Trefoil factor family (TFF) proteins in cervical discharge as a screening test of endocervical glandular lesions

• Project/Area Number: 17K09010
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Shinshu University
• Principal Investigator: Ota Hiroyoshi 信州大学, 学術研究院保健学系, 教授 (50273107)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 子宮頸部腺癌 / トレフォイルファクター / 分葉状頸管腺過形成 / LEGH / TFF / 子宮頸部腺系病変 / 子宮頸部胃型腺癌 / 病理学

Outline of Final Research Achievements

Endocervical glandular hyperplasia (LEGH), 36 adenocarcinoma in situ (AIS) and 66 invasive endocervical adenocarcinoma (ECA) samples were immunohistochemically analyzed using cell lineage‐specific markers. All LEGHs were categorized as gastric-type. The AISs and ECAs were classified as gastric (5.6%/22.7%), intestinal (27.8/13.6), gastrointestinal (8.3/10.6), Mullerian-type (50/34.8), and NOS (8.3/18.2). TFF1, TFF2, and TFF3 in cervical discharge were measured by ELISA. Both TFF1/TFF3 and TFF2/TFF3 in LEGH group [(TFF1/TFF3, 3.18‰ (IQR, 1.87‰-6.04‰); TFF2/TFF3, 4.95 (1.70-10.37)] were significantly higher than those in non‐neoplastic group (TFF1/TFF3, 0.10 (0.04-0.30); TFF2/TFF3, 0.57 (0.28-1.33) According to ROC analysis, the optimal cut-off values of TFF1/TFF3 and TFF2/TFF3 in the discrimination between LEGH patients and non-tumor patients were 0.58‰ (sensitivity, 93.8%; specificity, 86.2%) and 1.57‰ (sensitivity, 78.1%; specificity, 78.1%), respectively.

Academic Significance and Societal Importance of the Research Achievements

子宮頸部腺系病変［分葉状内頸腺過(LEGH)、上皮内癌（AIS）、浸潤癌(ECA)］は免疫組織化学的解析による構成細胞の細胞系列により胃型、腸型、胃腸混合型、ミュラー管型とその他に分類することができた。今後、子宮頸部腺系病変の診断および腫瘍発機序の研究は細胞系列に基づいた解析が可能と考える。子宮頸部腺系病変においてTFF2は胃型病変に特異的に発現しているの対してTFF1は胃型以外にも発現がみられるため、頸管分泌物のTFF‐ELISAによるTFF2/TFF3比は子宮頸部胃型病変の、一方、TFF1/TTF3比は子宮頸部腺系病変全般のスクリーニング検査への応用が期待される。

Research Products

• [Journal Article] Immunophenotype analysis using CLDN18, CDH17, and PAX8 for the subcategorization of endocervical adenocarcinomas in situ: gastric-type, intestinal-type, gastrointestinal-type, and Mullerian-type (2020)
  • Author(s): Shiho Asaka, Tomoyuki Nakajima, Kaori Kugo, Risako Kashiwagi, Nozomi Yazaki, Tsutomu Miyamoto, Takeshi Uehara, Hiroyoshi Ota
  • Journal Title: Virchows Archiv Volume: 476 Issue: 4 Pages: 499-510
  • DOI: 10.1007/s00428-019-02739-x
  • Peer Reviewed
• [Presentation] Invasive Endocervical Adenocarcinoma with Gastric and Intestinal Immunophenotype Correlates with Adverse Clinicopathological Features and Patient Outcome (2020)
  • Author(s): Shiho Asaka, Tomoyuki Nakajima, Koichi Ida, Ryoichi Asaka, Tsutomu Miyamoto, Takeshi Uehara, Hiroyoshi Ota
  • Organizer: USCAP 109th Annual Meeting
  • Int'l Joint Research
• [Presentation] Immunophenotypic Classification of Endocervical Adenocarcinoma in situ Based on Comprehensive Immunohistochemical Markers: Gastric-Type, Gastrointestinal-Type, Intestinal-Type, and Mullerian-Type (2019)
  • Author(s): Shiho Asaka, Tomoyuki Nakajima, Takeshi Uehara, Hiroyoshi Ota
  • Organizer: USCAP 108th Annual Meeting
  • Int'l Joint Research
• [Presentation] An Immunophenotypic Classification of Endocervical Adenocarcinoma in situ Based on Comprehensive Immunohistochemical Markers: Gastric-Type, Gastrointestinal-Type, Intestinal-Type, and Muellerian-Type (2019)
  • Author(s): Shiho Asaka, Tomoyuki Nakajima, Takeshi Uehara, Hiroyoshi Ota
  • Organizer: United States and Canadian Academy of Pathology (USCAP) 108th Annual Meeting
  • Int'l Joint Research