Dario de Biase

Two possible entities of endometriosis-associated ovarian cancer: correlated or incidental?

This study aimed to describe 2 types of endometriosis-associated ovarian cancer: those with transitional elements (atypical endometriosis and borderline tumors) termed endometriosis-correlated or incidental benign endometriosis vs ovarian cancer cases not associated with endometriosis. This was a prospective, observational, monocentric study conducted from November 2021 to December 2023. Patients with ovarian cancer eligible for surgery were enrolled and classified into endometriosis-correlated ovarian carcinoma, endometriosis-incidental ovarian carcinoma, or ovarian carcinoma without endometriosis groups based on the presence or not of endometriosis and transitional lesions. Clinical, sonographic, surgical and pathological data and progression-free survival were recorded. Logistic regression models for accurate patient classification were developed from pre-surgical variables. Of the 170 patients included, 83 (48.82%) had ovarian carcinoma without endometriosis, 39 (22.94%) had endometriosis-incidental ovarian carcinoma, and 48 (28.24%) had endometriosis-correlated ovarian carcinoma. Patients with endometriosis-incidental ovarian carcinoma and endometriosis-correlated ovarian carcinoma were diagnosed at younger ages (p = .002) and had lower post-menopausal rates than patients with ovarian carcinoma without endometriosis (p = .011). Patients with endometriosis-correlated ovarian carcinoma had fewer pregnancies (p < .001) and higher CA-19.9 levels (p = .002) presented with unilateral and multilocular solid lesions than patients with ovarian carcinoma without endometriosis (p < .001). Patients with endometriosis-incidental ovarian carcinoma showed intermediate lesion morphology. Endometriosis-correlated ovarian carcinoma was mostly diagnosed at early Federation of Gynecology and Obstetrics stages (range; I-II) compared with endometriosis-incidental ovarian carcinoma and ovarian carcinoma without endometriosis (p < .001), had less extensive disease (p < .001), and a higher likelihood of complete cytoreduction (p = .035). Endometriosis-correlated ovarian carcinoma was more likely to include clear cell, endometrioid, and mesonephric-like adenocarcinomas, whereas serous histotype predominated in the other groups (p < .001). Logistic regression models accurately identified patients with endometriosis-correlated ovarian carcinoma vs patients with endometriosis-incidental ovarian carcinoma (area under the curve [AUC] = 0.926) and ovarian carcinoma without endometriosis (AUC = 0.968) but could not reliably differentiate endometriosis-incidental ovarian carcinoma from ovarian carcinoma without endometriosis (AUC = 0.668). The 2-year progression-free survival rates were 91% in endometriosis-incidental ovarian carcinoma, 80% in endometriosis-correlated ovarian carcinoma, and 59% in ovarian carcinoma without endometriosis (p = .024). Our study indicates that ovarian cancer associated with endometriosis consists of 2 clinical entities, with endometriosis-incidental ovarian carcinoma emerging as a bridging group between endometriosis-correlated ovarian carcinoma and ovarian carcinoma without endometriosis.

Adult granulosa cell tumours of the testis analogous to ovarian counterparts are exceptionally rare: analysis of a multicentric series and review of the literature

Aims Testicular adult granulosa cell tumours (AGCTs) are rare and show several clinical–pathological differences with their ovarian counterparts. In a limited number of prior studies, FOXL2 p.Cys134Trp, the hallmark molecular alteration of ovarian AGCT, appeared to be infrequent in testicular AGCTs. However, the number of cases analysed to date is relatively small. Methods and results Twenty testicular AGCTs were analysed de novo using two different next‐generation sequencing ( NGS ) panels that cover sex cord‐stromal tumour ( SCST )–relevant genes, including FOXL2 , CTNNB1 , FH and DICER1 . Among 12 tumours (12/20; 60%) that were sequenced successfully, none harboured FOXL2 mutations. Eight tumours (8/12, 66.7%) showed a wild‐type ( WT ) status for all genes assessed with the panels. Three tumours harboured pathogenic or likely pathogenic CTNNB1 alterations. One of these exhibited predominant spindle cell morphology, while the other two showed focal tubular architecture. Immunohistochemistry performed in one of these tumours with available material showed β‐catenin expression in ~70% of tumor cell nuclei. The remaining AGCTs showed variants of uncertain significance (likely benign) in KIT and MED12 . Considering the tumors asseseed in this study and those previously reported in the literature, only 2 of 29 neoplasms classified as testicular AGCTs have shown a FOXL2 p. Cys134Trp mutation to date. Conclusions The present study confirms that SCSTs classified as AGCTs differ from their ovarian counterparts in that they largely lack FOXL2 mutations.

Endometrial carcinoma and immune escape: prognostic relevance of HLA class I loss in NSMP subtype

Aims This study aims to define and characterize human leukocyte antigen class I (HLA‐I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer–immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results HLA‐I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE ‐mutated, MMR‐deficient (MMRd), p53‐abnormal (p53abn) and NSMP subtypes. Loss of HLA‐I was identified in 31% of cases and was associated with adverse features including high‐grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an ‘excluded’ immune phenotype. While HLA‐I loss showed no significant prognostic impact in POLE , MMRd or p53abn tumours, it significantly correlated with worse disease‐free survival in NSMP tumours ( P  &lt; 0.001). Multivariate analysis confirmed HLA‐I loss as an independent prognostic factor in early‐stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer–immune phenotypes. Integration of HLA‐I status improved the performance of predictive models over time. Conclusions HLA‐I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA‐I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.

miRNA levels are associated with body mass index in endometrial cancer and may have implications for therapy

AbstractEndometrial cancer (EC) is the most prevalent gynecological cancer in high‐income countries. Its incidence is skyrocketing due to the increase in risk factors such as obesity, which represents a true pandemic. This study aimed to evaluate microRNA (miRNA) expression in obesity‐related EC to identify potential associations between this specific cancer type and obesity. miRNA levels were analyzed in 84 EC patients stratified based on body mass index (BMI; ≥30 or &lt;30) and nine noncancer women with obesity. The data were further tested in The Cancer Genome Atlas (TCGA) cohort, including 384 EC patients, 235 with BMI ≥30 and 149 with BMI &lt;30. Prediction of miRNA targets and analysis of their expression were also performed to identify the potential epigenetic networks involved in obesity modulation. In the EC cohort, BMI ≥30 was significantly associated with 11 deregulated miRNAs. The topmost deregulated miRNAs were first analyzed in 84 EC samples by single miRNA assay and then tested in the TCGA dataset. This independent validation provided further confirmation about the significant difference of three miRNAs (miR‐199a‐5p, miR‐449a, miR‐449b‐5p) in normal‐weight EC patients versus EC patients with obesity, resulting significantly higher expressed in the latter. Moreover, the three miRNAs were significantly correlated with grade, histological type, and overall survival. Analysis of their target genes revealed that these miRNAs may regulate obesity‐related pathways. In conclusion, we identified specific miRNAs associated with BMI that are potentially involved in modulating obesity‐related pathways and that may provide novel implications for the clinical management of obese EC patients.

Mesonephric-like adenocarcinoma of the ovary: features of a rare and aggressive entity associated with endometriosis.

Mesonephric-like adenocarcinoma is a rare, aggressive ovarian cancer subtype, newly classified by the World Health Organization in 2020. This study examines the clinical, ultrasound, pathological features, and survival outcomes of ovarian mesonephric-like adenocarcinoma. This observational, prospective, single-center study included patients with ovarian mesonephric-like adenocarcinoma treated between January 2020 and December 2023. Clinical data and ultrasound findings were collected. Ultrasound examinations were performed according to the International Ovarian Tumor Analysis guidelines and qualitatively described in correlation with pathological findings. Histopathological evaluation was conducted based on the 2020 World Health Organization classification. Progression-free survival and overall survival were calculated from the time of diagnosis to recurrence or death. Among 467 patients with ovarian cancer treated at our center, 14 (3.0%) were diagnosed with ovarian mesonephric-like adenocarcinoma, with a mean age of 60 ± 8 years. Ultrasound commonly showed unilateral solid lesions (57.2%) with moderate-to-strong blood flow, heterogeneous echogenicity, and hyperechoic "cotton candy" regions. Most patients (57.1%) had International Federation of Gynecology and Obstetrics stage III to IV disease; 78.5% underwent upfront surgery, achieving complete cytoreduction in 92.8%. Pathology revealed mesonephric-like adenocarcinoma alone in 44.4% and mixed histotypes in 55.6% (endometrioid, mucinous, or high-grade serous components), with endometriosis in 64.2%. K-RAS mutations were present in all cases. Median progression-free survival was 17.5 months (IQR 13.5-35.9), with 57.1% experiencing recurrence, mostly as peritoneal metastases. Median overall survival was not reached, with one death recorded. Mesonephric-like adenocarcinoma is a rare yet aggressive ovarian cancer strongly associated with endometriosis and characterized by K-RAS mutation. Unique ultrasound features, such as "cotton candy" hyperechoic regions, may assist in early recognition and pre-surgical diagnosis.