Studies have shown that the adenoma–carcinoma sequence may also be applied in the development of CRC in families with Lynch syndrome. Since the 1980s, colonoscopic surveillance has been recommended for these families. The following question is relevant.
Question: does colonoscopic surveillance of the colorectum lead to early detection of CRC or adenoma and reduction of CRC‐related mortality?
A literature search showed that nine studies have addressed at least the first part of the question.33,34,35,36,37,38,39,40,41
Table 5 summarises the nature of these studies, the number of families involved and the categories of evidence produced. All the studies showed that surveillance led to the detection of CRC at an earlier stage compared with the stage in historical controls. The only prospective controlled trial showed that surveillance led to a 63% reduction of CRC.38
Two studies assessed the effect of surveillance on CRC‐associated mortality. A Finnish study showed that colonoscopic surveillance significantly decreased the mortality associated with CRC.38,42
A study from the Netherlands evaluated the relative mortality in a large series of families over a period of 45 years. In the Netherlands, a national registry of families with Lynch syndrome was established in 1985 to promote the identification of such families and to encourage participation in surveillance programmes.35
Mortality in these families has decreased significantly in the last 15 years.
Table 5Studies on surveillance of families with Lynch syndrome
Conclusion: periodic examination by colonoscopy leads to the detection of CRC at an earlier stage, to a 63% reduction of the risk of CRC and to a significant reduction of the mortality associated with CRC (category of evidence IIb).
The protocols that have been used in studies of surveillance have varied with respect to the surveillance intervals. Some studies advised a 3‐yearly colonoscopy and others colonoscopy every year.
Question: what is the optimal surveillance protocol for Lynch syndrome in terms of surveillance interval?
A search of the literature did not reveal any studies that compared different surveillance intervals. The Finnish trial showed that 3‐yearly colonoscopy significantly reduced the incidence of CRC and CRC‐related mortality.38
Therefore, the only evidence available suggests that a 3‐yearly interval may be adequate. However, several observational studies suggest that (interval) cancers can occur within a 3‐year interval after colonoscopy. In a Finnish study on surveillance of 56 families, the stage distribution of CRC was significantly more favourable in patients (n
35) with cancer detected by surveillance than in patients (n
115) with symptomatic presentation of CRC.39
However, a total of 21 cancers were diagnosed after a previous “clean” colonoscopy, and half of them were diagnosed within (or at) an interval of 3 years. These included two Dukes C cancers diagnosed 15 and 20 months after the previous examination. In a Dutch long‐term follow‐up study, a number of interval cancers were also observed. Advanced cancers (Dukes C) were only observed at intervals of >2 years, whereas all Dukes A and B tumours were detected within an interval of <2 years. These observations, together with the finding that adenomas observed in HNPCC more often show high‐grade dysplasia and villosity, suggest that the adenoma–carcinoma sequence is accelerated in Lynch syndrome.32,43
Therefore, the most appropriate surveillance interval probably lies between 1 and 2 years. In highly selected cases—for example, mutation carriers who have recurrent adenomas—a prophylactic subtotal colectomy may be discussed as an option.
Conclusion: a 3‐year interval is proven to be (at least partly) effective (category of evidence IIb); in view of the observation of advanced CRC detected 2–3 years after colonoscopy, the optimal interval probably lies between 1 and 2 years (category of evidence III, grade C).
Question: at what age should surveillance be started and at which age might surveillance be discontinued?
Many studies have shown that the risk of developing CRC before the age of 25 years is very low.7,8,9,10
In a series of 246 CRC from families with Lynch syndrome known at the Dutch HNPCC Registry, only 2 (0.8%) patients developed CRC before the age of 20 years and another two between age 20 and 25 years.44
Based on these data, the group advises to start surveillance between age 20 and 25 years. In the literature, recommendations regarding the upper age limit of surveillance are very sparse. One study has reported that the risk of mutation carriers aged 70–75 years developing CRC in the next 10 years is significant.44
However, at the age of 80 years, they found that the risk of developing CRC in the next 10 years relative to their life expectancy was low. Based on these findings, the authors recommended continuing surveillance up to the age of 80 years in mutation carriers if they were in good health. However, the European group advises that decisions on the upper age limit of surveillance should be made on an individual basis. For example, in a 75‐year‐old mutation carrier with severe cardiovascular disease, surveillance can be discontinued. On the other hand, in an 80‐year‐old mutation carrier who is still in good health, especially if there is a personal history of adenomas and colon cancer, it is reasonable to continue surveillance.
Conclusion: surveillance should start between age 20 and 25 years. Decisions on the upper age limit of surveillance depend on the patient's general state of health and should be made on an individual basis (category of evidence III, grade C).
Question: which surveillance protocol should be recommended in families with clustering of CRC without evidence of MSI in the tumours?
In a significant proportion (approximately 30%) of families that meet the Amsterdam criteria, the results of the MSI and IHC analysis of the colorectal tumour(s) are negative.45
Clustering of CRC by chance or genetic defects other than those of MMR may be responsible for the disease in such families, and they do not have Lynch syndrome. These families are characterised by a more advanced age of onset of CRC than in families with Lynch syndrome, and the absence of endometrial cancer and multiple tumours. A recent study reported that the risk of developing CRC in such families is increased only by a factor of 2.3.45
Another study compared the results of surveillance in families with clustering of CRC with and without MSI.46
The results showed that the yield of adenomas was the same in both types of families. However, CRC was identified only in the families with MSI tumours. In families without evidence for MMR deficiency, a less intensive colonoscopic surveillance programme (eg, colonoscopy: 1×/3–5 years, starting 5–10 years before the first diagnosis of CRC or at >45 years) might be appropriate. In view of the absence of endometrial cancer in such families, surveillance of the endometrium is not indicated.
Conclusion: in families with clustering of CRC but without evidence of MMR deficiency (families without Lynch syndrome), a less intensive surveillance protocol is recommended—that is, colonoscopy at 3–5 year intervals, starting 5–10 years before the first diagnosis of CRC or at >45 years (category of evidence III, grade C)