Thyroid Cancer

Key Points

Thyroid Nodule Fine Needle Aspiration (FNA) Biopsy

Thyroid nodules discovered by palpation or imaging are most often evaluated by fine needle aspiration (FNA) biopsy for diagnosis by a cytopathologist. Only ~10% of nodules are malignant. Molecular markers are useful for establishing a diagnosis of malignancy in cases that are called “indeterminate” or “atypical” on cytologic evaluation in order to prevent excessive surgery in patients who have benign pathology. Markers may also be useful in follicular or Hürthle cell histology types (NCCN, 2013; ATA, 2009).

  • BRAF

    Biology

    BRAF gene encodes a protein that activates the MEK/ERK portions of the mitogen-activated protein kinase (MAPK) pathway, which directs cell proliferation, differentiation, and survival

    BRAF gene mutations

    Fairly specific for papillary thyroid carcinoma subtypes – found in ~50% of papillary thyroid carcinomas

    • Rarely found in follicular variant papillary thyroid carcinoma
    • Presence in indeterminate pathology – diagnostic for carcinoma

    V600E mutation

    • Most common

    Other BRAF gene mutations

    • Codon 601
    • AKAP9-BRAF translocation
      • Found in papillary carcinoma associated with radiation exposure

    Clinical Indications

    Diagnosis

    • Useful for clarifying diagnosis in cases of indeterminate or atypical FNA biopsy cytology
    • Positive BRAF point mutation – highly suggestive of papillary carcinoma

    Prognosis

    • Has been reported to be associated with more aggressive disease
    RAS

    Biology

    HRAS, NRAS, KRAS genes encode for similar guanosine-nucleotide-binding (G) proteins that activate the tyrosine kinase/MAPK pathway, which affects cell proliferation, differentiation, and survival

    RAS gene mutations

    Found in benign and malignant follicular subtype tumors

    • KRAS codons 12 and  13
    • NRAS codons 12 and 61 or HRAS codon 61 – most often seen in thyroid cancer

    Clinical Indications

    Diagnosis

    • Not useful for specific diagnosis of indeterminate or atypical FNA specimen cytology as mutation exists in benign tumors
    • Isolated mutation is not diagnostic for malignancy, but suggestive for malignancy in a nodule

    Prognosis

    • Not well-defined
    RET/PTC

    Biology

    Encodes a receptor tyrosine kinase protein that activates the MAPK pathway, which affects cell proliferation, differentiation, and survival

    RET/PTC rearrangements

    Most common in papillary thyroid carcinoma (PTC) – relatively specific for this subtype

    • RET/PTC1 – common in classic PTC
    • RET/PTC3 – more common in solid variant of PTC

    Clinical Indications

    Diagnosis

    • Useful for diagnosis of indeterminate or atypical FNA biopsy cytology
      • Particularly seen in tumors associated with radiation exposure
    • Positive RET/PTC rearrangement – highly suggestive of PTC
    • Usually found in more aggressive tumors (lymph node early metastatic disease)

    Prognosis

    • Not well-defined
    PAX8/PPARG

    Biology

    Fusion of PAX8 and PPARG genes

    PAX8/PPARG mutation

    Found in benign and malignant follicular subtype tumors

    Clinical Indications

    Diagnosis

    • Not useful for specific diagnosis of indeterminate or atypical FNA biopsy cytology as mutation exists in benign tumors
    • Isolated mutation is not diagnostic for malignancy

    Prognosis

    • Has been associated with good prognosis

Diagnosis

Indications for Testing

  • Thyroid nodule, abnormal cervical nodes, abnormal imaging

Laboratory Testing

  • Thyroid stimulating hormone (TSH)
    • Low or suppressed TSH – order free T4
      • Elevated free T4 – proceed to thyroid radioisotope study after thyroid ultrasound
    • Normal or elevated TSH – consider thyroid ultrasound and fine needle aspiration (FNA) biopsy
  • Genetic testing
    • Family history – consider MEN/PTEN testing

Histology

  • Molecular tissue studies to identify known genetic associations
    • See Key Points
  • Immunohistochemistry
    • Target stains – galectin-3, HBME-1, CK 19
      • May be useful in diagnosis of follicular thyroid tumors
    • Other available stains include calcitonin, chromogranin A, TSH, thyroglobulin, TTF-1, and PTH

Imaging Studies

  • Ultrasound – initial evaluation for thyroid nodules to aid in determining
    • Nodule size
    • Solid or cystic nature of nodule(s)
    • Single or multiple nodules
  • FNA biopsy
    • Procedure of choice for evaluating suspicious thyroid nodules
    • Preferably performed with ultrasound guidance
    • FNA biopsy nondiagnostic – repeat with a new specimen

Differential Diagnosis

Screening

  • Thyroid ultrasound
    • Not recommended for screening general population or patients with normal thyroid by palpation but at risk for thyroid cancer
    • Recommended for the following
      • Patient with palpable nodule
      • Patient with history of neck irradiation
      • Presence of unexplained cervical adenopathy and family history of multiple endocrine neoplasia (MEN2), medullary thyroid cancer (MTC),  or papillary thyroid carcinoma
  • RET oncogene testing – presymptomatic testing of at-risk family members when family history of MTC is known  
    • If gene mutation is present, thyroid fine needle aspiration biopsy is suggested

Monitoring

  • NCCN, 2013, and ATA, 2009, 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)
    • Patient must have undergone thyroidectomy and remnant ablation for these to be useful
    • Annually thereafter if disease free
    • Thyroglobulin measurement should be done after TSH stimulation – withdraw thyroid replacement
    • All specimens should be processed in same lab
    • If presence of thyroglobulin antibodies detected, use tandem mass spectometry measurements to mediate antibody interference
  • Medullary thyroid carcinoma (MTC) – sequential calcitonin levels and carcinoembryonic antigen
    • Calcitonin levels >100 ng/mL may occur in MTC, leukemias, and myeloproliferative neoplasms
    • Provocative testing (pentagastrin stimulation) – suggested in patients with MTC if calcitonin is not clearly diagnostic
      • Calcium infusion alone, with peak calcitonin ≥100-500 ng/mL, indicates MTC or C-cell hyperplasia
  • Nodule evaluation – clinical follow-up; if nodule growth, repeat fine needle aspiration or consider surgery

Clinical Background

Thyroid cancer is the most common endocrine malignancy and represents 7-10% of all diagnosed malignancies.

Epidemiology

  • Incidence – 9/100,000
    • Incidence increased ~310% from 1950-2004; mortality rate decreased 44% during same time frame
      • Diagnosis rate doubled during 1975-2004
    • Estimated >60,000 new cases of thyroid carcinoma diagnosed in U.S. in 2013 (NCCN, 2013)
  • Age – incidence increases with age
    • Peak is 49 years
  • Sex – M<F, 1:2
    • 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
    • Differentiated – papillary, follicular, Hürthle cell (in decreasing order of occurrence)
      • Represents ~94% of all thyroid carcinomas
    • Medullary thyroid cancer (MTC)
    • Anaplastic – aggressive undifferentiated carcinoma
      • Almost uniformly fatal

Risk Factors

  • Exposure to ionizing radiation
    • Childhood exposure associated with greater risk; adults uncommon
  • Gene mutations – PTEN, MEN, RET
  • Familial syndromes
    • Syndromic with predominance of nonthyroidal tumors (predominantly autosomal dominant inheritance)
    • Nonsyndromic or familial with preponderance of non-medullary thyroid carcinoma
      • Familial papillary thyroid carcinoma
      • Familial papillary thyroid carcinoma associated with renal neoplasia
      • Familial multinodular goiter
      • Familial non-medullary thyroid carcinoma type 1
  • Family history of thyroid cancer

Pathophysiology

  • Classification based on tumor cell type
    • Papillary
      • Prevalence – 80% of thyroid malignancies
      • Sex – M<F
      • Tumor growth
        • Slow, local spread; high correlation between tumor size and local extension
      • Prognosis – excellent
    • Follicular
      • Prevalence – 10-14% of thyroid malignancies (includes 4% Hürthle cell)
      • Sex – M<F, 1:3
      • Age – 50s
      • Risk factors – iodine deficiency
      • Tumor growth – greater risk of hematogenous spread to lungs, bone, brain, bladder and skin than papillary subtype
        • Includes Hürthle cell cancer (3%)
      • Prognosis – excellent if no hematogenous spread of cancer
    • Medullary (calcitonin-secreting tumor)
      • Prevalence – 4% of thyroid malignancies
      • Two types – sporadic (most cases), familial
      • Age
        • Sporadic – older adults
        • Familial – children
      • Risk factors – MEN2A and 2B, RET oncogene (familial predisposition in 20-25% of cases)
        • Certain mutations have higher risk for disease
      • Tumor growth – more aggressive with early metastases to lung, bone, mediastinum, abdominal nodes
        • Elevated calcitonin is a marker
      • Prognosis – good if discovered early; aggressive if part of familial syndrome
    • Anaplastic
      • Prevalence – 2% of thyroid malignancies
      • Sex – M<F, 1:3
      • Age – 70s
      • Risk factors – prior differentiated thyroid cancer
      • Tumor growth – poorly differentiated; aggressive growth with metastases to lungs, pleura, bone, and brain
        • Three main subtypes – spindle cell, pleomorphic giant cell, squamoid
      • Prognosis – poor; nearly uniformly fatal
    • Thyroid lymphoma (nongastric MALT lymphoma)
      • Incidence – 2/million
      • Sex – M<F, 1:4
      • Tumor growth – moderate aggressiveness
      • Prognosis – excellent if discovered early

Clinical Presentation

  • Enlarged thyroid
  • Thyroid nodule
  • Hoarseness or enlarged cervical adenopathy suggests metastasis

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Use to identify risk in palpable thyroid nodule

   
Thyroglobulin, Serum or Plasma with Reflex to LC-MS/MS or CIA 2006685
Method: Quantitative Chemiluminescent Immunoassay/High Performance Chromatography-Tandem Mass

Aids 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

Reflex pattern – reflexes to LC-MS/MS if anti-thyroglobulin antibody is present

Test result, regardless of concentration, should not be interpreted as absolute evidence for the presence or absence of papillary or follicular thyroid cancer and is not recommended for use as a screening procedure to detect presence of cancer in general population

 
Thyroglobulin by LC-MS/MS, Serum or Plasma 2006550
Method: High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended test for surveillance of residual or recurrent thyroid cancer in individuals who have developed antibodies to thyroglobulin

   
Calcitonin 0070006
Method: Quantitative Chemiluminescent Immunoassay

Diagnose and monitor medullary thyroid carcinoma (MTC)

Secondary test to assist in diagnosing multiple endocrine neoplasia 2 (MEN2) and familial MTC

May be useful in diagnosing islet cell tumors

Elevated basal calcitonin levels that are unresponsive to stimulating tests are found in patients with disorders other than MTC

 
BRAF V600E Mutation Detection by Allele-Specific PCR, Fine Needle Aspirate 2006516
Method: Polymerase Chain Reaction

Aids in diagnosis of nodules that are indeterminate by cytology

Aids in prognostication and therapeutic decisions for nodules that are diagnosed as papillary thyroid carcinoma

Diagnosis, prognosis, and therapeutic decisions in a variety of tumors

For tissue block or formalin-fixed, paraffin-embedded (FFPE) cell blocks prepared from FNA, BRAF codon 600 Mutation Detection by Pyrosequencing may be used

Clinical sensitivity – limit of detection is 0.02% mutant alleles

Mutations in other locations within the BRAF gene or in other genes will not be detected

BRAF V600E mutations may also be detected in poorly differentiated or anaplastic thyroid carcinomas that also have a PTC component

Test not intended to detect minimal residual disease

 
Thyroglobulin, Fine Needle Aspiration (FNA) 0020753
Method: Quantitative Chemiluminescent Immunoassay

Aids in diagnosis of metastatic differentiated thyroid carcinoma (papillary thyroid carcinoma and follicular thyroid carcinoma) from tissue specimens (eg, lymph nodes, thyroid nodules)

   
Parathyroid Hormone, Fine Needle Aspiration (FNA) 2001491
Method: Quantitative Electrochemiluminescent Immunoassay

Aid in differentiating parathyroid tissue from thyroid tissue

   
Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing 0051390
Method: Polymerase Chain Reaction/Sequencing

Confirm multiple MEN2 familial syndromes

   
Calcitonin by Immunohistochemistry 2003481
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Cytokeratin 19 (CK 19) by Immunohistochemistry 2003845
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
HBME-1 (Mesothelial Cell) by Immunohistochemistry 2003914
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Parathyroid Hormone (PTH) by Immunohistochemistry 2004118
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Thyroglobulin by Immunohistochemistry 2004145
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Thyroid Transcription Factor (TTF-1) by Immunohistochemistry 2004166
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
BRAF V600E by Immunohistochemistry 2008710
Method: Immunohistochemistry

Aid in histologic diagnosis of thyroid cancer

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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

Use to predict effectiveness of therapies targeting the EGFR pathway

Evaluate thyroid specimens (tissue blocks or FFPE cell blocks prepared from fine needle aspirates) for BRAF mutations for purpose of diagnosis, prognosis, and possible therapeutics

For fine needle aspirate direct smears, BRAF V600E Mutation Detection with FNA is preferred

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay
Thyroxine, Free (Free T4) 0070138
Method: Quantitative Electrochemiluminescent Immunoassay
Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
Method: Massively Parallel Sequencing

Prognosis/treatment of individuals with solid tumor cancers at initial diagnosis or with refractory disease

Assess for responsiveness to BRAF inhibitor therapy

48-gene panel assay for detection of mutations, including KRAS, EGFR, BRAF, and ERBB2 genes