The changing landscape of gynaecological pathology: WHO 2020 and beyond

This Histopathology Annual Review Issue is devoted to gynaecological pathology; in addition to highlighting the many new developments in the field, we have attempted to broaden the scope of this issue beginning with the first paper, a look back at the most important discoveries during the course of his 50 years as a gynaecological pathologist, by Professor Steven Silverberg. You may be surprised by his choices, some of which are specific to gynaecological pathology [the roles of hormones and human papillomavirus (HPV) in the aetiology of genital tract cancers], while others have been broadly impactful in surgical pathology (introduction of immunohistochemistry and international consensus classification systems). Fifty years ago, gynaecological pathology was in its infancy, but the discoveries highlighted by Professor Silverberg can be seen to have had a clear impact in most of the subsequent papers in this issue of the journal. The first paper providing an update on recent advances in gynaecological pathology relates to ovarian sex cord-stromal tumours. Rabban and colleagues show how the categories within this fascinating and diverse group of tumours have now been related to specific underlying genetic abnormalities. It is inspiring to see how the early academic gynaecological pathologists were so consistently able to identify specific tumour types, based solely on light microscopy, that we now know show consistent and characteristic molecular abnormalities. Molecular markers, including immunostains, have made it possible for all of us to attain the high level of diagnostic accuracy achieved by these experts, even for rare tumour types that we might encounter once or twice in our careers. This paper also highlights an important example of a hereditary cancer susceptibility syndrome (DICER1 syndrome), where surgical pathologists can play a role in diagnosis by recognition of tumour types associated with the syndrome and recommending referral to a hereditary cancer programme. Professor Berney and colleagues provide a comparison between germ cell tumours of testis and ovary, noting differences and similarities and proposing a modification to the current classification of ovarian germ cell tumours to align it with the one used for the more common malignant germ cell tumours arising in the testis. The gynaecological tract is unique in there being a significant portion of cases where there is metastasis between sites within the genital tract, but the clinical behaviour is more compatible with that of low-stage, organ-confined disease. This phenomenon of multifocality of tumour within the female genital tract has caused great confusion over the years, but next-generation sequencing of tumour samples has allowed for elucidation of the molecular underpinnings, and this is discussed, as well as a strategy for handling these tumours in practice, in the paper by Casey and Singh. Unlike ovarian carcinoma, where routine light microscopic examination and classification based on cellular features results in the highly reproducible diagnosis of tumour histotypes with different risk factors, molecular events during oncogenesis, patterns of spread and precursor lesions, endometrial carcinoma histotype assignment, especially for high-grade tumours, is only moderately reproducible and does not accurately reflect the underlying molecular pathology. The most important discovery to emerge from the>$100M Cancer Genome Atlas project, with detailed molecular characterisation of multiple cancer types, was arguably the recognition of four molecular subtypes of endometrial carcinoma, including ultramutated and hypermutated subtypes. Vermij and colleagues, drawing upon their own experience related to the PORTEC clinical trials, and the rapidly developing literature, show how molecular subtypes can be assigned in practice and how molecular classification could be used to inform treatment. Nowhere has molecular diagnostics been more impactful than in sarcoma pathology. Momeni-Boroujeni and Chiang provide a comprehensive review of recent developments related to uterine mesenchymal tumours. Gone are the days when uterine spindle cell tumours were all smooth muscle tumours, low-grade stromal sarcomas or undifferentiated uterine sarcomas. The category of high-grade endometrial stromal sarcoma, that was reintroduced in the fourth edition of the World Health Organisation (WHO) Blue Book in 2014, has grown and become more clearly defined. An exciting recent development is the identification of fibrosarcoma-like tumours of the uterus; these tumours are associated with potentially targetable translocations, making recognition important.