Cervical adenocarcinoma: integration of HPV status, pattern of invasion, morphology and molecular markers into classification

Cervical adenocarcinoma is a heterogenous group of tumours with various aetiologies, molecular drivers, morphologies, response to treatment and prognosis. It has become evident that human papillomavirus (HPV) infection does not drive all adenocarcinomas, and appropriate classification is critical for patient management, especially in the era of the HPV vaccine and HPV-only screening. Identified as one of the most important developments in gynaecological pathology during the past 50 years, the separation of cervical adenocarcinomas into HPV-associated (HPVA) and HPV-independent has resulted in a transformation of the classification system for cervical adenocarcinomas. HPVA has been traditionally subclassified by morphology, such as usual type (UEA), mucinous and villoglandular, etc. However, it has become evident that cell type-based histomorphological classification is not clinically meaningful, and the newly proposed International Endocervical Adenocarcinoma Criteria and Classification (IECC) is a necessary and relevant break from this prior system. Non-HPV-associated adenocarcinomas can be divided by their distinct morphology and molecular genomics with very different responses to standard therapies and potential for future targeted therapies. These include gastric-type, clear-cell, mesonephric and endometrioid adenocarcinomas. So-called 'serous' carcinomas of the cervix probably represent morphological variants of UEA or drop metastases from uterine or adnexal serous carcinomas, and the existence of true cervical serous carcinomas is in question. This review will discuss the advances since WHO 2014, and how HPV status, pattern of invasion as described by Silva and colleagues, histological features and molecular markers can be used to refine diagnosis and prognostication for patients with cervical adenocarcinoma.