MYH-associated polyposis is a recently recognized condition that is associated with intestinal polyposis and an increased risk of CRC in patients with germ-line biallelic mutations and possibly in monoallelic carriers.1,3,7,9,24,25
Given that the inheritance pattern is usually autosomal recessive, a family history may be lacking. A characteristic pathological appearance would therefore be helpful in raising the suspicion of this disorder, as is seen in patients with HNPCC, who have MSI-H carcinomas. Descriptions of the pathological features of carcinomas arising in those with MYH
mutations are few and are limited in the number of histological parameters assessed.2,26,27
In this study, the biallelic MYH
mutation carriers were significantly younger (51 years), than the heterozygous (59 years) or control (62 years) subjects. These figures concur with the reported ranges for average age of onset of CRC in these groups.2–4,10,28–31
We reviewed 16 invasive cancers from 14 biallelic MYH
mutation carriers and 25 cancers from 22 monoallelic carriers. Tumours from biallelic carriers were low grade, demonstrated mild levels of extraglandular necrosis, and were often associated with synchronous adenomatous polyps. The main histological patterns in tumours in biallelic patients were tubular, papillary and cribriform. There was no significant difference in the depth of tumour invasion (T-stage) according to MYH genotype, but there was a non-significant trend to lower frequency of positive lymph nodes in biallelics and higher frequency of pNl disease in monoallelic carriers. This observation for biallelic carriers is in contrast with some studies that report higher-stage tumours in MYH-associated carcinomas,31
but in concordance with others.4
Of the remaining histopathological features that were assessed, carcinomas occurring in patients with biallelic MYH
mutations did not manifest a significant difference in comparison with those present in heterozygotes and in controls with wild-type or non-pathogenic polymorphisms.
Genetic factors such as attenuated FAP and HNPCC have been shown to influence tumour location.32,33
Previous series of MYH-associated cancers have reported divergent findings with respect to patterns of tumour location. Some studies have shown more right-sided carcinomas in biallelics. 4,5,27
Conversely, in other studies there is a marked left-sided predominance noted in up to 70% of carcinomas.2,28,29,34
Although we did not observe a significant difference in tumour location according to MYH
mutation status, we did note that 46% of tumours from biallelic carriers arose in the caecum or ascending colon. Although an increase in right-sided tumours has been observed in recent years in sporadic carcinomas, this figure is still greater than reported for patients in a similar age range (25.4%) in one recent study based on material from the California tumour registry.35
None of the 16 carcinomas present in biallelics in this series was high grade, in contrast to 16% of those in patients with monoallelic mutations and 37.5% of controls (P
= 0.002). The absence of high-grade carcinomas in biallelics has been observed in one other study that included three carcinomas from two patients,27
but other studies do not support this finding.2,15,31
In addition, we observed that 25% of biallelic mutation carriers did not have synchronous polyps in their colectomy specimen. The original phenotype attributed to MYH-associated cancers was derived from series of highly-selected clinic-based polyposis patients, 3,10
and the inconsistent association between MYH and polyps has been previously reported by our group.7
Although polyp counts were derived from partial colectomy specimens and not full colonic assessments, this observation supports the findings of others8,31
that a polyposis phenotype may not be as severe as originally described, or may be absent in some cases.
Preliminary review of a subset of cases from patients with biallelic MYH
mutations in our centre suggested that a serrated pattern might be more frequent in these carcinomas. However, none of the biallelic carcinomas had a serrated pattern in the majority of the tumour and only a single case showed a minor serrated component (1/16, 6.3%). Three carcinomas with a predominantly serrated morphology were identified, all from heterozygotes. This gives an incidence of 5.3% for serrated carcinoma, which is close to the reported incidence of up to 7.5%.18,36,37
Although there was no significant difference evident between the groups with regard to a predominantly serrated morphology, it is interesting that all of the cases were observed in heterozygotes. Loss of heterozygosity in chromosome 1p has been noted more frequently in carcinomas arising in heterozygotes, 38
a finding that has also been described in some hyperplastic polyps, some adenomas and as an early event in CRC.39
It may not be surprising that serrated carcinomas are not observed in biallelics, as KRAS
mutations are common in MYH-associated tumours,2
mutations are not generally present, which are often seen in association with the serrated neoplasia pathway, particularly where hypermethylation is present.36,40,41
The majority of serrated adenocarcinomas are microsatellite stable or have low-level microsatellite instability, and these tend to be associated with traditional serrated adenomas, whereas serrated carcinomas arising in sessile serrated adenomas are frequently microsatellite unstable.18
Of interest, all of the serrated carcinomas in our study were microsatellite stable, and one had an adjacent traditional serrated adenoma.
Microsatellite instability was found in two biallelic cancers in our series. This co-occurrence of biallelic MYH
mutations and MSI-H has been reported previously27
and would appear to challenge the suggestion by some that deficiency of MMR and base excision repair pathways is incompatible with cellular survival.2,38
Colebatch et al
have demonstrated that one of the three carcinomas in two biallelic patients was microsatellite unstable and all three showed prominent intraepithelial lymphocytes. This tumour had MLH1 inactivation by biallelic promoter methylation rather than somatic mutations secondary to loss of MYH function. The authors concluded that in this case biallelic MYH
mutations had played a role in the early stages of colorectal carcinogenesis, but had been superseded by the effects of loss of MLH1 function, and also suggest that MYH
mutation testing might be worth considering in younger individuals with MSI-H tumours that have developed because of MLH1 methylation. It is interesting to note that in our series the two biallelic MYH MSI-H cancers did not have features typically associated with MSI-H cancers as the main histological pattern, but rather demonstrated papillary and tubular features, with one tumour having mucinous features as a secondary pattern.
Overall, carcinomas in biallelic MYH
mutation carriers do not appear similar to MSI-H tumours, but rather share common histological features with CRC with chromosomal instability (CIN). The histological pattern observed in biallelic MYH cancers may correlate with aspects of molecular carcinogenesis, since both MYH cancers and CIN tumours undergo early somatic inactivation of APC and KRAS.1,2,42
In contrast, although MSI-H tumours can also undergo early mutations in APC
, these cancers tend to accumulate mutations in genes with repetitive sequences in the coding region including: TGF-βRII, BAX, IGF-2R, E2F-4 and (β-catenin.43-48
A recent study has shown that when APC
mutations are present in sporadic MSI-H CRC
, they are likely to be frameshift mutations of short nucleotide repeats, implying that microsatellite instability precedes the development of APC
The observed phenotypic similarities between biallelic MYH cancers and CIN tumours may support recent findings by Cardoso et al
which demonstrated a high frequency of aneuploid changes in MYH-associated tumours and similar patterns of chromosomal gains and losses between MYH- and FAP-associated polyps. Cancers found in monoallelic MYH
mutation carriers appear to be somewhat more heterogeneous, and the frequency of various histopathological features appears to be similar to that of sporadic CRC.
In this study, MYH immunohistochemistry failed to discriminate between biallelics, heterozygotes and controls. Granular cytoplasmic immunoreactivity in normal colonic mucosa and in CRC was observed with similar frequency in each group. No nuclear reactivity was identified. Sections from these tumours were stained in two other external laboratories with similar results. This contrasts with the findings of DiGregorio et al
who found nuclear and cytoplasmic reactivity in normal colonic mucosa and in sporadic CRC, but loss of nuclear reactivity and prominent cytoplasmic granular reactivity in patients with biallelic MYH
mutations. Although we used the same antibody, it is possible that technical factors such as differences in fixation or the age of the paraffin blocks may have influenced the results of our immunohistochemistry. However, to our knowledge, the majority of tumours were fixed in 10% neutral buffered formalin and the presence or absence of immunoreactivity did not appear to be related to the age of the block.
In our experience, therefore, neither immunohistochemical nor histological features can distinguish reliably between carcinomas arising in those with MYH mutations and in sporadic colorectal carcinomas.