Sunday, January 27, 2019

CPT 81504, 81540, 81599 - Assays for Cancers of Unknown Primary

Policy Coverage Criteria 

Type of Test Investigational

Gene expression profiling Gene expression profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, or to distinguish a primary from a metastatic tumor.

Coding   code Description CPT

81479 Unlisted molecular pathology procedure

81504 Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores

81540 Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

81599 Unlisted multianalyte assay with algorithmic analysis


A primary site is the part of the body where cancer started. Cancers are named on this primary site, even when they spread to other parts of the body. For example, if cancer starts in the breast but spreads to the bones, lungs, or liver, it is still classified as breast cancer. Cancer treatment is often based on the primary cancer. In rare cases, a cancer may have already spread before the original cancer is found. This is known as cancer of unknown primary. Cancers of unknown primary happen in three to four percent of all cancers in the United States. Certain genetic tests are being studied as one way to try to find the original site of the cancer. There is not yet enough scientific evidence about how these genetic tests might affect overall health outcomes. These tests are considered unproven (investigational).

Related Information 

Genetics Nomenclature Update 

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA
Previous  Updated  Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
 Variant Change in the DNA sequence 

Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification  Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of  genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing,  including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the  utilization of genetic testing substantially and may reduce  inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review 


Cancers of unknown primary represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment may improve health outcomes.


Cancers of Unknown Primary

Cancers of unknown primary (CUPs), or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up about 3% to 4% of all cancers in the United States. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome, and prognosis.

Most CUPs are adenocarcinomas or undifferentiated tumors; less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce CUPs. The most common primary sites of CUPs are the 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 CUP include a thorough history and physical examination; computed tomography scans of the chest, abdomen, and pelvis; routine laboratory studies; and targeted evaluation of specific signs and symptoms.

Diagnosis and Classification

Biopsy of a CUP with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC analysis identifies different antigens present in different types of tumors and can usually distinguish an epithelial tumor (ie, carcinoma) from melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. Results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification to improve the identification of the site of origin of a CUP. The molecular classification of cancers is based on the premise that, despite different degrees 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 CUP, to aid in the identification of the tumor type and organ of origin. The feasibility of using molecular classification schemes with gene expression profiling (GEP) to classify these tumors of uncertain origin has been demonstrated in several studies.

Tissue of Origin Testing, Treatment Selection, and Health Outcomes 

Patients with CUP have generally poor prognoses. For example, patients with disease limited to lymph nodes have a median survival of 6 to 9 months, and those with a disease that is extranodal 2 to 4 months.

The premise of tissue of origin testing in CUPs is that identifying a likely primary tumor site will inform treatment selection leading to improved survival and other outcomes or as a predictive test. To evaluate whether treatment selection can be improved, the ability of a test to suggest a likely site of origin (clinical validity) must be first be shown. But demonstrating clinical validity may be problematic because patients with CUPs have no identified primary tumor for a reference standard.
Imperfect reference standards must be relied on such as the available presumptive or a reference pathologic diagnosis, known tumor types, or comparisons IHC. A primary tumor diagnosed during follow-up might also be used as a reference standard, but its use would be subject to potential selection bias. Therefore, even substantial evidence supporting the ability of a test to suggest a likely site of origin will be insufficient to infer benefit. Convincing evidence for benefit requires demonstrating that using a test to select treatment will improve outcomes. 

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