Alessandro Vanoli1, Antonio Di Sabatino2, Daniela Furlan1, Catherine Klersy3, Federica Grillo4, Roberto Fiocca4, Claudia Mescoli5, Massimo Rugge5, Gabriella Nesi6, Paolo Fociani7, Gianluca Sampietro8, Sandro Ardizzone9, Ombretta Luinetti10, Antonio Calabrò11, Francesco Tonelli12, Umberto Volta13, Donatella Santini14, Giacomo Caio13, Paolo Giuffrida2, Luca Elli15, Stefano Ferrero16, Giovanni Latella17, Antonio Ciardi18, Roberto Caronna19, Gaspare Solina20, Aroldo Rizzo21, Carolina Ciacci22, Francesco P D'Armiento23, Marianna Salemme24, Vincenzo Villanacci24, Renato Cannizzaro25, Vincenzo Canzonieri26, Luca Reggiani Bonetti27, Livia Biancone28, Giovanni Monteleone28, Augusto Orlandi29, Giuseppe Santeusanio29, Maria C Macciomei30, Renata D'Incà31, Vittorio Perfetti32, Giancarlo Sandri33, Marco Silano34, Ada M Florena35, Antonino G Giannone35, Claudio Papi36, Luigi Coppola37, Paolo Usai38, Antonio Maccioni39, Marco Astegiano40, Paola Migliora41, Rachele Manca10, Michele Martino2, Davide Trapani1, Roberta Cerutti1, Paola Alberizzi10, Roberta Riboni10, Fausto Sessa1, Marco Paulli10, Enrico Solcia10, Gino R Corazza2. 1. Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. 2. Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. 3. Biometry and Statistics Service, San Matteo Hospital, Pavia, Italy. 4. Pathology Unit, Department of Surgical and Diagnostic Sciences, San Martino/IST University Hospital, Genova, Italy. 5. Pathology Unit, Department of Medicine, University of Padua, Padua, Italy. 6. Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. 7. Units of Pathology. 8. IBD Surgery. 9. Gastroenterology, Luigi Sacco University Hospital, Milan, Italy. 10. Departments of Molecular Medicine. 11. Departments of Experimental and Clinical Biomedical Sciences. 12. Surgery and Translational Medicine, University of Florence, Florence, Italy. 13. Divisions of Gastroenterology. 14. Pathology, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. 15. Center for Prevention and Diagnosis of Coeliac Disease, Fondazione IRCCS Ca' Granda, Milan, Italy. 16. Division of Pathology, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy. 17. Gastroenterology Unit, Department of Life and Enviromental Sciences, University of L'Aquila, L'Aquila, Italy. 18. Departments of Radiological, Oncological, Pathological Sciences. 19. Surgical Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy. 20. Units of General Surgery. 21. Pathology, Cervello Hospital, Palermo, Italy. 22. Department of Medicine and Surgery, University of Salerno, Salerno, Italy. 23. Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. 24. Pathology Section, Spedali Civili Hospital, Brescia, Italy. 25. Departments of Gastroenterology. 26. Pathology, National Cancer Institute, Aviano, Italy. 27. Section of Pathology, Department of Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy. 28. Departments of Systems Medicine. 29. Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy. 30. Pathology Unit, San Camillo-Forlanini Hospital, Rome, Italy. 31. Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. 32. Internal Medicine, S.S. Annunziata Hospital, ASST-Pavia, Varzi, Italy. 33. Clinical Nutrition Unit, Sant'Eugenio Hospital, Rome, Italy. 34. Unit of Human Nutrition and Health, Istituto Superiore di Sanità, Rome, Italy. 35. Institute of Pathologic Anatomy, Giaccone University Hospital, University of Palermo, Palermo, Italy. 36. Units of IBD. 37. Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy. 38. Department of Internal Medicine, University of Cagliari, Cagliari, Italy. 39. Pathology Unit, SS. Trinità Hospital, Cagliari, Italy. 40. General and Specialistic Surgery, Città della Salute e della Scienza-Molinette Hospital, Turin, Italy. 41. Unit of Pathological Anatomy, Sant'Andrea Hospital, Vercelli, Italy.
Abstract
BACKGROUND AND AIMS: An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. METHODS: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. RESULTS: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. CONCLUSIONS: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.
BACKGROUND AND AIMS: An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. METHODS: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. RESULTS: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. CONCLUSIONS: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.