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Molecular tests improve the detection of medullary thyroid cancer for patients with thyroid nodules

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Medullary thyroid cancer (MTC), a rare type of thyroid cancer, is usually more aggressive with higher death rates than the more common papillary or follicular thyroid cancers. To improve the outcome, it is important to detect and treat MTC early when the disease is confined to the thyroid gland, prior to the development of spread to the neck lymph nodes or distant metastases. Thyroid biopsy is an accurate and safe test available to differentiate between benign and suspicious or cancerous thyroid nodules; the results of this test have been used to guide treatment for thyroid nodules. However, diagnosing MTC on thyroid biopsies is challenging; more than 50% of MTCs are missed. In addition, according to the American Thyroid Association guidelines, routine screening for the presence of the MTC blood marker, calcitonin, is not recommended in patients with thyroid nodules, since MTC is very rare and other conditions not related to thyroid disease can result in falsely elevated levels. Because of frequent early neck lymph node involvement, more aggressive surgery is recommended at the time of the initial thyroid surgery for MTC. Failure to identify MTC in a thyroid nodule prior to surgery can result in insufficient initial thyroid surgery with a lower chance of cure and the need for re-operations.

The use of molecular testing in thyroid biopsies has improved the diagnosis for papillary and follicular thyroid cancer. These tests identify mutations in genes that are seen in thyroid cancer. If a thyroid biopsy has negative mutations, it is considered benign. However, initial molecular tests did not perform well for MTC. Veracyte Inc. has developed a novel algorithm to detect MTC in thyroid biopsies. The aim of this study is to report the development of and evaluate the performance of this commercially available MTC classifier.

Randolph GW et al 2022 Preoperative identification of medullary thyroid carcinoma (MTC): Clinical validation of the Afirma MTC RNA-sequencing classifier. Thyroid 32:1069–1076. PMID: 35793115.

Genes only expressed in MTC were identified using biopsy samples from 483 thyroid nodules and 97 surgical tissue samples. Among these, 21 biopsy specimens were from surgically confirmed MTC thyroid nodules and 462 specimens were from non-MTC thyroid nodules. A total of 8 different candidate gene groups were evaluated. The selected classifier included 108 genes.

The classifier was then validated using a separate group of 211 biopsy samples from patients with benign and cancerous thyroid nodules (21 MTC, 190 non-MTC) who underwent surgery and also had surgical tissue samples available. The classifier correctly identified as positive all 21 MTC samples and as negative all non-MTC samples. Of the MTC samples, 38% were initially diagnosed as atypical biopsy samples (Bethesda category III), 29% as indeterminate samples (Bethesda IV), and 33% as suspicious samples (Bethesda V). The non-MTC samples included benign thyroid nodules, malignant thyroid nodules (papillary, Hürthle, follicular, and poorly differentiated cancers), and chronic lymphocytic thyroiditis.

A commercially available gene classifier showed excellent accuracy in diagnosing MTC in thyroid biopsy samples. The addition of molecular gene analysis can be useful in identifying this condition prior to the thyroid surgery. Given that MTC is rare, further studies will need to address how to select the patients with thyroid nodules who would benefit from this test.

— Alina Gavrila, MD, MMSC


Thyroid nodule: an abnormal growth of thyroid cells that forms a lump within the thyroid. While most thyroid nodules are non-cancerous (benign), 5-10% are cancerous (malignant).

Medullary thyroid cancer (MTC): a rare type of thyroid cancer that often runs in families. MTC arises from the C-cells in the thyroid.

Cancer metastasis: spread of the cancer from the initial organ where it developed to other organs, such as the lungs and bone.

Thyroid biopsy: a simple procedure that is done in the doctor’s office to determine if a thyroid nodule is benign (non-cancerous) or cancer. The doctor uses a very thin needle to withdraw cells from the thyroid nodule.

Calcitonin: a hormone that is secreted by cells in the thyroid (C-cells). Calcitonin levels are increased in patients with medullary thyroid cancer.

Molecular markers: genes and microRNAs that are expressed in benign or cancerous cells. Molecular markers can be used in thyroid biopsy specimens to either to diagnose cancer or to determine that the nodule is benign. The two most common molecular marker tests are the Afirma™ Gene Expression Classifier and Thyroseq™

Genes: a molecular unit of heredity of a living organism. Living beings depend on genes, as they code for all proteins and RNA chains that have functions in a cell. Genes hold the information to build and maintain an organism’s cells and pass genetic traits to offspring.

Mutation: A permanent change in one of the genes.

Indeterminate thyroid biopsy: this happens a few atypical cells are seen but not enough to be abnormal (atypia of unknown significance (AUS) or follicular lesion of unknown significance (FLUS)) or when the diagnosis is a follicular or Hurthle cell lesion. Follicular and Hurthle cells are normal cells found in the thyroid. Current analysis of thyroid biopsy results cannot differentiate between follicular or Hurthle cell cancer from noncancerous nodules. This occurs in 15-20% of biopsies and often results in the need for surgery to remove the nodule.

Suspicious thyroid biopsy: this happens when there are atypical cytological features suggestive of, but not diagnostic for malignancy. Surgical removal of the nodule is required for a definitive diagnosis.