Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated

Abstract

BACKGROUND: The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. METHODS: In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. RESULTS: MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. CONCLUSIONS: In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

Assessing the genomic feature of Chinese patients with ampullary adenocarcinoma: potential therapeutic targets

“…In western AMPAC patients, the incidence of MMR-deficiency (MMRd) was higher than those with colorectal cancer. Previous studies found that 18% (23/127) of western patients with AMPAC had MMRd as evaluated by IHC [ 34 ]. However, in current study, we only identified two AMPAC patients (1.38%) with MSI-H, which was significantly lower than the incidence in the western patients (8.75%, p < 0.01) [ 35 ].…”

Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country

“…Biliary tract cancers may harbor mismatch repair gene mutations which may explain the associations with colon and pancreatic cancers [26,27]. Recently, these mutations have also been found in ampullary cancer [34]. The association of ampullary cancers with male breast cancer may be related to BRCA1/2 mutations which are found in this cancer [35].…”

Ampulla of Vater carcinoma: advancement in the relationships between histological subtypes, molecular features, and clinical outcomes

“…The damaged mismatch repair system (MMR deficiency) for DNA, including the alteration in the MLH1 , MSH2 , or MSH6 gene, could cause MSI. However, MMR deficiency often has a Lynch-suggestive profile, and routine testing for Lynch syndrome is warranted ( 29 ). MSI may be a dependable marker for prognosis.…”

“…AVC patients with MSI phenotypes who underwent resection therapy had no evidence of recurrent disease at the cutoff time in a study of 59 patients ( 65 ). The AVC patients ( 29 ) with MMR deficiency accounted for up to 18% (23/128). Regarding the relationship between histological subtypes and MSI, a study reported that both AVC patients with MSI had the intestinal subtype of AC ( 65 ).…”