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P301 Non-familial small bowel carcinomas in Crohn's disease: clinico-pathological, molecular and prognostic features

Di Sabatino A.*1, Vanoli A.2, Furlan D.3, Giuffrida P.1, Klersy C.4, Grillo F.5, Fiocca R.5, Mescoli C.6, Rugge M.6, Nesi G.7, Fociani P.8, Sampietro G.9, Ardizzone S.10, Luinetti O.2, Calabrò A.11, Tonelli F.7, Volta U.12, Santini D.13, Caio G.12, Elli L.14, Ferrero S.15, Latella G.16, Ciardi A.17, Solina G.18, Rizzo A.18, Ciacci C.19, D'Armiento F.P.20, Salemme M.21, Villanacci V.21, Cannizzaro R.22, Canzonieri V.23, Reggiani Bonetti L.24, Biancone L.25, Monteleone G.25, Orlandi A.25, Santeusanio G.26, Macciomei M.C.26, D'Incà R.6, Perfetti V.27, Sandri G.28, Silano M.29, Florena A.M.30, Giannone A.G.30, Papi C.31, Coppola L.31, Usai P.32, Maccioni A.33, Astegiano M.34, Migliora P.35, Manca R.36, Martino M.37, Trapani D.3, Cerutti R.3, Alberizzi P.36, Riboni R.36, Sessa F.3, Paulli M.36, Solcia E.2, Corazza G.R.1

1Fondazione IRCCS Policlinico San Matteo, University of Pavia, First Department of Medicine, Pavia, Italy 2Fondazione IRCCS Policlinico San Matteo, University of Pavia, Department of Molecular Medicine, Pavia, Italy 3University of Insubria, Department of Surgical and Morphological Sciences, Varese, Italy 4University of Pavia, Biometry and Statistics Service, San Matteo Hospital, Pavia, Italy 5Azienda Ospedaliera Universitaria San Martino, Genova, Italy 6Azienda Ospedaliera di Padova, Padova, Italy 7Azienda Ospedaliera Universitaria Careggi, Firenze, Italy 8Luigi Sacco University Hospital, Chair of Pathology, Milan, Italy 9Luigi Sacco University Hospital, Surgery Division, Department of Clinical Sciences, Milan, Italy 10Luigi Sacco University Hospital, Gastroenterology Unit, Department of Biomedical and Clinical Sciences, Milan, Italy 11University of Florence, Department of Experimental and Clinical Biomedical Sciences, Florence, Italy 12University of Bologna, Division of Gastroenterology and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy 13University of Bologna, Pathology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy 14Ca' Granda-Ospedale Maggiore Policlinico, Gastroenterology and Endoscopy Unit, Milan, Italy 15Ca' Granda-Ospedale Maggiore Policlinico, Division of Pathology, Milan, Italy 16Ospedale San Salvatore, L'Aquila, Italy 17Umberto I Hospital, Department of Radiological, Oncological and Pathological Sciences, Rome, Italy 18Ospedale V. Cervello, Palermo, Italy 19University of Salerno, Department of Medicine and Surgery, Salerno, Italy 20Federico II University of Naples, Department of Advanced Biomedical Sciences, Naples, Italy 21Spedali Civili di Brescia, Brescia, Italy 22Centro di Riferimento Oncologico, Aviano, Italy 23National Cancer Institute, Department of Pathology, Aviano, Italy 24University of Modena and Reggio Emilia, Section of Pathology, Modena, Italy 25Policlinico Tor Vergata, Roma, Italy 26San Camillo-Forlanini Hospital, Pathology Unit, Rome, Italy 27University of Pavia, Section of Oncology, Department of Onco-haematology, San Matteo Hospital, Pavia, Italy 28Sant'Eugenio Hospital, Clinical Nutrition Unit, Rome, Italy 29Istituto Superiore di Sanità, Unit of Nutrition and Health, Department of Veterinary Public Health and Food Safety, Rome, Italy 30University of Palermo, Institute of Pathologic Anatomy, Giaccone University Hospital, Palermo, Italy 31Azienda Ospedaliera San Filippo Neri, Roma, Italy 32University of Cagliari, Department of Internal Medicine, Cagliari, Italy 33SS. Trinità Hospital, Pathology Unit, Rome, Italy 34Città della Salute e della Scienza-Molinette Hospital, General and Specialistic Surgery, Turin, Italy 35Sant'Andrea Hospital, Unit of Pathological Anatomy, Vercelli, Italy 36University of Pavia, Department of Molecular Medicine, San Matteo Hospital, Pavia, Italy 37University of Pavia, First Department of Internal Medicine, San Matteo Hospital, Pavia, Italy

Background

An increased risk for small bowel carcinoma (SBC) has been reported in Crohn's disease (CrD). We aimed to explore clinical, histopathologic, molecular and prognostic features of CrD-associated SBC (CrD-SBC) in comparison to both coeliac disease (CD)-associated SBC (CD-SBC) and sporadic SBC (spo-SBC).

Methods

Seventy-six patients, who underwent surgical resection for non-familial SBC (25 CrD-SBC26, CD-SBC and 25 spo-SBC), were retrospectively recorded to investigate survival together with histological and molecular features detected by immunohistochemistry, multiplex PCR and sequencing.

Results

CD-SBC showed a significantly (p=0.004) better sex-, age- and stage-adjusted overall and cancer-specific survival in comparison to CrD-SBC, while no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly (p=0.001) higher rate of microsatellite instability (MSI, 65%) compared to both CrD-SBC (16%) and Spo-SBC (16%). The median number of tumor-infiltrating lymphocytes (TIL) correlated with MSI status and was significantly higher in CD-SBC than in both CrD-SBC (p<0.001) and spo-SBC (p=0.002). Among CD-SBC, MSI allowed to separate two subgroups with different outcome, stage and TP53 mutation rate. MSI was the result of MLH1 methylation in all cases (with the exception of one case of CrD-SBC). No BRAF mutation was observed in any SBC. Mutations in KRAS, NRAS, and PIK3CA were detected in 30%, 4% and 13% of cases, respectively. HER2 gene amplification was identified in two CD-SBC, two CrD-SBC and one spo-SBC.

Conclusion

In comparison to CrD-SBC, CD-SBC harbor much more frequently MSI and show a more favorable prognosis, likely related to their high density of TILs, which have independent prognostic value in SBC. MSI status, KRAS/NRAS mutations and HER2 amplifications might contribute to stratify patients for targeted anti-cancer therapy.