International Journal of Gynecological Pathology最新文献

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

Synchronous endometrial and ovarian endometrioid carcinoma, which simultaneously involves the endometrium and ovary, is a relatively rare entity among gynecological cancers. Precise diagnosis and risk stratification are crucial for disease management. We present a unique case of a 40-year-old woman diagnosed with synchronous endometrial and ovarian endometrioid carcinoma carrying a monoallelic pathogenic MUTYH germline variant. Despite the histological morphology of the right ovarian tumor exhibiting some differences compared to the uterine tumor, we identified three identical somatic mutations shared between the uterine tumor and right ovarian tumor, along with four additional mutations exclusive to the uterine tumor, through the utilization of massively parallel sequencing of a 196-gene panel. These findings enabled us to elucidate the clonal relatedness and potential clonal evolution of the tumor across the two anatomical sites. Furthermore, in accordance with the 2023 FIGO staging system, the patient was diagnosed with Stage IIIB2 uterine cancer, and consequently, adjuvant radiation and chemotherapy were administered after surgery. She is being followed periodically and is normal 15 months after surgery. To the best of our knowledge, this study presents the first case of a patient with synchronous endometrial and ovarian endometrioid carcinoma harboring a monoallelic pathogenic MUTYH germline variant.

TRPS1 is a novel immunohistochemical marker, so far quite specific and sensitive for breast cancer and especially useful for the diagnosis of triple-negative breast cancer. TRPS1 expression has recently been reported in normal skin appendages, as well as in a variety of benign and malignant cutaneous tumors, including adnexal tumors. However, it has not yet been reported in hidradenoma papilliferum (papillary hidradenoma), a benign adnexal neoplasm, accepted to originate from mammary-like glands in the vulvar or anogenital region of middle-aged women. We report consistent nuclear expression of TRPS1 in the epithelium of 9/9 cases of hidradenoma papilliferum, while in 2/2 cases with foci of oxyphilic metaplasia, these foci were consistently negative for TRPS1 immunohistochemistry. Our findings are in line with the theory that hidradenoma papilliferum is derived from mammary-like glands and showed that TRPS1 can be an additional sensitive immunohistochemical marker for hidradenoma papilliferum.

Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2-mutant non-small cell lung cancer. This study aimed at evaluating the detailed clinical, histomorphological, immunohistochemical, and molecular characteristics of gynecologic malignancies with ERBB2/HER2 mutations. We identified 16 tumors with 19 ERBB2/HER2 mutations in our departmental archives: 11 endometrial primaries, 2 endocervical adenocarcinomas, 1 ovarian mucinous adenocarcinoma, 1 tubo-ovarian undifferentiated carcinoma, and 1 high-grade endometrioid adenocarcinoma of Mullerian origin. ERBB2/HER2 mutations most often involved the tyrosine kinase domain (52.6%), and the most frequent specific mutation was R678Q (31.6%), involving the juxtamembrane domain. More than half (54.5%) of endometrial carcinomas and half of all tumors were MMR-deficient, resulting from MSH6 loss in all but 2 tumors. None of the tumors (0%) were POLE-mutated, while 18.8% were TP53-mutated. HER2 IHC was negative (score 0 or 1+) in 12 tumors (67%) and equivocal (score 2+) in 4 tumors (33%), whereas none of the tumors were scored as HER2 3+. Score 2+ was associated with R678Q, L755S, I767M mutations, and ERBB2/HER2 rearrangement with a breakpoint in exon 23. Concurrent ERBB2/HER2 amplification was identified in 2 endometrial carcinomas, with HER2/CEP17 ratios of 3.1 and 3.5. We also queried the cBioportal database, which revealed 70 ERBB2/HER2-mutant gynecologic tumors with a total of 77 ERBB2/HER2 mutations, most often involving the active site of the tyrosine kinase domain (n=36; 46.8%), and the most common specific mutation was S310F (n=20; 26%), located in the extracellular domain. Our results provide important details regarding the clinicopathological and molecular associations of potentially actionable ERBB2/HER2 mutations in endometrial carcinoma and other gynecological cancer types and contribute to addressing clinical treatment needs and improving pathology testing recommendations in the future.

The objective of this study was to analyze the expression and prognostic role of cancer-associated proteins in uterine leiomyosarcoma (uLMS). p53, DAXX, ATRX, HMGA2, IMP3, Stathmin, and phospho-Stathmin (p-Stathmin) protein expression by immunohistochemistry was analyzed in tissue microarrays from 244 uLMS. Expression was assessed for association with clinicopathologic parameters in 173 patients with available data. Tissue microarrays were informative in 230 cases. p53 was aberrant in 44% of tumors. DAXX, ATRX, HMGA2, IMP3, and Stathmin were expressed in 90%, 55%, 40%, 33%, and 97% uLMS, respectively. Cytoplasmic and nuclear p-Stathmin staining was seen in 77% and 68% of tumors, respectively. Stathmin expression was significantly related to higher mitotic count (P < 0.001), a higher degree of atypia (P = 0.006), and vascular invasion (P = 0.016), whereas p-Stathmin expression was significantly related to advanced stage (P < 0.001), higher mitotic count (P < 0.001), and vascular invasion (P = 0.001). In univariate survival analysis for 165 patients with informative tissue microarrays, aberrant p53 (P = 0.026) and higher IMP3 (P = 0.024), Stathmin (P < 0.001), cytoplasmic p-Stathmin (P < 0.001), and nuclear p-Stathmin (P < 0.001) expression was associated with poor disease-specific survival. Clinicopathologic parameters significantly related to poor disease-specific survival were older age (P = 0.006), extrauterine disease at diagnosis (International Federation of Gynecology and Obstetrics (FIGO) stage ≥2; P < 0.001), high mitotic count (P = 0.02), and grade 2 to 3 atypia (P = 0.017). In multivariate analysis, age (P = 0.002), FIGO stage (P < 0.001), and Stathmin expression (P < 0.001) were independent prognosticators. Stathmin was the only prognosticator in a multivariate analysis limited to patients with FIGO stage I disease (P = 0.013). In conclusion, Stathmin expression is strongly associated with poor survival in uLMS and may be a new prognostic marker in this malignancy.

Androgen receptor splicing variant 7 (AR-V7) is a truncated variant of the AR mRNA that may be a predictive biomarker for AR-targeted therapy. AR-V7 has been described in prostate, breast, salivary duct, and hepatocellular carcinomas as well as mammary and extra-mammary Paget disease. We report 2 gynecologic cancers occurring in the lower uterine segment and ovary and both harboring AR-V7 by targeted RNA sequencing. The uterine tumor was an undifferentiated carcinoma consisting of epithelioid cells and focally spindled cells arranged in sheets, nests, and cords associated with brisk mitotic activity and tumor necrosis. The ovarian tumor consisted of glands with cribriform and solid architecture and uniform cytologic atypia. ER and PR were positive in the ovarian tumor and negative in the uterine tumor. Both were positive for AR and negative for HER2, GATA3, and NKX3.1. DNA methylation profiling showed epigenetic similarity of the AR-V7-positive gynecologic cancers to AR-V7-positive breast cancers rather than to prostate cancers. AR-V7 may underpin rare gynecologic carcinomas with undifferentiated histology or cribriform growth reminiscent of prostatic adenocarcinoma and breast invasive ductal carcinoma.

The molecular subtype classification of endometrial carcinomas has conceptually changed our approach to this disease. However, open questions remain about how to integrate certain histotype diagnoses with the molecular subtype. We report 2 cases with morphologic suspicion for endometrial carcinosarcoma, that still fell short of the essential criteria for diagnosing carcinosarcoma. On subsequent molecular testing pathogenic POLE mutations were detected and a descriptive diagnosis of endometrial endometrioid carcinomas, low-grade with a homologous sarcoma component was rendered. This challenges the existence of POLE-mutated "carcinosarcoma."

The clinical imaging and pathology of a rare case of immature teratoma of the placenta is presented with a discussion of controversies related to classification and clinical suggestions for therapy and follow-up.

Endometrial and endocervical polyps not uncommonly exhibit focal benign "hobnail" change/metaplasia within the glandular epithelium, sometimes in association with inflammation or infarction. In most cases, this is readily recognized as benign but occasionally, especially in endometrial polyps, this change prompts consideration of a premalignant or malignant lesion, including early serous or clear cell carcinoma. Herein we highlight the previously unreported phenomenon of positive staining of this hobnail epithelium with Napsin A which has the potential to exacerbate concern for clear cell carcinoma. Endometrial (n = 22) and endocervical (n = 17) polyps showing hobnail change were stained with Napsin A. Six cases were positive (4 of 22 endometrial and 2 of 17 endocervical polyps). In all cases, Napsin A positivity was confined to the hobnail epithelium. The hobnail epithelium was positive with estrogen receptor and hepatocyte nuclear factor 1- beta and exhibited wild-type immunoreactivity with p53 in all cases where these markers were performed. In addition, in 2 of 3 uterine adenosarcomas with focal hobnail change the epithelium was Napsin A positive. Pathologists should be aware that Napsin A may be expressed in benign/reactive hobnail epithelium in endometrial and endocervical polyps and should not consider positivity with this marker as a diagnostic of clear cell carcinoma.

Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree. Though rare, intracytoplasmic inclusions have been reported in ovarian fibromas. This study evaluates a series of torsed ovarian fibromas with intracytoplasmic inclusions resembling MDBs. Forty-three ovarian fibromas were retrieved from the pathology archives. The H&E slides were evaluated for the presence of MBD-like inclusions and histologic evidence of torsion. The cases with histologic features of torsion were included in the study group while the nontorsed fibromas formed the control group. Among the 15 cases of fibromas with torsion, MBD-like intracytoplasmic inclusions were seen in 5 cases, predominantly in the interface between necrotic areas and viable stroma. None of the cases from the control group showed any inclusions. There was no significant difference in the size of the fibroma or patient demographics between cases with and without inclusions. The inclusions were positive for cytokeratin and ubiquitin while being negative for per acidic Schiff and periodic acid-Schiff with diastase reaction, in the 3 cases selected for immunohistochemistry and special stains. Electron microscopy of the index case revealed a predominance of type 3 Mallory hyaline. This is the first report describing MDB-like inclusions in ovarian fibromas. These MDB-like inclusions appear to be limited to a fraction of ovarian fibromas that underwent torsion, suggesting that these inclusions likely result from subacute hypoxic damage to the cells.