Medical Policy: 02.04.52 

Original Effective Date: July 2015 

Reviewed: June 2020 

Revised: June 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Molecular topographic genotyping, also called molecular anatomic pathology, combines advanced molecular genetics with current pathology practices for a definitive diagnosis from existing specimens. The results are advertised to provide useful information for physicians to plan the best course of treatment for each patient's unique diagnosis.

 

The ‘PathFinderTG®’ test is not a single test, but is an advanced pathology service that includes microdissection, selection of regions to be analyzed, analysis of these regions using a variety of molecular tests (i.e., topographic genotyping). This patented diagnostic testing system is marketed under the specific test names of PancraGEN® and BarreGEN, is also being studied for pancreatobiliary cancer. It is available only through Interpace Diagnostics.

 

The testing involves the following steps:

  • Manual microdissection to identify and procure abnormal cells from existing pathology specimens
  • DNA extraction and amplification (e.g., polymerase chain reaction [PCR])
  • DNA sequencing to identify oncogenic mutations
  • Integration of this molecular information with the cytologic or histologic findings provided by the pathologist of record to provide a definitive diagnosis

 

For some specimens such as fluid aspirates, DNA is extracted from the fluid, since there may be little or no cellular content. The molecular testing consists of applying panels of molecular markers previously defined for each organ system or clinical question.

 

There is insufficient evidence in the published, peer-reviewed, scientific literature to demonstrate that topographic genotyping pathology can be used as methods to assist in the diagnosis or management of individuals with cancer when microscopic analysis and staining fail to provide a definitive diagnosis. This testing has not been adequately compared with established testing methods and impact on health outcomes is not known at this time. The clinical utility of topographic genotyping and the PathfinderTG® in the diagnosis and management of cancer has not yet been established through well-designed clinical trials. Peer reviewed studies that describe the analytical validity or investigate the clinical utility of the topographic genotyping tests are lacking. The manufacturer has indicated that the technology is meant as an adjunct to first-line testing but no algorithm for combining with consensus guidelines for decision making has been proposed.

 

This molecular test is marketed as a way to provide definitive diagnoses and prognostic information and predict responses to chemotherapy. While integrating the molecular information that a test like PathFinderTG® provides is of interest and the subject of research for neoplasms, currently the specific molecular features, associated genetic biomarkers and their relationships with clinical outcomes, are not well-defined. Accordingly, their role in clinical decision making, including selecting treatment options, has not been defined.

 

Normal Management of Conditions of Interest

Solid Pancreaticobiliary Lesions

Management

Currently, if a transabdominal ultrasound confirms the presence of a lesion, an abdominal computed tomography scan is performed to confirm the presence of the mass and determine disease extent. If the computed tomography provides enough information to recommend a resection and if the patient is able to undergo the procedure, no further testing is necessary. If the diagnosis remains unclear, additional procedures may be recommended. Symptomatic patients undergo cytology testing. If results from cytology testing are inconclusive, fluorescent in situ hybridization molecular testing of solid pancreaticobiliary lesions is recommended.

 

Barretts Esophagus

Management

Surveillance for esophageal adenocarcinoma is recommended for those diagnosed with Barrett esophagus. However, there are few data to guide recommendations about management and surveillance, and many issues are controversial. In 2015 guidelines from the American College of Gastroenterology (ACG) and a consensus statement from an international group of experts (Benign Barrett's and Cancer Taskforce) on the management of Barrett esophagus were published., ACG recommendations for surveillance are stratified by the presence of dysplasia. When no dysplasia is detected, ACG has reported the estimated risk of progression to cancer for patients ranges from 0.2% to 0.5% per year and ACG has recommended endoscopic surveillance every 3 to 5 years. For low-grade dysplasia, the estimated risk of progression is about 0.7% per year, and ACG has recommended endoscopic therapy or surveillance every 12 months. For high-grade dysplasia, the estimated risk of progression is about 7% per year, and ACG has recommended endoscopic therapy.  The Benign Barrett's and Cancer Taskforce consensus group did not endorse routine surveillance for people with no dysplasia and was unable to agree on surveillance intervals for low-grade dysplasia.

 

Neoplasms of the Pancreas

Management

Given the rare occurrence but the poor prognosis of pancreatic cancer, there is a need to balance potential early detection of malignancies while avoiding unnecessary surgical resection of cysts. Several guidelines address the management of pancreatic cysts, but high-quality evidence to support these guidelines is not generally available. Although recommendations vary, first-line evaluation usually includes an examination of cyst cytopathologic or radiographic findings and cyst fluid carcinoembryonic antigen. An international consensus panel published statements on the management of IPMN and mucinous cystic neoplasm of the pancreas. These statements are referred to as the Fukouka Consensus Guidelines. The panel recommended surgical resection for all surgically fit patients with main duct IPMN or mucinous cystic neoplasm. For branch duct IPMN, surgically fit patients with cytology suspicious or positive for malignancy are recommended for surgical resection, but patients without "high-risk stigmata" or "worrisome features" may be observed with surveillance. "High-risk stigmata" are obstructive jaundice in proximal lesions (head of the pancreas); the presence of an enhancing solid component within the cyst; or 10 mm or greater dilation of the main pancreatic duct. "Worrisome features" are pancreatitis; lymphadenopathy; cyst size 3 cm or greater; thickened or enhancing cyst walls on imaging; 5 to 10 mm dilation of the main pancreatic duct; or abrupt change in pancreatic duct caliber with distal atrophy of the pancreas.

 

Practice Guidelines and Position Statements

NCCN (National Comprehensive Cancer Network)

The NCCN Guidelines on Pancreatic Adenocarcinoma (Version 1.2020), Hepatobiliary Cancers (Version 3.2020), Esophageal and Esophagogastric Junction Cancers (Version 2.2020), Central Nervous System Cancers (Version 1.2020) do not mention Molecular topographic genotyping.

 

The American Gastroenterological Association

The American Gastroenterological Association guidelines have no recommendations for the use of topographic genotyping for evaluating pancreatic cysts.

 

The American Society of Gastrointestinal Endoscopy

The American Society of Gastrointestinal Endoscopy guideline (2016) states Molecular analysis (which requires only 200 mL of fluid) may be most useful in small cysts with nondiagnostic cytology, equivocal cyst fluid CEA results, or when insufficient fluid is present for CEA testing. However, additional research is needed to determine the precise role molecular analysis of cyst fluid will play in evaluating pancreatic cystic lesions.

 

American College of Gastroenterology

The College (2018) published guidelines on the diagnosis and management of pancreatic cysts. The guidelines stated that the evidence for the use of molecular biomarkers for identifying high-grade dysplasia or pancreatic cancer is insufficient to recommend their routine use. However, molecular markers may help identify intraductal papillary mucinous neoplasms and mucinous cystic neoplasms in cases with an unclear diagnosis and if results are likely to change the management (conditional recommendation; very low quality evidence).

 

Current evidence-based guidelines from other medical professional organizations do not include topographic genotyping with strong evidence for recommendation.

 

Prior Approval:

Not applicable

 

Policy:

Refer to policy 02.01.23 Treatment of GERD and Barrett’s esophagus for additional information on treatment of Barrett’s esophagus

 

Molecular topographic genotyping including PathFinderTG® system, PancraGen™ and BarreGen™or any other test utilizing molecular topographic genotyping is considered investigational for all indications including, but not limited to:

  • evaluation of pancreatic cyst fluid (now called PancraGen™)
  • evaluation of Barrett’s esophagus (now called BarreGen™)
  • evaluation of biliary strictures (PathFinderTG® Biliary)
  • evaluation to differentiate tumors
  • evaluation of pancreaticobiliary lesion (PathFinderTG® Biliary)

 

There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure. The testing accuracy is questioned by currently available studies. The clinical utility of topographic genotyping in the diagnosis and management of cancer has not yet been established through well-designed clinical trials.

 

This test has multiple potential uses including use in diagnosis, determining prognosis, and predicting response to therapies. All uses, in all conditions, are considered investigational.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 84999 Unlisted chemistry procedure
  • 89240 Unlisted miscellaneous pathology test
  • 81599 Unlisted multianalyte assay with algorithmic analysis
  • 81479 Unlisted molecular pathology procedure

 

Selected References:

  • Nikiforova MN, et al. Molecular diagnostics of gliomas. Arch Pathol Lab Med 2011 Jul;135(7):558-68.
  • Sawhney MS, et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc 2009;69:1106-10.
  • Shen J, et al. Molecular analysis of pancreatic cyst fluid. Cancer Cytopathol 2009;117:217-227.
  • Sreenarasimhaiah J, et al. A comparative analysis of pancreas cyst fluid CEA and histology with DNA mutational analysis in the detection of mucin producing or malignant cysts. JOP 2009;10(2):163-8.
  • Trikalinos TA, et al. A systematic review of loss-of-heterozygosity based topographic genotyping with PathfinderTG®. AHRQ Technology Assessment Program (Project ID GEND0308). 2010 Mar 1
  • Tse DT, et al. Microdissection genotyping analysis of the effect of intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland adenoid cystic carcinoma. Am J Ophthalmol 2006 Jan;141(1):54-61.
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma, version 1.2020.
  • RedPath Integrated Pathology Overview & copy;2013.
  • Centers for Medicare and Medicaid Services, CMS Manual System and other CMS publications and services
  • Oh HC, Kim MH, Hwang CY, et al. Cystic lesions of the pancreas: challenging issues in clinical practice. Am J Gastroenterol. 2008;103(1):229-239.
  • Khalid A, Brugge W. ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol. 2007;102(10):2339-2349.
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: central nervous system cancers, version 2.2020.
  • Loren D, Kowalski T, Siddiqui A, et al. Influence of integrated molecular pathology test results on real-world management decisions for patients with pancreatic cysts: analysis of data from a national registry cohort. Diagnostic Pathology. 2016;11:5.
  • Muthusamy, V. Chandrasekhara, V. Acosta, R. et. al The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms, ASGE Standards of practice committee,  Gastrointest Endosc 2016;84:1-9 
  • Singhi AD, Zeh HJ, Brand RE, et al. American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data. Gastrointest Endosc. 2016; 83(6):1107-1111.
  • National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers. Version 2.2020.
  • Kowalski T, Siddiqui A, Loren D, et al. Management of patients with pancreatic cysts: analysis of possible false negative cases of malignancy. J Clin Gastroenterol. Sep 2016;50(8):649-657. PMID 27332745
  • Tamura K, Ohtsuka T, Date K, et al. Distinction of invasive carcinoma derived from intraductal papillary mucinous neoplasms from concomitant ductal adenocarcinoma of the pancreas using molecular biomarkers. Pancreas. Jul 2016;45(6):826-835. PMID 26646266
  • National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: hepatobiliary cancers. Version 3.2020
  • Kushnir VM, Mullady DK, Das K, et al. The diagnostic yield of malignancy comparing cytology, fish, and molecular analysis of cell free cytology brush supernatant in patients with biliary strictures undergoing endoscopic retrograde cholangiography (ERC): a prospective study. J Clin Gastroenterol. Aug 13 2018. PMID 30106834
  • Gonda TA, Viterbo D, Gausman V, et al. Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures. Clin Gastroenterol Hepatol. Jun 2017;15(6):913-919 e911. PMID 28017843
  • ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. American Journal of Gastroenterology. 113(4):464–479, APR 2018 DOI: 10.1038/ajg.2018.14. 
  • Tanaka, M., Fernandez-Del Castillo, C., Kamisawa, T., Jang, J. Y., Levy, P., Ohtsuka, T., . . . Wolfgang, C. L. (2017). Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology, 17(5), 738-753.

 

Policy History:

  • June 2020 - Annual Review, Policy Revised
  • June 2019 - Annual Review, Policy Revised
  • June 2018 - Annual Review, Policy Revised
  • June 2017 - Annual Review, Policy Revised
  • June 2016 - Annual Review, Policy Revised
  • July 2015 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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