Thyroid nodules and thyroid cancer

I. Problem/Condition.

Thyroid nodules are small circumscribed masses found in the thyroid gland. Nodules are formed from unchecked growth of thyroid epithelial cells or medullary cells. The clinical signficance of thyroid nodules includes the possibility of cancer (approximately 5%), thyroid dysfunction, and in rare circumstances, development of local compression of structures in the neck. Growth of nodules can lead to development of multinodular goiter.

The prevalence of nodules ranges from 20 to 76% in the United States, and increases with age and female gender. Smoking and alcohol use may increase prevalence as well. Most nodules are asymptomatic and are found incidentally on exam or on imaging obtained for other reasons.

Thyroid cancers are nodules that contain evidence of neoplasia. The rate of malignancy is higher in nodules found in children and adolescents than those found in adult patients. The most common subtypes include papillary, follicular, medullary and anaplastic. Other possibilities include primary lymphoma, and metastases from primary breast, renal, colon cancers or melanoma.

Thyroid cancers are associated with family history of thyroid cancer or Multiple Endocrine Neoplasia 2 (MEN2), prior irradiation to the head and neck, age <30 years or >70 years, and male gender.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential diagnosis for thyroid nodules can initially be divided into benign and malignant causes.

Benign Etiologies of Thyroid Nodules:

Adenomas (macrofollicular, microfollicular)

Colloid nodules

Congenital abnormalities

Simple or hemorrhagic cysts

Lymphocytic or granulomatous nodules

Hyperplastic nodules

Subacute and Hashimoto’s thyroiditis

Malignant Etiologies of Thyroid Nodules:

Differentiated: Papillary and Follicular carcinoma

Undifferentiated: Anaplastic carcinoma, poorly differentiated carcinoma

Medullary Carcinoma

Other: primary thyroid lymphoma, sarcoma, teratoma, metastases

Note: Microfollicular adenomas are technically not considered follicular cancers because they lack capsular or vascular invasion. However, they otherwise microscopically look like follicular carcinoma and so are often treated like malignant lesions.

B. Describe a diagnostic approach/method to the patient with this problem.

The purpose of diagnostic approaches in palpable or incidental thyroid nodules is to identify nodules that are hyperfunctioning, and to rule out malignancy. The prevalence of thyroid nodules is high, but only a subset of nodules are actually malignant. It is not feasible or cost effective to surgically remove and complete a functional evaluation of every nodule. Therefore providers should complete a structured assessment of the patient that takes into account risk factors, and uses a cost effective approach to diagnosis. Clinical features need to be taken into account with imaging and cytologic diagnosis to determine need for surgical removal.

1. Historical information important in the diagnosis of this problem.

Many nodules are asymptomatic. If you do happen to find a nodule on exam or on imaging several questions can be helpful in trying to suggest the diagnosis.

  • Have you noticed this nodule in your neck before? If so, has it been growing and over what time frame? Malignancy often grows slowly.

  • Do you have sweats, diarrhea, heat intolerance, diarrhea, a feeling of shakiness? This may suggest an autonomous nodule causing hyperthyroidism.

  • Is the mass ever painful or has it enlarged rapidly recently? This may suggest bleeding into a cyst.

  • Have you noticed a loss of voice or hoarseness? This could suggest tracheal compression from a multinodular goiter, or in absence of a goiter could be concerning for a malignancy.

  • Do you have a family history of cancer, specifically papillary thyroid cancer, medullary thryoid cancer, or MEN 2? Family history or MEN 2 increases the risk of thyroid cancer.

  • Do you have a history of neck irradiation? Neck irradiation increases the risk of thyroid cancer.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Examination should include inspection, auscultation, and palpation of the thyroid gland. Specifics including size of any palpated nodules and mobility should be noted. Nodules that are hard, fixed to adjacent structures, and with regional lymphadenopathy are associated with a higher risk for malignancy. Lymphadenopathy should be evaluated as well, including size, texture and mobility of any enlarged nodes.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

In patients who are asymptomatic diagnostic work up can be started in the outpatient setting after the patient has been discharged. For symptomatic individuals, or in specific patients who desire initiation of the work up in the hospital, the following approach can be used (seeFigure 1).

Figure 1.

Flowchart for work up of thyroid nodule.

Initial laboratory testing for patients with thyroid nodules should include TSH, thyroid peroxidase antibodies, and a free thyroxine or FT4 to assess thyroid function. In patients with a history of MEN2, a serum calcitonin level should be measured. All patients with a palpable thyroid nodule, evidence of a goiter, or incidental finding on computed tomography (CT) or magnetic resonance imaging (MRI) should also undergo ultrasound. Ultrasound can help identify the number of nodules, their size and location, and any evidence of worrisome sonographic signs.

Thyroid gland fine needle aspiration (FNA) is the diagnostic test of choice to evaluate if a nodule has malignant cells. FNA can be performed with palpation or with ultrasound guided FNA and aspirate is sent for cytologic diagnosis. U/S FNA should be performed in patients in whom palpation guided FNA was insufficient, U/S shows a complex (solid and cystic components) nodule, the nodule is small <1.5cm, there is an impalpable incidentaloma, abnormal cervical nodes, nodule with suspicious ultrasound features, or a cold nodule on scintigraphy. Thyroid FNA in experienced hands has been reported to have a mean sensitivity of 83 (65-98%) and mean specificity of 92% (72-100%) with a positive predictive value of 75%.

If there are symptoms, evidence of thyroid dysfunction, worrisome ultrasound characteristics, or questions as to how frequently to follow up, patients should be referred to an endocrinologist.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

  • If the TSH is normal, no further lab testing is necessary. Proceed with ultrasound assessment.

  • If the TSH is high, the patient should get a free T4 and thyroid peroxidase antibodies checked to evaluate for hypothyroidism. High TPOAb are suggestive of an autoimmune thyroiditis as cause of the nodular thyroid. Proceed with ultrasound assessment given Hashimoto’s thyroiditis is associated with lymphoma.

  • If the TSH is low, the patient should get a free T4 and a free triiodothyronine to evaluate for hyperthyroidism. Thyroid scintigraphy can also be checked to assess for “hot nodules”. If the nodule is found to be hyperfunctioning, the risk of cancer is very low and patient likely does not need FNA.

Sonographic features that predict malignancy include microcalcifications, irregular nodule margins, and chaotic intranodal vasculature. Evidence of any of these with a hypoechoic nodule suggests a malignancy. Any two of these features predicts malignancy in 85-93% of thyroid gland neoplasia.

Cytologic analysis may yield benign results (colloid nodule, macrofollicular adenoma, benign cyst, lymphocytic thyroiditis, or granulomatous thyroiditis). Cytology may return with a positive result suggesting papillary carcinoma, follicular carcinoma, anaplastic carcinoma, medullary carcinoma, primary thyroid lymphoma, sarcoma, teratoma or other metastases. In general, 70% FNA yield benign diagnoses, 5% are malignant, 10% are suspicious, and the remainder are unsatisfactory specimens. Nondiagnostic results should prompt repeat U/S guided FNA.

Malignant, suspicious, or persistently nondiagnostic results require surgical treatment.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.


III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Thyroid Nodules and Thyroid Cancer.

The work up of thyroid nodules is rarely emergent. If a patient has signficant airway problems from compression from a large goiter then work up should be expedited. Otherwise incidental finding of thyroid nodules found on the inpatient service can be deferred to outpatient workup and management.

If the nodule does not have historical, physical exam, or sonographic features concerning for malignancy the nodules may be followed with periodic testing and repeat evaluation by ultrasound.

If a patient has symptomatic hyperthyroidism this can be treated with medications initially, and the nodule itself with radioactive iodine or surgery.

If cytologic diagnosis confirms a benign condition, further workup and treatment is typically not necessary. Some suggest routine follow up every 6 to 24 months. For large nodules or MNG, surgery is sometimes pursued. Percutaneous ethanol injection can be helpful in shrinking cystic lesions.

If cytologic diagnosis confirms a malignancy or shows microfollicular adenoma, surgery is done to remove tissue.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Major pitfalls can occur in failure to hand off and follow up a documented nodule seen incidentally on inpatient imaging or exam. Frontline providers should determine if patient needs immediate diagnosis and management. If not, appropriate communication with the patient regarding need to follow up as outpatient should occur and be documented routinely. In addition, the inpatient providers should communicate with the outpatient primary care physician to ensure appropriate steps are taken for diagnosis.

Other pitfalls in diagnostic workup are assuming that small nodules are not cancerous. Size itself is not a marker for or against malignancy. In addition, in patients with more than one nodule, the more dominant nodule may not be the more likely to harbor neoplasia.

IV. What's the evidence?