Dear Editor

In reply to the letter of Dr Jass,[1] we would like to make some points.

We agree with Dr Jass that, after the new discoveries and advances in the knowledge of HNPCC, the diagnosis of the syndrome has become a matter of conscience. The Amsterdam clinical criteria are useful, but not definitive in the diagnosis of the disease, and other parameters (pathological, biological, molecular) must be taken into account. Besides, family history is not reliable in every case. So, what should we do?

We think that, as a first step, the classical clinical approach of tracing a genealogical tree focused on malignancies in the family should be pursued on each proband, just to try to estimate the probability of disclosing an hereditary form of colorectal cancer. Doing this, we do not dare to label a family as an HNPCC only on clinical grounds, but we think that such family should be studied and followed with particular attention in order to find other clues and proofs of the syndrome and to provide the appropriate counselling measures.

From an epidemiological point of view, we agree that the estimation of the frequency of the syndrome based upon clinica criteria should be considered with caution, but it is the only practical way. When a population approach was used, defining the microsatellite status of all registered tumours in a period, and then searching for constitutional mutations in patients with unstable tumours, as high as 2.7% of total patients with colorectal tumours were labeled as HNPCC.[2] These figures are similar to those obtained with clinical criteria,[3] although not confirmed in other settings.[4] So, we think that it is not a burden for the family if we choose to follow it with a special care. Moreover, it has been demonstrated that an active follow-up can reduce the number of newly developed carcinomas in families with HNPCC (not all with the molecular diagnosis) and reduce cancer mortality.[5]

References

(1) Jass JR. Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) [electronic response to Ponz de Leon et al. Aetiology of colorectal cancer and relevance of monogenic inheritance] gutjnl.com 2004http://gut.bmjjournals.com/cgi/eletters/53/1/115#228

(2) R Salovaara, A Loukola A, P Kristo, H Kaariainen, H Ahtola, M Eskelinen, N Harkonen, R Julkunen, E Kangas, S Ojala, J Tulikoura, E Valkamo, H Jarvinen, J-P Mecklin, and A de la Chapelle. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000; 18: 2193-2200.

(3)M Ponz de Leon, P Benatti, F Borghi, M Pedroni, A Scarselli, C Di Gregorio, L Losi, A Viel, M Genuardi, G Abbati, G Rossi, M Menigatti, I Lamberti, G Ponti, and L Roncucci. Aetiology of colorectal cancer and relevance of monogenic inheritance. Gut 2004; 53: 115-122.

(4) A Percesepe, F Borghi, M Menigatti, L Losi, M Foroni, C Di Gregorio, G Rossi, M Pedroni, E Sala, F Vaccina, L Roncucci, P Benatti, A Viel, M Genuardi, G Marra, P Kristo, P Peltomaki, and M Ponz de Leon. Molecular screening for Hereditary Nonpolyposis Colorecal Cancer: a prospective, population-based study. J Clin Oncol 2001; 19: 3944-3950.

(5) HJ Jarvinen, M Aarnio, H Mustonen, K Aktan-Collan, LA Aaltonen, P Peltomaki, A de la Chapelle, and J-P Mecklin. Controlled 15-year trial on screening for colorectal cancer in families with Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 2000; 116: 829-834, 2000.

Dear Editor

The paper addressing the role of monogenic inheritance in the aetiology of colorectal cancer highlights the importance of achieving a meaningful working diagnosis of HNPCC.[1] The diagnosis of HNPCC may be achieved in two ways:
1. by equating the Amsterdam criteria with a clinical diagnosis,
2. by compiling a comprehensive set of clinical, pathological and molecular features that would together support the diagnosis of a specific condition caused by a germ-line mutation in a DNA mismatch repair gene such as hMLH1 or hMSH2. It is clear that there is potential for considerable confusion if the label HNPCC is used in these very different ways.

The original Amsterdam criteria were not developed to serve as the diagnostic criteria for HNPCC, but merely to introduce a uniform approach to the selection of families for collaborative studies.[2] It was originally considered that the criteria would be relatively specific rather than sensitive. However, colorectal cancer is a common disease, and the finding of three close relatives affected by bowel cancer within a single large family would not necessarily equate with a specific autosomal dominant disorder, even if one of the subjects happened to be aged below 50 years. Ponz de Leon et al. [1] show in Table 3 that families meeting the Amsterdam criteria but having cancers that are DNA microsatellite stable do not display the clinical features of HNPCC (see below). This is not altogether surprising. In fact it was shown nearly 10 years ago that colorectal cancers in such Amsterdam criteria-positive kindreds were frequently DNA microsatellite stable and that the clinical and pathological features of these families were unlike HNPCC (see below).[3] Of course, the latter findings do not preclude a genetic basis for such clustering of colorectal cancer within a family.

The diagnostic features of HNPCC have accumulated and been refined over time. HNPCC is now defined by a set of clinical, pathological and molecular features that encompass: a family history of colorectal cancer, a particular spectrum of extracolonic neoplasms, multiple colorectal neoplasia, early onset neoplasia, particular histological features among colorectal cancers, the presence of DNA microsatellite instability, loss of expression of DNA mismatch repair proteins as shown by immunohistochemistry, and a germ-line mutation in a DNA mismatch repair gene.[4] It may not be possible to identify the germ-line mutation in all families, even when cancers show evidence of deficient DNA mismatch repair. This is merely the result of technical limitations which should not preclude a diagnosis when the other features are met. Close mimicry of HNPCC may occur when hMLH1 has been methylated, perhaps through a familial predisposition to this chemical modification of DNA.[5] In the latter instance colorectal cancers may develop in a background of multiple hyperplastic polyps.[6]

Now that there is international agreement that the term HNPCC equates to a specific clinico-pathological entity,[4] there would seem to be little merit in applying the diagnosis when only the limited set of clinical features encompassed by the Amsterdam criteria is met. The reporting of a family history of colorectal cancer has been shown to be unreliable.[7] What would we think of a judge who chose to base his verdict only on hearsay and rumour and to ignore all evidence of a scientific nature? Why should a family be burdened unnecessarily with the label HNPCC and all its ramifications and how may epidemiological research be advanced by the application of a vague and unreliable diagnostic label?

References

1. M Ponz de Leon, P Benatti, F Borghi, M Pedroni, A Scarselli, C Di Gregorio, L Losi, A Viel, M Genuardi, G Abbati, G Rossi, M Menigatti, I Lamberti, G Ponti, and L Roncucci. Aetiology of colorectal cancer and relevance of monogenic inheritance. Gut 2004; 53: 115-122

2. Vasen HFA, Mecklin J-P, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG- HNPCC). Dis Colon Rectum 1991;34:424-425.

3. Jass JR, Cottier DS, Jeevaratnam P, et al. Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet 1995;346:1200-1201.

4. Vasen HF, Watson P, Mecklin J-P, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999;116:1453-1456.

5. Frazier ML, Xi L, Zong J, et al. Association of the CpG island methylator phenotype with family history of cancer in patients with colorectal cancer. Cancer Res 2003;63:4805-4808.

6. Jass JR, Cottier DS, Pokos V, Parry S, Winship IM. Mixed epithelial polyps in association with hereditary non-polyposis colorectal cancer providing an alternative pathway of cancer histogenesis. Pathology 1997;29:28-33.

7. Mitchell RJ, Brewster D, Campbell H, et al. Accuracy of reporting of familial history of colorectal cancer. Gut 2004;53:291-295.