Mojgan Devouassoux-Shisheboran

Molecular Relationship Between Ovarian Sertoli-Leydig Cell Tumors and Their Heterologous Elements

Since the histogenesis of heterologous elements within Sertoli-Leydig cell tumors (SLCTs) is poorly understood, we aimed to study the molecular relationship between Sertoli cells and the heterologous elements in 16 ovarian SLCTs. We performed a comprehensive molecular study on both SLCT and heterologous components, separately. Eleven tumors (68.7%) had one heterologous element and 5/16 (31.3%) had 2. Heterologous elements were epithelial (7/21 [81%]) (benign mucinous epithelium [9/21, 42.9%], borderline mucinous tumor [1/21, 4.8%], infiltrative mucinous adenocarcinoma [3/21, 14.3%], carcinoid tumor [3/21, 14.3%], and hepatocytes [1/21,4.8%]) or mesenchymal (4/21, 19%) (rhabdomyosarcoma [3/21,14.3%] and chondrosarcoma [1/21, 4.8%]). A DICER1 pathogenic variant was shared between SLCT and the heterologous elements in all cases with interpretable results (15/15), and other common likely-pathogenic/pathogenic variants were shared between SLCTs and heterologous components (3/16, 18.75%), favoring a clonal relationship. In contrast, the identification of distinct variants between components favored a different evolution. The molecular profile of heterologous elements differed from that of their ovarian counterparts occurring without SLCT (eg, mucinous heterologous elements were KRAS wild-type). Chromosome 8 gains, TERT and NRAS/KRAS variants, and absence of fusion transcript, were the hallmark of rhabdomyosarcoma components (3/3, 100%). The progression-free survival rate was significantly shorter for patients with TERT pathogenic variant ( P =0.0029). One patient had pleomorphic Sertoli cells associated with TP53 variants and very poor prognosis with early recurrence after complete initial surgery of a stage IA tumor. These data highlight the biological relationship between SLCTs and their heterologous elements, and the clinical usefulness of identifying pathogenic variants (ie, TERT and TP53 ), although this last point needs to be confirmed in a larger series.

Relevance of Molecular Pathology for the Diagnosis of Sex Cord–Stromal Tumors of the Ovary: A Narrative Review

Ovarian sex cord–stromal tumors (SCSTs) account for 8% of all primary ovarian neo-plasms. Accurate diagnosis is crucial since each subtype has a specific prognostic and treatment. Apart from fibrosarcomas, stromal tumors are benign while sex cord tumors may recur, sometimes with a significant time to relapse. Although the diagnosis based on morphology is straightforward, in some cases the distinction between stromal tumors and sex cord tumors may be tricky. Indeed, the immunophenotype is usually nonspecific between stromal tumors and sex cord tumors. Therefore, molecular pathology plays an important role in the diagnosis of such entities, with pathognomonic or recurrent alterations, such as FOXL2 variants in adult granulosa cell tumors. In addition, these neoplasms may be associated with genetic syndromes, such as Peutz–Jeghers syndrome for sex cord tumors with annular tubules, and DICER1 syndrome for Sertoli–Leydig cell tumors (SLCTs), for which the pathologist may be in the front line of syndromic suspicion. Molecular pathology of SCST is also relevant for patient prognosis and management. For instance, the DICER1 variant is associated with moderately to poorly differentiated SLCTS and a poorer prognosis. The present review summarizes the histomolecular criteria useful for the diagnosis of SCST, using recent molecular data from the literature.

Assessing the Status of Cyclin E1 (CCNE1) From Gene to Protein Level in Ovarian and Endometrial Carcinomas: A Systematic Review

Twenty percent and 45.4% of high-grade ovarian carcinomas (OC) and endometrial carcinomas (EC) exhibit CCNE1 amplification (CCNE1-amp), respectively, which is related to poor prognosis, but could serve as predictive biomarker for response to innovative targeted therapies. However, there is no consensus regarding how to evaluate the CCNE1 status (at the DNA, RNA, and/or protein level). Therefore, we conducted a systematic review of CCNE1 status testing in tubo-ovarian neoplasms and EC, comparing their performance for clinical purposes and highlighting the test's interpretation criteria (CRD420250651291). Among the 734 records initially found on PubMed and Google Scholar, 48 reports were finally included. Molecular analyses and immunohistochemistry (IHC) were reported on 9774 tubo-ovarian neoplasms and 750 EC, and 6966 tubo-ovarian neoplasms and 856 EC, respectively. The most frequently morphological used method to detect CCNE1-amp was fluorescent in situ hybridization (13/16 studies, 81.3%), with quite consensual criteria to defined amplification (ie, CCNE1/chromosome 19 ratio ≥2, and/or >8/≥8 copies of CCNE1 per nucleus, and/or ≥4 CCNE1 copies in ≥40% of cells). The proportion of tubo-ovarian neoplasms with CCNE1 immunohistochemical overexpression varied from 13.5% to 96%, and 14.6% to 86.1% in EC. The sensitivity and specificity of CCNE1 IHC to detect/exclude CCNE1-amp varied from 54.5% to 100% and 59.3% to 90.1%, respectively. Given the reported data, CCNE1 overexpression should be considered either when an H-score is ≥100 or when the staining is >60% with >5% of cells strongly stained. Both CCNE1-amp and CCNE1 overexpressions were associated with poor prognosis and with response to Wee1 and CDK2 inhibitors in high-grade serous OC (overall response rate up to 53%, objective response rate of 32%-40%). In contrast, CCNE1 messenger RNA overexpression had no prognostic value. Thus, both CCNE1-amp detection by fluorescent in situ hybridization and CCNE1 protein levels quantification using IHC represent today the most validated tools to determine the CCNE1 status in OC/EC.

The KAT6B::KANSL1 Fusion Defines a New Uterine Sarcoma With Hybrid Endometrial Stromal Tumor and Smooth Muscle Tumor Features

Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median, 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA, all neoplasms clustered together, close to LG-ESS, and pathway enrichment analysis showed cell proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration.

Role of gene sequencing in classifying struma ovarii: BRAF p.G469A mutation and TERT promoter alterations favour malignant struma ovarii

AimsStruma ovarii (SO) are rare, accounting for 0.3–1% of ovarian tumours, and include benign and malignant lesions. In most cases, histology is not predictive of clinical outcome and prognosis. The prognosis of histologically malignant thyroid‐type carcinomas can indeed be excellent, while SO, composed of normal thyroid tissue, can recur and are designated highly differentiated follicular carcinoma of the ovary. Clearer diagnostic criteria are therefore required.Methods and resultsWe retrospectively studied 31 SO using DNA and RNA sequencing with pan‐cancer gene panels, including eight biologically malignant SO (BMSO) defined based on ovarian serosal or extra‐ovarian dissemination at presentation or during follow‐up, 10 stage IA histologically malignant SO (HMSO) with thyroid‐type carcinoma morphology and 13 biologically and histologically benign SO (BSO), with none of the above‐mentioned characteristics. Molecular alterations were observed in 87.5% of BMSO, 70% of HMSO and 7.7% of BSO (P < 0.001). All patients with a peritoneal dissemination at presentation or during follow‐up had at least one gene alteration. BRAF mutations (44.5%) were only observed in malignant forms (HMSO and BMSO) and TERT promoter alterations (25%) only in cases of BMSO. The BRAF p.G469A mutation, which is extremely rare in thyroid carcinomas, was the molecular alteration most frequently associated with malignant SO (28.5%).ConclusionOur results highlight the clinical utility of molecular sequencing in SO, based on this limited number of cases. However, as malignant SO evolve slowly, more extensive molecular studies in SO with more than 10 years’ follow‐up are required to draw any conclusions on the prognostic value of the associated gene alterations.