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Cytologic examination of fine needle aspiration (FNA) samples from a thyroid lesion to identify which patients need to undergo surgery has diagnostic limitations. Assays using molecular markers have been developed in an attempt to improve the accuracy of thyroid FNA biopsies.
Thyroid nodules are common, present in 5-7% of the U.S. adult population. The vast majority are benign, and most cases of thyroid cancer are curable by surgery if detected early. Fine needle aspiration of the thyroid is currently the most accurate procedure to distinguish benign thyroid lesions and malignant ones, reducing the rate of unnecessary thyroid surgery for patients with benign nodules and triaging patients with thyroid cancer to appropriate surgery.
About 60-70% of thyroid nodules are classified cytologically as benign, and 4-10% of nodules are cytologically deemed malignant. However, the remaining 20-30% have equivocal findings (inclusive, indeterminate, atypical or suspicious), usually due to overlapping cytologic features between benign and malignant nodules; these nodules usually require surgery for a final diagnosis. Guidelines from the American Thyroid Association recommend repeat FNA for patients with a diagnosis of “atypia of undetermined significance” and lobectomy with or without intraoperative pathology consultation for those with a suspicious diagnosis.
Approximately 80% of patients with indeterminate cytology undergo surgical resection, postoperative evaluation reveals a malignancy rate ranging from 6-30%, making this clinical process one with very low specificity.
Preoperative planning of optimal surgical management in patients with equivocal cytologic results is challenging, as different thyroid malignancies may require different surgical procedures (e.g. unilateral lobectomy versus total or sub-total thyroidectomy with or without lymph node dissection) depending on several factors, including histologic subtype and risk-stratification strategies (tumor size, patient age). If a diagnosis cannot be made intraoperatively, a lobectomy is typically performed, and if on postoperative histology the lesion is malignant, a second surgical intervention may be necessary for completion thyroidectomy.
Most thyroid cancers originate from thyroid follicular cells and include well-differentiated papillary thyroid carcinoma (PTC) (80% of all thyroid cancers) and follicular carcinoma (15%). Poorly differentiated and anaplastic thyroid carcinomas are uncommon and can arise de novo or from preexisting well-differentiated papillary or follicular carcinomas. Medullary thyroid carcinoma originates from parafollicular or C cells and accounts for about 3% of all thyroid cancers.
The diagnosis of malignancy in the case of PTC is primarily based on cytologic features. If a fine-needle aspiration in a case of PTC is indeterminate, surgical biopsy with intraoperative consultation is most often diagnostic, although its efficacy and therefore use will vary between institutions, surgeons, and pathologists.
For follicular carcinoma, the presence of invasion of the tumor capsule or of blood vessels is diagnostic, and cannot be determined by cytology, as tissue sampling is necessary to observe these histologic characteristics. Intraoperative diagnosis of follicular carcinoma is challenging and often not feasible, as extensive sampling of the tumor and capsule is usually necessary and performed on postoperative permanent sections.
New approaches for improving the diagnostic accuracy of thyroid FNA include mutation analysis for somatic genetic alterations, to more accurately classify which patients need to proceed to surgery (and may include the extent of surgery necessary) and a gene expression classifier to identify patients who do not need surgery and can be safely followed.
Mutations Associated with Thyroid Cancer
Various mutations have been discovered in thyroid cancer. The four gene mutations that are the most common and carry the highest impact on tumor diagnosis and prognosis and BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements.
Papillary carcinomas carry point mutations of the BRAF and RAS genes, as well as RET/PTC and TRK rearrangements, all of which are able to activate the mitogen-activated protein kinase (MAPK) pathway. These mutually exclusive mutations are found in more than 70% of papillary carcinomas. BRAF mutations are highly specific for PTC. Follicular carcinomas harbor either RAS mutations or PAX8/PPARγ rearrangement. These mutations are also mutually exclusive and identified in 70-75% of follicular carcinomas. Genetic alterations involving the PI3K/AKT signaling pathway also occur in thyroid tumors, although they are rare in well-differentiated thyroid cancer and have higher prevalence in less differentiated thyroid carcinomas. Additional mutations known to occur in poorly differentiated and anaplastic carcinomas involve the TP53 and CTNNB1 genes. Medullary carcinomas, which can be familial or sporadic, frequently possess point mutations located in the RET gene.
Available Molecular Diagnostic Testing
In addition to standard Sanger sequencing or rtPCR-based mutation testing for genes associated with thyroid cancer, next-generation sequencing (NGS) panels that simultaneously evaluate for point mutations or gene fusions in multiple genes have been developed. For example, the ThyroSeq® v.2 Next Generation Sequencing panel (CBLPath, Ocala, FL) includes sequencing of more than 60 genes. According to the ThyroSeq’s manufacturer’s website, the test is indicated when FNA cytology indicates atypia of uncertain significance or follicular lesion of undetermined significance, follicular neoplasm or suspicious for follicular neoplasm, or suspicious for malignancy. In particular, it has been evaluated in patients with follicular neoplasm/suspicious for follicular neoplasm on FNA as a test to increase both sensitivity and specificity for cancer diagnosis.
The ThyGenX™ Thyroid Oncogene Panel (formerly miRInform® Thyroid; Interpace Diagnostics, Parsippany, NJ; testing done at Asuragen Clinical Laboratory) is another NGS sequencing panel designed to be used in patients with indeterminate thyroid FNA results. It includes sequencing of 8 genes associated with papillary thyroid carcinoma and follicular carcinomas.
Gene Expression Profiling
Veracyte also markets 2 “malignancy classifiers” that use mRNA expression-based classification to evaluate for BRAF mutations or mutations associated with medullary thyroid carcinoma (Afirma BRAF and Afirma MTC, respectively). In a description of the generation of the Afirma BRAF test, the authors outline the following proposed benefits of the mRNA-based expression test for BRAF mutations: (1) PCR based methods may have low sensitivity, requiring that a large proportion of the nodule have a relevant mutation; (2) testing for only one mutation may not detect patients with low-frequency mutations that result in the same pattern of pathway activation; and (3) PCR-based approaches with high analytic sensitivity may require a large of amount of DNA that is difficult to isolate from small FNA samples. The Afirma MTC is an option when the Afirma GEC is ordered for thyroid nodules with an “intermediate” classification on FNA, and can also be used for thyroid nodules with “malignant” or “suspicious” results on Afirma GEC. The Afirma BRAF is designed to be used for nodules with “suspicious” results on Afirma GEC.
Testing for mutations associated with thyroid cancer via sequencing or rtPCR are laboratory-developed tests (LDTs). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Improvement Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing.
In 2013, the U.S. Food and Drug Administration (FDA) approved through the premarket approval process the THxID™-BRAF kit, which is an in vitro diagnostic device to assess specific BRAF mutations in melanoma tissue via rtPCR. However, there are currently no diagnostic tests for thyroid cancer mutation analysis with approval from FDA.
POLICYMutation analysis in fine-needle aspirates of the thyroid is considered to be investigational.
The use of a gene expression classifier in fine-needle aspirates of the thyroid that are cytologically considered to be indeterminate, atypical or suspicious for malignancy, is considered to be investigational.
POLICY GUIDELINESInvestigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY03/22/2012: Approved by Medical Policy Advisory Committee.
01/14/2013: Added CPT codes 81404, 81405, and 81479 to the Code Reference section.
09/03/2013: Policy title changed from "Mutation Analysis in Fine Needle Aspirates of the Thyroid" to "Molecular Markers in Fine Needle Aspirates of the Thyroid." The policy statement was changed from mutation analysis in fine-needle aspirates of the thyroid that are cytologically considered to be indeterminate, atypical or suspicious for malignancy is considered to be investigational. It was updated to two separate policy statements as follows: 1) Mutation analysis in fine-needle aspirates of the thyroid is considered to be investigational. 2) The use of a gene expression classifier in fine-needle aspirates of the thyroid that are cytologically considered to be indeterminate, atypical or suspicious for malignancy, is considered to be investigational.
07/11/2014: Policy reviewed; no changes to policy statement. Removed deleted CPT codes from the Code Reference section: 83891, 83896, 83898, 83902, 83907, 83909, 83912, and 83913.
12/31/2014: Code Reference section updated to revise the description of the following CPT codes: 81404 and 81405.
07/31/2015: Code Reference section updated for ICD-10.
09/11/2015: Policy description updated to add information regarding mutation testing and gene expression profiling. No change in policy statements. Investigative definition updated in the Policy Guidelines section.
12/31/2015: Code Reference section updated to add new 2016 CPT code 81545.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.78
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.