PD-1 and PD-L1 expression in pulmonary carcinoid tumors and their association to tumor spread.

Tiina Vesterinen,Aija Knuuttila,Harri Mustonen,Maarit Ahtiainen,Caj Haglund,Kaisa Salmenkivi,Teijo Kuopio,Johanna Arola

doi:10.1530/ec-19-0308

Abstract

Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.

Highlights

Pulmonary carcinoid (PC) tumors are low- and intermediate-grade neoplasms that are subdivided into typical carcinoid (TC) and atypical carcinoid (AC) based on the mitotic count and presence of necrosis (1)
PCs are uncommon neoplasms with a rising incidence and prevalence. This rise together with limited therapeutic options for metastatic disease has accentuated the need for new treatment strategies
The immune checkpoint-based therapy targeting PD-1 or programmed death ligand 1 (PD-L1), that has shown its efficacy in other malignancies, could be a feasible option for the treatment of metastatic or inoperable PC tumors

Summary

Introduction

Pulmonary carcinoid (PC) tumors are low- and intermediate-grade neoplasms that are subdivided into typical carcinoid (TC) and atypical carcinoid (AC) based on the mitotic count and presence of necrosis (1). PCs belong to pulmonary neuroendocrine tumors together with high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). PCs constitute a totally different entity based on a low number of genetic mutations, low metastatic potential and a generally good prognosis, especially when resected (2, 3, 4). The main treatment for local PC tumors is resection while metastatic diseases are treated with cytotoxic agents, radiation therapy and somatostatin analogs, there is no consensus on these treatments (5). From an epidemiological point of view, PCs are rare tumors accounting for approximately 1% of all lung cancers (6). As the number of PC tumors diagnosed yearly is increasing, mainly due to the increased use of imaging techniques and general awareness of clinicians, there might be a need to establish novel therapeutic options for these patients (7)

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