Comprehensive Pathology Division Department of
Pathology Jichi Medical University School of Medicine
Activities
A. Past achievements in the field of pancreatic and biliary tumor pathology
Pancreatic and biliary tract cancers are cancers with a steady increase in both incidence and mortality, and even with the current advances in diagnosis and treatment of various cancers, they are still difficult to detect early and are representative of cancers with poor prognosis. In particular, many pancreatic cancers are already advanced at the time of discovery, and because of their anatomical location, they are difficult to visualize with imaging equipment, so there are many unknowns about precursor lesions, early pancreatic cancer, and the process by which pancreatic cancer develops and progresses.
In this context, it has been discovered that precursor lesions of human pancreatic ductal carcinoma include pancreatic intraepithelial neoplasia (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), while precursor lesions of biliary duct cancer include biliary intraepithelial neoplasia (Bil-INs) and intraductal papillary neoplasms (IPNBs).
I have attempted to clarify the characteristics of the development and progression of precursor lesions of pancreatic cancer and to search for diagnostic markers from the perspectives of abnormal protein expression, abnormal methylation, comprehensive gene expression analysis, and clinical pathological analysis.
Among them, we found that aberrant methylation, which is often detected in pancreatic cancer cells, is also found in PanINs, and that the frequency of this increases in correlation with the increase in the histopathological grade of PanINs [Am J Pathol (2002), Modern Pathol (2008)]. It has also been shown that such aberrant methylation genes can be detected in pancreatic juice and applied to early diagnosis [Cancer Bio Ther (2003)]. Comprehensive gene expression analysis using RNA extracted from tumor cells of PanIN and IPMN showed that abnormalities in the Heghog pathway are observed in the development of PanIN [Cancer Res (2005)], and genes (S100A4, Claudin4, etc.) that are highly expressed in invasive IPMN compared to noninvasive cancer were identified [Am J Pathol (2004)].
Meanwhile, detailed investigation of the expression and distribution of periostin, a secretory protein highly expressed in the stroma of invasive pancreatic ductal carcinoma, has revealed that in the process of IPMN progression from benign (adenoma) to noninvasive carcinoma and then to invasive carcinoma, changes occur not only in the tumor cells themselves but also in the tissue surrounding the tumor [Modern Pathol (2008)]. Even in noninvasive IPMN, when the lesion becomes highly dysplastic, periostin is frequently positive in the stroma adjacent to the tumor, making it clear that interactions between the tumor and surrounding stromal cells begin at the noninvasive cancer stage. Using such secretory proteins as markers may enable detection of tumors at the noninvasive cancer stage.
In a comprehensive gene expression analysis focusing on tissue changes around pancreatic cancer, it was found that HIP/PAP genes and HC gp39 genes were highly expressed in the parenchymal tissues around pancreatic cancer (acinar cells, islets of Langerhans, etc.) compared to the parenchymal tissues distant from the cancer. Furthermore, when the amount of HC gp39 protein in serum was examined using ELISA, it was found to be significantly elevated in pancreatic cancer patients [Modern Pathol (2005)].
Since then, we have conducted comprehensive analysis of early-stage lesions of pancreatic and biliary cancer, including tumor cells, stromal cells, and surrounding parenchymal cells, and have demonstrated that matriptase expression is highly expressed in the stroma of extrahepatic bile duct cancer and that it is an independent prognostic factor.
Recently, we have been working on 3D Ki-67 (proliferation potential) analysis using tissue clearing technology in pancreatic neuroendocrine tumors (PanNET) (Pancreatology), 3D analysis of neovascular tumor blood vessels, and artificial intelligence analysis of pathological images (Scientific Report).
C. Clarification of international pathological disease concepts
Internationally, I have been involved in the organization of classifications related to pancreatic cancer, including WHO Tumor Classification (Pancreas, author), WHO Reporting System (Pancreatobiliary, editor), and as a pancreas member of ICCR (International Committee on Cancer Research), and domestically as a member of the Pancreatic Cancer Treatment Committee.
① International consensus on the histological subtypes of pancreatic intraductal tumors (Virchows Arch, 2005): The histological subtype classification jointly created here is still used in current international classifications such as the WHO classification.
② Pancreatic Cancer Screening (CAPS) Summit (Gut, 2013): I was invited to participate in this summit, which brought together experts from various fields to discuss early diagnosis of pancreatic cancer.
③ International consensus on precursor lesions of pancreatic cancer (Am J Surg Pathol, 2004, Am J Surg Pathol, 2015):
I participated as an early member in the consensus conference known as the "Baltimore Consensus" conference on the current diagnostic criteria and classification of intraductal neoplasms (intraductal papillary mucinous neoplasms (IPMN), intraductal papillary tubular neoplasms (ITPN), and intraductal oncocytic neoplasms (IOPN)) and neoplastic lesions (intraepithelial neoplasms (PanIN)). This consensus classification has become so widespread both in Japan and overseas that it is thought that there are almost no people involved in the research and treatment of pancreatic cancer who are unaware of it.
④ Japan-Korea Joint Statement on Intraductal Papillary Neoplasms (IPNB) (J HPBPS, 2018):
There had been considerable confusion internationally about how to organize and classify papillary tumors that develop within the bile duct, but this joint Japan-Korea project (with four Japanese members) was able to consolidate a certain amount of opinion by classifying these tumors into type 1 and type 2 based on their similarity to intraductal tumors of the pancreas. This was then adopted in the international classification, the WHO classification (published in 2019).
⑤Amsterdam Statement on Post-Treatment Pancreatic Cancer Evaluation (Mod Pathol, 2021, Br J Surg, 2022):
Chemotherapy for pancreatic cancer has been improved, and treatment outcomes have improved slightly. In response to this, chemotherapy is administered to both resectable and unresectable cases, and pancreatic resection is performed for resectable cases, and pancreatic resection is performed for unresectable cases that become resectable. Therefore, standardization of histological evaluation of the therapeutic effect after chemotherapy became an international issue, and a conference was held in Amsterdam in 2019, where I was the only Japanese person invited to participate in consensus building.
⑥Pancreatic Cancer Guidelines 7th and 8th English Edition Committee Members (2016, 2017, 2023):
While keeping abreast of international trends, we are contributing to the creation of standards for the handling of pathological specimens and lesions that are suited to the actual clinical situation in Japan.
⑦ WHO Classification of Gastrointestinal Tumors 4th Edition Editorial Committee (2009), 5th Edition Author (2019):
Currently, the international standard for the histological classification of tumors is the so-called “WHO Classification” issued by the International Health Organization (WHO) and the International Agency for Research on Cancer (IARC). During the production of the fourth edition, I was invited to become one of the editors, the first Japanese person in the field of pancreaticobiliary cancer to join the team.
⑧ WHO Pancreaticobiliary Cytology Reporting System 1st Edition Editorial Board (2022):
The need for international standardization of cytology reports has come to be called for, and WHO/IARC has decided to create the "WHO system" in collaboration with the International Society of Cytology. I was invited as the only Japanese person to serve as an expert member in the creation of the pancreatic and biliary cytology reporting system, and participated in the editing work.
⑨ International Committee on Cancer Pathology Reporting (ICCR) Pancreatic Committee (2020):
I was invited to be the only Japanese expert member to participate in the editing work for the pancreatic dataset created by ICCR (International Collaboration on Cancer Reporting), which aims to internationalize the format of pathological diagnosis reports.
⑩ Carcinoma of the Papilla of Vater (PERIPAN Project: Submitted):
From 2022 to 2023, I was the only Japanese person invited to participate in a consensus project on duodenal papilla tumors, which had been slow to be organized, through email meetings and face-to-face meetings in Italy.
B. Achievements in domestic and international multi-center collaborative research
In addition to research conducted in laboratories and testing rooms, we are contributing domestically and internationally to intractable cancers such as pancreatic cancer and bile duct cancer from the perspective of pathology and pathological diagnosis through participation in international consensus conferences and international multi-center collaborative studies.
① Pancreatic mucinous cystic neoplasm (Pancreas, 2011): The differences between intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) have been discussed for a long time, mainly in Japan, and the concept of the disease has now been clarified internationally as well. We conducted a clinical and pathological study by collecting a large number of cases (156 cases) from within Japan and reported it jointly.
② Pancreatic serous cystic tumor (Pancreas, 2012): Pancreatic serous cystic tumor is considered a benign tumor, but in rare cases it can metastasize to the liver. A large number of cases (172 cases) were collected, analyzed, and reported jointly in a multi-institutional collaborative study conducted in Japan.
③ Pancreatic solid pseudopapillary tumor (Pancreas, 2018): Pancreatic solid pseudopapillary tumor is common in young women and most follow a benign course, but biologically it is considered to be a tumor of definite malignancy. However, since most studies have been conducted on a small number of cases, a multi-institutional collaborative study in Japan collected a large number of cases (288 cases, the largest number of cases internationally), analyzed the clinicopathological characteristics, and jointly reported the results.
④ Intraductal papillary mucinous neoplasm (Pancreas, 2019): In recent years, classification of intraductal papillary mucinous neoplasm, such as its histological subtype and histological grade, has been established. However, there is still considerable variation in the diagnostic criteria among pathologists. Therefore, we gathered pathologists in Japan who are knowledgeable in pancreatic pathology to hold a consensus conference, clarify the issues, and jointly report them.
⑤ Development of EUS-FNA pathology AI (Sci Rep., 2021): We jointly attempted to train and build a deep learning model for histopathological evaluation of PDAC on endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) using whole slide images (WSI).
⑥ Construction of an EUS-FNA pathological diagnostic algorithm (Pancreas, 2022): In order to achieve accurate pathological diagnosis of EUS-FNB specimens of pancreatic lesions, we jointly attempted to identify important features and establish a reliable and reproducible classification diagnostic system.
⑦Autoimmune pancreatitis (Virchows Arch, 2022)
We conducted a multi-institutional, interobserver study on the differential diagnosis between autoimmune pancreatitis type 1 and pancreatic ductal carcinoma.
⑧ EUS-FNA Rapid Diagnosis (EbioMedicine, 2022): An international collaborative study evaluated in vitro fluorescence confocal microscopy (FCM), a new digital tool for real-time microscopic evaluation of fresh, unfixed biological specimens.
