This study indicates an increased risk of urothelial cancer of both the urinary bladder and the upper urinary tract (ureter and renal pelvis) in patients with Lynch syndrome carrying a germline MSH2
mutation. Furthermore, this study indicates that cancer of the urinary bladder, ureter and renal pelvis is also, though rarely, associated with MSH6
mutations. A causal relation between MSH2 deficiency and bladder cancer is likely: in the first place, because bladder cancers in these families often show MSI and/or absence of IHC staining of the MSH2 protein, just like upper urothelial tract cancer and colorectal cancer; in the second place, because of the presence of two MSH2
mutation families, each of which contained two first degree family members with bladder cancer, and with three of the bladder cancers diagnosed under the age of 50 (as illustrated in ). It is interesting that especially MSH2
mutation carriers are at increased risk of urothelial cancer, as observed in this cohort and in previous studies.2 12 16
The diversity in the function of the MSH2, MLH1 and MSH6 protein might be responsible for the variation in cancer risk. Environmental factors (eg, smoking status) may also affect the urologic tract cancer occurrence rates, but we do not have the necessary information to determine if this might contribute to the differences.
Pedigree of a Lynch syndrome family with two MSH2 mutation carriers with urinary bladder cancer. CRC, colorectal cancer.
In eight out of 21 patients with bladder cancer, this was their first cancer diagnosis, whereas at this stage five of them developed another Lynch syndrome associated cancer at an older age. Therefore, early diagnosis of Lynch syndrome may prevent development of a second primary cancer, especially colorectal cancer (CRC) by regular colonoscopy with polypectomy.26
The diagnosis of Lynch syndrome in healthy relatives may lead to prevention or early detection of cancer, which improves the prognosis.26
Thus bladder cancer, just like upper urothelial tract cancer, can be added to the Bethesda criteria21
and the Amsterdam II criteria,27
and lead to the clinical suspicion of Lynch syndrome. The occurrence of bladder cancer can be used in family history taking and molecular diagnostics to identify the families that are at risk of Lynch syndrome.
Cumulative risks of colorectal and endometrial cancer are within the ranges published by other studies.2–5 8 13 28 29
Bladder cancer risk observed in our cohort was significantly higher than that observed in previous studies.6 9 12 16 18
These studies differed from our study by: (1) type of risk that was calculated; (2) by type of population; and (3) whether or not the type of mutation was distinguished. The data from these studies are given in . Additionally the discrepancy in bladder cancer risk between our study and other studies may result from our systematic data collection approach (obtaining up-to-date information). This led to the discovery of nine new cases of bladder carcinoma, previously unrevealed with the standard procedure of a clinical geneticist taking the family history.
Overview of risk of bladder cancer in previous studies
Considering the high risk of urothelial tract cancer in MSH2
mutation carriers, a surveillance programme needs to be developed. At present various recommendations have been published. The present European guidelines for families with an MMR mutation include ultrasound and urinalysis every 1–2 years with patients from the age of 30 to 35 only in cases where upper urinary tract cancer runs in the family (two or more cases of UC).11
The American guidelines include urinalysis with cytology every 1–2 years with patients from the age of 25 to 35 for all family members with Lynch syndrome.30
Watson et al
proposed (unspecified) surveillance of patients starting with the age of 50, especially for families that carry mutations in MSH2
Although cytology is the superior marker in terms of specificity,31
Myrhoy et al
showed that the sensitivity of urine cytology in diagnosing asymptomatic upper urinary tract cancer in Lynch syndrome is approximately 30%. Therefore, cytology only is not a proper method of surveillance.32
The most important biomarker of urothelial cancer is macro- or microscopically haematuria, which occurs in 85% of patients with bladder cancer.33
Consequently, Koornstra et al
recommend annual surveillance for haematuria, by urinary dipstick, of all patients with Lynch syndrome, beginning at the age of 45 to 50.34
The recent use of sensitive transducers has improved imaging of the upper urinary tract and bladder by ultrasonography. It was shown to be as accurate in the detection of renal masses and bladder filling defects as intravenous urography and computed tomography scanning.35
Further studies are needed to develop an optimum early detection strategy concerning the appropriate interval, methods to be used, and patient groups to be included. Until then, we propose a combination of ultrasonography of the bladder and upper urinary tract, urinary cytology and urine sediment (erythrocytes) every 1–2 years. We recommend a surveillance programme for UC of the bladder and upper urinary tract for all MSH2
mutation carriers starting at the age of 40, which is based on the youngest Lynch syndrome patient with bladder cancer reported in the literature (age 40) and observed in our study (age 41).36
The top age limit of surveillance for UC can be similar to that of surveillance for colorectal cancer. Surveillance should not be limited to families with a history of UC, because in our study clustering of urinary tract cancer was only observed in five families, while 19 patients had a negative family history of urinary tract cancer.
In conclusion, our data suggest that in addition to upper urinary tract cancer, urothelial cancer of the urinary bladder is part of the Lynch syndrome tumour spectrum. Carriers of an MSH2 mutation are particularly at increased risk of urinary tract cancer including cancer of the bladder. In these cases we consider surveillance necessary.
Recommendations for urothelial carcinomas surveillance in Lynch syndrome
- Surveillance with a combination of ultrasound of the bladder and upper urinary tract, urinary cytology and sediment.
- In every MSH2 mutation carrier
- From age 40 and up
- Performed every 1–2 years