CAM 293

Pancreatic Cancer Risk Testing Using Molecular Classifier in Pancreatic Cyst Fluid

Category:Laboratory   Last Reviewed:July 2021
Department(s):Medical Affairs   Next Review:July 2022
Original Date:June 2009    

Description:
Pancreatic cancer is the fourth leading cause of death among cancers in the United States, and neoplasms frequently arise from pancreatic cysts that require investigation to differentiate benign neoplasms from malignant ones.

Integrated molecular pathology (IMP) testing combines molecular analysis with first-line test results (cytology, imaging, and fluid chemistry) to assess malignant potential. 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.

Regulatory Status 
A search for “pancreatic risk” and “pancreatic cyst” on the FDA device database on March 23, 2020, yielded 0 results. 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.

Policy
The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

Pancreatic cancer risk testing using the molecular classifier such as PancraGEN test is investigational/unproven and therefore is considered NOT MEDICALLY NECESSARY for all indications, including the evaluation of pancreatic cyst fluid and of suspected or known gliomas and Barrett esophagus.

Rationale
Discovery of pancreatic cysts is becoming more and more common as imaging technologies improve. Classifying these cysts is crucial as these cysts may be neoplastic with malignant potential, whereas non-neoplastic cysts only require treatment if they are symptomatic. However, these non-neoplastic cysts are often only identified after a surgical resection. Proprietary tests are available that propose that they can estimate the chances of pancreatic cancer with pancreatic cyst fluid.

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. RedPath developed 5 different Pathfinder GT tests (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.

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 to test tumor suppressor genes (such as PTEN and TP53) and oncogenes (such as KRAS and NRAS). PancraGen is intended as a supplement to other diagnostic tools such as cytology and imaging, and is proposed to enhance assessments of malignancy risk (Interpace, 2020). 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 and GNAS. The report provides summary of specific molecular results and details of each result with the possible clinical meanings of those results.

Another test revolving around pancreatic cyst fluid testing is PancraSeq, from UPMC. This test “detects single nucleotide variants (SNVs) and insertions/deletions (indels) in targeted regions of 20 pancreatic cancer-related genes (which are as follows: AKT1, APC, BRAF, CTNNB1, GNAS, HRAS, IDH1, IDH2, KRAS, MEN1, MET, NF2, NRAS, PIK3CA, PTEN, STK11, TERT, TP53, TSC2, and VHL), and copy number alterations in 4 genes (RNF43, SMAD4, TP53, and VHL)” and is intended to aid in diagnosis of several categories of pancreatic cyst, such as pseudocysts and mucinous cystic neoplasms (MCNs). The test reports alterations in any of its genes, its allele frequency, and whether the variant is of clinical or “potential” clinical significance.

Clinical Validity and Utility
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 examined the diagnostic accuracy of IMP for pancreatic adenocarcinoma. 492 samples were assessed, and out of the benign or indolent IMP diagnoses, 97% had a benign follow-up for up to 7 years, 8 months after IMP testing. Statistically higher risk and aggressive diagnoses had hazard ratios for malignancy of 30.8 and 76.3, respectively. The Sendai surveillance criteria had identical chances of benign follow-up over the same timeframe, but the Sendai surgical criteria only had a hazard ratio of 9.0. The authors concluded, “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) performed a study evaluating the impact of IMP testing on clinical management decisions. 491 patients were examined, and 66 had a malignant outcome (425 benign). The IMP testing was compared to the 2012 International Consensus Guideline (ICG) recommendations. When the two methods agreed, surveillance and surgery was undertaken in 83% and 88% of the cases, respectively. However, when the methods disagreed, the clinicians tended to agree with the IMP method. 88% of patients had an intervention when ICG recommended surveillance but IMP indicated “high-risk”, and 55% of patients underwent surveillance when ICG recommended surgery but IMP indicated low risk. The authors concluded 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.”

Springer and colleagues (2015) evaluated “whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients”. 130 patients with resected pancreatic cystic neoplasms were enrolled. The cyst fluid was evaluated for the following genetic alterations: “BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53 and VHL); loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and aneuploidy”. The authors found this panel to identify 67 of the 74 patients who did not require surgery and estimated the sensitivity to be 90-100% and the specificity to be 92-98%.

Singhi et al. (2016) assessed the accuracy of the AGA guidelines in detecting advanced neoplasia and presented an alternative approach to pancreatic cysts. The clinical findings 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 with 13 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.”

Singhi et al. (2018) also evaluated the accuracy of pancreatic cyst fluid (PCF) DNA testing. A total of 626 PCF samples were taken from 595 patients. KRAS/GNAS mutations were identified in 308 samples (49%), and PIK3CA/PTEN/TP53 mutations were identified in 35 samples (6%). 102 patients had a surgical follow-up, and KRAS/GNAS mutations were detected in 56 intraductal papillary mucinous neoplasms (IPMNs) and 3 mucinous cystic neoplasms (MCNs), which corresponded to an 89% sensitivity and 100% specificity for a mucinous pancreatic cyst. Next generation sequencing identified the combination of KRAS/GNAS mutations and TP53/PTEN/PIK3CA alterations at an 89% sensitivity and 100% specificity. The authors concluded, “In contrast to Sanger sequencing, preoperative NGS of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia.”

Das and colleagues (2015) investigated the cost efficiency of IMP in a “third-party-payer perspective Markov decision model” of a hypothetical cohort of 1,000 asymptomatic patients with a 3 cm solitary pancreatic cyst.  They used four different strategies to evaluate the cost efficiency in terms of quality-adjusted life-years (QALY): “Strategy I used cross-sectional imaging, recommended surgery only if symptoms or risk factors emerged. Strategy II considered patients for resection without initial EUS. Strategy III (EUS + CEA + Cytology) referred only those with mucinous cysts (CEA > 192 ng/mL) for resection. Strategy IV implemented IMP; a commercially available panel provided a ‘Benign,’ ‘Mucinous,’ or ‘Aggressive’ classification based on the level of mutational change in cyst fluid. ‘Benign’ and ‘Mucinous’ patients were followed with surveillance; ‘Aggressive’ patients were referred for resection.” The authors report that the IMP-based Strategy IV provided the greatest increase in QALY at approximately the same cost as the “cheapest approach”, concluding that “use of IMP was the most cost-effective strategy, supporting its routine clinical use (Das et al., 2015).” It should be noted, however, that two of the authors listed on the study were employed by RedPath Integrated Pathology, the developer of the IMP test.

Laquiere et al. (2019) investigated the concordance of mutation analysis between pancreatic cyst fluid and neoplastic tissue. The authors used next-generation sequencing to compare DNA collected from both cystic fluid (CF) and neoplastic tissue (NT). 17 patients were included, and concordant CF-NT genotypes were found in 15 of 17 patients. A higher proportion of mutated alleles were found in CF compared to NT. The authors also noted that “the sensitivity and specificity of KRAS/GNAS mutations in CF to predict an appropriate indication for surgical resection were 0.78 and 0.62, respectively. The sensitivity and specificity of RAF/PTPRD/CTNNB1 /RNF43/POLD1/TP53 mutations in CF were 0.55 and 1.0, respectively”. Although the authors remarked that mutational analysis between both media were highly concordant, they also stated that the results “need to be confirmed on a larger scale”.

Volckmar et al. (2019) published preliminary results from the “prospective ZYSTEUS biomarker study”. This study is intended to investigate “(i) whether detection of driver mutations in IPMN [intraductal papillary mucinous neoplasm] by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics”. 15 patients with pancreatic cysts larger than 10 mm were included, 12 of which had an IPMN and 3 acute pancreatitis controls. All 12 IPMN cases were found to harbor at least one mutation in either KRAS (n = 11) or GNAS (n = 4), with 3 cases harboring both mutations. In 3 cases with “pseudocysts”, no alterations were identified. The authors also found that DNA yields were higher and showed higher mutation diversity in the cellular fraction and concluded that “mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction”. The authors also suggested that their results, “targeted sequencing supports discrimination of IPMN from pseudocysts” when combined with imaging.

Herranz Pérez et al. (2021) studied the impact of molecular analysis on the detection of mucinous cysts and malignancy. Currently, recommendations suggest endoscopic ultrasound fine-needle aspiration (EUS-FNA) with molecular analysis to improve the diagnosis of pancreatic cysts. EUS-FNA and next-generation sequencing was performed in 36 pancreatic cysts, which were classified as mucinous, non-mucinous, and malignant. Of the 36 lesions, 28 (82.4%) were classified as mucinous, 6 (17.6%) were classified as non-mucinous, and 5 (13.9%) were classified as malignant lesions. KRAS and GNAS genes were analyzed for mutations. Analysis of KRAS and GNAS showed 83.33% sensitivity, 60% specificity, 88.24% positive predictive value, and 50% negative predictive value for the diagnosis of mucinous cystic lesions. Mutations in KRAS and GNAS were found in 2/5 (40%) of the lesions classified as non-mucinous, so they were recategorized as mucinous neoplasms. These led to a modification of the follow up plan in 8% of the cysts. Additionally, 1 indeterminate cyst showed a mutation in both KRAS and GNAS, so it could also be classified as mucinous. Therefore, performing molecular analysis in cases of uncertain diagnosis improved categorization of the cyst. 100% of the malignant cysts had mutations in KRAS and/or GNAS. However, the presence of a mutation was not related to malignancy. Overall, the authors conclude that "molecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous. This is important as mucinous cysts are premalignant lesions and have a higher risk of concomitant pancreatic adenocarcinoma, thus implying long-term follow-up."

American Gastroenterological Association (AGA)
In 2015, the AGA published guidelines on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. These guidelines only state, “Molecular techniques to evaluate pancreatic cysts remain an emerging area of research, and the diagnostic utility of these tests is uncertain."

American College of Gastroenterology (ACG)
In 2018, the ACG updated its recommendations (Elta et al., 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).”

The ACG also acknowledges the cost of cyst analysis, noting: “The cost of cyst analysis and cyst surveillance is high, and the benefit in terms of cancer prevention is unproven. There have been no dedicated cost effectiveness analyses about surveillance of incidental pancreatic cysts.”

American Society for Gastrointestinal Endoscopy
The ASGE states that “additional research is needed to determine the precise role molecular analysis of cyst fluid will play in evaluating pancreatic cystic lesions”. However, the ASGE suggests that “molecular testing of the cyst be considered when initial ancillary testing of cytology and CEA is inconclusive and when test results may alter management.”

National Comprehensive Cancer Network
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 assessment of pancreatic cyst fluid.

International Consensus Fukuoka Guidelines
The International Association of Pancreatology (IAP) 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.” Overall, the guideline remarked that molecular analysis of cyst fluid is “still evolving”.

European Study Group on Cystic Tumours of the Pancreas
This guideline is considered “a joint initiative of the European Study Group on Cystic Tumors of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy”.

The guidelines state that “DNA markers, in particular, mutations in GNAS and KRAS, have shown promise in identifying mucin-producing cysts. In cases in which the diagnosis is unclear, and a change in diagnosis will alter management, analysis of these mutations using highly sensitive techniques, such as next-generation sequencing (NGS), may be considered”. This recommendation was given a grade of “2C”. The guidelines also remarked that there is “insufficient evidence” to support the use of RNA or non-carcinoembryonic antigen protein markers in pancreatic cysts. This recommendation was given a grade of “1B”.

International Cancer of the Pancreas Screening (CAPS) Consortium
The CAPS Consortium was convened to update the consensus recommendations for “management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).” In this Consortium, the authors state that “In some cases, evidence of pancreatic neoplasia can be inferred by the presence of mutations detected in secretin-stimulated pancreatic fluid samples…but further investigation is needed to determine the value of these tests for patients under pancreatic surveillance.”

World Gastroenterology Organization (WGO)
THE WGO Global Guidelines provided key guidelines in diagnosis and management of pancreatic cystic lesions. The following recommendations were made:   

  1. “At the initial cyst fluid aspiration: carry out carcinoembryonic antigen (CEA), amylase, and cytology testing.
  2. Molecular testing is not routinely done because of limited data and the expense, but it does hold promise for the future.
  3. When fluid is aspirated, the following tests are recommended in the sequence described, depending on the volume of the aspirate:  
  • Cytology: glycogen-rich cells (SCNs) or mucin-containing cells (MCNs and IPMNs), but the sensitivity is low.
  • Tumor markers: CEA level, an accurate tumor marker for diagnosing a mucinous PCN (the accuracy and cut-off level vary among laboratories).
  • Diagnostic molecular markers: KRAS, GNAS, VHL, CTNNB1.
  •  Prognostic molecular markers: TP53, PIK3CA, PTEN.
  • Mucins: assessment of cyst mucin is complementary to cyst CEA levels and cytology
  • Viscosity: the “string sign” concept is an indirect, inexpensive, but subjective measurement of viscosity, assessed by placing a sample of aspirated fluid between the thumb and index finger and measuring the length of stretch prior to disruption.
  • Amylase (or lipase).”

American College of Radiology
The Expert Panel on Gastrointestinal Imaging of the American College of Radiology created guidelines to determine the appropriate initial imaging study to further evaluate a pancreatic cyst that was incidentally detected on a nondedicated imaging study. ACR mentions that molecular assays for markers such as K-ras, GNAS, PTEN, VHL, TP53, and PIK3CA “may also assist in differentiating neoplastic cystic lesions and predicting cyst behavior. When performed in centers with expertise in EUS-FNA, cytological evaluation can identify atypia, dysplasia, or neoplasia.

References: 

  1. 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
  2. Das, A., Brugge, W., Mishra, G., Smith, D. M., Sachdev, M., & Ellsworth, E. (2015). Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy. Endosc Int Open, 3(5), E479-486. doi:10.1055/s-0034-1392016
  3. 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
  4. ESG. (2018). European evidence-based guidelines on pancreatic cystic neoplasms. Gut, 67(5), 789-804. doi:10.1136/gutjnl-2018-316027
  5. Fábrega-Foster, K., Kamel, I. R., Horowitz, J. M., Arif-Tiwari, H., Bashir, M. R., Chernyak, V., . . . Carucci, L. R. (2020). ACR Appropriateness Criteria® Pancreatic Cyst. J Am Coll Radiol, 17(5s), S198-s206. doi:10.1016/j.jacr.2020.01.021
  6. Finkelstein, S. D., & Finkelstein, P. A. (2001). United States Patent No. patft.uspto.gov: U. S. Patent.
  7. Goggins, M., Overbeek, K. A., Brand, R., Syngal, S., Del Chiaro, M., Bartsch, D. K., . . . Bruno, M. (2020). Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut, 69(1), 7. doi:10.1136/gutjnl-2019-319352
  8. Herranz Pérez, R., de la Morena López, F., Majano Rodríguez, P. L., Molina Jiménez, F., Vega Piris, L., & Santander Vaquero, C. (2021). Molecular analysis of pancreatic cystic neoplasm in routine clinical practice. World journal of gastrointestinal endoscopy, 13(2), 56-71. doi:10.4253/wjge.v13.i2.56
  9. Interpace. (2019). Molecular Testing with PancraGEN. Retrieved from https://pancragen.com/wp-content/uploads/2019/07/PancraGen_ReportGuide_v03i_DOWNLOAD.pdf
  10. Interpace. (2020). How PancraGEN Works. Retrieved from https://pancragen.com/how-it-works/
  11. Khalid, A., McGrath, Kevin. (2020). Classification of pancreatic cysts. Retrieved from https://www.uptodate.com/contents/classification-of-pancreatic-cysts?search=pancreatic%20cyst&source=search_result&selectedTitle=1~98&usage_type=default&display_rank=1#H812371950
  12. Laquiere, A. E., Lagarde, A., Napoleon, B., Bourdariat, R., Atkinson, A., Donatelli, G., . . . Olschwang, S. (2019). Genomic profile concordance between pancreatic cyst fluid and neoplastic tissue. World J Gastroenterol, 25(36), 5530-5542. doi:10.3748/wjg.v25.i36.5530
  13. Longnecker, D. (2021). Pathology of exocrine pancreatic neoplasms. Retrieved from https://www.uptodate.com/contents/pathology-of-exocrine-pancreatic-neoplasms?search=Pancreatic%20ductal%20adenocarcinoma&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  14. 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
  15. Malhotra, N., Jackson, S. A., Freed, L. L., Styn, M. A., Sidawy, M. K., Haddad, N. G., & Finkelstein, S. D. (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. doi:10.1186/1471-230x-14-135
  16. Muthusamy, V. R., Chandrasekhara, V., Acosta, R. D., Bruining, D. H., Chathadi, K. V., Eloubeidi, M. A., . . . DeWitt, J. M. (2016). The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms. Gastrointest Endosc, 84(1), 1-9. doi:10.1016/j.gie.2016.04.014
  17. NCCN. (2021a). Central Nervous System Cancers. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf
  18. NCCN. (2021b). Esophageal and Esophogastric Junction Cancers. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
  19. NCCN. (2021c). Hepatobiliary Cancers. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf
  20. NCCN. (2021d). Pancreatic Adenocarcinoma. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  21. Singhi, A. D., McGrath, K., Brand, R. E., Khalid, A., Zeh, H. J., Chennat, J. S., . . . Nikiforova, M. N. (2018). Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut, 67(12), 2131-2141. doi:10.1136/gutjnl-2016-313586
  22. 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
  23. Springer, S., Wang, Y., Dal Molin, M., Masica, D. L., Jiao, Y., Kinde, I., . . . Lennon, A. M. (2015). A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology, 149(6), 1501-1510. doi:10.1053/j.gastro.2015.07.041
  24. 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
  25. UPMC. (2020a). PANCREASEQ® RESULTS SUMMARY. Retrieved from https://mgp.upmc.com/Content/PancreaSeq_Example_Positive.pdf
  26. UPMC. (2020b). Pancreatic Cyst Fluid NGS Analysis. Retrieved from https://mgp.upmc.com/Home/Test/PanSeq_details
  27. Vege, S. S., Ziring, B., Jain, R., & Moayyedi, P. (2015). American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology, 148(4), 819-822; quize812-813. doi:10.1053/j.gastro.2015.01.015
  28. Volckmar, A. L., Endris, V., Gaida, M. M., Leichsenring, J., Stogbauer, F., Allgauer, M., . . . Stenzinger, A. (2019). Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study. Genes Chromosomes Cancer, 58(1), 3-11. doi:10.1002/gcc.22682
  29. WGO. (2019). Pancreatic cystic lesions. Retrieved from https://www.worldgastroenterology.org/UserFiles/file/guidelines/pancreatic-cystic-lesions-english-2019.pdf

Coding Section

Codes Number Description
CPT  84999  Unlisted chemistry procedure
  89240

Unlisted miscellaneous pathology test 

  81479 

Unlisted molecular pathology proedure 

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     

07/14/2021 

Annual review, no change to policy intent. Updating description, rationale and references. 

07/14/2020 

Annual review, no change to policy intent. Reformatting for clarity. 

07/12/2019 

Annual review, no change to policy intent.

07/19/2018 

Annual review, policy will be reformatted and retitled as PathFinder TG was sold and renamed. No change to intent of policy. 

07/12/2017 

Annual review, no change to policy intent. 

04/25/2017 

Updated category to Laboratory. No other changes. 

09/27/2016 

Updated the word guideline to policy when applicable. No change to policy intent. 

07/06/2016 

Annual review, no change to policy intent. Updating background, description, rationale, references and appendix 1. 

07/21/2015

Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding and appendix 1.

07/16/2014

Updated adding Barrett's esophagus as investigational use, updated description, background, rationale, refernces and policy guidelines.

06/23/2014

Annual review. Updated background, description and guidelines. No change made to policy intent.


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