Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma

Abstract

Background: Periampullary adenocarcinomas, including pancreatic cancer, are a heterogeneous group of tumors with poor prognosis, where classification into intestinal type (I-type) or pancreatobiliary type (PB-type) is a relevant prognostic factor. The clinical significance of deficient mismatch repair (dMMR) in periampullary adenocarcinoma is comparatively unexplored. Herein, we examined the associations of MMR immunophenotype with long-term survival in patients with resected periampullary adenocarcinoma, with particular reference to morphology and adjuvant treatment response.

Methods: MMR protein expression was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective cohort of 175 patients with periampullary adenocarcinoma treated with pancreaticoduodenectomy during 2001-2011 in Malmö and Lund University Hospitals, Sweden. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: After a mean follow-up of 46.5 (1.9-185.1) months, 35 patients (20.3%) were alive, 24 with I-type and 11 with PB-type tumors. MMR protein expression could be evaluated in 172 cases, in which dMMR was denoted in 20 (11.6%) cases, 13/63 (20.6%) in I-type and 7/109 (6.4%) in PB-type tumors. dMMR was associated with a significantly prolonged overall survival in the entire cohort (HR = 0.28, 95% CI 0.13-0.57), and in I-type tumors (HR = 0.20, 95% CI 0.06-0.68), however not independent of conventional prognostic factors. In PB-type tumors, dMMR was not prognostic, but there was a significant negative interaction between dMMR and adjuvant treatment (p_interaction = 0.015).

Conclusions: dMMR is more frequent in I-type compared to PB-type periampullary adenocarcinoma, and is a prognostic factor for long-term survival only in the former. The finding of the small number of PB-type tumors with dMMR potentially lacking benefit from adjuvant chemotherapy is however noteworthy and merits further validation.

Keywords: Adjuvant therapy; Immunohistochemistry; MMR; Periampullary adenocarcinoma; TMA.

Fig. 1

Sample immunohistochemical images of MMR protein expression in an MMR deficient duodenal cancer (MHL1 and PMS2 negative, MSH2 and MSH6 positive)

Fig. 2

The distribution of MMR immunophenotype according to anatomical subsite

Fig. 3

Sample immunohistochemical images of CD8+ (membranous/cytoplasmic staining) and FoxP3 (nuclear staining) lymphocytes in the same tumor as in Fig. 1

Fig. 4

Kaplan–Meier estimates of overall survival in the entire cohort (a), in PB-type (b) and I-type (c) tumors stratified by MMR immunophenotype

Fig. 5

Kaplan–Meier analysis of overall survival in strata according to MMR immunophenotype and adjuvant treatment in the entire cohort (a), PB-type (b), and I-type tumors (c)