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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, sarcoma, or neuroendocrine tumors.  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 dedifferentiation, 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 (such as that used in the Pathwork® test) enables large numbers of genes to be evaluated at the same time, it is complex and time-consuming, and is limited in its use as mostly 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 Pathwork® Pathchip. 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.

MiReview mets® (Rosetta Genomics, Philadelphia, PA) is another microarray technology which 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, miReview® mets2, has recently been developed, which expands the number of tumor types to 42 primary origins with a panel of 64 miRNAs.

An alternative method to measure gene expression is real-time quantitative polymerase chain reaction (RT-PCR). RT-PCR 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 less so (71%) the more undifferentiated the tumor tested. (4) One assay that uses qRT-PCR is the CancerTypeID® (CancerTypeID; bioTheranostics, Inc., San Diego, CA) assay, which measures the expression of messenger RNA in a CUP tissue sample. Samples for this are 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.

In July 2008, test “Pathwork® Tissue of Origin” (Pathwork Diagnostics, Inc., Sunnyvale, CA) 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 pathologic 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, prostate, and 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:

The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathologic practice, (e.g., carcinoma of unknown primary). It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathologic practice, nor to predict disease course, or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork® Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications.

In June 2010, the “Pathwork® Tissue of Origin Test Kit-FFPE” (Pathwork Diagnostics) 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.

Both CancerTypeID® and miReview® have not submitted their test for FDA approval.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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.

All codes billed for this procedure are considered investigational and not eligible for coverage. 

Non-Covered Codes       

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