title: Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity.
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 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.
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Nora
authors.initials: N
authors.lastname: Sahnane
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy daniela.furlan@uninsubria.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Furlan
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Monti
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Vicari
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Section of Anatomic PathologyDepartment of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, ItalyCRIBI Biotechnology CenterUniversity of Padova, Padova, ItalyDepartment of Molecular MedicineInstitute of Pathology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, ItalyDepartment of PathologyOspedale di Circolo, Varese, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged
keywords: MANEC; NEC; gene methylation; microsatellite instability; mismatch repair; neuroendocrine carcinomas