Association of primary treatment modality and programmed death-ligand 1 expression with survival outcomes in locally advanced human papillomavirus-independent endocervical adenocarcinoma.

OBJECTIVE

Endocervical adenocarcinoma comprises biologically heterogeneous sub-types classified as human papillomavirus (HPV)-associated and HPV-independent, practically based on p16 immunohistochemistry according to the 2020 World Health Organization (WHO) classification. This study explored the prognostic relevance of WHO-defined HPV-associated versus HPV-independent histologic classification and examined associations between primary treatment modality and clinical outcomes in locally advanced endocervical adenocarcinoma.

METHODS

We conducted a single-center retrospective cohort study including patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3 to IVA endocervical adenocarcinoma treated between 2007 and 2024. All cases underwent expert slide review, and pre-treatment HPV testing was assessed when available. Patients were analyzed according to histologic sub-type and heterogeneous primary treatment approaches, including radical hysterectomy-based treatment with or without adjuvant therapy (n = 65) and definitive concurrent chemoradiation therapy-based treatment with or without completion hysterectomy (n = 37). Progression-free survival and overall survival were evaluated using Cox proportional hazards models.

RESULTS

Among 102 patients, 53 had HPV-associated tumors and 49 had HPV-independent tumors, the latter predominantly gastric-type adenocarcinoma. HPV-independent tumors were associated with significantly worse progression-free survival and overall survival compared with HPV-associated tumors. Within the HPV-independent cohort, primary treatment modality was independently associated with both progression-free and overall survival, with radical hysterectomy-based treatment showing more favorable progression-free survival estimates compared with definitive chemoradiation therapy. A programmed death-ligand 1 combined positive score <1 was independently associated with overall survival.

CONCLUSIONS

WHO-defined HPV-associated versus HPV-independent histologic classification was a strong prognostic marker in locally advanced endocervical adenocarcinoma. In exploratory analyses of HPV-independent tumors, associations between primary treatment modality and survival outcomes were observed; however, these findings should be interpreted with caution because of treatment selection bias and the retrospective study design. Further prospective studies are warranted to refine risk stratification and multi-disciplinary treatment strategies for this aggressive sub-group.