Thyroid Cancer

Primary Authors: Chadwick, Barbara E., MD. Geiersbach, Katherine, MD, FCAP.

  • Key Points
  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Molecular Testing

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, but >90% carry certain gene mutations. 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, 2015; ATA, 2012). Finally, markers may be helpful in targeted therapeutic decision-making (NCCN, 2015).

Indications for Testing

  • Thyroid nodule, abnormal cervical nodes, abnormal imaging

Laboratory Testing

Genetic Testing

  • Positive family history of thyroid cancer – consider MEN/PTEN testing
  • Consider testing in the following (ACMG, 2015)
    • Medullary thyroid cancer (MTC)
    • Non-MTC with one additional Carney complex criterion
    • No MTC with 2 additional Cowden syndrome criteria
    • Papillary thyroid cancer (cribriform-morular variant)

Histology

  • Molecular testing
    • >90% of thyroid cancers carry certain gene mutations
    • Mutation detection may aid in diagnosis/prognostication
    • See Key Points section for more information
    • Other potential molecular markers for FDA-approved therapies include
      • MTC – RET, EGFR, VEGFR, TIE2, MEN, TRKR
      • Thyroid – VEGFR, FGFR, RET, KIT, PDGFR
  • 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)
    • Number of nodules present
  • FNA biopsy
    • Procedure of choice for evaluating suspicious thyroid nodules
    • Preferably performed with ultrasound guidance
    • If FNA biopsy nondiagnostic – repeat with a new specimen

Differential Diagnosis

  • Thyroid ultrasound
    • Not recommended
      • For general population
      • In 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
  • NCCN (2015) and ATA (2012) 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 measurement should be done after TSH stimulation and withdrawal of 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

Thyroid cancer is the most common endocrine malignancy, although the lifetime risk of developing thyroid cancer is low.

Epidemiology

  • Incidence – ~13.5/100,000
    • Incidence increased >3-fold from 1950-2004, but no difference in mortality rate during same time frame
    • >62,000 new cases of thyroid carcinoma diagnosed in U.S. in 2013 (NCCN, 2015)
  • Age – incidence increases with age
    • Peaks in 40s
  • 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 (NCCN, 2015)
    • Differentiated – papillary (80%), follicular (~10%), Hürthle cell (3%) (in decreasing order of occurrence)
    • Medullary thyroid cancer (MTC) (4%)
    • Anaplastic – aggressive undifferentiated carcinoma (2%)
      • Almost uniformly fatal

Risk Factors

  • Exposure to ionizing radiation
    • Childhood exposure associated with greater risk; adults uncommon
  • Genetic 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

    Clinical Presentation

    • Usually presents as a thyroid nodule – most nodules are benign
    • Enlarged thyroid
    • Hoarseness or enlarged cervical adenopathy
      • Suggests metastatic disease

    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.

    Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
    Method: Quantitative Electrochemiluminescent Immunoassay

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

    Limitations

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

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

    Should not be interpreted as absolute evidence for the presence or absence of papillary or follicular thyroid cancer

    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

    Limitations

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

    Calcitonin 0070006
    Method: Quantitative Chemiluminescent Immunoassay

    Limitations

    Elevated levels not specific for MTC

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

    Thyroid Translocation and Mutation Panel 2012755
    Method: Polymerase Chain Reaction/Pyrosequencing

    Limitations

    See Additional Technical Information document for limitations

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

    Limitations

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

    Diagnostic errors can occur due to rare sequence variations

    Calcitonin by Immunohistochemistry 2003481
    Method: Immunohistochemistry

    Chromogranin A by Immunohistochemistry 2003830
    Method: Immunohistochemistry

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

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

    Parathyroid Hormone (PTH) by Immunohistochemistry 2004118
    Method: Immunohistochemistry

    Thyroglobulin by Immunohistochemistry 2004145
    Method: Immunohistochemistry

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

    BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
    Method: Polymerase Chain Reaction/Pyrosequencing

    Limitations

    Limit of detection for pyrosequencing is 10% mutant alleles

    Oncogenic mutations other than codon 600 will not be detected

    HRAS Mutation Detection by Pyrosequencing 2012175
    Method: Polymerase Chain Reaction/Pyrosequencing

    Limitations

    Limit of detection for pyrosequencing is 10% mutant alleles

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

    KRAS Mutation Detection 0040248
    Method: Polymerase Chain Reaction/Pyrosequencing

    Limitations

    Limit of detection for pyrosequencing is 10% mutant alleles

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

    NRAS Mutation Detection by Pyrosequencing 2003123
    Method: Polymerase Chain Reaction/Pyrosequencing

    Limitations

    Limit of detection for pyrosequencing is 10% mutant alleles

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

    RET-CCDC6 and RET-NCOA4 (RET-PTC1 and RET-PTC3) Translocations Detection by PCR 2012605
    Method: Polymerase Chain Reaction

    Limitations

    Mutations other than RET-CCDC6 (PTC1) and RET-NCOA4 (PTC3) will not be detected

    Limit of detection for RT-PCR is 10% mutant alleles

    RET Gene Rearrangements by FISH 2012654
    Method: Fluorescence in situ Hybridization

    Limitations

    Does not identify the translocation partner or variant

    PAX8-PPARG Translocations Detection by PCR 2012603
    Method: Polymerase Chain Reaction

    Limitations

    Limit of detection for RT-PCR is 10% tumor cells

    Mutations other than PAX8-PPARG will not be detected

    Solid Tumor Mutation Panel by Next Generation Sequencing 2007991
    Method: Massively Parallel Sequencing

    Limitations

    Does not detect translocations

    Not intended to detect minimal residual disease

    Related Tests

    Guidelines

    American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009; 19(6): 565-612. PubMed

    Cobin RH, Gharib H, Bergman DA, Clark OH, Cooper DS, Daniels GH, Dickey RA, Duick DS, Garber JR, Hay ID, Kukora JS, Lando HM, Schorr AB, Zeiger MA, Thyroid Carcinoma Task Force. AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract. 2001; 7(3): 202-20. PubMed

    Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

    Haugen BR, Alexander EK, Bible KC, Doherty G, Mandel SJ, Nikiforov YE, Pacini F, Randolph G, Sawka A, Schlumberger M, Schuff KG, Sherman SI, Sosa JAnn, Steward D, Tuttle M, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015; PubMed

    NCCN Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

    Pacini F, Castagna MG, Brilli L, Pentheroudakis G, ESMO Guidelines Working Group. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 Suppl 7: vii110-9. PubMed

    Protocol for the Examination of Specimens from Patients with Carcinomas of the Thyroid Gland. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

    Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, Kebebew E, Lee NY, Nikiforov YE, Rosenthal S, Shah MH, Shaha AR, Tuttle M, American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012; 22(11): 1104-39. PubMed

    Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal S, Santoro M, Schlumberger M, Shah M, Waguespack SG, American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6): 567-610. PubMed

    General References

    Bhaijee F, Nikiforov YE. Molecular analysis of thyroid tumors. Endocr Pathol. 2011; 22(3): 126-33. PubMed

    Boufraqech M, Patel D, Xiong Y, Kebebew E. Diagnosis of thyroid cancer: state of art. Expert Opin Med Diagn. 2013; 7(4): 331-42. PubMed

    Fischer S, Asa SL. Application of immunohistochemistry to thyroid neoplasms. Arch Pathol Lab Med. 2008; 132(3): 359-72. PubMed

    Fnais N, Soobiah C, Al-Qahtani K, Hamid JS, Perrier L, Straus SE, Tricco AC. Diagnostic value of fine needle aspiration BRAF(V600E) mutation analysis in papillary thyroid cancer: a systematic review and meta-analysis. Hum Pathol. 2015; 46(10): 1443-54. PubMed

    Howell GM, Hodak SP, Yip L. RAS mutations in thyroid cancer. Oncologist. 2013; 18(8): 926-32. PubMed

    Kang G, Cho EYoon, Shin JHee, Chung J, Kim JWon, Oh YLyun. Role of BRAFV600E mutation analysis and second cytologic review of fine-needle aspiration for evaluating thyroid nodule. Cancer Cytopathol. 2012; 120(1): 44-51. PubMed

    Keutgen XM, Filicori F, Fahey TJ. Molecular diagnosis for indeterminate thyroid nodules on fine needle aspiration: advances and limitations. Expert Rev Mol Diagn. 2013; 13(6): 613-23. PubMed

    Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin. 2009; 59(2): 99-110. PubMed

    Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med. 2011; 135(5): 569-77. PubMed

    Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011; 24 Suppl 2: S19-33. PubMed

    Omur O, Baran Y. An update on molecular biology of thyroid cancers. Crit Rev Oncol Hematol. 2014; 90(3): 233-52. PubMed

    Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am. 2012; 96(2): 329-49. PubMed

    Pusztaszeri MP, Bongiovanni M, Faquin WC. Update on the cytologic and molecular features of medullary thyroid carcinoma. Adv Anat Pathol. 2014; 21(1): 26-35. PubMed

    Soares P, Celestino R, Melo M, Fonseca E, Sobrinho-Simões M. Prognostic biomarkers in thyroid cancer. Virchows Arch. 2014; 464(3): 333-46. PubMed

    Spencer C, Fatemi S. Thyroglobulin antibody (TgAb) methods - Strengths, pitfalls and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2013; 27(5): 701-12. PubMed

    Theoharis C, Roman S, Sosa JAnn. The molecular diagnosis and management of thyroid neoplasms. Curr Opin Oncol. 2012; 24(1): 35-41. PubMed

    References from the ARUP Institute for Clinical and Experimental Pathology®

    Bentz BG, Miller BT, Holden JA, Rowe LR, Bentz JS. B-RAF V600E mutational analysis of fine needle aspirates correlates with diagnosis of thyroid nodules. Otolaryngol Head Neck Surg. 2009; 140(5): 709-14. PubMed

    Fnais N, Soobiah C, Al-Qahtani K, Hamid JS, Perrier L, Straus SE, Tricco AC. Diagnostic value of fine needle aspiration BRAF(V600E) mutation analysis in papillary thyroid cancer: a systematic review and meta-analysis. Hum Pathol. 2015; 46(10): 1443-54. PubMed

    Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF, Hunt JP. BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. Laryngoscope. 2014; 124(9): E389-93. PubMed

    Kushnir MM, Rockwood AL, Roberts WL, Abraham D, Hoofnagle AN, Meikle W. Measurement of thyroglobulin by liquid chromatography-tandem mass spectrometry in serum and plasma in the presence of antithyroglobulin autoantibodies. Clin Chem. 2013; 59(6): 982-90. PubMed

    Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin. 2009; 59(2): 99-110. PubMed

    Layfield LJ, Morton MJ, Cramer HM, Hirschowitz S. Implications of the proposed thyroid fine-needle aspiration category of "follicular lesion of undetermined significance": A five-year multi-institutional analysis. Diagn Cytopathol. 2009; 37(10): 710-4. PubMed

    Li QKay, Nugent SL, Straseski J, Cooper D, Riedel S, Askin FB, Sokoll LJ. Thyroglobulin measurements in fine-needle aspiration cytology of lymph nodes for the detection of metastatic papillary thyroid carcinoma. Cancer Cytopathol. 2013; 121(8): 440-8. PubMed

    Margraf RL, Calderon FR O, Mao R, Wittwer CT. RET mutation scanning update: exon 15. Clin Chem. 2009; 55(11): 2059-61. PubMed

    Oakley GM, Curtin K, Layfield L, Jarboe E, Buchmann LO, Hunt JP. Increased melanoma risk in individuals with papillary thyroid carcinoma. JAMA Otolaryngol Head Neck Surg. 2014; 140(5): 423-7. PubMed

    Rowe LR, Bentz BG, Bentz JS. Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules. Cytojournal. 2006; 3: 10. PubMed

    Szankasi P, Reading S, Vaughn CP, Prchal JT, Bahler DW, Kelley TW. A quantitative allele-specific PCR test for the BRAF V600E mutation using a single heterozygous control plasmid for quantitation: a model for qPCR testing without standard curves. J Mol Diagn. 2013; 15(2): 248-54. PubMed

    Medical Reviewers

    Last Update: April 2016