# Presentation: 379206

## Urinary Risk Factors for Bladder Cancer 

- ICD-9-CM Coordination
- and
- Maintenance Committee Meeting
- September 29, 2006

*Louis S. Liou, MD, PhD*
*Assistant Professor of Urology and Pathology*
*Director of Urological Oncology Research*
*Boston University School of Medicine*
*Boston Medical Center *

- Disclosure: Consultant and Speaker for Abbott Molecular and Quest Diagnostics

**Notes:**
Good morning
I would like to thank the committee for allowing me to speak on an issue that is important in urologic oncology
The question is how can we categorize qualitatively the people that are at risk for bladder cancer and be able to precisely track their healthcare.
In the way of disclosure, I have spoken for and consulted with Abbott Molecular and Quest diagnostics.

## Bladder Cancer Incidence

- Most common type of urinary tract cancer
- More than 61,000 new cases of bladder cancer and approximately 13,000 deaths in 2005.
- Approximately 70% of new cases occur in men and 30% in women

- American Cancer Society. Cancer facts and figures 2006 graphs and figures. _[http://www.cancer.org/docroot/MED/content/MED_1_1_Most-Requested_Graphs_and_Figures_2006.asp](http://www.cancer.org/docroot/MED/content/MED_1_1_Most-Requested_Graphs_and_Figures_2006.asp)_.

**Notes:**
As a urologist, a filling defect seen here is highly suspicious for cancer
In addition, through the cystoscope, the papillary tumor can be actively bleeding or not but bladder cancer is very vascular.

## Types of Bladder Cancer 

- Transitional cell carcinoma is the most common, followed by squamous cell carcinoma
- Cancer is staged by the layers of the bladder invaded and by cancer spread
- As cancer penetrates the layers, it has a higher chance to spread and becomes harder to treat

- Tis:	carcinoma in situ
- Ta:	noninvasive papillary 	carcinoma
- T1:	invasion of subepithelial 	connective tissue
- T2:	invasion of muscle layer
- T3:	invasion of perivesical 	tissue
- T4:	invasion of nearby organs

**Notes:**
Staging and grading is the current method to predict aggressiveness of the disease. 
The staging system is familiar to many of you and does predict mortality.
T2- muscle invasive disease is usually when a patient is counseled for cystectomy.

## Causes of Bladder Cancer 

- Bladder cancer is believed to develop primarily as a result of environmental factors
- Chronic damage to the cells lining the bladder ultimately leads to DNA changes (Somatic Mutation)
- True inherited mutations are rare (Germline Mutation), although genetics raise other issues
- Increases with age
- 	>70     RR=15-20
- 	55-69  RR=7-10
- 	30-54  RR=1.

- American Cancer Society. Cancer facts and figures 2006 graphs and figures. _[http://www.cancer.org/docroot/MED/content/MED_1_1_Most-Requested_Graphs_and_Figures_2006.asp](http://www.cancer.org/docroot/MED/content/MED_1_1_Most-Requested_Graphs_and_Figures_2006.asp)_

**Notes:**
Nature of Nurture
With increasing age, somatic mutations accumulate and there is a higher incidence of cancer (in particular the risk of bladder cancer is markedly increased)
The analogy is “spell check” on your computer, with age the spell check program performs progressively worse.

## Cardinal Symptom: Hematuria 

- Hematuria is a common symptom and sign with many causes that can range in clinical importance:
- 		insignificant, eg. urethral polyps
- 		significant requiring observation, eg. cystocele
- 		significant requiring treatment, eg. pyelonephritis
- 		life-threatening, eg. bladder cancer

- Most common presenting symptom or sign for bladder cancer is hematuria

**Notes:**
How do urologist diagnose bladder cancer- the first symptom or sign is really hematuria.
As you know, microscopic hematuria is really a Urine analysis (not a dipstick) while gross or frank hematuria is what the patient sees.
Hematuria is not just found in bladder cancer and from the AUA best practice guideline, these disease entities can be categorized as insignificant, significant with observation, significannt with treatment, and life threatening. 

## “Good” and “Bad” Hematuria 

- Gross hematuria is always cause for concern and requires intensive work-up
- 	 	30% of patients with gross hematuria are 	diagnosed with bladder cancer
- Microscopic hematuria may also require intensive work-up depending on degree
- 	 	greater numbers of bladder cancer patients 	present with microscopic hematuria
- Patients at high risk for bladder cancer have additional *risk factors*

- BJU Int. 2002 Sep;90(4):355-7.Comment in:    BJU Int. 2003 Feb;91(3):301.Is microscopic haematuria a urological emergency? Khan MA, Shaw G, Paris AM.

**Notes:**
Therefore, as a urologist, I tend to categorize the hematuria patient as having “good or bad” hematuria.  This not only means the actual presenting sign or symptom but also the associated risk factors for that patient.  

## Tumor Progression and Invasion

**The silence of the genes. **Bruce R. Zetter and Jacqueline Banyard. NATURE.VOL 419 10  OCTOBER 2002

**Notes:**
Tumor biology or life cycle of the cancer
Where microhematuria is found is in the first 3 images while gross hematuria is in the latter three
Therefore, micro and gross hematuria can sometime act as a surrogate for progression  (you will have microhematuria before gross hematuria)

## Visualization of Urine

**Notes:**
This concept is not NEW-  Our urologic ancestors knew that the visual image of the urine was a very important diagnostic tool.  In fact, the used this chart to “code” those visual differences (If I may suggest, the original ICD code!-)

## Best Practices  

*“**The American Urological Association (AUA) convened the Best Practice Policy Panel on asymptomatic microscopic hematuria to formulate policy statements and recommendations for the evaluation of asymptomatic microhematuria in adults.*
*The literature agrees that gross hematuria warrants a thorough diagnostic evaluation.*
*[B]efore a decision is made to defer evaluation in patients with one or two red blood cells per high-power field, risk factors for significant disease should be taken into consideration.  High-risk patients should be considered for full urologic evaluation after one properly performed urinalysis documenting the presence of at least three red blood cells per high-power field.   *
*In patients at low risk for disease, some components of the evaluation may be deferred.”*

- Am Fam Physician 2001;63:1145-54

- Urology 57**: **599–610, 2001

**Notes:**
Fast forward to today and the AUA has formulated a best practice guideline and these recommendations again state that the quality and quantity of hematuria is important in establishing the medical risk of bladder cancer and hence dictate the diagnostic workup.
Low risk – non smoker, no gross hematuria, no exposure to chemicals, no prior urological history
I will now address each of these risk factors for bladder cancer

## Risk Factor : Smoking 

- Smoking is the greatest  risk factor
- Both current smoking and a prior history of smoking raise the risk

- Carcinogens in tobacco become concentrated in the urine and eventually damage the bladder lining
- Repeated exposure leads to cell mutation

- Scher HI, Motzer RJ. Bladder and renal cell carcinomas. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds. *Harrison’s Principles of Internal Medicine*. 16th ed. New York, NY: McGraw-Hill; 2005:539-543

## Risk Factor : Urinary Disorders 

- Chronic inflammation of the bladder increases the risk of bladder cancer
- Irritative effect leads to cell damage over time

- Common history includes:
- 		repeated urinary tract infection, eg. cystitis
- 		recurrent kidney, ureter or bladder calculi
- 		chronic urinary retention requiring catheter 	(spinal cord injury or neurogenic bladder)

- Bladder Cancer Chapter 44, page 637 in Clinical Urology 1994 Lippincott  Ed Krane, Siroky, Fitzpatrick

## Risk Factor : Irradiation  

- Bladder cells are known to be reactive to ionizing radiation

- Int J Radiat Oncol Biol Phys. 2006 Aug 1; Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up. Liauw SL, Sylvester JE, Morris CG, Blasko JC, Grimm PD.

- May occur as a result of therapeutic exposure, eg. radiation for cervical, prostate, or rectal cancer
- May occur as a result of environmental exposure, eg. nuclear power plant workers

## Risk Factor : Chemical Exposure

- Exposure to aromatic  hydrocarbons increases risk
- 	benzenes
- aromatic amines
- Aromatic hydrocarbons can  be produced by burning and  are common in manufacturing:
-  		petroleum  		paint
- 		textiles 		dyes

- J Natl Cancer Inst. 2004 Oct 6;96(19):1425-31. Alkylaniline-hemoglobin adducts and risk of non-smoking-related bladder cancer. Gan J, Skipper PL, Gago-Dominguez M, Arakawa K, Ross RK, Yu MC, Tannenbaum SR.

## Risk Factor : Arsenic Exposure

- Arsenic is a naturally  occurring element found in soil and rocks
- High levels of arsenic can be  found in well water, as well as drinking water near farms and mines

- Environ Health Perspect. 2006 Jul;114(7):1077-82. Arsenic cancer risk confounder in southwest Taiwan data set. Lamm SH, Engel A, Penn CA, Chen R, Feinleib M.

- Long-term exposure to arsenic raises the risk of bladder cancer

## Risk Factor : Family History 

- Bladder cancer is typically   *not* inherited as a genetic mutation
- However, some people with family history of bladder cancer may have:
- 		increased sensitivity to risks
- 		impaired ability to detoxify 	carcinogens

- Cancer. 2006 Jul 14;107(4):705-711 Bladder cancer risk as modified by family history and smoking. Lin J, Spitz MR, Dinney CP, Etzel CJ, Grossman HB, Wu X.

**Notes:**
Genetics are better at de-toxifying agents before it gets to the urine

## Risk Factors for Bladder Cancer

- 	Age (incidence increases with age; median age of bladder cancer patient is 73 years)
- 	Race (incidence is 2 times greater in whites vs African-Americans)
- 	Gender (incidence is 4 times greater in men)

- 	Exposure to cigarette smoke
- 	History of external beam radiation
- 	Neurogenic bladder, recurrent urinary tract infections, urinary stones, chronic indwelling catheter

- 	Infection with *Schistosoma haematobium*
- 	Ingestion of *Aristolochia fangchi* (herb used in some weight-loss formulas)

- Exposure to chemicals (hair dyes, aniline, organic solvents, etc)
- Exposure to arsenic
- Personal or family history of bladder cancer

**Notes:**
To summarize:
The categories in risk factor for bladder cancer include
Demographics which is easily obtained
Risk factors that currently can be coded for and identified
Interesting but rare siituations in the US that have shown to be related to bladder cancer
And finally known risk factors for bladder cancer that are currently not coded and able to be identified. 

## Data Issues

- Difficulty consistently identifying and tracking patients at high risk
- Hindrance of data review and analysis
- Inability to differentiate patients with hematuria based on risk for bladder cancer
- Patient Navigator

- ICD-9-CM currently has unique codes for some of the risk factors in bladder cancer, but not for other major risk factors.  This has lead to :

**Notes:**
Hematuria as a “catch all” term poorly categorized the heterogenous population of patients.  
One example is “Patient Navigator”-  person to help high risk patient “navigate” through diagnosis and potentially treatment-  great need to be able to identify those high risk patients that are being workup up for hematuria and potential bladder cancer.  

## Questions?