Xiaoming Zhang

Folate receptor alpha ( FRα / FOLR1 ) and HER2 immunohistochemical staining in high‐grade endometrial carcinoma with aberrant p53 expression

Aims Mirvetuximab soravtansine is an anti‐FOLR1 (folate receptor 1/alpha) antibody–drug conjugate with a companion diagnostic immunohistochemical (IHC) biomarker for platinum‐resistant ovarian, fallopian tube and primary peritoneal carcinoma. Its effectiveness has sparked interest in FOLR1 expression in endometrial carcinoma. We evaluate the relationship of FOLR1 and HER2‐IHC expression in high‐grade p53‐aberrantly expressed endometrial carcinomas, as overexpression of both is associated with high‐grade histologic features and aggressiveness. Methods and results Carcinomas were scored for HER2‐IHC by both gastric and endometrial serous criteria and FOLR1‐IHC by Ventana package insert on tissue microarray cores. Intratumoral heterogeneity was quantified for HER2 and FOLR1 expression across multiple cores from the same tumour. A total of 291 cores (226 endometrial serous, 47 high‐grade endometrioid and 18 high‐grade Müllerian carcinoma, nos) were collected from 66 cases (discrete accession dates) from 62 patients. When stratified by two‐category HER2‐IHC status (0/1+ vs. 2+/3+, either criteria), significantly more HER2 2+/3+ cores (16/133, 12%) were FOLR1‐positive by a ≥75% cut‐off than HER2 0/1+ specimens (8/158, 5%, P  = 0.031). Results were similar by a ≥25% cut‐off (49/133, 37% vs. 38/158, 24%; P  = 0.018). More cases with high HER2‐IHC heterogeneity (2–3‐pt difference) also demonstrated FOLR1‐IHC heterogeneity (≥50% score difference between cores from the same case) than cases with no or low (1‐pt) HER2‐IHC heterogeneity, though most cases did not show high HER2 or FOLR1 intratumoral heterogeneity (16.7%–18.2% 2–3‐pt difference and 12.1% ≥50% score difference). Conclusions A positive correlation between HER2 and FOLR1 overexpression may be seen in high‐grade endometrial carcinomas with aberrant p53 expression, which may extend to intratumoral heterogeneity of biomarker expression.

SOX17 expression in mesonephric‐like adenocarcinomas and mesonephric remnants/hyperplasia of the female genital tract: Expanding its utility as a Müllerian biomarker

AimsRecently, SOX17 has emerged as a promising biomarker for non‐mucinous Müllerian (ovarian and endometrial) carcinomas, demonstrating increased specificity in comparison to PAX8 while maintaining similar sensitivity. However, expression of SOX17 in mesonephric‐like adenocarcinoma (MLA), a carcinoma of the female genital tract with uncertain, but probably Müllerian histogenesis, remains unexplored. This study aims to address this gap.Methods and resultsSOX17 immunohistochemistry was performed on whole tissue sections from 68 MLAs originating from the endometrium or ovary and seven cervical mesonephric carcinomas, as well as six mesonephric remnants/hyperplasias. Using a four‐tiered scoring system based on distribution and intensity of staining, 68% of MLA displayed a negative/low (< 10%) SOX17 expression pattern, which contrasts with the high expression observed in most Müllerian carcinomas. However, 22% of MLA demonstrated high SOX17 expression, similar to other endometrial and ovarian carcinomas. Similarly, five of seven (72%) mesonephric carcinomas of the cervix were SOX17‐negative, but two cases (28%) were positive. All mesonephric remnants/hyperplasias were SOX17 negative.ConclusionsThe majority of MLA are negative or exhibit low SOX17 expression, in contrast to the diffuse and strong expression commonly seen in other types of Müllerian carcinoma. However, a subset of MLAs demonstrate high SOX17 expression. Therefore, absence of SOX17 staining is supportive for MLA when the differential includes another non‐mucinous Müllerian carcinoma. SOX17 may also be useful for differentiating mesonephric remnants/hyperplasias from Müllerian malignancies and benign Müllerian glandular lesions.

PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma is Associated with Poor Progression-Free Survival and is Mutually Exclusive with CCNE1 Amplification

As a critical tumor suppressor, PTEN has gained much attention in cancer research. Emerging evidence suggests an association between PTEN status and clinical outcome in certain tumors, and may be predictive of response to several therapies. However, the significance of PTEN deficiency in tubo-ovarian high-grade serous carcinomas (HGSCs) is still poorly understood. We evaluated PTEN expression in HGSCs and determined its clinical relevance. A cohort of 76 HGSC specimens was profiled using tissue microarray. Immunohistochemistry (IHC) of PTEN, ER, PR, AR, CD8, FOXP3, and PD-L1 was performed. Targeted gene panel testing by massively parallel sequencing was performed in 51 cases. PTEN deficiency (complete or subclonal loss) detected by IHC was identified in 13 of the 62 HGSCs (21%) and was significantly correlated with reduced expression of ER and worse first progression-free survival (P < .05) but not with PD-L1 expression, the density of intratumoral T lymphocytes, or overall survival. In our cohort, tumor progression within 1 year of PARP inhibitor therapy was found more frequently in PTEN-deficient cases than in PTEN-intact cases (100% vs 52%). Molecular profiling showed that intragenic mutation or deletion was not the predominant mechanism for PTEN inactivation in HGSCs. In addition, CCNE1 amplification was found to be mutually exclusive with PTEN deficiency at both protein and DNA levels. An analysis of the genomic data from 1702 HGSC samples deposited with The Cancer Genome Atlas database obtained from cBioPortal confirmed the low rate of detection of PTEN gene alterations and the mutually exclusive nature of PTEN loss and CCNE1 amplification in HGSCs. These findings indicate that PTEN deficiency defines a distinct clinically significant subgroup of HGSCs with a tendency for ER negativity, wild-type CCNE1 status, inferior clinical outcomes, and potential drug resistance. These tumors may benefit from PI3K pathway inhibitors in combination with other ovarian cancer regimens, which deserves further investigation.

Highly immunosuppressive HLADRhi regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer‐induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADRhi Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADRhi Tregs express high levels of a panel of inhibition and activation markers and the TCR‐responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADRhi Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADRhi Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor‐infiltrating HLADRhi Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context‐based quantification revealed that a high frequency of stromal HLADRhi Tregs in patients is significantly associated with worse progression‐free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADRhi Tregs in CSCC patients. An increased HLADRhi Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno‐oncology studies.