Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD‐L1 expression, and favourable prognosis

Aim Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB‐MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM‐SBAs). Methods and Results Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB‐MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM‐SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death‐ligand 1 (PD‐L1) and mismatch repair proteins was performed in both SB‐MCs and NM‐SBAs. SB‐MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein–Barr virus (EBV)‐encoded RNAs by in‐situ hybridization. MLH1 promoter methylation status was evaluated in MLH1‐deficient cases. Eleven SB‐MCs and 149 NM‐SBAs were identified. One (9%) SB‐MC was EBV‐positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB‐MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB‐MCs, both with isolated loss of ARID1A. Compared with NM‐SBAs, SB‐MCs exhibited an association with coeliac disease ( P < 0.001), higher rates of dMMR ( P < 0.001), and PD‐L1 positivity by both tumour proportion score and combined positive score ( P < 0.001 for both), and a lower rate of CK20 expression ( P = 0.024). Survival analysis revealed a better prognosis of SB‐MC patients compared to NM‐SBA cases ( P = 0.02). Conclusion SB‐MCs represent a distinct histologic subtype, with peculiar features compared to NM‐SBAs, including association with coeliac disease, dMMR, PD‐L1 expression, and better prognosis.