Thyroid Cancer

Key Points

Thyroid Nodule Fine Needle Aspiration (FNA)

Thyroid nodules discovered by palpation or imaging are most often evaluated by fine needle aspiration biopsy (FNA) and diagnosis by a cytopathologist.  Molecular markers are useful for establishing a diagnosis of malignancy in cases that are called “indeterminate” or “atypical” on cytologic evaluation.

• BRAF

  Biology	Activates the MKE/ERK portions of the mitogen activated protein kinase (MAPK) pathway via phosphorylation; member of the RAF family of proteins
  BRAF mutations	Fairly specific for papillary thyroid carcinoma subtypes – found in ~50% of papillary thyroid carcinomas Rarely found in follicular variant papillary thyroid carcinoma V600E mutation Most common Other BRAF mutations Mutation of 601 codon 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 cytology Positive BRAF point mutation – highly suggestive of papillary carcinoma Prognosis Has been reported to be associated with treatment failure and tumor recurrence in papillary carcinoma

  RET/PTC

  Biology	Activates the MAPK pathway; member of the tyrosine kinase receptor family
  RET/PTC rearrangements	Most common in papillary subtypes – relatively specific for this subtype RET/PTC1 – common in classic papillary subtypes RET/PTC3 – more common in solid variant of papillary
  Clinical Indications	Diagnosis Useful for diagnosis of indeterminate or atypical FNA cytology Particularly seen in tumors associated with radiation exposure Positive RET/PTC rearrangement – highly suggestive of papillary carcinoma Usually found in more aggressive tumors (early lymph node metastatic disease) Prognosis Not well defined

  RAS

  Biology	HRAS, NRAS, KRAS mutations encode for G proteins on the cell membrane  and activate the tyrosine kinase/MAPK pathways
  RAS mutations	Found in benign and malignant follicular subtype tumors Mutations KRAS codon 12/13 mutation NRAS codon 61 and HRAS codon 61 mutations – more often seen in thyroid cancer
  Clinical Indications	Diagnosis Not useful for specific diagnosis of indeterminate or atypical FNA cytology Isolated mutation  is not diagnostic for malignancy, but suggestive for malignancy in a nodule Prognosis Not well defined

  PAX8/PPARG

  Biology	Fusion of PAX8 gene and peroxisome proliferator-activated receptor (PPARG) gene
  PAX8/PPARG mutation	Most common in follicular subtypes
  Clinical Indications	Diagnosis Not useful for diagnosis of indeterminate or atypical FNA cytology Isolated mutation is not diagnostic for malignancy Prognosis Has been associated with good prognosis

Diagnosis

Indications for Testing

• Thyroid nodule, abnormal cervical nodes

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)
• 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
  • Reveal nodule size
  • Solid or cystic nature of nodules
  • Single or multiple nodules
• FNA
  • Procedure of choice for evaluating suspicious thyroid nodules
  • Preferably performed with ultrasound guidance
  • FNA nondiagnostic – perform aspiration at least once more

Differential Diagnosis

• Lymphadenopathy
  • Infectious
    • Epstein-Barr virus
    • Cytomegalovirus
    • Atypical/typical mycobacteria
    • Fungal disease
  • Cancer
    • Metastatic head and neck cancer
    • Lymphoma
• Thyroid enlargement/nodule
  • Benign nodule
  • Goiter
  • Autoimmune thyroiditis
  • Intrathyroid – metastatic disease (renal cell is most common)
  • Infectious etiology
    • Viral, bacterial, mycobacterial, fungal

Screening

Monitoring

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
    • Rate doubled during 1975-2004
  • Estimated 48,000 new cases of thyroid carcinoma diagnosed in U.S. in 2011 (NCCN, 2012)
• Age – incidence increases with age
  • Peak is 49 years of age (NCCN, 2012)
• 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 types
  • Differentiated – papillary, follicular, Hürthle cell (in decreasing order of occurrence)
    • Represents ~95% of all thyroid carcinomas
  • Medullary thyroid cancer (MTC)
  • Anaplastic – aggressive undifferentiated carcinoma
    • Almost uniformly fatal

Risk Factors

• Childhood exposure to ionizing radiation
• Genetic mutations – PTEN, MEN, RET
• Familial syndromes
  • Syndromic with predominance of nonthyroidal tumors (predominant autosomal dominant inheritance)
    • PTEN mutation – multiple hamartoma syndrome (Cowden disease)
    • Carney complex – autosomal dominant version of Cushing syndrome
    • Peutz-Jeghers syndrome – familial pancreatic cancer
    • 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)
  • Nonsyndromic or familial with preponderance of nonmedullary thyroid carcinoma
    • Familial papillary thyroid carcinoma
    • Familial papillary thyroid carcinoma 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
  • Papillary

    Prevalence – 86% of thyroid malignancies Sex – M<F Tumor growth Slow, local spread; high correlation between tumor size and local extension Prognosis – excellent

  • Follicular

    Prevalence – 10-12% of thyroid malignancies 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 – 4-7% of thyroid malignancies Two types – sporadic, familial Age Sporadic – older adults Familial – children Risk factors – MEN2A and 2B, RET oncogene (familial predisposition in 20-25% of cases) 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 found to be part of familial syndrome

  • Anaplastic

    Prevalence – 2% of thyroid malignancies Sex – M<F, 1:3 Age – 50s Tumor growth – poorly differentiated; aggressive growth with metastases to lungs, pleura, bone, and brain Prognosis – poor

  • Thyroid lymphoma (nongastric MALT lymphoma)

    Incidence – 2/1,000,000 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 metastases

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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

Diagnostic Algorithm

  Thyroid Nodules Testing Algorithm