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DESCRIPTIONCancers of unknown primary (CUP) represent 3% of all cancer cases in the U.S. A detailed history and physical, as well as radiologic and histologic testing, can identify some but not all primary sources of secondary tumor. It is suggested that identifying a likely primary source with microarray-based gene expression testing and directing treatment accordingly may improve health outcomes.
Cancers of Unknown Primary
Cancers of unknown primary, or occult primary malignancies, are tumors that have metastasized from an unknown primary source, and make up approximately 3% of all cancer cases in the U.S. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome and prognosis.
Most cancers of unknown primary are adenocarcinomas or undifferentiated tumors; less commonly they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce cancers of unknown primary. The most common primary sites of cancers of unknown primary are lung and pancreas, followed by colon and stomach, then breast, ovary, prostate and solid-organ carcinomas of the kidney, thyroid, and liver. Conventional methods used to aid in the identification of the origin of a cancer of unknown primary include a thorough history and physical examination, CT scans of the chest, abdomen and pelvis; routine laboratory studies and targeted evaluation of specific signs and symptoms.
Biopsy of a cancer of unknown primary with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC identifies different antigens present on different types of tumors, and can usually distinguish an epithelial tumor (i.e., carcinoma) from a melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of a carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. The results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
The current success rate of the diagnostic workup of a cancer of unknown primary is 20–30%, including consideration of clinical, radiologic, and extensive histopathologic methods. Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification as a way to improve the identification of the site of origin of a cancer of unknown primary.
Molecular Classification of Cancers
The molecular classification of cancers is based on the premise that, despite different degrees of loss of differentiation, tumors retain sufficient gene expression "signatures" as to their cell of origin, even after metastasis. Theoretically, it is possible to build a gene expression database spanning many different tumor types to compare to the expression profile of very poorly differentiated tumors or a cancer of unknown primary, to aid in the identification of the tumor type and organ of origin. The feasibility of using molecular classification schemes with gene expression profiling to classify these tumors of uncertain origin has been demonstrated in several studies.
Ramaswamy and co-workers, using microarray gene expression analysis of over 16,000 genes, showed 78% classification accuracy of 14 common tumor types. Su and colleagues, using large-scale RNA profiling with microarrays, accurately predicted the anatomical site of tumor origin for 90% of 175 carcinomas. Bloom et al. combined multiple tumor microarray databases, creating a large collection of tumors, including 21 types, resulting in a molecular classification scheme that reached 85% accuracy. Although microarray technology enables large numbers of genes to be evaluated simultaneously, it is complex and time-consuming, and is limited to use primarily as a research tool. In addition, since formalin fixation can degrade RNA, fresh/frozen tissue is preferred for better accuracy with microarray technology; however, formalin-fixed is the standard for pathology material in current practice.
One such microarray technology is the ResponseDX: Tissue of Origin™ test (formerly known as the Pathwork® Tissue of Origin Test; Response Genetics Inc., Los Angeles, CA). The test measures the expression of more than 1,500 genes and compares the similarity of the GEP of a CUP to a database of known profiles from 15 tissues with more than 60 histologic morphologies. The report generated for each tumor consists of a “similarity score,” which is a measure of similarity of the GEP of the specimen to the profile of the 15 known tumors in the database. Scores range from 0 (very low similarity) to 100 (very high similarity), and sum to 100 across all 15 tissues on the panel. If a single similarity score is greater than or equal to 30, it indicates that this is likely the tissue of origin. If every similarity score is between 5 and 30, the test result is considered indeterminate, and a similarity score of less than 5 rules out that tissue type as the likely origin. The test was developed by Pathwork Diagnostics, but the company filed for bankruptcy in early 2013, and their assets were purchased by Response Genetics Inc.
An alternative method to measure gene expression is real-time quantitative polymerase chain reaction (RT-qPCR). RT-qPCR can be used at the practice level; however, it can only measure, at most, a few hundred genes, limiting tumor categorization to 7 or fewer types. Tumor classification accuracy rates using RT-PCR have been reported to be as high as 87%, but lower (71%) the more undifferentiated the tumor tested. One assay that uses RT-qPCR is the CancerTypeID® (bioTheranostics, Inc., San Diego, CA) assay, which measures the expression of messenger RNA in a CUP tissue sample. Samples for this are formalin-fixed, paraffin-embedded (FFPE) tissue sections or unstained 10 micron sections on glass slides. The expression levels of 92 genes (87 tumor-associated genes and 5 reference genes for normalization) are used to detect 27 tumor types in a known database of 578 tumors with a range of 5 to 49 tumors per type. The report generated is the probability for the main cancer type, possible subtypes, tumor types not able to be excluded, and those ruled out with 95% confidence calculated by K nearest neighbor analysis.
MiReview mets® (Rosetta Genomics, Philadelphia, PA) is another RT-qPCR test that uses microRNAs (miRNA), small non-coding, single-stranded RNA molecules that regulate genes post-transcription, as a signature for tumor differentiation. The expression levels of these miRNAs have been shown to be a sensitive biomarker across various pathologic conditions. Samples for this test are formalin-fixed paraffin-embedded (FFPE) tissue. The miReview® test utilizes 48 panel markers used to detect 22 tumor types in a known database of 336 tumors with a range of 1 to 49 tumors per type. The results from the test provide a tumor of origin but may list multiple possibilities calculated by a binary decision tree and K nearest neighbor algorithm. A second generation test, the Rosetta Cancer Origin Test™ (formerly miReview® mets2), has recently been developed; this test expands the number of tumor types to 42 primary origins with a panel of 64 miRNAs.
In July 2008, the Pathwork® Tissue of Origin Test™ was cleared with limitations* for marketing by the U.S Food and Drug Administration (FDA) through the 510(k) process. The FDA determined that the test was substantially equivalent to existing tests for use in measuring the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated, and metastatic cases) that were diagnosed according to current clinical and histopathologic practice. The database contains examples of RNA expression patterns for 15 common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, and prostate cancers; thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkin’s lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.
*Limitations to the clearance were as follows:
In June 2010, the Pathwork® Tissue of Origin Test Kit-FFPE was cleared for marketing by the FDA through the 510(k) process. The 2010 clearance is an expanded application, which allows the test to be run on a patient’s formalin-fixed, paraffin-embedded (FFPE) tumor and has the same indications and limitations. In May 2012, minor modifications to the Pathwork® Tissue of Origin Test Kit-FFPE were determined to be substantially equivalent to the previously approved device by the U.S. Food and Drug Administration (FDA) through the 510(k) process.
Neither CancerTypeID® nor miReview® (or Rosetta Cancer Origin™) have been submitted to FDA approval.
POLICYGene expression profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, and to distinguish a primary from a metastatic tumor.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
3/2/2009: Policy added.
04/22/2010: Policy description and statement unchanged. FEP verbiage added to the Policy Exceptions section.
12/28/2010: Policy description and statement updated regarding the Pathwork® Tissue of Origin test and test kit-FFPE. The new test for FFPE specimens added as investigational.
01/17/2012: Policy reviewed; no changes.
01/14/2013: Added the following new 2013 CPT code to the Code Reference section: 81479.
02/20/2013: Policy description revised to add information regarding other tests commercially available besides Pathwork. The policy statement was changed to be generalizable to gene expression profiling and not specific to the Pathwork test.
02/26/2014: Policy reviewed; no changes to policy statement. Removed deleted molecular diagnostic procedure codes from the Code Reference section. Added the following new 2014 CPT code(s) to the Code Reference section: 81504.
12/31/2014: Added the following new 2015 CPT code to the Code Reference section: 81519.
01/08/2015: Policy title changed from "Microarray-based Gene Expression Testing for Cancers of Unknown Primary" to "Gene Expression-Based Assays for Cancers of Unknown Primary." Policy description updated regarding devices. Policy statement unchanged.
04/27/2015: Removed CPT code 81519 from the Code Reference section.
07/20/2015: Code Reference section updated for ICD-10.
SOURCESBlue Cross and Blue Shield Association policy #2.04.54
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.