Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.
Female ; Humans ; Middle Aged ; Class I Phosphatidylinositol 3-Kinases/metabolism* ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis* ; DNA Mismatch Repair/genetics* ; Endometrial Neoplasms/pathology* ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2/genetics* ; Molecular Typing

OBJECTIVES: To uncover gynecologic conditions with similar transvaginal sonographic findings of thick uterine endometrium with honeycomb appearance in pre-and postmenopausal women.METHODS: We retrospectively reviewed cases of patients with endometrial tissue biopsy from January 2010 to December 2016. We also collected office flexible hysteroscopic findings and surgical pathologic results. We analyzed data from 393 patients with confirmed endometrial pathology. Among these patients, 69 had transvaginal ultrasonographic images with thick uterine endometrium and honeycomb or “Swiss cheese” appearance.RESULTS: We found gynecologic conditions such as submucosal leiomyoma with degeneration, endometrial polyp, pseudocystic endometrial change associated with tamoxifen use, progesterone associated endometrial change, pyometra, retained placenta, and uterine synechiae manifested with similar thick endometrium with “Swiss cheese” appearance in transvaginal sonographic images. The most common diagnosis in postmenopausal women was atrophic endometritis, followed by endometrial cancer and endometrial polyps. The most common diagnosis in premenopausal women was abnormal uterine bleeding without pathologic conditions.CONCLUSIONS: Sonographic findings of thick uterine endometrium with “Swiss cheese” appearance need to be considered together with a thorough review of the patient's history and chief complaint before making a tentative diagnosis due to the various conditions sharing the feature.
Biopsy ; Diagnosis ; Endometrial Neoplasms ; Endometritis ; Endometrium ; Female ; Gynatresia ; Humans ; Hyperplasia ; Leiomyoma ; Menopause ; Pathology ; Placenta, Retained ; Polyps ; Progesterone ; Pyometra ; Retrospective Studies ; Tamoxifen ; Ultrasonography ; Uterine Hemorrhage

OBJECTIVE: To assess the clinical usefulness and diagnostic accuracy of ultrasonographic measurement of endometrial thickness (ET) in women with endometrial hyperplasia or cancer (EH+). METHODS: This retrospective cohort study included 29,995 consecutive women who underwent transvaginal ultrasonography (TVS) for an incidental finding of a thickened endometrium at the health screening and promotion center at Asan Medical Center between 2006 and 2010. Among 959 patients with endometrial abnormalities, 92 patients were included in this study. A total of 867 patients were excluded: 416 were lost to follow-up; 263 did not undergo endometrial biopsy; 155 had endometrial polyps; 17 had submucosal myomas; and 16 had insufficient tissue samples. Endometrial histology was the reference standard for calculating accuracy. RESULTS: Of the 92 patients, 78 (84.8%) had normal pathology, while 14 (15.2%) had endometrial pathology (EH+), including 5 patients (35.7%) with simple hyperplasia without atypia, 3 (21.4%) with complex hyperplasia, and 6 (42.9%) with endometrial carcinoma, all stage Ia. The area under the receiver-operating characteristic curve was 0.75 (95% confidence interval [CI], 0.593–0.906). The cut-off value for ET was 8 mm, indicating that TVS ET had a fair accuracy in diagnosing carcinoma, had a sensitivity of 100% (95% CI, 62.9–100.0%) and a specificity of 24.3% (95% CI, 15.2–36.3%). CONCLUSION: TVS is useful for detecting EH+, with a cut-off value for ET of 8 mm having a high sensitivity for detecting endometrial pathologies and the ability to identify women highly unlikely to have EH+, thereby avoiding more invasive endometrial biopsy.
Biopsy ; Chungcheongnam-do ; Cohort Studies ; Diagnosis ; Endometrial Hyperplasia ; Endometrial Neoplasms ; Endometrium ; Female ; Humans ; Hyperplasia ; Incidental Findings ; Lost to Follow-Up ; Mass Screening ; Myoma ; Pathology ; Polyps ; Retrospective Studies ; Sensitivity and Specificity ; Ultrasonography

OBJECTIVE: To describe the endometrial pathologic lesions in premenopausal breast cancer patients with a history of tamoxifen (TMX) use. METHODS: We retrospectively reviewed the medical records of 120 premenopausal breast cancer patients with a history of TMX use that had undergone a gynecological examination. RESULTS: Among 120 patients, 44.2% (n=53) were asymptomatic with an endometrial thickness ≥5 mm, as assessed by transvaginal ultrasonography. Of the patients that reported abnormal uterine bleeding, 5% (n=6) had an endometrial thickness <5 mm and 20% (n=24) had an endometrial thickness ≥5 mm by transvaginal ultrasonography. The final group of patients were asymptomatic, but showed an abnormal endometrial lesion, such as an endometrial polyp, by transvaginal ultrasonography (30.8%, n=37). Of the 56 benign lesions that were histologically reviewed, 50 (41.7%) were endometrial polyps, 3 (2.5%) were submucosal myomas, 2 (1.7%) were endometrial hyperplasias, and 1 (0.8%) was chronic endometritis. There were 64 (53.3%) other non-pathologic conditions, including secreting, proliferative, and atrophic endometrium, or in some cases, there was insufficient material for diagnosis. In our data, only one case was reported as a complex hyperplasia without atypia arising from an endometrial polyp, and one patient was diagnosed with endometrioid adenocarcinoma. CONCLUSION: For premenopausal breast cancer patients with a history of TMX use, the majority of the patients were asymptomatic, and endometrial polyps were the most common endometrial pathology observed. Therefore, we believe that endometrial assessment before starting TMX treatment, and regular endometrial screening throughout TMX treatment, are reasonable suggestions for premenopausal breast cancer patients.
Breast Neoplasms* ; Breast* ; Carcinoma, Endometrioid ; Diagnosis ; Endometrial Hyperplasia ; Endometritis ; Endometrium ; Female ; Gynecological Examination ; Humans ; Hyperplasia ; Hysteroscopy ; Mass Screening ; Medical Records ; Myoma ; Pathology ; Polyps* ; Retrospective Studies ; Tamoxifen* ; Ultrasonography ; Uterine Hemorrhage

OBJECTIVE: The aim of this paper was to demonstrate the techiniqes of single-port laparoscopic transperitoneal infrarenal paraaortic lymphadenectomy as part of surgical staging procedure in case of early ovarian cancer and high grade endometrial cancer. METHODS: After left upper traction of rectosigmoid, a peritoneal incision was made caudad to inferior mesenteric artery. Rectosigmoid was mobilized, and then the avascular space of the lateral rectal portion was found by using upward traction of rectosigmoid mesentery. Inframesenteric nodes were removed without injury to the ureter and the left common iliac nodes were easily removed due to the upward traction of the rectosigmoid. The superior hypogastric plexus was found overlying the aorta and sacral promontory, and presacral nodes were removed at subaortic area. Peritoneal traction suture to right abdomen was needed for right para-aortic lymphadenectomy. After right lower para-aortic node dissection, operator was situated between the patient's legs. After upper traction of the small bowel, left upper para-aortic nodes were removed. To prevent chylous ascites, we used hemolock or Ligasure application (ValleyLab Inc.) to upper part of infrarenal and aortocaval nodes. RESULTS: Single-port laparoscopic transperitoneal infrarenal para-aortic lymphadenectomy was performed without serious perioperative complications. CONCLUSION: Even though the technique of single-port surgery is still a difficult operation, the quality of single-port laparoscopic transperitoneal infrarenal para-aortic node dissection is excellent, especially mean number of para-aortic nodes. In cases of staging procedures for ovary and endometrial cancer, single-port transperitoneal para-aortic lymphadenectomy is acceptable as an oncologic procedure.
Endometrial Neoplasms/diagnosis/*pathology ; Female ; Humans ; Laparoscopy/adverse effects/methods ; Lymph Node Excision/adverse effects/*methods ; Neoplasm Staging/adverse effects/methods ; Ovarian Neoplasms/diagnosis/*pathology

BACKGROUNDLiquid-based cytology (LBC) offers an alternative method to biopsy in screening endometrial cancer. Cell block (CB), prepared by collecting residual cytological specimen, represents a novel method to supplement the diagnosis of endometrial cytology. This study aimed to compare the specimen adequacy and diagnostic accuracy of LBC and CB in the diagnosis of endometrial lesions.

METHODSA total of 198 women with high risks of endometrial carcinoma (EC) from May 2014 to April 2015 were enrolled in this study. The cytological specimens were collected by the endometrial sampler (SAP-1) followed by histopathologic evaluation of dilatation and curettage or biopsy guided by hysteroscopy. The residual cytological specimens were processed into paraffin-embedded CB after LBC preparation. Diagnostic accuracies of LBC and CB for detecting endometrial lesions were correlated with histological diagnoses. Chi-square test was used to compare the specimen adequacies of LBC and CB.

RESULTSThe specimen inadequate rate of CB was significantly higher than that of LBC (22.2% versus 7.1%, P < 0.01). There were 144 cases with adequate specimens for LBC and CB preparation. Among them, 29 cases were atypical endometrial hyperplasia (11 cases) or carcinoma (18 cases) confirmed by histology evaluation. Taking atypical hyperplasia and carcinoma as positive, the diagnostic accuracy of CB was 95.1% while it was 93.8% in LBC. When combined LBC with CB, the diagnostic accuracy was improved to 95.8%, with a sensitivity of 89.7% and specificity of 97.4%.

CONCLUSIONSCB is a feasible and reproducible adjuvant method for screening endometrial lesions. A combination of CB and LBC can improve the diagnostic accuracy of endometrial lesions.

Adult ; Aged ; Biopsy ; methods ; Cross-Sectional Studies ; Cytodiagnosis ; methods ; Early Detection of Cancer ; methods ; Endometrial Hyperplasia ; diagnosis ; Endometrial Neoplasms ; diagnosis ; Endometrium ; pathology ; Female ; Humans ; Middle Aged ; Sensitivity and Specificity ; Specimen Handling

OBJECTIVE: Recent investigations have revealed DNA mismatch repair (MMR) gene mutations are closely related with carcinogenesis of endometrial cancer; however the impact of MMR protein expression on prognosis is not determined. Correlations between MMR-related protein expression and clinicopathological factors of endometrial cancers are analyzed in the present study. METHODS: A total of 191 endometrial cancer tissues treated between 1990 and 2007 in our hospital were enrolled. Immunoreactions for MSH2, MLH1, MSH6, and PMS2 on tissue microarray specimens and clinicopathological features were analyzed retrospectively. RESULTS: Seventy-six cases (40%) had at least one immunohistochemical alteration in MMR proteins (MMR-deficient group). There were statistically significant differences of histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and histological grade between MMR-deficient group and the other cases (MMR-retained group). Response rate of first-line chemotherapy in evaluable cases was slightly higher in MMR-deficient cases (67% vs. 44%, p=0.34). MMR-deficient cases had significantly better progression-free and overall survival (OS) compared with MMR-retained cases. Multivariate analysis revealed MMR status was an independent prognostic factor for OS in endometrial cancers. CONCLUSION: MMR-related proteins expression was identified as an independent prognostic factor for OS, suggesting that MMR was a key biomarker for further investigations of endometrial cancers.
Adaptor Proteins, Signal Transducing/deficiency/metabolism ; Adenosine Triphosphatases/deficiency/metabolism ; Adult ; Aged ; Aged, 80 and over ; Chemotherapy, Adjuvant ; *DNA Mismatch Repair ; DNA Repair Enzymes/deficiency/*metabolism ; DNA-Binding Proteins/deficiency/*metabolism ; Endometrial Neoplasms/*diagnosis/drug therapy/genetics/pathology ; Female ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; MutS Homolog 2 Protein/deficiency/metabolism ; Neoplasm Proteins/deficiency/metabolism ; Nuclear Proteins/deficiency/metabolism ; Prognosis ; Retrospective Studies ; Tumor Markers, Biological/*metabolism

OBJECTIVE: We investigated the features of endometrial hyperplasia with concurrent endometrial cancer that had been diagnosed by endometrial sampling. Further, we attempted to identify an accurate differential diagnostic method. METHODS: We retrospectively studied 125 patients who underwent a diagnostic endometrial biopsy or were diagnosed after the surgical treatment of other gynecological lesions, such as leiomyoma or polyps. Patients were diagnosed between January 2005 and December 2013 at Busan Paik Hospital. Clinical and histopathological characteristics were compared in patients who had atypical endometrial hyperplasia with and without concurrent endometrial cancer. RESULTS: The patients were grouped based on the final pathology reports. One hundred seventeen patients were diagnosed with endometrial hyperplasia and eight patients were diagnosed with endometrioid adenocarcinoma arising from atypical hyperplasia. Of the 26 patients who had been diagnosed with atypical endometrial hyperplasia by office-based endometrial biopsy, eight (30.8%) were subsequently diagnosed with endometrial cancer after they had undergone hysterectomy. The patients with endometrial cancer arising from endometrial hyperplasia were younger (39.1 vs. 47.2 years, P=0.0104) and more obese (body mass index 26.1+/-9.6 vs. 23.8+/-2.8 kg/m2, P=0.3560) than the patients with endometrial hyperplasia. The correlation rate between the pathology of the endometrial samples and the final diagnosis of endometrial hyperplasia was 67.3%. CONCLUSION: In patients with atypical endometrial hyperplasia, the detection of endometrial cancer before hysterectomy can decrease the risk of suboptimal treatment. The accuracy of endometrial sampling for the diagnosis of concurrent endometrial carcinoma was much lower than that for atypical endometrial hyperplasia. Therefore, concurrent endometrial carcinoma should be suspected and surgical intervention should be considered in young or obese patients who present with atypical endometrial hyperplasia.
Biopsy* ; Busan ; Carcinoma, Endometrioid ; Diagnosis ; Endometrial Hyperplasia ; Endometrial Neoplasms* ; Female ; Humans ; Hyperplasia* ; Hysterectomy ; Leiomyoma ; Pathology ; Polyps ; Retrospective Studies

In 2014, 9 topics were selected as major advances in clinical research for gynecologic oncology: 2 each in cervical and corpus cancer, 4 in ovarian cancer, and 1 in breast cancer. For cervical cancer, several therapeutic agents showed viable antitumor clinical response in recurrent and metastatic disease: bevacizumab, cediranib, and immunotherapies including human papillomavirus (HPV)-tumor infiltrating lymphocytes and Z-100. The HPV test received FDA approval as the primary screening tool of cervical cancer in women aged 25 and older, based on the results of the ATHENA trial, which suggested that the HPV test was a more sensitive and efficient strategy for cervical cancer screening than methods based solely on cytology. For corpus cancers, results of a phase III Gynecologic Oncology Group (GOG) 249 study of early-stage endometrial cancer with high-intermediate risk factors are followed by the controversial topic of uterine power morcellation in minimally invasive gynecologic surgery. Promising results of phase II studies regarding the effectiveness of olaparib in various ovarian cancer settings are summarized. After a brief review of results from a phase III study on pazopanib maintenance therapy in advanced ovarian cancer, 2 outstanding 2014 ASCO presentations cover the topic of using molecular subtypes in predicting response to bevacizumab. A review of the use of opportunistic bilateral salpingectomy as an ovarian cancer preventive strategy in the general population is presented. Two remarkable studies that discussed the effectiveness of adjuvant ovarian suppression in premenopausal early breast cancer have been selected as the last topics covered in this review.
Biomedical Research/*trends ; Endometrial Neoplasms/drug therapy/pathology/surgery ; Female ; Genital Neoplasms, Female/diagnosis/*therapy ; Humans ; Ovarian Neoplasms/drug therapy/pathology/surgery ; Uterine Cervical Neoplasms/drug therapy/pathology/surgery

OBJECTIVE: The aim of this study was to estimate the survival impact of lymphadenectomy in patients diagnosed with uterine clear cell cancer (UCCC). METHODS: Patients with a diagnosis of UCCC were identified from Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t-test, Kaplan-Meier survival methods, and Cox proportional hazard regression were performed. RESULTS: One thousand three hundred eighty-five patients met the inclusion criteria; 955 patients (68.9%) underwent lymphadenectomy. Older patients (> or =65) were less likely to undergo lymphadenectomy compared with their younger cohorts (64.3% vs. 75.9%, p<0.001). The prevalence of nodal metastasis was 24.8%. Out of 724 women who had disease clinically confined to the uterus and underwent lymphadenectomy, 123 (17%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival. Patients who underwent lymphadenectomy were 39% (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52 to 0.72; p<0.001) less likely to die than patient who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared to patients with 0 nodes removed, patients with more extensive lymphadenectomy (1 to 10 and >10 nodes removed) were 32% (HR, 0.68; 95% CI, 0.56 to 0.83; p<0.001) and 47% (HR, 0.53; 95% CI, 0.43 to 0.65; p<0.001) less likely to die, respectively. CONCLUSION: The extent of lymphadenectomy is associated with an improved survival of patients diagnosed with UCCC.
Adenocarcinoma, Clear Cell/*diagnosis/mortality/pathology/*surgery ; Adult ; Aged ; Aged, 80 and over ; Endometrial Neoplasms/*diagnosis/mortality/pathology/*surgery ; Female ; Humans ; *Lymph Node Excision ; Lymphatic Metastasis ; Middle Aged ; Pelvis ; Prognosis ; Retrospective Studies ; Survival Rate ; Uterine Neoplasms/diagnosis/mortality/pathology/surgery