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Mullerian adenosarcoma is an uncommon mesenchymal tumor of the gynecologic tract, usually of uterine origin. Tumors are generally low-grade and associated with good prognosis, whereas high-grade adenosarcomas are rare and less well studied. Herein, we sought to characterize the molecular features of 27 adenosarcomas (primary uterine, n = 19, cervical, n = 3, ovarian, n = 4, peritoneal, n = 1), enriched for high-grade tumors (n = 17) subjected to targeted panel sequencing. Recurrent genetic alterations in adenosarcomas included TP53 mutations (n = 4, 15%), restricted to high-grade cases, BAP1 homozygous deletions (n = 4, 15%), DICER1 mutations (n = 4, 15%), ARID1A mutations (n = 3), TERT promoter mutations (n = 2) and amplification (n = 1), ATRX frameshift mutation/homozygous deletions (n = 3), MDM2 (n = 2), CDK4 (n = 2) and CCNE1 (n = 2) amplifications, as well as alterations involving members of the PI3K (PTEN, n = 3; PIK3CA, n = 4; AKT1, n = 2) and MAPK (KRAS, n = 4, BRAF, n = 2) signaling pathways. One tumor harbored an ESR1-NCOA3 fusion and another had an MLH1 homozygous deletion, associated with loss of MLH1 and PMS2 protein expression. The fraction of genome altered was significantly higher in high-grade compared to low-grade adenosarcomas (P = 0.001). Somatic ATRX frameshift mutations were found in two patients with low-grade adenosarcoma with high-grade recurrences and one case of high-grade adenosarcoma with an adjacent low-grade component. Immunohistochemical analysis for BAP1 revealed loss of nuclear expression in 6/24 (25%) cases, including all 4 tumors with BAP1 deletions. Notably, out of 196 mesenchymal neoplasms of gynecologic origin, BAP1 homozygous deletion was only found in adenosarcomas (4/27,15% adenosarcomas vs 0/169, 0% other mesenchymal neoplasms, P = 0.0003). This study demonstrates that high-grade adenosarcomas are heterogeneous at the molecular level and are characterized by genomic instability and TP53 mutations; ATRX loss may be involved in high-grade transformation of low-grade adenosarcoma; and BAP1 inactivation appears to be a specific pathogenic driver in a subset of adenosarcomas.

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Supplement 3: Baseline characteristics for the 105 women that underwent extensive sampling of thefallopian tube.

Supplementary Table 1

Purpose:We examined whether prospective molecular characterization of advanced metastatic disease can reveal grade and/or histology-specific differences to inform diagnosis and facilitate enrollment onto clinical trials.Experimental Design:Patients with uterine sarcoma consented to a prospective study of next-generation sequencing (NGS). Clinical annotations were extracted from their medical record. Tumor and matched normal DNA were subjected to NGS, and the genomic landscape was explored for survival correlations and therapeutic targetability.Results:Tumors from 107 women were sequenced and included leiomyosarcoma (n = 80), high-grade non-leiomyosarcoma (n = 22), low-grade endometrial stromal sarcoma (LG-ESS, n = 4), and smooth muscle tumor of uncertain malignant potential (STUMP, n = 2). Genomic profiling influenced histologic diagnosis in three cases. Common uterine leiomyosarcoma alterations were loss-of-function mutations in TP53 (56%), RB1 (51%), and ATRX (31%). Homozygous deletions of BRCA2 were present in 5% of these patients. PTEN alteration frequency was higher in the metastases samples as compared with the primary samples. Genomes of low-grade tumors were largely silent, while 50.5% of high-grade tumors had whole-genome duplication. Two metastatic uterine leiomyosarcoma cases were hypermutated. Both had prolonged disease-free survival. Potentially actionable mutations were identified in 48 patients (45%), 8 (17%) of whom received matched therapy with 2 achieving clinical responses. Among patients with uterine leiomyosarcoma with somatic BRCA2 alterations, sustained partial responses were observed with PARP inhibitor–containing therapy.Discussion:Prospective genomic profiling can contribute to diagnostic precision and inform treatment selection in patients with uterine sarcomas. There was evidence of clinical benefit in patients with uterine leiomyosarcoma with somatic BRCA2 alterations treated with PARP inhibitors.

Supplementary Figures

The mutant protein FOXL2(C134W) is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2(C134W) contributes to tumorigenesis is not known. Here we show that mutant FOXL2(C134W) acquires the ability to bind SMAD4, forming a FOXL2(C134W)/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2(C134W) mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2(C134W) also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2(C134W) binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2(C134W). Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2(C134W) and its interaction with SMAD4 as potential therapeutic targets to this condition.

Context.—A large variety of tumors and lesions arise in the female genital tract. Although the majority of these can be correctly recognized on routine hematoxylin-eosin– stained slides, occasional cases present a diagnostic challenge. Immunohistochemical stains are extremely useful in resolving many of these problematic cases. As the knowledge in this area is constantly expanding, it is useful to have this updated information in a review form for easy access. Objective.—To present our current knowledge of immunohistochemistry of the lesions of the female genital tract in a readily accessible form. Data Sources.—The review is based on previously published articles on this topic. Conclusions.—Immunohistochemical stains help in reaching a conclusive diagnosis in a variety of problematic lesions seen in gynecologic pathology. As in any other system, immunohistochemical findings need to be interpreted in light of the clinical history and morphologic findings.

PURPOSE: To determine long-term survival and predictors of recurrence in a retrospective cohort of patients with epithelial ovarian cancer treated with intraperitoneal (IP) chemotherapy. PATIENTS AND METHODS: Records were reviewed of 433 patients who received IP therapy for ovarian cancer between 1984 and 1998; follow-up data were available for 411 patients. IP therapy was provided as consolidation therapy (n = 89), or for treatment of persistent (n = 310) or recurrent (n = 12) disease after surgery and initial systemic therapy; therapy usually consisted of platinum-based combination therapy. Statistical analysis included tests for associations between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox proportional hazard model. RESULTS: The mean age of patients was 52 years (range, 25 to 76 years). Distribution by stage and grade was as follows: stage I, 7; II, 24; III, 342; IV, 52; not available (NA), 8; and grade 1, 30; 2, 99; and 3, 289; NA, 15. The median survival from initiation of IP therapy by residual disease was none, 8.7 years; microscopic, 4.8 years; less than 1 cm, 3.3 years; more than 1 cm, 1.2 years. In a multivariate analysis, the only significant predictors of long-term survival were grade and size of residual disease at initiation of IP therapy. CONCLUSION: Prolonged survival was observed in selected patients receiving IP platinum-based therapy. It is not possible to determine the contribution of IP therapy to survival in this study. A relationship between size of disease at the initiation of IP therapy and long-term survival was demonstrated.