Young patients rarely present with BC and there are multiple studies that indicate a good clinical disease course where patients present with solitary tumors and a low recurrence and progression rate. Since BC patients are monitored cystoscopically according to an intensive surveillance protocol, gaining more insight into the molecular pathways of BC tumors in young patients could define a subset of patients that can be monitored less frequently, hereby improving patient quality of life and reducing associated costs.
We presented a unique case of a 26-year-old male with multiple multifocal NMI bladder tumors recurring at a high frequency. After starting intravesical maintenance therapy with MMC the recurrence rate decreased and up to date the patient stayed recurrence free. Molecular analysis of the primary tumor revealed an S249C mutation in FGFR3
(Figure ) and overexpression of FGFR3 (Figure ). LOH on chromosome 9 was detected by MA and confirmed by the genome wide SNP array analysis. We also found other regions of loss and gain that are considered minor when compared to tumors of the same stage and grade (Figure ). There was no increased expression of TP53 (Figure ). Hence, this young patient appears to have the typical genetic changes found in older patients with NMI-BC. This implies that the patient could have a disease course comparable to older patients and warrants regular controls due to the risk of additional recurrences or progression. These findings combined with previous studies suggest that not only a patient's age, but also the molecular characteristics of the tumor determine the clinical disease course. Since it takes time to accumulate typical genetic changes involved in BC - e.g. mutations in FGFR3
and LOH on chromosomes 8, 9, 10, 11, 17- leading to tumor formation, most BC patients will present at an older age. Possible explanations are that older patients have a longer exposure time to BC associated exogenous risk factors and secondly that pathophysiological changes in elderly causing urinary stasis in the bladder due to urine retention lead to an increased exposure to carcinogenic substances. We suggest that this could be the reason why tumors of young BC patients mostly have few genetic alterations and may represent a biologically distinct group of tumors with an overall good clinical disease course (Figure ). This is in concordance with one of the few molecular studies on BC in patients <19 years (n = 14) that found no mutations in FGFR3
, no deletions on chromosome arms 9p, 9q or 17p, no MSI and only one mutation in TP53
]. On the other hand other clinical studies of patients <40 years demonstrate a disease course comparable to older patients with typical aggressive behavior in the young presenting with a primary muscle invasive tumor, but unfortunately no molecular analyses of these tumors have been performed [2
FGFR3 mutation detection on urinary derived DNA. FGFR3 mutation analysis of an FGFR3 tumor without a mutation (A), mutation S249C on tumor DNA (B) and urinary derived DNA (C) from the same patient used in panel B.
Figure 2 Protein expression levels of FGFR3 and TP53 in bladder tumor tissue. (A) Haematoxylin-Eosin staining of a papillary tumor. Original magnification ×20. (B) High levels of FGFR3 expression with a cytoplasmic and membranous patter. Original magnification (more ...)
Overview of copy number alterations for all chromosomes. Red: loss, green: gain.
Figure 4 Age related occurrence of BC due to exposure to carcinogenic factors and BC-associated genetic changes. (A) Young BC patients, age <20, with a low carcinogenic exposure having chromosomal stable tumors, no mutations in FGFR3 and TP53 and no loss (more ...)
Exogenous risk factors that could have contributed to BC in our patient are smoking, exposure to diesel exhaust and depleted uranium (DU). First our patients smoking status is 5.5 pack-years, which is known to be associated with an increased risk of BC. Secondly, a meta-analysis of BC and diesel exhaust exposure demonstrated a relative risk of 1.44 for occupations exposed to high diesel fume levels [14
]. Our patient worked as a driver of a diesel armed truck and was exposed to diesel exhaust fumes, working in a valley were the fumes were retained in a cloud of exploded ammunition. Lastly, although some believe that there is a link between exposure to DU and cancer development no hard evidence has been found to support this hypothesis. While evidence from Hiroshima data shows a latency period of 10-15 years to develop cancer this concerns an acute high-dose exposure and other studies were not able to demonstrate this link in Balkan veterans [15
]. On the other hand two studies by Miller et al
. demonstrated in vitro
tumorigenic transformation of osteoblasts when exposed to DU [17
Since Van der Aa et al
. demonstrated that specifically young patients perceive a cystoscopic investigation as burdensome this emphasizes the need for patient stratification [19
]. To determine whether a young BC patient should be monitored according to the standard follow-up protocol or can be monitored less frequently by cystoscopy, we propose to determine the FGFR3
mutation status of the primary tumor. One possibility is that the tumor will have few genetic changes and secondly that the tumor will have genetic changes comparable to those found in older patients (Figure ). Mutations in FGFR3
are tumor-specific and are not found in normal tissue, meaning that detection of a mutation in voided urine indicates the presence of tumor cells in the urinary tract. The results of the follow-up in time for our patient are indicated in Additional file 1
. We demonstrate that the S249C mutation in FGFR3
detected in the tumor was also detected in the urine (Figure ), indicating that the detected tumor cells were shed by the resected tumor. Our results demonstrate that urine cytology does not detect the tumor in two cases, which is in concordance with previous studies that demonstrate a low sensitivity of urine cytology for the detection of tumors of low stage and grade [20
]. Although this concerns just one patient, our results imply that patient monitoring by FGFR3
mutation analysis could be a feasible non-invasive method in the follow-up of young NMI-BC patients presenting with a mutation in FGFR3
and indicate that future research is required to investigate this.