BMJ  2005;331:1033-1034 (5 November), doi:10.1136/bmj.331.7524.1033

Editorial

Patients at risk of familial colorectal cancer

Surveillance of patients not covered by established criteria is controversial

What is ordinary? The single case! What is special? Millions of cases!

Johann Wolfgang von Goethe (1749-1832)¹

Management of hereditary non-polyposis colorectal cancer (HNPCC) is a textbook example for the translation of molecular knowledge into clinical decision making. Different mutations in mismatch repair genes were identified on the basis of clustering of colorectal and associated cancers in affected families. In the meantime adequate proof that colonoscopic surveillance indeed reduces incidence of and morbidity from HNPCC had been obtained.² The situation, however, is less clear in individuals at moderate risk of colorectal cancer because of a positive family history but not fulfilling any of the Amsterdam or Bethesda criteria.^{3 4} Dove-Edwin and colleagues have to be commended for providing urgently needed data on this group of patients in their paper in this week's BMJ.⁵

In 1913 Aldred Warthin, a pathologist, published a family pedigree including several hereditary tumours⁶ that matches our present HNPCC criteria put forward by Lynch in 1966.⁷ Warthin knew of this family as one of its members worked as his seamstress. This woman predicted her death from a colorectal or a gynaecological malignancy after reviewing her own family pedigree and was proved right. She died of endometrial cancer at a young age and was obviously at high risk, with her family fulfilling our present Amsterdam criteria. The Amsterdam criteria, introduced in 1991, are highly specific and are thus regarded as clinical proof of HNPCC. With our current knowledge of clinical and molecular criteria for HNPCC, Warthin's seamstress would have certainly qualified for an intensified surveillance programme.

As the Amsterdam criteria showed a rather low sensitivity of around 30%,⁴ the Bethesda criteria were introduced in 1996 (see box). These criteria were used to select those tumours in need of testing for microsatellite instability, the molecular characteristic of HNPCC. This heterogeneous set of clinical characteristics achieved a sensitivity of nearly 90%, but specificity fell to under 50%.²

In 2001 our group published an analysis of the validity of the different Bethesda criteria in relation to microsatellite instability status in order to simplify their use in clinical practice.⁸ Only Bethesda criteria 1, 3, and 4 showed an appreciably different distribution of the microsatellite instability status when compared with those of the remaining patients registered (see box). When applying these criteria only, we achieved a cumulative detection rate of 77% high microsatellite instability cases, thereby identifying 89% of tumours with microsatellite instability among the Bethesda positive patients.⁹ For general medical practice outside academic centres, these three criteria are reasonably accurate for adequate selection of tumours with high microsatellite instability.⁹

However, there is another important group of individuals with a supposedly increased risk for colorectal cancer. In their paper Dove-Edwin et al focus on this group—patients with a substantial familial burden of colorectal cancer not meeting the Amsterdam criteria and only inadequately described by the Bethesda criteria. We know little about what and how much surveillance these patients need. Recommendations are difficult to make as this group is obviously very heterogeneous.⁹

Whether patients with HNPCC should be screened with colonoscopy every two years or annually is under investigation by the German HNPCC Consortium funded by German Cancer Aid.⁸ Colonoscopy is one of the accepted pillars of surveillance in families with a history of HNPCC—merely the intervals between screening remain under debate. This is in contrast with the uncertainty of the recommendations for patients with a family history of colorectal cancer but without proved HNPCC.⁸

Counselling individuals who think they are at increased risk of a hereditary tumour is a difficult task. Compassion for the worried and sometimes grief stricken individual will occasionally mislead a physician—encouraged by the person at risk—to recommend an intensified surveillance programme even though little evidence exists to endorse this. Although this may comfort the affected person and his or her family, the possible medical risks and socioeconomic consequences of an intensified surveillance programme must be borne in mind.

Bethesda criteria (meeting all features listed under any single criterion is sufficient) Individuals with cancer in families that fulfil the Amsterdam criteria Individuals with two HNPCC related cancers (that is, endometrial, small intestine, ovarian, and stomach) Individuals with colorectal cancer and a first degree relative with colorectal cancer or HNPCC related extracolonic cancer (that is, endometrial, small intestine, ovarian, and stomach) or colorectal adenoma; one of the cancers diagnosed before age 45, and the adenoma diagnosed before age 40 Individuals with colorectal cancer or endometrial cancer diagnosed before age 45 Individuals with right sided colorectal cancer with an undifferentiated pattern on histopathology diagnosed before age 45 Individuals with signet ring cell type colorectal cancer diagnosed before age 45 Individuals with adenomas diagnosed before age 40

For responsible patient guidance, we have to detach ourselves from the individual case to a certain extent and, keeping Goethe's words in mind, take a look at the big picture. Only if we are able to merge the recent diagnostic advances in familial colorectal cancer with its clinical presentation will we be able to provide better recommendations for adequate surveillance of patients at variable risk of colorectal cancer. Then, indeed, we will have gone from bench to bedside.

(hanns-peter.knaebel{at}med.uni-heidelberg.de)
Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany

Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany

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Competing interests: None declared.

Papers p 1047

References

1. Dobel R. Das Lexikon der Goethe-Zitate. Vienna: Albatros, 2001.
2. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348: 919-32.[Free Full Text]
3. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on hereditary non-polyposis colorectal cancer (ICGHNPCC). Dis Colon Rectum 1991;34: 424-5.[CrossRef][ISI][Medline]
4. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999;116: 1453-6.[CrossRef][Medline]
5. Dove-Edwin I, Sasieni P, Adams J, Thomas HJW. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ 2005:331: 1047-9.[Abstract/Free Full Text]
6. Warthin AS. Hereditary with reference to carcinoma. Arch Intern Med 1913;12: 546.[ISI]
7. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1966;117: 206-12.[CrossRef][ISI][Medline]
8. Knaebel HP, Kienle P, Buchler MW, Weitz J. Surgical strategies for the prevention of gastrointestinal tumours. Z Gastroenterol 2005;43: 257-66.[Medline]
9. Wullenweber HP, Sutter C, Autschbach F, Willeke F, Kienle P, Benner A, et al. Evaluation of Bethesda guidelines in relation to microsatellite instability. Dis Colon Rectum 2001;44: 1281-9.[CrossRef][Medline]

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Relevant Article

Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study

Isis Dove-Edwin, Peter Sasieni, Joanna Adams, and Huw J W Thomas
BMJ 2005 331: 1047. [Abstract] [Full Text] [PDF]