Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluate the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2Tumor(T) > 4, PD-1Stromal(S) > 0, CD8S < 1, and HLA-IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12-2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2T > 4, PD-1S > 4, HLA-IS < 1, HLA-IT < 2, HLA-DRS < 6 (HR 1.77; 95% CI, 1.58-1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30-10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28-24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67-18.47; PI = 5: HR 2.87; 95% CI, 1.21-6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52-13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints.
Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms / M. Milione, R. Miceli, F. Barretta, A. Pellegrinelli, P. Spaggiari, G. Tagliabue, G. Centonze, C. Paolino, A. Mangogna, K. Kankava, S. Pusceddu, L. Giacomelli, A. Corti, C. Cotsoglou, V. Mazzaferro, G. Sozzi, F. de Braud, G. Pruneri, A. Anichini. - In: THE JOURNAL OF PATHOLOGY. CLINICAL RESEARCH. - ISSN 2056-4538. - 5:4(2019 Oct), pp. 217-226.
|Titolo:||Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms|
PRUNERI, GIANCARLO (Penultimo)
|Parole Chiave:||Ki-67; disease-free survival; gastro-entero-pancreatic neuroendocrine neoplasm; immune and inflammatory markers; microenvironment; morphology|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||ott-2019|
|Data ahead of print / Data di stampa:||28-mag-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/cjp2.135|
|Appare nelle tipologie:||01 - Articolo su periodico|
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