Programmed cell death protein 1/programmed death ligand 1 but not HER2 is a potential therapeutic target in gastric neuroendocrine carcinoma

Histopathology. 2021 Feb;78(3):381-391. doi: 10.1111/his.14230. Epub 2020 Sep 26.


Aims: Gastric neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. We aim to investigate expression profiles of HER2 and programmed death ligand 1 (PD-L1) in gastric NEC to test the potential applicability of drugs targeting these molecules.

Methods and results: Expression levels of HER2 and PD-L1 were evaluated in 25 gastric NECs, including 10 pure NECs and 15 mixed adenocarcinoma-NECs, and a combined positive score (CPS) was used to evaluate PD-L1 expression. The correlations of expression levels with both clinicopathological features and the expression of p53, retinoblastoma protein (Rb) and mismatch repair proteins were also analysed. Eighteen of the 25 (72%) cases showed a PD-L1 CPS of ≥ 1, which was previously shown to be associated with response to pembrolizumab. Positive nodal metastasis and low tumour-infiltrating lymphocyte (TIL) levels at the invasive margin were significantly associated with a PD-L1 CPS of < 1. The NEC component was HER2-negative in all cases, whereas HER2 positivity was observed in the adenocarcinoma component of six of 15 (40%) mixed adenocarcinoma-NECs. Mismatch repair deficiency, a mutant pattern of p53 expression and loss of Rb expression were observed in four (16%), 17 (68%) and nine (36%) cases, respectively, although these alterations were not associated with the PD-L1 CPS or other clinicopathological characteristics.

Conclusions: HER2 is unlikely to be an effective target in gastric NEC owing to the lack of HER2 expression, whereas the PD-1/PD-L1 pathway is a potential therapeutic target for gastric NEC because of the relatively high prevalence of a PD-L1 CPS of ≥ 1 in this subtype.

Keywords: HER2; combined positive score; gastric neuroendocrine carcinoma; molecular targeted therapy; programmed death ligand 1.

MeSH terms

  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / metabolism*
  • B7-H1 Antigen / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Neuroendocrine* / drug therapy
  • Carcinoma, Neuroendocrine* / metabolism
  • Carcinoma, Neuroendocrine* / pathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / metabolism*
  • Peptide Fragments / therapeutic use
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-2 / therapeutic use
  • Retrospective Studies
  • Stomach / pathology
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / pathology


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • HER2 peptide (369-377)
  • Peptide Fragments
  • Programmed Cell Death 1 Receptor
  • Receptor, ErbB-2