Elsevier

The Lancet Oncology

Volume 10, Issue 4, April 2009, Pages 400-408
The Lancet Oncology

Review
Management of extracolonic tumours in patients with Lynch syndrome

https://doi.org/10.1016/S1470-2045(09)70041-5Get rights and content

Summary

Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2–3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin cancer. In this Review, we discuss the risks, surveillance tests, and guidelines for the management of extracolonic tumours associated with Lynch syndrome. For all types of extracolonic cancer, evidence supporting surveillance is scarce. A benefit of surveillance is evident only for endometrial cancer, where transvaginal ultrasound and endometrial sampling detect tumours in early stages. Surveillance is generally recommended for urinary tract and gastric cancer, especially in families with more than one member with these types of cancer. For the other types of cancer, surveillance is typically not recommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be considered for women with Lynch syndrome who are past childbearing age, especially during surgery for colorectal cancer. No data show efficacy of chemopreventive drugs in reducing the risk of extracolonic cancers for 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

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

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