Rachelle P. Mendoza

Clinicopathologic and Molecular Characterization of Gynecologic Carcinosarcomas With a Mesonephric-Like Carcinomatous Component

Carcinosarcoma with a mesonephric-like carcinomatous component (MLCS) is a rare subtype of gynecologic malignancy recently described in the literature. This study aims to expand the genomic characterization of MLCS by performing independent molecular analysis of the carcinomatous and sarcomatous components in a series of MLCS. Eight cases of gynecologic MLCS (endometrial, lower uterine segment, and ovarian) were identified and underwent clinicopathologic evaluation. Genomic DNA extraction and next-generation sequencing (NGS) were performed separately from the carcinomatous and sarcomatous components of 4 tumors, while 2 tumors underwent NGS of combined carcinomatous and sarcomatous components. The average age at diagnosis was 65.6 years (range 50 to 83 years). MLCS patients were diagnosed at FIGO stage I (n=3), stage II (n=2), stage III (n=2), and stage IV (n=1). The carcinomatous and sarcomatous components were observed to harbor the same single nucleotide variations. All cases had less than 10 mutations/Mb and were microsatellites stable. All cases (6/6, 100%) harbored KRAS point mutations in codon 12, including the following variants: p.G12D (n=2), p.G12A (n=2), and p.G12V (n=2). Five cases showed additional alterations in ARID1A (case 1), PTEN (case 2), PIK3CA (case 4), SPOP (case 6), TET1 (case 6), BUB1 (case 7), LYN (case 7) and PTPRD (case 7). The presence of both KRAS and PTEN/PIK3CA alterations suggests a combined endometrioid and mesonephric differentiation in MLCS.

Molecular and Clinicopathologic Characterization of HER2-overexpressed Squamous Cell Carcinoma of the Cervix

HER2 amplification in cervical cancer has been associated with worse clinical prognosis and a potential favorable response to HER2 inhibitors. Immunohistochemistry for the HER2 receptor is a universally accepted surrogate test for HER2 amplification, but no standardized scoring system currently exists for cervical carcinomas. In this study, we investigated HER2 overexpression in cervical squamous cell carcinoma and correlated it with HER2 amplification using fluorescence in situ hybridization (FISH) and molecular methods. Seventy-two cases of human papillomavirus-associated cervical cancer were retrospectively reviewed, and at least 2 representative tumor sections were stained for HER2. HER2 scoring was performed using the 2018 American Society of Clinical Oncology/College of American Pathologist breast cancer criteria, and cases with equivocal (2+) to positive (3+) expression were analyzed for HER2 amplification using FISH and next-generation sequencing. The average patient age was 50 yrs (range: 27–85 yr), with most patients being African American (73.6%) and diagnosed at FIGO stage I (65.3%). Nineteen (26.4%) had equivocal HER2 expression and 4 (5.5%) showed positive expression. Three of the 4 cases with positive expression had enough tumors for FISH, and all 3 were amplified. Three cases with equivocal expression showed HER2 polysomy on FISH, and none showed HER2 amplification. Late clinical stage, high tumor grade, and regional lymph node metastasis were significantly correlated with HER2 overexpression and HER2 amplification. Next-generation sequencing of the 3 HER2-amplified tumors showed amplification of various genes, including CD274, JAK2, BIRC3, and ERBB2, and a PIK3CA missense mutation. In summary, HER2 immunohistochemistry is a reliable predictive marker of HER2 amplification in cervical cancer.

Practical Approach to the Evaluation of Malignant Peritoneal Fluids in the Setting of Gynecologic Neoplasms

Background: Evaluation of peritoneal fluid cytology, either from ascitic fluids or as a result of peritoneal washings, is a fundamental aspect in the evaluation of women presenting with clinically concerning or histologically confirmed gynecologic neoplasms. Summary: Ascitic fluid samples are often the initial and only source of diagnostic material in women presenting with gynecologic malignancies, and important therapeutic decisions will result from the information provided in the cytology report. On the other hand, cytologic evaluation of peritoneal washing specimens obtained during surgical excision of a presumed gynecologic neoplasm provides crucial information to the clinical team regarding tumor staging, often with significant therapeutic implications. While recognition of high-grade tumors in either of these samples is generally straightforward, low-grade tumors and unusual neoplasms can prove to be more difficult to recognize, differentiate from benign mimics, and correctly diagnose, particularly in low-cellularity specimens. Even with high-grade tumors, a mere diagnosis of “positive for malignancy” in diagnostic ascitic fluid specimens might not suffice to guide clinical management, and the use of ancillary techniques to further and more definitively characterize the lesional cells is required. Key Messages: This review will focus on the clinically relevant issues surrounding interpretation of peritoneal fluid cytology specimens in the setting of gynecologic neoplasms, making emphasis on the salient cytomorphologic and immunocytochemical features of the various neoplastic processes, in an attempt to provide a practical yet effective guide on how to best evaluate, diagnose, and report these samples.