Ovarian serous borderline tumors with recurrent or extraovarian lesions: a Japanese, retrospective, multi-institutional, population-based study.

BACKGROUND: Ovarian serous borderline tumors (SBT) are typically unilateral and are primarily treated using hysterectomy and bilateral salpingooophorectomy (SO). However, most young patients prefer fertility-sparing surgeries (FSS) with tumorectomy or unilateral SO. Micropapillary morphology and invasive implants have been designated as histopathological risk indicators for recurrence or metastasis, but their clinical impact remains controversial because of limitations like diagnostic inconsistency and incomplete surgical staging. METHODS: A nationwide multi-institutional population-based retrospective surveillance was conducted with a thorough central pathology review to reveal the clinical features of SBT. Of 313 SBT patients enrolled in the Japanese Society of Clinical Oncology's Surveillance of Gynecologic Rare Tumors, 289 patient records were reviewed for clinical outcomes. The glass slides of patients at stage II-IV or with recurrence or death were re-evaluated by three gynecological pathologists. RESULT: The 10-year overall and progression-free survival (PFS) rates were 98.6% and 92.3%. The median recurrence period was 40 months and 77.0% was observed in the contralateral ovary within 60 months. Patients aged ≤ 35 years underwent FSS more frequently and relapsed more (p < .001). A clinic-pathological analysis revealed diagnosis during pregnancy, FSS, and treatment at non-university institutes as well as advanced stage and large diameter were independent risk factors of recurrence. Among patients having pathologically confirmed SBTs, PFS was not influenced by the presence of micropapillary pattern or invasive implants. CONCLUSION: The recurrence rate was lower in this cohort than previous reports, but the clinical impacts of incomplete resection and misclassification of the tumor were still significant on the treatment of SBT.

Histopathological Findings of Ectopic Pregnancy in Contraceptive-Wearing Woman.

In normal pregnancy, the egg is fertilized in the fallopian tube. It later moves into the uterus, where it implants into the uterine endometrium. Therefore, implantation of the fertilized egg into the endometrium is not observed in many women using contraceptives. However, if the fallopian tubes are diseased or abnormal, the fertilized egg cannot travel to the endometrium. Thus, the fertilized egg is implanted in tissues other than the uterus, resulting in an ectopic pregnancy. In most cases of ectopic pregnancy, the fertilized egg is implanted into the left or right fallopian tube or in tissues other than the fallopian tubes such as the ovary. With laparoscopic surgery, the scars are small, and the pain and physical burden are also much lesser than those with open surgery; thus, the patient can be rehabilitated immediately. Laparoscopic surgery is preferred for the termination of ectopic pregnancies because the patients recovered quickly physically after surgery and can be discharged in a short period. This paper presents our experience in treating a 37-year-old woman who had a tubal pregnancy despite using a contraceptive. Contrast-enhanced magnetic resonance imaging showed a gestational sac within the right fallopian tube. Laparoscopic surgery was performed to resect the right fallopian tube. Pathological examination suggested that the ectopic pregnancy occurred at the organogenesis stage 9 weeks after fertilization. The pathological findings revealed subpopulations of cells from the ectoderm that were separated from other cells and more specifically formed spinal and ovarian structures. The implantation of the fertilized egg into the endometrium is not observed in many women using contraceptives. However, in rare cases, ectopic pregnancy occurs in women using contraceptives; thus, caution is necessary in diagnosis and treatment. This report presents valuable surgical pathological findings from such a rare case of ectopic pregnancy to understand the differentiation into each tissue during organogenesis.

Characteristic of Endometrial Stromal Sarcoma by Algorithm of Potential Biomarkers for Uterine Mesenchymal Tumor.

The benign tumor uterine leiomyoma (UL) develops from the smooth muscle tissue that constitutes the uterus, whereas malignant tumor uterine sarcoma develops from either the smooth muscle tissue or stroma and is different from UL and endometrial cancer. Uterine sarcoma is broadly classified into three types: uterine leiomyosarcoma, endometrial stromal sarcoma (ESS), and carcinosarcoma. Although uterine leiomyosarcoma and ESS are both classified as uterine sarcoma, they significantly differ in terms of their sites of occurrence, symptoms, and treatment methods. Uterine leiomyosarcoma develops from the muscle tissue constituting the wall of the uterus and accounts for approximately 70% of all uterine sarcoma cases. In contrast, ESS develops from the stromal tissue beneath the endometrium and accounts for approximately 25% of all uterine sarcoma cases. ESS is classified as either low grade (LG) or high grade (HG). This case report aimed to highlight the importance of histopathologic examinations based on surgical specimens. Herein, we reported the case of a 45-year-old woman suspected of having submucosal leiomyoma of the uterus based on imaging results. Transvaginal ultrasonography and endometrial biopsy or partial dilation and curettage were performed. Contrast-enhanced magnetic resonance imaging (MRI) revealed a 32-mm mass projecting from the posterior wall of the uterus into the uterine cavity. T2-weighted imaging revealed a low signal within the mass; thus, submucosal UL was suspected. Histopathologic examination of surgical specimens obtained from a patient suspected of having submucosal UL after contrast-enhanced MRI indicated that the patient had ESS. Despite the remarkable advancements in medical imaging technology, the accuracy of contrast-enhanced MRI for detecting uterine mesenchymal tumors is limited. Therefore, histopathologic diagnosis based on surgical specimens should be performed when medical grounds for diagnosing a benign tumor on contrast-enhanced MRI are lacking.

Pyruvate kinase deficiency mutant gene carriage in stray cats and rescued cats from animal hoarding in Hokkaido, Japan.

The mutant allele frequency of the Pyruvate kinase (PK) gene has been investigated mostly in pure breed cats. We investigated the PK mutant gene in stray and animal hoarding mongrel cats in Hokkaido, Japan. We also investigated the kinship of individuals carrying the mutant gene. Genotyping was conducted using the previously reported real-time PCR method. Fourteen microsatellite markers were used to identify the parents and offspring of cats carrying the PK mutant gene, and some kinship such as parent-offspring and siblings was observed. Some stray and animal hoarding cats carried the PK mutation gene and that consanguinity was confirmed among these cats indicated that the PK mutation gene was spread by unregulated interbreeding.

Familial Gastrointestinal Stromal Tumor Associated with Zebra-like Pigmentation.

Purpose: According to clinical studies, gastrointestinal stromal tumors (GISTs) are predominantly sporadic. GISTs associated with familial syndromes are very rare, and most patients exhibit wild-type KIT and platelet-derived growth factor alpha (PDGFRA). To date, GISTs associated with germline KIT pathogenic variants have been observed in only 30 kindreds worldwide. The efficacy of imatinib, a multityrosine kinase inhibitor, in patients with GIST presenting germline KIT variants has been poorly reported, and the efficacy in clinical trials of treatments with tyrosine kinase inhibitors remains unclear. Therefore, imatinib is not yet recommended for treating GIST patients with germline KIT variants. Experimental Design: We performed cancer genomic testing on samples from a 32-year-old male patient with advanced GISTs throughout the upper stomach and cutaneous hyperpigmentation to determine diagnosis and treatment strategies. Results: We detected a germline W557R pathogenic variant of KIT. The patient was diagnosed with familial multinodular GIST based on the clinical findings and familial history of malignant tumors. Treatment with imatinib resulted in long-term regression of GISTs. Conclusions: Pathogenic variants detected by cancer genome testing can be used to diagnose malignant tumors and select new therapeutic agents for patients with advanced malignancies.

Development of an Algorithm to Differentiate Uterine Sarcoma from Fibroids Using MRI and LDH Levels.

BACKGROUND: This study aimed to establish an evaluation method for detecting uterine sarcoma with 100% sensitivity using MRI and serum LDH levels. METHODS: One evaluator reviewed the MRI images and LDH values of a total of 1801 cases, including 36 cases of uterine sarcoma and 1765 cases of uterine fibroids. The reproducibility of the algorithm was also examined by four evaluators with different imaging experience and abilities, using a test set of 61 cases, including 14 cases of uterine sarcoma. RESULTS: From the MRI images and LDH values of 1801 cases of uterine sarcoma and uterine fibroids, we found that all sarcomas were included in the group with a high T2WI and either a high T1WI, an unclear margin, or high LDH values. In addition, when cases with DWI were examined, all sarcomas had high DWI. Among the 36 sarcoma cases, the group with positive findings for T2WI, T1WI, margins, and serum LDH levels all had a poor prognosis (p = 0.015). The reproducibility of the algorithm was examined by four evaluators and the sensitivity of sarcoma detection ranged from 71% to 93%. CONCLUSION: We established an algorithm to distinguish uterine sarcoma if tumors in the myometrium with low T2WI and DWI are present.

Molecular Histopathology for Establishing Diagnostic Method and Clinical Therapy for Ovarian Carcinoma.

Ovarian carcinoma (OC) is considered the deadliest gynecological malignancy. It is typically diagnosed in the advanced stages of the disease, with metastatic sites widely disseminated within the abdominal cavity. OC treatment is challenging due to the high rate of disease recurrence, which is further complicated by acquired chemoresistance caused by the reversion of the pathological variant. Therefore, more effective treatments are still being sought. Histologically, OC is classified into serous, mucinous, endometrioid, clear cell, and transitional cell carcinomas and malignant Brenner tumor. Recent clinicopathological and molecular biological studies demonstrated that these subtypes differ in histogenesis and anti-tumor agent sensitivity. In Japan, the incidence rates of the histological types of OC, namely, serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear cell adenocarcinoma, are 39%, 12%, 16%, and 23%, respectively. Serous carcinoma is classified as high or low grade, with the former accounting for the overwhelming majority. In this study, the molecular pathological classification of OC has been described based on the characteristics of the two types of OC, types 1 and 2. Compared with Europe and the United States, Japan has a higher prevalence of type 1 OC and a lower prevalence of type 2 OC. The prevalence of each type of OC varies by race. It has been elucidated that the prevalence rate of each type of ovarian cancer in Asian countries is similar to that in Japan. Thus, OC is a heterogeneous disease. Furthermore, OC has been attributed to molecular biological mechanisms that vary among tissue subtypes. Therefore, it is necessary to conduct treatment based on accurate diagnoses of each tissue type and establish an optimal treatment strategy, and now is the transition period.

Trends and future projections of cervical cancer-related outcomes in Japan: What happens if the HPV vaccine program is not implemented?

Contrary to other developed countries, in Japan, recent years have seen increases in cervical cancer incidence and mortality among young people. However, the human papillomavirus (HPV) vaccine program, a key measure for avoiding cervical cancer, has been virtually suspended. Temporal changes in cervical cancer profiles in this unique situation have not been fully investigated epidemiologically. Our study aimed to determine the current status and future trends of the incidence and mortality of cervical cancer and precancerous lesions in Japan. Mortality rates of cervical cancer during 1975 to 2016 and incidence rates of cervical cancer and cervical intraepithelial neoplasia (CIN) 3 during 1975 to 2013 were examined using vital statistics and population-based cancer registry data in Japan. Bayesian age-period-cohort analyses were performed to analyze temporal changes of the three cervical cancer-related outcomes. We also calculated projections to 2028 for the three outcomes, assuming that HPV vaccination coverage and screening rates in Japan would be maintained at the current level after the resumption of the national vaccination program. The risk of occurrence of the three outcomes showed similar changes by birth cohort, peaking in the mid-1890s to 1900s birth cohorts, declining sharply in the 1940s birth cohort, and persistently increasing in the 1950s and later birth cohorts. Projections to 2028 show increases in cervical cancer incidence and mortality in the 30 to 69 age group, with a particular increase in CIN3 incidence in the 25 to 49 age group, if HPV vaccine programs and screening are not effectively implemented. These findings revealed an increasing cervical disease burden among reproductive age females in Japan.

Treatment With Antitumor Agents Recommended by Cancer Genome Panel for Uterine Leiomyosarcoma.

To date, cancer genomic medicine, using cancer gene panel covered by health insurance from June 2019, has been performed for advanced malignant tumors under public medical insurance. In gynecology, the first-line treatment for uterine leiomyosarcomas, which is a mesenchymal uterine tumor, is surgery. In uterine leiomyosarcoma cases, recurrence is observed within 2 years postoperatively; however, to date, clinical trials have not shown efficacy with existing antitumor agents. We noted efficacy in two cases with advanced/recurrent uterine leiomyosarcoma using an antitumor agent selected on the basis of cancer gene panel testing results. Following uterine leiomyosarcoma diagnosis, they underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy as standard surgical treatment. After the surgical treatment, the imaging test revealed recurrent tumors; subsequently, they were treated with doxorubicin alone or doxorubicin combined with Gemzar. However, cancer genome gene panel test was performed because the malignant tumor worsened. Based on the cancer genome gene panel test results, the two cases with advanced uterine leiomyosarcoma were associated with increased tumor mutational burden (TMB) or pathogenic variants (PVs) of AKT serine/threonine kinase 1 (AKT1). Therefore, treatment with pembrolizumab, which is a drug covered by insurance for patients with TMB-high, or treatment with kinase inhibitors for patients with PVs in AKT, was considered. Cancer genomic medicine using cancer gene panel provides a new treatment strategy for intractable malignant tumors. This study aimed to discuss the usefulness of cancer genomic medicine by cancer gene panel testing using the cases of advanced and recurrence uterine leiomyosarcoma and the latest findings.

Targeting TMEM205 mediated drug resistance in ovarian clear cell carcinoma using oncolytic virus.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) accounts for approximately 8-10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high grade serous ovarian cancer HGSOC. The objective of this study was to examine the therapeutic relevance of combining oncolytic virus with cisplatin for ovarian cancer clear cell carcinoma (OCCC). RESULTS: We identified that TMEM205, a recently discovered transmembrane protein, contributes to chemoresistance in OCCC cells via the exosomal pathway. Mechanistically, TMEM205 undergoes ligand-independent constitutive endocytosis and co-localizes with Rab11 to contribute to the late recycling endosomes in a clathrin-independent manner. Further, we observed that oncolytic virus (oHSV) pretreatment followed by treatment with cisplatin decreases TMEM205 expression and sensitizes cells to cisplatin in a synergistic manner in OCCC cells. TMEM205 interacts with glycoprotein-C of oHSV post-infection; both of these proteins undergo ubiquitination and ultimately get shuttled outside the cell via exosomes. Thus, we demonstrate the mechanotransduction pathway of TMEM205-mediated chemoresistance along with targeting this pathway using oHSV and cisplatin as a powerful therapeutic strategy for OCCC. oHSV combination with cisplatin inhibits OCCC tumor growth in vivo in immunodeficient and immunocompetent mice models. CONCLUSION: Our results suggest that the combination of oHSV and cisplatin in immunocompetent as well as immune deficient OCCC tumor bearing mice reduces overall tumor burden as well as metastatic disease thereby providing survival benefit. Additionally, the detection of TMEM205 in exosomal cargo early in OCCC development has potential to be exploited as a biomarker.

Pathological Evidence for Residual SARS-CoV-2 in the Micrometastatic Niche of a Patient with Ovarian Cancer.

In previous clinical studies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients has a high risk of aggravation and mortality than in healthy infected individuals. Inoculation with coronavirus disease 2019 (COVID-19) vaccine reduces the risk of SARS-CoV-2 infection and COVID-19 severity. However, vaccination-induced anti-SARS-CoV-2 antibody production is said to be lower in cancer patients than in healthy individuals. In addition, the rationale for why the condition of patients with cancer worsens with COVID-19 is not well understood. Therefore, we examined the infection status of SARS-CoV-2 in the primary tumor and micrometastasis tissues of the patient with cancer and COVID-19. In this study, the expression of angiotensin-converting enzyme 2 (ACE2) was observed, and SARS-CoV-2 particles was detected in ovarian tissue cells in contact with the micrometastatic niche of the patient with high-grade serous ovarian cancer. We believe that the severity of COVID-19 in patients with cancer can be attributed to these pathological features. Therefore, the pathological findings of patients with advanced and recurrent ovarian cancer infected with SARS-CoV-2 may help decrease COVID-19 severity in patients with other cancer types.

Characteristic of Concurrent Uterine Lipoleiomyoma and Hemangioma by Algorithm of Candidate Biomarkers for Uterine Mesenchymal Tumor.

(1) Background/Aim: In clinical practice, uterine lipoleiomyomas are variants of uterine leiomyomas that are often found incidentally and do not require surgical treatment unless the patient is symptomatic. Therefore, these should be clinically differentiated from lesions that need surgical treatment. Conversely, hemangiomas, or blood vessel benign tumors, rarely develop in the uterus; however, many clinical complications such as abdominal pain and excessive vaginal bleeding result from a uterine hemangioma. Hemangiomas can occur at any age and primarily affect pregnant women. (2) Materials and Methods: The oncological properties of uterine lipoleiomyoma and hemangioma in adults were investigated using molecular pathological examination on tissue excised from patients with a uterine tumor. (3) Results: Through molecular pathological studies, which included potential biomarkers for uterine mesenchymal tumors, a differential diagnosis was established for a case of mesenchymal tumor. Herein, we report a 54-year-old non-pregnant woman who presented with vaginal bleeding and underwent hysterectomy after detection of a 140 × 100 mm intramural mass diagnosed as a concurrent uterine hemangioma and lipoleiomyoma after molecular histopathologic examinations. (4) Conclusion: As far as we know, our case is the first patient of concurrent uterine hemangioma and lipoleiomyoma. Hence, the possibility of several types of mesenchymal tumors must be considered in the differential diagnosis of patients with abnormal vaginal bleeding. As such, molecular pathological examination and close monitoring of the MRI results should be conducted by medical staff while considering the patient's desire for pregnancy, including surgical treatment options for uterine hemangioma.

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics.

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

Spontaneous Myocarditis in Mice Predisposed to Autoimmune Disease: Including Vaccination-Induced Onset.

Nonobese diabetic (NOD)/ShiLtJ mice, such as biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with moderate glycosuria and nonfasting hyperglycemia. Previously, in NOD/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of nuclear factor-kappa B1 (NF-κB1) (also known as p50) in the development of type 1 diabetes was investigated. In response to these arguments, NOD mice with inconsistent NF-κB1 expression were established. Surprisingly, the majority of NOD Nfκb1 homozygote mice were found to die by the eighth week of life because of severe myocarditis. The incidence of spontaneous myocarditis in mice was slightly higher in males than in females. Furthermore, insulitis was observed in all NOD Nfκb1 heterozygote mice as early as 4 months of age. Additionally, in NOD Nfκb1 heterozygote mice, myocarditis with an increase in cTnT levels due to influenza or hepatitis B virus vaccination was observed with no significant gender difference. However, myocarditis was not observed with the two types of human papillomavirus vaccination. The results of immunological assays and histopathological examinations indicated that vaccination could induce myocarditis in genetically modified mice. In this study, we report that NOD Nfκb1 heterozygote mice can be used for investigating the risk of myocarditis development after vaccination.

Possibility of SARS-CoV-2 Infection in the Metastatic Microenvironment of Cancer.

According to a report from the World Health Organization (WHO), the mortality and disease severity induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly higher in cancer patients than those of individuals with no known condition. Common and cancer-specific risk factors might be involved in the mortality and severity rates observed in the coronavirus disease 2019 (COVID-19). Similarly, various factors might contribute to the aggravation of COVID-19 in patients with cancer. However, the factors involved in the aggravation of COVID-19 in cancer patients have not been fully investigated so far. The formation of metastases in other organs is common in cancer patients. Therefore, the present study investigated the association between lung metastatic lesion formation and SARS-CoV-2 infectivity. In the pulmonary micrometastatic niche of patients with ovarian cancer, alveolar epithelial stem-like cells were found adjacent to ovarian cancer. Moreover, angiotensin-converting enzyme 2, a host-side receptor for SARS-CoV-2, was expressed in these alveolar epithelial stem-like cells. Furthermore, the spike glycoprotein receptor-binding domain (RBD) of SARS-CoV-2 was bound to alveolar epithelial stem-like cells. Altogether, these data suggested that patients with cancer and pulmonary micrometastases are more susceptible to SARS-CoV-2. The prevention of de novo niche formation in metastatic diseases might constitute a new strategy for the clinical treatment of COVID-19 for patients with cancer.