Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC)

Lung Cancer. 2019 Apr:130:179-186. doi: 10.1016/j.lungcan.2019.02.022. Epub 2019 Feb 21.


Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes.

Methods: Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells.

Results: PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumor CD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumor CD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively).

Conclusions: PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed.

Keywords: CD8; Large cell neuroendocrine carcinoma; Lung cancer; PD-L1; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • CD8 Antigens
  • Carcinoma, Large Cell / diagnosis
  • Carcinoma, Large Cell / epidemiology*
  • Carcinoma, Large Cell / genetics
  • Carcinoma, Neuroendocrine / diagnosis
  • Carcinoma, Neuroendocrine / epidemiology*
  • Carcinoma, Neuroendocrine / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / epidemiology*
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Netherlands / epidemiology
  • Phenotype
  • Population Groups
  • Prevalence
  • Prognosis
  • Retrospective Studies
  • Survival Analysis


  • B7-H1 Antigen
  • CD274 protein, human
  • CD8 Antigens