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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.

Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1gene fusion. The EWSR1-WT1gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < −2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1positive tumors may represent discrete entities, but further study is necessary.

Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2amplification, we identified cases of uterine serous carcinoma (n?=?93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2amplification by NGS was determined by the relative number of reads mapping to ERBB2in tumor DNA compared to control nonneoplastic DNA. Cases with copy number =6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number =6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2amplification. NGS is highly accurate in detecting ERBB2amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.

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.

/Background: There is a paucity of data on patient reported outcome measures (PROMs) associated with surgical treatment of osteochondritis dissecans (OCD). As a result, preoperative patient and family counseling regarding expected outcomes is difficult. The purpose of this study was to compare pre-to post-operative changes in PROMs amongst cohorts of patients with OCD that underwent one of three lesion-specific surgical treatments: 1) transarticular drilling for stable lesions, 2) drilling and fixation for unstable lesions 3) grafting for unsalvageable lesions.

Mullerian clear cell carcinomas (CCC) are often aggressive, chemoresistant tumors. The prognostic significance of molecular subclassification of endometrioid carcinomas is well-established. However, less is known about the molecular landscape of CCC. The aim of this study was to better characterize the genetic landscape of a large cohort of CCC and correlate these findings with clinicopathologic features. CCC of the ovary (n=72), endometrium (n=24), and peritoneal/abdominal wall (n=5) were retrospectively identified. Tumors had undergone tumor-only targeted sequencing using a hybrid capture next-generation sequencing panel. Median tumor mutational burden (TMB) was 6.8 mutations/megabase (range 1.3-185, 21% were ≥10 mut/Mb). The most frequently mutated genes were ARID1A(48%), PIK3CA(45%), TP53(23%), and PTEN(10%). ERBB2amplification occurred in 4%. When classified according to the TCGA/ProMisE endometrial carcinoma molecular subgroups, 3 (3%) were POLE ultramutated, 5 (5%) were microsatellite unstable (MSI-H), 20 (20%) were TP53-mutant subgroup and 73 (72%) were no specific molecular profile (NSMP). Immunohistochemical expression of estrogen receptor, progesterone receptor, and programmed death-ligand 1 (PD-L1) were not associated with molecular subgroup. POLE and MSI-H tumors were characterized by an excellent prognosis, and the TP53-mutant subgroup had a worse disease-free survival than NSMP. NSMP tumors could be further substratified as high-risk NSMP if they lacked PIK3CA, PIK3R1, and ARID1Amutations, and/or harbored a TERTpromoter mutation. The overall TCGA and NSMP-specific stratifications were prognostic for both the entire cohort and the subset of stage 1 ovarian tumors. On multivariable analysis, stage, lymphovascular invasion, and TMB were prognostic for disease free survival, while advanced stage and TP53-mutant subgroup – but not a TP53mutation in isolation – were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatment such as immunotherapy and anti-HER2 agents.