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Heterogenous mismatch-repair status in colorectal cancer

Patrick Joost1*, Nynke Veurink1, Susanne Holck2, Louise Klarskov3, Anders Bojesen4, Maria Harbo4, Bo Baldetorp1, Eva Rambech1 and Mef Nilbert1

Author Affiliations

1 Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, SE-22381, Lund, Sweden

2 Department of Pathology and Clinical Research Centre, University Hospital of Copenhagen, DK-2650, Hvidore, Denmark

3 Department of Pathology, Herlev Hospital, DK-2730, Herlev, Denmark

4 Department of Clinical Genetics, Vejle Hospital, DK-7100, Vejle, Denmark

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Diagnostic Pathology 2014, 9:126  doi:10.1186/1746-1596-9-126

Published: 26 June 2014



Immunohistochemical staining for mismatch repair proteins is efficient and widely used to identify mismatch repair defective tumors. The tumors typically show uniform and widespread loss of MMR protein staining. We identified and characterized colorectal cancers with alternative, heterogenous mismatch repair protein staining in order to delineate expression patterns and underlying mechanisms.


Heterogenous staining patterns that affected at least one of the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 were identified in 14 colorectal cancers. Based on alternative expression patterns macro-dissected and micro-dissected tumor areas were separately analyzed for microsatellite instability and MLH1 promoter methylation.


Heterogenous retained/lost mismatch repair protein expression could be classified as intraglandular (within or in-between glandular formations), clonal (in whole glands or groups of glands) and compartmental (in larger tumor areas/compartments or in between different tumor blocks). These patterns coexisted in 9/14 tumors and in the majority of the tumors correlated with differences in microsatellite instability/MLH1 methylation status.


Heterogenous mismatch repair status can be demonstrated in colorectal cancer. Though rare, attention to this phenomenon is recommended since it corresponds to differences in mismatch repair status that are relevant for correct classification.

The virtual slide(s) for this article can be found here: webcite

Mismatch repair; immunohistochemistry; heterogeneity; MLH1; MSH2; MSH6; PMS2