Clinicopathological and molecular characterization of HPV-associated cervical poorly cohesive carcinoma: a rare aggressive entity.

Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as 'HPV-associated cervical poorly cohesive carcinomas' (HPV-associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV-associated CPCC cases were analyzed and classified into three histological subtypes: signet-ring cell carcinoma (n = 4), not otherwise specified (n = 6), and mixed types (n = 6). All patients were Chinese (median age: 46 years; range: 30-66). Vaginal bleeding was the primary presenting symptom (100.0%). High-risk human papillomavirus (HPV) was identified in all tumors, with HPV-18 as the predominant genotype (n = 13), HPV-16 in two cases, and a single case exhibiting concurrent infection with HPV-16, -18, and -58. Overall, 56.3% presented with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB-IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody-drug conjugate targets was observed, with HER2-low expression (33.3%), and positive staining for Trop-2 (85.7%), nectin-4 (42.9%), and tissue factor (92.3%). During follow-up, disease-specific mortality was 50.0%. The 3-year overall survival rate was 56.3%, which was significantly lower in advanced-stage disease (45.0%) than in early-stage disease (75.0%). Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.