Medical Policy



Subject: Topographic Genotyping
Document #: LAB.00025 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses topographic genotyping which is being explored as a means to provide diagnostic and prognostic information based on the analysis of specimens.

Topographic genotyping (TG) utilizes microdissection and subsequent molecular analysis to directly correlate genetic alterations with histology in different areas within a specimen.  TG has been proposed as a tool to facilitate the diagnosis of and optimal treatment of individuals with certain tumors, cysts or masses when microscopic analysis and special staining methods cannot provide a definitive diagnosis on specimens.

Position Statement

Investigational and Not Medically Necessary:

Topographic genotyping is considered investigational and not medically necessary for all indications.

Rationale

Topographic genotyping is purported to provide a quantitative genetic mutational analysis when staining methods and microscopic analysis fail to provide a definitive diagnosis on specimens.  The PancraGen® (Interpace Diagnostics, Parsippany, N.J.), formerly known as Pathfinder® (RedPath Integrated Pathology, Pittsburgh, PA), is a patented test that uses topographic genotyping to provide a quantitative genetic mutational analysis of the specimen and is being explored as an adjunctive tool when a definitive pathologic diagnosis cannot be determined using specimens.

The potential impact of topographic genotyping to influence the medical management of an individual with cancer and possibly improve outcomes by providing a definitive diagnosis for previously equivocal conditions has been under investigation for years.  The published peer-reviewed scientific literature has investigated the correlation between genetic findings and histology, cytology and fluid specimens, pathology of surgical or biopsy specimens.  Al-Haddad and colleagues (2015) reported the results of a multicenter study to determine if integrated molecular pathology (IMP), a combined molecular analysis with cytology, imaging, and fluid chemistry, could be used to determine: (1) the malignant potential of pancreatic cysts, and (2) the utility of IMP testing under current guideline recommendations for managing pancreatic cysts.  The authors analyzed the clinical outcomes data obtained from retrospective review of the medical records of individuals included in the National Pancreatic Cyst Registry.  A total of 492 participants who had undergone previous PancraGen testing and for whom clinical outcomes were available, were included in the study.  The performance of each case was categorized according to the four IMP diagnostic categories: "benign," "statistically indolent," "statistically higher risk (SHR)," and "aggressive" or an International Consensus Guideline (Sendai 2012) criteria model for "surveillance" vs. "surgery."  The Cox proportional hazards model was used to determine hazard ratios for malignancy.  Cases diagnosed as benign using the PancraGen test had a 97 % probability follow-up for up to 7 years and 8 months after the initial PancraGen testing.  Cases that were categorized as SHR and aggressive had relative hazard ratios for malignancy of 30.8 and 76.3, respectively (both P < 0.0001).  The Sendai surveillance criteria demonstrated a 97 % probability of benign follow-up for up to 7 years and 8 months, but for surgical criteria the hazard ratio was 9.0 (P < 0.0001).  Amongst those participants who met Sendai surgical criteria, benign and statistically indolent IMP diagnoses had a >  93 % probability of benign follow-up, with relative hazard ratios for SHR and aggressive IMP diagnoses of 16.1 and 50.2, respectively (both P < 0.0001).  The authors concluded that IMP (the PancraGen test) may improve patient management by justifying more relaxed observation in individuals meeting Sendai surveillance criteria.

Loren and colleagues (2016) investigated whether an initial adjunctive IMP testing using the PancraGen test affected future real-world pancreatic cyst management decisions for intervention or surveillance relative to 2012 International Consensus Guideline (ICG) recommendations, and if this resulted in improved patient outcomes.  Utilizing data from the National Pancreatic Cyst Registry, researchers evaluated the relationship between real-world decisions (intervention vs. surveillance), ICG model recommendations (surgery vs. surveillance) and IMP (PancraGen) diagnoses (high-risk vs. low-risk) using 2 × 2 tables.  Kaplan Meier and hazard ratio analyses were used to assess time to malignancy.  Logistic regression was used to determine odds ratios for surgery decision.  Of 491 participants, 206 received clinical intervention at follow-up (183 surgery, 4 chemotherapy, 19 presumed by malignant cytology).  At 2.9 years follow-up, 13% (66/491) of participants had a malignant outcome and 87% (425/491) had a benign outcome.  When ICG and IMP were concordant for surveillance/surgery recommendations, 83% and 88% of participants actually underwent surveillance or surgery, respectively.  However, when ICG recommended surveillance and IMP indicated high risk, 88% of subjects underwent an intervention within 1 year of IMP testing, suggesting that IMP influenced the decision for intervention.  At 2.9 years follow-up, this subgroup demonstrated a malignant outcome rate of 57%.  Similarly, when ICG recommended surgery but IMP indicated low risk, approximately 55% of subjects opted for surveillance.  At 2.9 years follow-up, this group demonstrated a benign outcome rate of 99%.

The Agency for Healthcare Research and Quality (AHRQ) conducted a technology assessment systematic review in 2010 of the published literature on loss-of-heterozygosity based topographic genotyping with the PathfinderTG (Trikalinos, 2010).  Most studies were excluded because they only described the molecular profile of different tumors, without assessing the impact of testing on diagnosis, prognosis, treatment guidance, or clinical outcomes.  The researchers conclude:

It is theoretically and biologically plausible that topographic genotyping (including loss-of-heterozygosity based topographic genotyping with PathfinderTG® ) may have prognostic and diagnostic ability, if one examines a suitable genetic marker panel for each type of cancer.  However, all studies are small, they have important methodological limitations, and they do not address patient-relevant outcomes. 

In a technical review published by the American Gastroenterological Association, the authors concluded the following:

Case series have confirmed that malignant cysts have a greater number and quality of molecular alterations, but no study has been properly designed to identify how the test performs in predicting outcome with regard need for surgery, surveillance or predicting interventions leading to improved survival.  This adjunct to FNA may provide value in distinct clinical circumstances, such as confirmation of a serous lesion due to a lack of KRAS or GNAS mutation in a macrocystic serous cystadenoma, but its routine use is not supported at the present time (Scheiman, 2015).

The American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Asymptomatic Neoplastic Pancreatic Cysts does not include the use of topographic genotyping in their recommendations for the evaluation of pancreatic cysts.  Likewise, the National Comprehensive Cancer Network Clinical Practice Guidelines on pancreatic adenocarcinoma do not address the use of topographic genotyping.  Similarly, the International consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) of the pancreas do not include topographic genotyping as a tool in the management of IPMN or MCN of the pancreas (NCCN, 2017; Tanaka, 2012; Vege, 2015).

According to the American Association for Gastrointestinal Endoscopy (ASGE):

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. (ASGE, 2016),

Currently, there is insufficient evidence in the published, peer-reviewed, scientific literature to demonstrate that topographic genotyping (for example, PancraGen) is an effective method to aid in the diagnosis or management of individuals with pancreatic cysts or other neoplasms when other testing methods (such as endoscopic ultrasound and microscopic analysis and staining) fail or are inconclusive.  There is a lack of peer-reviewed evidence demonstrating that the use of topographic genotyping in the diagnosis and management of individuals with pancreatic cysts or other neoplasms results in clinical utility or improved clinical outcomes.

Background/Overview

Topographic genotyping (TG) has been proposed as a tool to facilitate the diagnosis and optimal treatment of individuals with certain cancers when microscopic analysis and special staining methods are unable to provide a definitive diagnosis using the specimens.  The PancraGen test (formerly marketed as the PathFinderTG test) is a pancreatic cyst molecular test that uses a sample of pancreatic cyst fluid to assist in pancreatic cyst diagnosis and pancreatic cancer risk assessment.

Definitions

Cytology:  The study of the formation and function of cells.

DNA (deoxyribonucleic acid): A type of molecule that contains the code for genetic information.

Genotype: The genetic structure (constitution) of an organism or cell.

Histology: The study of the microscopic structure of tissue and cells.

Mutation: A permanent, structural change in the DNA.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT  
81479 Unlisted molecular pathology procedure [when specified as a topographic genotyping]
84999 Unlisted chemistry  procedure [when specified as a topographic genotyping]
   
ICD-10 Diagnosis  
  All diagnoses
   
References

Peer Reviewed Publications:

  1. Al-Haddad MA, Kowalski T, Siddiqui A, et al. Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. Endoscopy. 2015; 47(2):136-142.
  2. Finkelstein SD, Marsh W, Demetris AJ, et al. Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology. 2003; 37(4):871-879.
  3. Finkelstein SD, Przygodzki R, Pricolo VE, et al. K-ras-2 topographic genotyping of pancreatic adenocarcinoma. Arch Surg. 1994; 129(4):367-372.
  4. Finkelstein SD, Przygodzki R, Pricolo VE, et al. Prediction of Biologic Aggressiveness in Colorectal Cancer by p53/K-ras-2 Topographic Genotyping. Mol Diagn. 1996; 1(1):5-28.
  5. Finkelstein SD, Tiffee JC, Bakker A, et al. Malignant transformation in sinonasal papillomas is closely associated with aberrant p53 expression. Mol Diagn. 1998; 3(1):37-41.
  6. Guido M, Rugge M, Thung SN, et al. Hepatitis C virus serotypes and liver pathology. Liver. 1996; 16(6):353-357.
  7. Holst VA, Finkelstein S, Colby TV, et al. p53 and K-ras mutational genotyping in pulmonary carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma: implications for histogenesis. Am J Surg Pathol. 1997; 21(7):801-811.
  8. Holst VA, Finkelstein S, Yousem SA. Bronchioloalveolar adenocarcinoma of lung: monoclonal origin for multifocal disease. Am J Surg Pathol. 1998; 22(11):1343-1350.
  9. Jacoby RF, Marshall DJ, Kailas S, et al. Genetic instability associated with adenoma to carcinoma progression in hereditary nonpolyposis colon cancer. Gastroenterology. 1995; 109(1):73-82.
  10. Jones MW, Kounelis S, Hsu C, et al. Prognostic value of p53 and K-ras-2 topographic genotyping in endometrial carcinoma: a clinicopathologic and molecular comparison. Int J Gynecol Pathol. 1997; 16(4):354-360.
  11. Jones MW, Kounelis S, Papadaki H, et al. The origin and molecular characterization of adenoid basal carcinoma of the uterine cervix. Int J Gynecol Pathol. 1997; 16(4):301-306.
  12. Kanbour-shakir A, Kounelis S, Papadaki H, et al. Relationship of p53 genotype to second-look recurrence and survival in ovarian epithelial malignancy. Mol Diagn. 1996; 1(2):121-129.
  13. Kounelis S, Jones MW, Papadaki H, et al. Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components. Hum Pathol. 1998; 29(1):82-87.
  14. 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. 2016; 50(8):649-655.
  15. 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. Diagn Pathol. 2016; 11(1):5.
  16. Papadaki H, Kounelis S, Kapadia SB, et al.  Relationship of p53 gene alterations with tumor progression and recurrence in olfactory neuroblastoma. Am J Surg Pathol. 1996; 20(6):715-721.
  17. Pollack IF, Finkelstein SD, Burnham J, et al. Children's Cancer Group. Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort. Cancer Res. 2001; 61(20):7404-7407.
  18. Pricolo VE, Finkelstein SD, Bland KI. Topographic genotyping of colorectal carcinoma: from a molecular carcinogenesis model to clinical relevance. Ann Surg Oncol. 1997; 4(3):269-278.
  19. Pricolo VE, Finkelstein SD, Wu TT, et al. Prognostic value of TP53 and K-ras-2 mutational analysis in stage III carcinoma of the colon. Am J Surg. 1996; 171(1):41-46.
  20. Przygodzki RM, Finkelstein SD, Keohavong P, et al. Sporadic and Thorotrast-induced angiosarcomas of the liver manifest frequent and multiple point mutations in K-ras-2. Lab Invest. 1997; 76(1):153-159.
  21. Przygodzki RM, Finkelstein SD, Langer JC, et al. Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. Am J Pathol. 1996; 148(5):1531-1541.
  22. Przygodzki RM, Koss MN, Moran CA, et al. Pleomorphic (giant and spindle cell) carcinoma is genetically distinct from adenocarcinoma and squamous cell carcinoma by K-ras-2 and p53 analysis. Am J Clin Pathol. 1996; 106(4):487-492.
  23. Przygodzki RM, Moran CA, Suster S, Ket al. Primary mediastinal and testicular seminomas: a comparison of K-ras-2 gene sequence and p53 immunoperoxidase analysis of 26 cases. Hum Pathol. 1996; 27(9):975-979.
  24. Ribeiro U Jr, Finkelstein SD, Safatle-Ribeiro AV, et al. p53 sequence analysis predicts treatment response and outcome of patients with esophageal carcinoma. Cancer. 1998; 83(1):7-18.
  25. Ribeiro U, Safatle-Ribeiro AV, Posner MC, et al. Comparative p53 mutational analysis of multiple primary cancers of the upper aerodigestive tract. Surgery. 1996; 120(1):45-53.
  26. Safatle-Ribeiro AV, Ribeiro Júnior U, Reynolds JC, et al. Morphologic, histologic, and molecular similarities between adenocarcinomas arising in the gastric stump and the intact stomach. Cancer. 1996; 78(11):2288-2299.
  27. Shen J, Brugge WR, Dimaio CJ, Pitman MB. Molecular analysis of pancreatic cyst fluid: a comparative analysis with current practice of diagnosis. Cancer Cytopathol. 2009; 117(3):217-227.
  28. 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.
  29. Trikalinos TA, Terasawa T, Raman G. A systematic review of loss-of-heterozygosity based topographic genotyping with PathfinderTG. Technology Assessment Report. Project ID: GEND0308. Prepared by the Tufts Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) under Contract No. HHSA 290 2007 10055 I. Rockville, MD: AHRQ; March 1, 2010.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. ASGE Standards of Practice Committee, Muthusamy VR, Chandrasekhara V, et al. The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms. Gastrointest Endosc. 2016; 84(1):1-9.
  2. NCCN Clinical Practice Guidelines in Oncology™. © 2015 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org. Accessed on February 23, 2016.
    • Pancreatic Adenocarcinoma (V.2.2015). Revised March 6, 2015.
  3. Scheiman JM, Hwang JH, Moayyedi P. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015; 148(4):824-848.e22.
  4. Tanaka M, Fernández-del Castillo C, Adsay V, et al.I nternational consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012; 12(3):183-197.
  5. Vege SS, Ziring B, Jain R, et al. American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015; 148(4):819-822.
Index

PancraGen
PathFinderTG
Topographic Genotyping

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated review date, Rationale, References and History sections of the document.
Reviewed 05/05/2016 MPTAC review.
Reviewed 05/04/2016 Hematology/Oncology Subcommittee review. Title changed to "Topographic Genotyping". Updated review date, Rationale, Background/Overview, References and History sections of the document. Removed ICD-9 codes from Coding section.
Reviewed 05/07/2015 MPTAC review.
Reviewed 05/06/2015 Hematology/Oncology Subcommittee review. Updated review date, Description/Scope, References and History sections of the document.
Reviewed 05/15/2014 MPTAC review.
Reviewed 05/14/2014 Hematology/Oncology Subcommittee review. Updated review date, Rationale, References and History sections of the document.
Reviewed 05/09/2013 MPTAC review.
Reviewed 05/08/2013 Hematology/Oncology Subcommittee review. Updated review date, References and History sections of the document.
Reviewed 05/10/2012 MPTAC review.
Reviewed 05/09/2012 Hematology/Oncology Subcommittee review. Updated review date, References and History sections of the document.
Reviewed 05/19/2011 MPTAC review.
Reviewed 05/18/2011 Hematology/Oncology Subcommittee review. Updated review date, Rationale, References and History sections of the document.
Reviewed 05/13/2010 MPTAC review.
Reviewed 05/12/2010 Hematology/Oncology Subcommittee review. Updated review date, References and History sections of the document.
Reviewed 05/21/2009 MPTAC review.
Reviewed 05/20/2009 Hematology/Oncology Subcommittee review. Updated review date, References and History sections of the document.
New 05/15/2008 MPTAC review.
New 05/14/2008 Hematology/Oncology Subcommittee initial document development.