LCD L39646: MolDX: Molecular Testing for Risk Stratification of Thyroid Nodules

This contractor will cover molecular diagnostic tests for use in a beneficiary with an indeterminate or suspicious thyroid nodule when all the following criteria are met:

• The patient:

• Has an index nodule that has not been tested with the same or similar assay for the same clinical indication AND

• The nodule is indeterminate as defined by Bethesda categories III-IV OR

• The nodule is Bethesda category V and molecular testing may aid in further stratifying the type of malignancy.

• If the patient has multiple nodules, concurrent or reflex testing may be medically necessary, provided the above criteria are also met.

• The results of the test will be used to aid in surgical decision making after a consideration of clinical, radiographic and cytologic features.

• The beneficiary is within the population and has the indication for which the test was developed. The laboratory providing the test is responsible for clearly indicating to treating clinicians the population and indication for test use.

• The test demonstrates analytical validity, including both analytical and clinical validation, on a cohort of patients appropriate for its intended use. If the test relies on an algorithm, the algorithm must be validated in a cohort that is not a development cohort for the algorithm.

• The test has demonstrated clinical validity and utility in peer-reviewed, published literature, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management decision in a clearly defined population.

• The test successfully completes a technical assessment that ensures the test is reasonable and necessary as described above.

• The performance characteristics of the test have been demonstrated to be as good or better than currently covered services.

NOTE: Next Generation Sequencing (NGS) performed to identify genetic variants in samples classified as malignant is not within the scope of this policy but may fall under other established policies.

Background

Thyroid cancer (TC) is the most common endocrine malignancy, consisting of nearly 3% of all newly diagnosed cancer cases in the United States each year. 1 Greater than 70% of those cases are women, representing the fifth most diagnosed malignancy in females. It is the second most common cancer among Hispanic and Asian/Pacific Islander women in the US, who also have the highest mortality rates. 2 Differentiated thyroid carcinoma is the most common form, accounting for around 90% of all cases and includes papillary thyroid carcinoma (PTC), follicular carcinoma (FC) and Hurthle cell carcinoma (HTC). 3,4 Medullary thyroid carcinoma (MTC), a rare neuroendocrine tumor that arises from the neural crest-derived parafollicular calcitonin-secreting thyroid C cells, represents 4% of all TC. 5 Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid tumor and while only around 1-2% of all TC, accounts for the majority of TC death. 6

The diagnosis of TC in the United States has tripled over the last 25 years. 1 Several studies attribute the significant increase to overdiagnosis of small indolent tumors that would otherwise not cause symptoms or require treatment with a majority of the increase being explained by PTC tumors 2 cm or smaller. 7-11 In fact, recent studies suggest the incidence rate of thyroid cancer stabilized between 2013-2016 and declined between 2016-2018. 12,13 This stabilization followed by decline has been postulated to be a result of changes in practice patterns and reclassification of some cancer types. In 2016, the Endocrine Pathology Society working group reported clinical outcomes and refined the diagnostic criteria for encapsulated follicular variant of papillary thyroid carcinoma (EFVPC) and proposed replacing the term with non-invasive follicular thyroid neoplasm with papillary-like nucleus features (NIFTP) to describe these tumors more accurately. 14 The American Thyroid Association (ATA) recommended this terminology change in 2017. 15 This led to the reclassification of approximately 10-20% of thyroid tumors from malignant to benign. 14 In addition, guidelines for the management of thyroid nodules have become increasingly more conservative regarding size thresholds for nodule biopsy and discourage biopsy for nodules 16,17 However, some studies have reported a true increase in advanced-stage and larger PTC tumors as well as incidence-based mortality that cannot be explained by overdiagnosis and suggest that lifestyle-related factors such as obesity may be contributory. 10,18 Also, there continue to be disparities in diagnosis and treatment of TC in patients based on race, ethnicity and socioeconomic status with patients from minority backgrounds more likely to present with larger tumors, and distant metastases than white patients. 2,19,20 However, a recent report from Ginzberg et al. suggests that the updated ATA guidelines ameliorated some of these disparities. 21

TC almost exclusively presents as thyroid nodules, occurring in 7-15% of cases depending on sex, age, radiation exposure, family history and other factors. 16 However, thyroid nodules are very common; most are asymptomatic and benign and do not require monitoring, treatment, or evaluation. In fact, over 60% of the population will have a thyroid nodule by the time they are over the age of 65. 16 Therefore, it is important to distinguish between benign and malignant nodules for patients to receive appropriate treatment and prevent unnecessary surgery.