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Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC)
  1. J R Jass
  1. Correspondence to:
    Professor J R Jass
    Department of Pathology, Duff Medical Building, 3775 University st, Montreal, Quebec, Canada H3A 2B4;
  1. L Roncucci2,
  2. M Ponz de Leon2,
  3. P Benatti2,
  4. F Borghi2,
  5. M Pedroni2,
  6. A Scarselli2,
  7. C di Gregorio2,
  8. L Losi2,
  9. A Viel2,
  10. M Genuardi2,
  11. G Abbati2,
  12. G Rossi2,
  13. M Menigatti2,
  14. G Ponti2
  1. 2University of Modena and Reggio Emilia, Modena, Italy

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The paper addressing the role of monogenic inheritance in the aetiology of colorectal cancer highlights the importance of achieving a meaningful working diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) (Gut 2004;53:115–22). 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 germline 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.1 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 and colleagues (Gut 2004;53:115–22) 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).2 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 germline mutation in a DNA mismatch repair gene.3 It may not be possible to identify the germline 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.4 In the latter instance colorectal cancers may develop in a background of multiple hyperplastic polyps.5

Now that there is international agreement that the term HNPCC equates to a specific clinicopathological entity,3 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. Reporting of a family history of colorectal cancer has been shown to be unreliable.6 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?


Author’s reply

In reply to the letter of Dr Jass we would like to make the following points.

We agree with Dr Jass that since the new discoveries and advances in our knowledge of hereditary non-polyposis colorectal cancer (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 believe that, as a first step, the classical clinical approach of tracing a genealogical tree focused on malignancies in the family should be pursued for each proband, to attempt to estimate the probability of disclosing an hereditary form of colorectal cancer. In doing this, we do not label a family as HNPCC on clinical grounds alone, but we think that such families should be studied and followed with particular attention to obtain other clues and proof of the syndrome and to provide appropriate counselling measures.

From an epidemiological point of view, we agree that estimation of the frequency of the syndrome based on clinical 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 patients with colorectal tumours were labelled as HNPCC.1 These values are similar to those obtained with clinical criteria (Gut 2004;53:115–22) although not confirmed in other settings.2 Therefore, we believe that it is not a burden for the family if we choose to follow them with special care. Moreover, it has been demonstrated that active follow up can reduce the number of newly developed carcinomas in families with HNPCC (not all with a molecular diagnosis) and reduce cancer mortality.3


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