Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas
Authors: Vanoli Alessandro , Grillo Federica , Guerini Camilla , Neri Giuseppe , Arpa Giovanni , Klersy Catherine , Nesi Gabriella , Giuffrida Paolo , Sampietro Gianluca , Ardizzone Sandro , Fociani Paolo , Fiocca Roberto , Latella Giovanni , Sessa Fausto , D’Errico Antonietta , Malvi Deborah , Mescoli Claudia , Rugge Massimo , Ferrero Stefano , Poggioli Gilberto , Rizzello Fernando , Macciomei Maria C. , Santini Donatella , Volta Umberto , De Giorgio Roberto , Caio Giacomo , Calabrò Antonio , Ciacci Carolina , D’Armiento Maria , Rizzo Aroldo , Solina Gaspare , Martino Michele , Tonelli Francesco , Villanacci Vincenzo , Cannizzaro Renato , Canzonieri Vincenzo , Florena Ada Maria , Biancone Livia , Monteleone Giovanni , Caronna Roberto , Ciardi Antonio , Elli Luca , Caprioli Flavio , Vecchi Maurizio , D’Incà Renata , Zingone Fabiana , D’Odorico Anna , Lenti Marco Vincenzo , Oreggia Barbara , Reggiani Bonetti Luca , Giannone Antonino Giulio , Orlandi Augusto , Barresi Valeria , Ciccocioppo Rachele , Amodeo Giuseppe , Biletta Elena , Luinetti Ombretta , Pedrazzoli Paolo , Pietrabissa Andrea , Corazza Gino Roberto , Solcia Enrico , Paulli Marco , Di Sabatino Antonio 
Published: August 2020

Abstract
Background
Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients and Methods
In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results
We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions
Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

Graphic Abstract