Thyroid Cancer

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Kukull

Benjamin J. Kukull, MD

Molecular Genetic Pathology Fellow, University of Utah School of Medicine

The thyroid gland is the endocrine organ most commonly affected by a primary malignancy. Thyroid cancers are usually detected as nodules found during physical examinations or as incidental findings during imaging procedures (see the ARUP Consult Thyroid Nodules topic). If a malignancy is confirmed or suspected based on cytology, or if cytology is indeterminate, pre- and postoperative histologic examination and testing for molecular markers can be used to confirm the diagnosis, differentiate between thyroid cancer subtypes, inform prognosis, and guide treatment. If a familial syndrome is suspected, germline testing may be warranted. Laboratory tests for tumor markers (including thyroid-stimulating hormone [TSH], thyroglobulin [Tg], and thyroglobulin antibody [TgAb]) are also used in thyroid cancer monitoring and surveillance. Medullary thyroid cancer (MTC) entails additional testing (see Testing for Medullary Thyroid Cancer).

Quick Answers for Clinicians

When should molecular testing be considered in thyroid cancer?

It is recommended that molecular testing be considered in addition to, rather than as a replacement for, cytologic evaluation. Molecular testing is recommended only if results will influence clinical decision-making and is generally not recommended in nodules that are clearly benign or clearly malignant based on cytologic evaluation. If cytology samples obtained via fine needle aspiration (FNA) are indeterminate, molecular testing may be useful to support tumor diagnosis, stratify risk for progression and recurrence, and guide therapeutic decision-making. For more information, see Molecular Markers.

What is the role of molecular marker panel tests in thyroid cancer?

Either multigene assays or single gene molecular marker tests may be useful in thyroid cancer, although specifically designed thyroid cancer gene panels may be especially helpful to establish the diagnosis in indeterminate nodules, given that there is no single molecular test that can definitively rule in or rule out malignancy. However, panel tests are not standardized, and most mutation panel tests are proprietary and utilize different technologies (eg, next generation sequencing [NGS], RNA expression signature analysis, micro RNA [miRNA] analysis, or a combination of technologies), with their own predictive advantages and disadvantages. For more information, see Molecular Markers.

How does pediatric thyroid cancer differ from adult thyroid cancer, and how does this affect laboratory testing?

The evaluation and management of thyroid nodules are similar in children and adults. However, pediatric thyroid nodules are more likely to be malignant than adult nodules. Furthermore, some thyroid cancer treatments may not be appropriate for children. This ARUP Consult topic focuses on laboratory testing for thyroid cancer in adults; for detailed information on thyroid cancer testing in children, see the Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer from the American Thyroid Association.

What are the major subtypes of thyroid cancer, and how are they distinguished?

Thyroid cancers may be histologically classified as differentiated thyroid cancer (DTC, which includes papillary thyroid cancer [PTC], follicular thyroid cancer [FTC], and Hürthle cell cancer); anaplastic thyroid cancer (ATC); or medullary thyroid cancer (MTC). The WHO classification system includes noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP). Thyroid cancer may also be poorly differentiated. Prognosis and recommended treatment vary by cancer type. In addition to histology, molecular markers may be useful to distinguish between thyroid cancer subtypes.

Indications for Testing

Testing for thyroid cancer is appropriate in individuals with:

Thyroid nodule(s) that are indeterminate, suspicious for malignancy, or malignant based on cytology
Increased risk of thyroid cancer (eg, due to history of radiation exposure, thyroid cancer in a first-degree relative, or genetic predisposition)
Abnormal cervical nodes

Screening for thyroid cancer in the general population is not recommended.

Laboratory Testing

Histology and molecular testing can be used to further investigate thyroid nodules that have been categorized as malignant, suspicious for malignancy, or indeterminate by fine needle aspiration (FNA) and cytology.

Histology

Histologic examination of thyroid tissue samples is used to establish or confirm the diagnosis of thyroid cancer, classify the cancer, stratify risk, and guide management after thyroid surgery. Histologic features may also suggest the need for germline testing for a variant associated with a familial cancer syndrome; for example, the cribriform-morular form of papillary thyroid carcinoma (PTC), characterized by distinctive histologic features, is associated with familial adenomatous polyposis (FAP). Tg, thyroid transcription factor 1 (TTF-1), and PAX8 are supportive of thyroid origin of malignancy, although TTF-1 expression may be absent in some cancers (eg, anaplastic thyroid carcinoma). Parathyroid hormone (PTH) immunostaining can be used to exclude parathyroid origin. Calcitonin can be evaluated by immunostaining in MTC. For more information on immunostaining, refer to ARUP Immunohistochemistry Stain Offerings.

Molecular Markers in Tumor Tissue

Molecular markers are useful to establish malignancy if cytology samples obtained via FNA are indeterminate, and are also used in risk stratification. The National Comprehensive Cancer Network (NCCN) recommends molecular diagnostic testing for nodules suspicious for follicular thyroid cancer (FTC) or atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) on FNA. Molecular markers may also guide targeted therapeutic decision-making. The appropriate specimen type (eg, fine needle aspirate or formalin-fixed paraffin embedded tissue) depends on the test to be used.

Specifically designed thyroid cancer gene panels may be especially helpful to establish the diagnosis of thyroid cancer because there is no single molecular test that can definitively rule in or rule out malignancy. Available panels include Afirma (from Veracye), ThyGenX and ThyraMIR (from Interpace Diagnostics), RosettaGX Reveal (from Rosetta Genomics/Genoptix), and ThyroSeq (from the University of Pittsburgh Medical Center). Several different methodologies (eg, next generation sequencing [NGS], multiplex polymerase chain reaction [PCR], and messenger RNA [mRNA] gene expression) may be used for these panel tests. In many cases, these molecular panel tests are based on proprietary algorithms, involve in-house interpretation, and are not standardized, making it difficult to compare one assay with another.

Molecular Markers in Thyroid Cancer
Type of Tumor (WHO Classification)	Molecular Markers	Clinical Implications
PTC	Classical: BRAF V600E, RET/PTC fusion, NTRK fusion, ALK fusion, 1q amplification Follicular variant: BRAF K601E, RAS, PAX8/PPARc, EIF1AX, THADA fusion, 22q deletion Tall, columnar, hobnail, and solid variants: BRAF V600E, 1q amplification, TERT promoter, TP53, PIK3CA, CTNNB1 Cribriform morular variant: consider germline testing for FAP (APC germline variants)	Most common thyroid cancer Nonaggressive variants have excellent prognosis Cancers with BRAF V600E variant are more aggressive: Low risk if tumor is <1 cm Intermediate risk if tumor is <4 cm High risk if pathogenic TERT variant Most fatal non-ATC thyroid cancers are PTC with BRAF or RAS variants with other pathogenic variants
NIFTP	RAS (without BRAF) BRAF K601E	Generally classified as indeterminate by cytology Low risk (indolent behavior) Histologic diagnosis with strict criteria (not cytologic diagnosis) Mutation profile not specific Molecular testing is used to suggest alternate diagnosis, not to confirm diagnosis of NIFTP
FTC	RAS, PAX8/PPARc, PTEN, PIK3CA, TSHR, TERT promoter, CNA Consider germline testing for PTEN hamartoma tumor syndromes, if supported by clinical presentation	Second most common thyroid cancer More common in iodine-deficient patients and in older populations than is PTC Generally less aggressive Hematogenous dissemination
Hürthle cell	RAS, EIF1AX, PTEN, TP53, CNA, mtDNA, GRIM-19	More aggressive and more likely to recur than FTC In contrast with FTC, disseminates lymphatically as well as hematogenously
Poorly differentiated	RAS, TERT promoter, TP53, PIK3CA, PTEN, CTNNB1, AKT1, EIF1AX, ALK fusion, histone methyltransferases, switch/sucrose nonfermentable chromatin remodeling complex	Currently being researched May arise from well-differentiated carcinomas Intermediate clinical behavior (between well-differentiated carcinomas and anaplastic carcinoma)
ATC	BRAF, RAS, TERT promoter, TP53; NTRK and ALK rearrangements	Very aggressive; poor prognosis Cancers with BRAF V600E variant can be treated with BRAF plus MEK inhibitor combination Variants in other genes (eg, ALK) may also be targetable May arise from well-differentiated carcinomas TTF-1 IHC negative
MTC	RET, RAS Consider germline testing for RET-associated MTC syndromes in young patients and/or those with suggestive family history	RET and RAS are expressed in the majority of MTCs Most sporadic MTCs with distant metastases have somatic RET mutations (often RET M918T) Somatic RET mutations are associated with more aggressive tumors Somatic RET testing is recommended if treatment with selective RET inhibitors is planned Cabozantinib may have clinical benefit for tumors with RET M918T or RAS variants
ATC, anaplastic thyroid cancer; NIFTP, noninvasive follicular thyroid neoplasm with papillarylike nuclear features Sources: ESMO, 2019; NCCN, 2019

Germline Genetic Testing

The cribriform-morular variant of PTC may occur in individuals with FAP and pathogenic variants in the APC gene; therefore, genetic counseling should be considered.

Follicular thyroid cancer may occur in individuals with PTEN hamartoma tumor syndrome and pathogenic variants in the PTEN gene; if the thyroid has the characteristic appearance of the syndrome, genetic counseling is recommended.

For more information on germline genetic testing in MTC (eg, RET and RAS mutations), see the Testing for Medullary Thyroid Cancer section.

Monitoring and Surveillance

Testing is recommended after treatment with thyroidectomy, both before and after radioactive iodine (RAI) remnant ablation (if indicated).

Monitoring and surveillance for recurrence in thyroid cancer consists of a combination of imaging and laboratory tests. Follow-up laboratory tests include tests for tumor markers such as TSH, Tg, and TgAb; calcitonin and carcinoembryonic antigen (CEA) are specific tumor markers used in MTC.

Thyroid-Stimulating Hormone

Serum TSH measurement after withdrawal of levothyroxine is recommended before RAI. Serum TSH measurements are recommended at least every 12 months after thyroid cancer treatment in patients receiving thyroid hormone therapy to guide dosing and to ensure TSH is maintained within the appropriate target range.

Serum Thyroglobulin and Antithyroglobulin Antibodies

Serum Tg is the primary tumor marker test for recurrence after thyroid cancer treatment. An undetectable level of Tg has a high negative predictive value for recurrence. In addition to its use for predicting recurrence, serum Tg may be used to assess the success of treatment, predict the likelihood of identifying metastatic thyroid cancer, predict the likelihood of successful remnant ablation, predict the risk of mortality, and guide clinical management and decision-making. Simultaneous measurement of the tumor marker TgAb with Tg is required because TgAb may interfere with Tg tests; thus, the presence of TgAb makes Tg values uninterpretable. Tg may either be measured in response to TSH stimulation or without stimulation. High-sensitivity Tg can be used instead of TSH-stimulated Tg to verify the absence of thyroid cancer. Because Tg assays are not fully standardized and harmonized, the same assay should be used for all Tg measurements throughout follow-up. Standalone measurement of TgAb over time may also provide useful information, given that TgAb may increase in the presence of recurrent cancer and tends to decrease if therapy was successful. However, TgAb assays are also prone to interference and a lack of standardization.

The European Society for Molecular Oncology (ESMO) and NCCN recommend that follow-up schedules and techniques be customized according to the type of cancer, type of treatment, response to treatment, and risk level. The American Thyroid Association (ATA) recommends measurement of serum Tg every 6-12 months during initial follow-up, or more frequently in high-risk patients. Serum Tg can be measured every 12-24 months thereafter in patients who have an excellent response, and should be measured at least every 6-12 months in patients at high risk or with an incomplete or indeterminate response to therapy.

See the Thyroid Cancer Monitoring and Surveillance algorithm for additional information.

Testing for Medullary Thyroid Cancer

Molecular markers for MTC are discussed in the Molecular Markers in Thyroid Cancer table above. Monitoring and surveillance recommendations for MTC are the same as for other thyroid cancers; refer to Monitoring and Surveillance section for additional information.

Confirmation of Diagnosis

Calcitonin and CEA are tumor markers that are useful in MTC, and calcitonin expression must be confirmed to diagnose MTC. If the serum calcitonin concentration is elevated, the test should be repeated. If the elevated concentration is confirmed, a calcium stimulation test is recommended. CEA is also expressed in MTC, but not in other primary thyroid cancers, so it may be particularly useful to measure CEA if a calcitonin-negative MTC is suspected. However, CEA expression is not specific to calcitonin-negative MTC but is associated with a number of other malignancies, and results should be interpreted with care. An elevated CEA result warrants ruling out coexisting CEA-expressing tumors and metastases, especially in cases of otherwise undetectable residual disease. As mentioned in the Histology section, calcitonin may also be evaluated by immunostaining in MTC.

Preoperative Testing

Preoperative testing for pheochromocytoma and hyperparathyroidism is recommended in patients with MTC, unless they are already known to have multiple endocrine neoplasia type 2B (MEN2B).

Prognosis

Because calcitonin and CEA are directly related to the mass of calcitonin-secreting cancer cells, they are also useful tumor markers for prognosis. However, calcitonin is the more specific tumor marker in cases of calcitonin-expressing tumors when compared with CEA. The measurement of both calcitonin and CEA increases sensitivity for the detection of persistent disease, particularly if tumors fail to express or cease to express calcitonin. Measurement of calcitonin and/or CEA is recommended 60-90 days after thyroidectomy to assess risk for recurrence.

Calcitonin and CEA doubling times are recommended for prognosis in postoperative MTC. When both markers are expressed, calcitonin doubling time is the superior marker of MTC progression. Shorter doubling times are associated with worse prognosis. At least four consecutive measurements over a 2-year period are recommended to enable calculation of doubling time.

Germline Genetic Testing

Genetic counseling and RET germline testing are recommended for all individuals with diagnosed MTC to determine whether MTC is familial. RET testing is also recommended for relatives of individuals diagnosed with a familial form of MTC.