Annual Report 2020
Division of Pathology
Atsushi Ochiai, Motohiro Kojima, Shingo Sakashita, Naoya Sakamoto, Su Yinghan, Yukino Nishina, Kosuke Ikeda, Ryotaro Kondo, Tetsuro Hiroi, Tomoko Nagai
Introduction
In the research field, we are endeavoring to create next-generation pathology by integrating innovations with the aim of developing new pathological fields. Specifically, we aimed for: 1) the acquisition of information regarding tissue physicality and histology; 2) the construction of pathological standards in the incorporation of AI techniques into routine pathology practice; and 3) the construction of novel models through the organoid technology and acquisition of information on them.
The Team and What We Do
We performed various clinicopathological studies in alliance with many departments in the Hospital East. With these studies, we began to build up new pathological fields to study the physical characters of tumors, to introduce AI into routine practice, and to study drug resistance from a pathological point of view through the organoids assay.
In addition to research activities, the staff of the Division of Pathology have also been working as members of the Department of Pathology and Clinical Laboratories at the Hospital East and have been involved in pathological diagnoses (13,274 biopsy samples, 3,222 surgical samples, 4,986 cytological specimens and 4 autopsy specimens were processed in 2020). At the same time, we have been holding Clinical Pathology Conferences (CPC) periodically with other Departments of the Hospital East with the goal of enhancing activities in practice and research. We have been proactively participating in the Expert Panel every Thursday in which the results of the genetic panel tests are medically interpreted; we therefore have been contributing not only to the practice as important leaders in genomic medicine but also in the education of physicians.
Research activities
Standardization of Pathology and Studies on Clinical Pathology
1. We proposed a novel pathological assessment method of the response after preoperative therapy in pancreatic cancer and reported that this method is superior to conventional methods with respect to its ability to stratify prognosis and perform concordant pathological diagnoses. We also collected information on pathological tumor sampling from multiple institutions to develop an adequate tumor sampling method for pancreatic cancer after presurgical treatment. We have also been contributing to the world standards under the Pancreatobiliary Pathology Society (PBPS), an affiliate of USCAP. We also compared imaging findings and pathological figures after the treatment of borderline resectable pancreatic cancer. We concluded that the prediction of the extent of tumor development after treatment is difficult with current imaging tools and that a detailed pathological assessment is essential.
2. Various clinicopathological studies were conducted this year. We studied the clinicopathological importance of tumor necrosis in pancreatic and kidney cancer and reported their significance as biomarkers. Next, we discovered that the morphology of lymph node metastasis differs between pancreatic duct cancer and pancreatic endocrine tumors. We demonstrated the importance of measuring the shortest diameter in diagnostic imaging, and showed that the developmental pattern of the lesion where pancreatic cancer has metastasized to the liver affects the prognosis. Lastly, we studied the immune microenvironment of biliary tract cancer using multiplex immunohistochemistry. As a result, we found that PD-1 and CD8 positive T-cells are abundant in smaller sized tumors and reported the effectiveness of immunotherapy on early lesions.
3. We conducted a molecular pathological study on serrated lesions in the large intestine, finding a variety of genetic mutations such as EIF3E-RSPO2 fusions and PIEZO1-RSPO2 fusions found in classical serrated adenoma, as well as GNAS and BRAF V600E mutations. We conducted a multi-center study on cases of colorectal cancer that had metastasized to the liver. We found that resectable colorectal cancer that had metastasized to the liver with the BRAF V600E mutation had high recurrence rates and that these cases require systemic chemotherapy.
4. Four biopsy samples of early esophageal cancer (2 cases of intramucosal cancer, and 2 cases of submucosa infiltrating cancer) were submitted to Tsuruoka Metabolomics Laboratory for metabolome analysis.
Acquisition of Information regarding the Tissue Physicality and the Histology
1. We measured the elasticity of human pancreatic cancer, finding that pancreatic cancer is harder than biliary tract cancer. Pancreatic cancer becomes harder as it develops but becomes softer after presurgical treatment. Meanwhile, we showed that the elasticity of human pancreatic cancer correlates to the number of CD3+ and CD8+ lymphocytes. Additionally, the elasticity of pancreatic cancer correlates to the tumor stroma, such as actin expression in fibroblasts, implying the likelihood of tumor stroma suppressing the antitumor immune response by immune cells. We will further study the data in detail and publish the results.
2. In addition to elasticity, the physical abnormality of tumors includes a variety of characteristics, such as viscosity, interstitial fluid pressure, and solid stress. We commenced collaborative research with Tokyo University and the University of Cyprus and constructed a system for measuring the internal pressure/solid stress of human tumors based on a mathematical model. As a result of this preliminary study, we found that the internal pressure/solid stress of human hepatocellular cancer might be affected by the elasticity and hardness of the surrounding tissue. Currently, we are accumulating data including frozen specimens to elucidate the association with gene expression.
3. In addition to the above study, we constructed a sharing system for our fibroblast library with Tokyo University and the University of Cyprus. We demonstrated that when the micellar formulation produced by Tokyo University was added to the cancer-associated fibroblast established by us, TGFb expression in the cancer-associated fibroblast was reduced.
Construction of Standards by Incorporating AI Technology
Annotations were added to the macro photographs of 179 surgically resected specimens of gastric carcinoma that were prepared from September 2018 to December 2019. We developed an AI for identifying pathological lesions in the macro photographs of surgically resected specimens of gastric carcinoma using the YOLOv5 model. The AI test was performed using the 25 specimens prepared from January 2020 to March 2020 as the test subjects. The accuracy of the system was approximately 68%, a result that was insufficient for practical realization; therefore, we have been attempting to enhance the accuracy by adding more cases, considering imaging procedures and the like.
Construction of Novel Models by the Organoid Technology
1. We established gastric cancer organoids using human gastric cancer samples and analyzed the mechanisms that underpin drug resistance in cancer cells.
2. The metabolome analyses of the organoid derived from the normal gastric mucosa, gastric cancer organoid, and 5-FU-resistant gastric cancer organoid revealed that TCA cycle-associated enzymes and metabolites were significantly upregulated in the 5-FU resistant gastric cancer organoid.
3. No growth-inhibitory effect of TCA cycle inhibitors were observed in the gastric cancer organoids without 5-FU resistance, MKN-45/MKN-74, and their 5-FU resistant version; however, a significant growth-inhibitory effect of the inhibitors was found in the gastric cancer organoid with 5-FU resistance. The results of this study were presented at the 31st Annual Meeting of the Japanese Society for Gastroenterological Carcinogenesis, and this presentation received the Outstanding Presentation Award.
Education
We have been mentoring and educating the residents, senior residents, and pathologists at the Hospital East, as well as the doctoral and masters graduate students at the Graduate School of Frontier Sciences, Tokyo University and Science University of Tokyo as a visiting professor.
Future Prospects
In the research field, we will continue endeavoring to create the next-generation pathology by integrating innovations with the aim of developing new pathological fields. Specifically, we aim for: 1) the acquisition of information regarding tissue physicality and histology; 2) the construction of pathological standards in the incorporation of AI techniques into routine pathology practice; and 3) the construction of novel models through the organoid technology and acquisition of information on them.
List of papers published in 2020
Journal
1. 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
2. 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, 153:56-65, 2021
3. 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, 153:1-10, 2021
4. 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. Adv Sci (Weinh), 8:2001917, 2021
5. 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. Sci Rep, 11:6586, 2021
6. 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. Endosc Int Open, 9:E271-E277, 2021
7. Umemoto K, Togashi Y, Arai Y, Nakamura H, Takahashi S, Tanegashima T, Kato M, Nishikawa T, Sugiyama D, Kojima M, Gotohda N, Kuwata T, Ikeda M, Shibata T, Nishikawa H. The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. Int Immunol, 32:273-281, 2020
8. Watanabe K, Mitsunaga S, Kojima M, Suzuki H, Irisawa A, Takahashi H, Sasaki M, Hashimoto Y, Imaoka H, Ohno I, Ikeda M, Akimoto T, Ochiai A. The "histological replacement growth pattern" represents aggressive invasive behavior in liver metastasis from pancreatic cancer. Cancer Med, 9:3130-3141, 2020
9. Koike Y, Aokage K, Ikeda K, Nakai T, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tanaka T, Suzuki K, Tsuboi M, Ishii G. Machine learning-based histological classification that predicts recurrence of peripheral lung squamous cell carcinoma. Lung Cancer, 147:252-258, 2020
10. Sato K, Mimaki S, Yamashita R, Togashi Y, Naito T, Udagawa H, Katsumata S, Nakasone S, Miyoshi T, Tane K, Aokage K, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Goto K, Tsuboi M, Tsuchihara K, Ishii G. Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma. Lung Cancer, 147:12-20, 2020
11. Kudo M, Kobayashi T, Gotohda N, Konishi M, Takahashi S, Kobayashi S, Sugimoto M, Okubo S, Martin J, Cabral H, Ishii G, Kojima M. Clinical Utility of Histological and Radiological Evaluations of Tumor Necrosis for Predicting Prognosis in Pancreatic Cancer. Pancreas, 49:634-641, 2020
12. Nishida Y, Nagatsuma AK, Kojima M, Gotohda N, Ochiai A. Novel stromal biomarker screening in pancreatic cancer patients using the in vitro cancer-stromal interaction model. BMC Gastroenterol, 20:411, 2020
13. Yasuta S, Kobayashi T, Aizawa H, Takahashi S, Ikeda M, Konishi M, Kojima M, Kuno H, Uesaka K, Morinaga S, Miyamoto A, Toyama H, Takakura N, Sugimachi K, Takayama W. Relationship between surgical R0 resectability and findings of peripancreatic vascular invasion on CT imaging after neoadjuvant S-1 and concurrent radiotherapy in patients with borderline resectable pancreatic cancer. BMC Cancer, 20:1184, 2020
14. Matsuda Y, Ohkubo S, Nakano-Narusawa Y, Fukumura Y, Hirabayashi K, Yamaguchi H, Sahara Y, Kawanishi A, Takahashi S, Arai T, Kojima M, Mino-Kenudson M. Objective assessment of tumor regression in post-neoadjuvant therapy resections for pancreatic ductal adenocarcinoma: comparison of multiple tumor regression grading systems. Sci Rep, 10:18278, 2020
15. Notohara K, Kamisawa T, Fukushima N, Furukawa T, Tajiri T, Yamaguchi H, Aishima S, Fukumura Y, Hirabayashi K, Iwasaki E, Kanno A, Kasashima S, Kawashima A, Kojima M, Kubota K, Kuraishi Y, Mitsuhashi T, Naito Y, Naitoh I, Nakase H, Nishino T, Ohike N, Sakagami J, Shimizu K, Shiokawa M, Uehara T, Ikeura T, Kawa S, Okazaki K. Guidance for diagnosing autoimmune pancreatitis with biopsy tissues. Pathol Int, 70:699-711, 2020
16. Kobayashi S, Takahashi S, Takahashi N, Masuishi T, Shoji H, Shinozaki E, Yamaguchi T, Kojima M, Gotohda N, Nomura S, Yoshino T, Taniguchi H. Survival Outcomes of Resected BRAF V600E Mutant Colorectal Liver Metastases: A Multicenter Retrospective Cohort Study in Japan. Ann Surg Oncol, 27:3307-3315, 2020
17. Takahashi D, Kojima M, Morisue R, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Ikeda M, Ochiai A. Comparison of morphological features in lymph node metastasis between pancreatic neuroendocrine neoplasms and pancreatic ductal adenocarcinomas. Pancreatology, 20:936-943, 2020
18. Sekine S, Yamashita S, Yamada M, Hashimoto T, Ogawa R, Yoshida H, Taniguchi H, Kojima M, Ushijima T, Saito Y. Clinicopathological and molecular correlations in traditional serrated adenoma. J Gastroenterol, 55:418-427, 2020
19. Okuyama H, Ikeda M, Okusaka T, Furukawa M, Ohkawa S, Hosokawa A, Kojima Y, Hara H, Murohisa G, Shioji K, Asagi A, Mizuno N, Kojima M, Yamanaka T, Furuse J. A Phase II Trial of Everolimus in Patients with Advanced Pancreatic Neuroendocrine Carcinoma Refractory or Intolerant to Platinum-Containing Chemotherapy (NECTOR Trial). Neuroendocrinology, 110:988-993, 2020
20. Kojima M, Yamauchi C, Oyamada S, Hojo T, Iwase S, Naito A, Yamano K, Takahashi S, Ochiai A. Assessment of Upper Limb Physiological Features in Patients with Lymphedema After Breast Surgery Using Multiple Instruments. Lymphat Res Biol, 18:239-246, 2020