Molecular Testing for the Management of Pancreatic Cysts and Solid Pancreaticobiliary Lesions

POLICY NUMBER

L.2.04.465

DESCRIPTION

Tests that integrate microscopic analysis with molecular tissue analysis are generally called topographic genotyping. Interpace Diagnostics offers two such tests that use the PathFinderTG® platform (PancraGEN®). These molecular tests are intended to be used adjunctively when a definitive pathologic diagnosis cannot be made because of the inadequate specimen or equivocal histologic or cytologic findings, to inform appropriate surveillance or surgical strategies.

Mucinous Neoplasms of the Pancreas

True pancreatic cysts are fluid-filled, cell-lined structures, which are most commonly mucinous cysts (intraductal papillary mucinous neoplasm [IPMN] and mucinous cystic neoplasm), which are associated with future development of pancreatic cancers. Incidence of IPMNs is generally equal between men and women, while mucinous cystic neoplasms occur almost exclusively in women (accounting for about 95% of cases). Pancreatic cancer arising from IPMNs and mucinous cystic neoplasms account for about 4% of pancreatic malignancies. Although mucinous neoplasms associated with cysts may cause symptoms (eg, pain, pancreatitis), an important reason that such cysts are followed is the risk of malignancy, which is estimated to range from 0.01% at the time of diagnosis to 15% in resected lesions.

ManagementGiven 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. In 2012, 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 and were based on a symposium held in Japan in 2010, which updated a 2006 publication (Sendai Consensus Guidelines) by this same group. 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.

In 2015, the American Gastroenterological Association published guidelines on the evaluation and management of pancreatic cysts; it recommended patients undergo further evaluation with endoscopic ultrasound-guided fine-needle aspiration only if the cyst has 2 or more worrisome features (size ≥3 cm, a solid component, a dilated main pancreatic duct). The guidelines also recommended that patients with these “concerning features” confirmed on fine-needle aspiration undergo surgery.

Solid Pancreaticobiliary Lesions

Solid pancreaticobiliary lesions refer to lesions found on the pancreas, gallbladder, or biliary ducts. A solid lesion may be detected as an incidental finding on computed tomography scans performed for another reason, though this occurs rarely. The differential diagnosis of a solid pancreatic mass includes primary exocrine pancreatic cancer, pancreatic neuroendocrine tumor, lymphoma, metastatic cancer, chronic pancreatitis, or autoimmune pancreatitis.

ManagementCurrently, 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. PancraGEN topographic genotyping is being investigated as either an alternative to or as an adjunct to fluorescent in situ hybridization in the diagnostic confirmation process.

Topographic Genotyping

Topographic genotyping, also called molecular anatomic pathology, integrates microscopic analysis (anatomic pathology) with molecular tissue analysis. Under microscopic examination of tissue and other specimens, areas of interest may be identified and microdissected to increase tumor cell yield for subsequent molecular analysis. Topographic genotyping may permit pathologic diagnosis when first-line analyses are inconclusive.

RedPath Integrated Pathology (now Interpace Diagnostics) has patented a proprietary platform called PathFinderTG; it provides mutational analyses of patient specimens. The patented technology permits analysis of tissue specimens of any size, “including minute needle biopsy specimens,” and any age, “including those stored in paraffin for over 30 years.”

Interpace Diagnostics stopped the acceptance of PancraGEN specimens on February 7, 2025, following the Centers for Medicare & Medicaid Services (CMS) decision to discontinue reimbursement for the test. Consequently, no specimens or orders for PancraGEN were accepted after May 2, 2025.

ERCP: endoscopic retrograde cholangiopancreatography.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Patented diagnostic tests (eg, PancraGEN®) are available only through Interpace Diagnostics (formerly RedPath Integrated Pathology) under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

PancraGEN assesses the cumulative DNA mutations in key oncogenes and tumor suppressor genes associated with pancreatic cancer. Specifically, PancraGEN identifies:

• High levels of intact DNA are associated with actively dividing cells;

• Oncogenes: KRAS and GNAS point mutations;

• Tumor suppressor genes (in parentheses) in the following genomic loci: 3p (VHL, OGG1), 10q (PTEN, MXI1), 17p (TP53), 18q (SMAD4, DCC), 9p (CDKN2A, CDKN2B), 17q (RNF43, NME1), 21q (PSEN2, TFF1), 1p (RUNX3, CMM1, LMYC), 5q (MCC, APC), 22q (NF2).

POLICY

Molecular testing using the PathFinderTG system is considered investigational for all indications including the evaluation of pancreatic cyst fluid and solid pancreaticobiliary lesions.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

4/29/2008: Policy added.

7/17/2008: Reviewed and approved by the Medical Policy Advisory Committee (MPAC).

4/27/2009: Policy reviewed, no changes.

07/09/2010: Policy description revised to define PCR as "polymerase chain reaction." Policy statement unchanged. 

08/02/2011: Policy reviewed; no changes.

07/17/2012: Policy reviewed; no changes.

08/14/2013: Policy reviewed; no changes.

07/31/2014: Policy reviewed; description revised. Policy statement revised to add "and Barrett esophagus." It previously stated: Molecular testing using the PathFinderTG® system is considered investigational for all indications including the evaluation of pancreatic cyst fluid and of suspected or known gliomas.

08/03/2015: Code Reference section updated for ICD-10.

09/22/2015: Policy reviewed; policy statement unchanged. Investigative definition updated in Policy Guidelines section.

06/06/2016: Policy number A.2.04.52 added.

08/19/2016: Policy description updated to remove tests that are no longer commercially available and to add information regarding management of mucinous neoplasms of the pancreas and Barrett Esophagus. Removed "suspected or known gliomas" from the investigational policy statement. Policy Guidelines updated to add genetic counseling information.

08/17/2017: Policy title changed from "PathFinderTG® Molecular Testing" to "Molecular Testing for the Management of Pancreatic Cysts or Barrett Esophagus." Policy description updated to change "mutations" to "variants." Policy statement unchanged. Policy Guidelines updated to add standard terminology for variant classification. Removed genetic counseling information.

10/25/2018: Policy title changed from "Molecular Testing for the Management of Pancreatic Cysts or Barrett Esophagus" to "Molecular Testing for the Management of Pancreatic Cysts, Barrett Esophagus, and Solid Pancreatic Lesions." Policy description updated regarding solid pancreaticobiliary lesions. Policy statement updated to add solid pancreaticobiliary lesions as an investigational indication. Policy Guidelines updated.

08/13/2019: Policy reviewed; no changes.

08/17/2020: Policy reviewed; no changes.

08/30/2021: Policy title updated to change "Pancreatic Lesions" to "Pancreaticobiliary Lesions." Policy description updated regarding PathFinderTG tests. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature information.

03/28/2022: Code Reference section updated to add new 04/01/2022 CPT code 0313U.

08/09/2022: Policy description updated regarding mucinous neoplasms of the pancreas and Barrett esophagus. Policy statement unchanged.

08/08/2023: Policy reviewed; no changes.

10/01/2024: Code Reference section updated to add new CPT code 0510U.

01/22/2025: Policy updated to move information regarding Barrett Esophagus to the Adjunctive Techniques for Screening, Surveillance, and Risk Classification of Barrett Esophagus and Esophageal Dysplasia medical policy. Policy title changed from "Molecular Testing for the Management of Pancreatic Cysts, Barrett Esophagus, and Solid Pancreaticobiliary Lesions" to "Molecular Testing for the Management of Pancreatic Cysts and Solid Pancreaticobiliary Lesions." Policy description updated regarding tests. Policy statement updated to remove "Barrett esophagus" as a listed indication.

07/18/2025: Code Reference section updated to add new CPT code 0573U. Effective 07/01/2025.

10/09/2025: Policy number changed from "A.2.04.52" to "L.2.04.465." Policy description updated regarding tests. Policy statement unchanged.

SOURCE(S)

Blue Cross & Blue Shield Association Policy # 2.04.52

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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