytomorphology that can difficult an accurate diagnosis.
Initially, the cytomorphologic features of our case were compatible with a lung small cell carcinoma; however, after an extensive immunohistochemical workup, the diagnosis of metastatic melanoma, small cell variant was reached. Small cell melanoma, first described by Reed in 1965, is a rare variant of malignant melanoma composed of small monomorphic cells with scant cytoplasm, round to oval nuclei with inconspicuous nucleoli.9 It may focally show nuclear molding, similar to small cell carcinoma, or a discohesive growth pattern, resembling lymphomas or plasmacytoma.5,9-10 Small cell melanoma is most frequently encountered in the setting of a malignant melanoma that has arisen in a giant congenital nevus or as a de novo childhood neoplasm.2,4-5 Given the histomorphologic features, small cell melanoma can resemble small round blue cell tumors such as PNET/Ewing sarcoma, malignant peripheral nerve sheath tumor, Merkel cell carcinoma, olfactory neuroblastoma and germ cell tumors.5
Achieving the correct diagnosis of MM commonly requires a combination of the medical history, morphologic features, immunohistochemical and/or molecular workup.5 Small cell lung carcinoma (SCLC) is typically positive for TTF-1, CD56, synaptophysin and chromogranin with an elevated Ki-67 proliferative index (typical rate for SCLC is 60%–100%).11 Of the melanocytic markers S-100 protein, HMB-45, Melan-A, SOX-10, tyrosinase and MITF, the most commonly used in clinical practice are: S-100 protein, with a ~88% to 91% sensitivity and 70% specificity; HMB-45, more specific (~96%) but less sensitive (75%) and SOX10, considered more sensitive and specific (97-100%) for the diagnosis of melanoma.5,12-16 However, primary or MM can show loss of melanocytic markers or demonstrate aberrant expression of nonmelanocytic associated antigens, such as cytokeratins, neuroendocrine markers, desmin and neurofilaments.5,11-14 In our case, CD56 which was focally positive, is a neural cell adhesion molecule, normally expressed on neurons, glial tissue, skeletal muscle, and natural killer cells. It is considered a nonspecific neuroendocrine marker and has been previously reported aberrantly expressed in melanoma.15,17
The majority of melanomas have been shown to harbor mutations associated with the mitogen-activated protein kinase (MAPK) pathway, a signal transduction pathway involved in cell growth, proliferation, and tumor survival.18-25 Approximately 40–60% of malignant melanoma contain an activating BRAF mutation, the most common is a single amino acid change at codon 600 (BRAF V600E), and ~15-30% of cases show NRAS mutation, both leading to the activation of the MAPK pathway.18-28 BRAF promotes cell invasion and metastasis in melanoma, and it is associated with poor prognosis in advance cases.25,27 Detection of BRAF V600E mutation is not only a highly sensitive and specific tool for diagnosis of primary and MM18-25, but it is also considered as a prognostic and predictive marker to treatment with BRAF inhibitors.18-28
In conclusion, malignant melanoma should be considered in the differential diagnosis of poorly differentiated neoplasms with small cell morphology and atypical immunoprofile, even in the absence of melanin pigment or a past medical history of melanoma. In such cases, molecular detection of BRAF V600E mutation should be performed.
References:
1. Data taken from https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html
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