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Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear transcription factor that shows consistent nuclear staining in colorectal adenocarcinoma and osteosarcoma. Following the observation of cytoplasmic staining with this marker in luteinized ovarian stromal cells, we studied the expression of SATB2 in ovarian stromal cells, various types of follicular cysts, and sex cord-stromal tumors. Eighty-five cases were stained for SATB2. Ovarian hilar Leydig cells (n = 12), luteinized stromal cells (n = 10), corpora lutea (n = 4), luteinized follicular cysts (n = 4), and stromal hyperthecosis (n = 6) exhibited consistent, usually diffuse, granular cytoplasmic staining. In addition, Leydig cell tumors (n = 1) and steroid cell tumors (n = 4) showed diffuse cytoplasmic staining. SATB2 also exhibited cytoplasmic staining in most Sertoli-Leydig cell tumors (n = 16) and gynandroblastomas (n = 3) confined to the Leydig cell component. Adult granulosa cell tumors (n = 14), juvenile granulosa cell tumors (n = 3), sex cord tumors with annular tubules (n = 3), cellular fibromas (n = 3), sclerosing stromal tumors (n = 1), and thecomas (n = 1) were negative apart from cytoplasmic staining in associated luteinized stromal cells. SATB2 cytoplasmic staining has not been previously described in these lesions but is characteristic of a variety of ovarian stromal cells and sex cord-stromal tumors, in particular, those exhibiting luteinization or a Leydig or steroid cell component. SATB2 staining may be of value in identifying luteinized or Leydig cells when these are morphologically inconspicuous., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Introduction: Endometriosis affects 10% of women of reproductive age. There is evidence for a left lateral predisposition of endometriotic lesions and a 1.9-fold greater risk of ovarian cancer in endometriosis. The aim of this study is to determine whether a left lateral predisposition of ovarian clear-cell carcinoma (CCC) and endometrioid carcinoma (EC) exists., Materials and Methods: A retrospective cohort study of all EC and CCC patients in Northern Ireland between March-2011 and June-2018. ANOVA was used to analyse preoperative prediction of stage, chi-squared (χ2) was used to compare left- and right-sided masses. Survival was estimated using Kaplan-Meier and log-rank test. A p-value <0.05 was considered significant., Results: 158 patients were identified (95 EC, 55 CCC, 8 mixed). Mean age was 57.65 years with 69% presenting at stage 1. The mean CA125 was 559 U/mL (p = 0.850) and mean abdominal mass size was 14.12 cm (p = 0.732). The most common presenting symptom was an abdominal mass (37%). Despite 67% of patients having endometriosis on final pathology, only 8.9% had a known history pre-operatively. 51% of tumours were located on the left (p = 0.036). For unilateral tumours this was significant for EC (P = 0.002) but not for CCC (P = 0.555). The 1-, 3- and 5-year overall survival for all types/stages was 85%, 78% and 71% respectively., Conclusion: While CCC and EC are associated with endometriosis, only EC exhibits a left lateral predisposition. There is no association between preoperative CA125 or abdominal mass size and stage of disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Expression of neuroendocrine (NE) markers in primary ovarian non-NE epithelial tumors has rarely been evaluated. The aim of our study was to evaluate the expression of the most widely used NE markers in these neoplasms and to determine any prognostic significance of NE marker expression. The cohort consisted of 551 primary ovarian tumors, including serous borderline tumors, low-grade serous carcinomas, high-grade serous carcinomas (HGSC), clear cell carcinomas, endometroid carcinomas, mucinous borderline tumors, and mucinous carcinomas. Immunohistochemical analysis was performed using antibodies against INSM1, synaptophysin, chromogranin, and CD56 on tissue microarray. Positivity for INSM1, synaptophysin, chromogranin, and CD56 was most frequently observed in mucinous tumors (48.7%, 26.0%, 41.5%, and 100%, respectively). The positivity for these NE markers was mostly restricted to nonmucinous elements distributed throughout the tumor. The mucinous borderline tumor and mucinous carcinomas groups had similar proportions of positivity (mucinous borderline tumor: 53%, mucinous carcinomas: 39%). In the other tumor types, except for HGSC, there was only focal expression (5%-10%) or negativity for NE markers. HGSC showed high CD56 expression (in 26% of cases). Survival analysis was only performed for CD56 in HGSC as this was the only group with sufficient positive cases, and it showed no prognostic significance. Except for mucinous tumors, expression of NE markers in non-NE ovarian epithelial tumors is low. CD56 expression in HGSC occurs frequently but is without diagnostic or prognostic value., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Aims: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT., Methods and Results: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs., Conclusion: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed., Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs., Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed., Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention., Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated., Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs., Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Ovarian steroid and Leydig cell tumors (SCT and LCT, respectively) are rare stromal tumors, with aggressive behavior described in approximately one third of SCTs. Previously reported features potentially predictive of malignancy include size ≥7 cm, gross hemorrhage, necrosis, grade 2 or 3 nuclear atypia, and mitoses ≥2/10 HPFs; however, no subsequent studies have corroborated these findings. Herein, we evaluated a series of 25 tumors (21 SCT, 4 LCT) to explore their clinicopathologic and molecular features. Patients ranged from 16 to 79 years (median: 53 y) and all tumors were FIGO stage I. Recurrences occurred in 3 patients, all of whom died from disease. At least 1 atypical feature was identified in 63% of SCT/LCT and included hemorrhage (n=9), grade 2 or 3 atypia (n=7), mitoses≥2/10 HPFs (n=7), size≥7.0 cm (n=6), and necrosis (n=2); only malignant SCTs demonstrated 4 or 5 atypical features. Next-generation sequencing revealed malignant SCTs were genomically unstable, with uncommon and nonrecurring gene-level alterations ( MDM2/CDK4 coamplification, ATRX rearrangement, BAP1 mutation). One SCT with limited follow-up harbored FH and TP53 mutations and occasional arm-level copy number alterations, while all other sequenced tumors (n=7) were genomically stable; 1 had a CTNNB1 mutation and another a CASP10 mutation. In summary, the presence of at least 1 atypical feature is common in SCT/LCT, but most patients demonstrate a benign clinical course. Genomic alterations are infrequent but occur in malignant SCTs as well as a subset of benign SCTs. Molecular analysis of additional malignant SCTs is necessary to identify recurring and/or potentially actionable targets., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Gliomatosis involving lymph nodes (nodal gliomatosis) is rarely encountered in association with an ovarian teratoma, with 12 cases previously reported. We report this rare occurrence in a 23-yr-old female with an ovarian immature teratoma. The ovary contained a grade 3 immature teratoma, with immature neuroepithelium. A subcapsular liver mass contained metastatic immature teratoma with neuroepithelium. The omentum and peritoneum contained mature glial tissue, consistent with gliomatosis peritonei with no evidence of immature elements. One pelvic lymph node contained multiple nodules of mature glial tissue, diffusely positive for glial fibrillary acidic protein, in keeping with nodal gliomatosis. In reporting this case, we review prior reports of nodal gliomatosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

In gynecological neoplasms, immunohistochemical (IHC) expression of p53 is generally an accurate predictor of TP53 mutation status if correctly interpreted by the pathologist. However, the literature concerning cut-offs, frequency and prognostic significance of p53 staining in ovarian mucinous tumours is limited and heterogeneous. We performed an analysis of 123 primary ovarian mucinous tumours including mucinous borderline tumours (MBT), mucinous carcinomas (MC), and tumours with equivocal features between MBT and MC. We assessed p53 expression for the three recognised patterns of aberrant staining in ovarian carcinoma [overexpression ('all'), null and cytoplasmic] but using a recently suggested cut-off for aberrant overexpression in ovarian mucinous tumours (strong nuclear p53 staining in ≥12 consecutive tumour cells) and correlated the results with next generation sequencing (NGS) in all qualitatively sufficient cases (92/123). Aberrant p53 expression was present in 25/75 (33.3%) MBT, 23/33 (69.7%) MC (75% of MC with expansile invasion and 61.5% with infiltrative invasion), and 10/15 (66.7%) tumours equivocal between MBT and MC. Regarding the 92 tumours with paired IHC and mutation results, 86 showed concordant results and six cases were discordant. Three discordant MBT cases showed aberrant expression but were TP53 wild-type on sequencing. Three cases had normal p53 expression but contained a TP53 mutation. Overall, IHC predicted the TP53 mutation status with high sensitivity (94.1%) and specificity (92.7%). The accuracy of IHC was 93.5% with a positive predictive value of 94.1% and a negative predictive value of 92.7%. When comparing MC cases with wild-type TP53 versus those with TP53 mutation, there were no significant differences concerning disease-free survival, local recurrence-free survival, or metastases-free survival (p>0.05). In the MBT subgroup, there were no events for survival analyses. In conclusion, using an independent large sample set of ovarian mucinous tumours, the results of our study confirm that the suggested refined cut-off of strong nuclear p53 staining in ≥12 consecutive tumour cells reflect high accuracy, sensitivity and specificity for an underlying TP53 mutation but the TP53 mutation status has no prognostic significance in either MC or MBT., (Copyright © 2023 Royal College of Pathologists of Australasia. All rights reserved.)

DICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1. However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls., (© 2023. The Author(s).)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Adult granulosa cell tumor is the most common malignant ovarian sex cord-stromal tumor and heterologous elements, in the form of hepatocytes or mucinous epithelium, have rarely been described in these neoplasms. Here, we report an adult granulosa cell tumor in a 61-year-old woman with classic and luteinized elements and exhibiting a previously unreported feature in the form of foci of mature adipocytes. In reporting this case, we review heterologous adipocytic elements and other heterologous elements in ovarian sex cord-stromal tumors and speculate on the pathogenesis of the adipocytic differentiation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

We report an unusual case of a pelvic extraovarian moderately differentiated Sertoli-Leydig cell tumor arising in a 4-yr-old female. The tumor contained a DICER1 pathogenic variant which was absent in the germline ruling out DICER1 syndrome. In reporting this case, we discuss the differential diagnosis and possible histogenesis and review reported cases of extraovarian Sertoli-Leydig cell tumor., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

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., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Sertoli-Leydig cell tumors (SLCTs) are uncommon ovarian sex cord-stromal neoplasms which are currently classified into well, moderately, and poorly differentiated and retiform types. Well-differentiated SLCT is the least common and typically occurs in pure form, whereas moderately and poorly differentiated and retiform types often comprise a morphologic spectrum with an admixture of all 3. DICER1 pathogenic variants are very common in SLCTs but, as far as we are aware, have not been reported in well-differentiated neoplasms, although the number of cases studied is small due to the rarity of this neoplasm. We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1 wild-type. None of the cases harbored the p. FOXL2 C134W hotspot mutation. Based upon the DICER1 molecular results, together with morphologic observations, we propose that well-differentiated SLCT is an unrelated neoplasm to the more common moderately/poorly differentiated and retiform SLCTs and is a fundamentally distinct and unrelated tumor type within the ovarian sex cord-stromal tumor family. The implications for tumor nomenclature and recommendations for future tumor classification are discussed within the context of tumors collectively known as SLCTs., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: IMP2 and IMP3 are mRNA binding proteins involved in carcinogenesis. We examined a large cohort of ovarian tumors with the aim to assess the value of IMP2 and IMP3 for differential diagnosis, and to assess their prognostic significance., Methods: Immunohistochemical analyses with antibodies against IMP2 and IMP3 were performed on 554 primary ovarian tumors including 114 high grade serous carcinomas, 100 low grade serous carcinomas, 124 clear cell carcinomas, 54 endometrioid carcinomas, 34 mucinous carcinomas, 75 mucinous borderline tumors, and 41 serous borderline tumors (micropapillary variant). The associations of overall positivity with clinicopathological characteristics were evaluated using the chi-squared test or Fisher's Exact test., Results: We found IMP2 expression (in more than 5% of tumor cells) in nearly all cases of all tumor types, so the prognostic meaning could not be analyzed. The positive IMP3 expression (in more than 5% of tumor cells) was most common in mucinous carcinomas (82%) and mucinous borderline tumors (81%), followed by high grade serous (67%) and clear cell carcinomas (67%). The expression was less frequent in endometrioid carcinomas (39%), low grade serous carcinomas (23%), and micropapillary variant of serous borderline tumors (20%). Prognostic significance of IMP3 could be evaluated only in low grade serous carcinomas in the case of relapse-free survival, where negative cases showed better RFS (p = 0.033)., Conclusion: Concerning differential diagnosis our results imply that despite the differences in expression in the different ovarian tumor types, the practical value for diagnostic purposes is limited. Contrary to other solid tumors, we did not find prognostic significance of IMP3 in ovarian cancer, with the exception of RFS in low grade serous carcinomas. However, the high expression of IMP2 and IMP3 could be of predictive value in ovarian carcinomas since IMP proteins are potential therapeutical targets., (© 2023. The Author(s).)

Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms, and their diagnosis may be challenging. We analyzed 124 primary ovarian mucinous tumors originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and the potential for diagnostic support by molecular profiling using a next-generation sequencing targeted panel of 727 DNA and 147 RNA genes. Fourteen experienced pathologists independently assigned a diagnosis from preset options, based on a review of a single digitized slide from each tumor. After excluding 1 outlier participant, there was a moderate agreement in diagnosing the 124 cases when divided into 3 categories (κ = 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT as a combined category and MC was found in only 36.3% of the cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic. After a reclassification of the tumors into near-consensus diagnostic categories on the basis of the initial participant results, a comparison of molecular findings between the MBT and MC groups did not show major and unequivocal differences between MBTs and MCs or between MCs with expansile vs infiltrative pattern of invasion. In contrast, HER2 overexpression or amplification was found only in 5.3% of MBTs and in 35.3% of all MCs and in 45% of MCs with expansile invasion. Overall, HER2 alterations, including mutations, were found in 42.2% of MCs. KRAS mutations were found in 65.5% and PIK3CA mutations in 6% of MCs. In summary, although the diagnostic criteria are well-described, diagnostic agreement among our large group of experienced gynecologic pathologists was only moderate. Diagnostic categories showed a molecular overlap. Nonetheless, molecular profiling may prove to be therapeutically beneficial in advanced-stage, recurrent, or metastatic MCs., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Signet-ring stromal tumor (SRST) is a rare ovarian stromal neoplasm characterized by a population of bland signet-ring cells, devoid of mucin or lipid, in a generally cellular fibromatous stroma. Previous reports have described heterogenous immunohistochemical and molecular genetic findings, including occasional nuclear β-catenin expression and/or CTNNB1 mutations. We report 10 ovarian stromal neoplasms originally diagnosed as SRST. All but 1 tumor underwent detailed immunohistochemical analysis (including β-catenin) and 5 of 10 had CTNNB1 mutation analysis performed. All tumors contained a population of morphologically bland signet-ring cells that ranged from 15% to 95% of the neoplasm, characterized by a single large empty intracytoplasmic vacuole, mostly with nuclear indentation. Six of the 10 tumors contained cellular fibroma-like areas, comprising from 10% to 85% of the neoplasm. Three of the 10 tumors were reclassified as microcystic stromal tumor with signet-ring cells on the basis of the microcyst formation and hyalinized stroma, beta-catenin and cyclin D1 nuclear expression and/or CTNNB1 mutation, CD10 staining and largely absent expression of inhibin and calretinin. In the remaining 7 tumors, the diagnosis of SRST remained, constituting the largest series of SRST reported in the literature to date. The results of our study suggest that a subset of tumors diagnosed as ovarian SRST, especially those which show β-catenin nuclear positivity and/or CTNNB1 mutation, likely represent microcystic stromal tumor with variant morphology. We also suggest that at least a subset of SRSTs without evidence of Wnt/β-catenin pathway abnormalities may be related to ovarian fibromas. We discuss the differential diagnosis of ovarian neoplasms containing signet-ring cells., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined., Experimental Design: We perform multiomic characterization of a large HGSOC cohort (n = 362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events., Results: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival [multivariable hazard ratios (HR) 0.40 and 0.51] and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, whereas PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (HR range, 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favorable survival within HRR-aberrant cases (multivariable HR, 0.50)., Conclusions: These data paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes., (©2022 The Authors; Published by the American Association for Cancer Research.)

We assessed the value of cytokeratin 17 (CK17) expression for the differential diagnosis between primary ovarian mucinous tumors and metastases from the gastrointestinal tract (GIT) and the significance of CK17 expression in a broad spectrum of primary ovarian tumors with respect to their prognosis. The sample set consisted of 554 primary ovarian tumors and 255 GIT tumors. In the primary ovarian tumors, a higher CK17 expression (in > 10% of tumors cells) was present only in 0-11.4% of all tumors (including mucinous tumors, micropapillary serous borderline tumors, clear cell, endometrioid, and high-grade serous carcinomas). The only exception was low-grade serous carcinoma, where higher CK17 expression was present in 24% of cases. Concerning GIT tumors, the higher levels of CK 17 expression (in > 10% of tumor cells) were observed in the upper GIT tumors (68.5% of pancreatic ductal adenocarcinoma, 61.6% of gallbladder adenocarcinoma, and 46% of gastric adenocarcinoma), which differs substantially not only from most of the primary ovarian tumors, but also from colorectal carcinoma (3.7%; p < 0.001). The results of our study suggest that expression of CK17 can potentially be used as an adjunct marker in differential diagnosis between primary ovarian mucinous tumors and metastases from the upper GIT, but not from colorectal carcinoma. However, in GIT tumors, CK17 can be used in the differential diagnosis between adenocarcinomas of the upper and lower GIT. Statistical analysis did not reveal strong association of CK17 expression with clinicopathological variables or patient outcomes in any primary ovarian tumors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer resection specimens are usually reported using standardised proformas that consist of a list of elements, which include core (required) and non-core (recommended) items. Although all elements are generally included in the reports, the clinical importance of a particular parameter often depends on a variety of factors, including the clinical setting, local management guidelines and other pathological parameters. In this review, we briefly outline how histopathology data are used to guide management of patients with endometrial and tubo-ovarian cancers, the most common gynaecological malignancies, and provide advice as to which data elements are important in particular scenarios., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Mesonephric-like adenocarcinoma (MLA) was introduced as a new tumor type in the endometrium and the ovary in the 2020 World Health Organization (WHO) Classification. This is a rare recently described (2016) and clinically aggressive carcinoma with a propensity for distant spread, especially to the lungs. MLA has a characteristic morphology and immunophenotype (hormone receptor negative; TTF1 and/or GATA3 positive). These neoplasms are commonly associated with KRAS and PIK3CA mutations and in the Cancer Genome Atlas (TCGA) molecular classification of endometrial carcinomas fall into the copy number low/no specific molecular profile category. Although they show significant morphological, immunophenotypic and molecular overlap with cervical mesonephric adenocarcinomas, there are other parameters which suggest a Mullerian origin and, as such, the term MLA seems apt. MLA can be added to the list of endometriosis-associated ovarian neoplasms. In this paper, I outline the series of events which lead to the first description of MLA and review the subsequent literature on this tumor type which has expanded on the morphologic features and immunophenotype, discovered the molecular underpinnings and elucidated the clinical behavior. The discovery of MLA represents an example of "new" entities still to this day being discovered through careful morphologic observations and referral of cases for specialist opinion., Competing Interests: The author has no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

A variety of unusual tumors are associated with both germline and somatic DICER1 pathogenic variants (PVs), including, in the female genital tract, embryonal rhabdomyosarcoma at various sites and ovarian Sertoli-Leydig cell tumor. There have been occasional reported cases of ovarian germ cell tumors [mainly yolk sac tumor (YST)] harboring DICER1 PVs but, as far as we are aware, none of these has been proven to have a germline provenance. We report an unusual enteric variant of ovarian YST in a 28-yr-old woman associated with a germline PV c.901C>T (p.Gln301Ter) in exon 7 of DICER1, accompanied by a somatic (YST-only) hotspot mutation: c.5437G>A, p.E1813K. To our knowledge, this is the first report of an ovarian germ cell tumor associated with a germline DICER1 PV. We review other reported cases of ovarian germ cell tumor with DICER1 PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Brenner tumors are uncommon ovarian neoplasms, most of which are benign, although borderline and malignant variants occur. We report 2 unusual ovarian neoplasms composed of an admixture of typical benign Brenner tumor and a low-grade epithelial neoplasm which we designate as low-grade basaloid carcinoma. The latter component morphologically and immunohistochemically resembled "salivary gland-type/myoepithelial" neoplasms with variable positive staining with cytokeratins, p63, S100, and CD117. One tumor exhibited aggressive behavior with local recurrence and distant metastasis. This neoplasm exhibited focal "high-grade" transformation with diffuse mutation-type p53 staining, in contrast to the wild-type immunoreactivity in the low-grade component. As far as we are aware, such neoplasms have not previously been reported in the literature and this represents a newly described morphologic variant of malignant Brenner tumor., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Microcystic stromal tumour (MST) is a rare, usually benign, ovarian neoplasm characterized morphologically in its classic form by a distinctive triad of features comprising microcysts, solid cellular regions and fibrous stroma. Variant morphology also occurs, including the presence of nests, tubules, cords and signet ring cells. Immunohistochemically, this neoplasm is characterized by diffuse nuclear expression of β-catenin, cyclin D1, Wilms' tumour 1 (WT1) and steroidogenic factor 1 (SF1), as well as diffuse staining with forkhead box ligand 2 (FoxL2) and CD10. Inhibin and calretinin are typically negative. At the genomic level, these neoplasms harbour mutually exclusive mutations in CTNNB1 or APC genes, with the former being significantly more common. This molecular characteristic raises possible links to other rare ovarian lesions, including solid pseudopapillary tumour, signet-ring stromal tumour and Sertoli cell tumour. Rarely, MST is an extracolonic manifestation of familial adenomatous polyposis (FAP) and serves as a sentinel event that could trigger the identification of the syndrome. Herein, we review the published literature on ovarian MST and provide practical advice for pathologists reporting these rare neoplasms., (© 2022 John Wiley & Sons Ltd.)

Ovarian endometrioid carcinoma, more than any other type of ovarian epithelial malignancy, demonstrates a varied morphology which can cause problems in diagnosis. In tubo-ovarian tumor pathology, WT1 is a commonly used marker as it is consistently expressed in low-grade and high-grade serous carcinomas and is often considered a specific marker of a serous phenotype. However, ovarian endometrioid neoplasms may also express WT1 which may contribute to misdiagnosis. We report our experience with 23 ovarian endometrioid neoplasms (4 borderline tumors, 19 carcinomas), mainly received in consultation, which were WT1 positive (diffuse in 11 cases) which often contributed to misdiagnosis. Endometriosis was identified in the same ovary in 6 cases and squamous elements in 7. We describe strategies for distinguishing such neoplasms, which may exhibit morphologic overlap with serous tumors, from low-grade and high-grade serous carcinomas and stress that a diagnosis of HGSC is unlikely with two grossly and histologically normal fallopian tubes. We also stress that a panel of markers should always be used rather than relying on a single marker and that when the morphology is classical of an endometrioid carcinoma, diagnostic immunohistochemistry is not needed given the potential for confusion in cases showing "aberrant" staining. We also discuss the phenomenon of "aberrant" immunohistochemical staining in endometrioid carcinomas which appears more common than in other ovarian carcinomas., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Background: Acceptance of the role of the fallopian tube in 'ovarian' carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among BRCA carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360)., Methods: In-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12., Results: Informational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied., Conclusion: Multiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach., Competing Interests: Competing interests: RM declares research funding from Cancer Research UK and The Eve Appeal outside this work, an honorarium for grant review from Israel National Institute for Health Policy Research and honorarium for advisory board membership from Astrazeneca/MSD. RM is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mesonephric-like adenocarcinomas (MLA) are rare neoplasms arising in the uterine corpus and ovary which have been added to the recent 2020 World Health Organization Classification of Female Genital Tumors. They have similar morphology and immunophenotype and exhibit molecular aberrations similar to cervical mesonephric adenocarcinomas. It is debated as to whether they are of mesonephric or Mullerian origin. We describe the clinical, pathologic, immunohistochemical, and molecular features of 5 cases of extrauterine mesonephric-like proliferations (4 ovary, 1 extraovarian), all with novel and hitherto unreported features. These include an origin of MLA in extraovarian endometriosis, an association of ovarian MLA with high-grade serous carcinoma, mixed germ cell tumor and mature teratoma, and a borderline ovarian endometrioid tumor exhibiting mesonephric differentiation. Four of the cases exhibited a KRAS variant and 3 also a PIK3CA variant. In reporting these cases, we expand on the published tumor types associated with MLA and report for the first time a borderline tumor exhibiting mesonephric differentiation. We show the value of molecular testing in helping to confirm a mesonephric-like lesion and in determining the relationship between the different neoplastic components. We provide further evidence for a Mullerian origin, rather than a true mesonephric origin, in some of these cases. We also speculate that in the 2 cases associated with germ cell neoplasms, the MLA arose out of the germ cell tumor., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ovarian seromucinous borderline tumors (SMBT) and clear cell tumors are both closely associated with endometriosis and share, in a proportion of cases, a molecular pathway involving ARID1A mutations, but they have been rarely described in association. We report a case series of 4 clear cell tumors (3 carcinomas, 1 borderline adenofibroma) coexisting in the same ovary with SMBT. In all cases, the SMBT was the predominant component and we highlight that adequate sampling of these tumors is important to detect small clear cell carcinomas, thus potentially altering the treatment and prognosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

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., (© 2021 John Wiley & Sons Ltd.)

The phenomenon of small human papillomavirus-associated cervical adenocarcinomas involving the ovary via a transuterine and transtubal route is uncommon but well described in the literature. We report a unique case of a small human papillomavirus-associated cervical adenocarcinoma spreading to both ovaries and the pelvis via this route 22 mo after loop excision and trachelectomy and developing into a high-grade neuroendocrine carcinoma in the metastasis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by the International Society of Gynecological Pathologists.)

This review covers the significant new developments in the pathological classification of gynecological tumors. Many of these were included in the updated World Health Organization Classification of Female Genital Tract Tumours, published in 2020. Topics include the compelling evidence that a large majority of extrauterine high-grade serous carcinomas arise from the fallopian tube; the Cancer Genome Atlas (TCGA) Classification of endometrial carcinomas; the discovery that most so-called synchronous endometrial and ovarian endometrioid carcinomas represent metastasis from the endometrium to the ovary; and the division of cervical, vaginal, and vulval carcinomas into clinically meaningful HPV-associated and HPV-independent types. Newly described tumor types are covered, including endometrial and ovarian mesonephric-like adenocarcinoma, uterine sarcoma types associated with specific molecular abnormalities, and gastric (gastrointestinal)-type adenocarcinomas of the endometrium and vagina. Important molecular events in ovarian sex cord-stromal tumors are also discussed., (International Journal of Gynecology & Obstetrics© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome., Competing Interests: Conflicts of Interest and Source of Funding: B.W. was funded in part by Breast Cancer Research Foundation, Cycle for Survival and Stand Up To Cancer grants. Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748; MSKCC). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mutations and other molecular events involving subunits of the SWI/SNF chromatin remodelling complex are common in a wide variety of malignancies, including those arising at various sites in the female genital tract. Endometrioid and clear cell carcinomas in the uterine corpus and ovary not uncommonly contain mutations in ARID1A and these also occur in other endometriosis-associated ovarian neoplasms such as seromucinous tumours. In these organs, mutations in SMARCA4, SMARCB1, ARID1A and ARID1B (with subsequent loss of corresponding protein expression as a reliable surrogate) are relatively common in undifferentiated carcinomas, including the undifferentiated component of dedifferentiated carcinoma. SMARCA4 mutations are extremely common (almost ubiquitous) in small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT), occurring in about 98% of these neoplasms, often in association with epigenetic SMARCA2 loss. SMARCB1-deficient vulval neoplasms include epithelioid sarcoma and myoepithelial carcinoma, as well as related malignancies which defy easy classification. Recently the spectrum of SWI/SNF deficient female genital malignancies has been expanded to include SMARCA4-deficient undifferentiated uterine sarcoma and mural nodules of anaplastic carcinoma in ovarian mucinous neoplasms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphologic, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behavior of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 MAs and MLAs (30 MAs of the uterine cervix, 44 MLAs of the endometrium, and 25 MLAs of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at an advanced stage (II to IV) (15/25 [60%] MA of the cervix, 25/43 [58%] MLA of the endometrium, and 7/18 [39%] MLA of the ovary). The majority (46/89 [52%] overall, 12/24 [50%] MA of the cervix, 24/41 [59%] MLA of the endometrium, and 10/24 [42%] MLA of the ovary) developed recurrences, most commonly distant (9/12 [75%] MA of the cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year disease-specific survival was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas., Competing Interests: Conflicts of Interest and Source of Funding: D.I.L. reports current full-time employment at Foundation Medicine which is a whole subsidiary of Roche. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: To report a series of benign ovarian seromucinous neoplasms, an uncommon and hitherto poorly described category of tumours included in the current 2014 World Health Organisation classification of tumours of the female reproductive organs., Methods and Results: We report the clinicopathological features of a series of 22 benign ovarian seromucinous neoplasms (cystadenomas and adenofibromas or admixtures). The neoplasms occurred in patients aged 32-83 years (mean = 62, median = 65.5) and involved the left ovary (n = 14), the right ovary (n = 6) or both ovaries (n = 2). There was a common association with endometrioid elements (endometrioid differentiation within the cystadenoma/adenofibroma and/or endometriosis) and other endometriosis-associated neoplasms., Conclusions: We speculate that some of these represent benign ovarian endometrioid neoplasms with foci of mucinous and/or serous differentiation, while others represent true mixed neoplasms., (© 2020 John Wiley & Sons Ltd.)

Background: Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy., Primary Objective: To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer., Study Hypothesis: Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy., Trial Design: Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause., Major Inclusion/exclusion Criteria: Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms)., Exclusion Criteria: post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline., Primary Endpoint: Sexual function measured by validated questionnaires., Sample Size: 1000 (333 per arm)., Estimated Dates for Completing Accrual and Presenting Results: It is estimated recruitment will be completed by 2023 and results published by 2027., Trial Registration Number: ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360)., Competing Interests: Competing interests: RM declares research funding from Barts and The London Charity and Roseetrees Trust for the PROTECTOR Study and is chief investigator. RM declares research funding from The Eve Appeal and Cancer Research UK outside this work, as well as an honorarium for grant review from Israel National Institute for Health Policy Research and from MSD and Astrazneca for advisory board meetings. RM is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing. UM has a financial interest in Abcodia, Ltd, a company formed to develop academic and commercial development of biomarkers for screening and risk prediction. The authors declare no conflict of interest. GE is supported through the NIHR Manchester Biomedical Research Centre (IS-BRC1215-20007)., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The ovary is a common site of metastatic mucinous adenocarcinoma. In most, but not all, cases the presence of a primary neoplasm elsewhere is already known and the metastasis is picked up at diagnosis or is discovered a relatively short time following the diagnosis of the primary neoplasm. We report 2 cases of metastatic gallbladder adenocarcinoma involving the ovaries of women aged 65 and 59 after long time periods of 8 and 5 yr following diagnosis of high-grade dysplasia or early adenocarcinoma of the gallbladder, respectively. In both cases, a review of the original operative notes suggested the possibility of intraoperative gallbladder rupture or bile leakage suggesting that the metastatic disease may have developed secondary to "seeding." In both cases, p53 immunohistochemistry revealed identical null mutation-type immunoreactivity within the gallbladder and ovarian neoplasms, assisting in confirming the ovarian disease as a metastasis from the gallbladder. The possibility of late ovarian metastasis of gallbladder dysplasia or adenocarcinoma secondary to rupture/bile leakage should be borne in mind.

Surface epithelial changes involving endometrioid carcinomas of the uterine corpus mimicking papillary syncytial metaplasia or cervical microglandular hyperplasia are relatively common. There have been rare reports of surface epithelial changes in endometrioid carcinomas mimicking ovarian serous borderline tumor or low-grade serous carcinoma. We report an endometrioid carcinoma of the uterine corpus with striking morphologic mimicking of an ovarian serous borderline tumor with only a minimal amount of conventional endometrioid carcinoma. The tumor was diffusely positive for estrogen receptor, negative for WT1, and showed wild-type immunoreactivity with p53. Targeted sequencing revealed a KRAS mutation (G12V/D/A), but no BRAF mutation. This close mimicry of a serous borderline tumor by a uterine endometrioid carcinoma has not been emphasized in the literature and this case is unique because the features involved almost the entire neoplasm. In reporting this case, we review surface changes in endometrioid carcinomas of the uterine corpus.

Ovarian high-grade neuroendocrine carcinomas (NECs) (small cell and large cell NEC) are rare neoplasms. They may arise in association with other ovarian tumors, most commonly epithelial neoplasms and rarely teratomas. We report a case of an 19-yr-old female with bilateral ovarian teratomas with a high-grade NEC (immunohistochemically positive with chromogranin, synaptophysin, and CD56 and MIB1 proliferation index in excess of 90%) arising within one of these. Although CK20 was negative, the NEC exhibited an immunophenotype suggestive of a Merkel cell carcinoma with diffuse positive staining with FLI-1, SATB2 and neurofilament, markers which are preferentially expressed in Merkel cell carcinoma compared with other NECs. There was also diffuse staining for SALL4. Immunohistochemistry and molecular studies for Merkel cell polyomavirus were negative. Immunohistochemical staining for CK20, FLI-1, SATB2, neurofilament, and SALL4 was performed in 6 additional primary ovarian high-grade NECs; One, 5, 5, 1, and 0 cases were positive for CK20, FLI-1, SATB2, neurofilament, and SALL4, respectively, usually with very focal immunoreactivity. Pathologists should be aware of these potential unexpected staining patterns in ovarian NECs as positivity may result in consideration of other neoplasms.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4 , which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer., (©2020 American Association for Cancer Research.)