Why is Increased Screening Recommended In Hereditary Colorectal Cancer Syndromes? Why is it Important and What Screening Can Be Done?

You may have wondered why cancer-screening recommendations for individuals with a known hereditary colorectal cancer(CRC) syndrome are so much different than those recommended for individuals with no strong family history of cancer.  Compared to average-risk screening, the recommendations for cancer screening in the hereditary CRC syndromes are typically to start screening much earlier, to screen with the most effective screening tool available and to screen more frequently.  I will use colon cancer screening in Lynch syndrome (LS) and familial adenomatous polyposis (FAP) to illustrate some of the rationale for these recommendations. 

Why start screening earlier?  Early age of cancer onset is one of the hallmarks of hereditary cancer syndromes.  The average age of onset of sporadic CRC in the US is about 72 years, the average age of CRC in LS is around 45 and it is even younger for FAP (average CRC age about 39).  In contrast to CRC screening starting at age 50 in the average risk population, colonoscopy screening is recommended to start by age 25 or earlier in LS mutation carriers and as early as age 10 in FAP.  

The extra-colonic cancers that occur in Lynch syndrome (endometrium/uterus, ovary, stomach, small bowel, ureter and renal pelvis among others) and FAP (stomach, small bowel, thyroid, and others) also occur earlier than the same cancers in the general population so when effective screening tests are available screening typically starts at an earlier age for these cancers too.    

Why use the most effective screening tool?  It seems intuitive that the most effective screening tool should be used in all populations.   Colonoscopy is thought by many to be the single most effective CRC screening test but it is much more expensive, more inconvenient and associated with a higher risk than other screening options.  Several acceptable options are available for CRC screening in the average risk population including fecal occult blood testing, endoscopy with flexible sigmoidoscopy as well as colonoscopy (newer tests such as CT colonography and stool DNA testing can also be used in special circumstances).  For LS and FAP, colonoscopy is recommended as the best choice for CRC screening and surveillance because of the exceptionally high CRC risk in these syndromes and location of the CRCs that is often in the upper colon.  Colonoscopy evaluates the entire colon whereas flexible sigmoidoscopy only examines the lower half and endoscopy is more effective as a one-time tool than fecal occult blood testing for detection of CRC and particularly for detection of colonic polyps.   Colonoscopy is the only screening test that can both identify and remove polyps from the entire colon in a single test.  Although sigmoidoscopy is sometimes used for initial screening in children with FAP, once polyps are initially found, colonoscopy is recommended to evaluate the extent of the polyposis and for further surveillance until the time of colectomy.

There have been no trials comparing colonoscopy to other screening strategies in either LS or FAP but there is evidence that individuals with LS or FAP who have regular colonoscopic screening are much less likely to develop or die of CRC than those who don’t have screening. 

There are screening tests for some of the extra-colonic cancers in LS and FAP but there is limited direct evidence of their effectiveness in decreasing the incidence or mortality of those cancers.  Upper endoscopy is routinely recommended in FAP and often recommended in LS to screen for gastro-duodenal polyps and cancers.  Similarly, endometrial aspirates, trans-vaginal ultrasounds and CA-125 levels in blood are sometimes offered for endometrial and ovarian cancer screening in LS but screening is not highly effective for these cancers and the option of prophylactic removal of the uterus and ovaries after childbearing is routinely discussed with women LS mutation carriers. Regular clinical exams and ultrasounds are often offered for thyroid cancer screening although the benefit of screening has not been established.  Similarly, regular urine analysis is often offered for screening of cancers of the ureter and renal pelvis although its benefit has not been proven.

Why screen more frequently?  If colonoscopy is used as the screening strategy in average risk individuals, the usual recommendation is to repeat the examination every 10 years if no polyps are found. In contrast, the recommendation is to repeat colonoscopy every 1-2 years in LS and FAP mutation carriers.  The rationale for the 10-year interval in the average risk population comes from data indicating that, on average, the progression from normal colonic mucosa through the adenoma to colon cancer (the polyp to cancer sequence) takes 10-15 years.  Interestingly, the rationale for the much shorter intervals in LS and FAP differs between the two syndromes. 

LS is due to a germline mutation in one copy of any of 4 genes necessary for DNA mismatch repair (MMR).  The DNA MMR system repairs mutations that occur during normal DNA replication.  Cells with one mutant and one normal copy of a DNA MMR gene function normally but if a mutation occurs in the remaining normal copy of the MMR gene in a cell, that cell can no longer repair DNA mismatches and has a markedly increased mutation rate.  This increased mutation rate can accelerate the polyp to cancer sequence.  This biologic rationale along with clinical observations of CRCs occurring within a few years of a normal colonoscopy are the reasons that 1-2 year intervals between colonoscopies is recommended in LS. 

There is no evidence that the polyp to cancer sequence is shortened in FAP.  The rationale for the recommendation of annual colonoscopies in FAP is because of the very high cumulative CRC risk (essentially 100% if the colon is not removed) and the large number of polyps present in the colon of these patients.  Although the average time of the polyp to cancer sequence may be 10-15 years there is thought to be substantial heterogeneity around this average and a few polyps can progress much more rapidly.  In FAP there are often hundreds to thousands of polyps in the colon and they cannot all be removed endoscopically.  Thus, colonoscopy is used in FAP to monitor the progression of the polyps in order to decide when a colectomy should be performed.  Progression of an existing polyp to a larger size or a more advanced histology occurs more rapidly than the entire polyp to cancer sequence.  In addition, the presence of many polyps in the colon makes it more likely that the endoscopist may miss seeing some of them. Taken together, this is the rationale for annual colonoscopy for patients with FAP.

The increased intensity of screening and surveillance in hereditary cancer syndromes is driven by their increased risk to develop cancer,  the early age of onset of cancers, as well as by the unique clinical (numerous polyps in FAP) and biologic (rapid polyp to cancer sequence in LS) features of the syndromes.

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