Background: Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. Aim: To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. Methods: The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. Results: Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of J3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became J2184 per life year gained. Sensitivity analysis showed these findings to be robust. Conclusions: MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.

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Present guidelines to identify hereditary non-polyposis colorectal cancer (HNPCC) families are criticized for limitations in accuracy. The Amsterdam criteria I and II (AC I and AC II) are used to predict a germline mutation in one of the mismatch repair genes. In families not fulfilling the AC I and AC II criteria, individual indications to test cancer specimens for microsatellite instability (MSI) are guided by the Bethesda Guidelines (BG). Germline mutation testing is then performed in patients who conform to the BG and show MSI. We investigated the sensitivity and specificity of AC I, AC II, and BG. A meta-analysis of studies on the value of the AC I and AC II criteria for predicting germline mutation, as well as a meta-analysis of BG for the detection of MSI was performed. For the AC I, sensitivity varied from 54 to 91% and specificity varied from 62 to 84%. For the AC II, the pooled sensitivity was 78% and specificity ranged between 46 and 68%. Post-test probabilities of a positive test result were 0.61 and 0.46 for the AC I and AC II, respectively. Post-test probabilities of a negative test result were 0.17 and 0.21 for the AC I and AC II, respectively. For the BG, the pooled sensitivity was 89% and pooled specificity was 53%. Post-test probability of a positive test result was 41%, and post-test probability of a negative test result was 9%. The sensitivity and specificity of the Amsterdam criteria for predicting a germline mutation that causes HNPCC is not sufficient. The BG are useful for the detection of MSI in a group of patients suspected of having familial colorectal cancer (CRC), but sensitivity is very low in the total group of newly diagnosed CRC patients. Therefore, a new strategy is needed for the identification of HNPCC.

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Hereditary non-polyposis colorectal cancer (HNPCC) is a dominant inherited disease and accounts for up to 5% of all colorectal cancer (CRC) patients. Despite the optimization of selection criteria and enhancements in molecular techniques for identifying more families with HNPCC, most cases are not recognized. Poor patient recollection of family history and inadequate family history-taking are main causative factors. We propose a new strategy for detecting HNPCC, one in which the pathologist selects patients for microsatellite instability (MSI) testing. Criteria for MSI analysis are: (1) CRC before the age of 50 years, (2) second CRC before 70 years, (3) CRC and HNPCC-associated cancer before 70 years, or (4) adenoma before 40 years. Additionally, patients with a positive MSI test and patients with a positive family history are offered referral for genetic counselling. With this strategy, at least twice the number of HNPCC patients will be identified among a population of CRC patients, and in a cost-effective, efficient and feasible way. The identification of patients with HNPCC is important because intensive surveillance can prevent death from CRC.

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