Annual Report 2018

Division of Pathology

Genichiro Ishii, Satoshi Fujii, Motohiro Kojima, Yuki Ohara, Shota Yamazaki, Erika Suzuki, Daiki Maruyama, Shoshi Hisamitsu, Su Yinghan, Asami Akutsu, BATTUGS OCHIRDARI, Hiroshi Nakamura, Jun Suzuki, Satoshi Okubo, Hiroko Hashimoto, Yoshiko Onuma

Introduction

 Our aim is to explore the pathogenesis of cancer and to develop novel diagnostic and therapeutic methods for cancer patients. To this end, our members should perform the following missions. 1) Translational research for cancer patients, 2) Pathological diagnoses in the National Cancer Center Hospital, East [NCCH-E], including 13,093 biopsy specimens, 2,958 surgical specimens, 4,440 cytology specimens and 4 autopsy cases. 3) Clinical resident training for diagnosis and translational research, 4) Support of biobank construction (tissue preparation and tissue microarray construction), and 5) Participate as a member of the expert panel.

The Team and What We Do

 Team members are responsible for basic and translational research of the pathogenesis of cancer, diagnosis, and treatment. We develop novel in vitro models and examine whether our hypothesis is correct or not. We further confirm our hypothesis by final validation studies using human samples.

 Members are also involved in all routine pathological and cytological diagnosis in the NCCH-E with the collaboration of staff pathologists of the Department of Pathology and Clinical Laboratories of the NCCH-E. Members educate clinical residents in pathological diagnosis and translational research using clinical samples from NCCH-E. Also, members train D. course students and M. course students from the University of Tokyo, Kashiwa. Moreover, members participate in clinicopathological conferences, research meetings between the NCCH-E and the Exploratory Oncology Research & Clinical Trial Center (EPOC) and expert panels.

Research activities

 Most of our research products are generated through collaborative investigations with clinicians. The following are the major research results of this year.

1) Abundant tumor promoting stromal cells is characteristic of the hypoxic tumor microenvironment in lung adenocarcinoma.

2) The tumor microenvironment of usual interstitial pneumonia-associated lung cancer acquires an immunosuppressive state.

3) In lung adenocarcinoma, the presence of podoplanin-positive CAFs was associated with higher numbers of SNVs in cancer cells.

4) Not only the invasive size but also the invasive character might be an important histologic prognostic parameter in lung adenocarcinoma.

5) Collagen type I induces EGFR-TKI resistance in EGFR-mutated cancer cells by mTOR activation through Akt-independent pathway.

6) Lower cancer cell-specific expression levels of hypoxia markers and a smaller number of tumor-promoting stromal cells in invasive component were characteristic features of lepidic component (+) lung adenocarcinomas.

7) Lung adenocarcinoma with PDPN (+) CAFs is typified by the immunosuppressive microenvironment, suggesting a close link between the tumor-promoting fibrous microenvironment and the immunosuppressive microenvironment.

8) Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients received neoadjuvant chemotherapy.

9) The extranodal extension grading system is a novel predictor of overall survival and recurrence-free survival in esophageal squamous cell carcinoma.

10) HER2 amplification was predictive of anti- EGFR therapy response and appeared to be prognostic in metastatic colorectal cancer patients.

11) Area of residual tumor is a robust prognostic marker for patients with rectal cancer undergoing preoperative therapy.

12) Immune microenvironments between pancreatic neuroendocrine neoplasms (pNENs) was different. The histologydependent variability among pNENs using a multispectral fluorescent imaging system would be useful.

13) Resection margin distance of 1 mm or less was a predictor for disease recurrence, particularly for locoregional recurrence in pancreatic cancer patients.
 Other clinicopathological research and case reports in collaboration with clinicians were published this year, especially for lung, head and neck, gastrointestinal and hepato-biliarypancreatic tumors.

Education

 Staff members give professional guidance for NCCH-E doctoral students of Juntendo University and Keio University. Some staff are faculty members of the Tokyo Medical and Dental University and Graduate School of Frontier Sciences, the University of Tokyo and instruct students in masters and doctoral courses. The Division members also give lectures on diagnostic training and pathological research to clinical residents in the NCCH-E.

Future prospects

 This year, we started pathological research using machine learning in collaboration with Keio University. Using this method, we will strongly promote our research on how morphology is related to cancer pathogenesis. Moreover, we are strengthening particularly in promotion of translational research of cancer pathogenesis, diagnosis and treatment.

List of papers published in 2018

Journal

 1. Miyashita T, Omori T, Nakamura H, Sugano M, Neri S, Fujii S, Hashimoto H, Tsuboi M, Ochiai A, Ishii G. Spatiotemporal characteristics of fibroblasts-dependent cancer cell invasion. J Cancer Res Clin Oncol, 145:373-381, 2019

 2. Miyoshi T, Yoshida J, Aokage K, Tane K, Ishii G, Tsuboi M. Stapling cartridge lavage cytology in limited resection for pulmonary malignant tumors: assessment of cytological status of the surgical margin. Heliyon, 5:e01240, 2019

 3. Katsumata S, Aokage K, Nakasone S, Sakai T, Okada S, Miyoshi T, Tane K, Hayashi R, Ishii G, Tsuboi M. Radiologic Criteria in Predicting Pathologic Less Invasive Lung Cancer According to TNM 8th Edition. Clin Lung Cancer, 20:e163-e170, 2019

 4. Oono Y, Shinmura K, Hori K, Yoda Y, Ishii G, Ikematsu H, Yano T. Endoscopic submucosal resection using a ligation device without injection for duodenal neuroendocrine tumors. Surg Endosc, 33:2008-2014, 2019

 5. Kadota T, Seo S, Fuse H, Ishii G, Itoh K, Yano T, Kaneko K, Tsukasaki K. Complications and outcomes in diffuse large B-cell lymphoma with gastric lesions treated with R-CHOP. Cancer Med, 8:982-989, 2019

 6. Suzuki J, Kojima M, Aokage K, Sakai T, Nakamura H, Ohara Y, Tane K, Miyoshi T, Sugano M, Fujii S, Kuwata T, Ochiai A, Ito M, Suzuki K, Tsuboi M, Ishii G. Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer. Virchows Arch, 474:569-575, 2019

 7. Miyoshi T, Aokage K, Katsumata S, Tane K, Ishii G, Tsuboi M. Ground-glass opacity is a strong prognosticator for pathologic stage IA lung adenocarcinoma. Ann Thorac Surg, 2019

 8. Kojima M, Chen Y, Ikeda K, Tsukada Y, Takahashi D, Kawano S, Amemiya K, Ito M, Ohki R, Ochiai A. Recommendation of longterm and systemic management according to the risk factors in rectal NETs patients. Sci Rep, 9:2404, 2019

 9. Hashimoto T, Ogawa R, Yoshida H, Taniguchi H, Kojima M, Saito Y, Sekine S. Acquisition of WNT Pathway Gene Alterations Coincides With the Transition From Precursor Polyps to Traditional Serrated Adenomas. Am J Surg Pathol, 43:132-139, 2019

 10. Ichikawa T, Aokage K, Sugano M, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Ishii G. The ratio of cancer cells to stroma within the invasive area is a histologic prognostic parameter of lung adenocarcinoma. Lung Cancer, 118:30- 35, 2018

 11. Nakasone S, Mimaki S, Ichikawa T, Aokage K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tsuboi M, Goto K, Tsuchihara K, Ishii G. Podoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of single nucleotide variants in cancer cells in lung adenocarcinoma. J Cancer Res Clin Oncol, 144:893-900, 2018

 12. Makinoshima H, Umemura S, Suzuki A, Nakanishi H, Maruyama A, Udagawa H, Mimaki S, Matsumoto S, Niho S, Ishii G, Tsuboi M, Ochiai A, Esumi H, Sasaki T, Goto K, Tsuchihara K. Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma. Cancer Res, 78:2179-2190, 2018

 13. Yamazaki S, Higuchi Y, Ishibashi M, Hashimoto H, Yasunaga M, Matsumura Y, Tsuchihara K, Tsuboi M, Goto K, Ochiai A, Ishii G. Collagen type I induces EGFR-TKI resistance in EGFR-mutated cancer cells by mTOR activation through Akt-independent pathway. Cancer Sci, 109:2063-2073, 2018

 14. Sakai T, Tane K, Usui Y, Miyoshi T, Matsumoto S, Aokage K, Goto K, Suzuki M, Ishii G, Tsuboi M. Utility of Site-Specific Biopsy for Diagnosis of Desmoplastic Malignant Mesothelioma. Ann Thorac Surg, 106:e125-e128, 2018

 15. Katsumata S, Aokage K, Miyoshi T, Tane K, Nakamura H, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Hayashi R, Tsuboi M, Ishii G. Differences of tumor microenvironment between stage I lepidic-positive and lepidic-negative lung adenocarcinomas. J Thorac Cardiovasc Surg, 156:1679-1688.e2, 2018

 16. Kanai R, Tane K, Ishii G, Suzuki J, Sakai T, Okada S, Miyoshi T, Aokage K, Tsuboi M. Clinical prediction of solitary pulmonary nodule after a curative resection for gastric cancer. Jpn J Clin Oncol, 48:1083-1087, 2018

 17. Sakai T, Aokage K, Neri S, Nakamura H, Nomura S, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Iyoda A, Tsuboi M, Ishii G. Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma. Lung Cancer, 126:64-71, 2018

 18. Hombu T, Yano T, Hatogai K, Kojima T, Kadota T, Onozawa M, Yoda Y, Hori K, Oono Y, Ikematsu H, Fujii S. Salvage endoscopic resection (ER) after chemoradiotherapy for esophageal squamous cell carcinoma: What are the risk factors for recurrence after salvage ER? Dig Endosc, 30:338-346, 2018

 19. Naito Y, Takahashi H, Shitara K, Okamoto W, Bando H, Kuwata T, Kuboki Y, Matsumoto S, Miki I, Yamanaka T, Watanabe A, Kojima M. Feasibility study of cancer genome alterations identified by next generation sequencing: ABC study. Jpn J Clin Oncol, 48:559-564, 2018

 20. Kadota T, Hatogai K, Yano T, Fujita T, Kojima T, Daiko H, Fujii S. Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients. Cancer Sci, 109:2046-2055, 2018

 21. Krishnan H, Rayes J, Miyashita T, Ishii G, Retzbach EP, Sheehan SA, Takemoto A, Chang YW, Yoneda K, Asai J, Jensen L, Chalise L, Natsume A, Goldberg GS. Podoplanin: An emerging cancer biomarker and therapeutic target. Cancer Sci, 109:1292- 1299, 2018

 22. Sawada K, Nakamura Y, Yamanaka T, Kuboki Y, Yamaguchi D, Yuki S, Yoshino T, Komatsu Y, Sakamoto N, Okamoto W, Fujii S. Prognostic and Predictive Value of HER2 Amplification in Patients With Metastatic Colorectal Cancer. Clin Colorectal Cancer, 17:198-205, 2018

 23. Takahashi D, Kojima M, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Nagino M. Pathologic Evaluation of Surgical Margins in Pancreatic Cancer Specimens Using Color Coding With Tissue Marking Dyes. Pancreas, 47:830-836, 2018

 24. Kumata H, Murakami K, Ishida K, Miyagi S, Arakawa A, Inayama Y, Kinowaki K, Ochiai A, Kojima M, Higashi M, Moritani S, Kuwahara K, Nakatani Y, Kajiura D, Tamura G, Kijima H, Yamakawa M, Shiraishi T, Inadome Y, Murakami K, Suzuki H, Sawai T, Unno M, Kamei T, Sasano H. Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms. Hepatol Res, 48:989-999, 2018

 25. Kudo M, Gotohda N, Sugimoto M, Kobayashi T, Kojima M, Takahashi S, Konishi M, Hayashi R. Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system. Hepatol Int, 12:368-376, 2018

 26. Okubo S, Mitsunaga S, Kato Y, Kojima M, Sugimoto M, Gotohda N, Takahashi S, Hayashi R, Konishi M. The prognostic impact of differentiation at the invasive front of biliary tract cancer. J Surg Oncol, 117:1278-1287, 2018

 27. Kondo A, Tsukada Y, Kojima M, Nishizawa Y, Sasaki T, Suzuki Y, Ito M. Effect of preoperative chemotherapy on distal spread of low rectal cancer located close to the anus. Int J Colorectal Dis, 33:1685-1693, 2018

 28. Takahashi D, Kojima M, Suzuki T, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Ikeda M, Nakatsura T, Ochiai A, Nagino M. Profiling the Tumour Immune Microenvironment in Pancreatic Neuroendocrine Neoplasms with Multispectral Imaging Indicates Distinct Subpopulation Characteristics Concordant with WHO 2017 Classification. Sci Rep, 8:13166, 2018

 29. Udagawa H, Umemura S, Murakami I, Mimaki S, Makinoshima H, Ishii G, Miyoshi T, Kirita K, Matsumoto S, Yoh K, Niho S, Tsuchihara K, Goto K. Genetic profiling-based prognostic prediction of patients with advanced small-cell lung cancer in large scale analysis. Lung Cancer, 126:182-188, 2018

 30. Abe S, Saito Y, Oono Y, Tanaka Y, Sakamoto T, Yamada M, Nakajima T, Matsuda T, Ikematsu H, Yano T, Sekine S, Kojima M, Yamagishi H, Kato H. Pilot study on probe-based confocal laser endomicroscopy for colorectal neoplasms: an initial experience in Japan. Int J Colorectal Dis, 33:1071-1078, 2018

 31. Oki T, Hishida T, Yoshida J, Goto M, Sekihara K, Miyoshi T, Aokage K, Ishii G, Tsuboi M. Survival and prognostic factors after pulmonary metastasectomy of head and neck cancer: what are the clinically informative prognostic indicators? Eur J Cardiothorac Surg, 2018

 32. Hashimoto T, Tanaka Y, Ogawa R, Mori T, Yoshida H, Taniguchi H, Hiraoka N, Kojima M, Oono Y, Saito Y, Sekine S. Superficially serrated adenoma: a proposal for a novel subtype of colorectal serrated lesion. Mod Pathol, 31:1588-1598, 2018

 33. Ishihara H, Yamashita S, Fujii S, Tanabe K, Mukai H, Ushijima T. DNA methylation marker to estimate the breast cancer cell fraction in DNA samples. Med Oncol, 35:147, 2018

 34. Ueda T, Aokage K, Mimaki S, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Kusumoto M, Suzuki K, Tsuchihara K, Nishikawa H, Goto K, Tsuboi M, Ishii G. Characterization of the tumor immune-microenvironment of lung adenocarcinoma associated with usual interstitial pneumonia. Lung Cancer, 126:162-169, 2018

 35. Ueda T, Aokage K, Nishikawa H, Neri S, Nakamura H, Sugano M, Tane K, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Kusumoto M, Suzuki K, Tsuboi M, Ishii G. Immunosuppressive tumor microenvironment of usual interstitial pneumonia-associated squamous cell carcinoma of the lung. J Cancer Res Clin Oncol, 144:835-844, 2018

 36. Aokage K, Miyoshi T, Ishii G, Kusumoto M, Nomura S, Katsumata S, Sekihara K, Tane K, Tsuboi M. Influence of Ground Glass Opacity and the Corresponding Pathological Findings on Survival in Patients with Clinical Stage I Non-Small Cell Lung Cancer. J Thorac Oncol, 13:533-542, 2018