Special Considerations for Upper Tract Urothelial Carcinoma and Lynch Syndrome

(UroToday.com) The AUA’s Drug Development in non-muscle invasive bladder cancer (NMIBC) From Scientific, Regulatory, Clinician, and Patient Perspectives 2021 Virtual Meeting included a session on the treatment of non-muscle-invasive urothelial carcinoma of the upper tract and a presentation by Dr. Jennifer Taylor.

Dr. Taylor notes that the 2020 NCCN guidelines for Lynch Syndrome delineate the following criteria for a Lynch Syndrome Evaluation:

  • A patient with endometrial or colon cancer who is (i) 50 years or younger, (ii) has another Lynch Syndrome-related cancer, (iii) one first- or second-degree relative with Lynch Syndrome-related cancer under the age of 50, or (iv) two or more first- or second-degree relatives with Lynch Syndrome-related cancer of any age
  • History of a tumor with MMR deficiency (by PCR, IHC, or next-generation sequencing)
  • Family history (per NCCN aforementioned criteria)
  • Patient with high prediction modeling (PREMM5, MMRpro, MMRpredict)

The original clinical screening criteria system was the Amsterdam II criteria, which noted that patients had to have three relatives with HNPCC-associated cancer (i) at least one first-degree relationship, (ii) two generations, (iii) at least one relative diagnosed before the age of 50, (iv) exclusion of familial adenomatous polyposis, and (v) tissue pathologic confirmation. The revised Bethesda clinical screening criteria (to test colorectal carcinoma for MSI) includes individuals with colorectal carcinoma (i) diagnosed before the age of 50, (ii) metachronous colorectal carcinoma or other HNPCC cancer of any age, (iii) MSI-H histology by age 60, (iv) one or more first-degree relative with colorectal carcinoma and another HNPCC cancer, with a first diagnosis before the age of 50, or (v) two or more first or second-degree relatives with HNPCC cancer at any age. Dr. Taylor notes that contemporary screening criteria systems are available online1 taking into account patient information, first-degree relatives, and second-degree relatives. A greater than 5% probability of Lynch Syndrome would prompt further evaluation. The 2020 NCCN guidelines denote Lynch Syndrome-related cancers like colorectal, endometrial, gastric, ovarian, pancreatic, glioblastoma multiforme, urothelial, biliary tract, small intestine, and sebaceous adenoma/carcinoma. Genes mutated in Lynch Syndrome include the mismatch repair mutations MLH1, MSH2, MSH6, PMS2, and EPCAM (adjacent to MSH2). 

The original seminal article assessing the association of Lynch Syndrome and urologic malignancies was published in 1990.2 This study found a cumulative risk of 0.2%-5% for renal pelvis/ureteral malignancy for patients >80 years of age, noting that Lynch Syndrome may cause 1-5% of all upper tract urothelial carcinomas. Additionally, Lynch Syndrome was associated with a 2%-7% cumulative risk for bladder cancer for those >80 years of age and conferring a 2.4% lifetime risk. Finally, prostate cancer was associated with a 4.4%-11.6% cumulative risk for those >80 years of age among those with Lynch Syndrome, and an 11.6% lifetime risk.

The NCCN guidelines note that patients with colorectal and endometrial carcinoma should be screened based on (i) the Amsterdam criteria, (ii) tumor immunohistochemistry (MMR protein loss), or (iii) PCR to detect the degree of MSI. Regarding upper tract urothelial carcinoma screening, there is no standard recommendation from the NCCN, but that screening can be considered in those with a family history of upper tract urothelial carcinoma, and that annual urinalysis should start at age 30-35. The European Association of Urology recommends screening by DNA testing for those at risk for Lynch Syndrome. 

In 2018, Dr. Surena Matin’s group looked at universal point of care testing for Lynch Syndrome in patients with upper tract urothelial carcinoma, screening 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch Syndrome from 2013-2016.3 All patients were evaluated for family history using the Amsterdam I and II criteria, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Among the 115 patients, 16 (13.9%) screened positive for potential Lynch syndrome, and of these patients, 7.0% met Amsterdam II Criteria, 11.3% had a loss of at least one mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, nine completed genetic analysis, and counseling, and six were confirmed to have Lynch syndrome. All seven patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for Amsterdam II Criteria and at least a single mismatch repair protein loss while five of six had high microsatellite instability.

There are several treatment opportunities for Lynch Syndrome patients with advanced/metastatic disease, given that microsatellite instability of these patients leads to immune susceptibility via tumor-infiltrating lymphocytes and impressive response rates to immune checkpoint inhibitors. Among these patients, previous studies have suggested an objective response rate of 53% (complete response rate of 21%) for those treated with pembrolizumab, an objective response rate of 21% (median PFS of 14.3 months) for those with MMR-D/MSI-H colorectal carcinoma treated with nivolumab, and an objective response rate of 55% (OS at 12 months of 85%) among those with colorectal carcinoma treated with nivolumab plus ipilimumab.

Recently, there has been a push for cancer prevention in known patients with Lynch Syndrome. CAPP2 encompasses 43 centers worldwide, treating patients with 600 mg/day versus no intervention. Those receiving aspirin had a marked reduction in colorectal carcinoma and other Lynch-associated cancers at two years, but with less benefit in obese patients. This ongoing trial is comparing 100/300/600 mg/day. In updated, 10-year follow-up (n=861) analyses, there was a reduced rate of colorectal carcinoma (HR 0.65, 95% CI 0.43-0.97), with a reduction in all Lynch-related cancers, including a reduction in endometrial cancers.4 As follows is the time to first colorectal cancer and time to any Lynch Syndrome cancer in all CAPP2 study participants:


Dr. Taylor then highlighted several important posters discussing Lynch Syndrome previously present at AUA meetings. Hayashi et al. assessed upper tract urothelial carcinoma immunohistochemistry expression of MMR, demonstrating that 2/126 (1.6%) patients had loss of expression of one MMR gene. Fujii et al. assessed upper tract urothelial carcinoma sequencing and methylation array, noting that 6/102 (5.9%) patients undergoing nephroureterectomy had hypermutation and/or MMR gene alterations. Finally, Donahue et al. assessed urothelial carcinoma in patients with known Lynch Syndrome, noting 14 patients with bladder urothelial carcinoma or upper tract urothelial carcinoma. The average age at diagnosis for these patients was 52.2 years, 57% had bladder cancer, and five presented with bladder urothelial carcinoma as their first Lynch Syndrome malignancy. 

Dr. Taylor also highlighted notable posters presented at GU ASCO 2021 discussing Lynch Syndrome. Rao et al. presented on 538 cases of upper tract urothelial carcinoma undergoing next-generation sequencing plus immunohistochemistry, of which 3.9% had dMMR/MSI-H mutations. Notably, all cases had high tumor mutational burden. Andreev-Drakhlin et al. assessed 10 patients with dMMR/MSI upper tract urothelial carcinoma, noting that seven patients were treated with pembrolizumab, two with nivolumab, and one with atezolizumab. There was 100% PFS and OS at 15.5 months, the objective response rate was 90% and eight patients had a complete response. Furthermore, the median time to best response was only 4 months, and three patients ended treatment secondary to toxicity. 

Dr. Taylor concluded her presentation of Lynch Syndrome and upper tract urothelial carcinoma with the following take-home messages:

  • Lynch-associated urothelial cancer may be more common than previously known or understood
  • There is no routine screening recommended in the guidelines, however, Lynch Syndrome-based clinics may employ urinalysis and imaging in conjunction with screening for other malignancies. Furthermore, it has been shown that point of care testing strategies identified upper tract urothelial carcinoma in 1.5-2% of new cases of Lynch Syndrome
  • Localized stages follow similar treatment strategies as standard urothelial carcinoma
  • There are promising response rates to immune checkpoint inhibitors, which are similar to conventional urothelial carcinoma, and there are potential opportunities for multimodal treatment

Presented by: Jennifer Taylor, MD, MPH, Baylor, College of Medicine, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md during the 4th annual bladder cancer translational research meeting, co-sponsored by the American Urological Association (AUA) and the Johns Hopkins Greenberg Bladder Cancer Institute, March 4-6, 2021


  1. Lynch syndrome prediction model MLH1, MSH2, MSH6, PMS2, and EPCAM gene mutations
  2. Lynch HT, Ens JA, Lynch JF. The Lynch syndrome II and urologic malignancies. J Urol. 1990 Jan;143(1): 24-28. 
  3. 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 Jan;199(1):60-65. 
  4. Burn J, Sheth H, Elliott F, et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: A double-blind, randomized, placebo-controlled trial. Lancet. 2020 Jun 13;395(10240):1855-1863.
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