Ki67 proliferative index of the neuroendocrine component drives MANEC prognosis

Massimo Milione, Patrick Maisonneuve, Alessio Pellegrinelli, Federica Grillo, Luca Albarello, Paola Spaggiari, Alessandro Vanoli, Giovanna Tagliabue, Eleonora Pisa, Luca Messerini, Giovanni Centonze, Frediano Inzani, Aldo Scarpa, Mauro Papotti, Marco Volante, Fausto Sessa, Nicola Fazio, Giancarlo Pruneri, Guido Rindi, Enrico SolciaStefano La Rosa, Carlo Capella

Research output: Contribution to journalArticle

Abstract

Mixed adenoneuroendocrine carcinomas (MANECs) are composed of a poorly differentiated neuroendocrine carcinoma (NEC) and a non-neuroendocrine (non-NEC) neoplastic epithelial component, each representing at least 30% of the tumor. At present, prognostic factors for MANECs remain largely unexplored. We investigated the clinical-pathologic features of a large multicenter series of digestive system MANECs. Surgical specimens of 200 MANEC candidates were centrally reviewed; diagnosis was confirmed in 160 cases. While morphology, proliferation (mitotic count (MC), Ki67 index) and immunophenotype (p53, SSTR2a, beta-Catenin, Bcl-2, p16, Rb1, ALDH, mismatch repair proteins and CD117) were investigated separately in both components, genomic (TP53, KRAS, BRAF) alterations were searched for on the entire tumor. Data were correlated with overall survival (OS). MANEC sites were: 92 colorectal, 44 gastroesophageal and 24 pancreatobiliary. Median OS was 13.2 months. After adjustment for primary site, Ki67 index of the NEC component (but not of the non-NEC component) was the most powerful prognostic marker. At multivariable analysis, patients with Ki67 ≥ 55% had an 8-fold risk of death (hazard ratio (HR) 7.83; 95% confidence interval (CI) 4.17-14.7; P < 0.0001) and a median OS of 12.2 months compared to those with Ki67 < 55% (median OS 40.5 months). MC (HR 1.51; 95% CI 1.03-2.20, P = 0.04) was a weaker prognostic index. Colorectal primary site (HR 1.60; 95% CI 1.11-2.32; P = 0.01) was significantly associated with poorer survival. No single immunomarker, in either component, was statistically significant. This retrospective analysis of a large series of digestive system MANECs, showed that the NEC component, particularly its Ki67 index, was the main prognostic driver.

Original languageEnglish
Pages (from-to)583-593
Number of pages11
JournalEndocrine-Related Cancer
Volume25
Issue number5
DOIs
Publication statusPublished - May 2018

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Carcinoma
Neuroendocrine Carcinoma
Survival
Digestive System
Confidence Intervals
DNA Mismatch Repair
beta Catenin
Neoplasms
Proteins

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Ki67 proliferative index of the neuroendocrine component drives MANEC prognosis. / Milione, Massimo; Maisonneuve, Patrick; Pellegrinelli, Alessio; Grillo, Federica; Albarello, Luca; Spaggiari, Paola; Vanoli, Alessandro; Tagliabue, Giovanna; Pisa, Eleonora; Messerini, Luca; Centonze, Giovanni; Inzani, Frediano; Scarpa, Aldo; Papotti, Mauro; Volante, Marco; Sessa, Fausto; Fazio, Nicola; Pruneri, Giancarlo; Rindi, Guido; Solcia, Enrico; La Rosa, Stefano; Capella, Carlo.

In: Endocrine-Related Cancer, Vol. 25, No. 5, 05.2018, p. 583-593.

Research output: Contribution to journalArticle

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AU - Milione, Massimo

AU - Maisonneuve, Patrick

AU - Pellegrinelli, Alessio

AU - Grillo, Federica

AU - Albarello, Luca

AU - Spaggiari, Paola

AU - Vanoli, Alessandro

AU - Tagliabue, Giovanna

AU - Pisa, Eleonora

AU - Messerini, Luca

AU - Centonze, Giovanni

AU - Inzani, Frediano

AU - Scarpa, Aldo

AU - Papotti, Mauro

AU - Volante, Marco

AU - Sessa, Fausto

AU - Fazio, Nicola

AU - Pruneri, Giancarlo

AU - Rindi, Guido

AU - Solcia, Enrico

AU - La Rosa, Stefano

AU - Capella, Carlo

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AB - Mixed adenoneuroendocrine carcinomas (MANECs) are composed of a poorly differentiated neuroendocrine carcinoma (NEC) and a non-neuroendocrine (non-NEC) neoplastic epithelial component, each representing at least 30% of the tumor. At present, prognostic factors for MANECs remain largely unexplored. We investigated the clinical-pathologic features of a large multicenter series of digestive system MANECs. Surgical specimens of 200 MANEC candidates were centrally reviewed; diagnosis was confirmed in 160 cases. While morphology, proliferation (mitotic count (MC), Ki67 index) and immunophenotype (p53, SSTR2a, beta-Catenin, Bcl-2, p16, Rb1, ALDH, mismatch repair proteins and CD117) were investigated separately in both components, genomic (TP53, KRAS, BRAF) alterations were searched for on the entire tumor. Data were correlated with overall survival (OS). MANEC sites were: 92 colorectal, 44 gastroesophageal and 24 pancreatobiliary. Median OS was 13.2 months. After adjustment for primary site, Ki67 index of the NEC component (but not of the non-NEC component) was the most powerful prognostic marker. At multivariable analysis, patients with Ki67 ≥ 55% had an 8-fold risk of death (hazard ratio (HR) 7.83; 95% confidence interval (CI) 4.17-14.7; P < 0.0001) and a median OS of 12.2 months compared to those with Ki67 < 55% (median OS 40.5 months). MC (HR 1.51; 95% CI 1.03-2.20, P = 0.04) was a weaker prognostic index. Colorectal primary site (HR 1.60; 95% CI 1.11-2.32; P = 0.01) was significantly associated with poorer survival. No single immunomarker, in either component, was statistically significant. This retrospective analysis of a large series of digestive system MANECs, showed that the NEC component, particularly its Ki67 index, was the main prognostic driver.

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