Neuroendocrinology

Research Article

Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin

Busico A.a · Maisonneuve P.b · Prinzi N.c · Pusceddu S.c · Centonze G.a · Garzone G.a · Pellegrinelli A.d · Giacomelli L.e,f · Mangogna A.g · Paolino C.a,h · Belfiore A.a · Kankava K.i · Perrone F.a · Tamborini E.a · Pruneri G.j,l · Fazio N.k · Milione M.a

Author affiliations

a1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy
bDivision of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy
cMedical Oncology Department, Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy
dDepartment of Pathology, ASST Franciacorta, Mellino Mellini Hospital, Chiari, Brescia, Italy
eDepartment of Surgical Sciences and Integrated Diagnostics, School of Medicine, University of Genoa, Genoa, Italy
fPolistudium SRL, Milan, Italy
gPathology Unit, Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Ospedale di Cattinara, Trieste, Italy
hDepartment of Research, Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy
iTeaching, Scientific and Diagnostic Pathology Laboratory, Tbilisi State Medical University, Tbilisi, Georgia
jSchool of Medicine, University of Milan, Milan, Italy
kDivision of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy
l2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan, Italy

Keywords: Neuroendocrine tumor G3Ki-67Targeted next-generation sequencingPD-L1

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Neuroendocrinology 2020;110:616–629
https://doi.org/10.1159/000503722

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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: June 08, 2019
Accepted: September 25, 2019
Published online: September 27, 2019
Issue release date: July 2020

Number of Print Pages: 14
Number of Figures: 5
Number of Tables: 2

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

Abstract

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2–89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9–169, p = 0.0007). Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.

© 2019 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: June 08, 2019
Accepted: September 25, 2019
Published online: September 27, 2019
Issue release date: July 2020

Number of Print Pages: 14
Number of Figures: 5
Number of Tables: 2

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

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