Kosuke Murakami

Synchronous endometrial and ovarian cancers originating from distinct clonal lineages in Lynch syndrome: A case report and review of the literature

Abstract Recent next‐generation sequencing (NGS) studies have shown that synchronous endometrial and ovarian cancers (SEOCs) are often derived from the same clone. However, the clonal relationship in Lynch syndrome remains unclear. A 45‐year‐old woman was diagnosed with grade 2 endometrial endometrioid carcinoma and an ovarian yolk sac tumor with clear cell carcinoma. Genetic testing revealed different MLH1 variants in the endometrial and ovarian cancers, and peripheral blood analysis identified an exon 5 deletion in MLH1 , confirming Lynch syndrome. The somatic variants in the tumors were distinct. A review of the literature found six cases of SEOC in Lynch syndrome with NGS‐based clonal analysis, four of which (67%) showed independent cancers with different somatic profiles. These findings suggest that, unlike sporadic SEOC, synchronous cancers in Lynch syndrome are more likely to arise from separate clones.

Histopathological subtyping of high-grade serous ovarian cancer using whole slide imaging

We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

Management of diffuse uterine leiomyomatosis for fertility preservation: Case series and systematic literature review

AbstractAimThe aim of this study was to evaluate the surgical, reproductive, and perinatal outcomes of patients with diffuse uterine leiomyomatosis desiring fertility preservation.MethodsPatients diagnosed with diffuse uterine leiomyomatosis based on magnetic resonance imaging at Kindai University Hospital between 2017 and 2024 were included in a case series. A systematic literature review on diffuse uterine leiomyomatosis desiring fertility preservation was carried out.ResultsThe case series showed that fertility preservation was desired in 8 of 18 cases, of which 1 was conceived after assisted reproductive technology and underwent cesarean section at 34 weeks of gestation for placenta previa accreta. A systematic literature review identified 31 cases from descriptive observational studies (1–8 cases per study). Although more fibroids (n = 87) were enucleated by extensive myomectomy than by hysteroscopic myomectomy (n = 33) (p < 0.0001), extensive myomectomy was often associated with massive blood loss and blood transfusion. Perinatal complications were more frequent in extensive myomectomy (5/7) compared to hysteroscopic myomectomy (2/12, p = 0.04). Preterm delivery before 36 weeks was more frequent in extensive myomectomy (4/6 cases) than in hysteroscopic myomectomy (1/11 cases, p = 0.03).ConclusionFertility preservation in diffuse uterine leiomyomatosis was previously considered difficult, but it is now recognized to be possible. Hysteroscopic myomectomy is a minimally invasive option. If conception is not achieved, extensive myomectomy may be considered. However, extensive myomectomy is more invasive, with a higher risk of perinatal complications. Large‐scale clinical trials are required to establish a management standard for diffuse uterine leiomyomatosis.

Frequent PIK3CA mutations in eutopic endometrium of patients with ovarian clear cell carcinoma

Recent studies have reported cancer-associated mutations in normal endometrium. Mutations in eutopic endometrium may lead to endometriosis and endometriosis-associated ovarian cancer. We investigated PIK3CA mutations (PIK3CAm) for three hotspots (E542K, E545K, H1047R) in eutopic endometrium in patients with ovarian cancer and endometriosis from formalin-fixed paraffin-embedded specimens by laser-capture microdissection and droplet digital PCR. The presence of PIK3CAm in eutopic endometrial glands with mutant allele frequency ≥ 15% were as follows: ovarian clear cell carcinoma (OCCC) with PIK3CAm in tumors, 20/300 hotspots in 11/14 cases; OCCC without PIK3CAm, 42/78 hotspots in 11/12 cases; high-grade serous ovarian carcinoma, 8/45 hotspots in 3/5 cases; and endometriotic cysts, 5/63 hotspots in 5/6 cases. These rates were more frequent than in noncancer nonendometriosis controls (7/309 hotspots in 5/17 cases). In OCCC without PIK3CAm, 7/12 (58%) cases showed multiple hotspot mutations in the same eutopic endometrial glands. In 3/54 (5.6%) cases, PIK3CAm was found in eutopic endometrial stroma. Multisampling of the OCCC tumors with PIK3CAm showed intratumor heterogeneity in three of eight cases. In two cases, PIK3CAm was detected in the stromal component of the tumor. Homogenous PIK3CAm in the epithelial component of the tumor matched the mutation in eutopic endometrial glands in only one case. Eutopic endometrial glands in ovarian cancer and endometriosis show high frequency of PIK3CAm that is not consistent with tumors, and multiple hotspot mutations are often found in the same glands. While the mutations identified in eutopic endometrium may not be driver mutations in the patient's cancer, these are still driver mutations but this specific clone has not undergone the requisite steps for the development of cancer.

Differentiation of uterine fibroids and sarcomas by MRI and serum LDH levels: a multicenter study of the KAMOGAWA study

In the differential diagnosis between uterine fibroids and uterine sarcomas, real-world magnetic resonance imaging (MRI) diagnostic information is scarce; furthermore, high diagnostic sensitivity is important in clinical practice. We previously developed a diagnostic algorithm to detect uterine sarcoma with high sensitivity using simple MRI images and serum lactate dehydrogenase (LDH) levels. In this multicenter study, we investigated the preoperative diagnosis of sarcoma in the real world and further validated the usefulness of our diagnostic algorithm. Of 154 uterine sarcomas and 154 uterine fibroids treated at 15 centers between January 2006 and December 2020, 139 sarcomas (16 smooth muscle tumors of uncertain malignant potential) and 141 fibroids with diffusion-weighted imaging information were included in the analysis. The diagnostic algorithm was validated by 3 radiologists who were blinded to the clinical information and pathologic diagnoses and who read the MRIs. The sensitivity/specificity of preoperative diagnosis was 77.7%/92.9% for the preoperative report; 92.1%/72.3% for algorithm A; and 82.0%/85.8% for algorithm B (McNemar's test p<0.05). Comparison of overall survival rates among 3 groups (Group 1: negative A, Group 2: positive A and negative B; Group 3: positive B) using algorithms A and B showed p=0.012. On multivariate analysis, stage, and serum LDH level were independent prognostic factors. MRI is useful for preoperative diagnosis of uterine sarcoma, and the sarcoma diagnostic algorithm presented in this study is an option for diagnosing sarcoma with greater sensitivity. This information should be shared with patients.