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 we characterized their clinico-pathologic and molecular features. MSI analysis and immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were performed in 89 GEP-NEC/MANECs (6 esophageal, 77 gastrointestinal, 3 pancreatic and 3 of the gallbladder). Methylation of 34 genes was studied by MS-MLPA. BRAF and KRAS mutation analysis was assessed by PCR-pyrosequencing. MSI was observed in 11 NEC/MANECs (12.4%): 7 intestinal and 4 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 (MSS) NEC/MANECs (40.6% versus 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 clinico-pathologic 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.

Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity.

Furlan D
;
Sessa F;La Rosa S
2015-01-01

Abstract

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 we characterized their clinico-pathologic and molecular features. MSI analysis and immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were performed in 89 GEP-NEC/MANECs (6 esophageal, 77 gastrointestinal, 3 pancreatic and 3 of the gallbladder). Methylation of 34 genes was studied by MS-MLPA. BRAF and KRAS mutation analysis was assessed by PCR-pyrosequencing. MSI was observed in 11 NEC/MANECs (12.4%): 7 intestinal and 4 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 (MSS) NEC/MANECs (40.6% versus 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 clinico-pathologic 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.
2015
2014
MANEC; NEC; gene methylation; microsatellite instability; mismatch repair; neuroendocrine carcinomas
Sahnane, N; Furlan, D; Monti, M; Romualdi, C; Vanoli, A; Vicari, E; Solcia, E; Capella, C; Sessa, F; La Rosa, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2007520
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