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

Margareta Heby, Sebastian Lundgren, Björn Nodin, Jacob Elebro, Jakob Eberhard, Karin Jirström, Margareta Heby, Sebastian Lundgren, Björn Nodin, Jacob Elebro, Jakob Eberhard, Karin Jirström

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 (pinteraction = 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.

Figures

Fig. 1
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
Fig. 2
The distribution of MMR immunophenotype according to anatomical subsite
Fig. 3
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
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
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)

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Source: PubMed

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