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Lynch syndrome and urologic malignancies

a contemporary review

Lim, Amya; Rao, Priyab; Matin, Surena F.a

doi: 10.1097/MOU.0000000000000639
CANCER GENETICS IN UROLOGIC PRACTICE: Edited by Todd M. Morgan and Brian Chapin

Purpose of review An overview of urologic malignancies in Lynch syndrome and the current state of research.

Recent findings Upper tract urothelial carcinoma (UTUC) is the third most common malignancy in Lynch syndrome. Establishment and utilization of a sensitive and practical screening method for Lynch syndrome in patients presenting with UTUC is overdue. Next-generation sequencing to evaluate for microsatellite instability (MSI) and detect mutations of mismatch repair (MMR) genes may be the future of Lynch syndrome screening. Epidemiologic data and molecular characterization suggest bladder urothelial carcinoma (BUC) and prostate cancer (PCA) as unrecognized components of Lynch syndrome. Small studies suggest that Lynch syndrome may predispose individuals to adrenocortical carcinoma. Testicular cancer literature focuses on characterizing MSI and MMR gene expression as it relates to chemotherapy sensitivity; outcomes suggest a potential avenue to investigate its relationship to Lynch syndrome.

Summary Patients with Lynch syndrome have an increased risk of urologic malignancies, including UTUC and likely BUC and PCA. BUC and PCA have a lower penetrance than UTUC for unknown reasons. Established Lynch syndrome-associated genitourinary tumors will necessitate the development of methods to diagnose Lynch syndrome in patients presenting with these malignancies, in addition to establishing screening guidelines for patients with Lynch syndrome-associated genitourinary tumors.

aDepartment of Urology

bDepartment of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to Surena F. Matin, MD, Department of Urology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1373, Houston, TX 77030, USA. Tel: +1 713 792 3250; fax: +1 713 794 4854; e-mail:

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Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition most commonly associated with an increased risk of colorectal and endometrial cancer. It is also associated with increased risk of cancers of the ovary, stomach, small bowel, hepatobiliary system, central nervous system, skin and urologic tract [1,2]. Lynch syndrome is a result of a mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM, which is a gene adjacent to MSH2 that when mutated, can cause the MSH2 gene to be inactivated. Mutations in these genes cause a defect in the proof reading system of DNA replication, which results in errors, most commonly in regions of short repeating sequences known as microsatellites, resulting in microsatellite instability (MSI). These mutations lead to the increased risk of the previously mentioned cancers that characterize Lynch syndrome. This review will focus on recent developments in Lynch syndrome as it relates to urologic malignancies. Current interest in the field focuses on screening approaches and methods for Lynch syndrome in patients who present with upper tract urothelial carcinoma (UTUC), if bladder urothelial carcinoma (BUC), prostate cancer (PCA) and adrenocortical carcinoma (ACC) should be included in the Lynch syndrome spectrum and how patients with Lynch syndrome be screened for urologic malignancies (Fig. 1).



Box 1

Box 1

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The most common urologic malignancy associated with Lynch syndrome is upper UTUC. UTUC is the third most common cancer in Lynch syndrome after colorectal and endometrial cancer. It is estimated that 1–5% of all UTUC may be in the setting of Lynch syndrome [3,4▪▪,5–7]. In patients with Lynch syndrome, there is a 14–22 times higher risk of developing UTUC than the general population [8,9].

Colorectal and endometrial cancers are the only malignancies routinely screened for Lynch syndrome through loss of MMR expression, MSI or for mutations in an MMR gene. The only recommendation for Lynch syndrome testing in UTUC is by the European Association of Urology, which proposes that UTUC patients with suspected Lynch syndrome undergo germline DNA sequencing; however, this may not be a good screening tool based on cost. In colorectal and endometrial cancer, screening approaches rely on the Amsterdam criteria (AMS) I/II, based on personal and family cancer history, tumor immunohistochemistry (IHC) for loss of MMR proteins and PCR to detect degree of MSI. Typically, MSI-high defined by having two or more of the five microsatellite markers with instability in the Bethesda panel [10] or MSI-intermediate, having one marker of instability, being the cutoff for most studies.

Metcalfe et al.[4▪▪] sought to determine if this same strategy would serve as a reliable point of care testing to screen for Lynch syndrome in patients with UTUC with no known history of Lynch syndrome. The study included 115 patients and found 13.9% meeting the criteria for possible Lynch syndrome and confirmed 5.2% with Lynch syndrome. AMSII and IHC criteria were sensitive enough to identify all patients suspected of Lynch syndrome. These data provide rationale for future prospective trials for Lynch syndrome screening methods for patients with UTUC.

Traditionally, MSI is identified using PCR-based methods and loss of MMR protein using IHC. Next-generation sequencing (NGS) has been utilized to assign an MSI sensor score which is determined through a computer-based algorithm using tumor and matched normal DNA to determine the percentage of unstable loci and may be more sensitive in detecting MMR loss or MSI than the PCR-based method [11,12]. Audenet et al.[13▪] looked at the genomic differences between UTUC and BUC to determine the relatedness of temporally distinct tumor by utilizing NGS. They also used NGS to assign MSI sensor scores and determine a mutational signature analysis to assess if these metrics could reliably identify Lynch syndrome-associated UTUC. Of the 12 tumors with an MSI at least 10, which they defined as being equivalent to MSI-H, 10 had a Lynch syndrome -associated germline mutation, one did not have consent for germline mutation analysis and one had a somatic Lynch-like MSI-high tumor. Of the 12 patients who had germline testing and likely had a mutation associated with Lynch syndrome, only 10 of them had an MSI at least 10, suggesting that an MSI cut-off of 10 may not be sensitive enough to detect every patient with Lynch syndrome. Mutational signature analysis for a predominant MMR/MSI signature only identified six of the 12 patients with Lynch syndrome. Although these data suggest that individually, these metrics are not sensitive enough to screen tumors for Lynch syndrome -associated germline mutations, it does introduce other molecular-based methods to screen for Lynch syndrome.

Recently, histopathologic features have been proposed as a marker of Lynch syndrome-associated UTUC. Intratumoral lymphocytes, presence of pushing borders [3], inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells [5] were some of the histopathologic features observed in tumors of patients with Lynch syndrome (Fig. 2). Although these are not pathognomonic for Lynch syndrome, it may be useful in combination with IHC for loss of MMR protein in identifying those at risk for Lynch syndrome. This is an area of continued research and will need to be further validated.



A cost-effective and reliable screening method is needed for Lynch syndrome in patients with UTUC. A combination of clinical history through the Amsterdam II criteria, IHC and molecular markers are the most likely candidates to screen for Lynch syndrome in UTUC based on current standards. MSI sensor scores and mutational signature analysis are promising new tools for Lynch syndrome screening that need to be trialed in more studies. Molecular subtyping, mutational analysis and further clinical data will aid in determining whether these tumors have a biologic basis for behaving differently from sporadic UTUC. Importantly, awareness by clinicians of the association of Lynch syndrome and UTUC is critical for patients and their families.

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The inclusion of BUC as Lynch syndrome-related malignancy is controversial. This is because of confounding factors such as seeding from the upper tract, environmental or other genetic factors [14]. Another complication factor is that studies evaluating urothelial cancers in Lynch syndrome often do not separate UTUC from BUC. From a molecular standpoint, a low frequency of MSI of 3–5% causes some speculation regarding its relationship to Lynch syndrome [15–18], although one study utilizing 52 markers in 32 BUC tumors reported an MSI-H rate of 28% [19]. However, MSI is not a sensitive assay for Lynch syndrome and studies have reported an increased BUC risk of 1–20% in Lynch syndrome patients [14,20–26].

Joost et al.[27] performed an analysis of 3235 mutation carriers and their first-degree relatives from the Danish HNPCC registry to determine the relationship between urinary tract malignancies, MSI, MMR mutations and Lynch syndrome. The cumulative risk estimate for BUC was 3.3% in men and 2.6% in women, with the highest risk in those who were carriers of an MSH2 mutation (4.4%) compared to MSH6 (1.7%) or MLH1 (2.2%), which was statistically significant. Only 20% of BUC tumors had MSI-H; however, 86% of BUC had loss of MMR protein expression. Together, these data support BUC as a component of the Lynch syndrome tumor spectrum. More recently, a retrospective review of 55 Japanese patients with Lynch syndrome treated at the Tokyo Metropolitan Cancer and Infectious Disease Center at Komagome Hospital demonstrated loss of MMR protein in five bladder cancer cases (one was not available for IHC) [22]. Four patients had MSH2 mutations and two had MLH1 mutations. One patient with an MSH2 mutation had BUC as the first diagnosed malignancy. Although this is a small study, it highlights the evolving data demonstrating a relationship between BUC, particularly those with MSH2 mutations.

These data highlight some of the growing evidence for an association between Lynch syndrome and BUC, more specifically in MSH2 carriers, perhaps providing a rationale for more aggressive screening in families with this mutation. Larger studies will help decrease confounding effects and help clarify whether or not BUC should be considered a Lynch syndrome-associated malignancy.

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PCA is the most common malignancy in men and the second leading cause of cancer deaths in the United States with an estimation of more than 31 000 deaths in 2019 [28]. Although some studies do not suggest a link between Lynch syndrome and PCA [29,30], several studies report an increased risk of PCA ranging from 2.1 to 4.87-fold in patients with Lynch syndrome [21,24,31–33].

The most commonly altered MMR gene in advanced PCA is MSH2 [34–36]. Guedes et al.[34] screened 1176 unique primary prostate carcinomas for loss of MSH2 expression and demonstrated a statistically significantly higher rate of MSH2 loss [8% in primary Gleason 5 cancers (9–10)] and neuroendocrine tumors (5%) compared to the 1% observed in other lower grades. Further, germline testing demonstrated that two cases (2% of primary Gleason 5 cancers) and one case (0.1% of primary Gleason 4 or less) of the 12 tested had a germline MSH2 inactivation, only one of which had a documented history of Lynch syndrome. The incidence of Lynch syndrome is potentially higher in this study as they only screened for one Lynch syndrome mutation.

Ryan et al.[37] performed a meta-analysis of 23 studies (six molecular studies, 18 risk studies) to evaluate risk in of developing PCA in patients carrying a DNA MMR gene mutation. The six molecular studies included 44 PCAs and demonstrated that 74% of PCAs were MMR deficient, which is equivalent to carriers having a 3.67-fold increase risk of PCA (95% confidence interval, 1.45–2.80). This was more common in MSH2 carriers; however, only one study was appropriately powered to make this conclusion. From the risk studies, there was an estimated 2.13-fold increase risk of PCA in carriers, although this was inconsistent among individual studies. Taken together, this meta-analysis supports at least the consideration of PCA in the Lynch syndrome spectrum of malignancies.

The Philadelphia Prostate Cancer Consensus Conference consisting of 71 experts from the United States, Canada, England and the Netherlands met in 2017 to discuss genetic testing for PCA [38]. On the basis of moderate-grade evidence, it was recommended to screen for MMR gene mutations in patients with PCA with a family history of Lynch syndrome or with two or more blood relatives with a cancer related to Lynch syndrome. In addition, men whose prostate tumor demonstrates mutations in MMR genes should undergo germline testing.

Although the Philadelphia Prostate Cancer Consensus made recommendations regarding who should be tested for germline MMR mutations, there are no clear guidelines for PCA screening patients with known Lynch syndrome. At this time, there does not appear to be a risk of developing PCA at an earlier age [31,37]; however, the data regarding more aggressive disease are mixed [31,34], therefore given the current state of data, it is difficult to make recommendations for screening in this population.

Taking recent molecular and epidemiologic data together, strong consideration should be taken to include PCA as a part of Lynch syndrome tumor spectrum. Although many PCA with MSI-high or absent MMR expression will harbor somatic mutations, the data suggest that a significant proportion will have associated germline inheritable mutations. Upon further data supporting the inclusion of PCA, future studies should focus on developing general PCA screening guidelines for patients with Lynch syndrome.

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ACC is rare with only 1–2 cases per million each year and is associated with a poor prognosis [39]. Although it is known to be part of the tumor spectrum of Li Fraumeni syndrome because of a TP53 mutation, its association with Lynch syndrome is less studied. Raymond et al.[40] identified and prospectively followed 94 patients with a diagnosis of ACC. Three (3.2%) were subsequently found to have germline mutations (MSH2, MLH1 or MSH6). Of the 135 patients from the retrospective cohort, two (1.5%) were identified, both with MSH2 mutations. Four tumors were available for analysis and interestingly did not demonstrate MSI, but did have a loss of MMR on IHC. Other studies include case reports of ACC in patients with Lynch syndrome and germline MSH2 mutations [41–44]. The rarity of this disease makes establishing a relationship to Lynch syndrome difficult, and will only be clarified with further studies. Routine screening recommendations cannot be made at this time; however, clinicians should maintain ACC in their differential in patients with Lynch syndrome with adrenal masses or stigmata of excess adrenal hormones.

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Testicular cancer is the most common malignancy in men between the ages of 15 and 44 in the United States [45]. Testicular cancer is currently not considered a part of the Lynch syndrome tumor spectrum, although there are reports of MSI and MMR deficiency in tumors. Most studies focus on the presence of MSI and MMR protein loss in testicular cancer as it relates to the clinical behavior of the disease. Although some studies suggest that MSI and loss of MMR proteins may be related to chemotherapy resistance, shorter time to or chance of recurrence [46–50], other studies demonstrated no association [51] or lack of or low frequency of MSI instability and/or loss of MMR protein expression in testicular tumors [52,53]. Although the data are mixed, it is likely still worthwhile to explore patients with chemoresistant or recurrent testicular cancer for a possible association with Lynch syndrome.

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Currently, UTUC is the only urologic malignancy that is definitively and widely accepted as part of the Lynch syndrome tumor spectrum, although emerging data support strong consideration of including BUC and PCA as well. The challenge in researching BUC and PCA is the apparent lower penetrance in Lynch syndrome, whereas there is high prevalence in the general population. Over 5% of UTUC may be associated with Lynch syndrome, therefore it is of utmost importance for the urologist to consider the possibility of a hereditary cause and refer for the appropriate screening. Even with BUC, PCA, ACC and testis cancers, the vigilant urologist can probably identify inheritable cases when a careful family history is obtained or clinical suspicion is raised. Although the relationship between these other urologic malignancies and Lynch syndrome is less well established, data continue to emerge and will inform future management in terms of recommendations for tumor tissue testing to screen for MSI, loss of MMR expression and germline testing for Lynch syndrome-associated mutations in addition to screening recommendations for these urologic malignancies in patients with Lynch syndrome.

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Financial support and sponsorship

This work was supported by the Eleanor and Scott Petty Fund for UTUC Research and the Monteleone Family Foundation for Research in Bladder and Kidney Cancer.

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Conflicts of interest

S.F.M. serves on the advisory board to Taris Biomedical, and consultant to QED. The remaining authors have no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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adrenocortical carcinoma; hereditary nonpolyposis colorectal cancer; Lynch syndrome; microsatellite instability; mismatch repair; prostate cancer; upper tract urothelial carcinoma; urothelial carcinoma

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