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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.

Leiomyomas are common hormone-responsive uterine neoplasms which can exhibit a variety of morphologic changes secondary to hormonal agents such as progestogens. They may increase in size during pregnancy as a result of hormonal stimulation but surprisingly the morphologic features of leiomyomas in pregnancy are not well described in the literature. In this report, we describe the morphologic features of a series of 29 uterine leiomyomas in pregnancy. The features include in decreasing order of frequency infarct-type necrosis, decidualization of the serosal surface, hyalinization, myxoid alteration of the stroma, edema (sometimes with cyst formation), and dystrophic calcification. We also report a feature which we term “deciduoid” change (seen in 10 of 29 leiomyomas) which takes the form of altered smooth muscle cells with an epithelioid morphology with abundant eosinophilic or clear cytoplasm. Furthermore, we show that the “deciduoid” cells commonly exhibit expression of sex cord markers inhibin and calretinin. We speculate on the pathogenesis of the “deciduoid” change which together with its “aberrant” immunophenotype may result in diagnostic problems and consideration of other neoplasms.

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.

Meticulous macroscopic examination of specimens and tissue sampling are crucial for accurate histopathology reporting. However, macroscopy has generally received less attention than microscopy and may be delegated to relatively inexperienced practitioners with limited guidance and supervision. This introductory paper in the minisymposium, Macroscopy Under the Microscope, focuses on issues regarding macroscopic examination and tissue sampling that have been insufficiently addressed in the published literature. It highlights the importance of specimen examination and sampling, discusses some general principles, outlines challenges and suggests potential solutions. It is critical to get macroscopy right the first time as it may not be possible to rectify errors even with expert histological assessment or to retrospectively collect missing data after the specimen retention period. Dissectors must, therefore, receive adequate guidance and supervision until they are proficient in macroscopic specimen examination. We emphasise the importance of the clinical context, optimal specimen fixation, succinct and clinically relevant macroscopic descriptions, macrophotography and judicious tissue sampling. We note that current recommendations based on the number of blocks to be submitted per maximum tumour dimension are ambiguous as the amount of tissue submitted in a cassette is not standardised and it is unclear whether ‘block’ refers to a tissue block or a paraffin block. Concerns around potential oversampling of ‘therapeutic’ specimens that could result in overdiagnosis due to detection of incidentalomas are also discussed. We hope that the issues discussed in this paper will engender debate on this clinically critical aspect of pathology practice.

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

Benign and malignant neoplasms of the vagina are rare. We report 3 primary vaginal polypoid lesions involving the upper or mid-vagina in patients aged 40, 60, and 67 years. The lesions bore a striking morphologic resemblance to benign endocervical or endometrial polyps and we suggest the designation Mullerian polyp of the vagina. As far as we are aware, similar cases have not been reported previously in the literature. Follow-up ranging from 6 to 21 months has been uneventful. In reporting these cases, we discuss the possible origin and differential diagnosis and review vaginal lesions with a benign glandular component.

In gynecological neoplasms, immunohistochemical (IHC) expression of p53 is generally an accurate predictor of TP53mutation 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 TP53wild-type on sequencing. Three cases had normal p53 expression but contained a TP53mutation. Overall, IHC predicted the TP53mutation 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 TP53versus those with TP53mutation, 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 TP53mutation but the TP53mutation status has no prognostic significance in either MC or MBT.

Uterine endometrial stromal sarcomas (ESS) with YWHAE::NUTM2gene fusions are typically morphologically high-grade tumors composed of atypical round cells, sometimes associated with a low-grade fibromyxoid component; they are currently included in the category of high-grade ESS (HGESS). We report 5 morphologically pure low-grade endometrial stromal tumors harboring YWHAE::NUTM2fusions, including 1 endometrial stromal nodule (ESN) and 4 low-grade endometrial stromal sarcomas (LGESS), an association only occasionally reported previously. Patients ranged from 30 to 51 (mean=43) years and tumors from 4.5 to 7.5 cm (mean=5.7). All were stage I at diagnosis (confined to the uterus). Microscopically, the 4 LGESS showed extensive “tongue-like” invasion of the myometrium, and the ESN was entirely confined to the endometrium with no myometrial invasion. All tumors were composed entirely of morphologically uniform bland ovoid cells resembling proliferative endometrial stroma. A fibromyxoid component was seen in 1 LGESS and the ESN; in the LGESS, this was the sole component. Atypical round cells characteristic of YWHAE::NUTM2HGESS were not identified. Mitotic count ranged from <1 to 13 per 10 high-power fields (mean: 3). CD10 was positive in 2/4 (focal), estrogen receptor in 5/5 (focal=1; diffuse=4), progesterone receptor in 5/5 (focal=1; diffuse=4) and cyclin D1 was diffusely positive in 3/4. Follow-up was available in all 5 patients and ranged from 6 to 159 months (mean=72). Two patients with LGESS had recurrent disease at 15 and 155 months; 1 showed predominantly LGESS with rare round cells in the initial recurrence and pure HGESS in a subsequent recurrence, while the other patient’s recurrent tumor was predominantly HGESS (90%) in a background of focal fibromyxoid LGESS (10%). Both patients rapidly progressed and died of disease within 5 months of high-grade recurrence. We show that rare cases of morphologically pure low-grade endometrial stromal tumors, some but not all with a fibromyxoid component, harbor YWHAE::NUTM2fusions and may recur rapidly, with transformation to HGESS and aggressive behavior. Our findings suggest that at least a subset of YWHAE::NUTM2HGESS evolves from LGESS. We suggest that cyclin D1 and CD10 staining should be performed in all LGESS. Diffuse staining for cyclin D1 and/or negative or focal staining for CD10 should suggest the possibility of a YWHAE::NUTM2fusion, and appropriate molecular testing should be undertaken. Since no single morphological or immunohistochemical parameter is entirely sensitive for fusion status, we also suggest that testing for a YWHAE::NUTM2gene fusion should be considered in all cases of LGESS and, if a fusion is present, this should raise the possibility of subsequent high-grade transformation and aggressive behavior, even though such cases should still be categorized as LGESS. Although seemingly rare, ESN and LGESS with YWHAE::NUTM2fusions may be under-recognized due to a lack of routine fusion testing.

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. DICER1pathogenic 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 DICER1molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1wild-type. None of the cases harbored the p.FOXL2C134W hotspot mutation. Based upon the DICER1molecular 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.

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 ALKrearrangements 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 situhybridization confirmed the presence of ALKrearrangement. 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.

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.

AimThere are many scenarios where high-risk human papillomavirus (HPV) detection in formalin-fixed paraffin-embedded (FFPE) specimens is important. However, there is no Food and Drug Administration (FDA)-approved and clinically validated technique for detecting high-risk HPV in FFPE tissues. In this study, we evaluated two commercially available HPV assays which are FDA-approved for use on cytology specimens, the Aptima HPV assay and the Beckton Dickinson (BD) Onclarity assay, to detect high-risk HPV in FFPE tissues of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC).MethodsA total of 189 cases (46 SCC, 107 HSIL and 36 benign/normal) were tested for high-risk HPV with the Aptima HPV assay and a subset of cases (n=97) with the BD Onclarity assay.ResultsThe sensitivities of the Aptima and BD Onclarity HPV assays were 99.4% (95% CI 96.46% to 99.98%) and 75.9% (95% CI 65.27% to 84.62%), respectively; the specificity and positive predictive value (PPV) of the two assays were 100%. Negative predictive values of the Aptima and BD Onclarity HPV assays were 97.3% (95% CI 83.61% to 99.61%) and 67.7% (95% CI 58.91% to 75.47%), respectively. The kappa value (0.96) for comparison of the distribution of high-risk HPV types between the two assays was high. HPV 16 was the most common high-risk HPV type for HSIL and SCC cases. However, SCC cases had higher percentages of HPV 16 and HPV 18/45 and lower percentages of other high-risk HPV types compared with HSIL cases.ConclusionBoth assays are reliable methods for high-risk HPV detection and genotype determination in FFPE specimens, with high PPV and specificity. The Aptima HPV assay has the advantage of higher sensitivity. As far as we are aware, this is the first study comparing the Aptima HPV assay and the BD Onclarity assay in FFPE tissues. Our study results should be tested and confirmed in larger cohorts.

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 CTNNB1mutations. 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 CTNNB1mutation 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 CTNNB1mutation, 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 CTNNB1mutation, 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.

Sebaceous carcinoma is an uncommon primary cutaneous neoplasm which may be associated with mismatch repair (MMR) abnormalities and sometimes with Muir-Torré syndrome. These neoplasms rarely arise in the ovary within a teratoma/ dermoid cyst. We report a sebaceous carcinoma arising in an ovarian teratoma in a 49-yr old (the 14th case reported in the literature) which exhibited loss of expression of MMR proteins MSH2 and MSH6. A germline mutation c.1102C>T was present in exon 7 of the MSH2 gene, the first report of a germline mutation associated with this tumor type. In reporting this case, we review prior reports of primary ovarian sebaceous carcinoma. We recommend that all sebaceous carcinomas of the ovary undergo immunohistochemistry for MMR proteins for investigation of possible Lynch syndrome.

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

The move toward consistent and comprehensive surgical pathology reports for cancer resection specimens has been a key development in supporting evidence-based patient management and consistent cancer staging. The International Collaboration on Cancer Reporting (ICCR) previously developed a data set for reporting of the ovarian, fallopian tube and primary peritoneal carcinomas which was published in 2015. In this paper, we provide an update on this data set, as a second edition, that reflects changes in the 2020 World Health Organization (WHO) Classification of Female Genital Tumours as well as some other minor modifications. The data set has been developed by a panel of internationally recognized expert pathologists and a clinician and consists of “core” and “noncore” elements to be included in surgical pathology reports, with detailed commentary to guide users, including references. This data set replaces the widely used first edition, and will facilitate consistent and accurate case reporting, data collection for quality assurance and research, and allow for comparison of epidemiological and pathologic parameters between different populations.

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

Comprehensive pathology reporting of cancers is important for patient management, tumor staging, and prognostication. Standardized cancer datasets are essential in guiding pathology reporting in a consistent and concise manner and this facilitates effective global cancer information exchange and comparison. The International Collaboration on Cancer Reporting (ICCR) is an alliance of several national and international pathology societies in many countries as well as bodies which are involved in tumor classification and staging. One function of the ICCR is to develop evidence-based, standardized reporting datasets for each cancer site. Herein, we report the development of an evidence-based cancer dataset by an ICCR panel of international experts for the reporting of primary uterine gestational trophoblastic neoplasia. We present the core elements that should be included and noncore elements that are recommended for inclusion in pathology reports. Lists of the response values are provided for each element, along with explanatory commentaries. The dataset also discusses controversial issues in the reporting of gestational trophoblastic neoplasia. Such evidence-based and structured pathology datasets developed through an international effort will facilitate consistent and accurate exchange and comparison of epidemiological and pathologic parameters among different populations and countries. This will ultimately improve gestational trophoblastic neoplasia patient care and facilitate future research.

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

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.

A cogent and comprehensive pathologic report is essential for optimal patient management, cancer staging, and prognostication. This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the vulval carcinoma reporting data set. It describes the “core” and “noncore” elements to be included in pathology reports for vulval carcinoma, inclusive of clinical, macroscopic, microscopic, and ancillary testing considerations. It provides definitions and commentary for the evidence and/or consensus-based deliberations for each element included in the data set. The commentary also discusses controversial issues, such as p16/human papillomavirus testing, tumor grading and measurements, as well as elements that show promise and warrant further evidence-based study. A summary and discussion of the updated vulval cancer staging system by the International Federation of Obstetricians and Gynaecologists (FIGO) in 2021 is also provided. We hope the widespread implementation of this data set will facilitate consistent and accurate reporting, data collection, comparison of epidemiological and pathologic parameters between different populations, facilitate research, and serve as a platform to improve patient outcomes.

Primary carcinomas of the vagina are uncommon and currently detailed recommendations for the reporting of resection specimens of these neoplasms are not widely available. The International Collaboration on Cancer Reporting (ICCR) is developing standardized, evidence-based reporting data sets for multiple cancer sites. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary vaginal carcinomas and present the core and noncore data elements with explanatory commentaries. This data set has incorporated the updates in the 2020 World Health Organization Classification of Female Genital Tumours, 5th edition. The data set addresses controversial issues such as tumor grading, margin assessment, and the role of ancillary studies. The adoption of this data set into clinical practice will help ensure standardized data collection across different countries, facilitate future research on vaginal carcinomas, and ultimately lead to improvements in patient care.

With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1(n=11) and KAT6A::KANSL1(n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.

High-grade endometrial stromal sarcoma (HGESS) is an uncommon tumor accounting for <1% of all uterine malignancies. Currently this designation is largely reserved for neoplasms harboring YWHAE-NUTM2A/Band ZC3H7B-BCORtranslocations. Here, we report a novel CIQTNF1-ERBB4translocation in a uterine neoplasm arising in a 49-yr-old woman with morphology suggestive of HGESS. Histologic examination of the 5 cm polypoid uterine corpus mass showed a neoplasm composed of a monotonous population of cells with moderately atypical ovoid to spindle shaped nuclei with easily identifiable mitotic activity and prominent vasculature with focal intravascular extension. Immunohistochemistry showed variable positivity with desmin, estrogen receptor, progesterone receptor, AE1/3 and cyclin D1, and molecular testing showed a translocation between CIQTNF1on chromosome 17 and ERBB4on chromosome 2. This represents the first report of this translocation in a uterine neoplasm and adds to the growing list of translocations identified in uterine sarcomas. Although the morphology is suggestive of HGESS, this neoplasm is currently best termed an ERBB4-rearranged uterine sarcoma until additional cases are reported to more fully characterize these neoplasms.

Vulval extramammary Paget disease (vEMPD) is an uncommon epithelial malignancy that may arise within the vulva (primary vEMPD) or represent vulval skin involvement by a noncutaneous carcinoma (secondary vEMPD). Primary vEMPD is most often an in situcarcinoma arising within the epidermis but may be associated with dermal invasion (invasive vEMPD) or represent intraepidermal spread of an adenocarcinoma originating in vulval skin adnexa or anogenital mammary-like glands. The latter, termed mammary gland-like adenocarcinoma (MGLA), exhibits morphologic, immunohistochemical, and molecular features of various breast carcinomas but, as far as we are aware, the metaplastic variant of MGLA has not been reported on the vulva. We report 2 cases of metaplastic MGLA of the vulva with associated Paget disease and postulate that some cases of vulval MGLA may arise from Paget disease rather than originating in mammary-like glands. We also report a unique case of secondary vEMPD resulting from spread of urothelial carcinoma in situthat subsequently progressed to invasive urothelial carcinoma within the vulva.

Neuroendocrine neoplasms are uncommon in the cervix with almost all representing neuroendocrine carcinomas (NECs), either small cell or large cell type. Cervical low-grade neuroendocrine tumors (NETs) are extremely rare with few recent reports using contemporary modern diagnostic criteria. We report 3 cases of cervical NET in patients aged 32 to 57 yr and undertake a review of the literature. The first case was a pure grade 2 NET with pelvic lymph node metastasis (FIGO stage IIIC1). In the second case, a grade 1 NET was associated with high-grade squamous intraepithelial lesion, adenocarcinoma in situand human papillomavirus (HPV)-associated adenocarcinoma and was FIGO stage IA1. The third patient underwent chemoradiotherapy following a biopsy diagnosis of a high-grade NEC which was radiologically FIGO stage IIIC1 and salvage hysterectomy revealed residual tumor with features of a grade 1 NET. In all cases, the NET was diffusely positive with at least 2 of the neuroendocrine markers chromogranin, synaptophysin, and CD56. The first tumor was p16 negative and the third exhibited block-type immunoreactivity. Molecular tests revealed high risk HPV types 18 and 51 in the third case but no HPV in the first case. p16 immunohistochemistry and HPV molecular testing was not available in the second case. The patients remain disease free with follow-up ranging from 2 to 8 yr. Since a combination of NET and NEC is extremely rare at all sites due to a different pathogenesis, we speculate that in the third case, the NET developed out of the NEC as a “maturation” phenomenon secondary to chemoradiotherapy.

We report a spindle cell sarcoma arising in the uterine corpus of a 26-yr-old patient. The patient underwent a simple hysterectomy and the uterine corpus contained a 9 cm tumor showing nodular and “finger-like” myometrial invasion. Histologically, the tumor was composed of a monomorphic population of atypical spindle cells which contained widespread foci of cytologically benign adipocytes. Immunohistochemistry revealed diffuse strong positivity for CD10, CD56, and CD99 and diffuse weak positive staining with ER and WT1 while smooth muscle markers, S100, TLE1, and cyclin D1 were negative. Total RNA sequencing identified an in-frame fusion between exon 6 of MEIS1and exon 12 of NCOA2. Copy number analysis revealed few aberrations with no deletions or amplifications identified. No adjuvant therapy was given and the patient is disease-free 9 yr after initial diagnosis. This case represents the second report of a uterine sarcoma harboring a MEIS1-NCOA2/1gene fusion and expands the morphologic spectrum of recently reported spindle cell sarcomas arising in the genitourinary tract harboring MEIS1-NCOA2/1gene fusions. This is the first reported case of such tumors with an adipocytic component.

We report a unique primary cervical neoplasm in a 44-yr-old woman which we believe, based on the morphology and immunophenotype, represents an extremely unusual small cell variant of paraganglioma. This represents the first report of a primary cervical paraganglioma. Following chemoradiation treatment, the tumor underwent malignant transformation into an S100 and SOX10 positive sarcoma, morphologically and immunohistochemically resembling a malignant peripheral nerve sheath tumor, which we believe represents a sarcoma derived from the sustentacular cells of the paraganglioma. Mutational analysis detected a nonsense mutation of NF1gene in the sarcoma. This further supports the diagnosis as both somatic and germline NF1mutations have been associated with paragangliomas and malignant peripheral nerve sheath tumors. Targeted RNA sequencing (ARCHER, expanded sarcoma panel) covering many known genes implicated in sarcoma development, did not reveal any other molecular alteration (fusion or internal tandem duplication).

A variety of unusual tumors are associated with both germline and somatic DICER1pathogenic 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 DICER1PVs 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 DICER1PV. We review other reported cases of ovarian germ cell tumor with DICER1PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma.

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 KRASand PIK3CAmutations 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.

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.

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.

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 KRASvariant and 3 also a PIK3CAvariant. 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.

BackgroundAcceptance 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 BRCAcarriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360).MethodsIn-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.ResultsInformational 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.ConclusionMultiple 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.

p16 is the most useful diagnostic marker for human papillomavirus (HPV)-associated anogenital lesions. In the cervix, the pattern of p16 immunoreactivity generally correlates with lesion severity. p16 expression in anal intraepithelial neoplasia (AIN) is far less studied. Whether such correlation holds true has to be determined. We correlated the degree and pattern of p16 immunohistochemistry (IHC) results with morphologic diagnoses of 1000 anal squamous and transitional zone biopsy specimens. Using the Lower Anogenital Squamous Terminology criteria, p16 IHC results were classified as block staining, partial staining, or negative. Among 150 samples without morphologic evidence of AIN, p16 was negative in 85% and partial staining in 15%. AIN 1 (n=400) revealed diverse results: 28% negative, 35% partial, and 37% block staining. Among AIN 2 (n=298), 89% were block, 9% partial staining, and 2% negative. AIN 3 (n=152) revealed block (95%) or partial staining (5%). For the detection of AIN 2/3, p16 block staining yielded 91% sensitivity, 73% specificity, 80% positive predictive value, 91% negative predictive value, and a Youden Index of 0.64. Combining block staining and partial staining slightly increased sensitivity (99%) and negative predictive value (98%), but significantly decreased specificity (43%), positive predictive value (59%) and Youden Index (0.42, P<0.001). As with the cervix, p16 immunoreactivity correlates with morphologic diagnoses of AIN. Block staining offers the optimal diagnostic value for AIN 2/3. Caution is required since AIN 1 frequently exhibits block staining; the prognostic value of p16 warrants further investigation.

Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (≤20%) of classic morphology, with anaplasia noted in four and tumor cell necrosis in three. The most frequent mutations detected were in DICER1(14/21), TP53(7/20), PI3K/AKT/mTOR pathway (7/20), and KRAS/NRAS(5/20). Copy-number alterations were present in 10/19 tumors. Overall, 8/14 DICER1-associated ucERMS showed concurrent loss of function and hotspot mutations in DICER1, which is a feature more likely to be seen in tumors associated with DICER1 syndrome. Germline data were available for two patients, both DICER1wild type (one with concurrent loss of function and hotspot alterations). DICER1-associated ucERMS were more likely to show a classic histological appearance including heterologous elements than DICER1-independent tumors. No differences in survival were noted between the two groups, but both patients with extrauterine disease at diagnosis and two with recurrences died from disease. As no patients had a known personal or family history of DICER1 syndrome, we favor most DICER1-associated ucERMS to be sporadic.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n= 68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n= 21), PAs (n= 178), and IGAs (n= 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53(41%), CDKN2A(18%), KRAS(18%), and STK11(10%). Potentially targetable mutations were identified in ERBB3(10%), ERBB2(8%), and BRAF(4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53(41% vs 5%, p< 0.01) and CDKN2A(18% vs 0%, p= 0.01), and fewer PIK3CAmutations (7% vs 33%, p= 0.01). TP53mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p< 0.05) and IGAs (41% vs 57%, p< 0.05). GCAs showed a higher frequency of STK11mutations than PAs (10% vs 2%, p< 0.05) and IGAs (10% vs 1%, p< 0.05). GCAs harbored more frequent mutations in ERBB2and ERBB3(9% vs 1%, and 10% vs 0.5%, both p< 0.01) compared to PAs, and in CDKN2A(18% vs 1%, p< 0.05) and KRAS(18% vs 6%, p< 0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of uncertain lineage and low malignant potential. Most tumors behave in a benign fashion, but a subset of UTROSCT exhibit an aggressive clinical course with recurrences and metastases. The recurrent molecular alterations in UTROSCT mostly represent gene fusions involving NCOA1-3. We performed a comprehensive clinicopathological, morphological, immunohistochemical, and molecular analysis on a cohort of 35 UTROSCT. The tumors exhibited various architectural patterns (diffuse, corded/trabecular, tubular, sertoliform, fascicular, whorled, nested, microfollicular, and pseudoglandular), often in combination. The immunohistochemical analysis confirmed the polyphenotypic immunoprofile, often with co-expression of sex cord-stromal, smooth muscle, and epithelial markers, as well as hormone receptors. NGS RNA analysis revealed recurrent NCOA1-3gene fusions in 22/32 analyzed cases (69%), including ESR1::NCOA3(11/22), GREB1::NCOA2(7/22), ESR1::NCOA2(3/22), and GREB1::NCOA1(1/22). Tumor mutation burden was low in all cases. The fusion-positive cases exhibited statistically significant association with whorled architecture, conversely necrosis was associated with fusion-negative status. We did not find a significant relationship between any architectural pattern and GREB1-alterations, but the NCOA2-altered tumors were associated with pseudoglandular architecture. The GREB1-altered cases occurred in older patients and tended to be more often intramural masses compared to ESR1-altered cases. On the contrary, the ESR1-altered cases presented more often like submucosal or polypoid tumors. Two tumors exhibited aggressive behavior with recurrent disease. Both of these cases harbored a GREB1::NCOA2fusion. Unsupervised hierarchical cluster analysis of our cohort revealed two main clusters. The tumors with GREB1or NCOA2fusion cluster together, suggesting that there are underlying molecular differences between these cases and cases with ESR1::NCOA3fusion or without fusion. Our findings contribute to the growing knowledge about a rare neoplasm with currently uncertain biological behavior.

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.

Embryonal rhabdomyosarcoma of the uterine cervix is a rare neoplasm which is almost invariably associated with pathogenic somatic or germline DICER1mutations; patients with germline mutations have DICER1 syndrome. We report 2 subtle cervical embryonal rhabdomyosarcoma, one occurring in a 21-yr-old woman with a known history of DICER1 syndrome and the other in a 19-yr-old woman with no history of DICER1 syndrome or DICER1-associated neoplasms. Both neoplasms focally involved otherwise benign endocervical polyps and were characterized histologically by subtle areas of increased stromal cellularity, nuclear atypia and mitotic activity; there was focal nuclear staining of these areas with the skeletal muscle markers myogenin and myoD1. In both cases, demonstration of a somatic DICER1RNase IIIb mutation in the tumor was instrumental in establishing the diagnosis. We believe these neoplasms represent the earliest discernible phase of cervical embryonal rhabdomyosarcoma. Pathologists should have a high index of suspicion when atypical stromal elements are present in endocervical polyps and immunohistochemistry together with DICER1sequencing will assist in diagnosis.

Cervical ectopic prostatic tissue and vaginal tubulosquamous polyp are rare lesions which exhibit variable, and often focal, immunohistochemical expression with traditional prostatic markers [prostate-specific antigen and prostatic acid phosphatase (PSAP)]. These lesions are thought to arise from periurethral Skene’s glands, the female equivalent of prostatic glands in the male. Adenoid basal carcinoma is a rare and indolent cervical neoplasm. Expression of the prostatic marker NKX3.1 in ectopic prostatic tissue and tubulosquamous polyp has been reported but no studies have examined immunoreactivity with this marker in adenoid basal carcinoma. We stained 19 cases [adenoid basal carcinoma (n=6), cervical ectopic prostatic tissue (n=11), and vaginal tubulosquamous polyp (n=3); 1 case contained both adenoid basal carcinoma and ectopic prostatic tissue] with NKX3.1. In all cases, the glandular component of these lesions exhibited diffuse nuclear immunoreactivity while normal endocervical glands were negative. Prostate-specific antigen was positive in 4 of 9 and 0 of 3 cases of ectopic prostatic tissue and tubulosquamous polyp, respectively, while PSAP was positive in 3 of 4 and 2 of 2 cases of ectopic prostatic tissue and tubulosquamous polyp respectively; 3 of 5 cases of adenoid basal carcinoma tested were focally positive with PSAP and all 5 were negative with prostate-specific antigen. While the specificity of NKX3.1 should be investigated in future studies, positivity with this marker may be useful in diagnosing these uncommon lesions. NKX3.1 appears a more sensitive marker of ectopic prostatic tissue and tubulosquamous polyp than traditional prostatic markers and positive staining provides further support that these lesions exhibit “prostatic” differentiation and are of Skene’s gland origin. NKX3.1 and PSAP positivity in adenoid basal carcinoma raises the possibility of an association with benign glandular lesions exhibiting prostatic differentiation and we critically discuss the possible association.

Müllerian adenosarcoma is an uncommon biphasic malignant tumor most often occurring in the uterine corpus and derived from native surface endometrium. We report a case of intramural uterine adenosarcoma arising in association with adenomyosis, in the absence of tumor involving the surface endometrium. This is an extremely rare phenomenon, with only 8 other published cases of uterine corpus adenosarcoma in the absence of surface endometrial involvement, 5 originating in adenomyosis and 3 in adenomyomas. We review these cases. The current FIGO staging system for uterine adenosarcoma assumes origin from the surface endometrium and does not address the rare occurrence of intramural tumors without a surface endometrial component. Such tumors are problematic to stage and could potentially be overtreated, particularly if there is deep myometrial involvement.

The role of lymphadenectomy in endometrial carcinomas is controversial, especially in low-grade endometrioid carcinomas. In many institutions, lymphadenectomy in the latter neoplasms is undertaken only when there is deep myometrial invasion, defined as invasion involving 50% or more of the myometrium (FIGO stage IB). There has been considerable debate as to the best modality to detect deep myometrial invasion. In Europe, preoperative magnetic resonance imaging (MRI) is the most commonly used modality while in North America, intraoperative assessment (IOA) is undertaken in most, but not all, institutions. The aim of this study was to compare the diagnostic accuracy of these 2 modalities in identifying deep myometrial invasion in low-grade endometrioid carcinomas. Two patient cohorts were studied from Belfast, UK (n=253) and Boston, USA (n=276). With respect to detecting deep myometrial invasion, MRI had a sensitivity of 72.84%, positive predictive value of 75.64% and a positive likelihood ratio of 6.59 (95% confidence interval; 4.23–10.28). IOA had a sensitivity of 78.26%, positive predictive value of 80% and a positive likelihood ratio of 20.00 (95% confidence interval; 10.35–38.63). The superior positive likelihood ratio suggests that IOA is better than MRI in determining deep myometrial invasion and the nonoverlapping 95% confidence intervals suggest this is a significant finding. However, there are significant resource implications associated with IOA and preoperative MRI carries other advantages that are discussed herein.

Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm occurring almost exclusively in the vulvovaginal region and which has a wide differential diagnosis. It has previously been suggested that the nuclear transcription factor HMGA2 is a useful marker of AA, although the number of studies is limited. We investigated HMGA2 immunoreactivity in a large series (n=284) of vulvovaginal mesenchymal lesions. HMGA2 nuclear staining was classified as diffuse (≥50%), focal (<50%), or negative. Of 38 cases of AA, 26 (68%) were positive; 77% (n=20) of these exhibited diffuse staining. Of the 41 smooth muscle tumors, 18 (44%) were positive with 16 (89%) exhibiting diffuse staining. 80 fibroepithelial stromal polyps were included and 15 (19%) were positive (8 diffuse; 7 focal). Most of the fibroepithelial stromal polyps that exhibited diffuse HMGA2 immunoreactivity were large and edematous. Occasional cases of a variety of other lesions were positive, including 1 of 30 superficial myofibroblastomas and 1 of 16 angiomyofibroblastomas. Cellular angiofibromas (n=12) and superficial angiomyxomas (n=6) were always negative. Our results confirm that HMGA2 is a useful marker of AA but a significant minority of cases are negative. The marker also lacks specificity, since a high percentage of smooth muscle tumors are positive, although these typically do not bear a close morphologic resemblance to AA. A novel observation in our study is positive staining of some fibroepithelial stromal polyps, particularly when large and edematous; these are particularly likely to be confused morphologically with AA and positive staining with HMGA2 represents a significant diagnostic pitfall.

Supplemental Digital Content is available in the text.Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n=37) and 66.5% (n=117) of cases, respectively, and with a 5% cutoff in 5.1% (n=9) and 39.8% (n=70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR)=5.236, 95% confidence interval (CI)=2.075-13.211, P=0.001, and OR=3.702, 95% CI=1.759-7.791, P=0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR=5.104, 95% CI=1.876–13.881, P=0.001, and for 5% cutoff: OR=3.322, 95% CI=1.540–7.166, P=0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR=6.102, 95% CI=1.280–10.096, P=0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR=6.757, 95% CI=1.569–29.109, P=0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor for IC PD-L1 positivity, with both 1% and 5% cutoffs. Using univariate analysis, we observed decreased disease-free survival for IC PD-L1 positivity ≥5%. Our study results should now be tested and proven in larger cohorts, with longer follow-up data.

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.

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.

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.