Thyroid Cancer

Thyroid cancer is the most common endocrine malignancy, although the lifetime risk of developing thyroid cancer is low. It is usually detected as a mass or nodule found during physical examination; however, incidental detection on imaging is also common. Initial laboratory testing includes thyroid stimulating hormone (TSH), also called thyrotropin, and free thyroxine (T4). There are no specific serum tumor markers for most thyroid cancers, although serum calcitonin concentrations may be increased by medullary thyroid cancer. Fine needle aspiration (FNA) is used to obtain tissue for definitive diagnosis of suspicious thyroid nodules and to determine the need for surgery.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

Indications for Testing

Thyroid nodule, abnormal cervical nodes, abnormal imaging

Laboratory Testing

  • Refer to Thyroid Nodules Testing algorithm for information regarding which nodules require additional follow-up (based on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer [Haugen, 2016])
  • Initial laboratory testing
    • TSH, also called thyrotropin
      • Low or suppressed TSH – order thyroxine (T4) (Gharib, 2016)
        • Elevated free T4 – proceed with thyroid radioisotope study after thyroid ultrasound
        • Normal or elevated TSH – consider thyroid ultrasound and FNA biopsy
  • FNA – used to obtain tissue for definitive diagnosis of suspicious thyroid nodules and determination of need for surgery
    • Need for biopsy is determined by size and characteristics of nodule on ultrasound
    • Biopsy may be obviated in the presence of compressive symptoms, which indicate need for immediate referral for surgical resection
  • Tumor markers – for medullary thyroid cancer (MTC) (Wells, American Thyroid Association [ATA], 2015)
    • Calcitonin  – most useful marker; concentrations are directly related to medullary carcinoma
    • Carcinoembryonic antigen (CEA) – not as useful for diagnosis but can be used for monitoring disease progression and for surveillance after thyroidectomy

Imaging Studies

  • Ultrasound – initial evaluation for thyroid nodules to aid in determining
    • Nodule size
    • Solid or cystic nature of nodule(s)
    • Number of nodules present
  • FNA biopsy (Haugen, ATA, 2016)
    • Procedure of choice for evaluating suspicious thyroid nodules
    • Ideally, performed with ultrasound guidance
    • If FNA biopsy is nondiagnostic, repeat with new specimen

Surgical Pathology

  • Molecular testing
    • Thyroid nodules discovered by palpation or imaging are most often evaluated by FNA biopsy for diagnosis by cytopathologist
    • Only 7-15% of nodules are malignant (Haugen, ATA, 2016), but many carry gene mutations
    • Calcitonin, thyroglobulin, and parathyroid hormone concentrations should be obtained on FNA washout of thyroid nodules when clinically appropriate (Gharib, 2016)
    • Molecular markers are useful in
      • Establishing diagnosis of malignancy in “indeterminate” or “atypical” cytologic evaluations in order to prevent excessive surgery in patients who have benign pathology
      • Follicular or Hürthle cell histology types (National Comprehensive Cancer Network [NCCN], 2017; Smallridge, ATA, 2012)
        • Not recommended for suspected Hürthle cell neoplasms (NCCN, 2017)
      • Targeted therapeutic decision making (NCCN, 2017)
    • Detection of vascular endothelial growth factors (VEGF) in MTC may be helpful in targeted therapy with vandetanib (Wells, 2012)
    • Other potential molecular markers for immunotherapy
      • MTC – RET, EGFR, VEGFR, c-KIT, MET, FGFR, PDGFR (NCCN, 2017; Priya, 2017)
      • Non-MTC thyroid – RET, VEGFR, c-KIT, FGFR, PDGFR (Priya, 2017)
  • Histology
    • Most diagnosis is possible using cytomorphology (on FNA specimens) or histomorphology (on surgical resection specimens)
    • Occasionally, immunohistochemical stains may be used to support diagnosis
      • Thyroglobulin, thyroid transcription factor 1 (TTF-1), and PAX8 are supportive of thyroid origin
      • Parathyroid hormone (PTH) immunostain may be used to exclude parathyroid origin
      • Calcitonin may be evaluated by immunostain and/or by serologic evaluation and is useful in MTC (see Monitoring)​

Germline Genetic Testing for Familial Cancer Syndromes

  • Evidence is insufficient to support a recommendation for genetic testing; however, the following general guidelines have been suggested
    • Consider MEN/PTEN testing in patients with positive family history of thyroid cancer
    • Consider testing in the following (American College of Medical Genetics and Genomics [ACMG], 2015)
      • MTC
      • Non-MTC with 1 additional Carney complex criterion
      • Non-MTC with 2 additional Cowden syndrome criteria
      • Papillary thyroid cancer (cribriform-morular variant)
    • MTC-specific testing recommendations (Wells, ATA, 2015)
      • Hereditary MTC – RET genetic mutation testing recommended; at-risk relatives should be notified of pertinent results
      • Sporadic MTC – RET genetic mutation testing recommended; testing for somatic HRAS, KRAS, or NRAS mutations not required

Differential Diagnosis

Screening

  • The U.S. Preventive Services Task Force (USPSTF, 2017) recommends against screening for thyroid cancer in the general population (neck palpitation or ultrasound)
    • USPSTF recommendation does not address screening in those with higher risk of thyroid cancer due to
      • History of radiation exposure to the head/neck
      • Exposure to radiation fallout
      • Family history in first-degree relative
      • Risk of genetic predisposition
  • Screening does not result in decreased mortality (National Cancer Institute, 2017)

Monitoring

  • NCCN, 2017, and ATA (Wells, 2015) recommendations
    • Papillary and follicular thyroid cancer – physical examination,TSH, thyroglobulin, and antithyroglobulin antibodies at 6 and 12 months, as well as whole-body imaging with radioiodine (I-131)
      • Only useful in patients with thyroidectomy and remnant ablation
      • Annually thereafter if scan evaluations are normal
      • Thyroglobulin should be measured after TSH stimulation and withdrawal of thyroid hormone replacement
      • If presence of thyroglobulin antibodies detected, thyroglobulin is not interpretable
    • MTC – sequential calcitonin levels and CEA levels
      • In patients with advanced MTC, marked elevation in serum CEA level that is out of proportion to a lower serum calcitonin level, or normal or low levels of both serum calcitonin and CEA, indicates poorly differentiated MTC
      • ​Patients with sporadic MTC should be tested for RET mutations to determine risk for related disorders (Wells, ATA, 2015)
    • Benign nodules not meeting criteria for FNA
      • Repeat ultrasound at 6 to 12 months
      • If stable after 1-2 years, consider 3- to 5-year monitoring by ultrasound

Background

Epidemiology

  • Incidence – ~14.2/100,000 (Surveillance, Epidemiology, and End Results [SEER], 2017)
    • Incidence increased more than threefold from 1950-2004 – no difference in mortality rate during same time frame
    • >56,870 new cases predicted in U.S. in 2017 (SEER,  2017)
  • Age – incidence increases with age
    • Peaks at age 50 (NCCN, 2017)
  • Sex – M<F, 1:2 or 1:3 (NCCN, 2017)
    • Fifth most common malignancy in women
    • Male sex associated with worse prognosis
  • Ethnicity – more common in Caucasian North Americans than in African Americans

Classification

  • Three main histologic types (NCCN, 2017; SEER, 2017)
    • Differentiated – papillary (~89%), follicular (~5%), Hürthle cell (2%)
    • MTC (1-2%)
    • Anaplastic – aggressive undifferentiated carcinoma (0.8%)
      • Almost uniformly fatal

Risk Factors

  • Exposure to ionizing radiation
  • Genetic mutations – PTEN, MEN, RET
  • Familial syndromes
    • Syndromic with predominance of nonthyroidal tumors (predominantly autosomal dominant inheritance)
      • PTEN gene mutation – multiple hamartoma syndrome (Cowden disease)
      • Carney complex – autosomal dominant version of Cushing syndrome
      • Peutz-Jeghers syndrome – characterized primarily by hamartomatous polyposis
      • Multiple endocrine neoplasia (MEN)
        • MEN1 (Wermer syndrome) – predisposition for tumors in three endocrine glands (parathyroid, pancreas, and pituitary)
        • MEN2 – associated with pheochromocytoma and MTC
          • 2A also associated with parathyroid tumors
          • 2B also associated with neuromas
      • Familial adenomatous polyposis (Gardner syndrome is one subtype)
    • Nonsyndromic or familial with preponderance of nonmedullary thyroid carcinoma
      • Familial papillary thyroid carcinoma (PTC)
      • Familial PTC associated with renal neoplasia
      • Familial multinodular goiter
      • Familial nonmedullary thyroid carcinoma type 1
  • Family history of thyroid cancer

Pathophysiology

  • Classification based on tumor cell type

Clinical Presentation

  • Usually presents as thyroid nodule on clinical examination or incidentally on imaging
    • Most thyroid nodules are benign
  • Enlarged thyroid
  • Hoarseness or enlarged cervical adenopathy (suggests metastatic disease)

Pediatrics

  • 1.8 % of all thyroid cancers are in children/adolescents (SEER, 2017)
  • Presentation, pathophysiology, and long-term outcome differ in pediatric versus adult thyroid cancers

Laboratory Testing

  • For patients ≤18 years (Francis, ATA, 2015)
    • TSH
      • Initial screen for hypo- or hyperfunction to assist in evaluation of thyroid nodule
    • Thyroglobulin
      • Measure for evaluation, treatment, and long-term follow-up
    • Thyroglobulin antibody (TgAb)
      • Measure in combination with thyroglobulin – if TgAb is present, thyroglobulin is not interpretable
    • Additional/supportive testing
      • Intact parathyroid hormone (iPTH) – measure perioperatively to identify patients at risk for hypoparathyroidism
      • Serum phosphorus – measure perioperatively; assists in risk assessment for  hypoparathyroidism
    • Tumor mutation testing
      • Not supported by current data, even in cases of indeterminate cytology

Histology

Histologic criteria do not differ between children and adults (refer to Histology in Surgical Pathology).

Screening

  • Data are insufficient to recommend for or against screening, even in survivors of childhood cancer or those with known predisposing genetic syndromes, except in
    • PTEN hamartoma tumor syndrome and APC-associated polyposis
      • Refer to a center of excellence for appropriate care
    • Nonsyndromic familial nonmedullary thyroid cancer (FNMTC)
      • Testing may be indicated; surveillance of family members has resulted in disease detection at earlier stages (Francis, 2015)

Monitoring

  • Postoperative staging and long-term follow-up (Francis, 2015)
    • Low, intermediate, and high risk
      • Measure TSH-suppressed thyroglobulin every 3-6 months
      • Measure TgAb to assist in interpretation of TSH-suppressed thyroglobulin
        • Positive TgAb negates use of thyroglobulin suppression; follow TgAb trend instead
    • Intermediate and high risk, only
      • Consider stimulated thyroglobulin testing and radioisotope (iodine-123) scanning every 1-2 years

Background

  • Risk factors
    • Iodine deficiency
    • Prior radiation (eg, in childhood cancer survivors treated with radiation therapy)
    • History of thyroid disease
    • Associated genetic/familial syndrome

ARUP Lab Tests

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Reflex pattern: if TSH is outside the reference range, then free T4 testing will be added

Use with FNA of thyroid nodules to diagnose benign or malignant nonmedullary thyroid nodules

Diagnose and monitor MTC

Secondary test to assist in diagnosing MEN2 and familial MTC

Results obtained with different assay methods or kits cannot be used interchangeably

Results, regardless of level, should not be interpreted as absolute evidence of the presence or absence of malignant disease

Aid in histologic diagnosis of thyroid cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

Aid in decision to use radioiodine therapy for individuals following differentiated thyroid carcinoma tumor resection

Monitor individuals with history of differentiated thyroid carcinoma for recurrence following surgery or radioiodine ablation

Limit of detection with LC-MS/MS: 0.5 ng/mL

Results obtained with different test methods or kits cannot be used interchangeably

Thyroglobulin results, regardless of concentration, should not be interpreted as absolute evidence for presence or absence of papillary or follicular thyroid cancer

Not recommended for use as a screening procedure to detect presence of thyroid cancer in general population

Reflex pattern: reflexes to LC-MS/MS if antithyroglobulin antibody is present

Recommended test for quantifying thyroglobulin in individuals with antithyroglobulin antibodies

Aid in surveillance of residual or recurrent thyroid cancer in individuals who have developed antibodies to thyroglobulin

Lower limit of detection with LC-MS/MS: 0.5 ng/mL

Use for diagnostic and predictive testing for MEN type 2A (MEN2A), MEN type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC)

Does not evaluate regulatory region mutations, deep intronic mutations, large deletions/duplications, or RET exons other than 5, 8, 10, 11, 13-16

Diagnostic errors can occur due to rare sequence variations

Detect activating BRAF mutations at codon 600, associated with thyroid cancer

Use to assess prognosis of certain thyroid cancers

Oncogenic mutations outside of codon 600 will not be detected

Determine BRAF V600E mutation status in patients with solid tumors to select candidates for targeted therapy with kinase (BRAF and/or MEK) inhibitors

Monitor response to therapy and disease progression in patients carrying BRAF V600E mutation

Detect KRAS mutations (codons 12, 13, 61) associated with thyroid cancer

Predicts response to anti-EGFR and MAPK pathway therapies in a variety of malignancies

Oncogenic mutations other than codons 12, 13, and 61 will not be detected

Predict response to anti-EGFR and MAPK pathway therapies in a variety of malignancies, including thyroid cancer

Oncogenic mutations outside of codons 12, 13, and 61 will not be detected

Detect RET gene rearrangements in solid tumors

Does not identify translocation partner or variant

Related Tests

Aid in differentiation of parathyroid tissue from thyroid tissue

Preferred test for screening and monitoring of thyroid function

Not the preferred initial thyroid disorder screening test

Order following an abnormal thyroid-stimulating hormone (TSH) result to diagnose thyroid disease

Order in conjunction with TSH in cases of suspected secondary hypothyroidism

  

Medical Experts

Contributor

Chadwick

Barbara E. Chadwick, MD

Assistant Professor of Anatomic Pathology, University of Utah

Medical Director, Cytology, and Staff Pathologist, Surgical Pathology at ARUP Laboratories

Contributor
Contributor

Mao

Rong Mao, MD, FACMG

Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories

Contributor
Contributor

Witt

Benjamin L. Witt, MD

Assistant Professor of Clinical Pathology, University of Utah

Laboratory Section Chief, Cytopathology, at ARUP Laboratories

References

Additional Resources
  • PDQ - Thyroid Cancer

    Thyroid Cancer Screening (PDQ)–Health Professional Version. National Cancer Institute. [Updated Aug 2017; Accessed: Sep 2017]

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  • Resources from the ARUP Institute for Clinical and Experimental Pathology®