CYLD-mutant cylindroma-like basaloid carcinoma of the anus: a genetically and morphologically distinct class of HPV-related anal carcinoma

Abstract

Rare reports of anal carcinoma (AC) describe histologic resemblance to cutaneous cylindroma, but mutations in the tumor suppressor CYLD, the gene responsible for familial and sporadic cylindromas, have not been systematically investigated in AC. Here, we investigate CYLD-mutant AC, focusing on molecular correlates of distinct histopathology. Comprehensive genomic profiling (hybrid-capture-based DNA sequencing) was performed on 574 ACs, of which 75 unique cases (13%) harbored a CYLD mutation. Clinical data, pathology reports, and histopathology were reviewed for each CYLD-mutant case. The spectrum of CYLD mutations included truncating (n = 50; 67%), homozygous deletion (n = 10; 13%), missense (n = 16; 21%), and splice-site (n = 3; 4%) events. Compared with CYLD-wildtype AC (n = 499), CYLD-mutant ACs were significantly enriched for females (88% vs. 67%, p = 0.0001), slightly younger (median age 59 vs. 61 years, p = 0.047), and included near-universal detection of high-risk HPV sequences (97% vs. 88%, p = 0.014), predominantly HPV16 (96%). The CYLD-mutant cohort also showed significantly lower tumor mutational burden (TMB; median 2.6 vs. 5.2 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (13% vs. 31%, p = 0.0015). On histopathologic examination, 73% of CYLD-mutant AC (55/75 cases) showed a striking cylindroma-like histomorphology, composed of aggregates of basaloid cells surrounded by thickened basement membranes and containing characteristic hyaline globules, while only 8% of CYLD-wildtype tumors (n = 34/409) contained cylindroma-like hyaline globules (p < 0.0001). CYLD-mutant carcinomas with cylindroma-like histomorphology (n = 55) showed significantly lower TMB compared with CYLD-mutant cases showing basaloid histology without the distinctive hyaline globules (n = 14) (median 1.7 vs. 4.4 mut/Mb, p = 0.0058). Only five CYLD-mutant cases (7%) showed nonbasaloid conventional squamous cell carcinoma histology (median TMB = 5.2 mut/Mb), and a single CYLD-mutant case showed transitional cell carcinoma-like histology. Within our cohort of ACs, CYLD mutations characterize a surprisingly large subset (13%), with distinct clinical and genomic features and, predominantly, a striking cylindroma-like histopathology, representing a genotype-phenotype correlation which may assist in classification of AC.

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

“…In a 2005 report of basaloid carcinomas of the anus, Chetty et al noted that the histologic features of basaloid cytomorphology, comedonecrosis, and basement membrane inclusions were shared by both the basaloid anal carcinomas and those occurring in the oropharynx [62]. In addition to these overlapping histopathologic changes, we further note that these carcinomas from both sites show consistent CYLD mutations, HPV positivity, low TMB, low frequency of PIK3CA mutations, and likely propensity to metastasize to the liver [16].…”

“…Here, we report that the presence of CYLD mutation defines a relatively frequent subset of HPV-related HNSCC that exhibits histopathologic features reminiscent of cylindroma and distinctive genomics. Our group recently demonstrated an analogous subset of HPV-positive, CYLD-mutant basaloid anal carcinomas with cylindroma-like histologic features [16]. In addition to similar histology, the HPV-positive CYLD-mutant anal carcinoma and HPV-positive CYLDmutant head and neck carcinoma share unusually low TMB, low frequency of PIK3CA mutation, and a possible predilection for liver metastases.…”

“…Given recent work by our group that correlated CYLD mutations in HPV-positive basaloid carcinomas of the anus with cylindroma-like histologic features, low tumor mutational burden (TMB), and low frequency of PIK3CA driver mutations [16], we hypothesized that CYLD-mutant, HPVpositive HNSCCs may have similarly distinctive histologic and genomic features. In the current study, we retrospectively assessed HPV-positive head and neck carcinoma samples analyzed by comprehensive genomic profiling (CGP) for CYLD mutations.…”

Molecular characterization of squamous cell carcinoma of the anal canal

“…J Gastrointest Oncol 2021 | https://dx.doi.org/10.21037/jgo-20-610 other HPV driven malignancies such as head and neck cancer, cervical cancer and other gynecologic cancers utilize p16 overexpression as a confirmation for HPV infection as well as a prognostic marker related to PFS and OS [8][9][10][11]. The prognostic value of HPV-DNA and p16 expression in SCCA has also been explored, with results revealing that patients testing positively for both HPV-DNA and p16 overexpression have longer OS [18][19]. Newer unlike other gastrointestinal malignancies such as colon or pancreatic adenocarcinomas, SCCA rarely harbors KRAS mutations, with an incidence of 3% or less, which is confirmed in this comprehensive analysis (27,28).…”

“…Few tumors in this study were tested for PD-1 or PD-L1, and PD-L1 expression is known to correlate with a worse prognosis in SCCA (17). Another study preformed comprehensive genomic profiling on 574 SCCA tumors to analyze the prevalence as well as mutational profiling details of tumor suppressor gene CYLD (18). CYLD mutations were seen in 13% of patients, and correlated with lower tumor mutational burden (TMB) and less alterations in PIK3CA.…”