Local Coverage Determination (LCD)

MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer


Expand All | Collapse All
Proposed LCD
Proposed LCDs are works in progress that are available on the Medicare Coverage Database site for public review. Proposed LCDs are not necessarily a reflection of the current policies or practices of the contractor.

Document Note

Note History

Contractor Information

LCD Information

Document Information

Source LCD ID
Original ICD-9 LCD ID
Not Applicable
LCD Title
MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer
Proposed LCD in Comment Period
Source Proposed LCD
Original Effective Date
For services performed on or after 07/18/2021
Revision Effective Date
For services performed on or after 08/06/2023
Revision Ending Date
Retirement Date
Notice Period Start Date
Notice Period End Date
AMA CPT / ADA CDT / AHA NUBC Copyright Statement

CPT codes, descriptions and other data only are copyright 2023 American Medical Association. All Rights Reserved. Applicable FARS/HHSARS apply.

Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein.

Current Dental Terminology © 2023 American Dental Association. All rights reserved.

Copyright © 2024, the American Hospital Association, Chicago, Illinois. Reproduced with permission. No portion of the American Hospital Association (AHA) copyrighted materials contained within this publication may be copied without the express written consent of the AHA. AHA copyrighted materials including the UB‐04 codes and descriptions may not be removed, copied, or utilized within any software, product, service, solution or derivative work without the written consent of the AHA. If an entity wishes to utilize any AHA materials, please contact the AHA at 312‐893‐6816.

Making copies or utilizing the content of the UB‐04 Manual, including the codes and/or descriptions, for internal purposes, resale and/or to be used in any product or publication; creating any modified or derivative work of the UB‐04 Manual and/or codes and descriptions; and/or making any commercial use of UB‐04 Manual or any portion thereof, including the codes and/or descriptions, is only authorized with an express license from the American Hospital Association. The American Hospital Association (the "AHA") has not reviewed, and is not responsible for, the completeness or accuracy of any information contained in this material, nor was the AHA or any of its affiliates, involved in the preparation of this material, or the analysis of information provided in the material. The views and/or positions presented in the material do not necessarily represent the views of the AHA. CMS and its products and services are not endorsed by the AHA or any of its affiliates.


Issue Description

This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity.

Issue - Explanation of Change Between Proposed LCD and Final LCD

Changes were made to reflect the addition of recently published guidelines. Additional references were added in the final draft consistent with comments received. Minor edits were also made for clarity.

CMS National Coverage Policy

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This contractor will cover molecular diagnostic tests for use in a beneficiary with bladder cancer when all of the following conditions are met:

  1. The beneficiary is being actively managed for bladder cancer.
  2. The beneficiary is within the population and has the indication for which the test was developed and is covered. The laboratory will make available the appropriate indications of the test to the treating/ordering physician.
  3. At least 1 of the 2 criteria are met:
    1. The patient is a candidate for multiple potential treatments, which could be considered to have varied or increasing levels of intensity based on a consensus guideline, and the physician and patient must decide among these treatments. OR
    2. The patient is a candidate for multiple therapies, and the test has shown that it predicts response to a specific therapy among accepted therapy options based on nationally recognized society consensus guidelines (i.e., National Comprehensive Cancer Network [NCCN], American Society of Clinical Oncology [ASCO], Society of Urologic Oncology [SUO], or American Urological Association [AUA]).
  4. If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content)
  5. The test demonstrates analytical validity including both analytical and clinical validations. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.
  6. The test has demonstrated clinical validity and utility, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management decision (in 4. above) in a clearly defined population.
  7. The test successfully completes a Molecular Diagnostic Services Program (MolDX®) technical assessment that ensures the test is reasonable and necessary as described above.
  8. Only 1 test may be performed prior to the initiation of therapy UNLESS a second test that interrogates different genomic content AND meets all the criteria established herein, is reasonable and necessary.
    • The genomic content interrogated by the test must be relevant to the therapy under consideration.
Summary of Evidence

In the United States, the annual incidence of new bladder cancer is 83,730 patients with approximately 17,200 annual deaths.1 The majority of bladder cancers originate from the urothelium, with the most important initial risk stratification decision made for these cancers based on whether it is invasive or non-invasive, and how deeply it is has invaded if invasive.2 Variant histology, common at higher grades, may represent risk of progression or different genetic derivation which may determine whether a more aggressive treatment approach should be considered.15 In patients who do not have evidence of metastasis at the time of diagnosis, guidelines recommend considering a number of possible treatment approaches of varying intensity and invasiveness, often with recommended follow-up and potential escalation of therapy when there is persistent evidence of cancer. For clinical non-invasive papillary urothelial carcinoma potential treatment approaches include intravesical Bacillus Calmette-Guerin (BCG), intravesical chemotherapy, or even observation.13 For clinical T1 tumors, potential treatment options include either transurethral resection of the bladder tumor (TURBT) or cystectomy. In patients with stage II or stage IIIa disease, potential treatment options include chemotherapy, radiation, chemoradiation, and surgery accompanied possibly by neoadjuvant and/or adjuvant chemotherapy.13 While guidelines base recommendations for treatment of localized urothelial cancers heavily on risk stratification, within individual risk groups, the guidelines recommend consideration of multiple treatment strategies of varying levels in intensity and known significant side effects within individual strata.13 Risk stratification for treatment decisions in patients who are not having or have not yet had a cystectomy are based on clinical staging information; evidence has shown that changes in staging based on pathologic information following cystectomy are common, altering disease risk.3 

Among the non-urothelial bladder cancers, squamous cell carcinoma, adenocarcinoma, and neuroendocrine (NE) tumors have been recognized as important for implications concerning treatment.2 Current recommendations do not suggest chemotherapy for pure squamous or adenocarcinoma of the bladder, with radiotherapy and/or surgical resection being the mainstays of treatment.2 NE and NE-like tumors and those tumors with small cell features have been recognized to be a poor prognostic subtype for which aggressive treatment (including chemotherapy and possibly cystectomy and radiotherapy) is recommended regardless of stage.2 The diagnosis of NE and NE-like tumors  in the bladder may be challenging, particularly on histology alone, and therefore often requires use of additional diagnostic information, such as special stains to look for NE features.5,6

With current standards of care, patients diagnosed with bladder cancer have 5-year relative survival rates (compared to peers without bladder cancer) of 95.8% in cases of in-situ carcinoma and 69.5% in cases of localized cancer with absolute survival rates of 51% and 34% for in-situ and local disease respectively.7

Molecular subtyping has emerged as a potential diagnostic aid in bladder cancer both to help identify the type of bladder cancer and to more accurately assess the risk and benefit profile of various treatment approaches and to aid in the diagnosis of bladder cancer subtype and risk.

Seiler and colleagues developed and validated an algorithm that predicts outcomes in urothelial carcinoma based on molecular subtyping using an algorithm based on gene expression data.8 The algorithm classified bladder cancer into 1 of 4 subtypes: Claudin-low, basal, luminal-infiltrated, and luminal. They found that the algorithm also predicted response to neoadjuvant chemotherapy. Luminal tumors (non-infiltrated) demonstrated a comparatively good prognosis that appeared minimally affected by differences between patients who did and did not receive neoadjuvant therapy.18 Basal tumors demonstrated a poor prognosis without neoadjuvant therapy. The prognosis was significantly improved with neoadjuvant therapy to be similar to luminal tumors. The same subtyping algorithm was evaluated in bladder cancers pre-cystectomy as a predictor of pathologic upstaging.9 Consistent with Seiler’s work showing better prognoses for luminal tumors, it was found that luminal tumors were less likely to be upstaged. Gene expression data has also been found to identify NE-like bladder cancers that histologically appear like urothelial carcinomas.10.19 This discernment helps to inform the most appropriate treatment, as noted above.

Ross and colleagues looked at a comprehensive genomic profile (CGP) of 295 cases of advanced urothelial carcinoma and were able to demonstrate that over 90% had at least 1 clinically relevant genetic alteration. The most common clinically relevant genetic alterations were cyclin dependent kinase inhibitor 2A (CDKN2A), fibroblast growth factor receptor 3 (FGFR3), phosphatidylinositol 3 kinase catalytic subunit alpha (PIK3CA), and erythroblastic oncogene B2 (ERBB2).14 Importantly, some of these are targetable mutations for therapies. For example, in advanced bladder cancer, FGFR3 and fibroblast growth factor receptor 2 (FGFR2) mutations have been found to be associated with response to erdafitinib, which has been Food and Drug Administration (FDA) approved for use in bladder cancer with FGFR3 and FGFR2 mutations.4

Currently, erdafitinib, a tyrosine kinase pan-FGFR inhibitor, has been FDA approved as a targeted therapy for patients with prespecified FGFR alterations who had either previously received chemotherapy or were cisplatin-ineligible and chemotherapy-naïve.16 In a study of 99 patients with locally advanced and unresectable or metastatic urothelial carcinoma, Loriot et al17 demonstrated that after a median of five cycles of erdafitinib the rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.17

Other molecular classifiers and tests will be considered when there is evidence of clinical validity and utility or if nationally recognized treatment guidelines call for their inclusion in the treatment regimen of the defined population in which they are to be used.

Analysis of Evidence (Rationale for Determination)

Numerous prior Medicare coverage decisions have considered the evidence in the hierarchical framework of Fryback and Thornbury11 where Level 2 addresses diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses on whether the information produces change in the physician's diagnostic thinking; Level 4 concerns the effect on the patient management plan and Level 5 measures the effect of the diagnostic information on patient outcomes. To apply this same hierarchical framework to analyze an in vitro diagnostic test, we utilized the ACCE Model Process for Evaluating Genetic Tests.12 The practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. When a proven, well established association or pathway is available, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.

For patients with bladder cancer, an array of treatment possibilities exists at all stages of disease. Clinicians must consider not only the potential treatment options but must also make an individualized risk-to-benefit assessment to determine how to treat a specific patient. Diagnostic tests that aid in this assessment are expected to change physician management in a way that improves patient outcomes. In this regard, the NCCN Bladder Cancer Panel recommends that molecular/genomic testing be conducted for Stages IVA and IVB and may be considered for IIIB bladder cancer. The NCCN Bladder Cancer Panel recommends that molecular testing be conducted early, ideally at diagnosis, to facilitate treatment decision-making, prevent delays in administrating therapy, and to screen for clinical trial eligibility.13

Proposed Process Information

Synopsis of Changes
Changes Fields Changed
Associated Information
Sources of Information
Open Meetings
Meeting Date Meeting States Meeting Information
Contractor Advisory Committee (CAC) Meetings
Meeting Date Meeting States Meeting Information
MAC Meeting Information URLs
Proposed LCD Posting Date
Comment Period Start Date
Comment Period End Date
Reason for Proposed LCD
Requestor Information
This request was MAC initiated.
Requestor Name Requestor Letter
View Letter
Contact for Comments on Proposed LCD

Coding Information

Bill Type Codes

Code Description

Revenue Codes

Code Description


Group 1

Group 1 Paragraph


Group 1 Codes



ICD-10-CM Codes that Support Medical Necessity

Group 1

Group 1 Paragraph:


Group 1 Codes:



ICD-10-CM Codes that DO NOT Support Medical Necessity

Group 1

Group 1 Paragraph:


Group 1 Codes:



Additional ICD-10 Information

General Information

Associated Information


Sources of Information


  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
  2. Flaig TW, Spiess PE, Agarwal N, et al. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(3): 329-354.
  3. Svatek RS, Shariat SF, Novara G, et al. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. BJU Int. 2011;107(6):898-904.
  4. U.S. Food and Drug Administration (FDA). Balversa™ prescribing information. Accessed May 3, 2023. 
  5. Helpap B. Morphology and therapeutic strategies for neuroendocrine tumors of the genitourinary tract. Cancer. 2002;95(7):1415-1420.
  6. Ali SZ, Reuter VE, Zakowski MF. Small cell neuroendocrine carcinoma of the urinary bladder: a clinicopathologic study with emphasis on cytologic features. Cancer. 1997;79(2):356-361.
  7. National Cancer Institute. Cancer Stat Facts: Bladder Cancer. https://seer.cancer.gov/statfacts/html/urinb.html Accessed May 3, 2023.
  8. Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol. 2017;72(4):544-554.
  9. Lotan Y, Boorjian SA, Zhang J, et al. Molecular subtyping of clinically localized urothelial carcinoma reveals lower rates of pathological upstaging at radical cystectomy among luminal tumors. Eur Urol. 2019;76(2):200-206.
  10. Batista da Costa J, Gibb EA, Bivalacqua TJ, et al. Molecular characterization of neuroendocrine-like bladder cancer. Clin Cancer Res. 2019;25(13):3908-3920.
  11. Fryback DG, Thornbury JR. The efficacy of diagnostic imaging. Med Decis Making. 1991;11(2):88-94.
  12. Centers for Disease Control and Prevention. ACCE Model List of 44 Targeted Questions Aimed at a Comprehensive Review of Genetic Testing. https://www.cdc.gov/genomics/gtesting/acce/acce_proj.htm. Accessed May 3, 2023.
  13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Bladder Cancer, Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed May 3, 2023.
  14. Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122(5):702-711.
  15. Mori K, Abufaraj M, Mostafaei H, et al. A systemic review and meta-analysis of variant histology in urothelial carcinoma of the bladder treated with radical cystectomy. J Urol. 2020;204(6):1129-1140.
  16. US Food and Drug Administration (FDA). Prescribing Information. BALVERSA (erdafitinib). 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212018s001lbl.pdf. Accessed May 3, 2023.
  17. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-348.
  18. Lotan Y, de Jong JJ, Liu VYT, et al. Patients with muscle-invasive bladder cancer with nonluminal subtype derive greatest benefit from platinum based neoadjuvant chemotherapy. J Urol. 2022;207(3):541-550. doi:10.1097/JU.0000000000002261
  19. Grivas P, Bismar TA, Alva AS, et al. Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy. Urol Oncol. 2020;38(4):262-268. doi:10.1016/j.urolonc.2019.11.004

Revision History Information

Revision History Date Revision History Number Revision History Explanation Reasons for Change
08/06/2023 R1

Under Coverage Indications, Limitations and/or Medical Necessity revised verbiage under 2, 3, and 3b. Replaced 4 with new verbiage, “If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content)”. Renumbered 4-6 and revised verbiage under 5, 6, and 7. Added verbiage to 8, “Only 1 test may be performed prior to the initiation of therapy UNLESS a second test that interrogates different genomic content AND meets all the criteria established herein, is reasonable and necessary. The genomic content interrogated by the test must be relevant to the therapy under consideration”. Under Summary of Evidence first paragraph, eighth sentence added in-text citation. Under fifth paragraph, fourth and ninth sentences, added in-text citations. Added last sentence. Under seventh paragraph, first sentence deleted “Balversa”. Deleted eighth paragraph. Revised last paragraph to read, “in which they are to be used”. Under Analysis of Evidence (Rationale for Determination) second paragraph added last two sentences.

Under Bibliography changes were made to citations to reflect AMA citation guidelines, and references number 18-19 were added. Formatting, punctuation, and typographical errors were corrected throughout the LCD. Acronyms were inserted where appropriate throughout the LCD.

  • Provider Education/Guidance


  • Bladder Cancer

Read the LCD Disclaimer