Thyroid Nodule Molecular Test (L38968) (2023)

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Molecular study of thyroid nodules

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For services performed on or after January 12, 2021

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CMS National Coverage Policy

Quoted language from the Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCD), and coverage provisions in interpretation manuals are italicized throughout the policy. NCDs and scope provisions in interpretation manuals are not subject to the Local Scope Determination (LCD) review process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). Also, an administrative law judge cannot review an NCD. see section 1869(f)(1)(A)(i) of the Social Security Act.

Unless otherwise noted, text in italics means a citation from one or more of the following CMS sources:

Title XVIII of the Social Security Act (USS):
Section 1862(a)(1)(A) excludes expenditure for items or services that are unreasonably necessary for the diagnosis or treatment of an illness or injury or for the improvement of the function of a disfigured limb.
Section 1833(e) prohibits Medicare from paying claims that do not contain the information necessary to process your claim.
Section 1862(a)(7) excludes routine physical examinations, unless otherwise provided by law.

CMS publications:
Publication CMS 100-02,Medicare Benefit Policy Handbook, Chapter 15, Section 80.1 - Laboratory Services must meet applicable CLIA requirements

Publication CMS 100-04,Medicare Claims Processing Manual, Chapter 16, Section 40.7 Billing for Uninsured Persons

Section on Clinical Laboratory Tests and 120.1 Explanation of the use of the term "screening" or "screening"

Publication CMS 100-04,Medicare Claims Processing Manual, Chapter 30, Section 50 Advance Notice to Beneficiary of No Insurance (ABN)

Publication CMS 100-08,Medicare Integrity Guide, Chapter 13, Local Coverage Findings

CMSNational Correct Coding Initiative (NCCI) Policy Handbook.for Medicare, Chapter 10, Pathology/Laboratory Services, (A) Introduction

Publication CMS 100-02,Medicare Benefit Policy Handbook, Chapter 15, Section 80.6. 5, which describes a surgical/cytopathological exception.

CMSNational Correct Coding Initiative (NCCI) Policy Handbook.for Medicare, Chapter 10 Pathology/Laboratory Services, which deals with reflex testing.

Publication CMS 100-03,National Medicare Coverage Guide (NCD)., Chapter 1, Part 3, Section 190.3 Cytogenetic Studies.

Code of Federal Regulations

Section 42 CFR 410.32 states that diagnostic tests may only be ordered by the treating physician (or other treating physician acting within the scope of their license and Medicare requirements) who consults or treats the beneficiary for a specific medical condition and who uses the results in the management of a beneficiary's specific medical problem. Tests not ordered by the physician (or other qualified non-physician) treating the beneficiary are not reasonable or necessary (see section 411.15(k)(1) of this section).

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Insurance indications, limitations and/or medical necessity

Insurance indications and limitations

The use of molecular tests (MT)* to evaluate thyroid nodules may be considered clinically necessaryONCEfor a global test whenALLthe following criteria are met:

  1. Fine-needle aspiration (FNA) of the thyroid performed according to established indications based on sonographic characteristics, size, and clinical findings (1)
  2. Presence of unspecified cytopathology of thyroid ANF described as (1,2)
    1. atypia of undetermined significance (AUS) or vesicular lesion of undetermined significance (FLUS) (i.e. Bethesda category III) or
    2. Follicular neoplasm (FN) or suspected follicular neoplasm (SFN) (ie, Bethesda category IV)
  3. The need to remove the thyroid gland is unclear after considering clinical, imaging, and cytological features (1,2)
  4. Local institutional malignancy rates are known and used for optimal extrapolation of results to thyroid cancer risk (1)
  5. Informed patient willing to potential surveillance (1)

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

summary of evidence

Thyroid cancer is the most common endocrine malignancy, with over fifty thousand new diagnoses in the United States in 2020 (3). Thyroid nodules are extremely common, with an incidence of up to 68%, being more common in the elderly (4). Although the majority (85-93%) of thyroid nodules are benign, diagnostic tests (history and physical examination, laryngoscopy, hormone and chemical analysis, ultrasound, CT scan, FNAB, and surgical excision) are required for confirmation. In the United States, over 600,000 thyroid FNABs are performed annually, and that number is increasing by 16% annually (5). Despite this diagnostic difficulty, approximately 20% of FNA results are classified as indeterminate (Bethesda III/IV) with a risk of malignancy of 10-40% (6). Cancer rates vary greatly by institution, ranging from 6-48% for Bethesda III and 14-34% for Bethesda IV. Repeat BKN of Bethesda III nodules should be seriously considered as it leads to a more definitive reclassification of 60-65% (1). Previously, most patients with unspecified FNAC, confirmed by repeated aspiration, had undergone diagnostic thyroid surgery (usually lobectomy), with the majority (75-95%) finally being confirmed as benign (6). The rate of postoperative complications specific to thyroid surgery (recurrent laryngeal nerve injury, persistent hypoparathyroidism, and postoperative hematoma) in large research centers ranges from 0.4 to 7.4%, but a population study has shown that it reaches to 12.3% (7) .

In 2012, molecular marker (MT) testing became widely available as a potential method to enhance risk stratification for indeterminate FNAB results, ideally reducing the need for diagnostic thyroid surgery or total thyroidectomy, along with their risks and associated costs. A patient with a low risk of TM malignancy is potentially recommended for serial ultrasound monitoring to ensure nodule stability. On the other hand, a high MT score with malignancy may reinforce the recommendation to proceed with surgical removal (lobectomy or total thyroidectomy). Molecular profiling includes genomic changes (such as point mutations, insertions, and deletions), gene fusions resulting in rearrangements or translocations, copy number changes, RNA-based gene expression, and/or micro-RNA (miRNA) expression (1) .

In 2016, the nomenclature of encapsulated papillary follicular carcinoma of the thyroid was changed to non-invasive papillary follicular carcinoma (NIFTP) due to its highly indolent nature. Thus, the value of TM may be due both to the avoidance of surgery and the fact that surveillance is now a safer and more informed option (8). On the other hand, given clinical guidelines that more limited cancer surgery can lead to equivalent results, the influence of molecular testing in guiding the extent of surgical resection is less (9).

Thyroseqv3 (CBLPath, Inc.; Rye Brook, Nowy Jork)

Thyroseqv3 is a next-generation targeted sequencing test that screens selected regions of 112 thyroid cancer-related genes for point mutations, insertions/deletions, gene fusions, copy number changes, or changes in gene expression (5). The "Genomic Classifier" assigns a value to each detected genetic change based on the strength of the association with cancer: 0 (no cancer association), 1 (low likelihood of cancer) or 2 (high likelihood of cancer). The score calculated for each sample is the sum of the individual values ​​of all detected lesions, with scores of 0 and 1 accepted as a negative test (score 1 commercially reported as currently negative) and scores of 2 and above as positive.

This evidence summary is limited to the current version of Thyroseq (version 3). Also excluded are publications that combine results from several versions of Thyroseq where results from version 3 could not be extracted (8,10,11).

In a multicenter, prospective, blinded clinical validation study of ThyroSeqv3, including 247 Bethesda III and Bethesda IV nodules, in which both the pathologist and clinicians were blinded to the results of TM, the sensitivity was 94% (95% CI, 86% - 98%) and specificity 82% (95% CI, 75%-87%). With a cancer/NIFTP incidence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%), the positive predictive value (PPV) was 66% (95% CI, 56%-75% ), with a soft calling rate (BCR) of 61% (5). The observed false-negative rate of 3% was similar to benign cytology, and all missed tumors were low-risk. Results for the 10 Bethesda V nodes are not reported separately.

In another validation study, Thyroseqv3, 238 surgically removed tissue samples were used as a training set and 175 undetermined ANFs (Bethesda III, n=84; Bethesda IV, n=74; Bethesda V, n=17) as a validation set (12 ). The sensitivity of the training set was 93.9% (95% CI, 88.4%-96.9%), the specificity was 89.4% (95% CI, 81.1%-94.3% ), with an accuracy of 92.1% (95% CI, 87.8%-95.0%). The sensitivity of the validation set was 98.0% (95% CI, 92.9%-99.4%), the specificity was 81.8% (95% CI, 71.8%-88.9% ), with an accuracy of 90.9% (95% CI, 85.7%-94.3%). Sensitivity and specificity for Hurthle cell lesions in the training set were 92.9% (95% CI, 80.52%-98.50%) and 69.3% (95% CI, 48.21%-85 ), respectively 0.67%). A separate case study also showed benefits in indeterminate cytopathology of Hürthle cells (13).

In an independent, single-center, unblinded observational study, a total of 50 cytologically indeterminate Bethesda III/IV nodules were tested with the ThyroSeqv3 test (14). Molecular analysis yielded 20 (40%) "positive" results and 24 (48%) "negative" results. Six (12%) of the results were classified as "currently negative" or "negative but limited". All 20 "positive" patients, as well as the "currently negative" patients (n = 2) and one "negative but limited" patient (n = 1) underwent surgery. All 26 'negative' patients and one 'negative but limited' patient (n=1) continued to be followed up. A total of 23 (46%) patients underwent surgical treatment and 27 (54%) conservative treatment. The BCR was calculated as ("negative" and "currently negative")/total, resulting in a BCR of 58%. Ninety-one percent (20 of 22) of the removed target nodules were malignant at final pathology. As surgery was not performed on patients with a negative test, the specificity, sensitivity and NPV of the test were not available.

In a 2019 retrospective review of 224 thyroid nodules with ThyroSeqv3 Bethesda III or IV cytology available, the BCR rate was 75% (15). In a hypothetical cost-effectiveness analysis, ThyroSeqv3 was superior to diagnostic lobectomy for unspecified nodules (Bethesda III/IV) (16).

Analysis of evidence (justification of conclusion)

Guidelines emphasize reserving TM for thyroid nodules with ambiguous clinical, cytopathological, and radiographic factors. The 2015 American Thyroid Association (ATA) guidelines for the treatment of thyroid nodules include several cautionary statements specific to TM (4): Uncertainty about therapeutic and long-term implications of clinical outcomes. (strong recommendation, low-quality evidence); 2/ In the case of nodules with AUS/FLUS cytology, tests such as repeated FNAB or molecular tests may be used to complement the malignancy risk assessment, rather than direct follow-up or diagnostic surgery, after considering the clinical and sonographic features of concern (weak recommendation medium quality evidence); 3/ Diagnostic surgical excision has long been recognized as the standard of care in the treatment of NF/SFN cytological nodules. However, after considering clinical and sonographic features, molecular testing can be used to supplement the data for malignant risk assessment rather than direct surgical treatment (weak recommendation, moderate-quality evidence); and 4/ When surgery is considered for patients with a single cytologically indeterminate nodule, lobectomy is recommended as the initial surgical method. This approach can be modified based on clinical or sonographic characteristics, patient preference, and/or molecular testing when performed. (Strong recommendation, moderate-quality evidence).

More recent guidelines are even more cautious due to a combination of transient factors (9). The 2020 American Association of Endocrine Surgeons (AAES) Guidelines reflect recent growing concerns about TM (1). They cite the following qualifiers: 1/ "independent follow-up studies generally report reduced utility"; 2/ “professionals and patients may also have difficulty interpreting TM results... potentially leading to over- or under-treatment”; 3/ before obtaining the MT, one must consider "the patient's willingness to continue surveillance"; 4/ the use of TM results for clinical decision-making is based on PPV and NPV, which depend on the regional and institutional incidence of cancer for each cytology category; and 5/ "since NIFTP reduces the risk of true malice for unspecified Bethesda categories, all MT PPVs will be affected." In other words, on the last point, since the molecular assays were developed and validated prior to this new labeling (and therefore designed to classify this potentially benign pathology as malignant), their performance measures have been shown to deteriorate significantly when the NFTP designation is included in the classification of indeterminate nodules (9). The impact of NFTP reclassification is not trivial, as its mean prevalence in unspecified thyroid nodules is estimated at 61% (range 33 to 88%) (17,18).

The AAES guidelines cite three specific recommendations for TM: 1/ If thyroidectomy is clinically preferred, then TM is not required. (Strong recommendation, moderate-quality evidence); 2/ When, after considering the clinical, imaging and cytological features, there is no clear need for thyroidectomy, TM can be considered as a diagnostic adjunct for cytologically indeterminate nodules. (Strong recommendation, moderate-quality evidence); and 3/ TM accuracy is based on institutional malignancy rates and should be tested locally for optimal extrapolation of results to thyroid cancer risk. (Strong recommendation, moderate-quality evidence). The use of MT for Bethesda V bosses is not recommended as they lack validation and usability testing. Specifically regarding TM to determine the extent of surgery, they note, "Future research will determine whether the genotype provides information that has not yet been obtained clinically by ultrasound and/or cytologic staging, and whether changing the initial extent of surgery based on the MT results will influence outcomes.” UpToDate also limits the potential use of MT to Bethesda nodes III and IV (6).

National Comprehensive Cancer Network (NCCN) guidelines have similar criteria (2). They add that: "Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular carcinoma, AUS, FLUS) as more or less likely to be benign or malignant based on the genetic profile..." but" must be interpreted with caution and in the context of the clinical, radiographic and cytological characteristics of each individual patient”.

In conclusion, the NGS supports the judicious use of molecular testing of thyroid nodules according to current guidelines. We await further independent prospective studies to further define clinical usefulness, especially in the context of recent improvements in imaging (the Thyroid Imaging, Reporting, and Data System (TIRADS) algorithm) and cytology grading.

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