Histopathology 2020, 76, 2–5 Editorial The changing landscape of gynaecological pathology: WHO 2020 and beyond DOI: 10.1111/his.14035 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 © 2019 John Wiley & Sons Ltd 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 Editorial Endometriosis is a common disease, and can show a wide range of pathological findings in practice This enigmatic process also has the potential for malignant transformation Professor McCluggage has provided practical guidance on handling diagnostically difficult areas in these commonly encountered, but morphologically complex, cases Williams and Ganesan have reviewed recent developments in two scenarios where pathologists are expected to provide a histopathological assessment of treatment response: in patients who have interval debulking surgery after neoadjuvant chemotherapy for high-grade serous tubo-ovarian carcinoma, and non-surgical treatment of patients with endometrial carcinoma or atypical hyperplasia with progestins In both instances we can assess histopathological features of response to treatment in ways, described in this review, that provide prognostic information and can be used to guide management The next two papers in this issue describe a major shift in how we subclassify endocervical adenocarcinoma In the upcoming fifth edition of the WHO Blue Book, the primary classifier of endocervical adenocarcinoma will not be cell type, but instead is based on whether the tumour is HPV-associated or -independent Professor Mikami tells the story of how gastrictype adenocarcinoma was recognised as an HPV-independent form of cervical adenocarcinoma, with a cautionary note illustrating the great care needed to translate clinical research into practice Dr Park describes the new international endocervical adenocarcinoma classification system, which takes into account HPV status; she also provides criteria for recognition of patterns of invasion in HPV-associated cervical adenocarcinoma, as first described by Silva and colleagues Moving forward, vulval squamous cell carcinoma and its precursors will also be subclassified based on HPV status, and we provide the rationale for this aetiology-based subclassification and describe the morphological features associated with HPV-associated and HPV-independent invasive squamous cell carcinoma and intra-epithelial lesions The HPV-independent precursor lesions [differentiated vulvar intraepithelial neoplasia (VIN) and differentiated exophytic vulvar intra-epithelial lesion] have been under-recognised in the past, leading to delays in treatment, but the past years have seen significant progress in our understanding of the morphological and molecular features of these uncommon but highly clinically relevant lesions Sentinel node biopsy in gynaecological cancer is emerging as a less morbid and equally effective © 2019 John Wiley & Sons Ltd, Histopathology, 76, 2–5 alternative to full node dissection for tumours at all sites in the gynaecological tract, and Eusher and Malpica, drawing on their extensive experience and a thorough review of the literature, provide guidance for the proper handling of these specimens when they reach the surgical pathology laboratory Later in 2020, the fifth edition of Classification of tumours of the female genital tract (the Blue Book), produced under the auspices of the WHO/IARC, will be released, and replace the very successful fourth edition released in 2014 The process for production of these volumes has evolved and the authors of the next review, from the International Agency for Research on Cancer (IARC) office in Lyon, France, describe the process used to identify and bring together the expert panels that generate the content for the new series The updates reviewed in this Annual Review Issue will feature very prominently in the upcoming fifth edition International consensus classification systems, identified by Professor Silverberg as one of the most important developments of the past 50 years, have been critical in allowing everyone in the world to move forward together as our speciality has evolved, and the fifth edition of the Blue Book will continue to be used as a reference worldwide Perhaps the most important development in the fifth edition, compared with earlier editions, is the emergence of subclassification systems for common carcinomas of the female genital tract that move beyond simple cell-type or pattern-based classification This began in the fourth edition, when the five ovarian carcinoma ‘histotypes’ were recognised to be different diseases, and diagnosis was no longer based on architecture/cell type alone It was appreciated, for example, that tubo-ovarian high-grade serous carcinoma can show a very wide range of architectural and cytological features; the presence of solid or transitional architecture or clear cell change did not warrant a diagnosis of mixed carcinoma A key development was clear separation of low-grade serous carcinoma and high-grade serous carcinoma; although the molecular differences were first described by Kurman and colleagues,1–3 Malpica et al showed that the two groups did not exist on a morphological continuum, but rather low-grade serous carcinoma and high-grade serous carcinoma were readily (and reproducibly) separable based on routine light microscopy4,5 (Figure 1) This trend towards subclassification of gynaecological tumours into types that reflect differences in underlying molecular events, rather than just differences in histological patterns, moves forward on multiple fronts in the fifth edition of the Blue Book (Table 1) These tumour Editorial 40 35 # cases 30 25 20 15 10 -1 16 -2 21 -2 26 -3 31 -3 36 -4 41 -4 46 -5 51 -5 56 -6 61 -6 66 -7 71 -7 65 -8 >8 11 1- 6- 10 Mitotic count LGSC HGSC Figure In cases of tubo-ovarian serous carcinoma separated based on the degree of nuclear atypia (greater versus less than threefold variation in nuclear size), there is clear separation of high-grade serous carcinomas (HGSC) and low-grade serous carcinomas (LGSC) based on mitotic count (data from Malpica et al.4) Table New approaches to subclassification of common gynaecological malignancies Site Basis of subtype Dx Vulva, squamous cell carcinoma Aetiology (HPV-associated/ HPV-independent) Cervix, adenocarcinoma Aetiology (HPVassociated/HPV-independent) Endometrium, carcinoma Genomic architecture (mutations/copynumber variants) HPV, Human papillomavirus; Dx, Diagnosis types show type-specific differences in prognosis and response to treatment The increased understanding of the molecular underpinnings of gynaecological cancers, including the cancer genome itself, its immune landscape and the specific molecular alterations and aberrant pathways that drive its progression, has important therapeutic implications The treatment of cancer has advanced dramatically with the evolution of molecular biology, resulting in the development of targeted agents While traditional chemotherapy simply inhibits DNA replication and mitosis, newer agents target a whole host of mechanisms, such as cancer signalling pathways, the stromal and immune microenvironment and tumour vasculature Crusz and Miller present an update on targeted therapies currently in use or under evaluation in the treatment of gynaecological cancers, including drugs targeting defective DNA repair such as poly ADP ribose polymerase (PARP) inhibitors, those targeting angiogenesis, immune checkpoint inhibitors such as anti-programmed cell death protein 1/programmed cell death ligand (PD-1/PD-L1) antibodies and a whole host of HPV-targeted therapies that are under development for HPV-related malignancies The last paper in the issue is a bookend to the first, which considered the most impactful discoveries of the past 50 years Dr Farnell and colleagues look instead to the future of gynaecological pathology They predict a move to fully digital anatomical pathology laboratories with scanned slides which will, in turn, enable the use of applications (‘apps’) that take advantage of artificial intelligence, and molecular pathology to enhance pathological diagnosis As they describe, the technology to this exists and it is now a matter of combining it seamlessly in the workplace We dedicate this Annual Review Issue to Professors Steven Silverberg and Philip Clement Steven G Silverberg is a Professor Emeritus in the Department of Pathology, at the University of Maryland School of Medicine After completing pathology training at Yale University and Memorial Sloan Kettering Cancer Center in New York, he held faculty positions at Johns Hopkins, George Washington University and the University of Colorado, before taking on the role of Director of Anatomic Pathology at the University of Maryland, a position he held until 2004 He is both a past president of the International Society of Gynaecological Pathologists and past editor of the International Journal of Gynecological Pathology Dr Clement is a Professor Emeritus at the University of British Columbia He undertook his residency at the Massachusetts General Hospital, followed by a fellowship in Gynecological Pathology under Dr Robert Scully, returning to his native British Columbia in 1975 to take up a faculty position at the University of British Columbia He was editor of the International Journal of Gynecological Pathology for 10 years, and is an author of the influential Atlas of Gynecologic Surgical Pathology, the fourth edition of which was just released He will retire in the summer of 2020, after 50 years in pathology Both Professor Silverberg and Professor Clement have been leaders in gynaecological pathology, mentors and role models, and we acknowledge their many contributions to the field We hope that you find this Annual Review Issue to be of value Naveena Singh1 and C Blake Gilks2 Queen Mary University of London, London, UK, and Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada © 2019 John Wiley & Sons Ltd, Histopathology, 76, 2–5 Editorial References Singer G, Shih IeM, Truskinovsky A, Umudum H, Kurman RJ Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor) Int J Gynecol Pathol 2003; 22; 37–41 Singer G, Oldt R III, Cohen Y et al Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma J Natl Cancer Inst 2003; 95; 484–486 © 2019 John Wiley & Sons Ltd, Histopathology, 76, 2–5 Singer G, St€ohr R, Cope L et al Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation Am J Surg Pathol 2005; 29; 218–224 Malpica A, Deavers MT, Lu K et al Grading ovarian serous carcinoma using a two-tier system Am J Surg Pathol 2004; 28; 496–504 Malpica A, Deavers MT, Tornos C et al Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma Am J Surg Pathol 2007; 31; 1168–1174 ... histological patterns, moves forward on multiple fronts in the fifth edition of the Blue Book (Table 1) These tumour Editorial 40 35 # cases 30 25 20 15 10 -1 16 -2 21 -2 26 -3 31 -3 36 -4 41 -4 46 -5 51 . .. when they reach the surgical pathology laboratory Later in 20 20, the fifth edition of Classification of tumours of the female genital tract (the Blue Book), produced under the auspices of the WHO/ IARC,... sites in the gynaecological tract, and Eusher and Malpica, drawing on their extensive experience and a thorough review of the literature, provide guidance for the proper handling of these specimens