Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

Massimo Milione; Patrick Maisonneuve; Federica Grillo; Alessandro Mangogna; Giovanni Centonze; Natalie Prinzi; Sara Pusceddu; Giovanna Garzone; Laura Cattaneo; Adele Busico; Paola Bossi; Paola Spaggiari; Alessio Pellegrinelli; Alessandro Del Gobbo; Stefano Ferrero; Ketevani Kankava; Giancarlo Pruneri; Luigi Rolli; Elisa Roca; Luisa Bercich; Andrea Tironi; Mauro Roberto Benvenuti; Maria Sole Gallazzi; Rosalia Romano; Alfredo Berruti; Ugo Pastorino; Carlo Capella

doi:10.1159/000508376

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

Massimo Milione, Patrick Maisonneuve, Federica Grillo, Alessandro Mangogna, Giovanni Centonze, Natalie Prinzi, Sara Pusceddu, Giovanna Garzone, Laura Cattaneo, Adele Busico, Paola Bossi, Paola Spaggiari, Alessio Pellegrinelli, Alessandro Del Gobbo, Stefano Ferrero, Ketevani Kankava, Giancarlo Pruneri, Luigi Rolli, Elisa Roca, Luisa BercichAndrea Tironi, Mauro Roberto Benvenuti, Maria Sole Gallazzi, Rosalia Romano, Alfredo Berruti, Ugo Pastorino, Carlo Capella

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.

METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.

RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).

CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

Original language	English
Pages (from-to)	475-489
Number of pages	15
Journal	Neuroendocrinology
Volume	111
Issue number	5
DOIs	https://doi.org/10.1159/000508376
Publication status	Published - 2021

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Milione, M., Maisonneuve, P., Grillo, F., Mangogna, A., Centonze, G., Prinzi, N., Pusceddu, S., Garzone, G., Cattaneo, L., Busico, A., Bossi, P., Spaggiari, P., Pellegrinelli, A., Del Gobbo, A., Ferrero, S., Kankava, K., Pruneri, G., Rolli, L., Roca, E., ... Capella, C. (2021). Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis. Neuroendocrinology, 111(5), 475-489. https://doi.org/10.1159/000508376

Milione, M , Maisonneuve, P , Grillo, F, Mangogna, A, Centonze, G , Prinzi, N , Pusceddu, S, Garzone, G, Cattaneo, L , Busico, A, Bossi, P, Spaggiari, P, Pellegrinelli, A, Del Gobbo, A , Ferrero, S, Kankava, K, Pruneri, G , Rolli, L, Roca, E, Bercich, L, Tironi, A, Benvenuti, MR, Gallazzi, MS, Romano, R, Berruti, A, Pastorino, U & Capella, C 2021, 'Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis', Neuroendocrinology, vol. 111, no. 5, pp. 475-489. https://doi.org/10.1159/000508376

@article{ea974ad105ca41909c31ec3286a5ae3e,

title = "Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis",

abstract = "BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.",

author = "Massimo Milione and Patrick Maisonneuve and Federica Grillo and Alessandro Mangogna and Giovanni Centonze and Natalie Prinzi and Sara Pusceddu and Giovanna Garzone and Laura Cattaneo and Adele Busico and Paola Bossi and Paola Spaggiari and Alessio Pellegrinelli and {Del Gobbo}, Alessandro and Stefano Ferrero and Ketevani Kankava and Giancarlo Pruneri and Luigi Rolli and Elisa Roca and Luisa Bercich and Andrea Tironi and Benvenuti, {Mauro Roberto} and Gallazzi, {Maria Sole} and Rosalia Romano and Alfredo Berruti and Ugo Pastorino and Carlo Capella",

note = "{\textcopyright} 2020 S. Karger AG, Basel.",

year = "2021",

doi = "10.1159/000508376",

language = "English",

volume = "111",

pages = "475--489",

journal = "Neuroendocrinology",

issn = "0028-3835",

publisher = "S. Karger AG",

number = "5",

}

TY - JOUR

T1 - Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

AU - Milione, Massimo

AU - Maisonneuve, Patrick

AU - Grillo, Federica

AU - Mangogna, Alessandro

AU - Centonze, Giovanni

AU - Prinzi, Natalie

AU - Pusceddu, Sara

AU - Garzone, Giovanna

AU - Cattaneo, Laura

AU - Busico, Adele

AU - Bossi, Paola

AU - Spaggiari, Paola

AU - Pellegrinelli, Alessio

AU - Del Gobbo, Alessandro

AU - Ferrero, Stefano

AU - Kankava, Ketevani

AU - Pruneri, Giancarlo

AU - Rolli, Luigi

AU - Roca, Elisa

AU - Bercich, Luisa

AU - Tironi, Andrea

AU - Benvenuti, Mauro Roberto

AU - Gallazzi, Maria Sole

AU - Romano, Rosalia

AU - Berruti, Alfredo

AU - Pastorino, Ugo

AU - Capella, Carlo

PY - 2021

Y1 - 2021

N2 - BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

AB - BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation.METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component.RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05).CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

U2 - 10.1159/000508376

DO - 10.1159/000508376

M3 - Article

C2 - 32365350

SN - 0028-3835

VL - 111

SP - 475

EP - 489

JO - Neuroendocrinology

JF - Neuroendocrinology

IS - 5

ER -

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

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