Napsin A Immunoreactivity in "Hobnail" Epithelium in Benign Endometrial and Endocervical Polyps.

Endometrial and endocervical polyps not uncommonly exhibit focal benign "hobnail" change/metaplasia within the glandular epithelium, sometimes in association with inflammation or infarction. In most cases, this is readily recognized as benign but occasionally, especially in endometrial polyps, this change prompts consideration of a premalignant or malignant lesion, including early serous or clear cell carcinoma. Herein we highlight the previously unreported phenomenon of positive staining of this hobnail epithelium with Napsin A which has the potential to exacerbate concern for clear cell carcinoma. Endometrial (n = 22) and endocervical (n = 17) polyps showing hobnail change were stained with Napsin A. Six cases were positive (4 of 22 endometrial and 2 of 17 endocervical polyps). In all cases, Napsin A positivity was confined to the hobnail epithelium. The hobnail epithelium was positive with estrogen receptor and hepatocyte nuclear factor 1- beta and exhibited wild-type immunoreactivity with p53 in all cases where these markers were performed. In addition, in 2 of 3 uterine adenosarcomas with focal hobnail change the epithelium was Napsin A positive. Pathologists should be aware that Napsin A may be expressed in benign/reactive hobnail epithelium in endometrial and endocervical polyps and should not consider positivity with this marker as a diagnostic of clear cell carcinoma.

Gynecologic Pathology Journal Club: A 2-year, Worldwide Virtual Learning Experience With a Focus on Mentorship and Inclusion.

Journal clubs (JCs) are a common format used in teaching institutions to promote trainee engagement and develop skills in seeking out evidence-based medicine and critically evaluating literature. Digital technology has made JC accessible to worldwide audiences, which allows for increased inclusion of globally diverse presenters and attendees. Herein we describe the experience of the first 2 years of a virtual gynecologic pathology JC designed with the goal of providing mentorship and increasing inclusivity. JC began in a virtual format in April 2020 in response to the need for remote learning during the coronavirus disease 2019 pandemic. Each JC had 1 moderator, lasted 1 hour, featured up to 3 trainees/early-career pathologists, and covered articles on gynecologic surgical pathology/cytopathology. Trainees were recruited through direct contact with moderators and advertising through social media (eg, Twitter). A template was used for all presentations, and before presenting, live practice sessions were conducted with the moderator providing constructive feedback and evaluations were provided to presenters and attendees for feedback. Recordings of the meetings were made publicly available after the event through YouTube, a society website, and emails to registrants. Fifty-nine presenters participated, covering 71 articles. Most were trainees (53/59; 89%) from North America (33/59; 56%), with additional presenters from Asia (14/59; 24%), Australia/Oceania (5/59; 8%), Africa (4/59; 7%), and Europe (3/59; 5%). An average of 20 hours were spent per month by moderators on the selection of papers, meeting preparation, and provision of mentorship/feedback. Live events had a total of 827 attendees, and 16,138 interactions with the recordings were noted. Among those who self-identified on provided surveys, the attendees were most commonly from Europe (107/290; 37%) and were overwhelmingly practicing pathologists (275/341; 81%). The experience, including mentorship, format, and content, was positively reviewed by attendees and presenters. Virtual JC is an inclusive educational opportunity to engage trainees and early-career pathologists from around the world. The format allowed for the JC to be widely viewed by attendees from multiple countries, most being practicing pathologists. Based on feedback received, virtual JC appears to expand the medical knowledge of the attendees and empower presenters to develop their expertise and communication skills.

Gastric-type glandular lesions of the female genital tract excluding the cervix: emerging pathological entities.

In the last two decades or so, a spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation has been described, with gastric-type adenocarcinoma representing the most common human papillomavirus (HPV)-independent cervical adenocarcinoma. More recently, limited literature has reported a variety of gastric-type glandular lesions at other sites within the female genital tract and, as in the cervix (the most common site for these lesions), a spectrum of benign, premalignant and malignant lesions has been proposed. We provide an update and review of the emerging spectrum of gastric-type glandular lesions at female genital tract sites other than the cervix. In the endometrium, putative gastric-type glandular lesions include mucinous metaplasia of gastric-type, atypical mucinous proliferation of gastric-type and gastric-type adenocarcinoma. Similarly in the vagina, gastric-type adenosis, atypical adenosis and adenocarcinoma have been described. There have also been occasional reports of gastric-type lesions involving the ovary and fallopian tube. We provide guidance on how to recognise gastric-type lesions morphologically and immunophenotypically and stress that sometimes these lesions occur at more than one site within the female genital tract (synchronous/multifocal gastric-type lesions of the female genital tract), sometimes in association with Peutz-Jeghers syndrome.

Macroscopic examination of gynaecological specimens: a critial and often underemphasised aspect of pathological reporting.

Pathological examination of surgical specimens and compilation of a surgical pathology report comprises a series of events which includes macroscopic examination and tissue sampling, either complete or selected. This step is critical but often overlooked in the literature and not given the attention it deserves. In this review, we discuss the macroscopic examination and grossing of gynaecological pathology specimens, with reference to national and international protocols. We provide guidance as to the degree of sampling necessary in different scenarios and stress that a common-sense approach is necessary with flexibility in the degree of sampling depending on a variety of factors.

Cervical Adenoid Basal Carcinoma With High-grade Squamous Component: True Mixed Carcinoma or Colonization of Adenoid Basal Carcinoma by High-grade Squamous Intraepithelial Lesion?

Adenoid basal carcinoma (ABC) is a rare clinically indolent human papillomavirus-associated cervical neoplasm with uniformly bland morphology which in pure form does not metastasize. Many cases co-exist with a human papillomavirus-associated high-grade squamous intraepithelial lesion (HSIL) or squamous cell carcinoma (SCC). The ABC and high-grade squamous components may be clearly separate, albeit intermingled, and when the high-grade squamous component is invasive, the tumor is designated a mixed carcinoma, with clinical behavior determined by the non-ABC component. In other cases, discrete nests of high-grade atypical squamous cells are intimately admixed and incorporated within the ABC. These are more difficult to classify but are also usually reported as mixed carcinomas. Herein, we report a series of 9 cases of ABC in patients aged 33 to 89 years (mean age: 63 y) with a high-grade squamous component. In 7 cases, the high-grade squamous cells partly replaced and expanded the nests of ABC, sometimes with a residual cuff of ABC cells, while in the other 2 cases the ABC and SCC were clearly separate. We propose that the aforementioned 7 cases represent colonization of ABC by HSIL rather than mixed carcinomas; as far as we are aware, this concept has not been proposed before. In all cases which we feel represent colonization of ABC by HSIL, the tumors were confined to the cervix (stages IA1 [3 tumors], IA2 [2 tumors], IB1 [2 tumors]) and follow-up was unremarkable with no evidence of metastasis. One case with separate components of ABC and SCC was stage IVA at diagnosis and the patient died of disease. The other was stage IB1 at diagnosis and the patient died of unrelated causes at 13 months. We discuss the clinical implications of distinguishing true mixed carcinomas from colonization of ABC by HSIL and provide an approach to diagnosis. We also report a unique case of colonization of so-called cervical ectopic prostatic tissue by HSIL.

FIGO 2023 endometrial cancer staging: too much, too soon?

An updated International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma was introduced in June 2023. The new system represents a significant departure from traditional endometrial and other gynecological carcinoma staging systems which are agnostic of parameters such as tumor type, tumor grade, lymphovascular space invasion, and molecular alterations. The updated system, which incorporates all of these 'non-anatomical' parameters, is an attempt to make staging more personalized and relevant to patient prognostication and management, and to align with the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) risk stratification. Herein, we present a critical review of the new staging system and discuss its advantages and disadvantages. The authors propose that the new FIGO staging system should be first appraised at a multi-institutional and global level with the input of all relevant societies (gynecology, pathology, gynecologic oncology, medical oncology, radiation oncology) to understand the impact, scope, and supporting evidence of the proposed changes. Such a process is fundamental to produce a robust system that pathologists and treating clinicians can adopt.

The diverse morphology and immunophenotype of ovarian endometrioid carcinomas.

Endometrioid carcinoma (EC) accounts for approximately 10-12% of ovarian epithelial malignancies but compared to its relative frequency, results in a disproportionate number of diagnostically difficult cases with potential for misdiagnosis. In this review the protean and diverse morphologies of ovarian EC are discussed, including 'metaplastic' changes, EC with spindle cell differentiation/corded and hyalinised features and EC with sex cord-like formations. The propensity for 'transdifferentiation' in ovarian ECs is also discussed, one example being the association with a somatically derived yolk sac tumour. Although immunohistochemistry may be extremely useful in diagnosing EC and in distinguishing between EC and other ovarian epithelial malignancies, metastatic neoplasms and sex cord-stromal tumours, this review also discusses the propensity for ovarian EC to exhibit an aberrant immunophenotype which may compound diagnostic uncertainty. The genomic characteristics of these tumours and the recent 'incorporation' of seromucinous carcinoma into the EC category are also discussed.

The role of HER2 as a therapeutic biomarker in gynaecological malignancy: potential for use beyond uterine serous carcinoma.

Human epidermal growth factor receptor 2 (HER2) is a prognostic biomarker and therapeutic target in carcinomas of the breast, stomach and colon. In 2018, clinical trial data confirmed the prognostic and predictive role of HER2 in uterine serous carcinoma, with a demonstrated survival benefit from combined chemotherapy and anti-HER2 targeted therapy in patients with advanced or recurrent disease. Approximately one-third of uterine serous carcinomas demonstrate HER2 protein overexpression and/or gene amplification and HER2 immunohistochemistry, supplemented by in situ hybridisation in equivocal cases, is fast becoming a reflex ancillary test at time of diagnosis. The potential role of HER2 in gynaecological tumours other than uterine serous carcinoma is yet to be firmly established. With the advent of personalised medicine, routine tumour sequencing and pursuit of targeted therapies, this is a field currently under active investigation. Emerging data suggest triaging endometrial carcinomas for HER2 analysis based on molecular classification may be superior to histotype-based testing, with copy-number high/p53 mutant tumours enriched for HER2 overexpression or amplification. Accordingly, many carcinosarcomas and a subset of clear cell and high-grade endometrioid carcinomas may be eligible for HER2 targeted therapy, although any clinical benefit in this context is currently undefined. For ovarian carcinomas, combined data support the role of HER2 as a prognostic biomarker, however its use as a therapeutic target is yet to be elucidated through clinical trials. In the cervix, reported rates of HER2 overexpression vary and are generally low, and currently there is insufficient evidence to justify routine HER2 testing in this context. Limited data suggest HER2 holds promise as a prognostic and predictive biomarker in vulvar Paget disease. Future clinical trials, with pathologist input to develop and refine site-specific scoring criteria, are required to establish what role HER2 might play more broadly in gynaecological cancer care.

Microscopic Sertoliform Sex Cord Proliferations: A Rare Incidental Finding Associated With Endometriosis and Ovarian Epithelial Neoplasia.

Microscopic sex cord proliferations are a rare incidental finding seen in association with ovarian and uterine stromal or epithelial neoplasms and more uncommonly non-neoplastic conditions such as endometriosis and adenomyosis. They may also occur in the absence of other pathology, as an incidental finding in the ovaries of pregnant women and in heterotopic locations such as the fallopian tube. Most reports of this phenomenon describe adult granulosa cell tumor-like morphology. Herein, we describe 4 cases of microscopic sex cord proliferations with Sertoliform features, occurring in the stromal component of endometriosis or in the wall of an epithelial ovarian neoplasm; 2 of the patients with endometriosis had concurrent endometrioid adenocarcinoma (1 uterine corpus, 1 ovary). The proliferations were positive with sex cord markers inhibin and calretinin. As far as we are aware, such Sertoliform proliferations have not been reported previously in endometriosis and have only rarely been described in association with ovarian epithelial neoplasia. It is likely that such proliferations represent a benign non-neoplastic phenomenon. Awareness of this phenomenon is important in order to avoid misdiagnosis as a sex cord or other neoplasm. In reporting this unusual phenomenon, we review incidental sex cord and sex cord-like proliferations in the female genital tract.

Microscopic Sertoliform Sex Cord Proliferation Involving Pelvic Peritoneum: Report of a Case Associated With Endosalpingiosis.

Microscopic sex cord proliferations are an uncommon finding, most often associated with ovarian or uterine stromal, epithelial, or mixed epithelial and stromal neoplasms. Rarely they occur in conjunction with a non-neoplastic process such as endometriosis or adenomyosis, and occasionally in the absence of concurrent pathology in locations such as the fallopian tube. Most reports of this phenomenon document adult granulosa cell tumor-like morphology but more uncommonly the proliferations exhibit Sertoliform features. We report a case of a multifocal sex cord proliferation (inhibin and calretinin positive; BerEP4 and epithelial membrane antigen negative) with Sertoliform features occurring in the pelvic peritoneum and associated with endosalpingiosis, a previously unreported phenomenon. We discuss the differential diagnosis and speculate that this represents a non-neoplastic phenomenon.

Dataset for the Reporting of Carcinoma of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Cervical carcinoma remains one of the most common cancers affecting women worldwide, despite effective screening programs being implemented in many countries for several decades. The International Collaboration on Cancer Reporting (ICCR) dataset for cervical carcinoma was first developed in 2017 with the aim of developing evidence-based standardized, consistent and comprehensive surgical pathology reports for resection specimens. This 4th edition update to the ICCR dataset on cervical cancer was undertaken to incorporate major changes based upon the updated International Federation of Obstetricians and Gynecologists (FIGO) staging for carcinoma of the cervix published in 2018 and the 5th Edition World Health Organization (WHO) Classification of Female Genital Tumors published in 2020 and other significant developments in pathologic aspects of cervical cancer. This updated dataset was developed by a panel of expert gynecological pathologists and an expert gynecological oncologist, with a period of open consultation. The revised dataset includes "core" and "noncore" elements to be reported; these are accompanied by detailed explanatory notes and references providing the rationale for the updates. Standardized reporting using datasets such as this helps facilitate consistency and accuracy, data collection across different sites and comparison of epidemiological and pathologic parameters for quality and research purposes.

Molecular subclassification of vulvar squamous cell carcinoma: reproducibility and prognostic significance of a novel surgical technique.

OBJECTIVES: Vulvar squamous cell carcinoma is subclassified into three prognostically relevant groups: (i) human papillomavirus (HPV) associated, (ii) HPV independent p53 abnormal (mutant pattern), and (iii) HPV independent p53 wild type. Immunohistochemistry for p16 and p53 serve as surrogates for HPV viral integration and TP53 mutational status. We assessed the reproducibility of the subclassification based on p16 and p53 immunohistochemistry and evaluated the prognostic significance of vulvar squamous cell carcinoma molecular subgroups in a patient cohort treated by vulvar field resection surgery. METHODS: In this retrospective cohort study, 68 cases treated by vulvar field resection were identified from the Leipzig School of Radical Pelvic Surgery. Immunohistochemistry for p16 and p53 was performed at three different institutions and evaluated independently by seven pathologists and two trainees. Tumors were classified into one of four groups: HPV associated, HPV independent p53 wild type, HPV independent p53 abnormal, and indeterminate. Selected cases were further interrogated by (HPV RNA in situ hybridization, TP53 sequencing). RESULTS: Final subclassification yielded 22 (32.4%) HPV associated, 41 (60.3%) HPV independent p53 abnormal, and 5 (7.3%) HPV independent p53 wild type tumors. Interobserver agreement (overall Fleiss' kappa statistic) for the four category classification was 0.74. No statistically significant differences in clinical outcomes between HPV associated and HPV independent vulvar squamous cell carcinoma were observed. CONCLUSION: Interobserver reproducibility of vulvar squamous cell carcinoma subclassification based on p16 and p53 immunohistochemistry may support routine use in clinical practice. Vulvar field resection surgery showed no significant difference in clinical outcomes when stratified based on HPV status.

Neuroendocrine Neoplasia of the Female Genital Tract.

Neuroendocrine neoplasia is relatively uncommon in the female genital tract (FGT) and occurs at any site, most often the ovary and cervix. A unified dichotomous nomenclature, introduced by the World Health Organization Classification of Tumors in all fifth edition volumes, divides neuroendocrine neoplasms (NENs) into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The term carcinoid tumor is retained in the ovary and represents the commonest FGT NEN. NEC is most common in the cervix and is usually admixed with another human papillomavirus-associated epithelial neoplasm. Despite shared neuroendocrine differentiation, NET and NEC show diverse etiology, morphology, and clinical behavior.

HPV42-associated Seborrhoeic Keratosis-like Lesion of the Cervix: First Reported Case With High-grade Morphology.

Seborrheic keratosis-like lesion (SKLL) is an extremely rare, morphologically distinct lesion occurring in the cervix and vagina that differs histologically from usual squamous intraepithelial lesions in these sites, by bearing close resemblance to cutaneous seborrheic keratosis and lacking koilocytosis. Like many vulvar seborrheic keratoses, which are associated with low-risk human papillomavirus (HPV), an association between SKLL and low-risk HPV is suggested based on the identification of HPV42, regarded as a low-risk genotype, in 4 of 8 reported cases. We report a further HPV42-associated SKLL of the cervix which differs from the previously reported cases by the presence of high-grade morphology and block-type p16 immunoreactivity. This novel finding challenges the classification of HPV42 as a low-risk genotype and expands the reported morphologic spectrum of SKLL, suggesting that they may not always be clinically indolent.

Precursor Lesions of Cervical Clear Cell Carcinoma: Evidence For Origin From Tubo-Endometrial Metaplasia.

Cervical clear cell carcinoma (CCC) is an HPV-independent tumor historically associated with in-utero exposure to diethylstilboestrol. With the cessation of diethylstilboestro use, most contemporary cases are sporadic and of uncertain pathogenesis, with no established precursor lesion. Following the detection of 3 incidental "early" (FIGO stage IA1) cervical CCCs, all of which displayed adjacent tubo-endometrial metaplasia, we examined further cases, including resection specimens, of this tumor in an attempt to delineate potential precursors. We identified tubo-endometrial metaplasia in proximity to the tumor in 5 of 5 additional primary cervical CCCs, with some tubo-endometrial glands exhibiting subtle mild cytologic atypia. This observation adds to the sparse existing literature proposing tubo-endometrial metaplasia as a precursor to sporadic cervical CCC, with possible progression via an "atypical" transitional phase to malignancy. We also review the published literature regarding possible precursor lesions of primary cervical CCC.

Ovarian mucinous and seromucinous neoplasms: problematic aspects and modern diagnostic approach.

The morphological spectrum of primary ovarian mucinous and seromucinous tumours is broad, and presents an array of diagnostic challenges, many unique to these tumour types. This reflects the heterogeneous nature of these lesions, their varied histogenesis and evolving classification systems over recent decades, with further modification to the seromucinous category incorporated in the recently published 5th edition of the World Health Organisation (WHO) Classification of female genital tumours. In this review we provide an update on the classification of these neoplasms and discuss their histogenesis and diverse morphology, focusing on areas which are diagnostically problematic. We also cover tumour grading, differential diagnosis, immunohistochemistry, the recent elucidation of the molecular underpinnings of ovarian mucinous neoplasia and discuss the gross and intra-operative handling of these tumours. A number of diagnostic issues remain unresolved, highlighting the importance of further research on this front, as well as a multidisciplinary approach in the care of patients with ovarian mucinous and seromucinous neoplasia.

Outcomes of women with positive oncogenic HPV and reflex cytology showing possible high-grade squamous intraepithelial lesion.

AIM: To examine outcomes in women following cervical screening detection of oncogenic human papillomavirus (HPV), with reflex cytology showing possible high-grade squamous intraepithelial lesion (pHSIL). MATERIALS AND METHODS: A retrospective observational study of 523 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020. RESULTS: Two hundred eighty-two (53.9%) women had histology-confirmed HSIL, encompassing CIN2 or worse (CIN2+), including seven cancers (1.3%) and two adenocarcinoma in situ (AIS) (0.4%). In 81.2% (229/282) of women with CIN2+, this was detected on cervical biopsy at initial colposcopy, with another 8.9% (25/282) of CIN2+ detected at cervical excision following initial colposcopy and the remaining 9.9% (28/282) at follow-up colposcopy thereafter. When discordant cervical biopsy results were discussed at multidisciplinary meeting (MDM), 66.7% of women with pHSIL cytology upgraded to definite HSIL were found to have CIN2+, but only 20.8% when pHSIL cytology was retained and none when downgraded to low-grade (LSIL) or normal. No significant difference was found in the proportion of CIN2+ based on patient age above or below 40, HPV16 and/or 18 versus non 16/18, or whether discordant findings were reviewed at MDM. CONCLUSIONS: We propose a pathway for management of women with positive oncogenic HPV and reflex pHSIL cytology. MDM review is recommended when CIN2+ is not identified on cervical biopsy at initial colposcopy. Conservative management is safe with low risk of CIN2+ when LBC prediction of pHSIL is confirmed or downgraded at MDM with no high-grade change on colposcopy or repeat cytology.

Seborrheic Keratosis-Like Lesion of the Cervix: First Report of the Cytological Features of a Low-Risk HPV 42-Associated Lesion.

INTRODUCTION: Seborrheic keratosis-like lesion of the cervix and vagina is a rare lesion and shows similar morphology to vulvar seborrheic keratosis; 3 of the 7 previously reported cases were associated with low-risk human papillomavirus (HPV) type 42. We report a case of seborrheic keratosis-like lesion of the cervix and provide the first description of the cytological features of this lesion. CASE PRESENTATION: A woman in her late forties presented with postcoital bleeding. She had a cervical screening test following which she underwent cervical biopsy, endocervical and endometrial curettage, large loop excision of the transformation zone of the cervix, and hysterectomy. RESULTS: The liquid-based cytology preparation showed cohesive groups of mildly atypical squamoid cells with a spindle cell morphology, mildly increased nuclear to cytoplasmic ratio, prominent nucleoli, and occasional nuclear grooves. No koilocytes were identified. Molecular genotyping revealed positivity for HPV type 42. DISCUSSION/CONCLUSION: This represents the first description of the cytological features of a seborrheic keratosis-like lesion of the cervix, which are distinctive and unusual. Whilst the mild squamous atypia raised the possibility of a low-grade squamous intraepithelial lesion, no koilocytes were identified. The association in our case with a low-risk HPV type, HPV 42, provides further evidence for a role of this HPV type in the pathogenesis of these lesions.

Grading of Endocervical Adenocarcinomas: Review of the Literature and Recommendations From the International Society of Gynecological Pathologists.

There is a lack of consensus regarding the prognostic value of grading endocervical adenocarcinomas and currently, no universally applied, validated system for grading exists. Several grading schemes have been proposed, most incorporating an evaluation of tumor architecture and nuclear morphology and these are often based on the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, although some schemes modify the proportion of solid tumor required to separate grades 1 and 2 from 5% to 10%. In the absence of a validated system, we endorse this approach for most human papillomavirus-associated endocervical adenocarcinomas and, based on the available evidence, recommend that tumors with ≤10% solid growth be designated grade 1, 11% to 50% solid growth grade 2 and >50% solid growth grade 3. Tumors should be upgraded in the presence of marked nuclear atypia involving the majority (>50%) of the tumor. Grading is not recommended for human papillomavirus-independent adenocarcinomas, since no validated system has been suggested and most of these neoplasms exhibit intrinsically aggressive behavior regardless of their morphologic appearance. Importantly, grading should not be performed for gastric-type adenocarcinomas, particularly as these tumors may appear deceptively "low-grade" yet still exhibit aggressive behavior. Recently devised, validated and reproducible etiology and pattern-based tumor classification systems for endocervical adenocarcinomas appear to offer more effective risk stratification than tumor grading and, in the future, these systems may render the provision of a tumor grade redundant.