The Diagnosis of Urological Neoplasm in Dialysis Patients – a Brief Review

1 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 “Carol Davila” Hospital of Nephrology, Bucharest, Romania 3 Department of Nephrology, “St. John” Emergency Clinical Hospital, Bucharest, Romania 4 “Dr. Victor Gomoiu” Children’s Clinical Hospital, Bucharest, Romania 5 “Prof. Dr. Theodor Burghele” Hospital of Urology, Bucharest, Romania Corresponding author: Merticariu Mircea, “Carol Davila” Hospital of Nephrology, 4th Grivitei Avenue, 1st District, 010731, Bucharest, Romania. E-mail: merticarium@gmail.com Abstract


INTRODUCTION
Th e ideea of this review arised from a small lot of patients recently evaluated by a joint team of urologists and nephrologists in one of the largest dialysis departments in Bucharest, Romania.We decided to review the existing medical literature in order to have a better grasp of the peculiarities regarding the incidence, symptoms, tumor markers and imaging studies for urological cancers in end stage renal disease (ESRD) patients undergoing dialysis.

INCIDENCE
In some available studies it is mentioned that patients with ESRD, undergoing hemodialysis or renal transplantation, have a higher risk of developing cancer, urological cancer being the most frequent type 1,2,3,4 .
One of the largest studies ever published was an international retrospective study conducted on aprox.800000 patients with ESRD on maintenance dialysis from Europe, Australia, New Zeeland and USA for a period of 14 years.Th e authors noted a 3.6-fold higher risk for kidney cancer and 1.5-fold increased risk for urinary bladder cancer compared to the general population.Furthermore, the authors noted a more pronounced risk in younger and female patients 5 .
Regarding renal cancer, the increased risk was greater for congenital disease, toxic nephropathy and miscellaneous conditions, the last two categories being mostly due to analgesic nephropathy and Balkan nephropathy 6 .Th e authors state that the increased risk for renal parenchymal cancers is related to the loss of renal function and its duration rather than to the primary renal disease or dialysis modality.Acquired cystic kidney disease (ACKD) alone has been considered a risk factor for cancer in ESRD patients 7 .
Another 7 year prospective nationwide study conducted in Korea followed the incidence of specifi c cancers in aprox.5000 patients.Athough the incidence of cancer was similar compared to that of the general population, the incidence of urinary tract carcinoma was higher in ESRD patients.Again, the authors note a higher risk for the female gender 8 .A similar Japanese study noted that the risk for Renal Cell Carcinoma (RCC) was higher than Transitional cell Carcinoma (TCC) in ESRD patiens on dialysis 8,9 .
In a 14 years study conducted in USA that observed the incidence of all types of cancer in a large group of over 35000 patients, the authors found that out of the 8 most common site-specifi c malignancies diagno-sed within 6 months from the initiation of dialysis, the incidence was highest for cancers of the kidney/renal pelvis and urinary bladder 10 .
Finally, in a large Taiwanese study following cancer incidence in patients on dialysis for at least 3 months, bladder cancer was the most frequent type of malingancy found in ESRD patients.Th e authors also noted that there was an increased incidence of overall cancers in young patients, particulary in the fi rst year of dialysis 11 .

SYMPTOMS
Screening of urinary neoplasia in hemodialysis patients is particulary challenging, one of the problems being the lack of signs and symptoms.
In 2012, Ofer Yossepowitch et.al correlated the clinical symptoms of patients diagnosed with bladder cancer which were on hemodialysis with disease outcome.During an 11 year follow-up, a total of 15 patients were included in the study.Th e most common clinical symptoms associated with urinary bladder carcinoma were hematuria and bloody urethral discharge 12 .Th e tumors detected were mostly large and multifocal.High grade urothelial tumors were detected in 73% of the patients 12,13 .
Th e most common symptoms noted in 73 Taiwanese patients with upper urinary tract TCC who underwent chronic dialysis were urethral bloody discharge and painless gross hematuria 14 .
A larger retrospective study reviewed aprox.1500 hemodialysed patients treated in a single Taiwanese hospital for 9 years; 26 patients presented with TCC.Th e most frequent symptom reported was gross hematuria (24 patients) followed by disuria (5 patients), fl ank pain (1 patient) and abdominal pain (1 patient).Th e most frequent location of the tumors was found in the upper urinary tract (54%), urinary bladder (18%), ureter (11%).Multifocal tumors were found in 27% of the patients 15 .

MARKERS
Markers are commonly used as screening tools to detect the presence of underlying neoplasia.Th ree of the most commonly used markers in detecting urological malignancies are the Prostate specifi c antigen (PSA), the Alpha-Feto Protein (AFP) and the Human Chorionic Gonadotropin (hCG).Th e authors reviewed the literature in order to fi nd out if dialysis has any eff ect on these markers.
Th e conclusion of a 3 year study published in 1995 by Morton et al., which followed the PSA values of 80 hemodyalised patients, was that dialysis does not aff ect the serum PSA values and that digital rectal examination (DRE) and serum PSA are equally eff ective in detecting underlying prostate cancer for this category of patients 16 .
Anothere study compared the stage of cancer at diagnosis in patients with ESRD with the one in the general population.Th e authors concluded that patients with ESRD were twice as likely to be diagnosed with a more advanced stage of prostate cancer partly due to lower use of PSA screening in this category of patients 17,18,19 .Furthermore, keeping in mind the high morbidity and mortality in dialysis patients it is advisable to reserve PSA screening for patients with a life expectancy of at least 10 years 17 .
Khairullah et.al stated in their study published in 2004 that routine screening using DRE and PSA was not sensitive enough to detect the disease and that PSA doubling-time improved the sensitivity and positive predictive value of prostate cancer detection 20 .
Finally, in a review published in 2014 the authors concluded that total PSA and free PSA serum levels can vary before and after hemodialysis, based on the type of membrane and dialysis modality used and that further studies are needed in order to determine the exact extent of these alterations 21,22 .Regarding AFP levels (commonly used for testicular cancer screening), the same authors concluded that the serum level is not infl uenced by ESRD or the type of dialysis 23,24 .As for hCG, this marker is excreted in urine, thus in patients with CKD and/or hemodialysis, there should be caution in interpreting it's values 25,26,27 .

IMAGING
Knowing that ESRD patients have a higher risk of developing RCC, regular imaging screening should be performed 28 .
One author recommends a screening protocol with computed tomography (CT) or ultrasound (US) every 3 years for all patients on dialysis and once a year for those with ACKD 29 .
Although ultrasound examination has been one of the most used screening tools for detection of RCC in dialysis patients, its accuracy may be challenged due to the pre-existing changes in ESRD kidneys regarding renal echogenicity, dimensions, contour and possible presence of hypertrophic tissue 28 .Other ultrasound limitations are represented by the possible mass eff ect of the hypertrophic tissue on the pyelocalyceal system which can simulate a renal neoplasm and also the inability to clearly distinguish between hemorrhagic cysts and RCC 30,31,32,33 .
ACKD is commonly observed in hemodialysis patients and it is related to the duration of chronic renal failure or dialysis 34,35 .Th e CT diagnosis of cancer in patients with ACKD can be diffi cult due to the marked deformation of the renal architecture 30 .One author has demonstrated that early enhanced helical CT is superior to the delayed enhanced CT in the detection of RCC in ACKD patients 36,37 .
Regarding MRI imaging with low dosages of ghadolinium, Holley et al. stated that although it is considered safe to use in patients with CKD, there is some concern about the association between sclerosing fi brosing dermopathy and ghadolinium exposure in these patients, particularly when hemodialysis is used for tracer removal 38 .
Another study group raised awareness about the possible association between nephrogenic systemic fibrosis and gadodiamide enhanced MRI imaging in renal failure patients.Based on their 13 case study, the authors decided to avoid its use in ESRD patients until further studies are conducted 39,40,41,42 .

CONCLUSIONS
Based on published data from current available literature it seems that patients undergoing dialysis have a higher risk of developing cancer than the general population and that urological malignancies (renal and urinary bladder cancers) tend to be more frequent in this group.
Th e most common symptoms associated with lower urinary tract neoplasia occuring in dialysis patients is gross hematuria and bloody urethral discharge.Th ese symptoms should raise suspicion and should prompt further investigations.
Although most markers used in the diagnosis of urological cancers remain unaltered after dialysis, careful interpretation is essential and most importantly, practicioners should integrate the results in the overall clinical context and adjust the therapy to the life-expectancy of these patients.
Imaging diagnosis of urological malignancies in ESRD patients can be diffi cult due to the modifi ed renal architecture or the presence of ACKD associated with ESRD and currently there is no 'perfect' imaging tool.
In conclusion, since there is a gross lack of peer reviewed information to clearly guide current clinical