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

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.

Prognostic value of PD-L1 expression in bronchopulmonary neuroendocrine tumours

“…Across all four BP-NEN entities, 85% of the tumours were PD-L1 positive. Prior investigations on PD-L1 expression in BP-NEN have been mostly limited to SCLC and have reported highly divergent results, ranging from 0% to 82.8% positivity for PD-L1 ( 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ). Possible explanations for these discrepancies include the following: use of different antibodies with different sensitivities; use of different detection systems; and use of diverse rating methods and dissimilar cut-off values for assigning tumour positivity.…”

“…Possible explanations for these discrepancies include the following: use of different antibodies with different sensitivities; use of different detection systems; and use of diverse rating methods and dissimilar cut-off values for assigning tumour positivity. Furthermore, many of these studies were conducted on tissue microarrays or (predominantly) on biopsies ( 11 , 12 , 13 , 14 , 16 , 18 , 20 , 22 , 23 , 24 , 26 , 27 , 30 ), which may not be representative of the entire tumour and, therefore, may result in an incorrect rating. In the present investigation, a distinct heterogeneity in PD-L1 expression within the BP-NEN samples was observed.…”

“…However, PD-L1 expression in BP-NEN was mostly determined in SCLC only, and the expression levels reported show a high variability between the different studies (11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30). Moreover, there are contradictory results regarding the prognostic significance of PD-L1 expression for anti-PD-1 or anti-PD-L1 treatment efficacy in naïve BP-NEN patients (11,15,17,18,19,20,23,25,26,28).…”

“…Currently, the best approach for predicting tumour response to anti-PD-1 or anti-PD-L1 therapy is determining the PD-L1 status of the tumour by immunohistochemistry ( 10 ). However, PD-L1 expression in BP-NEN was mostly determined in SCLC only, and the expression levels reported show a high variability between the different studies ( 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ). Moreover, there are contradictory results regarding the prognostic significance of PD-L1 expression for anti-PD-1 or anti-PD-L1 treatment efficacy in naïve BP-NEN patients ( 11 , 15 , 17 , 18 , 19 , 20 , 23 , 25 , 26 , 28 ).…”

"Present and future of immunotherapy in Neuroendocrine Tumors"

“…However, PD-L1 presence was strickling associated with mediastinal lymph-node metastasis at baseline. In this view, immunotherapy might represent a possible therapeutic option in the management of these neoplasms, undoubtedly to be investigated with further studies [61]. In this scenario, a recent case report described a patient with metastatic AC and persistent mediastinal lymphadenopathy refractory to first line treatment with platinum-based chemotherapy and etoposide.…”