Annual Report 2019
Division of Pathology
Genichiro Ishii, Satoshi Fujii, Motohiro Kojima, Shota Yamazaki, Su Yinghan, Hojong Lee, Asami Akutsu, Battugs Ochirdari, Yukino Nishina, Kosuke Ikeda, Hiroko Hashimoto, Yoshiko Onuma
Introduction
Our members perform the following missions: 1) Translational research for cancer patients, 2) Pathological diagnoses in the National Cancer Center Hospital, East [NCCH-E], including 13,254 biopsy specimens, 3,095 surgical specimens, 4,562 cytology specimens and 4 autopsy cases this year, 3) Clinical resident training for pathological diagnosis and translational research, 4) Support of biobank construction (tissue preparation and tissue microarray construction), and 5) Participation as a member of the expert panel.
The Team and What We Do
We develop novel in vitro models to perform translational research of the pathogenesis of cancer, diagnosis, and treatment. Team members also do clinicopathological studies of several types of cancers. All members are involved in routine pathological and cytological diagnosis in the NCCH-E with the collaboration of the 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 the NCCH-E. Also, some members educate 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
The following are the major research results of this year.
1) We clarified clinicopathological characteristics of invasive mucinous adenocarcinoma of the lung.
2) The secretion of higher amounts of HGF is a robust feature of EGFR-TKI resistance-promoting CAFs.
3) Organoid culture containing cancer cells and stromal cells revealed that podoplanin-positive cancer-associated fibroblasts enhance proliferation of lung cancer cells.
4) Interactions between cancer cells and CAFs may significantly enhance cancer cell regrowth within the tumor microenvironment after cisplatin treatment.
5) We found a correlation between the maximum standardized uptake values for FDG-PET and microenvironmental factors in patients with clinical stage IA radiologic pure-solid lung adenocarcinoma.
6) Smoking history is associated with the necrosis area in pulmonary metastases from colorectal cancer.
7) Fibroblast-dependent cancer cell invasion is characterized by the progression in cell cycle and formation of small cancer cell nests.
8) Cancer cells presenting with alveolar space filling represents a "less invasive phenotype" in peripheral squamous cell carcinoma of the lung.
9) The extranodal extension grading system is a novel predictor of overall survival and recurrence-free survival in esophageal squamous cell carcinoma.
10) Immune microenvironments according to the intratumoral location have different effects on the survival of patients with esophageal squamous cell carcinoma.
11) Macrodissection should not be performed on specimens exhibiting histopathological factors associated with poor DNA quality. In particular, the use of tissue blocks with a storage period of <3 years allows the extraction of genomic DNA suitable for NGS.
12) The area of residual tumor-based pathological assessment may become a useful method to predict patient outcomes after post NAT resection of pancreatic ductal adenocarcinoma.
13) The longitudinal slicing method may have some advantages for accurate assessment of resection margin especially in low-lying rectal cancer.
14) We proposed recommendation of long-term and systemic management according to the risk factors in rectal NETs patients.
Other clinicopathological research and case reports in collaboration with clinicians were published this year, especially for lung, head and neck, gastrointestinal and hepato-biliary-pancreatic tumors.
Education
Staff members give lectures on diagnostic training and pathological research training to clinical residents in the NCCH-E. They also give professional guidance for NCCH-E doctoral students of Juntendo University. Some staff are faculty members of the Tokyo Medical and Dental University and Graduate School of Frontier Sciences, University of Tokyo and instruct students in masters and doctoral courses.
Future prospects
We are strengthening promotion of translational research of cancer diagnosis and treament. We started pathological research using machine learning methods in collaboration with Keio University. We will strongly promote our research on how morphology is related to malignant potential, genomic profile and immunophenotype of cancer cells.
List of papers published in 2019
Journal
1. Sekihara K, Aokage K, Miyoshi T, Tane K, Ishii G, Tsuboi M. Perioperative pirfenidone treatment as prophylaxis against acute exacerbation of idiopathic pulmonary fibrosis: a single-center analysis. Surg Today, 50:905-911, 2020
2. Hatogai K, Fujii S, Kitano S, Kojima T, Daiko H, Yoshino T, Ohtsu A, Takiguchi Y, Doi T, Ochiai A. Relationship between the immune microenvironment of different locations in a primary tumour and clinical outcomes of oesophageal squamous cell carcinoma. Br J Cancer, 122:413-420, 2020
3. Kakinuma R, Muramatsu Y, Asamura H, Watanabe SI, Kusumoto M, Tsuchida T, Kaneko M, Tsuta K, Maeshima AM, Ishii G, Nagai K, Yamaji T, Matsuda T, Moriyama N. Low-dose CT lung cancer screening in never-smokers and smokers: results of an eight-year observational study. Transl Lung Cancer Res, 9:10-22, 2020
4. Fujii S, Magliocco AM, Kim J, Okamoto W, Kim JE, Sawada K, Nakamura Y, Kopetz S, Park WY, Tsuchihara K, Kim TW, Raghav K, Yoshino T. International Harmonization of Provisional Diagnostic Criteria for ERBB2-Amplified Metastatic Colorectal Cancer Allowing for Screening by Next-Generation Sequencing Panel. JCO Precision Oncology, 4:6-19, 2020
5. Takashima K, Fujii S, Komatsuzaki R, Komatsu M, Takahashi M, Kojima T, Daiko H, Minashi K, Chiwaki F, Muto M, Sasaki H, Yano T. CD24 and CK4 are upregulated by SIM2, and are predictive biomarkers for chemoradiotherapy and surgery in esophageal cancer. Int J Oncol, 56:835-847, 2020
6. Kubota Y, Kawazoe A, Sasaki A, Mishima S, Sawada K, Nakamura Y, Kotani D, Kuboki Y, Taniguchi H, Kojima T, Doi T, Yoshino T, Ishii G, Kuwata T, Shitara K. The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer. Clin Cancer Res, 26:3784-3790, 2020
7. Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, Tane K, Sato E, Ishii G, Goto K, Shintani Y, Okumura M, Tsuboi M, Nishikawa H. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci Immunol, 5:eaav3937. doi: 10.1126/sciimmunol.aav3937, 2020
8. Maeda M, Takeshima H, Iida N, Hattori N, Yamashita S, Moro H, Yasukawa Y, Nishiyama K, Hashimoto T, Sekine S, Ishii G, Ochiai A, Fukagawa T, Katai H, Sakai Y, Ushijima T. Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3. Gut, 69:243-251, 2020
9. Fujii S, Lam AK. Macroscopic Assessment and Sampling of Endoscopic Resection Specimens for Squamous Epithelial Malignancies with Superficial Involvement of Esophagus. Methods Mol Biol, 2129:63-81, 2020
10. Shinmura K, Ikematsu H, Kojima M, Nakamura H, Osera S, Yoda Y, Hori K, Oono Y, Ochiai A, Yano T. Safety of endoscopic procedures with monopolar versus bipolar instruments in an ex vivo porcine model. BMC Gastroenterol, 20:27, 2020
11. 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, 2020
12. Imaizumi K, Suzuki T, Kojima M, Shimomura M, Sakuyama N, Tsukada Y, Sasaki T, Nishizawa Y, Taketomi A, Ito M, Nakatsura T. Ki67 expression and localization of T cells after neoadjuvant therapies as reliable predictive markers in rectal cancer. Cancer Sci, 111:23-35, 2020
13. 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
14. Yamamoto Y, Kadota T, Yoda Y, Hori K, Hatogai K, Kojima T, Fujii S, Akimoto T, Yano T. Review of early endoscopic findings in patients with local recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma. Esophagus, 2020
15. Miyashita T, Neri S, Hashimoto H, Akutsu A, Sugano M, Fujii S, Ochiai A, Ishii G. Fibroblasts-dependent invasion of podoplanin-positive cancer stem cells in squamous cell carcinoma. J Cell Physiol, 235:7251-7260, 2020
16. 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
17. 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, 55:942-947, 2019
18. Naito T, Umemura S, Nakamura H, Zenke Y, Udagawa H, Kirita K, Matsumoto S, Yoh K, Niho S, Motoi N, Aokage K, Tsuboi M, Ishii G, Goto K. Successful treatment with nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a high tumor mutation burden: A case report. Thorac Cancer, 10:1285-1288, 2019
19. Omori T, Aokage K, Nakamura H, Katsumata S, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Ikeda N, Tsuboi M, Ishii G. Growth patterns of small peripheral squamous cell carcinoma of the lung and their impacts on pathological and biological characteristics of tumor cells. J Cancer Res Clin Oncol, 145:1773-1783, 2019
20. 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, 108:249-255, 2019
21. Nakamura H, Sugano M, Miyashita T, Hashimoto H, Ochiai A, Suzuki K, Tsuboi M, Ishii G. Organoid culture containing cancer cells and stromal cells reveals that podoplanin-positive cancer-associated fibroblasts enhance proliferation of lung cancer cells. Lung Cancer, 134:100-107, 2019
22. Katsumata S, Aokage K, Ishii G, Nakasone S, Sakai T, Okada S, Miyoshi T, Tane K, Tsuboi M. Prognostic Impact of the Number of Metastatic Lymph Nodes on the Eighth Edition of the TNM Classification of NSCLC. J Thorac Oncol, 14:1408-1418, 2019
23. Suzuki E, Yamazaki S, Naito T, Hashimoto H, Okubo S, Udagawa H, Goto K, Tsuboi M, Ochiai A, Ishii G. Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer-associated fibroblasts with EGFR-TKI resistance-promoting phenotype: A study of 18 cases of cancer-associated fibroblasts. Pathol Int, 69:472-480, 2019
24. Ota T, Niho S, Kirita K, Ishii G, Tsuboi M, Goto K. Impressive response to nivolumab of non-small-cell lung cancer containing sarcomatoid components. Respirol Case Rep, 7:e00477, 2019
25. Oki T, Aokage K, Ueda T, Sugano M, Tane K, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Funai K, Tsuboi M, Ishii G. Proportion of goblet cell is associated with malignant potential in invasive mucinous adenocarcinoma of the lung. Pathol Int, 69:526-535, 2019
26. Ichikawa T, Aokage K, Miyoshi T, Tane K, Suzuki K, Makinoshima H, Tsuboi M, Ishii G. Correlation between maximum standardized uptake values on FDG-PET and microenvironmental factors in patients with clinical stage IA radiologic pure-solid lung adenocarcinoma. Lung Cancer, 136:57-64, 2019
27. Hisamitsu S, Miyashita T, Hashimoto H, Neri S, Sugano M, Nakamura H, Yamazaki S, Ochiai A, Goto K, Tsuboi M, Ishii G. Interaction between cancer cells and cancer-associated fibroblasts after cisplatin treatment promotes cancer cell regrowth. Hum Cell, 32:453-464, 2019
28. Naito T, Udagawa H, Umemura S, Sakai T, Zenke Y, Kirita K, Matsumoto S, Yoh K, Niho S, Tsuboi M, Ishii G, Goto K. Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden. Lung Cancer, 138:35-42, 2019
29. Okada N, Daiko H, Kanamori J, Sato A, Horikiri Y, Sato T, Fujiwara H, Tomioka T, Fujita T, Kojima T, Fujii S. Impact of pathologically assessing extranodal extension in the thoracic field on the prognosis of esophageal squamous cell carcinoma. Surgery, 165:1203-1210, 2019
30. Naito T, Udagawa H, Sato J, Horinouchi H, Murakami S, Goto Y, Kanda S, Fujiwara Y, Yamamoto N, Zenke Y, Kirita K, Matsumoto S, Yoh K, Niho S, Motoi N, Ohe Y, Ishii G, Goto K. A Minimum Of 100 Tumor Cells in a Single Biopsy Sample Is Required to Assess Programmed Cell Death Ligand 1 Expression in Predicting Patient Response to Nivolumab Treatment in Nonsquamous Non-Small Cell Lung Carcinoma. J Thorac Oncol, 14:1818-1827, 2019
31. Ota T, Kirita K, Matsuzawa R, Udagawa H, Matsumoto S, Yoh K, Niho S, Ishii G, Goto K. Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified. J Cancer Res Clin Oncol, 145:2495-2506, 2019
32. Nakamura Y, Sawada K, Fujii S, Yoshino T. HER2-targeted therapy should be shifted towards an earlier line for patients with anti-EGFR-therapy na?ve, HER2-amplified metastatic colorectal cancer. ESMO Open, 4:e000530, 2019
33. Fujii S, Yoshino T, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shinozaki E, Shitara K, Bando H, Mimaki S, Nakai C, Matsushima K, Suzuki Y, Akagi K, Yamanaka T, Nomura S, Esumi H, Sugiyama M, Nishida N, Mizokami M, Koh Y, Abe Y, Ohtsu A, Tsuchihara K. Histopathological factors affecting the extraction of high quality genomic DNA from tissue sections for next-generation sequencing. Biomed Rep, 11:171-180, 2019
34. Okubo S, Kojima M, Matsuda Y, Hioki M, Shimizu Y, Toyama H, Morinaga S, Gotohda N, Uesaka K, Ishii G, Mino-Kenudson M, Takahashi S. Area of residual tumor (ART) can predict prognosis after post neoadjuvant therapy resection for pancreatic ductal adenocarcinoma. Sci Rep, 9:17145, 2019
35. Maishi N, Kikuchi H, Sato M, Nagao-Kitamoto H, Annan DA, Baba S, Hojo T, Yanagiya M, Ohba Y, Ishii G, Masutomi K, Shinohara N, Hida Y, Hida K. Development of Immortalized Human Tumor Endothelial Cells from Renal Cancer. Int J Mol Sci, 20:4595, 2019
36. Sakai T, Miyoshi T, Umemura S, Suzuki J, Nakasone S, Okada S, Tane K, Aokage K, Goto K, Motoi N, Ishii G, Tsuboi M. Large pulmonary sclerosing pneumocytoma with massive necrosis and vascular invasion: a case report. Oxf Med Case Reports, 2019:omz066, 2019
37. Martin JD, Panagi M, Wang C, Khan TT, Martin MR, Voutouri C, Toh K, Papageorgis P, Mpekris F, Polydorou C, Ishii G, Takahashi S, Gotohda N, Suzuki T, Wilhelm ME, Melo VA, Quader S, Norimatsu J, Lanning RM, Kojima M, Stuber MD, Stylianopoulos T, Kataoka K, Cabral H. Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment. ACS Nano, 13:6396-6408, 2019
38. 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
39. Sukeda A, Nakamura Y, Nishida Y, Kojima M, Gotohda N, Akimoto T, Ochiai A. Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma. Pancreas, 48:1102-1110, 2019
40. Hashimoto T, Ogawa R, Yoshida H, Taniguchi H, Kojima M, Saito Y, Sekine S. EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma. Histopathology, 75:266-273, 2019
41. Matsunaga R, Kojima M, Nishizawa Y, Yokota M, Hasegawa H, Saito N, Ito M, Ochiai A. The utility of longitudinal slicing method for rectal specimen: pathological analysis of circumferential resection margin of intersphincteric resection for low-lying rectal cancer. Pathol Int, 69:272-281, 2019