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Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma
  1. Aya Kawanishi1,
  2. Kenichi Hirabayashi2,
  3. Misuzu Yamada3,
  4. Yumi Takanashi2,
  5. Atsuko Hadano1,
  6. Yoshiaki Kawaguchi1,
  7. Toshio Nakagohri3,
  8. Naoya Nakamura2,
  9. Tetsuya Mine1
  1. 1Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Kanagawa, Japan
  2. 2Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
  3. 3Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan
  1. Correspondence to Dr Kenichi Hirabayashi, Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan; kenichi.hirabayashi{at}


Aims The loss, or decreased expression, of nectin-like molecule 4 (Necl-4; an immunoglobulin-like cell adhesion molecule) is reported to be associated with the development and progression of certain types of cancer. We investigated the clinicopathological significance of Necl-4 expression in patients with pancreatic ductal adenocarcinoma (PDAC).

Methods Immunohistochemical analyses of Necl-4 (n=258) and E-cadherin (n=256) expression were performed using tissue microarray blocks of PDAC samples. Necl-4 expression of 38 pancreatic intraepithelial neoplasia (PanIN) lesions included in tissue microarray cores was also evaluated. Necl-4 and E-cadherin expression was considered positive if >30% of cells were stained, and negative if ≤30% of cells were stained.

Results Necl-4 expression was positive in 45.7% (n=118) and negative in 54.3% (n=140) of PDAC cases. Necl-4 staining was positive in 96.7% (n=29) and negative in 3.3% (n=1) of low-grade PanIN cases, and positive in 62.5% (n=5) and negative in 37.5% (n=3) of high-grade PanIN cases. The number of cases with positive Necl-4 expression decreased in the order low-grade PanIN>high-grade PanIN>PDAC (p<0.001). Negative Necl-4 expression was significantly associated with a larger tumour size of >30 mm, perineural invasion, lymphatic involvement, lymph node metastasis (pN1), an advanced TNM (tumour, node, metastases) stage (stage IIB–IV), an advanced histological grade (G2/3), and shorter overall survival. E-cadherin staining was positive in 46.1% (n=118) and negative in 53.9% (n=138) of PDAC cases. Necl-4 expression correlated positively with E-cadherin expression (r=0.405, p<0.001).

Conclusions The results suggest that Necl-4 is associated with carcinogenesis and aggressiveness of PDAC.


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  • Handling editor Cheok Soon Lee

  • Contributors AK and KH interpreted the immunohistochemical staining, performed the statistical analyses, and drafted the manuscript. MY constructed the tissue microarray blocks. AH, MY, TN and YK provided the clinical information. NN, TM and YT critically revised the manuscript for important intellectual content.

  • Funding This study was supported by the Research and Study Project of the Tokai University Educational System's General Research Organisation and a Tokai University School of Medicine Research-Aid Grant 2016.

  • Competing interests None declared.

  • Ethics approval The study protocol was approved by the research ethics committee (No 13R244) of the Tokai University School of Medicine (Kanagawa, Japan).

  • Provenance and peer review Not commissioned; externally peer reviewed.