Cytology of HPV-Independent Cervical Carcinomas: Morphologic Spectrum, Clinical Correlates, and Ancillary Testing

Cervical cancer is one of the most common cancers that can be diagnosed by cytologic features. While the past focus was mostly on human papillomavirus (HPV)-associated cervical carcinomas, the studies on HPV-independent cervical carcinomas have become more extensive with the advancement in ancillary tests, including molecular tests. The development of digital pathology also provides additional opportunities for more accurate cytologic diagnosis. We would like to summarise the current knowledge on the epidemiology, cytomorphology, and ancillary studies for different types of HPV-independent cervical carcinomas, and explore the use of digital pathology in the diagnosis of HPV-independent cervical carcinomas. Case reports, case series, and research articles are identified on PubMed using keywords “HPV-independent”, “cervical carcinomas”, “digital pathology”, and the specific names of subtypes of HPV-independent cervical carcinomas. The studies are selected based on their relevance to cytology, with an emphasis on new updates of ancillary tests. HPV-independent cervical carcinomas are classified based on the histological features, with distinct cytomorphological, immunocytochemical, and molecular features for each subtype. The prognosis is generally worse than HPV-associated cervical carcinomas. Accurate diagnosis is limited by a small number of cases and limited exposure among cytotechnicians and cytopathologists. The use of digital pathology can potentially improve diagnostic accuracy, while more studies are required before the adoption of digital pathology for the diagnosis of HPV-independent cervical carcinomas. Recognition of suspicious clinical features, liberal use of immunocytochemistry, and molecular testing are essential to accurate cytologic diagnosis of HPV-independent cervical carcinomas.