Immunophenotype analysis using CLDN18, CDH17, and PAX8 for the subcategorization of endocervical adenocarcinomas in situ: gastric-type, intestinal-type, gastrointestinal-type, and Müllerian-type

  • Shiho AsakaEmail author
  • Tomoyuki Nakajima
  • Kaori Kugo
  • Risako Kashiwagi
  • Nozomi Yazaki
  • Tsutomu Miyamoto
  • Takeshi Uehara
  • Hiroyoshi Ota
Original Article
Part of the following topical collections:
  1. Quality in Pathology


A classification system for invasive endocervical adenocarcinoma (ECA) focusing on high-risk human papillomavirus (HPV) detection has been recently developed. However, precursor lesions of each ECA subtype and immunohistochemical markers that effectively subcategorize ECAs with gastric and intestinal differentiation have not been fully described. Here, we aimed to subcategorize endocervical adenocarcinoma in situ (AIS) by immunophenotype and to characterize the histopathology of each AIS subtype. We immunohistochemically analyzed 36 AIS and 25 lobular endocervical glandular hyperplasia (LEGH) samples using three cell lineage–specific markers (CLDN18, gastric epithelial cells; CDH17, intestinal epithelial cells; and PAX8, Müllerian epithelial cells). The AISs were immunophenotypically classified as gastric-type (G-AIS; n = 2), intestinal-type (I-AIS; n = 10), gastrointestinal-type (GI-AIS; n = 3), Müllerian-type (M-AIS; n = 18), and AIS, not otherwise specified (AIS-NOS; n = 3). All 25 LEGHs were categorized as gastric-type. G-AIS had pale eosinophilic or clear cytoplasm with a small amount of apical mucin and fewer mitotic bodies. I-AIS comprised various numbers of goblet cell-type tumor cells. GI-AIS showed intermediate or mixed features of G-AIS and I-AIS. M-AIS, as with the usual-type ECA, was typically characterized by mucin depletion; however, several lesions had abundant cytoplasmic mucin. High-risk HPV was detected in most AISs but was negative in 100% (2/2) of G-AIS, 10% (1/10) of I-AIS, and 6% (1/18) of M-AIS lesions. In summary, the AIS subtypes defined by immunophenotype had distinct histopathological and etiological characteristics. Thus, immunophenotyping with CLDN18, CDH17, and PAX8 might improve the diagnostic accuracy of histopathological classifications of ECAs.


Endocervical adenocarcinoma in situ Immunohistochemistry Gastric type Intestinal type Lobular endocervical glandular hyperplasia Human papillomavirus 



We thank Kayo Suzuki and Misako Yamada (Research Center for Supports to Advanced Science, Shinshu University) and Chinatsu Kobayashi and Masayuki Ito (Department of Clinical Laboratory Sciences, Shinshu University School of Medicine) for providing expert technical assistance. We also thank Editage ( for English language editing.


Conceptualization: Shiho Asaka and Hiroyoshi Ota; Methodology: Shiho Asaka, Tomoyuki Nakajima, Takeshi Uehara, and Hiroyoshi Ota; Formal analysis and investigation: Shiho Asaka, Tomoyuki Nakajima, Kaori Kugo, Risako Kashiwagi, Nozomi Yazaki, and Hiroyoshi Ota; Writing—original draft preparation: Shiho Asaka; Writing—review and editing: Hiroyoshi Ota; Funding acquisition: Shiho Asaka and Hiroyoshi Ota; Resources: Tsutomu Miyamoto and Takeshi Uehara; Supervision: Hiroyoshi Ota. All authors gave final approval for publication. Shiho Asaka takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Funding information

This work was funded by the Japan Society for the Promotion of Science (JSPS), Grants-in-Aid for Scientific Research (KAKENHI) to Shiho Asaka (17K15641) and Hiroyoshi Ota (17K09010).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2019_2739_MOESM1_ESM.pdf (1.5 mb)
ESM 1 (PDF 1495 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Laboratory MedicineShinshu University School of MedicineMatsumotoJapan
  2. 2.Department of Diagnostic PathologyShinshu University HospitalMatsumotoJapan
  3. 3.Department of Clinical Laboratory SciencesShinshu University School of MedicineMatsumotoJapan
  4. 4.Department of Obstetrics and GynecologyShinshu University School of MedicineMatsumotoJapan

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