Prevalence of Occult Ovarian Cancer and Metastatic Breast Cancer in Ovarian Ablation Specimens of Patients With Hormone Receptor-Positive Breast Cancer: Implications for Tissue Sampling Strategies, Early Ovarian Cancer Detection and Resource Utilization.

Bilateral oophorectomy is one method of hormone suppression for premenopausal patients with hormone receptor-positive breast cancer. Such specimens could, in theory, harbor occult early ovarian cancer and/or metastatic breast cancer but guidelines for tissue sampling for pathologic examination remain to be addressed. Therefore, we evaluated oophorectomy specimens from 166 patients who underwent ovarian ablation for hormone receptor-positive breast cancer. Results of germline genetic testing were documented by the surgeon in only 31.3% of the pathology specimen requisition forms, whereas that information was available for 81.3% of patients elsewhere in the electronic medical records. All but 5.2% tested negative for a hereditary ovarian cancer gene pathogenic variant before oophorectomy. Complete tissue sampling was performed in 77.1% of the cases and representative sampling in the remainder. No cases of ovarian cancer were observed. Ovarian metastasis of breast cancer was identified in 9.6% of patients, all of whom were already known to have advanced-stage disease. The number of tissue cassettes per ovary required for complete tissue submission was on average three times higher than that for representative tissue sampling (P < 0.01) and ranged up to 20 cassettes per ovary when multiple follicle cysts were present. We propose that guidelines for tissue sampling in this context be defined by a combination of hereditary risk and macroscopic examination; representative sampling is reasonable for macroscopically normal ovaries in hormone receptor-positive breast cancer patients whose germline genetic testing is negative. Positive genetic test results merit complete tissue submission even if macroscopically normal. This strategy balances the goals of early ovarian cancer detection and optimal resource utilization. However, it depends on clear documentation of genetic test results. Our study demonstrates that many opportunities remain to close gaps in the communication of genetic test results by clinicians submitting oophorectomy specimens for pathologic evaluation.

Perceptions of Controversies and Unresolved Issues in the 2014 FIGO Staging System for Endometrial Cancer: Survey Results From Members of the International Society of Gynecological Pathologists and International Gynecologic Cancer Society.

Long-standing controversial and unresolved issues in the current "International Federation of Gynecology and Obstetrics" staging system for endometrial cancer are well-recognized by pathologists and clinicians alike and exist primarily as a result of limitations to the existing literature. To guide the design of future outcome-based studies specifically aimed at resolving such gaps, the International Society of Gynecologic Pathologists developed a survey of the current perceptions of pathologists (n = 172) and clinicians (n= 135) from the International Society of Gynecological Pathologists and from the International Gynecologic Cancer Society on areas for potential refinement of the current International Federation of Gynecology and Obstetrics staging system. The highest priority issues for pathologists and clinicians alike were the need to determine whether stage IIIA patients (ovarian/fallopian tube involvement) can be reliably separated into favorable versus unfavorable outcome groups to avoid over-treatment of the former group and to determine whether stage IIIC patients (lymph node metastases) can be separated into favorable versus unfavorable outcome groups based on the size of lymph node metastases. The majority of pathologists and clinicians viewed lymphovascular space invasion as an independent prognostic variable and favored incorporating lymphovascular space invasion into staging, though the level of support did not meet the threshold of 75% in support that we used to define a formal consensus. While pathologists did agree on the prognostic value of reporting the extent of lymphovascular space invasion, there was no consensus on the diagnostic criteria to distinguish focal versus substantial involvement. The majority of pathologists and clinicians viewed that a universally accepted protocol for sentinel lymph node ultra-staging is lacking. Both survey groups conveyed a slight preference for incorporating tumor histotype and molecular classification into staging but the support was short of the 75% threshold for formal consensus. Collectively, this survey permits the International Society of Gynecological Pathologists to develop a pathologist and clinician-driven long-term strategy for prioritizing and designing outcome-based studies specifically targeted to resolving controversial and unresolved issues in the International Federation of Gynecology and Obstetrics staging of endometrial cancer.

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.

ALK Immunoexpression is Specific for Inflammatory Myofibroblastic Tumor Among Vulvovaginal Mesenchymal Neoplasms.

Gynecologic tract origin of inflammatory myofibroblastic tumor (IMT), a receptor tyrosine kinase fusion driven tumor with malignant potential, is uncommon and mostly involves the uterine corpus where misclassification as a smooth muscle tumor may occur due to overlapping morphologic features. With rare exception, uterine IMT involves ALK rearrangements and exhibits ALK immunoexpression. Molecularly confirmed vulvovaginal IMT has not been reported, but several low-grade mesenchymal tumors in this region exhibit myxoid stroma and/or inflammatory infiltrates that may resemble IMT. The aims of this study were to define the diagnostic specificity of ALK immunoexpression for IMT among a broad spectrum (107 cases) of vulvovaginal mesenchymal tumors in the differential diagnosis of IMT and to report the clinicopathologic features of vulvovaginal IMT identified in our archives or via retrospective ALK staining of otherwise classified vulvovaginal tumors. Review of archives from 5 different centers revealed a single case of vulvar IMT in a 62-yr-old woman. The 2.5 cm well-circumscribed tumor exhibited the typical microscopic features of IMT, namely a loose fascicular distribution of bland spindle cells within a myxoid stroma, accompanied by an infiltrate of plasma cells, lymphocytes, and eosinophils. The tumor cells exhibited expression for smooth muscle actin, desmin, h-caldesmon, and ALK. Break-apart fluorescence in situ hybridization confirmed the presence of ALK rearrangement. The patient did not receive any treatment and is alive without disease 32 mo later. No evidence of ALK expression was detected in any of the other 107 vulvovaginal tumors, which included 14 aggressive angiomyxomas, 2 superficial angiomyxomas, 12 angiomyofibroblastomas, 8 cellular angiofibromas, 15 smooth muscle neoplasms, 10 peripheral nerve sheath tumors, 20 fibroepithelial polyps, and a variety of other low grade mesenchymal tumors. Although vulvovaginal ALK- rearranged IMT is exceedingly rare, the behavior remains to be fully understood. ALK immunohistochemistry, which appears specific for IMT in this anatomic site, is advised in the evaluation of vulvovaginal mesenchymal tumors exhibiting myxoid stroma and/or an inflammatory infiltrate.

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.

Data Set for Reporting of Uterine Malignant and Potentially Malignant Mesenchymal Tumors: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) seeks to produce standardized, evidence-based protocols for the reporting of tumors with the aim of ensuring that all cancer reports generated worldwide will be of similar high quality and record the same elements. Herein, we describe the development of the data set for the reporting of uterine malignant and potentially malignant mesenchymal tumors by a panel of expert pathologists and a single clinician and provide the commentary and rationale for the inclusion of core and noncore elements. This data set, which incorporates the recent updates from the 5th edition of the World Health Organization Classification of Female Genital Tumors, addresses several subjects of debate including which mesenchymal tumors should be graded, how to document extent of invasion, mitotic counts, and the role of ancillary testing in tumor diagnosis and patient management. The inclusion of elements is evidence-based or based on consensus of the expert panel with clinical relevance being the guiding standard.

Hereditary leiomyomatosis and renal cell carcinoma syndrome associated uterine smooth muscle tumors: Bridging morphology and clinical screening.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome that results from germline mutation in the fumarate hydratase (FH) gene and is associated with an increased risk for smooth muscle tumors of the uterus and skin and renal cell carcinoma. HLRCC associated RCC develop in up to 25% of patients, often presenting in the fourth decade and are high stage, aggressive tumors with poor clinical outcome. Most women with HLRCC develop large and bulky uterine smooth muscle tumors (USMT) in the second to third decade, thus presenting the ideal opportunity for early detection of HLCC to enable timely implementation of surveillance for their RCC risk. However, the concept of screening women with USMT for HLRCC is challenging given that HLRCC is rare but USMT are common. In addition, FH deficiency in USMT can also result from sporadic FH gene aberrations, unrelated to HLRCC, further complicating any potential screening process. Recent studies show that tumor morphology can be used to identify FH deficiency in USMT and thereby direct patients to formal genetic counseling. The low magnification clues of staghorn shaped blood vessels and alveolar pattern should prompt for high magnification examination for eosinophilic cytoplasmic inclusions and oval nuclei containing prominent eosinophilic macronucleoli surrounded by a halo. Additional clues include Schwannoma-like growth and chain-like distribution of the tumor cells. Although immunostains exist for FH and 2SC, their role is limited in the presence of well-developed FH deficient morphology. The prevalence of germline pathogenic mutation in FH among women with USMT with FH deficient morphology is as high as 50% in some studies, with somatic FH mutation accounting for the remainder. Therefore, morphologic evaluation of USMT for features of FH deficiency can serve as a screening tool for HLRCC syndrome by triaging patients to formal hereditary risk assessment.

Uterine plexiform tumourlets: multifocal and solitary cases with subsets expressing melanocytic markers.

AIMS: Uterine plexiform tumourlets are traditionally regarded as microscopic epithelioid leiomyomas. They are typically solitary incidental findings, but may be multifocal (plexiform leiomyomatosis). We aim to report novel immunohistochemical and morphological findings, specifically the presence of spindled and epithelioid cell nodules, in these lesions. METHODS AND RESULTS: Three cases of plexiform leiomyomatosis and 16 solitary plexiform tumourlets were included. Two cases of plexiform leiomyomatosis and four solitary plexiform tumourlets demonstrated spindled and epithelioid cell nodules which, in one of the former cases, formed expansile masses up to 15 mm. The nodules demonstrated mild cytological atypia and occasional mitotic activity, and they were associated with a myxoid stroma and a lymphohistiocytic infiltrate which imparted a granulomatous appearance to the microscopic lesions. The plexiform tumourlets (solitary and multifocal) consistently expressed desmin, smooth muscle actin, ER and PR, and they commonly co-expressed melanocytic and perivascular epithelioid cell (PEC) markers HMB45, MiTF and cathepsin K. The spindled and epithelioid cell nodules were generally negative for myoid markers and hormone receptors, but expressed p16, cyclin D1 and TFE3. All lesions tested were negative for cytokeratin, S100, melanA, inhibin, EMA, ALK and BCOR; fluorescence in-situ hybridisation was negative for ALK, TFE3 and BCOR rearrangements in one of the larger spindled and epithelioid cell nodules. CONCLUSIONS: Plexiform tumourlets commonly co-express myoid and melanocytic markers and may represent part of the spectrum of gynaecological PEC-related lesions. Some cases are associated with spindled and epithelioid cell nodules that could potentially mimic other uterine myxoid neoplasms.

The ISGyP Endocervical Adenocarcinoma Project: Master Plan Summary, Acknowledgment of Participants, and Participant Responses to Final Recommendations of the Expert Panels.

The International Society of Gynecological Pathologists carried out a multifaceted project with the broad aim of improving the pathological reporting of endocervical adenocarcinoma (EAC). The intentions were to promote and align practices with the WHO 2020 classification, which endorses HPV status-based classification of EAC and the Silva pattern-based assessment of HPV-associated EAC, to promote uniformity in applying the recent FIGO staging revisions on cervical carcinoma, and to provide best practice guidelines on all aspects of EAC pathology reporting. To facilitate the use of the new WHO/IECC classification and the Silva system, two online educational portals were set up with training and test sets of scanned slides; these remain available to society members on the ISGyP educational website. In addition, a large international collaborative individual data collection project is ongoing, aiming to ascertain the prognostic value of EAC categories, and to provide a database with the potential to address unanswered questions. A single on-site meeting was held on February 29, 2020 in Los Angeles, in advance of the USCAP Annual Meeting; all other correspondence was by email and through electronic surveys. Project participants were invited to vote and comment on the recommendations contained within the practice guideline articles. The project received an enthusiastic response from pathologists across the world. This report includes an overview and summary of all aspects of the project, a list of participants and the results of polling on practice recommendations.

Corded and Hyalinized Endometrioid Adenocarcinoma (CHEC) of the Uterine Corpus are Characterized by CTNNB1 Mutations and Can Show Adverse Clinical Outcomes.

Corded and hyalinized endometrioid adenocarcinoma (CHEC) is a morphologic variant of endometrioid adenocarcinoma that is typically low-grade [International Federation of Gynecology and Obstetrics (FIGO) grade 1-2]. CHEC exhibits a biphasic appearance with gland forming adenocarcinoma merging with a diffuse component with corded growth often in a hyalinized matrix; squamous differentiation is frequent and osteoid production can be seen. This morphologic appearance can invoke a large differential diagnosis including carcinosarcoma. CHEC is thought to be associated with good clinical outcome although the available data is sparse. We performed detailed clinical, morphologic, immunohistochemical, and molecular analyses on a cohort of 7 CHEC. Six cases exhibited features of classic low-grade CHEC while one case showed greater cytologic atypia (high-grade CHEC). Patient age ranged from 19 to 69 yr. Four patients presented at stage I, 2 at stage II, and 1 at stage III. All tumors demonstrated nuclear staining for beta-catenin and loss of E-cadherin in the corded and hyalinized component. There was relative loss of epithelial markers. Loss of PTEN and ARID1A was seen in 4 and 3 tumors, respectively, and 1 tumor displayed loss of MLH1 and PMS2. Next-generation sequencing revealed CTNNB1 and PI3K pathway mutations in all 7 cases with TP53 and RB1 alterations in the high-grade CHEC. Clinical follow-up was available for 6 patients; 2 died of disease (48 and 50 mo), 2 are alive with disease (both recurred at 13 mo), and 2 have no evidence of disease (13 and 77 mo). Our study shows that CHEC universally harbors CTNNB1 mutations with nuclear staining for beta-catenin, can rarely show high-grade cytology, and can be associated with adverse clinical outcomes.

Survey Results on Pathologic Aspects of Endocervical Adenocarcinoma by the International Society of Gynecological Pathologists.

The International Society of Gynecological Pathologists (ISGyP) undertook a project to provide evidence-based recommendations for pathologic reporting of all aspects of endocervical adenocarcinoma. The first step in the process was the design of an extensive survey to collect baseline information on existing practices regarding grossing, processing, diagnosing, and reporting of endocervical adenocarcinoma among the members of the society. The web-based survey of 98 questions was emailed to all members of ISGyP and there were 175 respondents (38.5% of ISGyP members). The responses, as expected, revealed areas of uniformity but also areas of substantial variation. The results of the survey are presented herein and assisted in developing the recommendations presented in the other reviews in this issue.

Endocervical Adenocarcinoma, Gross Examination, and Processing, Including Intraoperative Evaluation: Recommendations From the International Society of Gynecological Pathologists.

The International Society of Gynecological Pathologists (ISGyP) Endocervical Adenocarcinoma Project aims to provide evidence-based guidance for the pathologic evaluation, classification, and reporting of endocervical adenocarcinoma. This review presents the recommendations pertaining to gross evaluation and intraoperative consultation of specimens obtained from patients in the setting of cervical cancer. The recommendations are the product of review of published peer-reviewed evidence, international guidelines and institutional grossing manuals, as well as deliberation within this working group. The discussion presented herein details the approach to the different specimen types encountered in practice: loop electrosurgical excision procedure, cone, trachelectomy, radical hysterectomy, pelvic exenteration, and lymphadenectomy specimens. Guidelines for intraoperative evaluation of trachelectomy and sentinel lymph node specimens are also addressed. Correlation with ISGyP recommendations on cancer staging, which appear as a separate review in this issue, is also included when appropriate. While conceived in the framework of endocervical adenocarcinoma, most of the discussion and recommendations can also be applied to other cervical malignancies.

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.

Regional air transportation of ovarian tissue for cryopreservation in a prepubertal female with cancer.

Ovarian tissue cryopreservation is the only fertility preservation (FP) option available to prepubescent females receiving gonadotoxic therapy, but it has limited availability. A 6-year-old female was diagnosed with high-risk rhabdomyosarcoma, and the planned treatment carried an 80% risk of ovarian failure. Her parents desired FP, but the nearest center was 500 miles away. The patient underwent oophorectomy at the cancer center with air transport of the tissue to the oncofertility center, where it was successfully cryopreserved. Formation of networks between full-service and limited oncofertility centers in a hub-and-spoke model would increase access to FP services, particularly in children.

Online Training and Self-assessment in the Histopathologic Classification of Endocervical Adenocarcinoma and Diagnosis of Pattern of Invasion: Evaluation of Participant Performance.

Histopathologic classification of endocervical adenocarcinomas (EAC) has recently changed, with the new system based on human papillomavirus (HPV)-related morphologic features being incorporated into the 5th edition of the WHO Blue Book (Classification of Tumours of the Female Genital Tract). There has also been the introduction of a pattern-based classification system to assess invasion in HPV-associated (HPVA) endocervical adenocarcinomas that stratifies tumors into 3 groups with different prognoses. To facilitate the introduction of these changes into routine clinical practice, websites with training sets and test sets of scanned whole slide images were designed to improve diagnostic performance in histotype classification of endocervical adenocarcinoma based on the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and assessment of Silva pattern of invasion in HPVA endocervical adenocarcinomas. We report on the diagnostic results of those who have participated thus far in these educational websites. Our goal was to identify areas where diagnostic performance was suboptimal and future educational efforts could be directed. There was very good ability to distinguish HPVA from HPV-independent adenocarcinomas within the WHO/IECC classification, with some challenges in the diagnosis of HPV-independent subtypes, especially mesonephric carcinoma. Diagnosis of HPVA subtypes was not consistent. For the Silva classification, the main challenge was related to distinction between pattern A and pattern B, with a tendency for participants to overdiagnose pattern B invasion. These observations can serve as the basis for more targeted efforts to improve diagnostic performance.

Müllerian Duct Anomalies: Role in Fertility and Pregnancy.

Müllerian duct anomalies (MDAs) have important implications for the reproductive health of female patients. In patients with both infertility and recurrent pregnancy loss, the incidence of MDAs is as high as 25%. Congenital uterine anomalies are often only part of a complex set of congenital anomalies involving the cervix, vagina, and urinary tract. Multiple classification systems for MDAs exist, each with different criteria that vary most for the diagnosis of septate uterus. Recognizing the features that guide clinical management is essential for interpretation. Identification of an MDA should prompt evaluation for associated urinary tract anomalies. In patients with infertility who seek to use assisted reproductive technologies such as intrauterine insemination, recognition of MDAs may have an affect on reproductive success, particularly in patients who have an incomplete and clinically occult septum that divides the cervix. Two-dimensional US is the first-line modality for evaluating the uterus and adnexa. Three-dimensional (3D) US or MRI may help to visualize the external uterine fundal contour and internal indentation of the endometrial cavity, which are two morphologic characteristics that are keys to the diagnosis of congenital uterine anomalies. Hysterosalpingo contrast-enhanced US may be performed in conjunction with 3D US to evaluate uterine morphologic characteristics, the endometrial cavity, and tubal patency in a single examination. MRI helps to characterize rudimentary uteri in patients with müllerian hypoplasia and allows assessment for ectopic ureters, abnormally positioned ovaries, or associated deep infiltrative endometriosis. Online supplemental material is available for this article. ©RSNA, 2021.

Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components.

Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multiregion whole-exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from ten females with ovarian immature teratomas, with bilateral tumors present in five cases and peritoneal dissemination in seven cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the four analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from nondisjunction errors during meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.

Classification and reporting guidelines for the pathology diagnosis of placenta accreta spectrum (PAS) disorders: recommendations from an expert panel.

The terminology and diagnostic criteria presently used by pathologists to report invasive placentation is inconsistent and does not reflect current knowledge of the pathogenesis of the disease or the needs of the clinical care team. A consensus panel was convened to recommend terminology and reporting elements unified across the spectrum of PAS specimens (i.e., delivered placenta, total or partial hysterectomy with or without extrauterine tissues, curetting for retained products of conception). The proposed nomenclature under the umbrella diagnosis of placenta accreta spectrum (PAS) replaces the traditional categorical terminology (placenta accreta, increta, percreta) with a descriptive grading system that parallels the guidelines endorsed by the International Federation of Gynaecology and Obstetrics (FIGO). In addition, the nomenclature for hysterectomy specimens is separated from that for delivered placentas. The goal for each element in the system of nomenclature was to provide diagnostic criteria and guidelines for expected use in clinical practice.

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli-Leydig cell tumour, microcystic stromal tumour and their mimics.

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord-stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli-Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord-stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.

NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.

AIMS: A unique fibrosarcoma-like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma-like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement. METHODS AND RESULTS: Three patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan-Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3-NTRK1, TPR-NTRK1, and SPECC1L-NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan-Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next-generation sequencing. CONCLUSIONS: Unusual adenosarcoma-like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan-Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.