Division of Pathology

Genichiro Ishii, Satoshi Fujii, Motohiro Kojima, Hiroko Hashimoto, Yoshiko Onuma, Yoshitaka Suda, Tomoyuki Miyashita, Syota Yamazaki, Erika Suzuki, Hojong Lee

Introduction

Our aim is to explore the causes of cancer, and to develop novel diagnostic and therapeutic methods for cancer patients. To accomplish this, our members need to perform the following missions.

1)Basic and translational research based on the clinicopathological characteristics of cancer

2)Pathological diagnoses in the National Cancer Center Hospital East (NCCH-E)

3)Clinical resident training for diagnosis and translational research

4)Biobank construction support (tissue preparation and tissue microarray construction).

Our team and what we do

Our team's goal is to explore the cause of cancer, and to develop novel diagnostic and therapeutic methods for cancer patients. Therefore, team members are responsible for basic and translational researches on cancer biology and cancer treatment fields. To this end, we build hypothesis through both pathological samples and clinicopathological information. Since the in vitro and in vivo models mimicking human cancer tissue are required to solve molecular mechanisms, we develop novel in vitro models and examine whether our hypothesis are correct or not. We must further confirm our hypothesis by final validation studies using human samples.

Team members are also involved in all routine pathological and cytological diagnosis in the NCCH-E, with the collaboration of pathologist staff of the Department of Pathology and Clinical Laboratories of the NCCH-E. Team members also educate clinical residents in pathological diagnosis and translational research using clinical samples from the NCCH-E. Moreover, team members participate in clinicopathological conferences and research meetings between the NCCH-E and the Exploratory Oncology Research & Clinical Trial Center (EPOC).

Research activities

Most of our research products are generated through collaborative investigation with clinicians. Major research results of this year are listed below.

1)We found that drastic microenvironmental changes (e.g., growth factor receptor expression, proliferative capacity of tumor cells, and structural changes in stromal cells) occur during both the process of lymphatic permeation, and the progression into lymph node macrometastases of lung cancer (#1).

2)Using a novel in vitro coculture system, we clarified two types of fibroblast-dependent cancer cell invasion that are dependent on, and independent of the remodeling areas generated by CAFs (#3).

3)The tumor microenvironment of poorly differentiated lung adenocarcinoma is characterized by more abundant stromal cells with tumor-promoting functions (#6).

4)We reported that mesenchymal progenitor cells are present in lung cancer associated fibroblasts (CAFs). Moreover, CAFs with higher osteogenic potential have a greater tumor-promoting function through the enhancement of cancer cell migration (#11).

5)Positive circumferential resection margin after multimodality treatment including surgery alone or combined neoadjuvant chemotherapy followed by surgery significantly affected the overall and relapse-free survival of esophageal squamous cell carcinoma patients with pT3 (#14).

6)Tumor regression grade is a critical prognostic factor in patients with esophageal squamous cell carcinoma patients who had undergone neoadjuvant chemotherapy followed by surgery (#20).

7)Positive PD-L1 expression was significantly associated with poor disease free survival of salivary gland carcinomas (SGCs), suggesting that antibody therapies targeting PD-1/PD-L1 may have potential application in SGCs (#21).

8)Invasive depth was an independent predictive factor for delayed cervical lymph node metastasis in tongue squamous cell carcinoma patients. Also the research suggested that tumors with invasion to lateral extrinsic tongue muscle might have to be excluded from the pathologic T4a category (#22).

9)We investigated the working environment of Japanese Pathologist, and reported difficult situations of pathologists in small institutions.

10) We examined pathological alteration after medication, and proposed proper pathological assessment method of therapeutic effect using the "Area of Residual Tumor (ART)" concept (#28).

11) Subperitoneal fibroblast plays an important role in the formation of tumor promoting microenvironment that was formed when tumor invade beyond peritoneal elastic lamina of colon cancer. Furthermore, we clarified subperitoneal fibroblast could influence on the cancer elasticity (#32).

12) In cooperation with the industry, we found specific serum microRNA as a diagnostic biomarker in early pancreas cancer. This year we obtained an international patent and a clinical trial is planned.

Other clinicopathological researches and case reports in collaboration with clinician were published this year, especially for lung, head and neck, gastrointestinal, and hepato-biliary-pancreatic tumors (#4, 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 23, 24, 25, 26, 27, 29, 30, and 31).

Education

Our division members give lectures about diagnostic training and pathological research for clinical residents in the NCCH-E. Moreover, staff members give professional guidance for doctoral students attending Juntendo University, and Keio University. Some members are faculty of Tokyo Medical and Dental University, and the Graduate School of Frontier Sciences, the University of Tokyo, which perform instruction to students in master and doctoral courses.

Future prospects

We are strengthening particularly in the promotion of basic and translational research on cancer biology, diagnosis, and treatment. Moreover, we will develop automated support tools for immunohistochemical diagnosis by using an artificial intelligence (AI)powered computer system in collaboration with clinician and industrial members.

List of papers published in 2016

Journal

1.Ikeda K, Kojima M, Saito N, Sakuyama N, Koushi K, Watanabe T, Sugihara K, Akimoto T, Ito M, Ochiai A. Current status of the histopathological assessment, diagnosis, and reporting of colorectal neuroendocrine tumors: A Web survey from the Japanese Society for Cancer of Colon and Rectum. Pathol Int, 66:94-101, 2016

2.Yokota M, Kojima M, Higuchi Y, Nishizawa Y, Kobayashi A, Ito M, Saito N, Ochiai A. Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer. Int J Cancer, 138:1422-1431, 2016

3.Mukaigawa T, Hayashi R, Miyazaki M, Shinozaki T, Tomioka T, Fujii S. Cystadenocarcinoma of the salivary glands with potential lymph node metastasis. Auris Nasus Larynx, 43:340-344, 2016

4.Kadota T, Fujii S, Oono Y, Imajoh M, Yano T, Kaneko K. Adenocarcinoma arising from heterotopic gastric mucosa in the cervical esophagus and upper thoracic esophagus: two case reports and literature review. Expert Rev Gastroenterol Hepatol, 10:405-414, 2016

5.Sekine S, Yamashita S, Tanabe T, Hashimoto T, Yoshida H, Taniguchi H, Kojima M, Shinmura K, Saito Y, Hiraoka N, Ushijima T, Ochiai A. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. J Pathol, 239:133-138, 2016

6.Aramaki N, Ishii G, Yamada E, Morise M, Aokage K, Kojima M, Hishida T, Yoshida J, Ikeda N, Tsuboi M, Ochiai A. Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma. J Cancer Res Clin Oncol, 142:37-46, 2016

7.Neri S, Hashimoto H, Kii H, Watanabe H, Masutomi K, Kuwata T, Date H, Tsuboi M, Goto K, Ochiai A, Ishii G. Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts. J Cancer Res Clin Oncol, 142:437-446, 2016

8.Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev, 99:186-196, 2016

9.Hisakane K, Saruwatari K, Fujii S, Kirita K, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Kuwata T, Ochiai A, Gemma A, Tsuboi M, Goto K, Ishii G. Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma. J Cancer Res Clin Oncol, 142:593-600, 2016

10.Sekihara K, Hishida T, Ikemura S, Saruwatari K, Morise M, Kuwata T, Fujii S, Kojima M, Ochiai A, Funai K, Aokage K, Yoshida J, Tsuboi M, Ishii G. The association of intravascular stromal cells with prognosis in high-grade neuroendocrine carcinoma of the lung. J Cancer Res Clin Oncol, 142:905-912, 2016

11.Saruwatari K, Ikemura S, Sekihara K, Kuwata T, Fujii S, Umemura S, Kirita K, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Ochiai A, Kohrogi H, Tsuboi M, Goto K, Ishii G. Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations. Lung Cancer, 91:7-14, 2016

12.Matsuzawa R, Kirita K, Kuwata T, Umemura S, Matsumoto S, Fujii S, Yoh K, Kojima M, Niho S, Ohmatsu H, Ochiai A, Tsuboi M, Goto K, Ishii G. Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma. Lung Cancer, 94:1-6, 2016

13.Hida K, Ishii G. Editorial: Targeting tumor microenvironment heterogeneity. Adv Drug Deliv Rev, 99:139, 2016

14.Hata K, Yoshida J, Udagawa H, Hashimoto H, Fujii S, Hishida T, Kuwata T, Aokage K, Kojima M, Ochiai A, Suzuki K, Tsuboi M, Ishii G. The difference in Ezrin-pAkt signaling axis between lepidic and papillary predominant invasive adenocarcinomas of the lung. J Cancer Res Clin Oncol, 142:1421-1430, 2016

15.Suzuki S, Aokage K, Hishida T, Yoshida J, Kuwata T, Yamauchi C, Tsuboi M, Ishii G. Interstitial growth as an aggressive growth pattern in primary lung cancer. J Cancer Res Clin Oncol, 142:1591-1598, 2016

16.Suda Y, Neri S, Hashimoto H, Higuchi Y, Ishibashi M, Sugano M, Masutomi K, Tsuboi M, Ochiai A, Ishii G. Clonal heterogeneity in osteogenic potential of lung cancer-associated fibroblasts: promotional effect of osteogenic progenitor cells on cancer cell migration. J Cancer Res Clin Oncol, 142:1487-1498, 2016

17.Nakagawa K, Asamura H, Tsuta K, Nagai K, Yamada E, Ishii G, Mitsudomi T, Ito A, Higashiyama M, Tomita Y, Inoue M, Morii E, Matsuura N, Okumura M. The novel one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node metastasis in patients with non-small cell lung cancer (NSCLC): Results of a multicenter prospective study. Lung Cancer, 97:1-7, 2016

18.Naito M, Aokage K, Saruwatari K, Hisakane K, Miyoshi T, Hishida T, Yoshida J, Masato S, Kojima M, Kuwata T, Fujii S, Ochiai A, Sato Y, Tsuboi M, Ishii G. Microenvironmental changes in the progression from adenocarcinoma in situ to minimally invasive adenocarcinoma and invasive lepidic predominant adenocarcinoma of the lung. Lung Cancer, 100:53-62, 2016

19.Motegi A, Fujii S, Zenda S, Arahira S, Tahara M, Hayashi R, Akimoto T. Impact of Expression of CD44, a Cancer Stem Cell Marker, on the Treatment Outcomes of Intensity Modulated Radiation Therapy in Patients With Oropharyngeal Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys, 94:461-468, 2016

20.Okada N, Fujii S, Fujita T, Kanamori J, Kojima T, Hayashi R, Daiko H. The prognostic significance of the positive circumferential resection margin in pathologic T3 squamous cell carcinoma of the esophagus with or without neoadjuvant chemotherapy. Surgery, 159:441-450, 2016

21.Osera S, Fujii S, Ikematsu H, Miyamoto H, Oono Y, Yano T, Ochiai A, Yoshino T, Ohtsu A, Kaneko K. Clinicopathological, endoscopic, and molecular characteristics of the "skirt" - a new entity of lesions at the margin of laterally spreading tumors. Endoscopy, 48:448-455, 2016

22.Hatogai K, Yano T, Kojima T, Onozawa M, Fujii S, Daiko H, Yoda Y, Hombu T, Doi T, Kaneko K, Ohtsu A. Local efficacy and survival outcome of salvage endoscopic therapy for local recurrent lesions after definitive chemoradiotherapy for esophageal cancer. Radiat Oncol, 11:31, 2016

23.Hatogai K, Fujii S, Kojima T, Daiko H, Kadota T, Fujita T, Yoshino T, Doi T, Takiguchi Y, Ohtsu A. Prognostic significance of tumor regression grade for patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy followed by surgery. J Surg Oncol, 113:390-396, 2016

24.Mukaigawa T, Hayashi R, Hashimoto K, Ugumori T, Hato N, Fujii S. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J Surg Oncol, 114:36-43, 2016

25.Mitani S, Tomioka T, Hayashi R, Ugumori T, Hato N, Fujii S. Anatomic Invasive Depth Predicts Delayed Cervical Lymph Node Metastasis of Tongue Squamous Cell Carcinoma. Am J Surg Pathol, 40:934-942, 2016

26.Enokida T, Fujii S, Kuno H, Mukaigawa T, Tahara M, Sakuraba M, Hayashi R. Combined salivary duct carcinoma and squamous cell carcinoma suspected of carcinoma ex pleomorphic adenoma. Pathol Int, 66:460-465, 2016

27.Nakamura H, Yano T, Fujii S, Kadota T, Tomioka T, Shinozaki T, Hayashi R, Kaneko K. Natural history of superficial head and neck squamous cell carcinoma under scheduled follow-up endoscopic observation with narrow band imaging: retrospective cohort study. BMC Cancer, 16:743, 2016

28.Koushi K, Nishizawa Y, Kojima M, Fujii S, Saito N, Hayashi R, Ochiai A, Ito M. Association between pathologic features of peripheral nerves and postoperative anal function after neoadjuvant therapy for low rectal cancer. Int J Colorectal Dis, 31:1845-1852, 2016

29.Kojima M, Ikeda K, Saito N, Sakuyama N, Koushi K, Kawano S, Watanabe T, Sugihara K, Ito M, Ochiai A. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis. Front Oncol, 6:173, 2016

30.Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, Arakawa H, Takemura S, Tanaka S, Marubashi S, Kinoshita M, Matsuda T, Shibata T, Nakagama H, Ochiai A, Kubo S, Nakamori S, Esumi H, Tsuchihara K. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis, 37:817-826, 2016

31.Sakuyama N, Kojima M, Kawano S, Akimoto T, Saito N, Ito M, Ochiai A. Histological differences between preoperative chemoradiotherapy and chemotherapy for rectal cancer: a clinicopathological study. Pathol Int, 66:273-280, 2016

32.Tsukada Y, Ito M, Watanabe K, Yamaguchi K, Kojima M, Hayashi R, Akita K, Saito N. Topographic Anatomy of the Anal Sphincter Complex and Levator Ani Muscle as It Relates to Intersphincteric Resection for Very Low Rectal Disease. Dis Colon Rectum, 59:426-433, 2016