A literature search of PubMed was done by use of the terms “Lynch syndrome” or “hereditary non-polyposis colorectal cancer” and each of the following: “endometrial”, “endometrium”, “ovarian”, “small bowel”, “small intestine”, “gastric”, “stomach”, “urinary”, “ureter”, “renal pelvis”, “kidney”, “bladder”, “pancreas”, “pancreatic”, “biliary”, “hepatocellular”, “brain”, “skin”, “cancer”, “tumour”, and “neoplasm”. Reference lists of identified articles were reviewed. Only full-text articles
ReviewManagement of extracolonic tumours in patients with Lynch syndrome
Introduction
Lynch syndrome, or hereditary non-polyposis colorectal cancer, is the most common hereditary colon cancer and is characterised by a predisposition to early onset colorectal cancer and several extracolonic malignancies (figure 1). In the past, diagnosis was based on family history and clinical criteria, such as the Amsterdam criteria.1 Identification of susceptibility genes for Lynch syndrome narrowed the diagnosis to families with pathogenic germline mutations in one allele of the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Mutations in mismatch repair genes on both alleles cause a rare form of childhood onset cancer that we do not discuss. Disrupted mismatch repair function leads to replication errors in repetitive DNA segments, known as microsatellites. Microsatellite instability also occurs in some sporadic cancers.
The most common malignancy in individuals with Lynch syndrome is colorectal cancer, with a cumulative lifetime risk of up to 70% at age 70 years.1 People who are carriers of mutations in mismatch repair genes also have a risk of extracolonic cancers; these include cancer of the endometrium, ovary, stomach, urinary tract, biliary tract, pancreas, small bowel, brain, and skin (Figure 1, Figure 2). Carcinogenesis and biological behaviour of colorectal tumours differ in individuals with and without Lynch syndrome.1 Whether the same is true for other cancers associated with Lynch syndrome is unknown.
Surveillance is done in asymptomatic individuals to diagnose malignant or premalignant lesions at an early stage to improve survival. For people with Lynch syndrome, colorectal surveillance via colonoscopy is recommended every 1–2 years beginning at age 20–25 years. This strategy has reduced the incidence of and mortality from colorectal cancer.2, 3 Surveillance of all other organs in which tumours might develop is not realistic with current methods. It is unclear for which extracolonic cancer types surveillance is beneficial, at what age to start, and how often. In this systematic Review, we outline the risks, surveillance tests, and guidelines for the management of extracolonic malignancies in Lynch syndrome.
Section snippets
Risk of extracolonic malignancies
Finding the best surveillance strategy for a tumour type first requires knowledge of the lifetime risk and age distribution at the time of diagnosis. Cancer risk is affected by external factors, such as diet and lifestyle, and by internal factors, such as genetic characteristics.
The risk of extracolonic tumours for people with Lynch syndrome depends on which mismatch-repair gene is mutated. Carriers of mutations in MLH1, MSH2, MSH6, and PMS2 have different cancer risks. However, most
Epidemiology
For women with a genetic predisposition for Lynch syndrome, lifetime risk of endometrial cancer is higher than that of colorectal cancer. Women with Lynch syndrome have a 27–71% cumulative lifetime risk of endometrial cancer compared with 3% in the general population. Risk is between 27% and 60% for women with mutations in MLH1 and MSH2 and 60–71% for those with mutations in MSH6. Annual incidence of endometrial cancer in women with Lynch syndrome who are older than 40 years is 2·5%.29 Mean age
Epidemiology
The lifetime risk of gastric cancer in people with Lynch syndrome varies substantially between populations (table 1).4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Lifetime risk is 2·1% in the Netherlands8 and around 30% in Korea.22 Clearly, risk is higher in areas that have high risk of gastric cancer in the general population, such as in Asia.22 Many patients with Lynch syndrome who develop gastric cancer are diagnosed before the age of 50 years,
Epidemiology
For people with Lynch syndrome, the lifetime risk of small bowel cancer is around 4%: over 100 times the risk in the general population.54 A review of available case series reported a median age at diagnosis of between 39 years and 53 years.54 Compared with the general population, patients with Lynch syndrome who develop small-bowel cancer usually present 10–20 years earlier, and the risk is slightly higher in men than in women.54 Tumours are usually in the duodenum or the jejunum, with a small
Epidemiology
Early single-family studies reported an association between Lynch syndrome and pancreatic or biliary cancer.59, 60, 61 The first larger series, done by Mecklin and co-workers,62 assessed 18 patients with pancreatic or biliary cancer from families with suspected Lynch syndrome. 15 patients had carcinoma of the biliary tract or papilla of Vater. Mean age at the time of diagnosis was 56 years.62 Geary and colleagues13 recently reported an incidence of pancreatic cancer seven times higher than in
Epidemiology
In patients with Lynch syndrome, the risk of urinary tract cancer, in particular cancer of the renal pelvis and ureter, is up to 12%.4, 7, 8, 10, 11, 12, 13, 14, 15, 16, 65 Watson and colleagues16 assessed 2683 proven or probable carriers of pathogenic MLH1 or MSH2 mutations and reported cumulative risks to the age of 70 years of: 6% (8% including bladder cancer risk) for the total group, 0·4 % (1%) for women with MLH1 mutations, 2% (4%) for men with MLH1 mutations, 9% (12%) for women with MSH2
Epidemiology
Sebaceous tumours (adenoma, epithelioma, or carcinoma) and keratoacanthomas are prevalent in people with Lynch syndrome: an association known as Muir-Torre syndrome. South and colleagues74 report Muir-Torre syndrome in 14 of 50 families and 14 of 152 individuals with Lynch syndrome. Although predominantly associated with MSH2 mutations, Muir-Torre syndrome can also occur in families with mutations in MLH1 or MSH6.74, 75 Skin tumours associated with Lynch syndrome often appear on the face, but
Epidemiology
Lynch syndrome is associated with an increased risk of brain tumours.7, 8, 11, 14, 15, 16, 77 In 6041 proven or probable carriers of pathogenic MLH1 or MSH2 mutations, or their first-degree relatives, cumulative risk of brain tumours to the age of 70 years was 2% for the total group, 1·7% for carriers of MLH1 mutations, and 2·5% for carriers of MSH2 mutations.16 Risks might have been underestimated because individuals who developed brain tumours as children were less likely to be identified.
Other tumours
Other tumour types that have been reported in patients with Lynch syndrome include breast, prostate, larynx, lung, thyroid, and testicular cancers, and melanoma, lymphoma, leukaemia, and soft tissue sarcomas.16, 79, 80, 81, 82, 83 Molecular findings showed that mismatch repair deficiency contributed to the development of those tumours.79, 80, 81, 82, 83 Evidence does not show an increased risk of breast or prostate cancer for individuals with Lynch syndrome, although breast cancer risk is
Conclusion
In this Review, we discussed management of extracolonic malignancies in Lynch syndrome with an emphasis on surveillance. For individuals with Lynch syndrome, the colorectum is the only organ in which surveillance reduces the risk of cancer and mortality. We advocate discussing with the patient the risks and surveillance strategies for other types of tumours associated with Lynch syndrome. Nilbert and colleagues86 confirmed the need to start surveillance at a young age by showing genetic
Search strategy and selection criteria
References (87)
- et al.
Controlled 15-year trial on surveillance for colorectal cancer in families with hereditary nonpolyposis colorectal cancer
Gastroenterology
(2000) - et al.
Decrease in mortality in Lynch syndrome families because of surveillance
Gastroenterology
(2006) - et al.
Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis
Gastroenterology
(1996) - et al.
Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset
Gastroenterology
(2005) - et al.
Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer
Gastroenterology
(2005) - et al.
Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer
J Gastrointest Surg
(1998) - et al.
Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counselling and surveillance
Gastroenterology
(2004) - et al.
Penetrance and expressivity of MSH6 germ line mutations in seven kindreds not ascertained by family history
Am J Hum Genet
(2004) - et al.
The German HNPCC Consortium. HNPCC-associated small bowel cancer: clinical and molecular characteristics
Gastroenterology
(2005) - et al.
Gynecologic surveillance in hereditary nonpolyposis colorectal cancer
Gynecol Oncol
(2003)