LCD L38968: Thyroid Nodule Molecular Testing

Indications and Limitations of Coverage

The use of molecular testing (MT)* to assess thyroid nodules may be considered medically necessary ONCE per nodule workup when ALL of the following criteria are met:

• Thyroid fine-needle aspiration (s) (FNA) performed secondary to established indications based on ultrasound characteristics, size and clinical findings (1)

• Presence of indeterminate thyroid FNA cytopathology described as (1,2)

• Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) (i.e., Bethesda category III), or

• Follicular neoplasm (FN) or suspicious for a follicular neoplasm (SFN) (i.e., Bethesda category IV)

• The need for thyroidectomy is unclear after consideration of clinical, imaging, and cytologic features (1,2)

• Local institutional malignancy rates are known and used for optimal extrapolation of results to thyroid cancer risk (1)

• Informed patient willing to potentially undertake surveillance (1)

*The scope of this LCD is limited to tests submitted on claims to NGS jurisdictions J6 and JK.

Thyroid cancer is the most common endocrine malignancy, with over fifty thousand new United States diagnoses in 2020 (3). Thyroid nodules are exceedingly common with prevalence rates of up to 68%, with higher frequencies in the elderly (4). While the majority (85-93%) of thyroid nodules are benign, diagnostic testing (history and physical, laryngoscopy, hormone and chemistry analysis, ultrasound, CT, FNA, and surgical excision) is required to confirm. Over 600,000 thyroid FNAs are performed every year in the United States, and the number has been increasing annually by 16% (5). Despite this diagnostic gauntlet, approximately 20% of FNA results are classified indeterminate (Bethesda III/IV) with a 10-40% risk of malignancy (6). Cancer rates vary widely by institution, ranging from 6-48% for Bethesda III and 14-34% for Bethesda IV. Repeat FNA of Bethesda III nodules should be strongly considered as it leads to a more definitive reclassification in 60-65% (1). Previously, the majority of patients with an indeterminate FNA, confirmed on repeat aspiration, had diagnostic thyroid surgery (usually lobectomy), with most (75-95%) ultimately confirmed to be benign (6). Rates of thyroid surgery-specific postoperative complications (recurrent laryngeal nerve injury, permanent hypoparathyroidism, and postoperative hematoma) in high-volume institution studies range between 0.4-7.4%, but a population-based study found it as high as 12.3% (7).

In 2012, molecular marker testing (MT) became widely available as a potential method to augment risk stratification of indeterminate FNA results, ideally reducing the need for diagnostic thyroid surgery or completion thyroidectomy, with their attendant risks and costs. A patient with a low MT malignancy risk is potentially recommended for surveillance with serial ultrasounds to ensure nodule stability. Conversely, a high malignancy MT result could strengthen a recommendation to move forward with surgical removal ( lobectomy or total thyroidectomy ). Molecular profiling includes genomic alterations (such as point mutations, insertions, and deletions), gene fusions resulting in rearrangements or translocations, copy number variations, RNA-based gene expression, and/or micro-RNA (miRNA) expression (1).

In 2016, the nomenclature of encapsulated follicular variant of papillary thyroid cancer was changed to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in recognition of its highly indolent nature. Thus, the value of MT may arise both from the avoidance of surgery and the fact that surveillance is now a safer and more informed option (8). Conversely, given clinical guideline recognition that more limited cancer operation can lead to equivalent outcomes, the impact of molecular testing in directing the extent of surgical resection is diminished (9).

Thyroseqv3 (CBLPath, Inc.; Rye Brook, NY)