II. Epidemiology

  1. Incidence of new Thyroid Nodules U.S.
    1. Overall: 9 Million/year
    2. Palpable Nodules: 300,000/year
  2. Prevalence: Palpable Thyroid Nodules
    1. Women: 7-8% lifetime Prevalence
    2. Men: 2% lifetime Prevalence
  3. Prevalence: Non-palpable Thyroid Nodules (incidental)
    1. Neck Ultrasound: 40%
    2. CT or MRI: 16%
    3. Autopsy: 36-50%
  4. Thyroid Cancer
    1. Palpable Nodules: 5-10% Incidence of Thyroid Cancer
    2. Incidental Nodules on Ultrasound: 1.5 to 5% Incidence of Thyroid Cancer
  5. Hyperfunctioning Thyroid Nodules (Toxic Thyroid Adenoma, Plummer Disease)
    1. Account for 5% of cases ("hot Nodules")
    2. Autonomously produce Thyroid Hormone
    3. Arises from mutation in TSH receptor or Gs alpha gene
    4. Rarely malignant
  6. References
    1. Dean (2008) Endocrinol Metab 22(6): 901-11 [PubMed]

III. Risk Factors; Thyroid Nodules

  1. Iodine deficiency (countries without Iodized Salt)
  2. Female Gender (4 fold higher risk than men)
  3. Older age
  4. Obesity (risk increases with BMI)

IV. Risk Factors: Thyroid Cancer (in Thyroid Nodules)

  1. Head and neck radiation history (especially radiation exposure in childhood)
    1. Palpable Thyroid Nodule is malignant in 20-50% of previously irradiated Thyroid Glands
  2. Age <20 years old or over 70 years old
  3. Male gender
  4. Graves Disease
    1. Hypofunctioning Thyroid Nodules have a risk of papillary Thyroid Cancer as high as 33 to 42%
  5. Family History of Thyroid Cancer
  6. Cancer Syndromes
    1. Familial Adenomatous Polyposis
    2. Multiple endocrine neoplasia (MEN) type 2A or 2B
      1. Associated with up to 25% risk of Thyroid Cancer
  7. Rapid Thyroid Nodule growth
  8. Hoarseness

V. Symptoms

  1. Typically asymptomatic
  2. Large Nodules may cause local compression
    1. Dysphagia
    2. Choking Sensation
  3. Hyperfunctioning Thyroid Nodules or "Hot Nodules" (5% of Thyroid Nodules)
    1. Hyperthyroidism symptoms

VI. Signs

  1. Discrete palpable Thyroid Nodules in lower anterior neck
    1. Nodules are not typically palpable if <1 cm
    2. Nodules are classified as small when 1-4 cm
    3. Usually solitary
  2. Usually cold Nodule on Thyroid scan
    1. Only 1% are active Nodules (Hyperthyroidism)

VII. Labs

  1. Thyroid Stimulating Hormone (TSH)
    1. TSH suppressed in 5% of Thyroid Nodules that are hyperfunctioning ("hot Nodules")
    2. Increased TSH has a higher risk of Thyroid malignancy
  2. Serum Calcitonin
    1. Increased with Medullary Thyroid Carcinoma (rare)
    2. Indicated only in Family History or clinical suspicion of Medullary Thyroid Carcinoma or MEN Type 2

VIII. Imaging

  1. Thyroid Ultrasound
    1. Indicated in all palpable Thyroid Nodule evaluations
    2. Suspicious Ultrasound findings
      1. Irregular lesion margins
      2. Microcalcifications
      3. Nodule taller than wide
      4. Extrathyroid extension
      5. Disrupted rim calcification
      6. Cervical Lymphadenopathy
  2. Radioactive Iodine Uptake Scan
    1. Indicated only if suppressed TSH (hyperfunctioning Thyroid Nodule or "hot Nodule")

IX. Grading: Bethesda System for Thyroid Cytopathology

  1. Bethesda Category 1
    1. Nondiagnostic or unsatisfactory cytology (1-4% malignancy risk)
    2. Repeat FNA in 6-12 weeks
  2. Bethesda Category 2
    1. Benign cytology (<3% malignancy risk)
    2. Repeat thyroid Ultrasound in 12-24 months
  3. Bethesda Category 3
    1. Atypia or follicular lesion of undetermined significance on cytology (5 to 15% malignancy risk)
    2. Diagnostic Thyroid lobectomy for suspicious Ultrasound OR suspicious molecular testing
    3. Repeat FNA in 6-12 weeks if molecular testing not performed and Ultrasound not suspicious
  4. Bethesda Category 4
    1. Follicular neoplasm or suspicious for follicular neoplasm on cytology (15 to 30% malignancy risk)
    2. Diagnostic Thyroid lobectomy for suspicious Ultrasound, suspicious molecular testing or no molecular test
  5. Bethesda Category 5
    1. Suspicious for malignancy on cytology (60-75% malignancy risk)
    2. Surgical Excision Recommended
  6. Bethesda Category 6
    1. Malignant cytology (97-99 % malignancy risk)
    2. Surgical Excision Recommended

X. Evaluation

  1. Precautions
    1. Routine screening for non-palpable Thyroid Nodules (exam, Ultrasound) is NOT recommended
      1. Bibbins-Domingo (2017) JAMA 317(18):1882-7 +PMID:28492905 [PubMed]
      2. Ahn (2014) N Engl J Med 371(19): 1765-7 [PubMed]
  2. Step 1: Indications
    1. Identify palpable Nodule on exam OR
    2. Incidental Thyroid Nodule identified on imaging
  3. Step 2: Obtain TSH
    1. TSH Low: Go to Step 3
    2. TSH Normal: Go to Step 4
  4. Step 3: Obtain Radioactive Thyroid Scan
    1. Hot Nodule
      1. Euthyroid
        1. Consider Subclinical Hyperthyroidism monitoring
      2. Hyperthyroidism
        1. Go to Hyperthyroidism Management
        2. Typically managed with Radioactive Iodine 131 Ablation (or Thyroidectomy or antithyroid agents)
        3. FNA not needed
    2. Cold Nodule
      1. More likely to be malignant (5-15% of cases)
      2. Go to Step 4
  5. Step 4: Thyroid Ultrasound
    1. Benign appearing Nodule <1 cm with negative clinical history
      1. Observe and follow
      2. Repeat thyroid Ultrasound in 6 months
    2. Nodule >1 cm
      1. Cystic lesion
        1. Go to Step 5 (FNA) and sample the solid component of lesion under Ultrasound guidance
        2. Spongiform Nodules or partially cystic Nodules without eccentricity do not need FNA unless >2 cm
          1. Repeat Ultrasound in 12-24 months
        3. Purely cystic Nodules (without a solid component) do not need aspiration unless symptomatic
        4. Recurrent benign cystic Nodules may be excised or ablated with Alcohol injection if symptomatic
      2. Solid Lesion
        1. Go to Step 5 (FNA)
    3. Nodules <1 cm with Thyroid Cancer risk factors or suspicious findings
      1. Repeat thyroid Ultrasound in 6 to 9 months and FNA when Thyroid Nodule >1 cm
      2. May discuss further with local Consultation
    4. Lesion with extracapsular invasion or associated Cervical Lymphadenopathy (Thyroid Nodule of any size)
      1. Go to Step 5 (FNA)
    5. Multiple Nodules >1 cm each
      1. Go to Step 5 (FNA) and sample up to 3 of the Nodules
      2. FNA site selection may be informed by suspicious Ultrasound findings or RAIU for cold Nodules
    6. Thyroid Nodule >4 cm
      1. Higher risk of malignancy (as well as False Negative FNA due to sampling error)
      2. Diagnostic lobectomy is preferred over FNA
    7. Other Highly Suspicious Ultrasound Features or clinical risk factors
      1. Diagnostic lobectomy is preferred
  6. Step 5: Fine needle aspiration (FNA)
    1. Indications
      1. Thyroid Nodule >1-2 cm
      2. Thyroid Cancer risk factors (see above)
      3. Ultrasound with suspicious findings
        1. Hypoechogenicity
        2. Solid Nodule with microcalcifications
        3. Intranodular vascularity
    2. Consider Ultrasound guided FNA (improves diagnostic accuracy of biopsy)
      1. Small Nodules
      2. Cystic Nodules with a solid component
    3. Molecular Testing
      1. FNA is often available with reflex molecular testing
      2. Molecular testing helps distinguish better define Bethesda Category 3-4 cytology
        1. Bethesda Category 3-4 cytology accounts for 25% of results and a 5-30% risk of malignancy
        2. However thryoid lobectomy of these lesions results in 80% benign pathology
  7. Step 6: FNA Interpretation
    1. Benign (Bethesda Category 2 or Category 3-4 with benign molecular tests)
      1. False Negative Rate: <10%
      2. Repeat thyroid Ultrasound in 12-24 months after initial Thyroid FNA
        1. Thyroid growth (>50% increase in Thyroid volume or 20% in 2 Nodule dimensions)
          1. Repeat Thyroid FNA
        2. No significant Thyroid Nodule growth
          1. Repeat thyroid Ultrasound in 3-5 years
      3. Slow serial growth of benign Thyroid Nodules
        1. Unlikely to be malignant if initial FNA negative
        2. Alexander (2003) Ann Intern Med 138:315-8 [PubMed]
      4. Levothyroxine suppression for benign Nodules is not recommended
    2. Indeterminate Cytology (Bethesda Category 3-4 with NO molecular tests performed)
      1. Bethesda Category 4
        1. Refer for diagnostic Thyroid lobectomy
      2. Bethesda Category 3
        1. Repeat FNA in 6-12 weeks
      3. Bethesda Category 1 (non-diagnostic cytology)
        1. Repeat FNA in 6-12 weeks
    3. Suspicious or Malignant (Bethesda Category 5-6 or Category 3-4 with suspicious molecular tests)
      1. Refer for Thyroid lobectomy or Thyroidectomy
      2. Low risk micropapillary Thyroid Cancer <1 cm may be followed with observation (with local Consultation)
        1. However, patients <40 years old are at much higher risk of progression than age >60 years old

XI. Evaluation: Thyroid Nodules in Pregnancy

  1. Thyroid Nodules do not have higher malignant potential in pregnancy than outside pregnancy
  2. Start with TSH and thyroid Ultrasound (as in evaluation above)
    1. Thyroid FNA if indicated (as in evaluation above)
  3. Exception: Suppressed TSH (Hyperthyroidism)
    1. Postpone Thyroid Uptake Scan until after Pregnancy and Lactation
    2. Treat symptomatic Hyperthyroidism with antithyroid medication

XII. Evaluation: Thyroid Nodules in Children and Adolescents

  1. Rare: 1-2% of children
  2. High risk of Thyroid Cancer: 22-26%
  3. Evaluation Strategy
    1. Thyroid Nodule size is unreliable alone as a risk marker (Thyroid volume increases with age)
      1. Ultrasound features become relatively more important in children
    2. Nodule excision indications (without Thyroid FNA)
      1. Children (Thyroid FNA is unreliable)
      2. Family History of Thyroid Cancer or MEN type 2
    3. Thyroid FNA
      1. Adolescents without Nodule excision indications

XIII. Differential Diagnosis

  1. Thyroid Carcinoma (5-10% in adults, 14-40% in children)
  2. Dominant follicle in Multinodular Goiter (23%)
  3. Thyroid cyst (simple or mixed)
  4. Thyroiditis
  5. Thyroid Adenoma
    1. Simple or colloid Macrofollicular Adenoma
      1. Most common type
      2. Follicles of normal size
    2. Embryonal (Trabecular) adenoma
      1. Mostly stroma and minimal follicles
    3. Fetal Microfollicular Adenoma
      1. Small follicles with minimal colloid
      2. Follicular cancer found in 5% of cases
    4. Hurthle Cell Adenoma (uncommon)

XIV. Prognosis

  1. Most Thyroid Nodules are benign (90-95%)

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Related Studies

Ontology: Thyroid Nodule (C0040137)

Definition (NCI) A nodular lesion that develops in the thyroid gland. Causes include adenoma, thyroiditis, fluid-filled cyst, multinodular goiter, and carcinoma.
Definition (MSH) A small circumscribed mass in the THYROID GLAND that can be of neoplastic growth or non-neoplastic abnormality. It lacks a well-defined capsule or glandular architecture. Thyroid nodules are often benign but can be malignant. The growth of nodules can lead to a multinodular goiter (GOITER, NODULAR).
Concepts Neoplastic Process (T191)
MSH D016606
SnomedCT 190234009, 237495005, 76917005
English Nodule, Thyroid, Nodules, Thyroid, Thyroid Nodules, Thyroid Gland Nodule, Thyroid Nodule, Thyroid Nodule [Disease/Finding], thyroid nodule, Nodule(s);thyroid, thyroid nodules, Thyroid nodule, Thyroid nodule (disorder), Nodule of Thyroid Gland, Nodule of Thyroid, Nodule of the Thyroid Gland, Nodule of the Thyroid, thryoid nodules
Dutch schildkliernodus, Nodus, schildklier-, Schildkliernodus
German Schildddruesenknoetchen, Schilddrüsenknoten
Italian Nodulo della tiroide, Nodulo tiroideo
Portuguese Nódulo da tiroideia, Nódulo da Glândula Tireoide
Spanish Nódulo tiroideo, nódulo tiroideo (concepto no activo), nódulo tiroideo (trastorno), nódulo tiroideo, Nódulo Tiroideo
Japanese 甲状腺結節, コウジョウセンケッセツ
Swedish Knuta i sköldkörtel
Czech tyreoidální uzel, Thyreoidální uzel
Finnish Kilpirauhaskyhmy
Polish Guzki tarczycy
Hungarian Pajzsmirigy-csomó
Norwegian Skjoldkjertelknute, Tyreoideaknute
French Nodule thyroïdien, Nodule de la thyroïde

Ontology: Toxic thyroid adenoma (C0302840)

Concepts Disease or Syndrome (T047)
SnomedCT 449097000
Dutch schildklieradenoom toxisch
French Adénome toxique de la thyroïde
German toxisches Schilddruesenadenom
Italian Adenoma della tiroide tossico
Portuguese Adenoma da tiroideia tóxico
Spanish Adenoma tiroideo tóxico, adenoma folicular de glándula tiroides hiperfuncionante (trastorno), adenoma folicular de glándula tiroides hiperfuncionante, adenoma tiroideo tóxico
Japanese 中毒性甲状腺腺腫, チュウドクセイコウジョウセンセンシュ
English toxic thyroid adenoma (diagnosis), toxic thyroid adenoma, toxic adenoma, Toxic thyroid adenoma, Hyperfunctioning follicular adenoma of thyroid gland, Hyperfunctioning follicular adenoma of thyroid gland (disorder), Thyroid adenoma toxic
Czech Toxický adenom štítné žlázy
Hungarian Toxikus pajzsmirigy adenoma

Ontology: Mass of thyroid gland (C0349453)

Concepts Neoplastic Process (T191)
SnomedCT 237557003, 276378000
Italian Massa della tiroide
Japanese 甲状腺腫瘤, コウジョウセンシュリュウ
Czech Rezistence v oblasti štítné žlázy
English Mass of thyroid gland, Mass of thyroid gland (finding), Thyroid lump (disorder), Thyroid lump, thyroid mass on exam (physical finding), thyroid mass on exam, mass thyroid, thyroid lumps, Lump(s);thyroid, Mass;thyroid, lump thyroid, masses thyroid, lumps thyroid, thyroid mass, Thyroid lump (finding), Thyroid gland mass, Thyroid mass, thyroid lump
Spanish tumoración tiroidea (trastorno), tumoración tiroidea (hallazgo), masa tiroidea, tumoración tiroidea, Masa tiroidea
Hungarian Pajzsmirigy térfoglaló folyamata
Portuguese Massa tireoidiana
Dutch schildkliergezwel
French Masse thyroïdienne
German Schilddruesenmasse