Mutational profile of atypical fibroxanthoma and pleomorphic dermal sarcoma further expands the spectrum of genomic alterations in rare cutaneous neoplasms.

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous mesenchymal tumours sharing clinical and histopathological features. Compared to AFX, PDS has an increased risk of local recurrence and metastasis. A precise diagnosis is critical to ensure proper clinical management and follow-up. AFX and PDS show a similar genetic background, but also a heterogeneous pattern of different molecular abnormalities still poorly investigated due to the rarity of these tumours. Multiple data from different institutions and geographical areas, facilitate the identification of molecular alteration/s of valuable diagnostic and/or sub-classification power. We investigated the DNA profile of 32 AFX and PDS samples using a custom targeted Next-Generation Sequencing panel including 228 cancer genes. We confirm a common pattern of gene mutations affecting TP53, CDKN2A and NOTCH1. Differences appeared in less frequently detected genes (e.g. TSC2) and in NF2 harbouring novel genetic alterations. Integrating our results with published datasets of AFX and PDS mutation profiles we observed a divergent distribution of alterations in genes signalling through angiogenic pathway (KDR, PDGFRB), DNA damage response (ATR), cellular migration/metastasis (DDR2, CDH1). These differences do not reach statistical significance, and histopathological evaluation remains the diagnostic gold standard, however, they offer valuable insights into the pathogenesis of these tumours.