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Abbreviations
HNPCC

hereditary non-polyposis colorectal cancer

MMR

mismatch repair

UTC

urinary tract cancer

UUT-UCC

upper urinary tract urothelial cancer.

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common hereditary cause of colorectal cancer, accounting for up to 7% of such tumours. Patients with HNPCC typically present 20 years earlier than with sporadic forms. It is inherited in an autosomal dominant fashion and predisposes individuals to a range of cancers in addition to colorectal [1]. Upper urinary tract urothelial cancer (UUT-UCC) is part of the ‘classic’ spectrum of HNPCC disorders; affected individuals have a 6% lifetime risk of developing UUT-UCC (22 times the risk seen in the general population) [2]. Despite this clear association, there are no well defined strategies in common use for the detection and surveillance of UUT-UCC in patients with Lynch syndrome.

The genetic anomaly is a mutation in one of the DNA mismatch repair (MMR) genes, ML1, MSH2, PMS2 and MSH6 [1]. Thus, the ability to repair mutations (instability) at the nucleotide (microsatellite) level is lost, and genetic mutations and cancer may ensue. Whilst UUT-UCCs share environmental causes with bladder cancers, tumours in the renal pelvis and ureters are commonly associated with high levels of microsatellite instability rarely found in their lower tract counterparts [3]. Therefore, members of Lynch syndrome families are at a higher risk of UUT-UCC than the general population, but not of bladder tumours [2].

A recent pooled analysis from four HNPCC research centres in the USA and Northern Europe studied 6041 members of 261 families and found an 8.4% risk of developing urinary tract cancer (UTC) by the age of 70. This risk was only reduced to 6% once bladder cancers were excluded [4]. The highest risks were for carriers of the MSH2 mutation: 28% for males and 12% for females. These observations are consistent with prior reports of high rates of UUT-UCC amongst HNPCC families, with tumours generally presenting in those over the age of forty years [4].

PRESENTATION TO THE UROLOGIST

  1. Top of page
  2. PRESENTATION TO THE UROLOGIST
  3. PROPOSED RISK STRATIFICATION
  4. FUTURE
  5. CONFLICT OF INTEREST
  6. REFERENCES
  7. Appendix

Broadly, there are four different scenarios a urologist may face in the context of Lynch syndrome related UUT-UCC. Three of these occur when a urologist is asked to offer screening and/or surveillance for patients with Lynch syndrome, and the fourth is when a urologist treats a young patient with a UUT-UCC and is concerned that this maybe in fact the first presentation of HNPCC.

Current guidelines regarding screening are variable and based upon opinion rather than evidence. Recommendations published in JAMA were for one to two yearly urine analysis with cytology, beginning at age 25 to 35 years [5]. Although there are no data to support the efficacy of this approach in this population, and insufficient evidence to determine the benefits and harm, the test is non-invasive and relatively inexpensive, and has therefore been accepted by patients and healthcare practitioners. In a retrospective study of screening for urinary tract cancer in a Lynch syndrome population, the sensitivity of urine cytology was reported as low at 29%[6]. Of the seven patients under surveillance who were diagnosed with UUT-UCC, two were discovered via cytology, and the remainder following evaluation for symptoms. Fourteen positive cytology results in this study had been ignored.

The collaborative group of European experts in hereditary gastroinstestinal cancer recommend screening of individuals with a family history of UUT-UCC with one to two yearly urine analysis, cytology and abdominal ultrasound [7]. More recently, annual surveillance for haematuria with dipstick testing and microscopy has been suggested [8].

Newer urinary-based markers are now available, including NMP22 and UroVysion. Although NMP22 has not been formally tested in patients with Lynch syndrome, it has been shown to have superior sensitivity to cytology in the detection of urothelial cancer [9].

PROPOSED RISK STRATIFICATION

  1. Top of page
  2. PRESENTATION TO THE UROLOGIST
  3. PROPOSED RISK STRATIFICATION
  4. FUTURE
  5. CONFLICT OF INTEREST
  6. REFERENCES
  7. Appendix

Surveillance should begin at the age of forty years, but if a family member had previously developed an UUT-UCC before the age of forty, screening in relatives should begin five years earlier than the age of diagnosis. In addition, it is essential that patients with Lynch syndrome are educated regarding the symptoms and risks of urinary tract cancer so that if they develop loin pain or haematuria they seek urgent referral for urological evaluation. We propose a surveillance strategy that takes into account risk stratification of individuals concerned (see Table 1).

Table 1.  Proposed risk stratification and surveillance strategies for Lynch syndrome patients
Risk groupDescriptionSurveillance strategy
  1. UTC, urinary tract cancer.

LowNo personal or family history of UTC, or MSH2 mutationAnnual urine cytology, NMP22 and dipstick
IntermediateFamily history of urothelial cancer or MSH2 mutationAs for low risk and renal tract ultrasound
HighPrior personal history of urothelial cancerAs for low risk plus annual contrast CT study and flexible cystoscopy. More frequent surveillance after diagnosis may be required, depending on histological features

Low risk: Patients with Lynch syndrome but no personal or family history of UUT-UCC, and whose mutation is not in MSH2, should be screened annually with urinary dipstick for blood, urinary cytology and urinary NMP22 with positive results prompting upper tract imaging.

Intermediate risk: Patients with Lynch syndrome and a family history of UUT-UCC or MSH2 mutation should be screened in the same way as low-risk patients, with the addition of annual renal ultrasound.

High risk: Patients with a personal history of UUT-UCC in the context of Lynch syndrome should be screened in the same way as low-risk patients, with the addition of annual contrast studies and cystoscopy to detect bladder tumours resulting from seeding from previous upper urinary tract tumours.

It is important to note that many patients will be under radiological surveillance, often with CT, having had prior colorectal cancer, so that surveillance strategies may be modified to optimize information from imaging, whilst minimizing ionizing radiation exposure.

The fourth group of patients to consider are young patients with an UUT-UCC but no known diagnosis of Lynch syndrome. These individuals must have a detailed family history taken. If the Amsterdam II criteria for clinical diagnosis (see Appendix) are met then prompt referral to a geneticist and either a colorectal surgeon or gastroenterologist is appropriate [10]. Also, tissue from an UUT-UCC presenting in a patient under the age of 60 years with no previous history of bladder cancer should be screened for microsatellite instability [11].

FUTURE

  1. Top of page
  2. PRESENTATION TO THE UROLOGIST
  3. PROPOSED RISK STRATIFICATION
  4. FUTURE
  5. CONFLICT OF INTEREST
  6. REFERENCES
  7. Appendix

It is important that urologists are aware of the need to initiate the diagnostic process for Lynch syndrome patients. This will allow appropriate genetic counselling of family members and screening and surveillance protocols to be instigated. At present, the most effective and safe surveillance protocols are unknown. Collaborative national audit will allow urologists to pool experience and shape optimal strategies for the future.

REFERENCES

  1. Top of page
  2. PRESENTATION TO THE UROLOGIST
  3. PROPOSED RISK STRATIFICATION
  4. FUTURE
  5. CONFLICT OF INTEREST
  6. REFERENCES
  7. Appendix

Appendix

  1. Top of page
  2. PRESENTATION TO THE UROLOGIST
  3. PROPOSED RISK STRATIFICATION
  4. FUTURE
  5. CONFLICT OF INTEREST
  6. REFERENCES
  7. Appendix

Revised International Group on HNPCC (Amsterdam II) clinical criteria for Lynch syndrome. Vasen et al. [10]

  • 1
    There should be at least 3 relatives with an HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis).
  • 2
    One should be a first-degree relative of the other 2.
  • 3
    At least 2 successive generations should be affected.
  • 4
    At least 1 should be diagnosed before age 50.
  • 5
    Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if any.
  • 6
    Tumours should be verified by pathological examination.