Diagnosis of Rare Cervical Tumors: IECC Classification, HPV Status, and Subtype-Directed Immunohistochemistry, with...

Background/Objectives: Rare histologic subtypes of cervical cancer are uncommon and may be misclassified during initial diagnosis. Their recognition depends on subtype-directed immunohistochemistry, which excludes metastatic mimics, and on high-risk HPV (hrHPV) testing, which establishes HPV status. Published series rarely report how the diagnosis was reached. We therefore documented the full diagnostic work-up, together with treatment and outcomes, in a consecutive single-center series. Methods: This was a retrospective, single-center case series (January 2020-January 2025). Rare tumors were defined per the 2020 WHO Classification as subtypes other than squamous cell carcinoma and usual-type adenocarcinoma. Immunohistochemistry was used to confirm lineage and exclude mimics. hrHPV DNA testing and p16 immunohistochemistry were performed where tissue permitted. A tumor was called HPV-associated only when diffuse block-type p16 positivity accompanied hrHPV DNA; HPV DNA alone was not accepted as evidence of an HPV-driven tumor. Results: Ten patients were included (median age 53 years). There were two signet-ring cell adenocarcinomas, two small cell neuroendocrine carcinomas (SCNECC), two serous adenocarcinomas, and one each of sarcomatoid carcinoma, clear cell carcinoma, granulocytic sarcoma, and poorly differentiated adenosquamous (glassy cell) carcinoma. hrHPV DNA was detected in six of the seven tumors tested. Three of these six were p16-negative: one serous, the clear cell, and the glassy cell carcinoma. Because diffuse block-type p16 expression is a validated surrogate marker of transcriptionally active hrHPV, we classified these three as HPV-independent. This matches the known biology of these histotypes. Lymphovascular space invasion was present in eight patients (80%). Over a median follow-up of 10.5 months, four patients developed distant metastases and three died. Conclusions: Accurate diagnosis of rare cervical tumors requires subtype-directed immunohistochemistry to exclude mimics and hrHPV testing interpreted together with p16; HPV DNA positivity alone does not establish HPV-association. Given the small, heterogeneous series, outcome data are descriptive and hypothesis-generating. We propose a diagnostic algorithm and immunohistochemical framework and advocate centralized review and prospective registries.