Abstract
BackgroundImmunohistochemical 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.MethodsHeterogenous 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.ResultsHeterogenous 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.ConclusionsHeterogenous 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.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1771940323126788
Highlights
Immunohistochemical staining for mismatch repair proteins is efficient and widely used to identify mismatch repair defective tumors
Mismatch repair (MMR) defects characterize 2-4% of colorectal cancers linked to Lynch syndrome and 15% of sporadic colorectal cancers caused by epigenetic MLH1 promoter methylation
Various heterogenous expression patterns co-existed in 9/14 tumors, most commonly as intraglandular and clonal heterogeneity
Summary
Immunohistochemical staining for mismatch repair proteins is efficient and widely used to identify mismatch repair defective tumors. We identified and characterized colorectal cancers with alternative, heterogenous mismatch repair protein staining in order to delineate expression patterns and underlying mechanisms. MMR protein immunostainings are generally stable and relatively easy to interpret; though challenges and pitfalls have been reported with false positive as well as false negative interpretations [10,11,12]. Most commonly, these observations relate to technical artifacts caused by suboptimal fixation or paraffin-embedding, necrotic areas, sample storage, antibody specificity, clone selection or staining conditions [13,14]. We systematically collected colorectal cancers with heterogenous MMR protein staining patterns for detailed analysis with correlations e.g. to MSI status and MLH1 promoter methylation
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