Urine Markers for Urothelial Bladder Cancer

Urothelial cancer refers to cancer of the lining of the urinary system and is most common in the bladder (rather than the kidney or ureter).  The modern, standard evaluation of a patient with suspicion of urothelial cancer involves axial imaging of the upper tract and bladder with an associated cystoscopy and urinary cytology.  A number of tests have been developed to supplant or act as adjuncts to the standard urothelial bladder cancer evaluation.  However, the current regimen of cystoscopy and urine cytology will detect 90% of urothelial bladder cancers.  This blog will review some of the common alternative urinary markers for bladder cancer used in practice.

Urinary cytology is the microscopic examination of cells found in the urine.  Cytology was first developed by Papanicolaou in 1945 and remains the gold standard urine test for the evaluation of suspected malignancy.  The sensitivity (meaning a negative test rules out disease) ranges from 40-60%, however the specificity (a positive test indicates cancer) is high, ranging from 94-100%.  The sensitivity and specificity of a urinary cytology depends on the tumor grade, tumor stage, the number of samples evaluated and the experience of the cytopathologist who evaluates the sample.  In addition, instrumented samples (i.e. from a bladder wash during cystoscopy) have a higher yield and better sensitivity that voided urine.[1]

Urinary cytology demonstrating cancer cells.
From http://www.pathologypics.com/PictView.aspx?ID=106

FISH stands for Fluorescence in situ Hybridization and refers to a technique where fluorescently-labeled DNA probes are designed to bind to intranuclear chromosomes (the genetic material of cells). While they can be used for a variety of cancers, FISH probes have been developed to look for common genetic abberations in bladder cancer including aneuploidy of chromosomes 3, 7, 17 and homozygous loss of 9p21.

Compared to urinary cytology, the sensitivity and specifity are 79% and 70% respectively.  FISH is highly dependent on an experienced laboratory to process and interpret the results of each test, however has been demonstrated to have a sensitivity dramatically improved when compared to urinary cytology.  Importantly, the sensitivity of FISH improves with increasing grade and stage of bladder tumors.  In some patients, FISH can provide confidence that no cancer is present.  However, false positive tests are relatively common and may indicate a “precurrence” of cancer or genetic abnormalities that exist in the normal urothelium.  The role of FISH in the everyday management of bladder cancer is not well-defined and utility may vary by practitioner.[2-4]

NMP-22 (Nuclear Matric Protein) is a molecule preferentially shed into the urine by bladder cancer cells to that NMP22 levels are, on average, 20x higher in patients with bladder cancer than those without cancer.  Unfortunately, the cutoff values for an abnormal NMP22 are not well established and a higher NMP22 level does not correlate to worse grade or stage of disease.  The sensitivity and specificity of NMP22, using a cutoff of 10units/mL, are reported to be 49% and 87% respectively.  The sensitivity does improve for higher stage tumors.  However, false positives have been noted in patients with active urinary tract infections and hematuria.[5-7]

A number of other promising markers are in development but are not clinically available for most patients.  These include tests like Lewis Blood Group Antigen X which is absent in normal cells and present in urothelial cancer cells of the bladder.[8]  CK20 and CYFRA21.1 are proteins found in the cytoskeleton of bladder cancer cells and can be detected by protein or RNA analysis of the urine.[9] Metabolomics is a promising avenue for discovery, where metabolites in the urine can vary between patients with and without cancer.  Preliminary studies demonstrate varying metabolite patterns for patients with and without cancer, however no test has proven superior to cystoscopy and cytology as of yet. 

[1] Volpe A, Racioppi M, D'Agostino D, Cappa E, Gardi M, Totaro A, Pinto F, Sacco E, Marangi F, Palermo G, Bassi PF.  Bladder tumor markers: a review of the literature. Int J Biol Markers. 2008 Oct-Dec;23(4):249-61.

[2] Sarosdy MF, Schellhammer P, Bokinsky G, Kahn P, Chao R, Yore L, Zadra J, Burzon D, Osher G, Bridge JA, Anderson S, Johansson SL, Lieber M, Soloway M, Flom K.  Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer. J Urol. 2002 Nov;168(5):1950-4.

[3] van Rhijn BW, van der Poel HG, and van der Kwast TH: Urine markers for bladder cancer surveillance: a systematic review. Eur Urol 2005; 47: pp. 736-748

[4] Yoder BJ, Skacel M, Hedgepeth R, et al: Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings. Am J Clin Pathol 2007; 127: pp. 295-301

[5] Atsu N, Ekici S, Oge OO, et al: False-positive results of the NMP22 test due to hematuria. J Urol 2002; 167: pp. 555-558

[6] Grossman HB, Soloway M, Messing E, et al: Surveillance for recurrent bladder cancer using a point-of-care proteomic assay. JAMA 2006; 295: pp. 299-305

[7] Keesee SK, Briggman JV, Thill G, and Wu YJ: Utilization of nuclear matrix proteins for cancer diagnosis. Crit Rev Eukaryot Gene Expr 1996; 6: pp. 189-214

[8] Sheinfeld J, Reuter VE, Melamed MR, et al: Enhanced bladder cancer detection with the Lewis X antigen as a marker of neoplastic transformation. J Urol 1990; 143: pp. 285-288

[9] Ramos D, Navarro S, and Villamon R: Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder. Cancer 2003; 97: pp. 1876-1883

Historical Contribution: 1954, DeKlerk, Scott & Scott, Renal Transplantation

1954
de Klerk JN, Scott HW, Scott WW. Renal Homotransplantation: I. The Effect of Crotisone on Transplant; II. The Effect of the Transplant on the Host. Annals of Surgery. 1954;140:5:711-19.


The first kidney transplant was performed in 1950, although the kidney was rapidly rejected as no immunosuppressive therapy was available. The first successful kidney transplant was performed in 1954 at the Brigham Hospital in Boston, by a team led by Dr. Joseph Murray (who later was awarded the Nobel Prize). This transplant was performed between a set of identical twins, eliminating rejection and the need for immunosuppression. It would take another decade before the discovery and perfection of tissue typing and the immunosuppressive regimen needed for a successful transplant between two unrelated individuals.

In the early 1950's, surgeons were still working to overcome the technical challenges of the disease – reinstituting blood supply to the kidney in a timely and functional manner. Working in models of autotransplantation (moving a kidney from its natural resting place to another abdominal location in the same subject), a number of investigators were unable to perform an operation that resulted in a well-functioning kidney that concentrated urine, excreted waste (urea) and resorbed electrolytes efficiently. Based on animal literature suggesting that adrenal insufficiency due to physiologic stress at the time of transplant led to the rapid decline of the animal after transplant; deKlerk, Scott and Scott sought to investigate the use of steroids (cortisone) at the time of transplant to supplant the adrenal insufficiency.

In a simultaneous dog experiment, where kidneys from a pair of dogs were exchanged, the researchers examined the use of daily cortisone (10mg/kg) on kidney function and a variety of blood and urine tests. The renal allografts were noted to make urine with a low specific gravity, increasing proteinuria and pyuria – consistent with prior studies where the transplant failed to work. In addition, the ureters were noted to become gray, slough and obstruct. In all animals, the transplants failed and the animals died of renal failure – with the longest living 21 days. The concepts of rejection were not well elucidated during this time period, however the transplanted kidneys were noted to have "progressive small round cell infiltration," cytoplasmic vacuolization, desquamation and loss of tubular architecture. Interestingly, the longest living animal, which was given cortisone, did not have the microscopic appearance seen in the other animals – indicating that the cortisone may have had a beneficial influence on graft function in this animal.

In the second part of the experiment, the authors looked at a variety of blood and urine tests. They demonstrated a rapid drop in eosinophil counts (eosinopenia), serum sodium levels, and rising potassium levels (see Figure). The eosinopenia was indicative of the mounting immune response – a phenomenon the authors were not aware of. The electrolyte imabalances were secondary to failing transplants.

 
The authors blamed the graft failures on the "severe stress which the act of renal homotransplantation produces in the animals." And felt that the addition of cortisone could "dampen" the effect on the adrenal before surgery.  

This manuscript offers a fascinating view of the state of renal transplantation in the early 1950's.



To read the entire manuscript: follow the link above, visit the Centennial Website or click here.


 
HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Basics of Renal Failure and Acute Kidney Injury

Acute kidney injury (AKI), previously known as acute renal failure, is a rapid reduction in kidney function that can represent a spectrum of injuries that involve failure to maintain fluid, electrolyte and acid-base balances. A variety of patients suffering from a variety of medical conditions can develop AKI. Patients with urological issues often experience AKI as a result of their disease, or occasionally treatments thereof. This blog will review the basics of AKI for urological patients.

Acute Kidney Injury Definitions

The hallmark of AKI is a rising creatinine value in the blood. Creatinine is a protein byproduct of muscle metabolism created at a constant rate by each individual and filtered by the kidneys at a constant rate. Decreases in kidney function lead to a rise in serum creatinine values (as the protein is not being released into the urine as readily). In general, a normal creatinine value for the average person is 1mg/dL and a 50% decrease in the filtering ability of the kidney results in a doubling of serum creatinine (see figure).

Campbell-Walsh Urology, 10th edition. Chapter 3: Evaluation of the Urologic Patient:
History, Physical Examination, and Urinalysis

The basic features of AKI are a rising serum creatinine and decreasing urine output. A number of stringent definitions have been created by nephrologists and other physicians to identify and risk-stratify patients with AKI. One such definition, created by the KDIGO (Kidney Disease: Improving Global Outcomes Research Group)[1] includes any of the following:

• An increase in serum creatinine of 0.3mg/dL or greater in a 48 hour period
• An increase in serum creatinine from baseline of 1.5x or greater within a week's time period
• Urine volume <0.5mL/kg/hour for 6 hours

Acute Kidney Injury Incidence

It is estimated that 2-5% of all patients admitted to a medical or surgical hospital unit have or will develop AKI. That number increases to 36% of ICU (Intensive Care Unit) patients, of whom 20% will progress to need renal replacement therapy (i.e. dialysis).[2]

For urological patients, many surgeries affect the urinary system and kidney surgeries have an important influence on short- and long-term kidney function. The incidence of AKI following partial nephrectomy (removing a portion of the kidney involving a tumor) is approximately 3.6%. However, looking at patients with normal pre-operative renal function, the incidence of AKI is less than 1%. For patients with existing renal disease, the risk of AKI rises from 6.2% (if CKD, chronic kidney disease, stage 3) to 34% (CKD stage 4).[3]

It should be mentioned that a rising creatinine after surgery is very different from a rising creatinine due to a medical illness or injury. Future blogs will address this important distinction.

 

Implications of Acute Kidney Injury 

AKI often results from a transient insult to the kidneys and will recover when that insult is corrected or treated (a future blog will cover the common causes of AKI). Most patients will recover from AKI without any residual or long-term deficits in kidney function or health. However, according to one study, an increase of 0.5mg/dL in serum creatinine can result in:

• 6.5 fold increase in odds of death
• 3.5 day increase in length of stay
• $7500 in excess hospital costs [3]

Therefore, prevention and awareness of AKI are important considerations for patients undergoing urological surgery. Stay tuned for future blogs regarding kidney failure as it relates to urologic patients.

 

 
[1] KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements. VOLUME 2 | ISSUE 1 | MARCH 2012. http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO%20AKI%20Guideline.pdf

[2] Ostermann M and Chang RS. Crit Care Med 2007; 35 (8): 1837-43.
[3] Lane BR, Babineau DC, Poggio ED et al. Factors predicting renal functional outcome after partial nephrectomy. J Urol 2008; 180 (6): 2363-2369.
[4] Chertow GM et al. J Am Soc Nephrol 2005; 16 (11): 3365-3370.

Classic Manuscripts in Urology: Neoadjuvant Hormones Prior to Radical Prostatectomy

With the emergence of prostate specific antigen (PSA) testing in the late 1980's and 1990's, the incidence of prostate cancer, specifically localized prostate cancer, increased dramatically. While the proportion of patients with localized treatment increased, a significant proportion of patients harbored cancer that extends beyond the prostatic capsule (pT3). Patients with disease outside of the prostate gland were known to be at higher risk for PSA recurrence, metastasis and death from prostate cancer. It was also know that advanced and metastatic prostate cancers could be treated with androgen deprivation therapy (ADT) – which could create a dramatic decrease in PSA level, metastases and prostate gland size (if present). It was therefore hypothesized that neoadjuvant (treatment before surgery) ADT could consolidate prostate cancers and facilitate a more complete, "better" surgical resection. 

 A number of urologists employed neoadjuvant ADT and retrospective analyses of these patients confirmed that the prostate would shrink under the influence of castration and hinted that the incidence of positive surgical margins may be decreased. Therefore a number of prospective, clinical trials were designed to investigate the role of neoadjuvant ADT, opened in the early 1990's and were published within a few years of each other. The results of those trials offer level I evidence regarding the use of neoadjuvant ADT still used today.

 
Soloway MS, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol. 1995 Aug;154(2 Pt 1):424-8.

Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A; Lupron Depot Neoadjuvant Prostate Cancer Study Group. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002 Jan;167(1):112-6.

 
The Lupron Depot Neoadjuvant Prostate Cancer Study Group led by Dr. Mark Soloway, MD, was the largest, prospective study of the time to investigate neoadjuvant ADT. Three-hundred three patients were randomized to radical prostatectomy or radical prostatectomy after 3-months of ADT with 7.5mg lueprolide acetate depot. All patients had biopsy-proven cT2b (able tumor occupying more than half of 1 lobe in a mobile gland) prostate cancer. All patients underwent radical prostatectomy with a consistent lymph node dissection template and all pathological specimens were analyzed in the same fashion according to protocol.

While the radical prostatectomies performed after ADT were rated as more difficult by the surgeons involved, there were no differences in blood loss, operative time or blood transfusion between the groups; and the surgery only group had a higher rate of rectal and ureteral injuries! With regard to oncologic outcomes, there were a number of important outcomes noted in the initial study:

• There was no difference in rates of patients with seminal vesical invasion or positive lymph nodes in either group.
• The neoadjuvant ADT group demonstrated:
  • decreased prostate volume/weight
  • decrease in preoperative PSA
  • less extraprostatic extension
  • a lower rate of positive surgical margins (18% vs. 48%, P<0.001)
    • specifically, rates of urethral margin involvement were lower
  • increased rate of Gleason upgrading to high-risk (8-10) disease
• In the neoadjuvant ADT group 29% of the patients had positive surgical margins, positive seminal vesicles or positive lymph nodes compared to 57% in the radical prostatectomy alone group (P<0.001).

Importantly, the follow-up study with 5-years of data demonstrated no difference in biochemical (PSA) recurrence rates, leading the authors to conclude:

"Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year follow-up does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated."

To explain this phenomenon, the authors demonstrated that biochemical (PSA) recurrence rates were, as expected, higher in patients with positive surgical margins. However, for patients undergoing neoadjuvant ADT, the biochemical recurrence rates were nearly double for patients with negative margins (33% vs. 17%) – indicating that ADT exerted a pathological effect that did not alter the biology of the disease. Explanations included that the lower rate of positive surgical margins may have been an artifact of ADT, making prostate cancer appear to be clear of the margin under hemaotxylin and eosin staining while it may, in fact, still be present at the border of the resection. Alternatively, ADT may have "pulled" prostate cancer back into the specimen leading to lower rates of positive surgical margins, but did not change the ability of that cancer to escape the gland.

 
Take home: This study confirmed the findings of other neoadjuvant ADT trials [1-3] that neoadjuvant ADT decreased the rates of positive surgical margins at the time of radical prostatectomy but did not influence long-term biochemical recurrence rates. This work is cited as the seminal work putting the "nail in the coffin" of neoadjuvant ADT before radical prostatectomy.



[1] C.C. Schulman, F.M.J. Debruyne, G. Forster, et al. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in 3N0M0 prostate cancer Eur Urol, 38 (2000), p. 706
[2] G. Aus, P. Abrahamsson, G. Ahlgren, et al. Hormonal treatment before radical prostatectomy: a 3-year followup J Urol, 159 (1998), p. 2013.

[3] F. Meyer, L. Moore, I. Bairati, et al. Neoadjuvant hormonal therapy before radical prostatectomy and risk of prostate specific antigen failure. J Urol, 162 (1999), p. 2024.

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic. 

Quality of Life after Surgery for Bladder Cancer

The treatment of muscle-invasive urothelial bladder cancer (MIUBC) often involves radical cystectomy (removal of the bladder) and reconstruction of the urinary system. Removing a major urological organ and reconstructing the urinary system can have major impact on the quality-of-life of patients both in the immediate post-operative period and long-term as they become survivors of the disease. This blog will review the current understanding of quality-of-life (QOL) after cystectomy and urinary reconstruction.

DIFFICULTIES ASSESSING QOL IN THE BLADDER CANCER POPULATION

Determining QOL can be difficult for patients undergoing major cancer surgeries. Many cancers and subsequent operations do not have questionnaires designed specifically to address the issues of a patient recovering from that disease and surgery. Bladder cancer and radical cystectomy is no exception. Determining the important questions to ask a patient with bladder cancer who is undergoing surgery can be challenging. In addition, there are a variety of urinary diversions offered to patients undergoing radical cystectomy including:

• Incontinent, Ileal Conduit (or other bowel segment conduit)
• Continent, Catheterizable Reservoir (i.e. Indiana Pouch, Koch Pouch, etc.)
• Orthotopic Neobladder - reservoir attached to the native urethra

Ileal conduit (left); Continent, Catheterizable Reservoir (Indiana Pouch, middle);
Orthotopic Neobladder (right)

Each urinary reconstruction carries different risks and benefits, and, in general, is offered to very different groups of patients. In general, older, sicker patients are often only offered an incontinent conduit; while neobladders are more common in younger, healthier patients. Creating a QOL questionnaire that address the concerns of each patient group can be challenging and frankly, does not exist.

TIMING OF QOL

Inherent to all cancer operations, patients must undergo a period of recovery which can be challenging both physically and emotionally. Knowing when to evaluate QOL relative to surgery date may give differing outcomes at different times for different patients. For instance, a patient who is slow to recover may have a worse QOL shortly after surgery when compared to a patient who recovers differently.  If they have different urinary diversions, parsing out QOL related to recovery and urinary diversion can be difficult.

It is known is that levels of psychological distress decrease significantly 1 month after surgery compared to preoperative levels. One study demonstrated that 45% of patients demonstrated psychological distress prior to cystectomy, which decreased to 34% one month after surgery and included significant improvements in general distress, depression and anxiety.[1] While recovery may affect QOL and vary from patient to patient, it is also demonstrated that psychological and health-related QOL stabilizes at about 12 months following radical cystectomy.[2]

From Kulaksizoglu etal. EurUrol, 2002 [2].

QOL AFTER SURGERY

Health and body image are two of the biggest concerns for patients facing radical cystectomy and urinary diversion. Family relationships, general health and finances are the biggest determinants of QOL following surgery for an individual.[3] 
Much emphasis has been placed on the QOL as related to different urinary diversions. Most patients assume that an incontinent diversion (conduit) will lead to an adverse QOL compared to a continent diversion (catheterizable reservoir or neobladder). However, each diversion has a different subset of complications and each patient group has different priorities that determine their QOL. In addition, most surgeons (and therefore researchers) do not routinely perform all diversions and have a preference for their patients. Importantly, no urinary diversion has been demonstrated to be superior to another with regard to QOL.

ILEAL CONDUIT COMPARED TO CONTINENT RESERVOIR

One of the only long-term study comparing ileal conduit to a continent reservoir demonstrated that QOL was good in all long-term survivors of bladder cancer. In general, all patients were satisfied with their diversion and had adapted well socially, physically and psychologically; and the type of urinary diversion does not appear to be associated with differential quality of life.[4] Another study demonstrated that, while patients with a continent reservoir had enhanced QOL regarding the stoma, travel and sleeping habits; they were bothered by night time self-catheterization.[5]

ILEAL CONDUIT COMPARED TO ORTHOTOPIC NEOBLADDER

In one study of 102 patients, neobladder patients were more able to adapt to their new life and had a better QOL with regard to self-confidence, rehabilitation; and restoration of leisure, professional, travelling, and social activities.[6] However other studies indicated that the QOL differences between neobladder and ileal conduit are non-existent or marginal at best, highlighting that the younger age and improved health in general of neobladder patients may account for the small differences in QOL.[7,8]

Results of individual SF-36 Questionnaire domains. GH, general health.
HC, health change. PF, physical functioning. PH, physical health.
EH, emotional health. SF, social functioning. Pain, overall pain.
Energy, energy/fatigue level. EWB, emotional well-being.
Asterisk indicates domains that significantly favored patients
with neobladder.[7]

No difference in overall global satisfaction after urinary diversion.[7]

COMPARISON OF ILEAL CONDUIT, CONTINENT CATHETERIZABLE RESERVOIR AND NEOBLADDER

A systematic review of all the literature comparing all urinary diversions after radical cystectomy failed to reveal a difference in QOL among the urinary reconstructions.[9]

 

SUMMARY

• A variety of reconstructive techniques exist for patients undergoing radical cystectomy for bladder cancer. These include continent and incontinent reconstructions that may use the native urethra or a new urostomy (opening).
• Determining QOL after surgery for bladder cancer is difficult given the heterogeneous nature of patients with bladder cancer and the complex decision-process to determine the most appropriate urinary diversion for a given patient.
• Given the limitations of QOL research for urinary diversion, a number of research studies fail to demonstrate superiority of any diversion type with regard to psychological or health-related QOL.
• The decision regarding urinary diversion should take into account a variety of patient, cancer and surgeon factors.  Consultation with a surgeon or center experienced in multiple diversions may help patients make the best decision for them.

 
[1] Palapattu GS, Haisfield-Wolfe ME, Walker JM, BrintzenhofeSzoc K, Trock B, Zabora J, Schoenberg M. Assessment of perioperative psychological distress in patients undergoing radical cystectomy for bladder cancer. J Urol. 2004 Nov;172(5 Pt 1):1814-7.
[2] Kulaksizoglu H, Toktas G, Kulaksizoglu IB, Aglamis E, Unlüer E. When should quality of life be measured after radical cystectomy? Eur Urol. 2002 Oct;42(4):350-5.
[3] Somani BK, Gimlin D, Fayers P, N'dow J. Quality of life and body image for bladder cancer patients undergoing radical cystectomy and urinary diversion--a prospective cohort study with a systematic review of literature. Urology. 2009 Nov;74(5):1138-43. doi: 10.1016/j.urology.2009.05.087. Epub 2009 Sep 20.
[4] Hart S, Skinner EC, Meyerowitz BE, Boyd S, Lieskovsky G, Skinner DG. Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. J Urol. 1999 Jul;162(1):77-81.
[5] Okada Y, Oishi K, Shichiri Y, Kakehi Y, Hamaguchi A, Tomoyoshi T, Yoshida O. Quality of life survey of urinary diversion patients: comparison of continent urinary diversion versus ileal conduit. Int J Urol. 1997 Jan;4(1):26-31.
[6] Hobisch A, Tosun K, Kinzl J, Kemmler G, Bartsch G, Höltl L, Stenzl A. Quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. World J Urol. 2000 Oct;18(5):338-44.
[7] Dutta SC, Chang SC, Coffey CS, Smith JA Jr, Jack G, Cookson MS. Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol. 2002 Jul;168(1):164-7.
[8] Autorino R, Quarto G, Di Lorenzo G, De Sio M, Perdonà S, Giannarini G, Giugliano F, Damiano R.Health related quality of life after radical cystectomy: comparison of ileal conduit to continent orthotopic neobladder. Eur J Surg Oncol. 2009 Aug;35(8):858-64. doi: 10.1016/j.ejso.2008.08.002. Epub 2008 Sep 27.
[9] Gerharz EW, Månsson A, Hunt S, Skinner EC, Månsson W.Quality of life after cystectomy and urinary diversion: an evidence based analysis. J Urol. 2005 Nov;174(5):1729-36.

 

Historical Contribution: 1952, Jewett, 5-year survival for bladder cancer

1952
Jewett HJ. Infiltrating Carcinoma of the Bladder; relation of early diagnosis to five-year suvival rate after complete extirpation. J Am Med Assoc. 1952. 148(3):187-9.

 

Hugh J. Jewett, MD

In 1946, Dr. Hugh Jewett wrote the first manuscript detailing the clinical staging of infiltrative bladder cancer. In this 1952 follow-up, Dr. Jewett details the outcomes of patients undergoing radical and partial cystectomy for invasive bladder cancers. Interestingly, radical cystectomy (including lymphatic resection) or exenteration were sparsely used due to the high mortality and postoperative disability with each procedure.

In total, 80 patients underwent extirpative surgery: 39 simple cystectomy and 41 partial cystectomy.

• For the 19 patients with tumors infiltrating less than halfway through the muscularis, 14 (74%) lived 5-14 years. 
•  Only 10% had extension of tumor beyond the bladder. 
•  37% were highly-malignant (high-grade).
• Only 2 patients (3%) with deeply invading tumors survived 5 years. 
•  85% of these patients had evidence of extension of their disease. 
•  54% were highly-malignant.

Jewett astutely noted that invasive tumors were more often high-grade, but that stage (invasion) was more important in determining outcome than grade.

Interestingly, cystoscopy was part of the diagnostic algorithm for voiding symptoms but not for resection or staging of bladder tumors. Most patient in this series presented with hematuria or irritative voiding symptoms. Hematuria was the overwhelmingly present symptom, with gross hematuria present in 65 patients and microscopic hematuria in another 7 cases. Jewett attempted to correlate the temporality and severity of symptoms with stage of disease. He found that invasive tumors trended to having a longer duration of symptoms – suggesting that bladder cancer may progress from more superficial to invasive disease with time.

In conclusion, Jewett urged that:

"The reasonably good prognosis associated with superficial tumors, in contrast to the very poor prognosis afforded by deep tumors, should emphasize to the general public, the general practitioner, and the specialist the vital importance to the patient of immediate evaluation of the cause of hematuria or vesical irritability."

 
To read the entire manuscript: follow the link above, visit the Centennial Website or click here.


 
HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Ureteral Stents: Necessarily a Pain?

A variety of ureteral stents.

Ureteral stents have been used in urology for over 50 years. Ureteral stents are soft, pliable, and, most often made of plastic, tubes designed to allow urine to flow through or around them to bypass an obstruction in the urinary system. Ureteral stents are commonly called "double-J" or "pig-tailed" catheters, referring to the soft coils at either end of the tube that prevent the stent from migrating in the urinary system. Common indications, or reasons for placing a ureteral stent include:

• Intrinsic (or internal) ureteral obstruction – as from kidney stone
• Extrinsic (or external) ureteral obstruction – as from a compressing malignancy
• Post-operatively following ureteroscopic surgery
  • Manipulation of a kidney stone
  • Biopsy of renal pelvis or ureteral malignancy
  • Dilation of a ureteral stricture

While the risk of complications while placing a stent or following are low, many patients can experience stent pain which can vary from a nuisance to excruciating, intolerable pain. This blog will focus on the mechanisms and treatment of ureteral stent pain.

 

EPIDEMIOLOGY OF STENT PAIN & SYMPTOMS

Stent pain of varying degrees is estimated to affect upwards of 80% of patients having one placed.[1,2] Specific symptoms and estimated incidences include:

• Irritative Voiding Symptoms (most common)
  • Frequency (50-60%)
  • Urgency (57-60%)
  • Dysuria (40%) – discomfort when voiding
  • Incomplete Emptying (76%)
• Pain or Discomfort
  • Flank (19-32%) – especially at the end of voiding
  • Suprapubic (30%)
• Incontinence
• Hematuria (25%) – visible blood in the urine

[1,3-9]

 

MECHANISMS OF STENT PAIN & SYMPTOMS

Ureteral stents can allow "reflux" of urine
from the bladder to the kidney.

Most symptoms associated stents are attributed to mechanical stimuli and irritation from the coil that rests in the bladder. The ureteral orifices (where the ureter enters the bladder) defines the lateral edge of the trigone (or central portion of bladder defined by the ureteral orifices and the urethra) so that the stent rests on this, very sensitive, area of the bladder. Most irritative symptoms are worse during the day, indicating that awareness plays a role in stent symptoms.[1] Alternatively, studies also demonstrate that stents can move as much as 2.5cm in movement of the stent based solely on patient position – indicating that daytime activity also likely plays a role in symptoms.[10] Interestingly, a randomized clinical trial demonstrated that longer stents were associated with more symptoms and worse quality-of-life.[11]

Flank pain is believed to be due to reflux of urine from the bladder to the kidney during voiding. While stents are designed to allow urine to flow from the kidney to the bladder, there is no mechanism to prevent urine flowing up from the bladder to the kidney – especially during voiding when bladder pressures can be quite high. Flank pain at the end of voiding is often mild to moderate and not related to stent length or positioning.[11-13] Expectation of flank pain can often alleviate many patient concerns with this phenomenon. Suprapubic pain is most often related to stent position and mechanical irritation of the trigone.

Incontinence is either due to severe mechanisms (as described above), or if the stent migrates distally and bypasses the urethral sphincter, allowing urine to pass unabated out of the bladder.

Hematuria can be related to the underlying process being treated (for example, obstructing kidney stone), result from the surgery (use of a laser or biopsy instruments) or the stent rubbing along the urothelium (lining of the urinary system).[14]


 

PREVENTING STENT PAIN & SYMPTOMS

The best way to prevent stent pain is to avoid placing a stent. However, it is important to note that most ureteroscopic procedures require a stent to be placed to prevent infection or injury; and failing to place a stent in a patient in whom it is necessary can lead to worse symptoms, hospital readmission, a possible second procedure or permanent injury. The American Urological Association (AUA) Guidelines on the Management of Ureteral Calculi state that "Stenting following uncomplicated ureteroscopy is optional."[15]

Stents come in a variety of lengths and calibers. Choosing an appropriate stent size and positioning appropriately can prevent most significant symptoms. While a number of systems have been developed for adult [5,14,16] and pediatric [17] patients to predict the "best" stent length for a patient, in general a stent should rest proximally in the renal pelvis and distally curl just into the bladder. While the proximal curl (in the kidney) has no correlation to stent symptoms, a distal curl that crosses the midline in the bladder is associated with more irritative voiding symptoms.[14]

A variety of medications and stent-coating materials have been tried to improve stent symptoms. Local anesthetics have demonstrated no benefit [7] while some stents coated with antibiotics, made of less irritative materials or of tapered design have demonstrated less discomfort in early studies.[18]

 

TREATING STENT PAIN & SYMPTOMS

A number of medications and routes of administration have been used to treat stent symptoms. A number of intravesical medications (given in the bladder) have demonstrated mixed results with no clear benefit. The best studied medications for stent discomfort include the alpha-blockers afluzosin,, tolterodine and tamsulosin. A number of studies have demonstrated improved symptoms, decreased use of pain medications, better sleep and quality-of-life with alpha blockers were compared to placebo.[19-22] Another study failed to demonstrate a benefit to the anticholinergic, oxybutynin, but a small benefit to phenazopyridine (pyridium).[23]

 

SUMMARY

• Many urologic conditions and procedures necessitate the use of ureteral stents.
• Symptoms related to stent placement can affect upwards of 80% of patients with the most common symptoms being irritative voiding symptoms and pain.
• Most symptoms related to an indwelling stent are related to mechanical irritation.
• Therefore, stent symptoms are best managed by:
  • Placing a stent only when needed
  • Placing a stent that is properly sized and positioned for the patient
  • Using medications that mitigate the reaction of the urinary system to the stent

 

 
[1] Joshi HB, Okeke A, Newns N, Keeley FX, Jr, Timoney AG. Characterization of urinary symptoms in patients with ureteral stents. Urology. 2002;59:511–9.
[2] Byrne RR, Auge BK, Kourambas J, et al. Routine ureteral stenting is not necessary after ureteroscopy and ureteropyeloscopy: a randomized trial. J Endourol. 2002;16:9–13.
[3] Chew BH, Knudsen BH, Denstedt D. The use of stents in contemporary urology. Curr Opin Urol.2004;14:111–5
[4] Haleblian G, Kijvikain K, de la Rosette J, Preminger G. Ureteral stenting and urinary stone management: a systematic review. J Urol. 2008;179:424–30.
[5] Hao P, Li W, Song C, Yan J, Song B, Li L. Clinical Evaluation Of Double-Pigtail in Patients with Upper Urinary Tract Diseases: Report of 2685 cases. J Endourol. 2008;22:65–70.
[6] Thomas R. Indwelling ureteral stents: Impact of material and shape on patient comfort. J Endourol. 1993;7:137–40. [PubMed]
[7] Sur RL, Haleblian GE, Cantor D, Springhart P, Albala D, Preminger G. Efficacy of intravesical ropivacaine injection on urinary symptoms following ureteral stenting: a randomized, controlled study. J Endourol. 2008;22:473–8.
[8] Rane A, Saleemi A, Cahill D, Sriprasad S, Shrotri N, Tiptaft R. Have stent-related symptoms anything to do with placement technique? J Endourol. 2001;15:741–4.
[9] Smedley FH, Rimmer J, Taube M, et al. 168 Double J (pigtail) ureteric catheter insertions: A retrospective review. Ann R Coll Surg Engl. 1988;70:377–9.
[10] Chew BH, Knudsen BE, Nott L, Pautler SE, Razvi H, Amann J, et al. Pilot Study of Ureteral Movement in Stented Patients: First Step in Understanding Dynamic Ureteral Anatomy to Improve Stent Discomfort. J Endourol. 2007;21:1069–75.

[11] Al-Kandari AM, Al-Shaiji TF, Shaaban H, Ibrahim HM, Elshebiny YH, Shokeir AA. Effects of Proximal and Distal Ends of Double-J Ureteral Stent Position on Postprocedural Symptoms and Quality of Life: a Randomized Clinical Trial. J Endourol. 2007;21:698–702.
[12] Ramsay JW, Payne SR, Gosling PT, Whitfield HN, Wickham JE, Levison DA. Effects of double-J stenting on unobstructed ureter: an experimental and clinical study. Br J Urol. 1985;57:630–4.
[13] Mosli H, Farsi H, al-Zemaity MF, Saleh TR, al-Zamzami MM. Vesico-ureteral reflux in patients with double pigtail stents. J Urol. 1991;146:966–9.
[14] Ho CH, Chen SC, Chung SD, Lee YJ, Chen J, Yu HJ, et al. Determining the Apropriate Length of a Double-Pigtail Ureteral Stent by Both Stent Configurations and Related Symptoms. J Endourol.2008;22:1427–31.
[15] Preminger, et al. Management of Ureteral Calculi: European Association of Urology (EAU) and American Urological Association (AUA) Nephrolithiasis Panel (2007). http://www.auanet.org/education/guidelines/ureteral-calculi.cfm

[16] Hruby GW, Ames CD, Yan Y, Monga M, Landman J. Correlation of ureteric length with anthropometric variance of surface body habitus. BJU Int. 2007;99:1119–22. 
[17] Palmer JS, Palmer LS. A simple and reliable formula for determining the proper JJ stent length in the pediatric patient: Age + 10. Urol. 2007;70:264.
[18] Ricardo Miyaoka and Manoj Monga. Ureteral stent discomfort: Etiology and management. Indian J Urol. 2009 Oct-Dec; 25(4): 455–460.
[19] Deliveliotis C, Chrisofos M, Gougousis E, Papatsoris A, Dellis A, Varkarakis IM. Is there a role for alpha1-blockers in treating double-J stent-related symptoms? Urology. 2006;67:35–9. [PubMed]
[20] Beddingfield R, Pedro RN, Hinck B, Kreidberg C, Feia K, Monga M. Alfuzosin to Relieve Ureteral Stent Discomfort: A Prospective, Randomized, Placebo Controlled Study. J Urol. 2009;181:170–6. [PubMed]
[21] Park SC, Seo IY, Jeong HJ, Oh SJ, Rim JS, Jeong YB. The effect of alfuzosin and tolterodine in treating double-J stent-related symptoms. J Urol. 2008;179:289.
[22] Damiano R, Autorino R, De Sio M, Giacobbe A, Palumbo IM, D'Armiento M. Effect of Tamsulosin in Preventing Ureteral Stent- Related Morbidity: A Prospective Study. J Endourol. 2008;22:651–5.
[23] Norris RD, Sur RL, Springhart WP, Marguet CG, Mathias BJ, Pietrow PK, et al. A Prospective, Randomized, Double-blinded, placebo-controlled comparison of extended release oxybutynin versus phenazopyridine for the management of postoperative ureteral stent discomfort. Urology. 2008;71:792.