Primary de‐differentiated, trans‐differentiated and undifferentiated melanomas: overview of the clinicopathological, immunohistochemical and molecular spectrum

Abstract

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in‐situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S‐100, SOX10, Melan‐A and HMB‐45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de‐ and trans‐differentiation in melanoma is rare but probably under‐recognised and under‐reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun‐damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre‐existing conventional melanoma. The de‐differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans‐differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre‐existing but often focal conventional melanoma together with molecular analysis.

Epithelioid and spindle rhabdomyosarcoma with TFCP2 rearrangement in abdominal wall: a distinctive entity with poor prognosis

“…Epithelioid sarcoma can show rhabdoid and spindle morphology with tumor necrosis, they generally express epithelial markers and CD34, and loss SMARCB1/INII1 expression and don’t express Myo-D1 and Myogenin [ 70 , 71 ]. Rare malignant melanoma can show RMS dedifferentiation, however, it usually presents previous history of melanoma and melanoma in situ and is diffusely positive for S-100, SOX10, HMB45 and Melan A in the classic components of melanoma cells, molecularly, BRAF VE600 mutation can be detected in some melanoma [ 72 , 73 ]. Other variants of RMS including ES-RMS, SS-RMS can be separated by the combination of cellular components and molecular testing in the appropriate clinical background.…”

Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma

“…12 Sequencing for recurrent melanoma-associated driver mutations such as BRAF and NRAS has been proposed as a more sensitive and specific method of establishing a diagnosis of melanoma when all melanoma immunostains are negative. [14][15][16][17][18][19][20] Recently, recurrent loss of function mutations in the vacuolar ATPase complex genes ATP6AP1 and ATP6AP2, which regulate endosomal pH, have been identified in 72% of GCTs, including atypical and malignant GCT. 21 These were frameshift mutations and premature stop codons.…”

PRAME expression in spindle cell melanoma, malignant peripheral nerve sheath tumour, and other cutaneous sarcomatoid neoplasms: a comparative analysis

“…In addition to MPNST, various primary cutaneous sarcomas and sarcomatoid carcinomas may occasionally enter the differential diagnosis of spindle cell melanoma. Of these, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are undifferentiated tumours that can be difficult to distinguish from rare cases of undifferentiated or dedifferentiated melanoma 30–32 . Cutaneous high‐grade leiomyosarcoma and poorly differentiated angiosarcoma are other neoplasms that may mimic sarcomatoid melanoma on histopathology.…”

“…Of these, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are undifferentiated tumours that can be difficult to distinguish from rare cases of undifferentiated or dedifferentiated melanoma. 30 , 31 , 32 Cutaneous high‐grade leiomyosarcoma and poorly differentiated angiosarcoma are other neoplasms that may mimic sarcomatoid melanoma on histopathology. Herein we examine the utility of PRAME IHC in distinguishing spindle cell melanoma from MPNST and various cutaneous sarcomatoid mimics.…”