Viral and Genomic Drivers of Squamous Cell Neoplasms Arising in the Lacrimal Drainage System

SIMPLE SUMMARY: Carcinomas arising in the lacrimal drainage system (LDS) are rare but notoriously aggressive tumors, causing substantial morbidity and mortality. The molecular drivers of the disease remain unexplored despite being a prerequisite for identifying targets for future prognostication and therapy. Therefore, we aimed to investigate the genomic aberrations in carcinomas arising in the LDS and correlate the findings to human papillomavirus (HPV) status. By detecting transcriptionally active HPV in 80% of LDS papillomas and 67% of LDS carcinomas, we suggest HPV to be an important contributor to carcinogenesis in this location. Further, the genomic profile of the HPV16-positive carcinomas, with activating mutations in the PI3K-AKT signaling cascade, wildtype status of TP53, and p16 overexpression, resembles that of HPV-driven disease at other locations with implications for future therapy. ABSTRACT: The pathogenesis of squamous cell neoplasms arising in the lacrimal drainage system is poorly understood, and the underlying genomic drivers for disease development remain unexplored. We aimed to investigate the genomic aberrations in carcinomas arising in the LDS and correlate the findings to human papillomavirus (HPV) status. The HPV analysis was performed using HPV DNA PCR, HPV E6/E7 mRNA in-situ hybridization, and p16 immunohistochemistry. The genomic characterization was performed by targeted DNA sequencing of 523 cancer-relevant genes. Patients with LDS papilloma (n = 17) and LDS carcinoma (n = 15) were included. There was a male predominance (68%) and a median age at diagnosis of 46.0 years (range 27.5–65.5 years) in patients with papilloma and 63.8 years (range 34.0–87.2 years) in patients with carcinoma. Transcriptional activity of the HPV E6/E7 oncogenes was detected in the whole tumor thickness in 12/15 (80%) papillomas (HPV6, 11, 16) and 10/15 (67%) squamous cell carcinomas (SCC) (HPV11: 3/15 (20%) and HPV16: 7/15 (47%)). Pathogenic variants in PIK3CA, FGFR3, AKT1, and PIK3R1, wildtype TP53, p16 overexpression, and deregulated high-risk E6/E7 transcription characterized the HPV16-positive SCC. The deregulated pattern of HPV E6/E7 expression, correlating with HPV DNA presence and p16 positivity, supports a causal role of HPV in a subset of LDS papillomas and carcinomas. The viral and molecular profile of LDS SCC resembles that of other HPV-driven SCC.