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

BACKGROUND: The 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. METHODS: The 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. RESULTS: Positive 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. CONCLUSIONS: Positive 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.

Endometrial cancer and endometrial changes in transgender men: Insights from Japanese individuals on testosterone.

AIM: Endometrial changes in Japanese transgender men (TGM) on testosterone use remain elucidated. This study aims to present TGM with endometrial cancer and insights from a literature review of similar cases. Furthermore, we investigated the correlation between endometrial cancer and severe obesity in TGM who underwent gender-affirming surgery. METHODS: Between July 2020 and April 2023, two groups were assessed: 2 TGM with endometrial cancer and 43 TGM without cancer who underwent gender-affirming surgery. A literature review for TGM with endometrial cancer was conducted. Clinical data were retrospectively collected, and histopathological evaluation of female genital organs was performed. RESULTS: Two TGM with endometrial cancer and an additional four similar cases were identified through a literature search. These TGM had severe obesity (body mass index [BMI] ≥30 kg/m2) and long-term testosterone use, indicating a possible link between endometrial cancer and these factors. Subsequently, we investigated the 43 TGM without cancer. We revealed 30% with obesity (BMI ≥25), only three cases of severe obesity (BMI ≥30), and a significant correlation between testosterone use duration and BMI in TGM without cancer. Histological examination revealed focal proliferative endometrium in 51% of cases and polycystic ovarian changes in 77%. CONCLUSIONS: Our observations suggest a potential link between severe obesity, prolonged testosterone use, and endometrial cancer in transgender men. Histological changes in the female genital tract highlighted frequent focal proliferative endometrium, even under testosterone therapy. Further research should focus on larger, multi-institutional studies to confirm these findings and establish endometrial cancer screening for Japanese TGM.

The efficacy and safety of lenvatinib plus pembrolizumab therapy in patients with uterine carcinosarcoma.

Lenvatinib plus pembrolizumab (LP) therapy is currently used in patients with advanced or recurrent endometrial cancer. However, patients with uterine carcinosarcoma (UCS) were not included in the KEYNOTE-775, and the efficacy of LP therapy for patients with UCS in clinical practice remains unclear. We administered LP therapy to five patients with UCS. We aimed to report our clinical experience with LP therapy in these patients and investigate the genomic characteristics of those who responded to LP therapy. We retrospectively reviewed patients with UCS (n = 5) who underwent LP therapy at our hospital from January 2019 to December 2023. Efficacy was assessed using the response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. Safety was evaluated in terms of adverse events. The median age was 65 (55-78) years, and the mismatch repair status was proficient in all of the patients. One patient had stage II disease, and four had stage III. The median number of LP therapy courses was 8 (1-35). The overall response rate was 40%. None of the patients experienced adverse events that were grade 3 or higher. The median follow-up duration was 9 (1-26) months, median progression-free survival was 9.1 (0.16 to NA) months, and median overall survival was 10.2 (1.41 to NA) months. LP therapy may be effective for patients with UCS. As this report was based on a limited number of patients, more cases are required to investigate the efficacy of LP therapy in patients with UCS.

Salvage hysterectomy for persistent residual cervical cancer: assessment of prognostic factors.

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005-2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progression-free survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55-4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20-8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs. 50.6%, aHR=4.54, 95% CI=2.60-7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

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 < 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.

Comparing qSMI and qCEUS for assessing vascularization in uterine cervical cancer: operable versus non-operable group.

Objective: The present study aimed to compare the effectiveness and reliability of quantified superb microvascular imaging (qSMI) and quantified contrast-enhanced ultrasonography (qCEUS) in assessing vascularization in both operable and non-operable uterine cervical cancer. Methods: A case-control study included 64 patients with pathology-proven and untreated cervical cancer, who underwent transvaginal ultrasonography combined with qSMI and qCEUS between January 2022 and June 2023. SMI results were quantified as the vascular index (VI), which were compared to 12 quantitative parameters of CEUS calculated with time-intensity curves (TIC). Results: According to FIGO staging and different treatment regimens, 64 patients with cervical cancer were divided into operable group (IA ~ IIA, n = 19) and non-operable group (IIB ~ IV, n = 45). In comparison to the operable group, the non-operable group showed significantly higher values in VI, peak intensity (PI), area under the curve (AUC), wash-in area (iAUC), wash-out area (oAUC), wash-in rate (WiR), mean intensity (Mean Int), and standard deviation (STD) (all P < 0.05). VI demonstrated strong correlations with CEUS parameters, notably PI (r = 0.854, P < 0.001) and AUC (r = 0.635, P < 0.001). Furthermore, VI showed a better predictive performance for treatment-group assignment than qCEUS parameters, with an 80.7% accuracy, 64.4% sensitivity and 89.5% specificity. Conclusion: Both qSMI and qCEUS exhibit significant and comparable utility in detecting microvascular hyperplasia and predicting treatment-group assignments in cervical cancer. Furthermore, qSMI may offer added convenience in implementation.

Excellent concordance of the molecular classification between preoperative biopsy and final hysterectomy in endometrial carcinoma.

OBJECTIVE: The 2023 International Federation of Gynecology and Obstetrics classification with molecular classification shows superior discriminatory ability compared to staging systems lacking molecular data. However, the accuracy of endometrial biopsy data in molecular classification remains uncertain. This study aimed to assess the concordance of molecular classifications between preoperative biopsy and hysterectomy to predict prognosis before surgical staging. METHODS: Endometrial biopsies and corresponding hysterectomy specimens were collected at the National Cancer Center Hospital between 2012 and 2023. Immunohistochemistry for p53 and mismatch repair (MMR) proteins and next-generation sequencing of all exons of polymerase epsilon (POLE) were performed. Given the limited number of POLE mut cases in prior studies, we prepared a POLE mut-enriched cohort. Cohen's kappa estimates were used to determine concordance for molecular and clinicopathological subgroup assignments. RESULTS: Among 70 patients classified into four molecular subtype groups, 33 exhibited POLE mutations, 15 showed loss of MMR protein expression, 13 had p53-abnormality, and 9 had no specific molecular profile. Concordance between biopsy and hysterectomy specimens was 100% (κ = 1.000). In contrast, histological types and grades between biopsy and surgical specimens showed moderate and substantial agreement (κ = 0.420 and κ = 0.780, respectively). CONCLUSIONS: Molecular subtypes were completely consistent with those derived from surgical specimens, demonstrating high concordance between preoperative and postoperative molecular classifications. This suggests that endometrial biopsies could reliably predict prognosis. Future studies should investigate how biopsy-based molecular profiling influences treatment planning and patient outcomes.

High cost of chemotherapy for gynecologic malignancies.

BACKGROUND: The prognosis of gynecological malignancies has improved with the recent advent of molecularly targeted drugs and immune checkpoint inhibitors. However, these drugs are expensive and contribute to the increasing costs of medical care. METHODS: The Japanese Clinical Oncology Group (JCOG) Health Economics Committee conducted a questionnaire survey of JCOG-affiliated facilities from July 2021 to June 2022 to assess the prevalence of high-cost regimens. RESULTS: A total of 57 affiliated facilities were surveyed regarding standard regimens for advanced ovarian and cervical cancers for gynecological malignancies. Responses were obtained from 39 facilities (68.4%) regarding ovarian cancer and 37 (64.9%) concerning cervical cancer, with respective case counts of 854 and 163. For ovarian cancer, 505 of 854 patients (59.1%) were treated with regimens that included PARP inhibitors, costing >500 000 Japanese yen monthly, while 111 patients (13.0%) received treatments that included bevacizumab, with costs exceeding 200 000 Japanese yen monthly. These costs are ~20 and ~10 times higher than those of the conventional regimens, respectively. For cervical cancer, 79 patients (48.4%) were treated with bevacizumab regimens costing >200 000 Japanese yen per month, ~10 times the cost of conventional treatments. CONCLUSIONS: In this survey, >70% of patients with ovarian cancer were treated with regimens that included poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or bevacizumab; ~50% of patients with cervical cancer were treated with regimens containing bevacizumab. These treatments were ~10 and ~20 times more expensive than conventional regimens, respectively. These findings can inform future health economics studies, particularly in assessing cost-effectiveness and related matters.

Genomic profiles of Japanese patients with vulvar squamous cell carcinoma.

The incidence of vulvar carcinoma varies by race; however, it is a rare disease, and its genomic profiles remain largely unknown. This study examined the characteristics of vulvar squamous cell carcinoma (VSCC) in Japanese patients, focusing on genomic profiles and potential racial disparities. The study included two Japanese groups: the National Cancer Center Hospital (NCCH) group comprised 19 patients diagnosed between 2015 and 2023, and the Center for Cancer Genomics and Advanced Therapeutics group comprised 29 patients diagnosed between 2019 and 2022. Somatic mutations were identified by targeted or panel sequencing, and TP53 was identified as the most common mutation (52-81%), followed by HRAS (7-26%), CDKN2A (21-24%), and PIK3CA (5-10%). The mutation frequencies, except for TP53, were similar to those of Caucasian cohorts. In the NCCH group, 16 patients of HPV-independent tumors were identified by immunohistochemistry and genotyping. Univariate analysis revealed that TP53-mutated patients were associated with a poor prognosis (log-rank test, P = 0.089). Japanese VSCC mutations resembled those of Caucasian vulvar carcinomas, and TP53 mutations predicted prognosis regardless of ethnicity. The present findings suggest potential molecular-targeted therapies for select VSCC patients.

Laparoscopic Posterior Pelvic Exenteration with Radical Vulvectomy for Intestinal-type Vulvar Adenocarcinoma.

Vulvar intestinal adenocarcinoma is a rare malignancy. The most significant predictor of advanced vulvar cancer is achieving complete resection, although determining the optimal treatment for this rare histologic type remains uncertain. We report the case of a 63-year-old woman with a primary vulvar tumor suspected of having rectal invasion and inguinal lymph node metastases based on preoperative magnetic resonance imaging and computed tomography scans. To achieve complete resection of stage IIIC intestinal-type vulvar adenocarcinoma, we performed a laparoscopic posterior pelvic exenteration (PPE) and radical vulvectomy, along with bilateral inguinal lymph node dissection. This case report highlights the use of a novel hybrid procedure that combines laparoscopic PPE with radical vulvectomy and bilateral inguinal lymph node dissection for vulvar adenocarcinoma of the intestinal type. Laparoscopic PPE can be considered a minimally invasive approach for vulvar tumor when complete resection is achievable with an appropriate safety margin.

Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

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.

Trop-2 expression and the tumor immune microenvironment in cervical cancer.

OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2 H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.

Potential utility of pretreatment serum miRNAs for optimal treatment selection in advanced high-grade serous ovarian cancer.

OBJECTIVE: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy. METHODS: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients. RESULTS: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively. CONCLUSIONS: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients.

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

The 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.

A survey of carboplatin desensitization therapy in Japan: A multicenter retrospective study.

INTRODUCTION: Hypersensitivity reactions (HSRs) to chemotherapy are serious adverse events associated with cancer drug therapy and can occur with any antitumor drug. This study investigated the safety and efficacy of carboplatin desensitization therapy in Japan and established a method for treating carboplatin HSRs. METHODS: Patients diagnosed with gynecological (ovarian, endometrial, or cervical) cancers who underwent carboplatin desensitization therapy between 2016 and 2020 at the Gynecologic Cancer Study Group of Japan Clinical Oncology Group were included. The carboplatin desensitization therapy at each institution and the implementation cases were registered in an online case report form. RESULTS: This retrospective study enrolled 136 patients (ovarian, 108; endometrial, 17; and cervical cancer, 11). Pre-existing allergies were present in 37 (27.2%) patients, and 32 (23.5%) patients exhibited prodromal symptoms during treatment before HSR onset. Erythema was the most common symptom at HSR onset, affecting 93 (68.4%) patients, followed by itching in 72 (52.9%) patients and decreased oxygen saturation in 43 (31.6%) patients. Loss of consciousness occurred in three (2.2%) patients. The most common timing of HSR onset was during the first recurrence treatment (47%). The mean total carboplatin dose until HSR onset was 7331 (2620-18,282) mg, and the mean number of doses was 14 (4-63). Desensitization treatment was completed in 75% of cases, and breakthrough HSRs occurred in 25% (34/136). No deaths occurred in the study cohort. The risk factors for HSRs were not identified. CONCLUSION: Although carboplatin desensitization therapy has high success rates in Japan, erythema and pruritus are important HSRs to consider.

Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. METHODS: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. RESULTS: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. CONCLUSION: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

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.

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.

Therapeutic target biomarkers of patient-derived xenograft models of gastric-type cervical adenocarcinoma.

Background: Most cervical adenocarcinomas are associated with human papillomavirus (HPV). Gastric-type cervical adenocarcinoma (GAS), an HPV-independent adenocarcinoma, shows an aggressive clinical feature, resulting in a poor prognosis. Resistance to chemotherapy poses a difficulty in managing patients with metastatic GAS. We aimed to establish patient-derived xenografts (PDXs) of tumors from two patients with GAS and evaluated protein biomarkers for drug development using immunohistochemistry. Methods: Two PDXs were established 78 and 48 days after transplanting the patient's tumor tissues into immunodeficient mice, respectively. PDX and patient's tumor samples were stained for HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A to evaluate biomarkers for therapeutic targets. In addition, whole exome sequencing and RNA sequencing were performed on available samples. Results: The pathological findings in morphological features and immunohistochemical profiles from the established PDXs were similar to those from the patients' surgical tumor specimens. HER3 was overexpressed in the patient's tumors, and the corresponding PDX tumors and HER2 was weakly stained in both types of tumor samples. In all PDX and patient tumor samples, PMS2, MSH6, and ARID1A were retained, and PanTrk was not expressed. In addition, a total of 10 samples, including tumor tissue samples from 8 other GAS patients, were evaluated for HER3 expression scores, all of which were 2 + or higher. Conclusions: In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2.

Utility of the revised FIGO2023 staging with molecular classification in endometrial cancer.

OBJECTIVES: Molecular classification was introduced in endometrial cancer staging following the transition of the International Federation of Gynecology and Obstetrics (FIGO) 2008 to FIGO2023. In the early stages, p53 abnormal endometrial carcinoma with myometrial involvement was upstaged to stage IICm, in addition to the downstaging of POLE mutation endometrial cancer to stage IAm. This study compared the goodness of fit and discriminatory ability of FIGO2008, FIGO2023 without molecular classification (FIGO2023), and FIGO2023 with molecular classification (FIGO2023m); no study has been externally validated to date. METHODS: The study included 265 patients who underwent initial surgery at the National Cancer Center Hospital between 1997 and 2019 and were pathologically diagnosed with endometrial cancer. The three classification systems were compared using Harrell's concordance index (C-index), Akaike information criterion (AIC), and time-dependent receiver operating characteristic (ROC) curves. A higher C-index score and a lower AIC value indicated a more accurate model. RESULTS: Among the three classification systems, FIGO2023m had the lowest AIC value (FIGO2023m: 455.925; FIGO2023: 459.162; FIGO2008: 457.901), highest C-index (FIGO2023m: 0.768; FIGO2023: 0.743; FIGO2008: 0.740), and superior time-dependent ROC curves within 1 year after surgical resection. In the stage IIIC, patients with p53 abnormalities had considerably lower 5-year overall survival than those with a p53 wild-type pattern (24.3% vs. 83.7%, p = 0.0005). CONCLUSIONS: FIGO2023m had the best discriminatory ability compared with FIGO2008 and FIGO2023. Even in advanced stages, p53 status was a poor prognostic factor. When feasible, molecular subtypes can be added to the staging criteria to allow better prognostic prediction in all stages.