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. 1998 May;42(5):673–679. doi: 10.1136/gut.42.5.673

Morphology of sporadic colorectal cancer with DNA replication errors

J Jass 1, K Do 1, L Simms 1, H Iino 1, C Wynter 1, S Pillay 1, J Searle 1, G Radford-Smith 1, J Young 1, B Leggett 1
PMCID: PMC1727100  PMID: 9659163

Abstract

Background—Up to 15% of colorectal cancers are characterised by DNA microsatellite instability (MIN), shown by the presence of DNA replication errors (RERs). 
Aims—To identify pathological features that are discriminating for colorectal cancer (CRC) showing extensive MIN. 
Subjects—A prospective series of 303 patients with CRC and no family history of either familial adenomatous polyposis or hereditary non-polyposis colorectal cancer. 
Methods—DNA was extracted from fresh tissue samples and the presence of MIN was studied at nine loci that included TGFβRII, IGFIIR, and BAX. The 61 cases showing RERs were compared with 63 RER negative cases with respect to a comprehensive set of clinical and pathological variables. Predictive utility of the variables was tested by decision tree analysis. 
Results—Twenty seven patients with CRC showed extensive RERs (three loci or more) (RER+) and 34 had limited RERs only (28= one locus; 6 = two loci) (RER+/−), yielding a bimodal distribution. RER+ cancers differed from RER− and RER+/− cases. Tumour type (adenocarcinoma, mucinous carcinoma, and undifferentiated carcinoma) (p=0.001), tumour infiltrating lymphocytes (p=0.001), and anatomical site (p=0.001) were the most significant of the discriminating variables. Algorithms developed by decision tree analysis allowed cases to be assigned to RER+ versus RER− and +/− status with a global sensitivity of 81.5%, specificity of 96%, and overall accuracy of 93%. 
Conclusion—Pathological examination of CRC allows assignment of RER+ status; assignment is specific and relatively sensitive. Conversely RER− and RER+/− CRC are indistinguishable. 



Keywords: colon; rectum; colorectal cancer; DNA replication errors; morphology; microsatellite instability

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Figure 1 .

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Example of cancer with extensive microsatellite instability implicating all six non-coding loci (row A) and TGFβRII and BAX in row B. The TGFβRII mutation is the most difficult to interpret, but confirmation by direct sequencing was achieved in seven cases including the one illustrated.25


Figure 2 .

Figure 2

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Number of microsatellite errors per cancer, showing cancers with errors in at least one of the coding genes: TGFβRII, IGFIIR, or BAX. 


Figure 3 .

Figure 3

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A well differentiated RER+ mucinous adenocarcinoma. Haematoxylin & eosin. 


Figure 4 .

Figure 4

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An undifferentiated RER+ carcinoma composed of solid aggregates of large cells. The tumour had a pushing margin (not shown). Foci of glandular differentiation were present (see fig 5). Haematoxylin & eosin. 


Figure 5 .

Figure 5

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High power view of fig 4 showing occasional lumina indicative of poorly differentiated adenocarcinoma. Tumour infiltrating lymphocytes are peppered throughout and many are intraepithelial. Haematoxylin & eosin. 


Figure 6 .

Figure 6

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Moderately differentiated RER+ adenocarcinoma showing intraepithelial lymphocytes with retraction artefact. Distinction from mitoses and apoptotic bodies is straightforward. Haematoxylin & eosin. 


Figure 7 .

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Decision tree analysis for adenocarcinomas. The ovals show the intermediate nodes and the boxes show the classifying groups and specify whether cancers are RER− or +/− versus RER+. Each box shows the sample size in the subgroup and the number that were correctly classified. Assessment of the predictive power of each variable is through the variable importance ranking and not the level shown on the tree. Relative rankings are: tumour infiltrating lymphocytes (TIL), 100; differentiation, 46; and site (RC), 13. 


Figure 8 .

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Decision tree analysis for mucinous carcinoma. Relative rankings are: stage D, 100; differentiation, 63; site (RC), 55; peritumoural lymphocytes, 45; and tumour infiltrating lymphocytes (TIL), 34. 


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