Coverage Policy Manual
Policy #: 2008017
Category: Laboratory
Initiated: April 2008
Last Review: April 2022
  Genetic Test: Molecular Testing for the Management of Pancreatic Cysts, Barrett Esophagus, and Solid Pancreaticobiliary Lesions (PathFinderTG®)

Description:
Tests that integrate microscopic analysis with molecular tissue analysis are generally called topographic genotyping. Interpace Diagnostics offers 2 such tests that use the PathFinderTG platform (e.g. PancraGEN, BarreGEN). 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.
 
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. Although mucinous neoplasms associated with cysts may cause symptoms (e.g. 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 (Tanaka, 2012).
 
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. In 2012, an international consensus panel published statements on the management of IPMN and mucinous cystic neoplasm of the pancreas (Tanaka, 2012). 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 (Tanaka, 2006). 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) (Vege, 2015). The guidelines also recommended that patients with these "concerning features" confirmed on fine-needle aspiration undergo surgery.
 
Barrett esophagus refers to the replacement of normal esophageal epithelial layer with metaplastic columnar cells in response to chronic acid exposure from gastroesophageal reflux disease. The metaplastic columnar epithelium is a precursor to esophageal adenocarcinoma. These tumors frequently spread before symptoms are present so detection at an early stage might be beneficial.
 
Surveillance for esophageal adenocarcinoma is recommended for those diagnosed with Barrett esophagus (Bennett, 2015). 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 (Shaheen, 2016; Bennett, 2015). 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 (Shaheen, 2016). 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 (Bennett, 2015).
 
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.
 
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. 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, 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 (Trikalinos, 2010).
 
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" (Finkelstein, 2016). Interpace currently describes in detail 1 PathFinderTG test called PancraGEN on its website and describes another PathFinder test called BarreGEN as in a "soft launch" (Interpace Diagnostics, 2016). As stated on the company website, PancraGEN integrates molecular analyses with first-line results (when they are inconclusive) and pathologist interpretation (Interpace Diagnostics, 2016). The manufacturer calls this technique integrated molecular pathology. Test performance information is not provided on the website.
 
PancraGEN is performed on pancreatobiliary fluid/ERCP brush, pancreatic masses, or pancreatic tissue. It uses loss of heterozygosity markers, oncogene variants, and DNA content abnormalities to stratify patients according to their risk of progression to cancer. BarreGEN is performed on esophageal tissue. It measures the presence and extent of genomic instability and integrates those results with histology.
 
Regulatory Status
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. Patented diagnostic test (e.g. PancraGEN) are available only through Interpace Diagnostics (formerly RedPath Integrated Pathology) under the auspices of the Clinical Laboratory Improvement Amendments. 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.
 
There is no CPT or HCPCS code specific for this type of testing.

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Molecular Testing using the PathFinderTG® system for the diagnosis of, but not limited to, pancreatic cysts or gliomas does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, molecular testing using the PathFinderTG® system for the diagnosis of, but not limited to, pancreatic cysts or gliomas is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
RedPath offers the PathFinderTG® molecular test as a way to provide definitive diagnoses, 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.
 
Because of the scope of claims by the company for widespread application of PathFinderTG® in multiple organ systems and clinical scenarios, and over 500 papers they reference “supporting the clinical efficacy of PathFinderTG®” (http://www.redpathip.com/publications.asp, accessed 04/05/2008), we chose 2 representative applications to address in this policy—pancreatic cysts and gliomas. Published studies reviewed for this policy include those cited by RedPath as providing “clinical validation” for PathFinderTG®, as well as those representative of the current medical literature describing what is known of the molecular profiles of various tumor types (specifically pancreatic cystic and glial neoplasms) and their potential role in clinical decision-making.
 
PANCREATIC CYSTS
The diagnosis of cystic pancreatic lesions is usually performed by endoscopic-ultrasound-guided fine-needle aspiration sampling the fluid and cyst wall for cytologic examination and analysis. Cytologic examination of these lesions can be difficult or indeterminate due to low cellularity, cellular degeneration, procedural difficulties, etc. Ancillary tests are often performed on the cyst fluid in an attempt to aid in the diagnosis (e.g., amylase, lipase, carcinoembryonic antigen levels), but results can still be equivocal. Information provided by additional testing modalities would, therefore, be potentially useful.
 
The PathFinderTG® test is suggested to serve the following purposes based on panels of molecular markers, including KRAS point mutations and loss of heterozygosity (LOH), in pancreatic cyst samplings/fluid:
    • definitively discriminate reactive from neoplastic conditions of the pancreas (especially in aspirated fluid specimens from pancreatic cysts)
    • identify which premalignant diseases (specifically, mucinous cystic neoplasms or MCN) will progress to cancer and those that will not
    • distinguish nonmucinous from mucinous cysts
 
Evidence
From a convenience sample of tissue specimens archived between 1999 and 2004 (Lapkus et al) described mutations in brushing samples from pancreatic and bile duct lesions. No description of patients or tumor stage was reported. Various molecular findings and mutations from 40 pancreatic duct and 21biliary brushing specimens were described, including LOH for a panel of 15 markers (1p, 3p, 5q, 9p, etc.) in addition to point mutation in KRAS-2 for cells obtained from cytologic preparations that had been diagnosed by conventional cytology as malignant (n=10), atypical (n=20) or benign (n=10).. The authors suggested “[knowing that cancer evolves through a temporal process of mutation acquisition raises the question whether this sequence can be determined in clinical specimens.” Tissue histology was available for 4 samples in the malignant group (all carcinomas); 4 in the benign group (3 were benign); and 9 in the atypical group (4 carcinomas). These results provide little evidence to support clinical value of the mutation patterns. Results from just 17 of 40 samples were compared to tissue diagnoses; measures of accuracy are not calculable. The cross-sectional study design further prevents meaningful conclusion.
 
Khalid et al. (2004) reported results from a retrospectively assembled case series using LOH in the diagnosis of pancreatic malignancy. In an apparent convenience sample of 26 patients with either surgical removal (n=25) or “long term follow-up” (n=1) there were 17 cancers (6 pancreatic and 11 cholangiocarcinomas) and 9 non-cancers. No description of patients or tumor stage was reported. Using “standard” microscopic analysis of the cytology specimens, 8 were judged malignant, 10 indeterminate and 8 benign. Results of various molecular tests (LOH, KRAS, etc.) were evaluated on cytology and tissue specimens. Reported sensitivity was 100% (95% CI: 83–100%) and specificity 100% (95% CI: 70–100%; CIs calculated) for a diagnosis of malignancy by PathFinderTG®. Whether the molecular findings would have had clinical impact was unclear. In addition, results were not presented in a manner that allowed direct comparison between the molecular and standard testing, both for the cytology analysis and the tissue specimens.
 
In a case series, Khalid et al. (2005) prospectively collected fluid from 116 pancreatic cysts. Molecular analyses were restricted to 31 patients who underwent surgery and “5 patients [who] reached a final diagnosis of malignancy based on cytology....” In this subgroup of 36, molecular analyses included KRAS point mutation and a broad panel of LOH markers. Whether those conducting molecular assays were blinded to confirmatory results was not reported. Cutoffs defining significant LOH at loci were established using normal specimens—more than a 2 standard deviation was defined as abnormal. The sensitivity and specificities of KRAS mutation alone distinguishing premalignant from malignant cysts were 93% (95% CI: 62–100%) and 87% (95% CI: 62–96%) (CIs calculated). Subsequent testing for LOH did not alter sensitivity and correctly reclassified one false–positive result increasing specificity to 93% (95% CI: 70–100%). Analysis from this small sample did not demonstrate incremental value for LOH testing added to KRAS.
 
These studies highlight important issues pertaining to test accuracy and whether there is evidence that PathFinderTG® results provide incremental information that informs diagnostic and prognostic decision-making for patients with pancreatic cysts, including the following:
    • whether progression of genetic mutations is sufficiently defined to use for diagnosis and prognosis
    • sampling variability of fluid and tissue specimens
    • study design and conduct including patient (sample) selection and blinding of personnel performing assays to clinical outcomes
    • small sample sizes and absence of sufficient tissue samples to compare with PathFinderTG® results for a substantial proportion of patients
    •  lack of adequate patient follow-up and validation/replication of findings
 
First, step-wise accumulation of KRAS mutations and allelic losses (LOH) accompanying cancer progression in pancreatic ductal adenocarcinomas have been found (Furukawa 2006, Koorstra 2008).  However, overlap between molecular findings in inflammatory and neoplastic conditions has also been described—specifically KRAS mutations in chronic pancreatitis (Popovic 2007, Khalid 2006, Muller 2001, Uehara 1999).  Progression of genetic mutations in mucinous pancreatic tumors has been described and although there appear to be similarities with pancreatic ductal adenocarcinomas, the precise pattern and progression of these mutations remains to be elucidated. For example, while suggesting the pattern of KRAS mutation followed by allelic loss predicts malignancy in pancreatic cysts, Khalid et al. also noted a lack of clarity in the “pattern and rate of mutation accumulation….”
 
Second, potential sampling discrepancies between the molecular profile of a pancreatic cyst wall aspirate or fluid and tissue specimen needs to be further addressed. This is particularly important in MCNs of the pancreas, which may show differing histology in different areas of the tumor, and may have focal invasion (Singh 2007). To further complicate this issue, RedPath does not address the genetic heterogeneity seen among the subtypes of MCNs (for example, KRAS mutations have been described as occurring in 20% of mucinous cystic adenomas, 33% of adenomas with moderate dysplasia, and 89% with carcinoma in situ.
 
Third, whether those performing the assay were blinded to surgical results was not stated in the studies reviewed. Clear description of case selection (e.g., consecutive or convenience) was absent.
 
Fourth, sample sizes were small as reflected in the wide confidence intervals calculated for reported sensitivities and specificities.
 
Finally, both adequate follow-up and replicated results (validation) are required to demonstrate whether PathFinderTG® results inform diagnostic and prognostic decision-making in a manner that will benefit patients. We are unaware of long-term studies with defined clinical outcomes using PathFinderTG® to differentiate neoplastic pancreatic cysts from those determined by the test as “definitely benign” implying progression to cancer improbable. RedPath suggests that some cases of MCN of the pancreas need not be resected based on “benign” molecular profiles that predict indolent behavior. However, international guidelines state that “unless there are contraindications for operation, all MCNs should be resected.” (Tanaka 2006) This is due to the uncertainty of the natural history of MCN and the presumed malignant potential of all types (Tanaka 2006, Khalid 2007, Oh 2008).
 
In summary, the evidence reviewed does not demonstrate that PathFinderTG® has incremental clinical value for diagnosis or prognosis of pancreatic cysts and associated cancer.
 
GLIOMAS
Limitations of pathologic examination for diagnosing and grading gliomas have been described (Aldape 2007, Coons 1997).  This is partly due to the small brain biopsy size as well as to interobserver variability between pathologists. In addition, different glial tumors may respond differently to therapy. Defining prognosis and predicting therapeutic response is therefore of considerable interest. The PathFinderTG® test is proposed to address these issues using panels of LOH markers from stereotactic brain biopsies or fine-needle aspirations to:
    • provide glioma diagnosis and classification
    • assess tumor aggressiveness (discriminating between low- and high-grade gliomas)
    • discriminate glioma from reactive gliosis
    • predict tumor response to certain chemotherapeutic regimens through analysis of the chromosomal 1p/19q deletion and identified LOH mutations
 
Evidence
In one study cited as clinical validation for PathFinderTG®, investigators retrospectively analyzed archived tissue from 197 gliomas, performing polymerase chain reaction (PCR) for a panel of 12 to 16 LOH markers (Mohan 2004).  Loss of 1p and 19q were analyzed in all cases, with a subset (n=93) undergoing an extended panel of 16 markers. They reported, “The qualitative and quantitative aspects of glioma allelic loss were correlated with the clinical impression of treatment response [to procarbazine, CCNU, vinblastine] as determined by imaging studies.” Treatment response was noted to be classified as none, partial (25% decrease in size with stable or decreasing steroid doses), or complete (“disappearance of all contrast enhancing tissue for gliomas and resolution of abnormalities on FLAIR sequences for low-grade gliomas”). However, tables reported “major response” (undefined) rather than “complete response.” Of 96 patients with high-grade gliomas, 49 had follow-up of 6 months or longer and were assessed for therapy response: 11 had “no response,” 17 “partial,” and 21 “major” response; deaths occurring prior to 6 months were not reported. Predictive values (calculated from reported data) of at least partial response for 1p loss were positive predictive value (PPV) 100% (95% CI: 89–100%), negative predictive value (NPV) 65% (95% CI: 41% to 83%); for 19q loss PPV 82% (95% CI: 64–92%), NPV 21% (95% CI: 8–43%). It is not clear whether the molecular data results were blinded for the classification of treatment response. The retrospective design, lack of follow-up information for 47 patients, and no report of any censoring due to mortality are significant study limitations.
 
In a retrospective case series, Finkelstein et al. (2004) described the use of LOH to make the distinction between neoplasm and reactive gliosis. The study included tissue from 15 cases of reactive gliosis, none of which showed allelic loss (LOH), and 54 patients with gliomas of varying histologic type and grade. Within the group of 54 patients, 14 of 19 (74%) of the well-differentiated neoplasms showed allelic loss; 35 of 35 high-grade gliomas showed at least one allelic loss alteration and 33 of 35 showed more than one loss. Within this same study, 16 “diagnostically challenging cases of reactive gliosis vs glioma” were analyzed in the same manner, with the conclusion that LOH analysis in 8 of 11 (73%) were correctly predicted by the analysis, based upon clinical follow-up of 13–16 months. The sample size was small and the confidence intervals wide and it will be necessary to apply the criteria determined in this study to additional validation samples.
 
The only molecular test currently being performed on a relatively frequent basis for gliomas is the 1p/19q chromosomal loss for oligodendrogliomas. Yet optimal use of this test in the clinical care of patients remains unclear (Lassman 2007).  Although LOH involving multiple chromosomes has been observed in gliomas, and in some studies, LOH is predictive of tumor response to particular chemotherapeutic regimens, it is not clear the information is meaningfully incremental to that provided by the 1p/19q data alone (Thiessen 2003).  Also,some studies have shown conflicting results in terms of chemoresponsiveness for tumors with LOH involving chromosomes other than 1p/19q…” (Thiessen).   As noted by Lassman, “Current wisdom suggests that one of the main reasons for the poor responsiveness (of gliomas to therapy) is the existence of multiple genetic subsets of gliomas and the related lack of molecular stratification prior to treatment. Therefore, several strategies have been employed to divide gliomas into molecular subgroups that are either more or less responsive to existing therapies. Whether such stratification will result in effective therapies specific for each glioma subset is not yet clear…. To what extent molecular subdivision of gliomas will be clinically useful remains to be seen.”
 
The evidence reviewed does not demonstrate that PathFinderTG® testing for diagnosis or predicting response to therapy provides a benefit in patients with gliomas.
 
Conclusion
The evidence reviewed has significant limitations as discussed. Demonstrating utility of a test for diagnostic and prognostic purposes, or to predict therapeutic response requires that results accurately inform clinical decision-making in a manner leading to a net health benefit defined by clinical outcomes. Results must also be clearly reproducible as shown by applying the test (with a priori defined cut-offs) to independent samples for validation. The impact of this technology on health outcomes is not known and outcomes with this technology compared with existing alternatives (i.e., incremental value) are not known.
 
2012 Update
A search of the MEDLINE database conducted through March 2012 did not identify any new literature that would prompt a change in the coverage statement.
 
Khalid et al. published the results of a prospective multicenter study to validate their initial results from a single center pilot study, (Khalid, 2005) and to evaluate the role of pancreatic cyst fluid DNA analysis in differentiating mucinous from nonmucinous cysts (Khalid, 2009). Patients included in the study were seen for endoscopic ultrasound (EUS)-guided evaluation of a pancreatic cyst between July 2004 and June 2006 at 1 of 7 participating centers. DNA analysis was performed only in cases that reached conclusion (defined as surgical resection of the lesion or a diagnosis of malignancy based on fine-needle aspiration cytology). DNA analysis consisted of direct sequencing of the first exon of the KRAS gene and PCR amplification of individual microsatellite markers to determine allelic imbalance (reported as allelic loss amplitude or ALA). A total of 391 patients were enrolled in the study, and after exclusions for various reasons including no cyst seen by EUS or insufficient cyst fluid, 299 patients remained, 124 of whom reached a final pathologic diagnosis based on surgical resection (n=98) or malignant cytology (n=26). An additional 11 cases were excluded for various pathologic diagnoses not included in the study methods (e.g., islet cell tumors). The remaining 113 cysts were classified as benign nonmucinous (n=25) or mucinous (n=88). Of the mucinous, 40 were malignant and 48 were premalignant. Cyst fluid KRAS mutation with allelic loss showed a specificity of 96% for the diagnosis of malignancy but low sensitivity of 37%. Optimal cutoff points for ALA were established and, at the level set, the sensitivity and specificity for distinguishing nonmucinous from mucinous cysts were 67% and 66%, respectively. A separate cutoff value for malignancy yielded a 90% sensitivity and 67% specificity. Limitations of the study were acknowledged. These included lack of investigator blinding to the results of the DNA analysis and potential selection bias, as only lesions with confirmed pathologic findings were included. Therefore, the study population consisted of a higher number of patients with malignant cysts than would have been expected.
 
A systematic review of LOH-based topographic genotyping with PathFinderTG® was prepared for the Agency for Healthcare Research and Quality (AHRQ) technology assessment program (Trikalinos, 2010). Key questions addressed the published evidence on the analytic test performance, diagnostic ability, and clinical validity of the test and what evidence there is comparing the PathFinder test with conventional pathology. The conclusions were that none of the studies included in the systematic review directly measured whether using LOH-based topographic genotyping with PathFinderTG® improved patient-relevant clinical outcomes and that the eligible studies on the diagnostic and prognostic ability of the test were small in sample size, had overt methodologic limitations, and all but one performed retrospective assessments. The review points out that the studies did not provide important information on patient selection, patient characteristics, treatments received, clinical endpoint definitions, justification of sample size, selection of test cutoffs, and selection among various statistical models. In addition, the review notes that there were strong indications that the selection of certain test cutoffs was determined post-hoc, in that the cutoffs varied widely across studies and were not validated in an external population.
 
Summary
The evidence reviewed for 2 representative uses for this test has significant limitations, as discussed. Demonstrating the utility of a test for diagnostic and prognostic purposes or to predict therapeutic response requires that results accurately inform clinical decision making in a manner leading to a net health benefit defined by clinical outcomes. Results must also be clearly reproducible, as shown by applying the test (with priori-defined cutoff points) to independent samples for validation. The impact of this technology on health outcomes is not known and outcomes with this technology compared with existing alternatives (i.e., incremental value) are not known. The coverage statement is unchanged.
 
2013 Update
A search of the MEDLINE database through March 2013 did not reveal any new literature that would support a change in the coverage statement.
  
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through February 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2011, RedPath Integrated Pathology established the National Pancreatic Cyst Registry and in 2015, final published results of 492 (26%) of 1864 registered patients (Al-Haddad, 2015). The Registry website describes the registry as a prospective study “to evaluate the performance characteristics and clinical utility of integrated molecular pathology and determine the predictive value of both traditional first-line tests and integrated molecular pathology.” Ten academic medical centers and community-based practices registered patients who had pancreatic cysts, underwent PathFinderTG® testing, and were followed for development of malignancy. Benign outcomes included benign surgical pathology results, low- or intermediate-grade dysplasia, resolution of cyst, or clinical follow-up by imaging for a minimum of 23 months without evidence of malignant outcome; malignant outcomes were determined by surgical pathology diagnosis of high-grade dysplasia, carcinoma in situ, or adenocarcinoma, newly diagnosed malignant cytology results, clinically confirmed pancreatic cancer in patient records, or death attributed to pancreatic cancer. Investigators compared the diagnostic performance of PathFinderTG® to that of an international consensus classification scheme (Tanaka, 2012). Both classification schemes categorize patients with pancreatic cysts as high- or low-risk for malignancy; those considered high-risk undergo surgical resection, and those considered low-risk may elect observation with surveillance. At median follow-up of 35 months (range: 23- 92), 66 patients (35%) were diagnosed with malignancy. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 83%, 91%, 58%, and 97% for PathFinderTG® versus 91% (p=0.17), 46% (p<0.001), 21% (p<0.001), and 97% (p=0.88) for international consensus classification. A strength of the study is the inclusion of both surgery and surveillance groups. Limitations include the retrospective design, resulting in the exclusion of 74% of all registered patients due primarily to insufficient follow-up; relatively short follow-up for observing malignant transformation of benign lesions; and the exclusion of patients classified as malignant by international consensus criteria who would not have undergone PathFinderTG® testing. Because of these limitations, it is unclear whether classification by PathFinderTG® improves treatment decision-making and health outcomes, such as overall survival, compared with current classification criteria.
 
Two studies attempted to show the incremental value of molecular analysis of pancreatic cyst DNA (from cytology slides or aspirated fluid) to cytological diagnosis of malignancy. Gillis and colleagues (2015) in Ireland conducted a systematic review of the literature but found sufficient evidence to evaluate incremental value of KRAS mutational status only (Gillis, 2015). Evidence for LOH and DNA quantification was insufficient to form conclusions. Malhotra and colleagues (2014) at RedPath retrospectively evaluated 30 patients who presented with pancreaticobiliary masses and had minimum follow-up of 3 months (Malhotra, 2014). Only 26 patients with a cytological diagnosis of atypical, negative, or indeterminate underwent PathFinderTG® mutational profiling, precluding assessment of diagnostic performance. 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%). Although the combination of positive cytology and positive PathFinderTG® results improved sensitivity to 57% (12 of 21), 9 malignant cases were missed by both tests. Two other studies from RedPath yielded inconclusive results due to their retrospective design and short follow-up (median: 27 months), use of a 3-tier classification scheme rather than the 4-tier classification currently used for PathFinderTG®, and diagnostic performance of uncertain clinical usefulness (sensitivity, specificity, PPV, and NPV of 75%, 88%, 82%, and 81%, respectively) (Kung, 2014; Winner, 2015).
 
2017 Update
A literature review conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
A literature search was conducted through March 2019.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
National Comprehensive Cancer Network
Current National Comprehensive Cancer Network guidelines for pancreatic adenocarcinoma (v.2.2018), central nervous system cancers (v.1.2018), and esophageal and esophagogastric junction cancers (v.2.2018), do not include recommendations for molecular anatomic pathology or integrated molecular pathology (NCCN, 2018).
 
2020 Update
A literature search was conducted through March 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81479Unlisted molecular pathology procedure
84999Unlisted chemistry procedure
89240Unlisted miscellaneous pathology test

References: Al-Haddad MA, Kowalski T, Siddiqui A, et al.(2015) Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. Endoscopy. Feb 2015;47(2):136-142. PMID 25314329

Aldape K, Burger PC, Perry A.(2007) Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med, 2007; 131:242-51.

Bennett C, Moayyedi P, Corley DA, et al.(2015) BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia. Am J Gastroenterol. May 2015; 110(5): 662-82; quiz 683. PMID 25869390

coons SW, Johnson PC, et al.(1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer, 1997; 75:1381-93.

Finkelstein et al.(2006) U.S. Patent #7,014,999. March 21, 2006. Topographic genotyping. http://patft.uspto.gov/netacgi/nph- Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch- adv.htm&r=16&f=G&l=50&d=PTXT&S1=(redpath+AND+specimen)&OS=redpath+AND+specimen&RS=(redpath +AND+specimen). Accessed August 30, 2018.

Finkelstein SD, Mohan D, et al.(2004) Microdissection-based genotyping assists discrimination of reactive gliosis from glioma. Am J Clin Pathol, 2004; 11:1346-58.

Furukawa T, Sunamura M, Horii A.(2006) Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci, 2006; 97:1-7.

Gillis A, Cipollone I, Cousins G, et al.(2015) Does EUS-FNA molecular analysis carry additional value when compared to cytology in the diagnosis of pancreatic cystic neoplasm? A systematic review. HPB (Oxford). May 2015;17(5):377-386. PMID 25428782

Gonda TA, Viterbo D, Gausman V, et al.(2017) 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

Interpace Diagnostics.(2016) Advancing patient care through molecular diagnostic testing. 2016; http://www.interpacediagnostics.com/. Accessed August 30, 2018.

Interpace Diagnostics.(2016) How PancraGEN works. http://www.interpacediagnostics.com/pancragen/how-it- works/. Accessed August 30, 2018.

Khalid A, Brugge W.(2007) ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol, 2007; 102:2339-49.

Khalid A, McGrath K, et al.(2005) The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol, 2005; 3:967-73.

Khalid A, McGrath K, Zahid M et al.(2005) The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol 2005; 3(10):967-73.

Khalid A, Nodit L, et al.(2006) Endoscopic ultrasound fine needle aspirate DNA analysis to differentiate malignant and benign pancreatic masses. Am J Gastroenterol, 2006; 101:2493-2500.

Khalid A, Pal R, et al.(2004) Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreatoticobiliary malignancy from brush cytology samples. Gut, 2004; 53:1860-5.

Khalid A, Zahid M, Finkelstein SD et al.(2009) Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc 2009; 69:1095-102.

Koorstra JB, Hustinx SR, et al.(2008) Pancreatic carcinogenesis. Pancreatology, 2008; 8:110-25.

Kowalski T, Siddiqui A, Loren D, et al.(2016) 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

Kung JS, Lopez OA, McCoy EE, et al.(2014) Fluid genetic analyses predict the biological behavior of pancreatic cysts: three-year experience. JOP. Sep 2014;15(5):427-432. PMID 25262708

Kushnir VM, Mullady DK, Das K, et al.(2018) 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

Lapkus O, Gologan O, et al.(2006) Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology. Mod Pathol, 2006; 19:907-13.

Lassman AB, Holland EC.(2007) Incorporating molecular tools into clinical trials and treatment for gliomas. Curr Opin Neurol, 2007; 20:708-11.

Malhotra N, Jackson SA, Freed LL, 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. 2014;14:135. PMID 25084836

Mohan D, Finkelstein SD, et al.(2004) Microdissection genotyping of gliomas: therapeutic and prognostic indications. Mod Pathol, 2004; 17:1346-58.

Muller P, Ostwald C, et al.(2001) Low frequency of p53 and ras mutations in bile of patients with hepato-biliary disease: a prospective study in more than 100 patients. Eur J Clin Invest. 2001; 8:240-7.

National Comprehensive Cancer Network (NCCN).(2018) NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed August 30, 2018.

Oh HC, Kim MH, et al.(2008) Cystic lesions of the pancreas: challenging issues in clinical practice. Am J Gastroenterol, 2008; 103:229-39.

Popovic HM, Korolija M, Jakic RJ.(2007) K-ras and Dpc4 mutations in chronic pancreatitis: case series. Croat Med J, 2007; 48:218-24.

Shaheen NJ, Falk GW, Iyer PG, et al.(2016) ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol. Jan 2016; 111(1): 30-50; quiz 51. PMID 26526079

Singh M, Maitra A.(2007) Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology, 2007; 7:9-19.

Spechler SJ, Sharma P, Souza RF, et al.(2011) American Gastroenterological Association technical review on the management of Barrett's esophagus. Gastroenterology. Mar 2011;140(3):e18-52; quiz e13. PMID 21376939

Tamura K, Ohtsuka T, Date K, et al.(2016) 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

Tanaka M, Chari S, et al.(2006) International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology, 2006; 6:17-32.

Tanaka M, Fernandez-del Castillo C, Adsay V, et al.(2012) International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. May-Jun 2012;12(3):183- 197. PMID 22687371

Thiessen B, Maguire JA, et al.(2003) Loss of heterozygosity for loci on chromosome arms 1p and 10q in oligodendroglial tumors: relationship to outcome and chemosensitivity. J Neuro-Oncol, 2003; 64:271-8.

Trikalinos TA, Terasawa T, Raman G et al.(2010) A systematic review of loss-of-heterozygosity based topographic genotyping with PathfinderTG®. AHRQ Technology Assessment Program (Project ID GEND0308). March 2010. Available online at: http://www.cms.gov/determinationprocess/downloads/id68ta.pdf . Last accessed April 2012.

Uehara H, Nakaizumi A, et al.(1999) Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with k-ras mutations. Am J Gastroenterol, 1999; 94:2513-18.

Vege SS, Ziring B, Jain R, et al.(2015) American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. Apr 2015; 148(4): 819-22; quize12-3. PMID 25805375

Winner M, Sethi A, Poneros JM, et al.(2015) The role of molecular analysis in the diagnosis and surveillance of pancreatic cystic neoplasms. JOP. 2015;16(2):143-149. PMID 25791547


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