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Nora Sahnane Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Daniela Furlan Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Matilde Monti Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Chiara Romualdi Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Alessandro Vanoli Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Emanuela Vicari Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Enrico Solcia Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Carlo Capella Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Fausto Sessa Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Stefano La Rosa Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are heterogeneous neoplasms characterized by poor outcome. Microsatellite instability (MSI) has recently been found in colorectal NECs showing a better prognosis than expected. However, the frequency of MSI in a large series of GEP-NEC/MANECs is still unknown. In this work, we investigated the incidence of MSI in GEP-NEC/MANECs and characterized their clinicopathologic and molecular features. MSI analysis and immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were performed in 89 GEP-NEC/MANECs (six esophageal, 77 gastrointestinal, three pancreatic, and three of the gallbladder). Methylation of 34 genes was studied by methylation-specific multiplex ligation probe amplification. Mutation analysis of BRAF and KRAS was assessed by PCR-pyrosequencing analysis. MSI was observed in 11 NEC/MANECs (12.4%): seven intestinal and four gastric. All but two MSI-cases showed MLH1 methylation and loss of MLH1 protein. The remaining two MSI-cancers showed lack of MSH2 or PMS2 immunohistochemical expression. MSI-NEC/MANECs showed higher methylation levels than microsatellite stable NEC/MANECs (40.6% vs 20.2% methylated genes respectively, P<0.001). BRAF mutation was detected in six out of 88 cases (7%) and KRAS mutation was identified in 15 cases (17%). BRAF mutation was associated with MSI (P<0.0008), while KRAS status did not correlate with any clinicopathologic or molecular feature. Vascular invasion (P=0.0003) and MSI (P=0.0084) were identified as the only independent prognostic factors in multivariate analysis. We conclude that MSI identifies a subset of gastric and intestinal NEC/MANECs with distinct biology and better prognosis. MSI-NEC/MANECs resemble MSI-gastrointestinal adenocarcinomas for frequency, molecular profile and pathogenetic mechanisms.

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Massimo Milione 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Patrick Maisonneuve Division of Epidemiology and Biostatistics, European Institute of Oncology (IEO), Milan, Italy

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Alessio Pellegrinelli 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Federica Grillo Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova and Policlinico San Martino, Genova, Italy

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Luca Albarello Pathology Unit, IRCCS San Raffaele Scientifica Institute, Milan, Italy

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Paola Spaggiari Cancer Center Humanitas, Milan, Italy

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Alessandro Vanoli Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

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Giovanna Tagliabue Lombardy Cancer Registry, Varese Province Cancer Registry Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Eleonora Pisa Division of Pathology, European Institute of Oncology (IEO), Milan, Italy

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Luca Messerini Diagnostic and Molecular Pathology, Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy

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Giovanni Centonze Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Clinical Research Lab (CRAB), Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Frediano Inzani Anatomic Pathology Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

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Aldo Scarpa ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University and Hospital Trust of Verona, Verona, Italy

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Mauro Papotti Department of Oncology, University of Turin, Turin, Italy

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Marco Volante Department of Oncology, University of Turin, Turin, Italy

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Fausto Sessa Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Nicola Fazio Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology (IEO), Milan, Italy

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Giancarlo Pruneri 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
University of Milan, School of Medicine, Milan, Italy

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Guido Rindi Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

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Enrico Solcia Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

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Stefano La Rosa Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland

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Carlo Capella Department of Medicine and Surgery, University of Insubria, Varese, Italy

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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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