Abstract
Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p < 0.0001), KMT2D (1% vs. 16%, p < 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p < 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment.
Highlights
Clinicopathologic analyses of head and neck carcinomas with CYLD mutations Outside institutional pathology reports that accompanied each specimen sent to Foundation Medicine for comprehensive genomic profiling (CGP) were reviewed to collect clinicopathologic data, including patient age, gender, tumor site, and AJCC stage (8th edition) [25]
We identified 703 distinct hrHPV-positive head and neck carcinoma specimens, of which head and neck adenocarcinoma and cases of salivary gland origin were excluded as no HPV-positive CYLD-mutant cases were identified in these groups
We report that the presence of CYLD mutation defines a relatively frequent subset of HPV-related head and neck squamous cell carcinomas (HNSCC) that exhibits histopathologic features reminiscent of cylindroma and distinctive genomics
Summary
The most recent World Health Organization classification of head and neck tumors divides squamous cell carcinoma (SCC) of the oropharynx into high-risk (hr) HPV-positive and hrHPV-negative tumors [1]. We retrospectively assessed HPV-positive head and neck carcinoma samples analyzed by comprehensive genomic profiling (CGP) for CYLD mutations. This analysis may enhance tumor categorization and inform further correlations with prognosis and potential therapeutic approaches to CYLDmutant tumors, such as recently investigated targeted inhibitors for cylindromatosis [17, 18]
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