Hiroshi Yoshida

Epithelioid leiomyosarcoma harboring HMGA2::RAD51B fusion: expanding the spectrum of RAD51B-rearranged uterine sarcoma

Impact of germline variants on breast and ovarian cancer risk in Japanese women: an original cohort study and meta-analysis

Pathogenic variants (PVs) of BRCA1 and BRCA2 predispose individuals to a higher risk of breast and ovarian cancer; however, the precise risks posed by other cancer susceptibility genes remain unclear, particularly in Asian populations. We executed a case-control study of 11 and 26 genes associated with breast and ovarian cancer susceptibility, respectively, in 7220 women with breast cancer, 2464 women with ovarian cancer, and 4032 controls from a multicentre, hospital-based registry in Japan. Furthermore, we conducted a meta-analysis of 23,193 patients with breast and/or ovarian cancer and 31,190 controls from six other hospital-based studies. Overall, 395 (5.5%) patients with breast cancer and 331 (13.4%) patients with ovarian cancer harboured PVs. Meta-analyses revealed that PVs of BRCA1, BRCA2, CHEK2, PALB2, and TP53 were associated significantly with breast cancer risk (P < 0.001), while PVs of ATM, BRCA1, BRCA2, MSH6, and RAD51D were associated significantly with ovarian cancer risk (P < 0.001). PVs in the BRCA1 DNA-binding domain were associated with a younger age at diagnosis after adjusting for cancer type and family history (β = -3.79, 95% CI = -7.16 to -0.41; P = 0.028). These results provide information about genes associated with breast and ovarian cancer risk in Asian women, as well as guidance for management of PV carriers. The study was funded by AMED (JP15ck010609, 19cm0106605h0003, 23ama221520h0001, and JP19kk0305010), by a Health Labour Sciences Research Grant (202108001B), by JSPS KAKENHI (JP18K16292, 20H03668, 23H02955, 17H06162, 20H03695, and 16H06277), and by a Grant-in-Aid for the Genome Research Project from Yamanashi Prefecture.

Underrecognized diagnostic discordance and delay in endometrial dedifferentiated and undifferentiated carcinoma

AbstractAimDedifferentiated and undifferentiated endometrial carcinoma (DC/UC) is a rare subtype of endometrial cancer characterized by undifferentiated carcinoma components. This study aimed to investigate diagnostic discrepancies and delays in DC/UC and compare them with low‐grade endometrioid carcinoma (LGEC).MethodsWe retrospectively analyzed 20 DC/UC and 40 LGEC cases finally diagnosed at our hospital (2016–2024). We compared the data of the two groups, including clinicopathologic characteristics and diagnostic intervals defined as the time from the date of initial biopsy to the date of definitive diagnosis. We assessed diagnostic discordances between preoperative diagnoses, including radiological, clinical, and biopsy, and final diagnoses with immunohistochemical analyses.ResultsDC/UC cases exhibited significantly longer diagnostic intervals (median 46 vs. 5 days, p = 0.037) and required more biopsy attempts (median two vs. 1, p = 0.002) and immunohistochemical tests (median 19 vs. 6, p = 0.001) than LGEC cases. In preoperative diagnoses, 60% of DC/UC cases showed diagnostic discrepancies. Radiological findings frequently suggested uterine sarcoma in DC/UC (30%, 6/20). Only 50% of DC/UC were suggested via initial biopsy. Immunohistochemistry revealed mismatch repair deficiency in 70% of DC/UC cases.ConclusionsFrequent diagnostic discrepancies and delays were observed in DC/UC, possibly due to its atypical imaging and histopathological features. Raising awareness of DC/UC's clinical and pathological characteristics is crucial to minimizing diagnostic delays. Given its frequency (at least 1% of endometrial cancers) and eligibility for emerging therapies, prioritizing DC/UC in differential diagnoses and improving diagnostic workflows through interdisciplinary collaboration are required for timely and effective treatment.

Ovarian Mesonephric-like Adenocarcinoma: Its Prevalence in a Japanese High-Volume Cancer Center and a Literature Review on Therapeutic Targets

Background: Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. This study aims to determine the frequency of ovarian MLA, review the existing literature, and elucidate its clinicopathological characteristics, including the potential therapeutic targets. Methods: We retrospectively reviewed the pathological diagnoses of 501 primary ovarian cancer surgical cases at our institution from 2010 to 2023. MLAs exhibiting typical morphological and immunohistochemical features were included. The frequency and clinicopathological characteristics of these cases were summarized. Additionally, we conducted a literature search using PubMed to collect and summarize previously reported cases of ovarian MLAs. Results: Among the 501 primary ovarian cancer cases, we identified 3 cases (0.6%) of MLA. The patients were 52–76 years old, and the initial FIGO stages were IC1 (two cases) and IIIB (one case). All the cases exhibited HRP, pMMR, PD-L1 negativity (CPS &lt; 1), and low HER2 expression. Two cases experienced metastatic recurrence. A literature review identified 97 cases of MLA. The MLAs frequently exhibited KRAS mutations (90%, 38/42), with a recurrence rate of 39% (26/67). Conclusion: MLAs accounted for 0.6% of malignant ovarian tumors at our institution, all of which were advanced or recurrent cases. These cases showed HRP, pMMR, and PD-L1 negativity, indicating a lack of current therapeutic targets. The literature also reported a high incidence of advanced and recurrent cases, highlighting the need for accurate diagnosis and the development of new treatments. The frequent KRAS mutations suggest a potential therapeutic target for recurrent or metastatic MLA.

Intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer: association for pathological factors and oncologic outcomes

To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression

This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

Endocrine Therapy for Endometrial Carcinoma: Current Evidence, Resistance Mechanisms, and Biomarker-Driven Patient Selection

The treatment landscape for endometrial carcinoma (EC) is undergoing a paradigm shift from traditional histopathological dualism to precision medicine grounded in the Cancer Genome Atlas (TCGA) molecular classification. The “No Specific Molecular Profile” (NSMP) subgroup, the largest molecular cohort, has emerged as a particularly promising target for endocrine-based strategies. While endocrine therapy (ET) has been a mainstay for over 60 years due to its favorable safety profile, its efficacy as monotherapy remains modest. This review provides a comprehensive overview of current endocrine strategies, including traditional agents like progestins and aromatase inhibitors, and focuses on novel combination therapies designed to overcome resistance. Recent clinical trials have demonstrated that integrating molecularly targeted agents, such as CDK4/6 and mTOR inhibitors, significantly improves clinical outcomes. Specifically, patients with TP53 wild-type status and CTNNB1 mutations exhibit exceptional responses to these combinations. Furthermore, we discuss the potential of next-generation selective estrogen receptor degraders (SERDs) and the importance of refining patient selection through robust predictive biomarkers. Driven by molecular insights, endocrine therapy is transitioning from a secondary palliative option into a definitive cornerstone of precision oncology, offering a personalized and effective treatment for patients with advanced or recurrent endometrial carcinoma.

Trend and characteristics of minimally invasive surgery for patients with endometrial cancer in Japan

Owing to the potential benefits of minimally invasive hysterectomy for endometrial cancer, the practice pattern has recently shifted in Japan. This study examined the trends in minimally invasive surgery (MIS) in patients with endometrial cancer in Japan. This retrospective observational study examined the Japan Society of Obstetrics and Gynecology Tumor Registry database between 2015-2019. This study examined the time-specific proportion change and predictors of MIS use in initial endometrial cancer treatment in Japan, and compared it with the use of abdominal surgery. Additionally, the association between hospital surgical treatment volume and MIS use was examined. A total of 14,059 patients (26.5%) underwent minimally invasive hysterectomy, and 39,070 patients (73.5%) underwent abdominal hysterectomy in the study period. Patients who underwent MIS were more likely to be treated at high-volume centers, younger, central, or western Japan residents, registered in recent years, and had a tumor with stage I disease, type 1 histology, and less myometrial invasion (all adjusted p<0.05). The proportion of MIS treatments increased from 19.1% in 2015 to 34.3% in 2019 (p<0.001). On multivariable analysis, treatment at high-volume centers was a contributing factor for MIS (adjusted odds ratio=3.85; 95% confidence interval=3.44-4.30). MIS at high-volume centers increased significantly from 24.8% to 41.0% (p<0.001) during the study period, whereas MIS at low-volume centers remained at median 8.8%. MIS has increased significantly in recent years, accounting for nearly 34% of surgical management of endometrial cancer in Japan. High-volume treatment centers take the lead in performing MIS.

Endometrioid Endometrial Carcinoma With NKX3.1 Expression in a Transgender Man: A Case Report

Endometrial cancer in transgender men is rare, and its histopathologic features remain unknown. A 30-yr-old transgender man with an intrauterine tumor, an ovarian mass, and a 2-yr history of testosterone use was referred to us for treatment. The presence of the tumors was confirmed via imaging, and the intrauterine tumor was identified as an endometrial endometrioid carcinoma via endometrial biopsy. The patient underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection. Pathologic examination revealed grade 3 endometrioid endometrial carcinoma, and the synchronous endometrial and ovarian tumors were collectively characterized as primary endometrial carcinoma. Metastatic carcinomas were discovered in both ovaries and the omentum, pelvic peritoneum, and a para-aortic lymph node. On immunohistochemistry, the tumor cells diffusely expressed p53, retained expression of PTEN, ARID1A, PMS2, and MSH6, and focally expressed estrogen receptors, androgen receptors, and NKX3.1. NKX3.1 was also expressed in glandular structures within the exocervical squamous epithelium. Prostate-specific antigen and prostatic acid phosphatase were focally positive. In conclusion, we describe a transgender man with NKX3.1-expressing endometrioid endometrial carcinoma who provides valuable suggestions regarding the effects of testosterone on endometrial cancer and appropriate gynecological care for transgender men.

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

Genetic features of endometrioid-type endometrial carcinoma arising in uterine adenomyosis

This study aimed to clarify the genetic features of endometrioid-type endometrial cancer arising in adenomyosis (EC-AIA) using targeted sequencing and immunohistochemistry (IHC) for both carcinoma and adjacent adenomyosis tissues. We identified three endometrioid-type EC-AIAs in 689 patients with endometrial cancer; two exhibited grade 3 endometrioid carcinoma. IHC revealed retained expression of PMS2, MSH6, ARID1A, and PAX2. Two of them showed diffuse strong p53 expression only in the carcinoma. PTEN expression was lost in carcinoma of only one of these cases. Carcinoma had many gene mutations than adjacent adenomyosis in all cases. KRAS and TP53 mutations were found in two of them. The other patient had mutations in KRAS, PIK3CA, and PPP2R1A. They were classified as two "p53-mutated" and one "non-specific molecular profile." These molecular alterations in endometrioid-type EC-AIA imply similar carcinogenesis to a subset of endometrial endometrioid carcinoma and might be used as targets of liquid biopsy after further validation.

Chemotherapy-associated foam cell aggregates as a prognostic factor in patients with pelvic high-grade serous carcinoma receiving neo-adjuvant chemotherapy

High-grade serous carcinoma (HGSC) tends to recur after treatment; therefore, the Chemotherapy Response Score (CRS) has been proposed as a histopathological prognostic scoring system for measuring the response to neo-adjuvant chemotherapy and the risk of recurrence. This study aimed to evaluate the CRS in only those with an R0 debulking status and to investigate new prognostic factors for progression-free survival (PFS). We reviewed the CRS of HGSC patients with R0 using surgical specimens of the omental sections. Patients were categorized according to foam cell change (FCC), defined as foam cells occupying more than half of the area of the chemotherapy-associated scar. In total, 100 HGSC patients were evaluated. PFS was significantly different according to the CRS. For CRSs of 1/2 and 3, the median PFS were 18 and 27 months, respectively (HR, 1.84; 95% CI 1.01-3.33, p = 0.045). Moreover, the FCC group showed significantly longer PFS than did the non-FCC group (20 vs 59 months; HR 2.43; 95% CI 1.15-5.14; p = 0.020). The present study validated the CRS of those in the R0 cohort. Furthermore, an increase in foam cells in the regression scar reflects the chemotherapy response and the FCC may be a useful novel prognostic factor for patients undergoing R0 resection. This finding must be further validated independently.

Development of Antibody–Drug Conjugates for Malignancies of the Uterine Corpus: A Review

Despite recent advances in cancer treatment, the prognosis for uterine malignancies (carcinoma and sarcoma) requires further improvement. Antibody–drug conjugates (ADCs) have emerged as a novel class of anti-cancer therapeutic agents, and multiple ADCs have been approved for other types of cancer. In 2024, trastuzumab deruxtecan received approval from the US Food and Drug Administration for cancer types and became the first ADC approved for the treatment of uterine malignancies. Many ADCs are currently being investigated in uterine malignancies, and therefore, there is a need to gain a deeper understanding of ADCs. In this article, we aim to provide a comprehensive overview of the advancements in ADCs. The contents of this article include the structure and mechanism of action, an analysis of recent clinical trials, and expected future clinical questions. This article also focuses on uterine sarcoma, which is not often highlighted as a target for ADC treatment.

Intraoperative peritoneal cytology for cervical gastric‐type adenocarcinoma: Cytopathology and clinical impact

AbstractBackgroundThe objective of this study was to elucidate the frequency and cytologic features of positive peritoneal washing cytology (PWC) in cervical gastric‐type adenocarcinoma (GAS) and to clarify the clinical significance of positive PWC.MethodsThe authors analyzed cases from their institution between 1991 and 2023 in which patients underwent surgery and PWC. The study included 62 patients who had cervical GAS (1991–2023; including seven patients with adenocarcinoma in situ and 26, 15, nine, and five patients with International Federation of Gynecology and Obstetrics 2018 stage I, II, III, and IV disease, respectively) and 100 patients who had usual‐type endocervical adenocarcinoma (2007–2023; including 65, 15, and 20 patients with stage I, II, and III disease, respectively). The frequency of positive PWC results and cytologic features was assessed, and correlations between positive PWC results and clinicopathologic factors were examined, including prognosis, in the GAS group.ResultsPositive PWC results were significantly more frequent in patients who had GAS at 24% (15 of 62 patients) compared with 7% (seven of 100 patients) in those who had usual‐type endocervical adenocarcinoma. The cytologic features of GAS included distinct cellular atypia (enlarged nuclei, nuclear irregularity) and frequent formation of spherical clusters (10 of 15 cases) without the golden‐yellowish mucus commonly seen in cervical smears. A positive PWC result in GAS was significantly correlated with larger tumor size, parametrium invasion, lymph node metastasis, and elevated carbohydrate antigen 19‐9 levels. In patients with stage I GAS, the PWC‐positive group had significantly shorter disease‐free survival and overall survival compared with the PWC‐negative group.ConclusionsPositive PWC findings are frequent in cervical GAS and are associated with pathologic factors indicative of tumor growth and progression. In patients who have stage I GAS, positive PWC results may indicate a poor prognosis, warranting further investigation.

HER2-negative or low expression as an unfavorable prognostic factor in patients with stage I/II uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status. HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Integrative analysis reveals early epigenetic alterations in high-grade serous ovarian carcinomas

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. To date, the profiles of gene mutations and copy number alterations in HGSOC have been well characterized. However, the patterns of epigenetic alterations and transcription factor dysregulation in HGSOC have not yet been fully elucidated. In this study, we performed integrative omics analyses of a series of stepwise HGSOC model cells originating from human fallopian tube secretory epithelial cells (HFTSECs) to investigate early epigenetic alterations in HGSOC tumorigenesis. Assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq) methods were used to analyze HGSOC samples. Additionally, protein expression changes in target genes were confirmed using normal HFTSECs, serous tubal intraepithelial carcinomas (STICs), and HGSOC tissues. Transcription factor motif analysis revealed that the DNA-binding activity of the AP-1 complex and GATA family proteins was dysregulated during early tumorigenesis. The protein expression levels of JUN and FOSL2 were increased, and those of GATA6 and DAB2 were decreased in STIC lesions, which were associated with epithelial-mesenchymal transition (EMT) and proteasome downregulation. The genomic region around the FRA16D site, containing a cadherin cluster region, was epigenetically suppressed by oncogenic signaling. Proteasome inhibition caused the upregulation of chemokine genes, which may facilitate immune evasion during HGSOC tumorigenesis. Importantly, MEK inhibitor treatment reversed these oncogenic alterations, indicating its clinical effectiveness in a subgroup of patients with HGSOC. This result suggests that MEK inhibitor therapy may be an effective treatment option for chemotherapy-resistant HGSOC.

Ovarian Mesonephric-Like Adenocarcinoma With Recurrent Liver Metastases: A Case Report with Analysis of Therapeutic Molecular Targets

Ovarian mesonephric-like adenocarcinoma (MLA) is a rare cancer subtype. We describe a patient with ovarian MLA wherein liver metastases developed 1 month after surgery. A phenotypic analysis of the tumor was performed to identify molecular therapeutic targets. A 53-year-old woman, without any symptoms, underwent uterine cancer screening. Transvaginal ultrasonography revealed an ovarian mass, and subsequent pelvic magnetic resonance imaging showed a 13 × 10 cm multicystic ovarian lesion with a solid part. No extra ovarian lesions were observed and a staging laparotomy was performed. Pathological examination revealed an MLA of the left ovary (stage IC1). The tumor comprised tumor cells in a tubular pattern with intraluminal eosinophilic material, as well as mixed glandular and papillary, cord-like, and solid patterns. Endometriosis was also observed. Immunohistochemically, the tumor cells were positive for PAX8, GATA3 (focal), TTF1 (focal), and CD10 (luminal) and negative for the estrogen receptor, progesterone receptor, and WT1. One month after surgery, computed tomography revealed multiple liver metastases. Additional immunohistochemistry for therapeutic targets revealed that the tumor cells were weakly positive for human epidermal growth factor receptor 2 (focal; score 1+), pan-tropomyosin receptor kinase-negative, programmed death-ligand 1-negative, and PMS2 and MSH6 intact. The companion homologous recombination deficiency test (MyChoice®) showed homologous recombination repair proficiency. These findings suggest that poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors may not be effective treatment options. A literature review revealed that data on therapeutic targets in MLA are scarce. In summary, we report a patient with ovarian MLA showing an aggressive clinical course and the phenotypic analysis of the tumor may contribute to the identification of therapeutic targets for MLA.

Ovarian Mucinous Tumor Presenting Atypical Lobular Endocervical Glandular Hyperplasia-Like Appearance in a Patient With Germline STK11 p.F354L Variant: A Case Report

Peutz-Jeghers syndrome (PJS) is associated with female genital lesions, such as cervical gastric-type adenocarcinoma and lobular endocervical glandular hyperplasia (LEGH). However, ovarian mucinous borderline tumors (OMBT) with atypical LEGH-like histology have not been described. The patient was a 60-year-old female with PJS clinically diagnosed at 23 years old with gastrointestinal polyposis. Abdominal distension was noted, and computed tomography scan revealed bilateral breast masses, multiple lung nodules, and a multicystic ovarian tumor. A needle biopsy revealed invasive ductal carcinoma of the breast. For the ovarian tumor, simple hysterectomy and bilateral salpingo-oophorectomy were performed. The left ovarian tumor was 25 × 20 × 12 cm in size and a multicystic tumor containing yellowish mucus without a solid part. Histologically, the cyst wall was covered with mucus cells with focal mild-to-moderate cellular atypia, forming LEGH-like architectures. The glandular cells were immunohistochemically positive for MUC5AC, MUC6 (focal), HIK1083 (focal), and HNF4α. Stromal invasion was not observed. Cervical lesions were not observed. The final pathological diagnosis was OMBT showing atypical LEGH morphology. Targeted sequencing of nontumor tissues revealed the germline STK11 p.F354L variant. Six months later, peritoneal dissemination of adenocarcinoma showing features similar to those of the ovarian tumor was observed, and the patient died of the disease. In summary, we report a case of OMBT with an atypical LEGH-like appearance in a patient with germline STK11 p.F354L variant. This case provides us with unresolved questions regarding the pathogenicity of this STK11 variant and the malignant potential of OMBT with this unusual morphology.

Gross mucinous multinodular appearance aids in the identification of ovarian metastases in low-grade appendiceal mucinous neoplasms during intraoperative consultation

Ovarian metastases of low-grade appendiceal mucinous neoplasms (LAMNs) show grossly abundant nodular mucous cells, with a gross mucinous multinodular appearance and a histological resemblance to primary ovarian mucinous tumors (POMTs). This study aimed to elucidate the utility of gross features including the gross mucinous multinodular appearance and available clinical information at the time of intraoperative consultation, in distinguishing the ovarian metastases of LAMNs from POMTs or the ovarian metastases of colorectal cancer (CRC). In total, 776 patients with primary ovarian tumor and 68 patients with ovarian metastases underwent intraoperative consultation during 1998-2018. Of the total cases, 4 ovarian metastases of LAMNs, 19 ovarian metastases of CRC, and 50 POMTs (36 borderline tumors and 14 carcinomas) were identified. The gross features including the gross mucinous multinodular appearance were analyzed based on the gross photographs obtained before formalin fixation and the available clinical information collected during intraoperative consultation. The analysis indicated that the ovarian metastases of LAMNs significantly presented with gross mucinous multinodular appearance (4/4 vs. 0/50, P < 0.0001), extraovarian disease (4/4 vs. 2/50, P < 0.0001), ovarian surface involvement (3/4 vs. 2/50, P = 0.0016), and abnormal appendix (4/4 vs. 0/50, P < 0.0001) as compared to POMT. Moreover, the gross mucinous multinodular appearance was a distinguishable feature between the ovarian metastases of LAMNs and ovarian metastases of CRC (4/4 vs. 0/19, P = 0.0001). Based on these results, we proposed an algorithm to diagnose ovarian tumors using the gross mucinous multinodular appearance. Thus, recognizing unique gross features including the gross mucinous multinodular appearance would be useful for both pathologists and surgeons to accurately diagnose ovarian metastases of LAMNs during intraoperative consultation.

Diagnostic Discordance in Intraoperative Frozen Section Diagnosis of Ovarian Tumors: A Literature Review and Analysis of 871 Cases Treated at a Japanese Cancer Center

Background This study examined the accuracy and pitfalls associated with frozen section diagnosis of primary ovarian tumors and ovarian metastases based on the 2014 World Health Organization classification (WHO) criteria and proposed improvements from a pathologist’s perspective. Methods We microscopically reviewed 871 cases of primary ovarian tumor (N = 802) and ovarian metastasis (N = 69) and compared the results of frozen sections with the final diagnosis. Malignant potential concordance (benign, borderline, or malignant) and specific discordant diagnosis rates were analyzed. Finally, we conducted a unique literature review of specific diagnostic errors in the frozen section diagnosis of primary ovarian tumors. Results Of 802 primary ovarian tumors, 50 (6.2%) cases showed discordant diagnoses in which mucinous carcinoma (40.5%), low-grade serous carcinoma (LGSC; 31.3%), and mucinous borderline tumor (18.4%) were frequently misinterpreted. Of 69 ovarian metastases, all 4 cases of low-grade appendiceal mucinous neoplasm (LAMN) were misdiagnosed as primary ovarian mucinous tumor. A literature review revealed that mucinous/serous borderline tumor or carcinoma accounted for approximately 70% of 217 reported discordant diagnoses. Conclusion In the present study, the concordance rate of malignant potential of the tumor was comparable to that previously reported. Even in the 2014 WHO classification, primary ovarian mucinous borderline tumor/carcinoma and LGSC still comprised the majority of discordant cases. Grossing methods that reduce sampling error are required. LAMN was frequently misinterpreted as a benign or borderline ovarian mucinous tumor. To prevent this error, a differential algorithm integrating clinical information and gross findings should be developed.

Efficacy of ascitic fluid cell block for diagnosing primary ovarian, peritoneal, and tubal cancer in patients with peritoneal carcinomatosis with ascites

To compare the efficacy of ascitic fluid cell block (ACB) with that of core needle biopsy (CNB) or the CA125/CEA ratio in diagnosing primary tubo-ovarian cancer in female patients with peritoneal carcinomatosis (PC) with ascites. This retrospective study examined female patients with PC with ascites who had available results for ACB, peritoneal tumor CNB, and the CA125/CEA ratio. Several measures of the accuracy of ACB and the CA125/CEA ratio were calculated and compared, with CNB as the reference standard. Of 81 patients with available results, 57 were clinically diagnosed with primary tubo-ovarian cancer. Overall, 52, 47, and 64 patients were diagnosed via CNB, ACB, and CA125/CEA ratio > 25, respectively. CNB and ACB identified the cancer origin in 91.4% and 82.7% cases, respectively. The concordance ratio of the immunohistochemical findings between ACB and CNB was 93.6%. Two patients with inconclusive CNB results were diagnosed with primary tubo-ovarian cancer via ACB. The sensitivity, specificity, positive predictive value, negative predictive value, and positive likelihood ratio were 86.5%, 93.1%, 95.7%, 79.4%, and 12.5, respectively, for ACB and 94.2%, 48.3%, 76.6%, 82.4%, and 1.82, respectively, for CA125/CEA ratio > 25. ACB is not inferior to CNB in diagnosing primary tubo-ovarian cancer; the two methods complement each other. ACB can substitute CNB in diagnosing primary tubo-ovarian cancer in selected PC patients. ACB is superior to a CA125/CEA ratio of >25 in diagnosing primary tubo-ovarian cancer. ACB is effective, reliable, and convenient for diagnosing primary tubo-ovarian cancer in PC patients with ascites.

Microcystic stromal tumor of the ovary: a recurrent case with somatic CTNNB1 missense mutation

Microcystic stromal tumors (MCSTs) of the ovary are rare sex cord-stromal tumors that are considered benign neoplasms because almost all cases display unilateral, localized lesions and have benign outcomes, except for one recurrent case with familial adenomatous polyposis and another initial metastatic case with a CTNNB1 mutation. We report herein a sporadic case that relapsed as intra-abdominal spread 9 years and 1 month after primary left salpingo-oophorectomy for torsion of the ovarian tumor pedicle. The tumor relapsed as multiple disseminations at the subabdominal wall, Douglas pouch, and omentum. Histologically, the tumor cells formed microcysts and infiltrated the surrounding adipose tissue, similar to the invasive implants of ovarian epithelial borderline tumors. Mutation analysis of the recurrent tumor revealed a somatic CTNNB1 p.S33Y activated missense mutation and a germline KDR p.Q472H variant. In conclusion, long-term clinical follow-up may be needed to detect any recurrence of MCST, irrespective of familial adenomatous polyposis.

Uterine Leiomyosarcoma Masquerading as a Malignant Perivascular Epithelioid Cell Tumor: A Diagnostic Challenge

Uterine sarcomas with myomelanocytic differentiation have been reported to be diagnostically challenging. We report a case of uterine leiomyosarcoma with extensive perivascular epithelioid cell tumor (PEComa)-like areas and extrauterine metastases. The patient was a 49-year-old gravida 3 para 2 Japanese woman with no relevant medical history. She noticed a vaginal mass with bleeding. Imaging examination revealed a uterine tumor and multiple liver and lung metastases. The vaginal tumor (3.5 cm) was resected and diagnosed as a malignant PEComa based on morphology and myomelanocytic marker expression. Clinically used targeted sequencing (FoundationOneCDx™) revealed gene alterations in RB1, TP53, and ATRX but not TSC1/2. Despite administration of an mTOR inhibitor, the tumor size increased, and subsequently, hysterectomy was performed to relieve the symptoms. The uterine tumor was composed of conventional leiomyosarcoma showing RB1 loss, wild-type TP53 staining, and retained ATRX expression, as well as adjacent predominant PEComa-like components with RB1 loss, TP53 overexpression, and ATRX loss, identical to the characteristics of the vaginal tumor. In the uterine tumor, both HMB-45 and MITF were weak to moderately positive for approximately 40% of tumor cells while Melan-A was negative. The tumor was finally diagnosed as leiomyosarcoma with PEComa-like features. This case exemplifies the tumorigenesis of diagnostically challenging tumors with myomelanocytic differentiation and demonstrates the importance of integrating multiple types of information, including genomic profiling, in making a correct diagnosis leading to appropriate treatment.

TP53 Mutations and PD-L1 Amplification in Vulvar Adenocarcinoma of the Intestinal Type: Insights From Whole Exome Sequencing of 2 Cases

Vulvar adenocarcinoma of the intestinal type (VAIt) is a rare subtype of primary vulvar carcinoma, with ∼30 cases documented in the English literature. This study presents 2 new cases of HPV-independent VAIt with lymph node metastasis and discusses their clinical presentation, histopathologic features, and whole exome sequencing (WES) analysis. Both cases exhibited histologic features consistent with VAIt, including tubular, papillary, and mucinous carcinoma components. Immunohistochemical analysis showed p16 patchy staining, CDX2, CK20, and SATB2 positivity, while being negative for ER, PAX8, and CK7. WES revealed pathogenic TP53 mutations in both cases, accompanied by distinct additional mutations (GRIN2A and KDM6A in Case #1; CHD4 in Case #2). Common copy number alterations (CNAs) included TP53 loss of heterozygosity and CD274/PD-L1 amplification. However, other CNAs varied between the cases. Immunohistochemistry for p53 suggests the presence of both wild-type and mutant subclones, indicating that TP53 abnormalities may be acquired during tumor progression. Both tumors showed mutational signatures SBS1 and SBS5, associated with aging and DNA damage. Our findings deepen the understanding of the genetic events involved in the tumorigenesis of HPV-independent VAIt. Given the TP53 abnormalities and CD274/PD-L1 amplification, emerging p53-based therapies and immune checkpoint inhibitors may represent potential treatment targets. While these findings contribute to the understanding of VAIt tumorigenesis, further research is required to validate these observations in a larger cohort.

Bartholin's glands commonly express NKX3.1: reconsideration of “prostatic differentiation” in gynaecological pathology

Gastric-type cervical adenocarcinoma with squamous differentiation: buried in adenosquamous carcinomas?

Gastric-type adenocarcinoma (GAS) of the cervix is a human papilloma virus (HPV)-independent, aggressive, and chemo-resistant adenocarcinoma. However, although the histopathological features of GAS have been extensively investigated, squamous differentiation has not been mentioned. This study aimed to elucidate the frequency of GAS with squamous differentiation and describe their clinicopathological characteristics. We retrospectively evaluated 78 patients with GAS (n = 13) and adenosquamous carcinoma (n = 65) diagnosed between 2000 and 2020. Two patients with GAS with squamous differentiation were identified. Both tumors showed advanced stage (pT2bN1) and had predominant GAS and merged squamous cell carcinoma components without p16-block positivity and HPV DNA. Gastric-type adenocarcinoma in situ was confirmed in both cases. Some cases of GAS could show squamous differentiation mimicking the usual, HPV-associated, adenosquamous carcinoma. GAS with squamous differentiation is recognized as an HPV-independent cancer.

Adenoid Basal Carcinoma with Adenoid Cystic Carcinoma Component of the Uterine Cervix: A Case Report and Literature Review

Adenoid basal carcinoma (ABC) is rare cancer with a favorable prognosis. However, some ABCs are associated with other histological types, such as squamous cell carcinoma. Here, we present a case of a mixed tumor of ABC and adenoid cystic carcinoma (ACC) of the cervix, with a detailed immunohistochemical study and literature review. We describe a case of a 66-year-old woman who underwent cervical cancer screening that led to the detection of a 0.7 cm nodular lesion. Cervical punch biopsies revealed a high-grade squamous intraepithelial lesion. Cervical conization revealed a mixed carcinoma composed of ABC and ACC, showing stromal invasion, lymphovascular invasion, and positive resection margins. Immunohistochemically, the ACC components were positive for KIT and αSMA and negative for NKX3.1. The tumor presented with proficient mismatch repair (MMR) and was negative for HER2, PD-L1, and TRKA (NTRK1). Subsequent radical hysterectomy with pelvic lymph node dissection revealed the presence of residual tumor cells in the cervix. Our literature review identified six similar cases, including one patient who died of disease recurrence. We report a rare tumor comprising both ABC and ACC. Prognostic data on mixed tumors are scarce; however, given the aggressive nature of ACC, attention should be paid to the detection of mixed tumors. Since ABC and ACC histology may overlap, adequate sampling and IHC for detecting ACC would be helpful.

Antitumor Effect of Farletuzumab Ecteribulin in Molecular Subtypes of Endometrial Cancer Patient-Derived Xenograft Models

Abstract Endometrial cancer represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage endometrial cancer remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody–drug conjugate targeting folate receptor α (FRα), as a potential new therapeutic agent for endometrial cancer. We utilized a panel of 22 patient-derived xenograft (PDX) models, representing various histologic and molecular subtypes of endometrial cancer with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 and 12.5 mg/kg on day 0. Intratumoral accumulation of eribulin, the payload of FZEC, was visualized using phosphor-integrated dot imaging. FZEC demonstrated dose-dependent antitumor effects across the endometrial cancer–PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared with 33.3% of FRα-negative models. FZEC also demonstrated broad activity across both histologic and molecular subtypes. Intratumoral eribulin accumulation was highly correlated with antitumor effects, even in models with low FRα expression. Follow-up studies confirmed FRα-dependent antitumor effects while also indicating potential FRα-independent mechanisms of action. FZEC demonstrated a robust antitumor effect against the FRα-high endometrial cancer–PDX models with significant antitumor effects also observed, even in FRα-low or FRα-negative models. Notably, intratumoral eribulin accumulation exhibited a stronger correlation with efficacy than with FRα expression alone. These findings support further clinical development of FZEC for endometrial cancer treatment and highlight the complexity of the mechanisms of action of antibody–drug conjugates.

TP53 gene and pathway alterations in gastric-type adenocarcinoma of the cervix

Abstract Background Human papillomavirus infection contributes to the development of almost all cervical malignancies, aside from gastric-type adenocarcinoma of the cervix, a rare aggressive subtype without human papillomavirus infection. Methods To address the carcinogenic mechanism of this disease, we performed a comparative multi-omics analysis of gastric-type adenocarcinoma of the cervix and usual-type endocervical adenocarcinoma in 3 independent cohorts of patients with gastric-type adenocarcinoma of the cervix and usual-type endocervical adenocarcinoma. The first cohort comprised 8 gastric-type adenocarcinoma of the cervix and 22 patients with usual-type endocervical adenocarcinoma treated at the National Cancer Center Hospital between 2002 and 2020, who were examined by targeted and whole transcriptome sequencing. The other 2 cohorts comprised 52 patients with gastric-type adenocarcinoma of the cervix and 109 patients with usual-type endocervical adenocarcinoma and 39 patients with gastric-type adenocarcinoma of the cervix and 232 patients with usual-type endocervical adenocarcinoma, whose mutational data were obtained from the Center for Cancer Genomics and Advanced Therapeutics (Japanese patients) and Genomics Evidence Neoplasia Information Exchange (US patients) public databases, respectively. Metabolomic analysis was performed in 8 patients, including 5 with gastric-type adenocarcinoma of the cervix. Results TP53 mutations were more prevalent in gastric-type adenocarcinoma of the cervix than in usual-type endocervical adenocarcinoma in all 3 cohorts. Transcriptome analysis consistently revealed frequent suppression of TP53-related pathways in gastric-type adenocarcinoma of the cervix. Metabolites preferentially detected in gastric-type adenocarcinoma of the cervix tissues suggest TP53 alterations are implicated in intratumoral metabolic properties. Conclusion The development of gastric-type adenocarcinoma of the cervix is likely driven by TP53 mutations, which play a large role in shaping intracellular signaling and metabolic profiles within tumor cells.

Establishing a comprehensive panel of patient-derived xenograft models for high-grade endometrial carcinoma: molecular subtypes, genetic alterations, and therapeutic target profiling

High-grade endometrial cancer (EC) has a poor prognosis, but molecular classification-based treatments present new therapeutic opportunities. Antibody-drug conjugates (ADC) emerge as promising tools, yet a deeper understanding of antigen dynamics, optimal therapeutic sequencing, and resistance mechanisms is essential. This study investigates the utility of patient-derived xenograft (PDX) models for EC as preclinical platforms, evaluating molecular subtypes and the ADC targets expression of patient and PDX tumors. We developed a comprehensive panel of molecularly characterized PDX models from patients with EC representing various histological types. Molecular subtypes and gene alterations were analyzed using sequencing and immunohistochemistry. ADC targets, including human epidermal growth factor receptor 2, trophoblast cell-surface antigen 2, B7-H4, folate receptor alpha, and cadherin-6, were profiled. Thirty-one EC-PDX models were successfully established, maintaining histological fidelity and 93.1 % molecular subtype consistency with the patient tumors. Notably, 80.6 % of the PDX models exhibited high expression (2+/3+) of at least one ADC target, and 54.8 % displayed high expression of multiple targets. Remarkably, 9.7 % showed high expression of all targets, with gene mutations also characterized. Meanwhile, patient tumors, 78.8 % showed high expression (2+/3+) of at least one ADC target, and 63.6 % showed high expression of multiple targets. The molecularly classified EC-PDX panel, enriched with detailed antigen profiles and genetic data, provides a robust platform for investigating novel ADC therapies and precision treatment strategies for high-grade EC.

Single‐Nucleus RNA Sequencing and Spatial Transcriptomics for Squamous Cell Carcinoma Arising From Ovarian Mature Teratoma

ABSTRACTSquamous cell carcinoma arising from mature teratoma (SCC‐MT) is a rare ovarian malignancy. The detailed molecular pathology of SCC‐MT is not well understood. Moreover, the prognosis of the patients remains poor because no standard treatment has been established. In this study, we performed single‐nucleus RNA sequencing and spatial transcriptomics using clinical SCC‐MT samples to identify novel therapeutic candidates. snRNA‐seq revealed three epithelial cell clusters, of which one was significantly associated with epidermis and keratinocyte development. Moreover, spatial transcriptomics revealed that the epithelial‐mesenchymal transition was significantly inhibited, and the MYC and E2F targets were significantly activated in cancer spots on specimen sections. We focused on KLF5, which was one of the upregulated genes in cancer cells, and performed a functional analysis using NOSCC‐1, a cell line derived from an SCC‐MT. KLF5 downregulation significantly decreased cell proliferation and increased apoptosis. Furthermore, we previously identified miR‐145‐5p as a downregulated miRNA in SCC‐MT. We demonstrated that miR‐145‐5p overexpression attenuated cell proliferation and decreased KLF5 expression. In conclusion, through multi‐omics analyses, we identified unique gene expression profiles of SCC‐MT and determined a role for KLF5 in SCC‐MT development. Therefore, KLF5‐related factors may be novel therapeutic targets, and further studies are needed to improve the diagnosis and treatment of SCC‐MT.

Prevalence and outcomes of germline pathogenic variants of homologous recombination repair genes in ovarian cancer

AbstractGermline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR‐related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR‐related PVs were examined. Kaplan–Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR‐related. HRR‐PV‐positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P &lt; 0.0001) and advanced disease (18.5% vs. 5.9%, P &lt; 0.0001). The HRR‐PV‐positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression‐free survival. HRR‐related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000–2019), the limited use of bevacizumab and poly (ADP‐ribose) polymerase inhibitors as maintenance therapy should be recognized.

Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers

The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer

AbstractThe clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5‐year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5‐year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log‐rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.