Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium.
OBJECTIVE
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.
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Alessandro
A
Vanoli
Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
Antonio
A
Di Sabatino
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Daniela
D
Furlan
Biometry and Statistics Service, San Matteo Hospital, Pavia, Italy.
Catherine
C
Klersy
Pathology Unit, Department of Surgical and Diagnostic Sciences, San Martino/IST University Hospital, Genova, Italy.
Federica
F
Grillo
Pathology Unit, Department of Surgical and Diagnostic Sciences, San Martino/IST University Hospital, Genova, Italy.
Roberto
R
Fiocca
Pathology Unit, Department of Medicine, University of Padua, Padua, Italy.
Claudia
C
Mescoli
Pathology Unit, Department of Medicine, University of Padua, Padua, Italy.
Massimo
M
Rugge
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Gabriella
G
Nesi
Units of Pathology.
Paolo
P
Fociani
IBD Surgery.
Gianluca
G
Sampietro
Gastroenterology, Luigi Sacco University Hospital, Milan, Italy.
Sandro
S
Ardizzone
Departments of Molecular Medicine.
Ombretta
O
Luinetti
Departments of Experimental and Clinical Biomedical Sciences.
Antonio
A
Calabrò
Surgery and Translational Medicine, University of Florence, Florence, Italy.
Francesco
F
Tonelli
Divisions of Gastroenterology.
Umberto
U
Volta
Pathology, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Donatella
D
Santini
Divisions of Gastroenterology.
Giacomo
G
Caio
Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
Paolo
P
Giuffrida
Center for Prevention and Diagnosis of Coeliac Disease, Fondazione IRCCS Ca' Granda, Milan, Italy.
Luca
L
Elli
Division of Pathology, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
Stefano
S
Ferrero
Gastroenterology Unit, Department of Life and Enviromental Sciences, University of L'Aquila, L'Aquila, Italy.
Giovanni
G
Latella
Departments of Radiological, Oncological, Pathological Sciences.
Antonio
A
Ciardi
Surgical Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy.
Roberto
R
Caronna
Units of General Surgery.
Gaspare
G
Solina
Pathology, Cervello Hospital, Palermo, Italy.
Aroldo
A
Rizzo
Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
Carolina
C
Ciacci
Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy.
Francesco P
FP
D'Armiento
Pathology Section, Spedali Civili Hospital, Brescia, Italy.
Marianna
M
Salemme
Pathology Section, Spedali Civili Hospital, Brescia, Italy.
Vincenzo
V
Villanacci
Departments of Gastroenterology.
Renato
R
Cannizzaro
Pathology, National Cancer Institute, Aviano, Italy.
Vincenzo
V
Canzonieri
Section of Pathology, Department of Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
Luca
L
Reggiani Bonetti
Departments of Systems Medicine.
Livia
L
Biancone
Departments of Systems Medicine.
Giovanni
G
Monteleone
Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy.
Augusto
A
Orlandi
Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy.
Giuseppe
G
Santeusanio
Pathology Unit, San Camillo-Forlanini Hospital, Rome, Italy.
Maria C
MC
Macciomei
Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Renata
R
D'Incà
Internal Medicine, S.S. Annunziata Hospital, ASST-Pavia, Varzi, Italy.
Vittorio
V
Perfetti
Clinical Nutrition Unit, Sant'Eugenio Hospital, Rome, Italy.
Giancarlo
G
Sandri
Unit of Human Nutrition and Health, Istituto Superiore di Sanità, Rome, Italy.
Marco
M
Silano
Institute of Pathologic Anatomy, Giaccone University Hospital, University of Palermo, Palermo, Italy.
Ada M
AM
Florena
Institute of Pathologic Anatomy, Giaccone University Hospital, University of Palermo, Palermo, Italy.
Antonino G
AG
Giannone
Units of IBD.
Claudio
C
Papi
Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy.
Luigi
L
Coppola
Department of Internal Medicine, University of Cagliari, Cagliari, Italy.
Paolo
P
Usai
Pathology Unit, SS. Trinità Hospital, Cagliari, Italy.
Antonio
A
Maccioni
General and Specialistic Surgery, Città della Salute e della Scienza-Molinette Hospital, Turin, Italy.
Marco
M
Astegiano
Unit of Pathological Anatomy, Sant'Andrea Hospital, Vercelli, Italy.
Paola
P
Migliora
Departments of Molecular Medicine.
Rachele
R
Manca
Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
Michele
M
Martino
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Davide
D
Trapani
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Roberta
R
Cerutti
Departments of Molecular Medicine.
Paola
P
Alberizzi
Departments of Molecular Medicine.
Roberta
R
Riboni
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Fausto
F
Sessa
Departments of Molecular Medicine.
Marco
M
Paulli
Departments of Molecular Medicine.
Enrico
E
Solcia
Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
Gino R
GR
Corazza
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002446:Celiac Disease / Q000150:complications* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D003424:Crohn Disease / Q000150:complications* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
D058534:Class I Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C117307:KRAS protein, human; C495901:TP53 protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human
Inflammatory bowel disease; MLH1 promoter methylation; microsatellite instability; survival; tumour-infiltrating lymphocytes