Pathology International

Primary extraovarian granulosa cell tumor of the mesentery

Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: Heterogeneous causes of an unusual immunophenotype

Immunohistochemically p16 (CDKN2A)‐negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16‐negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co‐existing Epstein–Barr virus infection. Another was positive for HPV6 categorized as low‐risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV‐negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16‐negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality.

miR‐16‐5p modulates the radiosensitivity of cervical cancer cells via regulating coactivator‐associated arginine methyltransferase 1

This study was to investigate the expression of coactivator‐associated arginine methyltransferase 1 (CARM1) and miR‐16‐5p in cervical cancer (CC), and explore their roles in radioresistance. Western blot and immunohistochemistry were used to detect the expression of CARM1 in tissues and cells. Reverse transcription‐polymerase chain reaction (RT‐PCR) was used to detect the expression of miR‐16‐5p. CC cells received different doses of X‐ray exposure, and then cell counting kit‐8 method and colony formation assay were used to detect cell proliferation. Apoptosis was detected by flow cytometry. Then we used Targetscan database to predict that CARM1 is a potential target of miR‐16‐5p, and further verified the targeting relationship between them by western blot, RT‐PCR and dual luciferase reporter experiments. We demonstrated that CARM1 were highly expressed in CC tissues and radio‐resistant CC cells, while miR‐16‐5p expression was low. Under irradiation, up‐regulation of CARM1 can induce radiotherapy resistance of CC cells, while overexpression of miR‐16‐5p or CARM1 knockdown could inhibit the survival of CC cell and induced apoptosis. CARM1 was verified as a target for miR‐16‐5p. Besides, up‐regulation of CARM1 reversed the increase in radiosensitivity induced by miR‐16‐5p. Collectively, we concluded that miR‐16‐5p promoted the radiosensitivity of CC cells by targeting CARM1.

Myoepithelioma of soft tissue and bone, and myoepithelioma‐like tumors of the vulvar region: Clinicopathological study of 15 cases by PLAG1 immunohistochemistry

We demonstrated the clinicopathological findings of 13 myoepitheliomas of soft tissue and bone (MESTBs) and two myoepithelioma‐like tumors of the vulvar region (MELTVRs), focusing on the association between nuclear atypia and clinical course, and the utility of immunohistochemistry (IHC) of pleomorphic adenoma gene 1 (PLAG1) for the pathological diagnosis of these tumors. Of the 13 MESTBs, eight, one and four cases exhibited mild, moderate and severe nuclear atypia, respectively. Two cases with venous invasion showed severe nuclear atypia and both died of advanced disease. Two MELTVR cases showed moderate nuclear atypia and had no evidence of disease after surgery. On IHC, 12 of 13 (92.3%) MESTBs showed PLAG1 immunoreactivity and none of the MELTVRs expressed PLAG1. In addition, MELTVRs showed loss of INI1 expression. In contrast, all MESTBs retained INI1 expression. Fluorescence in situ hybridization detected EWSR1, FUS and PLAG1 rearrangement in 5 (38.5%), 0 (0%) and 2 (15.4%) of the 13 MESTBs, respectively. No EWSR1, FUS and PLAG1 rearrangement were observed in the METLVRs. In conclusion, MESTBs with both severe nuclear atypia and venous invasion would be indicative of malignant potential. PLAG1 might be a useful IHC marker in MESTB diagnosis.

Progressive Estrogen Receptor Acquisition During Malignant Transformation: Insights From MCN‐Derived Anaplastic Pancreatic Carcinoma

ABSTRACT Anaplastic pancreatic carcinoma (APC) arising from mucinous cystic neoplasm (MCN) is rare, with only 12 cases reported. The relationship between pregnancy‐associaed hormonal changes and MCN progression remains poorly understood, particularly regarding hormone receptor expression patterns during malignant transformation. A 34‐year‐old woman presented with persistent abdominal pain 9 months post‐delivery. Imaging revealed an 11 cm multilocular cystic mass in the pancreatic body and tail with mural nodules showing blood flow signals. Laboratory findings demonstrated normal. She underwent distal pancreatectomy and splenectomy and no recurrence at 6‐month follow‐up. Histopathological examination revealed MCN with ovarian‐type stroma progressing from low‐to‐high grade dysplasia, invasive ductal carcinoma, and anaplastic carcinoma with osteoclast‐like giant cells. Immunohistochemically, estrogen receptor (ER) expression showed stepwise pattern: negative in low‐grade dysplasia, strongly positive in high‐grade dysplasia and anaplastic components. Progesterone receptor positivity was observed in stromal and epithelial components, with elevated Ki‐67 correlating with ER expression. This represents first documentation of progressive ER acquisition during MCN malignant transformation, suggesting autonomous hormone production by ovarian‑type stroma may help sustain tumor growth beyond pregnancy. Stepwise ER expression may serve as a biomarker for risk stratification and a potential target for therapy in hormone‐sensitive pancreatic neoplasms.

New clinicopathological concept of endometrial carcinoma with integration of histological features and molecular profiles

AbstractThe dual‐stratified pathway of endometrial carcinomas (ECs) has long been dominant. However, in 2013, The Cancer Genome Atlas (TCGA) defined four EC subgroups with distinctive prognoses. Inspired by TCGA, in 2018, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) provided four pragmatic molecular classifiers to apply surrogate immunohistochemical markers to TCGA subgroup categorization. These trends prompted the revision of 2020 WHO Classification of Female Genital Tumors, 5th edition (2020 WHO classification), in which four molecular subtypes are recognized: POLE‐ultramutated; mismatch repair‐deficient; p53‐mutant; and no specific molecular profile. In the 2020 WHO classification, the diagnostic algorithm is characterized by prioritizing POLEmut over other molecular abnormalities. Following the 2020 WHO classification, Federation of International Gynecology and Obstetrics (FIGO) proposed a new staging system in 2023. The updated system focuses on diagnostic parameters, such as histological type and grade, lymphovascular space invasion, and molecular alterations. These new histomolecular diagnostic concepts of ECs are being accordingly introduced into the routine pathology practice. For the first time, the 2020 WHO classification includes mesonephric‐like adenocarcinoma (MLA) as a novel histological entity, mimicking the conventional mesonephric adenocarcinoma, but is considered of Müllerian ductal origin.

GATA3 expression in tumor‐infiltrating mononuclear inflammatory cells is associated with poor prognostic factors in tubo‐ovarian carcinomas

AbstractThe study investigated the expression of GATA3, a transcription factor involved in immune regulation, in tubo‐ovarian carcinomas and its association with clinicopathological factors and prognosis. Immunohistochemical analysis was performed on 91 tubo‐ovarian carcinoma samples to determine the presence of GATA3‐positive inflammatory cells in the tumor microenvironment. A threshold of 10% or higher was considered a positive expression. The results showed that 46.7% of tubo‐ovarian carcinomas exhibited positive expression of GATA3 in inflammatory cells. There was no significant difference in GATA3 expression between patients who received pre‐surgical chemotherapy and those who underwent primary surgery. However, high‐grade serous carcinomas had a significantly higher proportion of GATA3‐positive inflammatory cells compared to other subtypes. Advanced‐stage tumors (stage III) had a higher percentage of GATA3‐positive inflammatory cells compared to stage II and I tumors. Patients with positive GATA3 expression had a significantly lower disease‐free survival rate. However, there was no significant association between GATA3 expression and chemotherapy response score. These findings suggest that increased expression of GATA3 in mononuclear inflammatory cells is associated with higher grade, advanced stage, and increased risk of recurrence in tubo‐ovarian carcinoma. This implies that heightened GATA3 expression negatively impacts anti‐tumor immunity, tumor growth progression, and invasiveness in tubo‐ovarian carcinomas.

Ovarian mucinous cystic tumor with an overwhelming fundic gland differentiation

An ovarian mucinous cystic tumor where fundic glands were broadly and evenly distributed. All components were FOXA2-positive. The diagnosis is difficult between "mucinous cystadenoma with fundic gland differentiation" and "monodermal cystic teratoma composed of gastric tissue derived from endoderm".

Tissue factor expression and tumor‐infiltrating T lymphocytes in ovarian carcinomas and their association with venous thromboembolism

Ovarian cancer is a known risk factor of venous thromboembolism (VTE). Thrombogenic factor expression and lymphocytic infiltrate have been reported in endometriosis and ovarian cancers. We reviewed 30 cases of ovarian carcinomas (high grade serous carcinoma, 10; endometrioid carcinoma, 10; clear cell carcinoma (CCC), 10) and 16 endometriotic lesions. We immunohistochemically investigated the expressions of tissue factor (TF), podoplanin, P‐selectin, and number of CD4 and CD8 positive lymphocytes in cancer tissue and endometriotic lesions, along with their relationship with VTE. The expression of TF was higher in CCC. The TF expression and the number of CD8 positive cells were higher in cancer tissues with VTE than in those without VTE. The podoplanin or P‐selectin expression did not differ among histological types or between cases with and without VTE. Our results demonstrated a high TF expression and intraepithelial CD8 cells in CCC, which were associated with VTE. The results suggest that infiltrating lymphocytes may affect TF expression that, in turn, influences VTE.

Association of Smoothelin, a Cytoskeletal Component of Smooth Muscle Cells, With the Proliferative Features of Uterine Smooth Muscle Tumors

ABSTRACT Smoothelin, a cytoskeletal protein expressed in smooth muscle cells (SMCs), colocalizes with α‐smooth muscle actin and is typically restricted to the cytoplasm. Interestingly, in malignant smooth muscle tumors (SMTs), particularly uterine leiomyosarcoma (LMS), aberrant nuclear localization of smoothelin has been observed, though the underlying mechanism remains unclear. To investigate, 99 uterine SMT cases were analyzed, comprising 26 LMS and 73 non‐LMS (typical leiomyoma, cellular leiomyoma, mitotically active leiomyoma, and tumors of uncertain malignant potential). Histopathological and immunohistochemical evaluations included mitotic activity, Ki‐67 index, and smoothelin expression. In vitro, two humans uterine LMS cell lines (SK‐LMS‐1, SK‐UT‐1) and a primary uterine SMC line under proliferative conditions were examined. Nuclear smoothelin expression was significantly more frequent in LMS compared with non‐LMS. Within LMS tissues, both cytoplasmic and nuclear positivity were noted. Smoothelin‐positive regions exhibited significantly higher mitotic activity, whereas Ki‐67 labeling and nuclear size variation showed no association with localization. In cultured LMS cells, proliferation correlated with increased nuclear smoothelin positivity. These findings suggest that smoothelin is linked to proliferative capacity in SMTs, and its altered subcellular distribution may have potential utility in the pathological evaluation of SMTs.

Endometrial gastric‐type mucinous carcinoma: A clinicopathological study of an unfavorable histological type of endometrial carcinoma

Endometrial carcinosarcoma with melanocytic differentiation

Dedifferentiated carcinoma of the uterine corpus associated with unusual stromal reaction

Clinicopathological and molecular characteristics of endometrial neuroendocrine carcinomas reveal preexisting endometrial carcinoma origin

AbstractEndometrial neuroendocrine carcinoma is a rare disease with unknown clinicopathological and molecular characteristics. Therefore, we conducted the present study to elucidate the clinicopathological and molecular characteristics of endometrial neuroendocrine carcinoma, as compared to conventional endometrial carcinoma, and to determine the origin of the former. We analyzed 22 endometrial neuroendocrine carcinomas and 22 conventional endometrial neoplasia cases with respect to clinical, histological and genetic features. Of these, 21/22 neuroendocrine carcinoma cases were admixed carcinomas, with 15 admixed with endometrioid adenocarcinoma. Genetic analysis of hotspot mutations in 50 cancer‐related genes revealed that the neuroendocrine carcinoma group carried mutations in PIK3CA (12/22 cases; 54%) and PTEN (8/22 cases; 36%), commonly encountered in endometrioid adenocarcinoma. Comparative statistical analysis of neuroendocrine carcinoma and conventional endometrial neoplasia cases showed a significant trend only in PIK3CA mutation. Moreover, in six mixed‐type neuroendocrine carcinoma cases, macrodissection was used to separate the neuroendocrine carcinoma and endometrioid adenocarcinoma components for next‐generation sequencing, which revealed several mutations common among the two. These findings suggest that endometrial neuroendocrine carcinoma could originate from conventional endometrial neoplasia, especially endometrioid adenocarcinoma.

Pathology of clear cell carcinoma of the ovary: A basic view based on cultured cells and modern view from comprehensive approaches

Clear cell carcinoma (CCC) is a distinct histologic type of ovarian carcinoma.CCC is more frequent in Japan than in the Western world. CCC is chemo‐resistant and often associated with paraneoplastic thromboembolism. Histologically, CCC is characterized by both cancer cells and stromas, being concordant with the cytological features. Clear cells contain abundant glycogen. Hepatocyte nuclear factor‐1β is a specific marker of CCC, and is likely to be involved in glucose metabolism. Extracellular matrix (ECM)‐deposited stroma and plasma cell‐rich inflammatory stroma are characteristic stromas of CCC. Studies using CCC cell lines showed that CCC cells produce ECMs and stimulate plasma cell differentiation in a paracrine manner. Most CCCs, as well as endometrioid carcinomas, originate from ovarian endometriosis. This is supported by molecular genetic data, although it remains unclear why different histologic types originate from the same precursor. CCC and endometrioid carcinoma are Lynch syndrome‐associated ovarian carcinomas. Recent comprehensive studies indicate that CCC is distinct not only in terms of histology but also in genomics, epigenomics and transcriptomics. This review summarizes the pathology of ovarian CCC along with a basic view based on cultured cells, and refers to recent genetic and omic data.

Phosphoglyceride crystal deposition disease in a rib bone and ovary mimicking malignancy: A report of two cases including a previously undescribed cystic case

Ovarian smooth muscle tumor of uncertain malignant potential (STUMP) associated with smooth muscle metaplasia of the endometriotic cyst

Sclerosing stromal tumor with marked atypia that mimics an undifferentiated sarcoma