Annual Report 2021
Division of Pathology
Atsushi Ochiai, Motohiro Kojima, Shingo Sakashita, Naoya Sakamoto, Ryo Morisue, Kenji Harada, Takahiro Iimura, Miki Kusumoto
Introduction
1. Research activities: As shown in Figure 1, we have attempted to integrate new technological developments and ideas toward the creation of next-generation pathology. During this innovative integration, we tried to feed back our results for the standardization of pathology as well as the advancement of medicine (Item A. Induction of new technology for pathology innovation & establishment of standardized pathology). The items related to new technological developments were Items B to D. Specifically, these were: Item B. Physical properties & pathological associations of cancer tissue, Item C. Establishment of a standard for pathological images for AI graphical analysis, and Item D. Creation of new biological models, including organoids. As an idea toward the creation of next-generation pathology, we proposed Item E. Immune-microenvironment analysis in sarcomatoid carcinoma. In addition to developing each item, we worked toward the creation of next-generation pathology through collaboration between each item’s staff.
2. Clinical activities: The staff of the Division of Pathology in EPOC assisted pathology diagnostic work at the National Cancer Center Hospital East (NCCHE). The pathology diagnostic work included 13820 biopsy specimens, 3349 surgical materials, 5127 cytology cases, and 7 autopsy cases. In addition to the pathological diagnoses, we contributed to the management of the biobank system. Regarding the management of the laboratory system, we maintained an ISO15189-approved standardized laboratory system, and also contributed to developing a laboratory system which met CAP-approval standards. We also joined in with the education of residents in NCCHE, and held clinical pathology conferences (CPCs) with each department in the hospital. In addition, we are holding weekly conferences with residents to accelerate research activities. Furthermore, every Thursday, we participate in an expert panel that medically interprets the results of gene panel tests, contributing to genome medicine as an important player in this field.
The Team and What We Do
The role of chief investigator for Items B to E was assigned to the following staff. Each investigator worked on the development of their item. In addition, they also collaborated toward the creation of next-generation pathology through the results of each item.
Motohiro Kojima. Item B. Acquisition of information on tissue properties and pathological analysis
Shingo Sakashita. Item C. Establishment of a standard for pathological images for AI graphical analysis
Naoya Sakamoto. Item D. Creation of new biological models, including organoids
Ryo Morisue. Item E. Immune-microenvironment analysis in sarcomatoid carcinoma.
All staff attempted to contribute to Item A, “Induction of new technology for pathology innovation & establishment of standardized pathology,” to create next-generation pathology.
Research activities
Item A. Induction of new technology for pathology innovation & establishment of standardized pathology
Establishment of standardized pathological diagnostics through the fusion of new technological developments and pathological ideas. We contributed to the standardization of endocrine tumor pathology in Japan through the development of guidelines for the treatment of neuroendocrine tumors (J Gastroenterol. 2021). Furthermore, we were involved in the establishment of world-standard pathology reports in the International Collaboration on Cancer Reporting. These achievements were reported at the Japanese Society of Clinical Oncology Symposium (Yokohama, 2021) and the Japanese Society of Pathology Symposium (Tokyo, 2021). Item A’s staff also cooperated with the staff for Item C, “Investigation of pathological image standardization for AI to standardize pathological diagnosis through automation.” They also worked with the staff for Item E, “Analysis of tumor immune microenvironments across organs in sarcomatoid carcinoma,” to develop a new pathological concept and standardize the diagnosis of sarcomatoid carcinoma (Int J Cancer. 2021). We established a starting point for the creation of next-generation pathology through the integration of innovations.
Item B. Acquisition of information on tissue properties and pathological analysis
We measured the physical properties of pancreatic cancer and found a correlation between tumor stiffness and tumor immunity for the first time in human tumor tissue. This information is currently being presented at academic conferences and submitted for publication. In addition to the stiffness, intra-tumor pressure is also measured as a physical property of cancer, and data is being accumulated for hepatocellular carcinoma. The measurement and analysis of intra-tumor pressure is being performed in collaboration with the University of Tokyo and the University of Cyprus as an international joint research project. The information to date indicates that intra-tumor pressure is affected by pathological features of surrounding normal tissue as well of tumor tissue.
Item C. Study on standardization of pathological images for AI
1. We developed an AI for detecting tumors in surgical gastrectomy materials, and showed that the focus, brightness, and contrast of the photo affect its inferences. (A paper is in progress.)
2. We signed a joint agreement with Sakura Finetek Japan and started research on comprehensive standardization of pathological diagnosis through automation by commencing research on development of a fully automated specimen preparation machine in addition to research on standardization of HE specimens (research on how the thickness and staining of HE specimens affect the AI). In addition, specimens were collected from surgical materials for gastric, esophageal, and colorectal cancer, and a research resource was established.
Item D. Acquisition of new model information, such as organoids
1. We constructed gastric cancer organoids using human gastric cancer patient samples, and investigated their drug resistance mechanisms.
2. We found that MYOF gene expression was significantly up-regulated in oxaliplatin-resistant gastric cancer organoids. In addition, MYOF over-expression was found in resected gastric cancer tissue, and was a prognostic marker of gastric cancer. Furthermore, in vitro studies showed that MYOF contributes to the development of oxaliplatin resistance. This study was presented at the 94th Annual Meeting of the Japanese Gastric Cancer Association and received the Best Poster Award.
Item E. Cross-organ analysis of tumor immune microenvironments in sarcoma-like carcinoma
1. Analysis of tumor immune microenvironments (TMEs) using fluorescence multiplex immunostaining showed that sarcomatoid hepatocellular carcinoma has a TME rich in tumor-infiltrating CD8+ T cells and high PD-L1 expression (Int J Cancer. 2021).
2. Analysis of the TMEs in sarcomatoid carcinomas of the lung, esophagus, pancreas, liver, biliary tract, kidney, uterus, and ovary showed that sarcomatoid carcinomas have a common inflammatory TME with prominent tumor-infiltrating CD8+ T cells and CD204+ tumor-associated macrophages across organs and high PD-L1 expression. (In preparation for submission.)
Education
We routinely provided education for clinical and pathological residents at the East Hospital, and had 6 English papers accepted for publication. Of these, the corresponding authors of 2 papers were from the Division of Pathology, and the papers were academic dissertations by residents. In addition, we provided research guidance and education for two master's course graduate students of the Graduate School of Frontier Sciences, The University of Tokyo. Currently, we are also providing research guidance and education for a doctoral course at the Graduate School of Biomedical Sciences, Hiroshima University.
Future Prospects
As a new direction for the Pathology Division in EPOC, we have set the creation of next-generation pathology through the integration of innovations as our goal. We have also set technological development items and pathological creation items necessary to achieve it. Through the development of these items, we can conduct research in an organized manner. We aim to create next-generation pathology by developing and integrating each item in cooperation with academic societies and companies.
List of papers published in 2021
Journal
1. Niimi T, Nakai T, Aokage K, Tane K, Miyoshi T, Samejima J, Miyazaki S, Taki T, Sakamoto N, Sakashita S, Watanabe R, Kojima M, Suzuki K, Tsuboi M, Ishii G. Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment. Cancer science, 113:1497-1506, 2022
2. Nomura K, Nakai T, Nishina Y, Sakamoto N, Miyoshi T, Tane K, Samejima J, Aokage K, Kojima M, Sakashita S, Taki T, Miyazaki S, Watanabe R, Suzuki K, Tsuboi M, Ishii G. 18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma. Cancer science, 113:1488-1496, 2022
3. Bando H, Tsukada Y, Inamori K, Togashi Y, Koyama S, Kotani D, Fukuoka S, Yuki S, Komatsu Y, Homma S, Taketomi A, Uemura M, Kato T, Fukui M, Wakabayashi M, Nakamura N, Kojima M, Kawachi H, Kirsch R, Yoshida T, Suzuki Y, Sato A, Nishikawa H, Ito M, Yoshino T. Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 28:1136-1146, 2022
4. Yagi N, Suzuki T, Mizuno S, Kojima M, Kudo M, Sugimoto M, Kobayashi S, Gotohda N, Ishii G, Nakatsura T. Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis. Cancer science, 113:1564-1574, 2022
5. Matsuda Y, Yamashita T, Ye J, Yasukawa M, Yamakawa K, Mukai Y, Machitani M, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Yamada S, Takei J, Kaneko MK, Kojima M, Kaneko S, Masaki T, Hirata M, Haba R, Kontani K, Kanaji N, Miyatake N, Okano K, Kato Y, Masutomi K. Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs. The Journal of pathology, 257:172-185, 2022
6. Notohara K, Kamisawa T, Furukawa T, Fukushima N, Uehara T, Kasashima S, Iwasaki E, Kanno A, Kawashima A, Kubota K, Kuraishi Y, Motoya M, Naitoh I, Nishino T, Sakagami J, Shimizu K, Tomono T, Aishima S, Fukumura Y, Hirabayashi K, Kojima M, Mitsuhashi T, Naito Y, Ohike N, Tajiri T, Yamaguchi H, Fujiwara H, Ibuki E, Kobayashi S, Miyaoka M, Nagase M, Nakashima J, Nakayama M, Oda S, Taniyama D, Tsuyama S, Watanabe S, Ikeura T, Kawa S, Okazaki K. Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study. Virchows Archiv: an international journal of pathology, 480:565-575, 2022
7. Loughrey MB, Webster F, Arends MJ, Brown I, Burgart LJ, Cunningham C, Flejou JF, Kakar S, Kirsch R, Kojima M, Lugli A, Rosty C, Sheahan K, West NP, Wilson RH, Nagtegaal ID. Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR). Annals of surgery, 275:e549-e561, 2022
8. Eguchi Y, Nakai T, Kojima M, Wakabayashi M, Sakamoto N, Sakashita S, Miyazaki S, Taki T, Watanabe R, Watanuki R, Yamauchi C, Iwatani T, Mukohara T, Onishi T, Ishii G. Pathologic method for extracting good prognosis group in triple-negative breast cancer after neoadjuvant chemotherapy. Cancer science, 113:1507-1518, 2022
9. Ishizu K, Hashimoto T, Naka T, Yatabe Y, Kojima M, Kuwata T, Nonaka S, Oda I, Esaki M, Kudo M, Gotohda N, Yoshida T, Yoshikawa T, Sekine S. APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum. Journal of gastroenterology, 56:988-998, 2021
10. Ito T, Masui T, Komoto I, Doi R, Osamura RY, Sakurai A, Ikeda M, Takano K, Igarashi H, Shimatsu A, Nakamura K, Nakamoto Y, Hijioka S, Morita K, Ishikawa Y, Ohike N, Kasajima A, Kushima R, Kojima M, Sasano H, Hirano S, Mizuno N, Aoki T, Aoki T, Ohtsuka T, Okumura T, Kimura Y, Kudo A, Konishi T, Matsumoto I, Kobayashi N, Fujimori N, Honma Y, Morizane C, Uchino S, Horiuchi K, Yamasaki M, Matsubayashi J, Sato Y, Sekiguchi M, Abe S, Okusaka T, Kida M, Kimura W, Tanaka M, Majima Y, Jensen RT, Hirata K, Imamura M, Uemoto S. JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis. Journal of gastroenterology, 56:1033-1044, 2021
11. Morishita Y, Sakashita S, Tomioka T, Okano W, Shinozaki T, Higashino T, Matsuura K, Hayashi R. Human papillomavirus-related multiphenotypic sinonasal carcinoma. Auris, nasus, larynx, 2021
12. Hoshino H, Aokage K, Miyoshi T, Tane K, Kojima M, Sugano M, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Ishii G. Correlation between the number of viable tumor cells and immune cells in the tumor microenvironment in non-small cell lung cancer after induction therapy. Pathology international, 71:512-520, 2021
13. Nomura K, Aokage K, Nakai T, Sakashita S, Miyoshi T, Tane K, Samejima J, Suzuki K, Tsuboi M, Ishii G. Prognostic impact of extranodal extension in patients with pN1-N2 lung adenocarcinoma. Journal of cancer research and clinical oncology, 147:3699-3707, 2021
14. Kobayashi S, Takahashi S, Nomura S, Kojima M, Kudo M, Sugimoto M, Konishi M, Gotohda N, Taniguchi H, Yoshino T. BRAF V600E potentially determines “Oncological Resectability” for “Technically Resectable” colorectal liver metastases. Cancer medicine, 10:6998-7011, 2021
15. Komine R, Kojima M, Ishi G, Kudo M, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Kobayashi T, Akimoto T, Murakami A, Sasaki M, Tanaka M, Matsuzaki A, Ohike N, Uchida K, Sugiyama T, Hirabayashi K, Tajiri T, Ishida K, Kai K, Omori Y, Notohara K, Yamaguchi H, Matsuda Y, Naito Y, Fukumura Y, Hamada Y, Mihara Y, Masugi Y, Gotohda N, Harada K, Fukushima N, Furukawa T. Recognition and pathological features of periampullary region adenocarcinoma with an indeterminable origin. Cancer medicine, 10:3499-3510, 2021
16. Kudo-Saito C, Ogiwara Y, Imazeki H, Boku N, Uemura Y, Zhang R, Kawano-Nagatsuma A, Kojima M, Ochiai A. CD11b+DIP2Ab+LAG3b+ cells facilitate immune dysfunction in colorectal cancer. American journal of cancer research, 11:5428-5439, 2021
17. Kameyama A, Ye J, Shimomura A, Yokohira M, Nakano-Narusawa Y, Yamakawa K, Mukai Y, Sanomura T, Okuyama H, Miyatake N, Furihata M, Tanaka C, Kitazawa R, Bando Y, Suemitsu Y, Kojima M, Mino-Kenudson M, Suzuki Y, Okano K, Matsuda Y. Reproducibility and prognostic significance of area of residual tumor (ART) in post-neoadjuvant resections of pancreatic ductal adenocarcinoma. Pancreatology: official journal of the International Association of Pancreatology (IAP) ... [et al.], 21:1506-1515, 2021
18. Okubo S, Suzuki T, Hioki M, Shimizu Y, Toyama H, Morinaga S, Gotohda N, Uesaka K, Ishii G, Takahashi S, Kojima M. The immunological impact of preoperative chemoradiotherapy on the tumor microenvironment of pancreatic cancer. Cancer science, 112:2895-2904, 2021
19. Naito Y, Tsuneki M, Fukushima N, Koga Y, Higashi M, Notohara K, Aishima S, Ohike N, Tajiri T, Yamaguchi H, Fukumura Y, Kojima M, Hirabayashi K, Hamada Y, Norose T, Kai K, Omori Y, Sukeda A, Noguchi H, Uchino K, Itakura J, Okabe Y, Yamada Y, Akiba J, Kanavati F, Oda Y, Furukawa T, Yano H. A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy. Scientific reports, 11:8454, 2021
20. Kudo M, Kobayashi S, Kojima M, Kobayashi T, Sugimoto M, Takahashi S, Konishi M, Ishii G, Gotohda N. Impact of previous history of choledochojejunostomy on the incidence of organ/space surgical site infection after hepatectomy. Asian journal of surgery, 44:1520-1528, 2021
21. Harada K, Sakamoto N, Ukai S, Yamamoto Y, Pham QT, Taniyama D, Honma R, Maruyama R, Takashima T, Ota H, Takemoto Y, Tanabe K, Ohdan H, Yasui W. Establishment of oxaliplatin-resistant gastric cancer organoids: importance of myoferlin in the acquisition of oxaliplatin resistance. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:1264-1277, 2021
22. Sekino Y, Han X, Kobayashi G, Babasaki T, Miyamoto S, Kobatake K, Kitano H, Ikeda K, Goto K, Inoue S, Hayashi T, Teishima J, Sakamoto N, Sentani K, Oue N, Yasui W, Matsubara A. BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma. Oncology, 99:240-250, 2021
23. Shimizu Y, Tamura T, Kemmochi A, Owada Y, Ozawa Y, Hisakura K, Matsuzaka T, Shimano H, Nakano N, Sakashita S, Oda T, Ohkohchi N. Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non-alcoholic steatohepatitis model. Journal of gastroenterology and hepatology, 36:800-810, 2021
24. Sakashita M, Sakashita S, Uesugi N, Tokunaga C, Hiramatsu Y, Noguchi M, Sakamoto N. An autopsy case of aortic dissection due to giant cell arteritis. Pathology international, 71:204-209, 2021
25. Ong Q, Sakashita S, Hanawa E, Kaneko N, Noguchi M, Muratani M. Integrative RNA-Seq and H3 Trimethylation ChIP-Seq Analysis of Human Lung Cancer Cells Isolated by Laser-Microdissection. Cancers, 13:2021
26. Pham QT, Taniyama D, Sekino Y, Akabane S, Babasaki T, Kobayashi G, Sakamoto N, Sentani K, Oue N, Yasui W. Clinicopathologic features of TDO2 overexpression in renal cell carcinoma. BMC cancer, 21:737, 2021
27. Takashima T, Taniyama D, Sakamoto N, Yasumoto M, Asai R, Hattori T, Honma R, Thang PQ, Ukai S, Maruyama R, Harada K, Kuraoka K, Tanabe K, Sasaki AT, Ohdan H, Morii E, Murai J, Yasui W. Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers. British journal of cancer, 125:65-77, 2021
28. Amano E, Yoshida T, Mizuta I, Oyama J, Sakashita S, Ueyama S, Machida A, Yokota T. Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease. Neurology. Genetics, 7:e626, 2021
29. Ortmann J, Rampášek L, Tai E, Mer AS, Shi R, Stewart EL, Mascaux C, Fares A, Pham NA, Beri G, Eeles C, Tkachuk D, Ho C, Sakashita S, Weiss J, Jiang X, Liu G, Cescon DW, O’Brien CA, Guo S, Tsao MS, Haibe-Kains B, Goldenberg A . Assessing therapy response in patient-derived xenografts. Science translational medicine, 13:eabf4969, 2021
30. Kuroe T, Watanabe R, Kojima M, Morisue R, Sugano M, Kuwata T, Masuda H, Kusuhara S, Matsubara N, Oda S, Ushiku T, Ishii G. Evaluation of the morphological features and unfavorable prognostic impact of dirty necrosis in renal cell carcinoma. Journal of cancer research and clinical oncology, 147:1089-1100, 2021
31. Mpekris F, Panagi M, Voutouri C, Martin JD, Samuel R, Takahashi S, Gotohda N, Suzuki T, Papageorgis P, Demetriou P, Pierides C, Koumas L, Costeas P, Kojima M, Ishii G, Constantinidou A, Kataoka K, Cabral H, Stylianopoulos T. Normalizing the Microenvironment Overcomes Vessel Compression and Resistance to Nano-immunotherapy in Breast Cancer Lung Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8:2001917, 2021
32. Ito R, Ikematsu H, Murano T, Shinmura K, Kojima M, Kumahara K, Furue Y, Sunakawa H, Minamide T, Sato D, Yamamoto Y, Takashima K, Yoda Y, Hori K, Yano T. Diagnostic ability of Japan Narrow-Band Imaging Expert Team classification for colorectal lesions by magnifying endoscopy with blue laser imaging versus narrow-band imaging. Endoscopy international open, 9:E271-E277, 2021
33. Inamori K, Togashi Y, Fukuoka S, Akagi K, Ogasawara K, Irie T, Motooka D, Kobayashi Y, Sugiyama D, Kojima M, Shiiya N, Nakamura S, Maruyama S, Suzuki Y, Ito M, Nishikawa H. Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer. JCI insight, 6:2021
34. Suzuki J, Aokage K, Neri S, Sakai T, Hashimoto H, Su Y, Yamazaki S, Nakamura H, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tsuboi M, Ishii G. Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma. Lung cancer (Amsterdam, Netherlands), 153:1-10, 2021
35. Amemiya R, Miyoshi T, Aokage K, Suzuki J, Hoshino H, Udagawa H, Tane K, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Goto K, Ikeda N, Tsuboi M, Ishii G. Prognostic impact of the tumor immune microenvironment in pulmonary pleomorphic carcinoma. Lung cancer (Amsterdam, Netherlands), 153:56-65, 2021
36. Yokohira M, Oshima M, Yamakawa K, Ye J, Nakano-Narusawa Y, Haba R, Fukumura Y, Hirabayashi K, Yamaguchi H, Kojima M, Okano K, Suzuki Y, Matsuda Y. Adequate tissue sampling for the assessment of pathological tumor regression in pancreatic cancer. Scientific reports, 11:6586, 2021
37. Shiraishi T, Ikeda K, Tsukada Y, Nishizawa Y, Sasaki T, Ito M, Kojima M, Ishii G, Tsumura R, Saijou S, Koga Y, Yasunaga M, Matsumura Y. High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer. BMC cancer, 21:302, 2021
38. Morisue R, Kojima M, Suzuki T, Nakatsura T, Ojima H, Watanabe R, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Ishii G, Gotohda N, Fujiwara T, Ochiai A. Sarcomatoid hepatocellular carcinoma is distinct from ordinary hepatocellular carcinoma: Clinicopathologic, transcriptomic and immunologic analyses. International journal of cancer, 149:546-560, 2021
39. Kobayashi S, Nakamura Y, Taniguchi H, Odegaard JI, Nomura S, Kojima M, Sugimoto M, Konishi M, Gotohda N, Takahashi S, Yoshino T. Impact of Preoperative Circulating Tumor DNA Status on Survival Outcomes After Hepatectomy for Resectable Colorectal Liver Metastases. Annals of surgical oncology, 28:4744-4755, 2021