Track

Abstract

Background: Melanoma of unknown primary (MUP) is uncommon and comprises 3-4% of all melanomas. History: 63-year-old male presented with painful axillary and cervical masses. Imaging demonstrated bulky lymph nodes in the cervical and axillary regions. Fine-needle aspiration revealed pleomorphic malignant cells with prominent nucleoli. Immunohistochemistry demonstrated scattered Melan-A and diffuse SOX-10 expression, consistent with metastatic melanoma. These findings were also confirmed on the excisional biopsy. Subsequently he underwent dermatologic consultation, and a scaly lesion identified on his cheek was biopsied to reveal basal cell carcinoma. No other suspicious lesions were identified. Next-generation sequencing analysis performed on his melanoma identified BRAF K601E mutation, CDKN2A and CDKN2B loss, MYC and EP300 amplification, MAP2K2 (MEK) E207K mutation, TERT promoter mutation, and TP53 mutation. Discussion: The etiology of MUP is unknown. The possible theories include a primary melanoma which has regressed, an unrecognized melanoma, a previously resected melanoma that was misclassified as benign or de-novo malignant transformation of an aberrant melanocyte within a lymph node. BRAF K601E mutation is a known driver that may guide targeted therapy. CDKN2A deletion is an early event linked to familial melanoma, while MYC and EP300 amplifications are associated with aggressive behavior. TERT promoter mutations enhance telomerase activity, promoting tumor growth and metastasis. MAP2K2 E207K mutation is associated with resistance to MEK inhibitors. Conclusion:  Guidelines for the study of MUP are presently lacking and are crucial for the delivery of consistent evidence-based care for the patients. The presence of multiple oncogenic alterations reflects molecular heterogeneity and aggressive biology.