Sarcomatoid Dedifferentiated Melanoma: The Diagnostic Role of Next-Generation Sequencing

Abstract

Sarcomatoid dedifferentiated melanoma (SDDM) represents a diagnostic challenge as this cutaneous spindle cell melanoma lacks expression of classic melanocytic markers including S100, SOX10, Melan-A, HMB45, and MITF. The expression of the emerging melanoma marker preferentially expressed antigen in melanoma (PRAME) in SDDM is largely unknown. In this article, a case of SDDM arising in association with a nodular melanoma is highlighted. A 65-year-old man presented with a several week history of an ulcerated lesion on the right medial knee. A shave biopsy of the lesion revealed a biphasic neoplasm, which consisted of a centrally located poorly differentiated spindle cell component and an adjacent nodular component consisting of atypical melanocytes arranged in nests and fascicles. While the nodular component stained for S100, SOX10, and Melan-A, the spindle cell component failed to stain for these conventional melanocytic markers, only staining diffusely for CD10 and faintly for CD68. Both components stained for PRAME diffusely albeit less intensely within the spindle cell component. Next-generation DNA sequencing assay of the microdissected biphasic components revealed a shared mutation of NRAS. The results of the PRAME immunohistochemical stain and nextgeneration DNA sequencing assay facilitated in establishing the diagnosis of SDDM in association with nodular melanoma.

PRAME Expression Is a Useful Tool in the Diagnosis of Primary and Metastatic Dedifferentiated and Undifferentiated Melanoma

“…17,20 Rare, isolated reports have documented strong and diffuse nuclear staining for PRAME in dedifferentiated melanomas, but no comprehensive studies are available testing the diagnostic usefulness of PRAME in this setting. 14,20,21 Our experience with 9 primary dedifferentiated and 2 undifferentiated melanomas demonstrated that nuclear PRAME expression is strong and diffuse with a median combined score of 7 of 7. It is seen in both the AFX/PDS-like areas as well as those with aberrant differentiation.…”

“…While a clinical history of a primary melanoma elsewhere is helpful in the metastatic setting, primary undifferentiated melanomas are likely underrecognized and underreported as their diagnosis relies entirely on mutational analysis with the detection of conventional melanoma driver mutations 1,4,18 . Primary dedifferentiated and undifferentiated melanomas closely resemble nonmelanocytic tumors, particularly AFX and PDS, and less commonly pleomorphic rhabdomyosarcoma or spindle cell squamous cell carcinoma (SCC) 3–8,11,13–15 . While primary cutaneous pleomorphic rhabdomyosarcoma is an exceptionally rare diagnosis, AFX, PDS, and spindle cell SCCs may appear morphologically and immunohistochemically inseparable from primary cutaneous dedifferentiated and undifferentiated melanomas presenting on chronically sun-damaged skin 5,19 …”

“…1,4,18 Primary dedifferentiated and undifferentiated melanomas closely resemble nonmelanocytic tumors, particularly AFX and PDS, and less commonly pleomorphic rhabdomyosarcoma or spindle cell squamous cell carcinoma (SCC). [3][4][5][6][7][8]11,[13][14][15] While primary cutaneous pleomorphic rhabdomyosarcoma is an exceptionally rare diagnosis, AFX, PDS, and spindle cell SCCs may appear morphologically and immunohistochemically inseparable from primary cutaneous dedifferentiated and undifferentiated melanomas presenting on chronically sun-damaged skin. 5,19 Over the past few years, PRAME IHC has become a helpful additional tool in separating benign nevi from melanoma.…”

“…Tumors showing a complete absence of melanocytic differentiation are referred to as undifferentiated melanomas 4,5 . Most dedifferentiated and undifferentiated melanomas are pleomorphic, epithelioid, or spindle cell tumors showing no specific line of differentiation, but rhabdomyosarcomatous or epithelial differentiation may be occasionally seen 1–15 . While a clinical history of a previous primary cutaneous or mucosal melanoma is diagnostically helpful in the metastatic setting, the diagnosis of primary dedifferentiated and undifferentiated melanomas is particularly challenging.…”

“…4,5 Most dedifferentiated and undifferentiated melanomas are pleomorphic, epithelioid, or spindle cell tumors showing no specific line of differentiation, but rhabdomyosarcomatous or epithelial differentiation may be occasionally seen. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] While a clinical history of a previous primary cutaneous or mucosal melanoma is diagnostically helpful in the metastatic setting, the diagnosis of primary dedifferentiated and undifferentiated melanomas is particularly challenging. Primary dedifferentiated melanomas show a wide anatomic distribution with a predilection for chronically sun-damaged skin of elderly patients.…”