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

Abstract

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.

Keywords: ARID1A; Epstein–Barr virus; immune‐mediated disorders; microsatellite instability; small bowel adenocarcinoma.

Figure 1

A duodenal medullary carcinoma in a coeliac patient. A pushing‐type tumour border is seen (A, hematoxylin and eosin [H&E]). The neoplasm features a solid structure with syncytial appearance of tumour cells, admixed with a nondesmoplastic stroma enriched in inflammatory cells, including lymphocytes and neutrophils (B, H&E). Areas of tumour necrosis are present (C, H&E). Tumour cells show loss of expression of MLH1, while MLH1 is retained in the adjacent mucosa and the inflammatory infiltrate (internal control) (D, MLH1 immunostaining). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

A jejunal medullary carcinoma associated with coeliac disease, with a glandular component. The glandular area (on the left; A, H&E) is focal, accounting for 10% of tumour surface, and exhibits retained ARID1A (B, ARID1A immunostaining) and CDX2 (C, CDX2 immunostaining) expression, whereas the medullary component shows lack of both proteins. Both components feature loss of MLH1 expression (inset of C; MLH1 immunostaining). Strong PD‐L1 membranous expression by neoplastic cells was only observed in the medullary component (D, PD‐L1 immunostaining). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

An ileal carcinoma in a patient with Crohn's disease, showing the typical histologic features of medullary carcinoma. Note the relative uniformity of tumour cells with a syncytial appearance, vesicular nuclei, prominent nucleoli, as well as a conspicuous cellular stroma rich in inflammatory cells (A, H&E). Tumour cells are positive for EBER (B, EBER in‐situ hybridization). [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Kaplan–Meier cancer‐specific survival estimates. (A) A comparison between SB‐MC patients and NM‐SBA patients. (B) A comparison between SB‐MC patients and patients with high‐grade SBA‐NOS. (C) A comparison between dMMR SB‐MC patients and dMMR NM‐SBA patients. (D) Comparison of six SBA subgroups based on histotype, histologic grade, and MMR status. 1: SB‐MCs; 2: poorly cohesive carcinomas; 3: Low‐grade dMMR SBAs‐NOS; 4: Low‐grade pMMR SBAs‐NOS; 5: High‐grade dMMR SBAs‐NOS; 6: High‐grade pMMR SBAs‐NOS. [Color figure can be viewed at wileyonlinelibrary.com]