Yuko Miyakami, Wenhua Shao, Mayuko Shimizu, Hirohisa Ogawa, Yuko Nakanishi and Koichi Tsuneyama : CAM5.2 immunostaining visualizes hemodynamic-driven ductular-like differentiation in the liver: a practical marker for distinguishing circulatory disturbance-related hyperplastic lesions from hepatocellular tumors, The Journal of Medical Investigation : JMI, 73, 1.2, 234-240, 2026.
(Summary)
Focal nodular hyperplasia (FNH) is thought to arise from intrahepatic circulatory disturbances, but its distinction from hepatocellular carcinoma (HCC) and hepatocellular adenoma (HCA) remains challenging, especially in lesions with minimal cytological atypia. CAM5.2 is widely available in routine pathology laboratories, yet its diagnostic significance in hepatic lesions is unclear. We investigated whether CAM5.2 immunostaining visualizes hemodynamic-driven phenotypic changes of hepatocytes and whether its spatial pattern is informative. CAM5.2 immunohistochemical staining was analyzed in surgically resected specimens of FNH, HCA (HNF1α-inactivated and inflammatory subtypes), and HCC. The localization, distribution, and spatial regularity of CAM5.2 expression in hepatocytes and bile duct structures were evaluated and correlated with histological features of vascular remodeling. In FNH, CAM5.2 showed a regular staining pattern confined to nodules and aligned along fibrous septa or abnormal vessels, highlighting ductular structures and adjacent hepatocytes. This pattern was absent in background liver parenchyma. In contrast, hepatocellular tumors showed irregular patterns:HNF1α-inactivated HCA exhibited weak focal positivity, inflammatory HCA diffuse staining, and HCC heterogeneous, patchy, or negative staining. CAM5.2 visualizes hemodynamic-driven, ductular reaction-like phenotypic modulation of hepatocytes. A regular spatial pattern supports circulatory disturbance-related hyperplastic lesions e.g., FNH and aids exclusion of HCC and HCA. J. Med. Invest. 73 : 234-240, February, 2026.
Hirohisa Ogawa, Kayu Kinouchi, Mayuko Shimizu, Nagisa Yawata, Zen Akazawa, Orgil Jargalsaikhan, Takaaki Koma, Shotaroh Tachibana, Takeshi Kageyama, Kengo Atsumi, Yuko Miyakami, Wenhua Shao, Yu Saitou, Masako Nomaguchi, Yuji Morine and Koichi Tsuneyama : HDV Infection Status in Tokushima Prefecture Based on Histopathological Evaluation: A Single-Institution Study, The Journal of Medical Investigation : JMI, 73, 1-2, 52-54, 2026.
(Summary)
Hepatitis D virus (HDV) is a defective RNA virus requiring hepatitis B virus (HBV) for replication, and co-infection of them significantly accelerates liver inflammation, fibrosis, and hepatocarcinogenesis. Recent studies have reported that the prevalence of HDV infection is extremely high in certain regions, such as Mongolia, exceeding 50% among individuals infected with HBV. To clarify the potential presence of HDV infection in Japan, we retrospectively examined 95 surgically resected cases for HBV-related hepatocellular carcinoma (HCC) at Tokushima University Hospital between 2003 and 2023. Formalin-fixed, paraffin-embedded liver tissues were subjected to immunohistochemistry using an antibody against large and small delta antigens of HDV. Plasma samples from 12 patients were additionally tested by ELISA. As a result, none of the HBV-related HCC cases showed immunoreactivity for HDV antigens in either tumor or non-neoplastic tissues, and all available plasma samples were negative by ELISA. These findings suggest that HDV infection is either absent or extremely rare among patients with HBV-related HCC in this cohort. Our results align with prior seroprevalence estimates and provide histopathological evidence supporting minimal contribution of HDV to liver carcinogenesis in Japan, contrasting sharply with patterns in hyperendemic regions. J. Med. Invest. 73 : 52-54, February, 2026.
Honoka Nakahara, Mayuko Shimizu, Shotaroh Tachibana, Orgil Jargalsaikhan, Cai Qinyi, Yuko Miyakami, Hirohisa Ogawa, Satoru Matsuda and Koichi Tsuneyama : Association of lipids in lipoprotein subfractions with liver fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis., The Journal of Medical Investigation : JMI, 72, 3.4, 375-384, 2025.
(Summary)
Metabolic dysfunction-associated steatohepatitis (MASH) exhibits inflammation and fibrosis in addition to lipid accumulation in the liver, which may progress to cirrhosis and liver failure. This study investigated whether the serum lipoprotein subfraction reflects fibrosis severity in a MASH mouse model. Nine-week-old male A/J and C57BL6/J mice were fed a high-fat/cholesterol/cholate-based diet to induce fibrotic MASH. To generate fibrosis of varying severity, mice were fed two diets with different cholesterol concentrations (1.25% and 2.5%). After 9 weeks of feeding, serum cholesterol and triglyceride levels of each lipoprotein were comprehensively analyzed, including chylomicron, very-large low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), with 20 subclasses according to particle size. Serum levels of very-large HDL-cholesterol, very-small HDL-cholesterol, very-small HDL-triglycerides, and very-small LDL-cholesterol were significantly higher in the stage 2 fibrosis group than the stage 1 fibrosis group. Serum very-small LDL-cholesterol levels were correlated with histological severity of MASH, which reportedly increases with the progression of MASH in humans. In conclusion, the serum lipoprotein subfraction reflects liver fibrosis severity even in early phase, independent of the severity of other MASH lesions in MASH model mice. Fractionating HDL, which have been measured in clinical practice, may help establish noninvasive markers of liver fibrosis. J. Med. Invest. 72 : 375-384, August, 2025.
We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype. This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA). Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01). The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.
Takumi Kakimoto, Masato Hosokawa, Mayuko Ichimura-Shimizu, Hirohisa Ogawa, Yuko Miyakami, Satoshi Sumida and Koichi Tsuneyama : Accumulation of α-synuclein in hepatocytes in nonalcoholic steatohepatitis and its usefulness in pathological diagnosis, Pathology, Research and Practice, 247, 154525, 2023.
(Summary)
Nonalcoholic steatohepatitis (NASH) is characterized by fat deposition, inflammation, and hepatocellular damage. The diagnosis of NASH is confirmed pathologically, and hepatocyte ballooning is an important finding for definite diagnosis. Recently, α-synuclein deposition in multiple organs was reported in Parkinson's disease. Since it was reported that α-synuclein is taken up by hepatocytes via connexin 32, the expression of α-synuclein in the liver in NASH is of interest. The accumulation of α-synuclein in the liver in NASH was investigated. Immunostaining for p62, ubiquitin, and α-synuclein was performed, and the usefulness of immunostaining in pathological diagnosis was examined. Liver biopsy tissue specimens from 20 patients were evaluated. Several antibodies against α-synuclein, as well as antibodies against connexin 32, p62, and ubiquitin were used for immunohistochemical analyses. Staining results were evaluated by several pathologists with varying experience, and the diagnostic accuracy of ballooning was compared. Polyclonal α-synuclein antibody, not the monoclonal antibody, reacted with eosinophilic aggregates in ballooning cells. Expression of connexin 32 in degenerating cells was also demonstrated. Antibodies against p62 and ubiquitin also reacted with some of the ballooning cells. In the pathologists' evaluations, the highest interobserver agreement was obtained with hematoxylin and eosin (H&E)-stained slides, followed by slides immunostained for p62 and α-synuclein, and there were cases with different results between H&E staining and immunostaining CONCLUSION: These results indicate the incorporation of degenerated α-synuclein into ballooning cells, suggesting the involvement of α-synuclein in the pathogenesis of NASH. The combination of immunostaining including polyclonal α-synuclein may contribute to improving the diagnosis of NASH.
Satoshi Sumida, Mayuko Ichimura-Shimizu, Yuko Miyakami, Takumi Kakimoto, Tomoko Kobayashi, Yasuyo Saijo, Minoru Matsumoto, Hirohisa Ogawa, Takeshi Oya, Yoshimi Bando, Hisanori Uehara, Shu Taira, Mitsuo Shimada and Koichi Tsuneyama : Histological and immunohistochemical analysis of epithelial cells in epidermoid cysts in intrapancreatic accessory spleen, The Journal of Medical Investigation : JMI, 70, 1.2, 251-259, 2023.
(Summary)
Epidermoid cysts in intrapancreatic accessory spleen (ECIPAS) are a rare lesion. Its pathogenesis, including the origin of cystic epithelium, is not well established. We aimed to elucidate new aspects of the pathological features of ECIPAS to clarify its pathogenesis. Six cases of ECIPAS were included in this study. As well as histopathological analysis, to elucidate the features and nature of cystic epithelial cells, immunohistochemical analysis including Pbx1 and Tlx1 and imaging mass spectrometry was performed. Histologically, the cysts were covered by either monolayered or multilayered epithelium. Immunohistochemistry revealed that the epithelial cells in multilayered epithelium exhibited different attributes between the basal and superficial layers. Few epithelial cells had abundant clear cytoplasm and were immunohistochemically positive for adipophilin, suggesting lipid-excreting function. The intracystic fluid contained cholesterol clefts and foamy macrophages, and imaging mass spectrometry revealed the accumulation of lipids. Immunohistochemical analysis indicated that the epithelial cells were positive for Pbx1 in some cases. Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.
(Keyword)
Epidermoid cyst in intrapancreatic accessory spleen / imaging mass spectrometry / lipid excretion / Pbx1 / Tlx1
Takayuki Noma, Masaaki Nishi, Chie Takasu, Yuuma Wada, Kozo Yoshikawa, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Toshiaki Yoshimoto, Yuko Miyakami, Kengo Atsumi, Hisanori Uehara and Mitsuo Shimada : Conversion surgery after successful response to chemotherapy (S-1 + oxaliplatin + nivolumab) in a patient with stage IV gastric cancer with peritoneal metastasis (P1, CY1): a case report., International Cancer Conference Journal, 13, 1, 11-16, 2023.
(Summary)
We here present a case report of a patient with Stage IV gastric cancer with peritoneal metastasis (P1, CY1) who underwent conversion surgery after a successful response to chemotherapy (S-1 + oxaliplatin + nivolumab). The patient was a woman in her 60 s. Her chief complaint was epigastric pain. Upper gastrointestinal endoscopy showed Type 4 advanced carcinoma on the lesser curvature of the gastric body. Biopsy showed Group 5 (poorly differentiated adenocarcinoma) and HER2 was negative. Staging laparoscopy revealed seeding in the round ligament of the liver (P1) and adenocarcinoma cells in ascites (CY1). Ten courses of chemotherapy (S-1 + oxaliplatin + nivolumab) were administered, after which contrast-enhanced computed tomography showed that the primary tumor had shrunk and seeding was no longer detectable. Upper gastrointestinal endoscopy revealed scar-like changes. A second staging laparoscopy revealed that ascites cytology was negative and a biopsy of the round ligament of the liver showed no malignant cells (P0, CY0). Conversion surgery comprising laparoscopic total gastrectomy with D2 lymph node dissection and resection of the round ligament of the liver was performed. The postoperative course was uneventful. Histopathological examination of the resected specimen revealed no tumor cells in the gastric mesentery or the round ligament of the liver. The pathological diagnosis was gastric cancer [M, U, L, Less, Ant, Post, type4, T3(SS), N0, M0 (H0, P0, CY0), ypStage IIA]. Adjuvant chemotherapy (S-1) was commenced. The patient is still alive 7 months later with no evidence of recurrence.
Mayuko Shimizu, Yuko Miyakami, Minoru Matsumoto, Yoshimura Kentaro, Tsutsui Akemi, Tsuchiyama Yosuke, Takaguchi Koichi, Takeda Sén and Koichi Tsuneyama : An algorithm based on serum phospholipid profiles to predict liver fibrosis degree in metabolic dysfunctionassociated steatotic liver disease, EASL, 2024.
Proceeding of Domestic Conference:
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Yuko Miyakami, Sumida Satoshi, Takayama Yoshimasa, Yoshimi Bando, Hisanori Uehara and Michiko Yamashita : A case of classic Hodgkin lymphoma nodular sclerosis, relapsing in the skin with T-cell receptor gene rearrangement, The journal of the Japanese Society of Lymphoreticular Tissue, Jun. 2024.