CYLD-mutated anal squamous cell carcinoma: An uncommon entity associated with cylindroma-like morphology and adverse...

Anal squamous cell carcinoma (SqCC) can be broadly divided into HPV-positive and HPV-negative groups, each with distinct clinicopathologic features and outcome. CYLD-mutant anal SqCC was recently characterized as having a strong association with cylindroma-like histologic features, HPV positivity, infrequent PIK3CA mutation, and low tumor mutational burden. The prognostic impact of CYLD mutation in this context has not been established. We performed CYLD mutational analysis on a cohort of 109 clinicopathologically well-characterized cases of anal SqCC including 98 HPV-positive and 11 HPV-negative carcinomas. CYLD mutation was present in 3 cases (2.8 % of total, 3.1 % of HPV-positive cases), all of which were HPV16-positive. CYLD mutation was significantly associated with more frequent cylindroma-like basement membrane inclusions (p = 0.0002) and basaloid cytomorphology (p = 0.017). Just 4 % of CYLD-wildtype carcinomas demonstrated cylindroma-like features, which were limited in extent relative to CYLD-mutant cases. Among the HPV-positive group, CYLD mutation and cylindroma-like morphology were associated with a higher rate of metastatic disease progression (p = 0.022 and p = 0.01, respectively), with 2 of 3 CYLD-mutant patients developing liver metastasis at 6 and 7 months after initial diagnosis. None of the CYLD-mutant cases had other mutations including PIK3CA and TP53 mutations. Our findings further establish CYLD-mutant anal SqCC as an infrequent but distinct clinicopathologic entity with characteristic pathogenetic features and a possible association with adverse clinical outcomes. Among HPV-positive anal SqCC, CYLD mutation represents a potentially useful novel marker for this distinct entity and cylindroma-like morphology serves as a useful feature to identify such cases.