Association of PD-L1 Expression with Tumor-Infiltrating Immune Cells and Mutation Burden in High-Grade Neuroendocrine Carcinoma of the Lung.

INTRODUCTION: The immune microenvironment of high-grade neuroendocrine carcinoma of the lung, including programmed death ligand 1 (PD-L1) expression, has not been well characterized. METHODS: On the basis of immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was scored as follows: TC0 and IC0 were defined as PD-L1 expression less than 1%, TC1 and IC1 as at least 1% but less than 10%, TC2 and IC2 as 10% or more but less than 50%, and TC3 and IC3 as 50% or more. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel (ThermoFisher Scientific, Waltham, MA) was used to identify mutations in all coding exons of 409 cancer-related genes. RESULTS: A total of 192 patients with large cell neuroendocrine carcinoma (LCNEC) (n = 72) and SCLC (n = 120) were studied. The prevalence of PD-L1 expression on TCs was 15.1% (29 of 192). IC infiltration and PD-L1 expression on ICs were observed in 34.4% of patients (66 of 192) and 31.3% of patients (60 of 192), respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% versus 23.3%, p < 0.01; 45.8% versus 22.5%, p < 0.01) and high nonsynonymous mutations (p = 0.05 and .04). PTEN loss was found in 9.5% of patients (18 of 189) and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 versus 6.8 months [p < 0.01]) and in patients with PD-L1 expression of IC1/2/3 than in those with expression of IC0 (median 11.3 versus 7.0 months [p = 0.03]). CONCLUSION: These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary high-grade neuroendocrine carcinoma and correlated with a higher mutation burden.

Spontaneous complete regression of gastric large-cell neuroendocrine carcinoma: mediated by cytomegalovirus-induced cross-autoimmunity?

Spontaneous regression of malignant tumour is a rare phenomenon. This report describes such an occurrence in a gastric large cell neuroendocrine carcinoma of a 77-year-old man. The patient presented with dyspepsia, and biopsy of the fungating mass in the cardia showed a high grade neuroendocrine carcinoma. The pre-operative biopsy taken after 3 months showed chronic inflammation and cytomegalovirus inclusions, but no tumour. In the gastrectomy specimen, no residual tumour was found. Instead, there were foamy histiocytes, chronic inflammatory cells and fibrovascular tissue splitting apart the muscularis propria. In addition, there was ganglionitis involving the myenteric plexus, even in areas of the stomach away from the inflamed site. Chemotherapy, radiotherapy or alternative medicine (including herbal medicine) had not been given. We postulate that cytomegalovirus infection initiated a cross-autoimmune reaction against neuronal cells, and this reaction "unintentionally" eliminated the carcinoma cells which also expressed neural antigens.