BlueCross BlueShield of Tennessee Medical Policy Manual

Microarray-based Gene Expression Testing for Cancers of Unknown Primary


Cancers of unknown primary (CUP) or occult primary malignancies are tumors that have metastasized from an unknown primary source, and make up approximately 2% - 4% of all cancer cases in the United States. These cancers are often accompanied by a poor prognosis.

Conventional methods used to aid in the identification of the origin of a cancer of unknown primary malignancy include a thorough history and physical examination, computed tomography (CT) scans of the chest, abdomen, and pelvis, routine laboratory studies; and targeted evaluated of specific signs and symptoms. Identifying the primary origin of a tumor can dictate cancer specific treatment, expected outcome, and prognosis.

Microarray-based gene expression testing (e.g., Tissue of Origin ®, Cancer TYPE ID®) also known as gene expression profiling, is being offered as possibly useful in identifying the origin of cancers of unknown primary site. The test measures the expression of more than 1,500 genes and compares the similarity of the gene expression profile of a cancer of unknown primary to a database of known profiles from 15 tissues with more than 60 histologic morphologies.

The National Comprehensive Cancer Network clinical practice guidelines on occult primary or cancer of unknown primary notes that outcomes data are not currently available that recommends the routine use of molecular profiling in the workup of occult primary tumors.


See also:  Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for Prenatal Evaluation and Evaluation of Children with Developmental Delays/Intellectual Disability, Autism Spectrum Disorder and/or Congenital Anomalies



The clinical utility of microarray-based gene expression testing (e.g., Tissue of Origin® test, Cancer TYPE ID®) has not been determined. The clinical application of gene expression profiling to direct patient management and tumor site-specific therapy also has not been demonstrated in prospective studies. The impact of this testing on clinical outcomes remains unknown.


Agency for Healthcare Research and Quality (2013, February) Technology assessment on genetic testing or molecular pathology testing of cancers with unknown primary site to determine origin. Retrieved November 3, 2016 from

Agwa, E., & Ma, P. (2013). Overview of various techniques/platforms with critical evaluation of each. Current Treatment Options in Oncology, 14 (4), 623-633. Abstract retrieved October 13, 2017 from PubMed database.

American Cancer Society. ( 2016, January) Cancer – unknown primary. Retrieved November 3, 2016 from

BlueCross BlueShield Association. Medical Policy Reference Manual. (3:2017). Gene expression-based assays for cancers of unknown primary (2.04.54). Retrieved October 13, 2017 from BlueWeb. (38 articles and/or guidelines reviewed)

National Comprehensive Cancer Network. (2016, October). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Occult primary (cancer of unknown primary, [CUP]) (V.2.2017). Retrieved November 3, 2016 from the National Comprehensive Cancer Network.

National Institute for Health and Clinical Excellence (NICE). (2010, July). Metastatic malignant disease of unknown primary origin. Retrieved February 28, 2013 from 

Palmetto GBA. (2017). Approved gene testing (M00041, v16). Retrieved October 13, 2017 from

Sokilde, R., Vincent, M., Moller, A., Hansen, A., Hoiby, P., Blondal, T., et al. (2014). Efficient identification of miRNAs for classification of tumor origin. The Journal of Molecular Diagnostics, 16 (1), 106-115. (Level 4 evidence)

U. S. Food and Drug Administration. (2008, July). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K080896. Retrieved February 28, 2013 from:

U. S. Food and Drug Administration. (2010, June). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K092967. Retrieved February 28, 2013 from:

U. S. Food and Drug Administration. (2012, May). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K120489. Retrieved February 28, 2013 from ;




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