Undifferentiated melanoma: a molecular study of a fatal metastatic “atypical fibroxanthoma (AFX)”

TL;DR

A case study shows how molecular analysis helped identify a deadly skin tumor as undifferentiated melanoma, despite its initial classification as atypical fibroxanthoma.

Contribution

The paper introduces molecular evidence supporting undifferentiated melanoma as a distinct entity resembling atypical fibroxanthoma.

Findings

NGS and methylomic analysis confirmed the skin tumor and bone metastases were the same neoplasm.

NF1 gene mutations were identified, supporting a diagnosis of undifferentiated melanoma.

Methylomic data grouped the tumors with AFX/PDS rather than conventional melanomas.

Abstract

Diagnosing undifferentiated spindle cell and pleomorphic tumours of the sun-exposed skin of elderly patients is common and challenging. This paper presents the case of a 64-year-old man with a tumour that was initially diagnosed as an atypical fibroxanthoma, but which metastasised to the bone and lung, resulting in death within two years. Extensive comparative molecular studies were performed using next-generation sequencing (NGS) and methylomic analysis, which demonstrated that the skin tumour and the bone metastases corresponded to the same neoplasms. In addition to other aberrations, NGS analysis of both tumour manifestations revealed NF1 gene mutations, suggesting a diagnosis of undifferentiated melanoma. Interestingly, however, the methylomic analysis grouped the tumours with the “atypical fibroxanthoma/pleomorphic dermal sarcoma (AFX/PDS)” class of the reference cases, rather than with conventional or desmoplastic melanomas. Molecular studies may help to reveal the genetic basis of difficult-to-classify undifferentiated skin neoplasms as well as help to estimate their biological potential.

The online version contains supplementary material available at 10.1007/s00428-025-04265-5.

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