Bladder cancer is defined as malignancy that develops from the tissues of the bladder. It is the most common cancer of the urinary system. The cancer typically arises from the urothelium, although it may originate in other locations such as the ureter or urethra (Lerner, 2018). Tumor biomarkers are proteins detected in the blood, urine, or other body fluids that are produced by the tumor itself or in response to it. They are used to help detect, diagnose, and manage some types of cancer (Hottinger & Hormigo, 2011).
URINARY BLADDER CANCER
Urinary bladder cancer, a relatively common form of cancer in the United States, results in significant morbidity and mortality. Bladder cancer (urothelial carcinoma), typically presents as a tumor confined to the superficial mucosa of the bladder. The most frequent symptom of early bladder cancer is hematuria; however, urinary tract symptoms (i.e., urinary frequency, urgency, dysuria) may also occur.
The 2012 guidelines from the American Urological Association on the evaluation of microscopic hematuria, which were reviewed and affirmed in 2016, have recommended cystoscopic evaluation of adults older than age 40 years with microscopic hematuria and for those younger than age 40 years with microscopic hematuria and risk factors for developing bladder cancer.1 Confirmatory diagnosis of bladder cancer is made by cystoscopic examination, considered to be the criterion standard, and biopsy. At initial diagnosis, approximately 70% of patients have cancers confined to the epithelium or subepithelial connective tissue. Non-muscle-invasive disease is usually treated with transurethral resection, with or without intravesical therapy, depending on the depth of invasion and tumor grade. However, a 50% to 75% incidence of recurrence has been noted in these patients, with 10% to 15% progressing to muscle invasion over a 5-year period. Current follow-up protocols include flexible cystoscopy and urine cytology every 3 months for 1 to 3 years, every 6 months for an additional 2 to 3 years, and then annually thereafter, assuming no recurrence.
While urine cytology is a specific test (from 90% to 100%), its sensitivity is lower, ranging from 50% to 60% overall, and it is considered even lower for low-grade tumors. Therefore, interest has been reported in identifying tumor markers in voided urine that would provide a more sensitive and objective test for tumor recurrence.
Adjunctive testing to urine cytology has used a variety of nuclear and cytoplasmic targets, and a range of molecular pathology and traditional (e.g., immunohistochemistry) methods.
Commercially available tests cleared by the U.S. Food and Drug Administration clearance as well as laboratory-developed tests are summarized in the Regulatory Status section.
On April 16, 1997, the FDA approved the Bard BTA stat™ Test, created by Bard Diagnostic Sciences Inc. From the FDA site: “the BTA stat test is an in vitro diagnostic immunoassay indicated for the qualitative detection of bladder tumor associated antigen in urine of persons diagnosed with bladder cancer. This test is indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy”.
On April 15, 1998, the FDA approved the BTA TRAK™ Test, created by Bard Diagnostic Sciences Inc. From the FDA site: “the BTA TRAK test is an in vitro diagnostic immunoassay indicated for the quantitative detection of bladder tumor associated antigen in human urine. This test is indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy”.
On July 2, 1996, the FDA approved the MATRITECH NMP22™ TEST KIT, created by Alere Scarborough Inc. From the FDA site: “THE MATRITECH NMP22 TEST KIT IS AN ENZYME IMMUNOASSAY (EIA) FOR THE IN VITRO QUANTITATIVE DETERMINATION OF NUCLEAR MATRIX PROTEIN NMP22 IN STABILIZED VOIDED URINE”.
On July 30, 2002, the FDA approved the NMP22 BladderChek, created by Matritech Inc. From the FDA site: “The Matritech NMP22 BladderChek Test is indicated for professional and prescription home use as an aid in monitoring bladder cancer patients, in conjunction with standard diagnostic procedures”. This assay is qualitative.
On January 24, 2005, the FDA approved the UROVYSION BLADDER CANCER KIT. From the FDA site: “The UroVysion Bladder Cancer Kit (UroVysion Kit) is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer”.
On February 23, 2000, the FDA approved the ImmunoCyt, created by Diagnocure Inc. From the FDA site: “ImmunoCyt is a qualitative direct immunofluorescence assay intended for use in conjunction with cytology to increase overall sensitivity for the detection of tumor cells exfoliated in the urine of patients previously diagnosed with bladder cancer. ImmunoCyt is indicated for use as an aid in the management of bladder cancer in conjunction with urinary cytology and cystoscopy” (FDA, 2018).
All of the FDA-approved tests apart from ImmunoCyt are approved for both diagnosis and surveillance of bladder cancer whereas ImmunoCyt is only approved for surveillance (Darwiche, Parekh, & Gonzalgo, 2015)
Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request
- Urinary biomarkers (bladder tumor antigen (BTA) test, nuclear matrix protein (NMP22) test, or fluorescence in situ hybridization (FISH) UroVysion Bladder Cancer test) is considered MEDICALLY NECESSARY.
- an adjunct in the diagnostic exclusion of bladder cancer for patients who have an atypical or equivocal cytology
- as an adjunct in the monitoring of high-risk, non-muscle invasive bladder cancer
- The use of fluorescence immunocytology (ImmunoCyt/uCyt) is considered MEDICALLY NECESSARY as an adjunct to cystoscopy or cytology in the monitoring of persons with bladder cancer.
- Urinary biomarkers (bladder tumor antigen (BTA) test, nuclear matrix protein (NMP22) test, or fluorescence in situ hybridization (FISH) UroVysion Bladder Cancer test) are considered INVESTIGATIONAL for screening of bladder cancer, evaluation of hematuria, and diagnosing bladder cancer in symptomatic individuals, and all other indications.
- The use of fluorescence immunocytology (ImmunoCyt/uCyt) is considered INVESTIGATIONAL in the evaluation of hematuria, diagnosing bladder cancer, or for screening for bladder cancer in asymptomatic persons and all other indications.
For the purpose of this policy,standard diagnostic procedures for bladder cancer consist of urine cytology and cystoscopy, with or without biopsy.
The BTA (bladder tumor antigen) stat® and nuclear matrix protein 22 (NMP22) are immunoassay tests.
When performed qualitatively in the physician’s office, CPT code 86294 Immunoassay for tumor antigen, qualitative and semiquantitative (e.g., bladder tumor antigen), may be used to describe the BTA stat test and CPT code 86386 Nuclear Matrix Protein 22 (NMP22), qualitative may be used to describe the NMP22 test.
For clinical laboratories performing a quantitative version of these tests, CPT code 86316 Immunoassay for tumor antigen; other antigen, quantitative (e.g., CA 50, 72-4, 549), each, may be used to describe the test. Other tumor assays that may be coded using 86316 are addressed in a separate policy (Policy No. 20302).
There are specific CPT codes for urinary FISH testing:
88120: Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual
88121: using computer-assisted technology.
The CertNDx™ test is likely to be reported with the unlisted molecular pathology procedure code 81479.
BlueCard®/National Account Issues
Some state or federal mandates (e.g., FEP) prohibit plans from denying FDA-approved technologies as investigational. In these instances, plans may have to consider the coverage eligibility of FDA-approved technologies on the basis of medical necessity alone.
In 2015, there were approximately 541,000 cases of bladder cancer and 188,000 deaths related to bladder cancer worldwide (Fitzmaurice et al., 2017). In the United States, there are approximately 79,000 cases per year and 17,000 deaths (Siegel, Miller, & Jemal, 2017). Bladder cancer commonly presents as painless hematuria (blood in urine) and may be gross (visible) or microscopic. Gross hematuria tends to increase the likelihood of bladder cancer, but hematuria as a whole may be transient or due to non-cancer related causes (Kurtz, 2018). Other common symptoms of bladder cancer include pain or irritative and obstructive voiding symptoms such as urge incontinence, dysuria, straining, or nocturia. These symptoms are often mistaken for another condition such as kidney stones, can be temporary, and are not necessarily specific for bladder cancer (Y. Lotan, Choueiri, Toni, 2017). In fact, hematuria is the most common symptom of bladder cancer, but a study reported a 13% prevalence rate of bladder cancer out of 6728 patients with hematuria (DeGeorge, Holt, & Hodges, 2017; Sutton et al., 2018). 70%-75% of patients present with superficial tumors (50 – 70% of which can recur but are usually not life threatening), and 25%-30% present as invasive with a high risk of metastasis (Chou & Dana, 2010; Kaufman, Shipley, & Feldman, 2009).
Cystoscopy (white light) is the gold standard for diagnosis of bladder cancer. This procedure involves examination of the bladder, and urine is obtained for cytology. Any lesions are observed and recorded. Cystoscopy does not detect all malignancies or visualize the upper urinary tract. Furthermore, although cystoscopy is minimally invasive, it can be uncomfortable and promote anxiety, which can lead to suboptimal compliance with management recommendations Fluorescent cystoscopy is somewhat better at detecting tumors than white light cystoscopy; although, it comes with its own set of issues (such as higher false-positive rate, higher cost, etc.) (Y. Lotan, Choueiri, Toni, 2017; Mitra, Birkman, & Penson, 2017) A study found the sensitivity of fluorescent cystoscopy to be 0.92 compared to white light cystoscopy’s 0.71; the specificity of fluorescent cystocopy was lower at 0.57 compared to white light’s 0.72. Furthermore, fluorescent cystoscopy’s sensitivity for carcinoma in situ (which are difficult to visualize) was measured to be 0.924 compared to white light’s 0.605, but these differences tended to decrease on higher grade lesions (Soubra & Risk, 2015). Cytology (analysis of cells in urine) is often done in addition to cystoscopy. Its overall sensitivity is low at 0.34 and its sensitivity for grade 1 and 2 tumors is even lower at 0.12 and 0.26, respectively (Yair Lotan & Roehrborn, 2003).
Urinary biomarkers may be another avenue to diagnosing bladder cancer. Urine is exposed to urothelial tissue in many different locations, so it can have some different biomarkers associated with cancer. Although cystoscopy has long been the gold standard for diagnosis of bladder cancer, its high cost and unpleasant burden has led to the search for a non-invasive test that can match the high specificities and sensitivities set by cystoscopy. Validation of these biomarkers could lessen use of cystoscopy as well as increase overall sensitivity for identifying bladder cancer (D'Costa, Goldsmith, Wilson, Bryan, & Ward, 2016). However, because of the lower disease prevalence in a screening population, even in those at increased risk, the use of biomarkers for screening is not cost effective or recommended (Y. Lotan et al., 2009). Despite the promise of urine biomarkers, cystoscopy remains the procedure of choice both for initial diagnosis and for surveillance in previously treated patients.
The two most studied urinary biomarkers are bladder tumor antigen (BTA) and nuclear matrix protein 22 (NMP22). The BTA test is designed to detect complement factor H-related protein (hCFHrp) which is elevated in cancer cells. It is available in both a quantitative and qualitive version, and its manufacturer-recommended cut-off is 14U/mL (Mahnert et al., 1999; Mitra et al., 2017). Similarly, the NMP22 test is designed to detect a protein that is more highly available in cancer cells than normal cells. In this case, cancer cells release more NMP22 into the urine following apoptosis than normal cells do. The NMP22 tests are also available in a quantitative and qualitative version, and its FDA-approved cut-off is 10U/mL (Grossman, Messing, Soloway, & et al., 2005; Mitra et al., 2017; Zuiverloon, de Jong, & Theodorescu, 2017).
The FDA has approved two additional tests for urinary biomarkers. One is UroVysion, which is designed to detect chromosomal alterations that are distinctive of bladder cancer. It is a fluorescent in situ hybridization assay (FISH), and it uses DNA probes to detect alterations (such as aneuploidies) on chromosomes 3, 7, and 17 or loss of the 9p21 locus. The other is called ImmunoCyt (or uCyt+), and it uses a similar fluorescent technique to detect certain glycoproteins that are expressed on cancer cells but not normal ones (Mitra et al., 2017).
Clinical Validity and Utility
A meta-analysis of 57 studies detailed the accuracy of several biomarkers for diagnosis and surveillance of bladder cancer. These included the six FDA-approved tests (quantitative and qualitive NMP22, quantitative and qualitative BTA, FISH, and uCyt+) as well as a laboratory developed test not requiring FDA approval, “CxBladder”. Sensitivities ranged from 0.57 (qualitative NMP22) to 0.82 (CxBladder), although the CxBladder cohort was only comprised of one study. The specificities ranged from 0.74 (quantitative BTA) to 0.88 (qualitative NMP22). Sensitivity increased as a tumor progressed (higher grade or stage) with low accuracy for lower stage or grade tumors. A cytologic evaluation done with a biomarker assessment increased sensitivity as well but ultimately missed about 10% of cases. Ultimately, the authors concluded that urinary biomarkers “missed a substantial proportion of patients with bladder cancer and were subject to false-positive results in others”. The authors also stated that “no studies at the time of writing had evaluated effects on clinical outcomes of using urinary biomarkers”. (Chou et al., 2015).
Another study comparing four diagnostic tests (cytology, NMP22, UroVysion, and CxBladder) found CxBladder to have the highest sensitivity at 74% and cytology to have the highest specificity at 95%. The authors report comparable values for sensitivity for cytology, NMP22, and UroVysion with 46%, 45.9% and 47.7% respectively. Even though CxBladder is reported to have the highest sensitivity, the specificity (81.7%) is the lowest. The other tests were reported to have superior specificities with NMP22 at 88%, and UroVysion at 87.7%. (Breen et al., 2015).
A third study (Sathianathen, Butaney, Weight, Kumar, & Konety, 2018) focusing on biomarkers in patients presenting with hematuria was done. This study encompassed BTA, NMP22, FISH, and uCyt+, as well as a fifth biomarker “AssureMDx”. Sensitivities ranged from 0.67 (BTA) to 0.95 (AssureMDx, second highest was uCyt+ at 0.83) while specificities ranged from 0.68 (BTA) to 0.93 (quantitative NMP22). However, this data is consistent with the previously published meta-analysis that covered all settings, not just hematuria (Chou et al., 2015). Cytology was also found to have superior specificity to all studied biomarkers, although biomarkers tended to have better sensitivity. The authors concluded that due to the high heterogeneity and small sample size, more studies were needed to validate biomarkers to replace diagnostic evaluation of hematuria (Sathianathen et al., 2018).
Although there are many studies touting the high validity of biomarkers such as NMP22 and BTA, these studies often have a high proportion of high-grade tumors which inflates the specificity and sensitivity; the problem of identifying low-grade cancers remains. There may be changes at the genetic level in a low-grade cancer, but the proteins tested in the urine may still be relatively normal (D'Costa et al., 2016). Another issue is the conflicting results for the validity of the biomarkers. For example, the sensitivity of the quantitative NMP22 test has been found to range from as low as 0.26 to 1.00 with its specificity ranging from 0.49 to 0.98. Similarly, the BTA STAT test’s sensitivity and specificity have been found to range from 0.29 to 0.91 and from 0.54 to 0.86 respectively. (Zuiverloon et al., 2017). For comparison, a study found the sensitivity and specificity of flexible cystoscopy (out of 778 hematuria patients) to be 0.98 and 0.938, respectively (Sutton et al., 2018).
The ideal marker will be “easier, better, faster, and cheaper” (Schmitz-Dräger et al., 2015). Overall, although there have been numerous promising studies for the clinical utility of these urinary biomarkers, the biomarkers do not yet measure up to the standards set by cystoscopy as the primary method of diagnosis. Most of the biomarkers are yet to be well-validated and the ones that are, such as NMP22 and BTA, fall short of cystoscopy’s standards (D'Costa et al., 2016). Furthermore, because of the lower disease prevalence in a screening population, even in those at increased risk, the use of biomarkers for screening is not cost effective or recommended (Y. Lotan et al., 2009). Although the cost of tests is non-clinical, it is still a crucial issue; the BTA and NMP22 tests are relatively inexpensive at $25 but ImmunoCyt costs around $80 and the CxBladder and UroVysion cost $325 and $800, respectively (Zuiverloon et al., 2017). For comparison, a cystoscopy cost around $210 in 2016, and a cystoscopy with a biopsy cost about $370 (Halpern, Chughtai, & Ghomrawi, 2017). These biomarkers to date have not been highly recommended within any clinical guidelines. Therefore, the authors concluded that biomarkers have not had significant effect on clinical decision-making (Schmitz-Dräger et al., 2015). The majority of studies performed on these biomarkers did not focus on their ability to predict the course of cancer (D'Costa et al., 2016) but some biomarkers may play a role in the diagnosis or surveillance of bladder cancer in the future (Schmitz-Dräger et al., 2015). Even this may be a difficult barrier to cross; Meleth et al prepared an assessment for the Agency for Healthcare Research and Quality that stated “although UroVysion is marketed as a diagnostic rather than a prognostic test, limited evidence from two small studies (total N=168) supported associations between test result and prognosis for risk of recurrence”. The authors went on to note that they found no studies that established clinical utility (Meleth et al., 2014).
National Comprehensive Cancer Network (NCCN, July 2018)
The NCCN states that an FDA-approved urinary biomarker test such as fluorescence in situ hybridization (FISH) or nuclear matrix protein 22 may be considered in monitoring for recurrence. “Urine molecular tests for urothelial tumor markers are now available. Most of these tests have a better sensitivity for detecting bladder cancer than urinary cytology, but specificity is lower. However, it remains unclear whether these tests offer additional information that is useful for detection and management of non-muscle-invasive bladder tumors. Therefore, the panel considers this to be a category 2B recommendation (NCCN, 2018).”
National Academy of Clinical Biochemistry Laboratory Medicine (NACB, 2010)
The NACB Laboratory Medicine Practice Guidelines do not recommend use of any FDA‒approved urinary tumor marker tests for diagnosis of bladder tumors or for monitoring bladder cancer patients. The guideline states “There are no prospective clinical trial data that establish the utility of any of the FDA cleared markers or the proposed markers for increasing survival time, decreasing the cost of treatment or improving the quality of life of bladder cancer patients." The NACB is now known as the AACC, or American Association for Clinical Chemistry and have not since released any further updates on this topic (NACB, 2010).
American Urological Association (AUA, 2012, 2016, 2017)
The AUA’s guidelines on the diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults do not recommend use of urine markers (NMP22, BTA-stat, UroVysion) as part of routine evaluation (Davis et al., 2012).
The AUA and Society of Urologic Oncology (SUO) joint guidelines on Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer (NMIBC) do not recommend using urinary biomarkers to replace cystoscopy when monitoring NMIBC (grade B), although a clinician can use biomarkers to evaluate a patient’s response to Bacillus Calmette-Guerin (BCG) therapy or a separate cytology such as FISH. However, a urinary biomarker should not be used for monitoring a patient with a normal cystoscopy or a history of low-risk cancer (Chang et al., 2016).
Similarly, the joint guidelines between the AUA, the SUO, the American Society of Clinical Oncology (ASCO), and the American Society for Radiation Oncology (ASTRO) regarding non-metastatic muscle-invasive bladder cancer note that molecular biomarkers may be important for staging cancer and deciding a course of treatment soon. Nevertheless, at this time the biomarkers have not been properly validated (Chang et al., 2017).
U.S. Preventive Services Task Force (USPSTF, August 2011)
The USPSTF concluded in 2011 that there was insufficient evidence to evaluate screening for bladder cancer in asymptomatic adults and gave a grade of “I”. Since then there have been no further guidelines on this topic (Moyer, 2011).
3rd International Consultation on Urological Diseases & Société Internationale d’Urologie (ICUD-SIU, 2017)
With a level of evidence of 3 and a grade of “B”, the ICUD-SIU recommends, “examination of urine cytology must be a part of the expectant management or active surveillance protocol.” Concerning the surveillance strategies for NMIBC, “Surveillance strategies following a negative 3 months surveillance cystoscopy should be: (1) for low risk disease, cystoscopy 6–9 months later and annually thereafter; consider cessation following five recurrence-free years. No upper tract imaging necessary unless hematuria present; (2) for intermediate risk, cystoscopy with cytology every 3–6 months for 2 years; then every 6–12 months during years 3 and 4; then annually for lifetime. Upper tract imaging every 1–2 years; (3) for high risk, cystoscopy with cytology every 3 months for 2 years; then every 6 months during years 3 and 4; then annually for lifetime [Level of evidence: 3; Grade C] (Monteiro et al., 2018).”
National Cancer Institute (NCI, 2018)
In the 2018 update to the NCI’s Bladder and Other Urothelial Cancers Screening (PDQ®)—Health Professional Version, they state, “There is inadequate evidence to determine whether screening for bladder and other urothelial cancers has an impact on mortality… Based on fair evidence, screening for bladder and other urothelial cancers would result in unnecessary diagnostic procedures with attendant morbidity (NCI, 2018).”
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- Soubra, A., & Risk, M. C. (2015). Diagnostics techniques in nonmuscle invasive bladder cancer. Indian J Urol, 31(4), 283-288. doi:10.4103/0970-1591.166449
- Sutton, A. J., Lamont, J. V., Evans, R. M., Williamson, K., O'Rourke, D., Duggan, B., . . . Ruddock, M. W. (2018). An early analysis of the cost-effectiveness of a diagnostic classifier for risk stratification of haematuria patients (DCRSHP) compared to flexible cystoscopy in the diagnosis of bladder cancer. PLoS One, 13(8), e0202796. doi:10.1371/journal.pone.0202796
- Zuiverloon, T. C. M., de Jong, F. C., & Theodorescu, D. (2017). Clinical Decision Making in Surveillance of Non-Muscle-Invasive Bladder Cancer: The Evolving Roles of Urinary Cytology and Molecular Markers. Oncology (Williston Park), 31(12), 855-862.
||Immunoassay for tumor antigen; qualitative or semiquantitative (e.g., bladder tumor antigen)
||Immunoassay for tumor antigen; other antigen, quantitative (e.g., CA 50, 72-4, 549), each
||Nuclear Matrix Protein 22 (NMP 22), qualitative
||Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual
||Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; using computer-assisted technology
||Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma
||Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma
||R82.81 (Effective 10/01/2019)
||R82.89 (Effective 10/01/2019)
||Other abnormal findings on cytological and histological examination of urine
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.
"Current Procedural Terminology© American Medical Association. All Rights Reserved"
History From 2014 Forward
Adding ICD-10 codes to Coding Section. No other changes made.
Major revision for clarity and specificity. No change to policy intent.
Interim review, no change to policy intent. Changing review month.
Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references.
Updated category to Laboratory. No other changes.
Annual review, no change to policy intent. Updating background, description, rationale and references.
Updated CPT codes. No other changes made.
Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added coding.
Annual review. Updated background, policy guidelines, rationale and references.