Our findings suggest that FGs may be associated with systemic disease, and that a previously unrecognised activation of the sebaceous glands system may occur in individuals carrying HNPCC gene mutations and/or patients with Amsterdam criteria positive CRC. This observation may be of help in identifying affected families. In the present study, the frequency of recognisable FGs was found to be approximately 50–90-fold higher in HNPCC patients than in controls.
At present, FGs are thought to be benign lesions on the oral surface in healthy individuals.8,9,10
Demonstration of cancers originating from FGs is rarely reported in the literature.18
The average frequency of FGs has been reported to increase by ~4.85-fold from childhood9
The mechanisms underlying the age dependent changes in the frequency of FGs remain unclear. As a consequence, the frequency of the observed FGs sign as a function of age at examination and/or development of CRC in HNPCC patients needs further investigation.
Moreover, the question of the biological specificity of the FGs sign in HNPCC remains to be addressed. Evidence of FGs in CRC negative HNPCC individuals and lack of FGs in patients with sporadic (Amsterdam negative) CRCs (S Parrini et al, unpublished data) seem to suggest a link between ectopic sebaceous glands and the MMR gene defect, rather than simple coexistence of the CRC itself.
The biological significance of the observed clinical association remains unclear to date. However, Hh, a signalling pathway regulating a variety of developmental processes, including vasculogenesis, has been shown to increase the size and number of sebaceous glands.11,12
Thus a conceivable working hypothesis is that Hh pathway activation may coexist in HNPCC, leading to sebaceous gland development, and recognisable FGs. In this regard, a specific role for the Hh signalling pathway in colonic cancerogenesis has been previously reported,19–21
lending support to this theory. In view of this clinical observation, it would be advisable to test the role of the Hh signalling pathway in HNPCC cancers. Interestingly, the only recognisable physical sign on clinical examination for HNPCC is skin changes related to neoplasms originating from the skin sebaceous glands in MTS, a rare variant of HNPCC.5
A strong correlation between MSH2
mutations and MTS has been recently reported.22,23
MTS is a cancer predisposing genodermatosis characterised by sebaceous gland tumours, including sebaceous adenomas, sebaceous epitheliomas, and sebaceous carcinomas, and less commonly keratoacantomas.24
mutations have also been found in at least two families.25,26
Interestingly, in both reports a MLH1
deletion was present and found to be similar to that identified in our family 1. Moreover, phenotypic variation seems to be present, even among carriers of the same MSH2 mutations. For instance, the splicing mutation affecting exon 5 identified in three MTS families is one of the most common HNPCC molecular defects,27
while no information regarding cutaneous tumours in the majority of families with the MSH2
mutation reported in the literature is available.23
Taken together, the reported evidence, along with other recent studies,28
would support the hypothesis that the molecular basis of MTS does not substantially differ from that of HNPCC.
As the Hh pathway has been shown to play a key role in cancer related angiogenesis,29,30
our previous report on increased microvascular complexity in the oral mucosa of patients with HNPCC 4,31
further supports this hypothesis.
In view of our findings, an interesting future study would be a comparison between HNPCC patients and non-HNPCC patients carrying CRCs with documented MSI, although in the latter cases both mutations in MMR genes are usually somatic. In these patients a distinct molecular pathway has been demonstrated to be caused by a defect in DNA MMR genes,32
although the concept that the first mutation is germinal in HNPCC patients and somatic in sporadic MSI colorectal tumours should be relevant in determining the associated phenotypic features.
Further prospective research in a larger population is certainly needed to confirm the reported clinical association, and to verify the predictive value of FGs in detecting HNPCC. Whether this clinical observation could be helpful in increasing the rate of HNPCC diagnosis in affected families warrants further investigation.