{"title":"Reactive Mesothelial Cells in the Lymphatic Network of the Serous Membrane in Prolonged Body Fluid Retention: An Autopsy Case Report.","authors":"Yuji Nitta, Tomoko Uchiyama, Hisae Suzuki, Fumi Okada, Maiko Takeda, Chiho Ohbayashi, Akihiko Yoshizawa","doi":"10.1111/pin.70028","DOIUrl":"10.1111/pin.70028","url":null,"abstract":"<p><p>Reactive mesothelial cells (RMCs) are of interest for differentiating mesothelioma from benign conditions and have been discussed in cytology and biopsy; however, their behavior in the body remains poorly understood. In this study, we report an autopsy case of an older woman with a long-standing pleural effusion due to cardiac disease, providing insights into the relationship between body cavities, and lymphatic vessels (LVs), mesothelial cells (MCs), and endothelial cells. Cytological examination of pleural effusion revealed RMCs with mild atypia, multinucleation, and intercellular phagocytosis. Immunohistochemistry confirmed the mesothelial origin of these cells. Autopsy findings showed extensive involvement of RMCs in the pleura, diaphragm, peritoneum, lymph vessels, and lymph node sinuses. The visceral pleural submesothelial LVs were dilated, had small openings in the thoracic cavity, and were lined with endothelial and mesothelial cells. Large cavernous LVs with MC clusters were observed on the diaphragm. These structures resembled \"stomata\" or \"lacunae,\" suggesting a mechanism by which RMCs migrate from the body cavities to the lymphatic network. This study focuses on the RMCs in LVs and shows the contiguity between body cavities and lymphatic networks, providing important insights into the flow of bodily fluids.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":"373-378"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MYCBP2 Expression Correlates With Poor Prognosis in Upper Tract Urothelial Carcinoma Patients.","authors":"Lee-Moay Lim, Yi-Chen Lee, Wei-Chi Hsu, Wen-Yu Chung, Hui-Hui Lin, Ting-Wei Lin, Hung-Lung Ke, Wei-Ming Li, Wen-Jeng Wu, Hung-Tien Kuo, A-Mei Huang","doi":"10.1111/pin.70029","DOIUrl":"10.1111/pin.70029","url":null,"abstract":"<p><p>The incidence of upper tract urothelial carcinoma (UTUC) in Taiwan is high, characterized by aggressive clinical behavior and a tendency to be more invasive at diagnosis. Identifying tumorigenic genes remains an important challenge. Myc binding protein 2 (MYCBP2) regulates the cAMP, p38MAPK, TSC/mTOR, and autophagy signaling pathways in mammalian cells. MYCBP2 dysfunction has been associated with poor prognosis in leukemia, melanoma, colon, and prostate cancer. Its role in UTUC needs to be clarified. We investigated the expression of MYCBP2 in UTUC and its relationship to patient outcomes. MYCBP2 expression levels were assessed by immunohistochemistry in 110 tissue samples from UTUC patients. Higher MYCBP2 protein expression was significantly correlated with worse disease-free survival (p = 0.001) and cancer-specific survival (p = 0.007). The major clinicopathological characteristics associated with MYCBP2 expression were stage, lymphovascular invasion, distant metastasis, recurrence, and cancer death. Based on multivariate analysis, pathological stage (HR:2.31, p = 0.017) and MYCBP2 expression (HR:2.75, p = 0.015) were significant predictors of disease-free survival in UTUC. MYCBP2 is elevated in UTUC cell lines compared with immortalized uroepithelial cells. Knocking down MYCBP2 significantly suppressed cellular migration and invasion activity in BFTC909 cells. In conclusion, MYCBP2 expression might predict poor survival among UTUC patients.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":"349-358"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ayuna Sugai, Kosuke Miyai, Keiichi Ito, Susumu Matsukuma, Kimiya Sato
{"title":"Kidney Injury Molecule-1 Expression in Pathological T1b Clear Cell Renal Cell Carcinoma: A Putative Biomarker of High Immune-Inflamed Status and Recurrence.","authors":"Ayuna Sugai, Kosuke Miyai, Keiichi Ito, Susumu Matsukuma, Kimiya Sato","doi":"10.1111/pin.70024","DOIUrl":"10.1111/pin.70024","url":null,"abstract":"<p><p>Kidney injury molecule-1 (KIM-1) is a potential prognostic marker of advanced-stage clear cell renal cell carcinoma (ccRCC) and is associated with tumor immunogenicity. Little is known about its role in early-stage ccRCC, especially in pathological T1b (pT1b) disease, which shows a higher recurrence rate than pT1a disease. Resected specimens from 112 pT1b ccRCC cases were reviewed and immunohistochemically analyzed for KIM-1 expression. High membranous KIM-1 expression was defined as H score ≥ 140, based on the immunoreactive intensity and area, and cytoplasmic expression in ≥ 10% of cancer cells was considered as high cytoplasmic KIM-1 expression. KIM-1 expression status was compared with clinicopathological variables, including tumor-associated immune cell (TAIC) status. Among the 112 cases, high membranous and cytoplasmic KIM-1 expression was observed in 30 (27%) and 38 (34%) cases, respectively. High membranous KIM-1 expression was significantly associated with a higher nuclear grade, tumor necrosis, hot TAIC status, and shorter recurrence-free survival (RFS) and cancer-specific survival, whereas high cytoplasmic expression was only related to a higher nuclear grade. Multivariate Cox regression analysis revealed that high membranous KIM-1 expression and tumor necrosis were independent predictors of shorter RFS. Our results indicate that membranous KIM-1 expression could be a biomarker for predicting postnephrectomy recurrence in pT1b ccRCC.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":"340-348"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Landscape of Cancer Metabolism as a Therapeutic Target.","authors":"Kenji Ohshima","doi":"10.1111/pin.70034","DOIUrl":"https://doi.org/10.1111/pin.70034","url":null,"abstract":"<p><p>Cancer cells reprogram their metabolism during progression to adapt to the tumor microenvironment, which is characterized by distinct differences in nutrient availability, oxygen concentrations, and acidity. This metabolic reprogramming can simultaneously create metabolic vulnerabilities unique to cancer cells, making cancer metabolism a promising therapeutic target. Since the clinical application of folate antimetabolites in the 1940s, numerous therapeutic strategies targeting cancer metabolism have been developed. In recent years, advancements in technologies such as metabolome analysis have facilitated the development of agents that more specifically target cancer cell metabolism. However, these newly developed agents often face challenges in demonstrating efficacy as monotherapies in clinical trials. Nevertheless, combination therapies, designed based on precise mechanistic insights and incorporating agents such as immune-checkpoint and signaling-pathway inhibitors, have shown promising efficacy. This review provides an overview of the current landscape of therapeutic strategies targeting cancer metabolism, with a particular focus on approaches targeting amino acid, fatty acid, and glucose metabolism in cancer cells.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Koki Nakashima, Hitomi Hoshino, Zui Zhang, Tomoya O Akama, Nobuyuki Kondo, Seiki Hasegawa, Yoshitaka Sekido, Mana Fukushima, Tamotsu Ishizuka, Motohiro Kobayashi
{"title":"Expression of Heart Development Protein With EGF-Like Domains 1 (HEG1) Decorated With Low-Sulfated Keratan Sulfate in Human Malignant Pleural Mesothelioma.","authors":"Koki Nakashima, Hitomi Hoshino, Zui Zhang, Tomoya O Akama, Nobuyuki Kondo, Seiki Hasegawa, Yoshitaka Sekido, Mana Fukushima, Tamotsu Ishizuka, Motohiro Kobayashi","doi":"10.1111/pin.70033","DOIUrl":"https://doi.org/10.1111/pin.70033","url":null,"abstract":"<p><p>The glycoform of heart development protein with EGF-like domains 1 (HEG1) recognized by the SKM9-2 monoclonal antibody is a useful diagnostic marker for malignant pleural mesothelioma (MPM). The putative glycoform includes core 2 O-glycans carrying sialyl poly-N-acetyllactosamine (LacNAc), but sulfation modifications are undetermined. Since sialyl 6-sulfo LacNAc-capped core 2 O-glycans are expressed in MPM and their structure overlaps with low-sulfated keratan sulfate (KS), we asked whether low-sulfated KS is expressed in MPM and whether HEG1 is decorated with low-sulfated KS. We performed immunohistochemical analysis of 41 MPM cases using anti-KS monoclonal antibodies and endoglycosidases, reversed-phase ion-pair high-performance liquid chromatography analysis of KS/sulfated LacNAc isolated from human pleural tissue, and western blot analysis of HEG1·IgG recombinant fusion proteins secreted from low-sulfated KS-expressing human embryonic kidney cells. Most MPM tissues were stained with anti-low-sulfated KS antibodies and staining was eliminated by endo-β-galactosidase and keratanase II but not by peptide-N-glycosidase F. Disaccharide composition analysis revealed that mono-sulfated LacNAc disaccharide and di-sulfated LacNAc disaccharide accounted for 83.1% and 16.9% of pleural KS/sulfated LacNAc, respectively. Western blot analysis of HEG1·IgG glycoforms indicated that HEG1 functions as a core protein for low-sulfated KS. Thus, HEG1 protein decorated with low-sulfated KS is expressed in MPM.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryo Kaimori, Haruto Nishida, Riko Kubota Furukawa, Kazuhiro Kawamura, Mari Tamura, Kohji Kuroki, Shinji Yano, Kumi Murata, Tsutomu Daa, Shinjiro Mori
{"title":"Unexpected Autopsy Case of Placental Transmogrification of the Lung With Lipomatous Change With Detailed Immunohistochemical Analysis.","authors":"Ryo Kaimori, Haruto Nishida, Riko Kubota Furukawa, Kazuhiro Kawamura, Mari Tamura, Kohji Kuroki, Shinji Yano, Kumi Murata, Tsutomu Daa, Shinjiro Mori","doi":"10.1111/pin.70031","DOIUrl":"https://doi.org/10.1111/pin.70031","url":null,"abstract":"<p><p>Placental transmogrification of the lung (PTL) is a rare cystic lesion characterized by a distinctive microscopic architecture resembling placental villi. Although its etiology remains unclear, PTL is frequently observed with emphysema, suggesting a potential association between these conditions. However, the precise nature of this relationship remains ambiguous, and whether PTL causes or results from emphysema remains unclear. This report presents an incidental finding of PTL without macroscopic emphysematous changes with detailed immunohistochemical and ultrastructural analysis. A 58-year-old man died from aspiration pneumonia due to methanol poisoning. Autopsy revealed pyothorax in the right lung cavity and hemorrhage in the bilateral putamen. Although the left lung showed no severe inflammatory changes, a white-yellowish granular lesion was observed. Histopathologically, the lesion demonstrated villi-like structures with interstitial adipocyte infiltration, without evidence of hamartomatous component, such as cartilage or smooth muscle. Thus, the lesion was diagnosed as PTL with lipomatous change. PTL is typically associated with emphysematous/cystic lesions and is often considered reactive due to these. Herein, the lesion was surrounded by microscopic emphysema, suggesting an early-stage PTL that may have contributed to the development of emphysematous changes. This report describes the PTL with detailed immunohistochemical analysis.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"High Frequency of RhoGAP Fusion and Muscularis Mucosae Invasion in pT1a Gastric Adenocarcinoma Harboring Lymph Node Metastasis.","authors":"Chiina Hata, Hiroto Noda, Kaoru Nakano, Seiji Sakata, Kazuma Moriya, Satoko Baba, Toshiaki Hirasawa, Manabu Takamatsu, Emiko Sugawara, Noriko Yamamoto, Souya Nunobe, Takuji Gotoda, Kenichi Ohashi, Kengo Takeuchi, Hiroshi Kawachi","doi":"10.1111/pin.70032","DOIUrl":"https://doi.org/10.1111/pin.70032","url":null,"abstract":"<p><p>Gastric cancer (GC) confined to the mucosa (pT1a-GC) has a low incidence (approximately 3%) of lymph node metastasis (LNM), making it a suitable candidate for endoscopic resection. However, the current risk stratification system inadequately identifies high-risk patients. Although RhoGAP fusion has been identified as a risk factor for LNM in pT1b-GC, its role in pT1a-GC remains unclear. In the present study, medical records of 1099 surgically resected pT1a-GC cases over 12 years were reviewed, identifying 33 cases (3.0%) with LNM. A case-control study compared these cases to 99 LNM-negative cases based on clinicopathological data. Histological reviews and fluorescence In Situ hybridization assays to evaluate RhoGAP fusions, represented by CLDN18::ARHGAP26, were conducted. Univariate analysis revealed significant associations between LNM and larger tumor size (> 30 mm), mixed histological type, muscularis mucosae invasion (MMI), microtubular-mucocellular histology, and RhoGAP fusion. Multivariate analysis identified RhoGAP fusion and MMI as independent LNM predictors. Among LNM-positive cases, RhoGAP fusion was observed in 51.5% (17/33) and was associated with younger age and less frequent MMI. In conclusion, RhoGAP fusion and MMI may be significant biomarkers for LNM in pT1a-GC. Incorporating these factors could enhance risk stratification and inform clinical management strategies for pT1a-GC.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Increased Expression of AXL and c-MET in High-Grade Clear Cell Renal Cell Carcinoma and Its Association With VEGFR-TKI Treatment and PD-L1 Expression.","authors":"Shuji Mikami, Ryuichi Mizuno, Nobuyuki Tanaka, Kyohei Hakozaki, Kimiharu Takamatsu, Mototsugu Oya","doi":"10.1111/pin.70030","DOIUrl":"https://doi.org/10.1111/pin.70030","url":null,"abstract":"<p><p>Cabozantinib, a newly developed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI), is an effective treatment for advanced renal cell carcinoma (RCC). However, the molecular mechanisms responsible for the superior effectiveness of cabozantinib to other drugs remain unclear. Since cabozantinib inhibits AXL and c-MET in addition to VEGFR, the expression of these molecules was immunohistologically examined in 110 cases of primary clear cell RCC (ccRCC) and eight of sunitinib (VEGFR-TKI)-treated primary ccRCC. AXL expression correlated with the primary tumor stage, while c-MET expression correlated with distant metastasis, the histological grade, and overall survival. Furthermore, the number of programmed death-ligand 1 (PD-L1)-positive tumor-infiltrating immune cells was higher in ccRCC tissues with high c-MET expression than in those with low c-MET expression. The expression of AXL and c-MET was higher in sunitinib-treated ccRCC tissues than in untreated tissues. These results suggest that AXL and c-MET play important roles in the progression of ccRCC and resistance to sunitinib. Furthermore, c-MET may modify the immune microenvironment by inducing PD-L1 expression in immune cells within RCC tissues. These molecular pathways may be related to responses to cabozantinib.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification of Target Genes Using Innovative Screening Systems.","authors":"Keisuke Sugita, Morito Kurata","doi":"10.1111/pin.70019","DOIUrl":"10.1111/pin.70019","url":null,"abstract":"<p><p>Advances in cancer biology have been achieved by the identification of oncogenes and tumor suppressor genes through the remarkable progression of next-generation sequencing. New techniques, such as single-cell analysis, help uncover cancer progression and heterogeneity. Reverse genetic screenings, including methods like random mutagenesis via retroviruses, transposons, RNA interference, and CRISPR, are useful for exploring gene functions and their roles in cancer. Especially in random mutagenesis, CRISPR screening and its modifications have recently emerged as powerful tools due to their comprehensiveness and simplicity in inducing genetic mutations. Initially, CRISPR screening focused on analyzing biological phenotypes in a cell population. It has since evolved to incorporate advanced techniques, such as combining single-cell and spatial analyses. These developments enable the investigation of cell-cell and spatial interactions, which more closely mimic In Vivo microenvironments, offering deeper insights into complex biological processes. These approaches allow for the identification of essential genes involved in cancer survival, drug resistance, and tumorigenesis. Together, these technologies are advancing cancer research and therapeutic development.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":" ","pages":"257-266"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}