Description of Procedure or Service

Integrated molecular pathology (IMP) testing combines molecular analysis with first-line test results (cytology, imaging, and fluid chemistry) to assess malignant potential (Al-Haddad et al., 2015). It is currently most commonly a second line testing strategy used adjunctively when a definitive pathologic diagnosis cannot be made, because of inadequate specimen or equivocal histologic or cytologic findings.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Pancreatic cancer risk testing using molecular classifier in pancreatic cyst fluid is considered investigational for all applications. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Pancreatic Cancer Risk Testing Using Molecular Classifier is covered

Not applicable.

When Pancreatic Cancer Risk Testing Using Molecular Classifier is not covered

Pancreatic cancer risk testing using the molecular classifier such as PancraGEN test is considered investigational for all indications, including the evaluation of pancreatic cyst fluid and of suspected or known gliomas and Barrett esophagus.

Policy Guidelines

Literature review

RedPath Integrated Pathology developed and patented a proprietary platform, PathFinderTG^®, based on topographic genotyping (TG), also called molecular anatomic pathology, which integrates microscopic analysis (anatomic pathology) with molecular tissue analysis and claims that TG may permit pathologic diagnosis when first-line analyses are inconclusive (Finkelstein & Finkelstein, 2001). RedPath developed 5 different Pathfinder GT test (Pancreas, biliary, Barrett, Glioma, and Metastasis versus Primary Tumors (MvP)) before the company was purchased by Interpace Diagnostics. Interpace Diagnostics has continued development of these molecular pathology panels and markets them separately as PancraGen (Diagnostics, 2017).

The PancraGen is a DNA-based, integrated molecular pathology test that helps to assess the cancer risk in aspirated pancreatic cyst fluid. This test uses extracted DNA from aspirated pancreatic cyst fluid for testing tumor suppressor genes (Loss of Heterozygosity) in a panel of microsatellite markers using PCR/capillary electrophoresis, and oncogene point mutations using Sanger sequencing and capillary electrophoresis. PancraGen formerly known as PathFinderTG has claimed molecular diagnostic sensitivity of 95% and is performed in CLIA certified laboratory.

• PancraGen is a second-line, multi-variate assay that combines molecular analysis with first line test results (cytology, fluid chemistry, and imaging) to assess the malignant potential of pancreatic cysts. PancraGen is not indicated for cases where the cytology is positive for malignancy. PanDNA is the molecular technology that drives PancraGEN. The DNA abnormalities identified by this technology include tumor suppressor gene panel (Loss of Heterozygosity) analysis of VHL, OGG1; PTEN, MXI1; TP53; SMAD4, DCC; CDKN2A; RNF43, NME1; PSEN2, TFF1; CMM1v; MCC, APC; NF2. Oncogene point mutations provided by this test are those in KRAS (codons 12, 13) and GNAS (codon 201). The report provides summary of molecular results, specific molecular results and details of each result with the possible clinical meanings of those results (Interpace Diagnostics, 2018).

Clinical Validity and Utility

PancraGEN:

Trikalinos et al (2010) conducted a systematic review of published literature on PathFinderTG^® for the Agency for Healthcare Research and Quality. They found that most studies on loss-of-heterozygosity based topographic genotyping with PathFinderTG^® were excluded because they did not assess the ability of the method to help make diagnosis, prognosis or treatment guidance. The review found no studies that directly measured whether using the PathFinderTG^® test improves patient-relevant clinical outcomes. Additionally, eligible studies on the diagnostic and prognostic ability of PathfinderTG were small in sample sizes, had overt methodological limitations, and did not report important characteristics of their designs.

Panarelli et al (2012) found that “the PathfinderTG panel may aid the classification of pancreatic lesions, but is often inaccurate and should not replace cytologic evaluation of these lesions.”

Malhotra et al (2014) evaluated the supporting role that mutational profiling of DNA may play in the diagnosis of malignancy in fine-needle aspirates (FNA) and biliary brushing specimens from patients with pancreaticobiliary masses. 30 patients who presented with pancreaticobiliary masses were evaluated and had minimum follow-up of 3 months. PathFinderTG^® mutational profiling was done and analyzed in 26 patients with atypical, negative or indeterminate cytology. Cytology correctly diagnosed 4 of 21 malignant cases (sensitivity, 19%), and identified 7 of 9 patients with non-aggressive disease (specificity, 78%). PathFinderTG^® correctly diagnosed 8 of 17 malignant cases (sensitivity, 47%) and identified all 9 patients with non-aggressive disease (specificity, 100%).When first line malignant cytology results were combined with positive second line mutational profiling results, sensitivity improved to 57% (12/21 cases of aggressive disease were identified). The investigators concluded that mutational profiling provided additional information regarding the presence of aggressive disease. When used in conjunction with first line cytology, mutational profiling increased detection of aggressive disease without compromising specificity in patients that were difficult to diagnose by cytology alone.

Al-Haddad et al (2015) published a study that found “IMP more accurately determined the malignant potential of pancreatic cysts than a Sendai 2012 guideline management criteria model. IMP may improve patient management by justifying more relaxed observation in patients meeting Sendai surveillance criteria. IMP can more accurately differentiate between the need for surveillance or surgery in patients meeting Sendai surgical criteria.”

Loren et al (2016) also found that “DNA-based IMP diagnoses were predictive of real-world management decisions. Importantly, when International Consensus Guidelines and IMP were discordant, IMP influence benefitted patients by increasing confidence in surveillance and surgery decisions and reducing the number of unnecessary surgeries in patients with benign disease.”

Kowalski et al (2016) reported “Adjunct use of IMP can provide evidence for relaxed surveillance of patients with benign cysts that meet Fukuoka criteria for closer observation or surgery. Although infrequent, FN results with IMP can be associated with EUS-FNA sampling limitations or high-risk clinical circumstances.”

Singhi et al (2016) assessed the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. The clinical findings, EUS features, cytopathology results, carcinoembryonic antigen analysis, and molecular testing of pancreatic cyst fluid of 225 patients who underwent EUS-guided FNA for pancreatic cysts were reviewed. “Diagnostic pathology results were available for 41 patients (18%), with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of intraductal papillary mucinous neoplasms with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 patients (15%) with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue magnetic resonance imaging (MRI) surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasias with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value.”

Applicable Federal Regulations

This test is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

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.

Guidelines and Recommendations

Practice Guidelines and Position Statements

American Gastroenterological Association (AGA)

In 2011, the AGA published a medical position statement on the management of Barrett’s Esophagus that stated that “we suggest against the use of molecular biomarkers to confirm the histologic diagnosis of dysplasia or as a method of risk stratification for patients with Barrett's esophagus at this time (weak recommendation, low-quality evidence)” (Spechler et al, 2011).

In 2015, the AGA published guidelines on the diagnosis and management of asymptomatic neoplastic pancreatic cysts (Vege et al, 2015). The guidelines do not address the use of molecular anatomic pathology for evaluating pancreatic cysts.

In 2018, the AGA updated its recommendations (Elta, Enestvedt, Sauer, & Lennon, 2018) on the diagnosis and management of pancreatic cysts to state: “Molecular markers may help identify IPMNs and MCNs. Their use may be considered in cases in which the diagnosis is unclear and the results are likely to change management (Conditional recommendation, very low quality of evidence).”

National Comprehensive Cancer Network (NCCN)

Current NCCN clinical practice guidelines for pancreatic adenocarcinoma, central nervous system cancers, esophageal and esophagogastric junction cancers and hepatobiliary cancers do not include recommendations for molecular anatomic pathology or integrated molecular pathology.

International Consensus Fukuoka Guidelines

The International Association of Pancreatology (Tanaka et al., 2017) held a consensus symposium to examine the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. They found that “At present, EUS-FNA with cytological and molecular analyses is still considered investigational and should be performed only in centers with expertise in performing EUS-FNA and interpreting the results. More data are needed to accurately determine the sensitivity, specificity, and safety of this procedure and if results can be generalized.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 84999, 89240

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Al-Haddad, M. A., Kowalski, T., Siddiqui, A., Mertz, H. R., Mallat, D., Haddad, N., . . . Catalano, M. F. (2015). Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. Endoscopy, 47(2), 136-142. doi:10.1055/s-0034-1390742

Beaudenon-Huibregtse, S., Alexander, E. K., Guttler, R. B., Hershman, J. M., Babu, V., Blevins, T. C., . . . Labourier, E. (2014). Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid, 24(10), 1479-1487. doi:10.1089/thy.2013.0640

Diagnostics, I. (2017). Interpace Diagnostics Molecular Diagnostics. Retrieved from http://www.interpacediagnostics.com/

Elta, G. H., Enestvedt, B. K., Sauer, B. G., & Lennon, A. M. (2018). ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. Am J Gastroenterol, 113(4), 464-479. doi:10.1038/ajg.2018.14

Finkelstein, S. D., & Finkelstein, P. A. (2001). United States Patent No. patft.uspto.gov: U. S. Patent.

Kowalski, T., Siddiqui, A., Loren, D., Mertz, H. R., Mallat, D., Haddad, N., . . . Al-Haddad, M. A. (2016). Management of Patients With Pancreatic Cysts: Analysis of Possible False-Negative Cases of Malignancy. J Clin Gastroenterol, 50(8), 649-657. doi:10.1097/mcg.0000000000000577

Labourier, E., Shifrin, A., Busseniers, A. E., Lupo, M. A., Manganelli, M. L., Andruss, B., . . . Beaudenon-Huibregtse, S. (2015). Molecular Testing for miRNA, mRNA, and DNA on Fine-Needle Aspiration Improves the Preoperative Diagnosis of Thyroid Nodules With Indeterminate Cytology. J Clin Endocrinol Metab, 100(7), 2743-2750. doi:10.1210/jc.2015-1158

Loren, D., Kowalski, T., Siddiqui, A., Jackson, S., Toney, N., Malhotra, N., & Haddad, N. (2016). 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. Diagn Pathol, 11. doi:10.1186/s13000-016-0462-x

Malhotra, N., Jackson, S.A., Freed, L.L., et al (2014). The added value of using mutational profiling in addition to cytology in diagnosing aggressive pancreaticobiliary disease: review of clinical cases at a single center. BMC Gastroenterol., 14:135.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma, version 1.2017. Retrieved online on April 20, 2017 from http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf

National Comprehensive Cancer Network (2016). NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers, version 1.2016. Retrieved online on April 20, 2017 from http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf

National Comprehensive Cancer Network (2017). NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, version 1.2017. Retrieved online on April 20, 2017 from http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers, version 1.2017. Retrieved online on April 20, 2017 from http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf

Panarelli, N. C., Sela, R., Schreiner, A. M., Crapanzano, J. P., Klimstra, D. S., Schnoll-Sussman, F., Yantiss, R. K. (2012). Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions. Am J Surg Pathol, 36(10), 1434-1443. doi:10.1097/PAS.0b013e31825d534a

Singhi, A. D., Zeh, H. J., Brand, R. E., Nikiforova, M. N., Chennat, J. S., Fasanella, K. E., . . . McGrath, K. (2016). 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, 83(6), 1107-1117.e1102. doi:10.1016/j.gie.2015.12.009

Spechler, S.J., Sharma, P., Souza, R.F. et al (2011). American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology, 140(3):1084-1091.

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. doi:10.1016/j.pan.2017.07.007

Trikalinos, T.A., Terasawa, T., Raman, G., et al (2010). A systematic review of loss-of-heterozygosity based topographic genotyping with PathfinderTG: Technology Assessment Report. Retrieved online on April 20, 2017 from https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id68ta.pdf

Vege, S.S., Ziring, B., Jain, R., and Moayyedi, P. (2015) Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology, 148(4):819-822.

Policy Implementation/Update Information

1/1/2019 New policy developed. Pancreatic cancer risk testing using the molecular classifier such as PancraGEN test is considered investigational for all indications, including the evaluation of pancreatic cyst fluid and of suspected or known gliomas and Barrett esophagus. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)