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Urologic implications of Lynch syndrome


Lynch syndrome (LS) is one of the most common hereditary cancer disorders and includes multiple urologic cancers within its spectrum. This autosomal dominant syndrome was one of the first hereditary cancer disorders to be identified and affects approximately 1 in 279 people.1 LS is historically known as hereditary nonpolyposis colorectal cancer (HNPCC) but is also associated with urothelial, prostate, testicular, and adrenal malignancies (Figure).

The carcinogenic mechanism of LS is caused by a mutation within the mismatch repair (MMR) genes, with the most common mutations being in the mutL homolog 1 (MLH1), mutS homolog 2 and 6 (MSH2, MSH6), and postmeiotic segregation increased 2 (PMS2).2 Mutations in the epithelial cellular adhesion molecule (EpCAM) can also lead to silencing of MSH2.3 MMR genes work together to identify and excise DNA mismatches during DNA synthesis, and mutation of a single protein in this pathway can lead to dysfunction of the entire repair system. The inherited germline mutation alone is not enough to lead to disruption of the MMR system. The second normal allele must be inactivated as well, typically through epigenetic silencing, somatic mutation, or loss of heterozygosity.

Urothelial cancer

Upper tract urothelial cancer: The most common urologic cancer associated with LS is upper tract urothelial cancer (UTUC). It is rare, with an incidence of 2 in 100,000 people per year.4 However, MMR deficiency is seen in 5% to 11% of all patients with UTUC. The MMR genes most commonly associated with UTUC are MSH2 and MSH6.3,5 Urologists evaluating patients with UTUC who display certain characteristics should suspect an underlying genetic syndrome. Young patients, bilateral tumors, abnormal pathologic analysis, or family history compatible with LS all warrant further evaluation for LS.

The risk of developing UTUC in a patient with LS is about 22 times higher than that of the general population and is estimated at between 0.4% and 20%.2 A review of 288 patients with LS in Denmark showed that 22% developed UTUC and 17% developed urothelial carcinoma of the bladder. The mean age at diagnosis was 61, and MSH2 mutations were seen in 73% of cases. In addition, men and women appear equally affected in those with LS.3,6 Tumor stage and development of subsequent bladder cancer do not appear to differ in patients with LS versus sporadic patients.3 Bilateral tumors are more common in LS, and previous studies have observed bilateral tumors in 46% of patients.7

Due to increased risk of UTUC among patients with LS, screening for urothelial cancer is recommended though there is no consensus on screening approach. Many groups use annual urinalysis with subsequent microscopic hematuria evaluation, because this is relatively low cost and minimally invasive.7 Other groups suggest addition of urogram phase to surveillance scans in those patients who had previous colorectal cancer (CRC).2 Annual computed tomography urogram or renal ultrasound may be particularly beneficial in patients with known MSH2 mutation, because this is the MMR gene most commonly associated with UTUC. The National Comprehensive Cancer Network (NCCN) specifically recommends starting yearly urinalysis in patients with MSH2 mutations who are aged 30 to 35 years.8

Genetic testing for MMR mutations should be performed in certain patients with UTUC. Metcalfe et al screened patients without prior history of LS and with UTUC for risk of LS using the Amsterdam II criteria (Table) and immunohistochemical (IHC) testing. This identified 13.9% of patients who were considered at risk for LS. Subsequent genetic testing confirmed that 5.2% of patients had LS.9 Therefore, those with positive screen using Amsterdam II criteria as well as those with positive IHC testing for MMR mutation should undergo genetic testing.

Urothelial cancer of the bladder: Bladder cancer occurring in multiple members of a family is still more likely to be a result of shared environmental risk factors than of heredity. However, emerging data demonstrate increased risk of bladder cancer in patients with LS, especially in men and those with MSH2 mutations. In the previously cited article from Denmark, 17% of patients with LS may develop urothelial cancer of the bladder.3 A second study, from Canada, showed a lower percentage (6.21%) of patients with LS and MSH2 mutations with bladder cancer; however, this was still significantly higher than the general Canadian population.11 These observations are likely high enough to justify a yearly urinalysis staring at age 30 in patients with known LS and MSH2 mutation.

Prostate cancer: Inclusion of prostate cancer as an LS-associated cancer remains controversial despite being clearly defined by Ryan et al in 2014.11This meta-analysis and systematic review showed that there is a 3.67-fold relative risk for developing prostate cancer in patients with MMR mutations, especially MSH2 (95% CI, 2.32-6.67). Other studies have shown comparable results confirming increased prostate cancer risk in patients with LS.2,13

Men with prostate cancer meeting certain criteria should be tested for LS. Based on the 2017 Philadelphia Prostate Cancer Consensus Conference, the recommendation is to screen for MMR gene mutations in men with family history of LS or with 2 or more blood relatives with an LS-associated cancer.11,13 These recommendations are similar to those for UTUC, though they do not specifically recommend use of the Amsterdam II criteria.

There are no data to suggest earlier onset of prostate cancer or higher stage at diagnosis. Some have proposed PSA screening starting at age 40; however, studies have shown a median age at diagnosis ranging from age 59 to 69 years.12 Therefore, men with LS should be strongly encouraged to undergo yearly PSA and physical exam testing. However, screening starting earlier than age 55 years is not supported by the literature.

Other urologic cancers

The relationship between LS and testicular cancer is not well established. Current literature is conflicting, with some data showing up to 33% of testicular germ cell tumors containing MSI compared to other studies showing no MSI and no MMR deficiency on histopathologic analysis.2,12

Due to the rarity of adrenocortical carcinoma (ACC), association with LS is difficult to establish. ACC is associated with poor prognosis and affects only about 1 to 2 patients per million each year.12 Various case studies have reported incidence of ACC within patients with LS and MSH2 mutations and, in a combined prospective and retrospective study, MMR mutations were found in 1.5% to 3.2% of patients with ACC.13 These data are not adequate to encourage screening for ACC in patients with LS; however, they do suggest that ACC should be a consideration when evaluating patients with LS with adrenal masses.


Lynch syndrome is one of the most common hereditary malignancy syndromes and is associated with multiple urologic cancers. To apply this knowledge of LS to daily practice, we should keep in mind the following:

UTUC is the third most common LS-associated cancer.

Patients with known LS and MSH2 mutations should undergo yearly urinalysis and microhematuria workup as indicated; they may also benefit from yearly renal ultrasound or CT urogram.

Patients with UTUC or prostate cancer meeting the Amsterdam II criteria or having abnormal immunohistochemical testing on pathology should undergo genetic screening for LS.

In patients with LS presenting with adrenal mass, ACC should be considered.

Beyond treating patients for urologic cancers, it is our role as urologists to identify patients at risk for undiagnosed Lynch syndrome and provide appropriate screening in this population.

Olson is a urology resident, Tyson is associate professor of urology, and Bryce is associate professor of medicine at Mayo Clinic, Phoenix, Arizona.


1. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2017;26(3):404-412. doi:10.1158/1055-9965.EPI-16-0693

2. Huang D, Matin SF, Lawrentschuk N, Roupret M. Systematic review: an update on the spectrum of urological malignancies in Lynch syndrome. Bladder Cancer. 2018;4(3):261-268. doi:10.3233/BLC-180180

3. Mork M, Hubosky SG, Rouprêt M, et al. Lynch syndrome: a primer for urologists and panel recommendations. J Urol. 2015;194(1):21-29. doi:10.1016/j.juro.2015.02.081

4. Rouprêt M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011;59(4):584-594. doi:10.1016/j.eururo.2010.12.042

5. Van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47(7):464-470. doi:10.1136/jmg.2010.076992

6. Hubosky SG, Boman BM, Charles S, et al. Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). BJU Int. 2013;112(6):813-819. doi:10.1111/bju.12008

7. Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17(9):1032-1041. doi:10.6004/jnccn.2019.0044

8. Metcalfe MJ, Petros FG, Rao P, et al. Universal point of care testing for Lynch syndrome in patients with upper tract urothelial carcinoma. J Urol. 2018;199(1):60-65. doi:10.1016/j.juro.2017.08.002

9. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology. 1999;116(6):1453-1456. doi:10.1016/s0016-5085(99)70510-x

10. Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol. 2013;63(2):379-385. doi:10.1016/j.eururo.2012.07.047

11. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23(3):437-449. doi:10.1158/1055-9965.EPI-13-1165

12. Lim A, Rao P, Matin SF. Lynch syndrome and urologic malignancies: a contemporary review. Curr Opin Urol. 2019;29(4):357-363. doi:10.1097/MOU.0000000000000639

13. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J Clin Oncol. 2013;31(24):3012-3018. doi:10.1200/JCO.2012.48.0988


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