福嶋 敬宜

INTRODUCTION: The Hippo pathway consists of mammalian sterile 20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and yes-associated protein (YAP)1. Herein, we present the first report on the significance of major Hippo pathway protein expression in oral squamous cell carcinoma (OSCC). METHODS: The analyses included oral epithelial dysplasia (OED, n = 7), carcinoma in situ (CIS, n = 14), and oral squamous cell carcinoma (OSCC, n = 109). RESULTS: Cytoplasmic expression of MST1, LATS1, and LATS2 was low in OED, CIS, and OSCC. The cytoplasmic expression of MST2 was high in OED (5/7 cases), CIS (9/14 cases), and poorly differentiated OSCC (8/8 cases) but was low/lost in a proportion of differentiated OSCC (60/101 cases). The expression of YAP1 was associated with differentiation; low YAP expression was significantly more frequent in well-differentiated OSCC (35/71 cases), compared to moderately and poorly differentiated OSCC (11/38 cases). An infiltrative invasion pattern was associated with a high expression of MST2 and high expression of YAP1. The high expression of YAP1 was associated with features of epithelial-to-mesenchymal transition (EMT), such as the loss of E-cadherin and high expression of vimentin, laminin 5, and Slug. High expression of protein arginine methyltransferase (PRMT) 1 or 5, which positively regulates YAP activity, was associated with the high expression of YAP1 (p < 0.0001). CONCLUSION: Among the major Hippo pathway proteins, MST2 displayed a distinctive expression pattern in a significant proportion of differentiated OSCC, suggesting a possible differential role for MST2 depending on the course of OSCC progression. A high YAP1 expression may indicate aggressive OSCC with EMT via PRMTs at the invasive front.

The present study immunohistochemically investigated trimethylation of lysine 27 of histone 3 (H3K27me3) expression in 769 endometrial carcinomas and 196 uterine mesenchymal tumors. One dedifferentiated endometrial carcinoma (DEC) and one carcinosarcoma showed H3K27me3 deficiency that was limited to undifferentiated and sarcomatous components, respectively. Switch/sucrose nonfermenting (SWI/SNF) complex subunits (SMARCA4, SMARCB1, and ARID1A/1B) and mismatch repair proteins were proficient in both tumors. The dimethylation of H3K27 (H3K27me2) was deficient in the undifferentiated component, whereas the sarcomatous component had scattered H3K27me2-positive cells. CXorf67, which inhibits PRC2 function, was diffusely expressed in the sarcomatous component. CXorf67 was negative in the undifferentiated component, which was submitted to a genetic analysis and showed no alterations in PRC2 core subunits or H3K27. The present results suggest H3K27 methylation dysregulation as a cause of SWI/SNF-proficient DEC and carcinosarcoma and imply differences in their level of and the mechanisms underlying H3K27 methylation dysregulation.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are a cystic precursor to pancreatic cancer. IPMNs deemed clinically to be at high-risk for malignant progression are frequently treated with surgical resection, and pathological examination of the pancreatectomy specimen is a key component of the clinical care of IPMN patients. METHODS: Systematic literature reviews were conducted around eight topics of clinical relevance in the examination of pathological specimens in patients undergoing resection of IPMN. RESULTS: This review provides updated perspectives on morphological subtyping of IPMNs, classification of intraductal oncocytic papillary neoplasms, nomenclature for high-grade dysplasia, assessment of T stage, distinction of carcinoma associated or concomitant with IPMN, role of molecular assessment of IPMN tissue, role of intraoperative assessment by frozen section, and preoperative evaluation of cyst fluid cytology. CONCLUSIONS: This analysis provides the foundation for data-driven approaches to several challenging issues in the pathology of IPMNs.

A 61-year-old woman was administered 35 cycles of pembrolizumab for the treatment of recurrent endometrial cancer, achieving a complete response. She presented with asymptomatic pancreatic enlargement and elevated hepatobiliary enzymes, but amylase and lipase levels were within the normal ranges. Intrapancreatic bile duct stenosis due to pancreatic enlargement was present, mimicking autoimmune pancreatitis on computed tomography performed before the onset of clinical manifestations. A histological examination of a biopsy specimen showed lymphocyte and plasma cell infiltration with dense fibrosis in the stroma. The patient was successfully treated with oral prednisolone. There were no manifestations of recurrent pancreatitis after tapering the prednisolone dose.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.