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Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas

Maartje Nielsen1, Noel FCC de Miranda2, Marjo van Puijenbroek2, Ekaterina S Jordanova2, Anneke Middeldorp2, Tom van Wezel2, Ronald van Eijk2, Carli MJ Tops1, Hans FA Vasen34, Frederik J Hes1 and Hans Morreau2*

Author Affiliations

1 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

2 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

3 Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands

4 The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands

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BMC Cancer 2009, 9:184  doi:10.1186/1471-2407-9-184

Published: 15 June 2009



MUTYH-associated polyposis (MAP) is a recessively inherited disorder which predisposes biallelic carriers for a high risk of polyposis and colorectal carcinoma (CRC). Since about one third of the biallelic MAP patients in population based CRC series has no adenomas, this study aimed to identify specific clinicopathological characteristics of MAP CRCs and compare these with reported data on sporadic and Lynch CRCs.


From 44 MAP patients who developed ≥ 1 CRCs, 42 of 58 tumours were analyzed histologically and 35 immunohistochemically for p53 and beta-catenin. Cell densities of CD3, CD8, CD57, and granzyme B positive lymphocytes were determined. KRAS2, the mutation cluster region (MCR) of APC, p53, and SMAD4 were analyzed for somatic mutations.


MAP CRCs frequently localized to the proximal colon (69%, 40/58), were mucinous in 21% (9/42), and had a conspicuous Crohn's like infiltrate reaction in 33% (13/40); all of these parameters occurred at a higher rate than reported for sporadic CRCs. Tumour infiltrating lymphocytes (TILs) were also highly prevalent in MAP CRCs. Somatic APC MCR mutations occurred in 14% (5/36) while 64% (23/36) had KRAS2 mutations (22/23 c.34G>T). G>T tranversions were found in p53 and SMAD4, although the relative frequency compared to other mutations was low.


MAP CRCs show some similarities to micro-satellite unstable cancers, with a preferential proximal location, a high rate of mucinous histotype and increased presence of TILs. These features should direct the practicing pathologist towards a MAP aetiology of CRC as an alternative for a mismatch repair deficient cause. High frequent G>T transversions in APC and KRAS2 (mutated in early tumour development) but not in P53 and SMAD4 (implicated in tumour progression) might indicate a predominant MUTYH effect in early carcinogenesis.