Thyroid Cancer

Essentials of Diagnosis

• Painless swelling in region of thyroid

• Thyroid function tests are usually normal

• Types of thyroid cancer

  • Differentiated thyroid carcinomas: papillary and follicular

  • Medullary thyroid carcinoma

  • Anaplastic thyroid carcinoma

• Possible history of childhood irradiation to head and neck region

• Positive thyroid fine-needle aspiration cytology

General Considerations

• Most thyroid cancers are microscopic and indolent. Larger ones require treatment

Papillary carcinoma

• Pure papillary or mixed papillary-follicular most common types of thyroid cancer (80%)

• Childhood head–neck radiation or nuclear fallout exposure imparts increased lifelong risk

• Least aggressive thyroid cancer

• Involves both lobes in 30% of patients

• About 80% of patients have microscopic metastases to cervical lymph nodes

Follicular carcinoma

• Second most common thyroid cancer

• Generally more aggressive than papillary carcinoma

• Metastases commonly found in neck lymph nodes, bone, and lungs

Medullary thyroid carcinoma

• 2–3% of thyroid cancers

• One-third sporadic, one-third familial, one-third associated with multiple endocrine neoplasia type 2 (MEN 2)

• Early metastases usually present locally; late metastases may occur in bones, lungs, adrenals, or liver

• Peptides (eg, serotonin) can cause symptoms and serve as tumor markers

Anaplastic thyroid carcinoma

• 2% of thyroid cancers

• Older patient with rapidly enlarging mass in multinodular goiter

• Most aggressive thyroid carcinoma

• Metastasizes early to surrounding lymph nodes and distant sites

Other thyroid malignancies

• 3% of thyroid cancers

• Thyroid lymphomas are most commonly B cell lymphomas (50%) or mucosa-associated lymphoid tissue (MALT; 23%)

• Other types include follicular, small lymphocytic, and Burkitt lymphoma; and Hodgkin disease

Symptoms and Signs

• Usually presents as palpable, firm, nontender nodule

• Larger cancers can cause neck discomfort, dysphagia, or hoarseness

• Papillary thyroid cancer

  • Presents with palpable lymph node involvement

  • May invade the trachea and local muscles

  • Occult metastases to the lung occur in 10–15%

• Follicular thyroid carcinoma commonly metastasizes to neck nodes, bones, and lung, but nearly every organ can be involved

• Metastatic differentiated carcinoma may secrete enough thyroid hormone to produce thyrotoxicosis

• Medullary carcinoma causes flushing, diarrhea, fatigue; ~5% develop Cushing syndrome

• Anaplastic thyroid carcinoma

  • More apt to be advanced at the time of diagnosis, presenting with signs of pressure or invasion of surrounding tissue, resulting in

    • Dysphagia

    • Hoarseness

    • Recurrent laryngeal nerve palsy

  • Patients may also have dyspnea with metastases to the lungs

• Lymphoma usually presents as a rapidly enlarging, painful mass arising out of a multinodular or diffuse goiter due to autoimmune thyroiditis, with which it may be confused microscopically. About 20% of cases have concomitant hypothyroidism

Differential Diagnosis

• Benign thyroid nodule

• Subacute thyroiditis

• Benign multinodular goiter

• Lymphadenopathy due to other cause

• Metastasis from head and neck cancer

• Lymphoma

Laboratory Tests

• TSH and T₄ normal unless concomitant thyroiditis; metastatic follicular carcinoma may secrete enough thyroxine to suppress TSH

• Tumor markers for recurrent or metastatic disease

  • Obtain levels preoperatively and follow postoperatively

  • Serum thyroglobulin level

    • High in most metastatic papillary and follicular tumors

    • Useful marker except if antithyroglobulin Ab present

  • Serum calcitonin level frequently elevated in medullary thyroid carcinoma, but nonspecific test

  • Serum carcinoembryonic antigen (CEA) level usually elevated with medullary carcinoma

• Genetic testing of siblings and children of patients with medullary carcinoma for RET protooncogene mutations, which occur in MEN 2 and familial medullary thyroid carcinoma

Imaging Studies

• Preoperative neck ultrasound

  • Especially useful if known metastases, persistent elevation in serum thyroglobulin, or detectable levels of antithyroglobulin antibodies

  • Useful for postoperative surveillance

• Radioactive iodine (RAI) scan is used after thyroidectomy for differentiated thyroid cancer

• Medullary thyroid cancer does not avidly uptake RAI

• CT scan

  • May demonstrate metastases, but its iodinated contrast reduces effectiveness of RAI scanning and therapy

  • Medullary carcinoma metastases in thyroid, nodes, and liver may calcify, but rarely in lung

• MRI is particularly useful for imaging bone metastases

• Positive emission tomography (PET) scan

  • Useful for detecting thyroid cancer metastases that do not have sufficient iodine uptake to be visible on RAI scans

  • Thyroid cancer metastases may be detected with ¹⁸FDG-PET whole-body scanning

  • Sensitive for detecting metastases from medullary thyroid carcinoma

  • Sensitivity of ¹⁸FDG-PET scan for differentiated thyroid cancer is enhanced if the patient is hypothyroid or receiving thyrotropin, which increases the metabolic activity of differentiated thyroid cancer

• Patients with medullary thyroid cancer are monitored with MRI and ¹⁸FDG PET/CT scanning

• ⁶⁸Ga-DOTATATE-PET imaging

  • Superior for detecting medullary thyroid cancer metastases in certain patients, particularly those with very high serum calcitonin levels (above 500 pg/mL)

  • Although this method is more specific for neuroendocrine tumors, other malignancies express somatostatin receptors and can have misleading uptake on this scan, including

    • Non-Hodgkin lymphoma

    • Meningioma

    • Breast cancer

    • Thyroid adenoma

    • Papillary thyroid carcinoma

Diagnostic Procedures

• Fine-needle aspiration biopsy for clinically suspicious nodules

Medications

• Levothyroxine is prescribed for differentiated thyroid cancer in doses to achieve a target serum TSH

  • For initial TSH suppression in high to medium risk patients, the target serum TSH is < 0.1 milli-international units/L while avoiding clinical hyperthyroidism

  • For initial TSH suppression in low-risk patients, for persistent indolent disease, and for 5–10 years after remission in high-risk patients, the target TSH is between 0.1 milli-international units/L and 0.5 milli-international units/L

  • For patients who are free of disease and at low risk for recurrence, the target TSH is 0.5 to 2 milli-international units/L

• Vandetanib and cabozantinib are approved for use against rapidly progressive metastatic medullary thyroid carcinoma; both require close surveillance for toxicity

  • Vandetanib should usually not be administered to patients with cardiac disease or a prolonged QT interval

  • Cabozantinib should usually not be administered to patients with small bowel or large bowel disease or prior radiation to the neck or mediastinum, since it increases the risk for GI perforation and tracheoesophageal fistula

  • Patients with MTC and diabetes should not receive diabetic therapy with glucagon-like peptide-1 (GLP-1) agonists that may stimulate the growth of MTC

• Vandetanib, 100 mg orally once daily

  • Produced a partial remission in 16% and stable disease in 53% of patients with locally advanced or metastatic medullary thyroid carcinoma

Surgery

• Total or near-total thyroidectomy is treatment of choice for most patients

• Lobectomy alone for papillary thyroid carcinomas < 1 cm in patients under age 45 years who have no history of head/neck irradiation and no evidence of lymph node metastasis on ultrasonography

• A central neck lymph node dissection is performed at the time of thyroidectomy for patients with nodal metastases that are clinically evident

• A lateral neck dissection is performed for patients with biopsy-proven lateral cervical lymphadenopathy

• Surgical resection for metastases to brain (radiation or radioactive iodide therapy ineffective), and for bulky recurrent tumor in neck region

• Total thyroidectomy for medullary thyroid carcinoma; repeated neck dissections often required over time

• Prophylactic total thyroidectomy, ideally at age 6, in persons with RET protooncogene mutations

• Local resection, combined with radiation therapy, for anaplastic carcinoma

Therapeutic Procedures

• After thyroidectomy, patients with differentiated thyroid carcinomas receive RAI neck and whole-body scan after rhTSH administration or while hypothyroid

• Treatment with ¹³¹I in patient with suspicious RAI uptake scan

  • Stage I differentiated thyroid cancer

  • ¹³¹I therapy does not improve survival but does reduce local recurrence

  • Some advocate ¹³¹I for those with a primary tumor > 1 cm, tumor at the surgical margin, or tumor with lymph node involvement

  • Stage II–IV thyroid cancer

• ¹³¹I therapy cautions

  • Pregnant women may not receive RAI therapy

  • Women are advised to avoid pregnancy for at least 4 months after RAI therapy

  • Men have abnormal spermatozoa up to 6 months after therapy and must use contraceptive methods during that time

• External-beam radiation therapy for bone metastases

• Zoledronate

  • Has proven useful for osteolytic metastases

  • For patients with asymptomatic osseous metastases, the dose is 4 mg intravenously every 6 months; for those with symptomatic osseous metastases, the dose is 4 mg intravenously every 3 months for the first year and then every 6 months

• Tyrosine kinase inhibitors

  • Vandetanib and sunitinib induce partial responses (PR) in about 40%

  • Lenvatinib induced PRs in about 65%

  • Median progression-free survival has only been about 18 months

  • Can cause serious adverse reactions

Follow-Up

• Monitor serum TSH, and adjust thyroxine dose

• Whole-body ¹³¹I or ¹²³I scans at 2–4 months postoperatively (detects ~65% of metastases) and then 6–12 months later

• Two successive whole-body scans without metastases are required for diagnosis of remission

• Monitor serum calcitonin and CEA periodically after surgery for medullary carcinoma

• Monitor bone densitometry periodically if patient is receiving thyroxine suppression therapy

• Family members of patients with medullary thyroid carcinoma should have thyroid surveillance every 6 months

• Patients who have had a thyroidectomy for differentiated thyroid cancer must take levothyroxine replacement for life

  • Stage I disease: serum TSH should be suppressed < 0.1–0.5 milli-international units/L

  • Stage II disease: below 0.1 milli-international units/L

  • Stage III–IV disease: below 0.05 milli-international units/L

Complications

• Metastases most frequently spread to local nodes, lungs, and bones, but nearly every organ can be involved, including pharynx, eyes, brain, muscles, pancreas, liver, adrenals, and ovaries

• Hyperthyroidism can develop in patients with a heavy tumor burden

• One-third of medullary carcinomas secrete serotonin and prostaglandins, producing flushing and diarrhea

• Coexistence of pheochromocytomas or hyperparathyroidism may complicate the management of medullary carcinomas

Prognosis

• Papillary thyroid carcinoma has an overall mortality rate of 3%

• Follicular thyroid carcinoma have a cancer mortality rate that is 3.4 times higher than patients with papillary carcinoma

• Palpable lymph node metastases in papillary thyroid cancer do not increase mortality, but do increase risk of local recurrence

• [¹⁸F]fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) scan: differentiated thyroid cancer metastases with low standard uptake value (SUV) scores are associated with a better prognosis

• Brain metastases (in 1%) reduce median survival to 12 months; prognosis is improved by surgical resection

• Mortality increased twofold by 10 years and threefold by 25 years in patients not receiving ¹³¹I ablation

• Prognosis for medullary thyroid carcinoma variable:

  • Overall 10-year survival rate is 90% when confined to thyroid, 70% with metastases to cervical lymph nodes, and 20% with distant metastases

  • In MEN 2A, cancers are less aggressive; in MEN 2B, cancers are more aggressive

  • Those staining heavily for calcitonin are usually less aggressive; there may be prolonged survival despite extensive metastases

• Prognosis for anaplastic thyroid carcinoma is poor

When to Admit

• Admit for thyroidectomy and keep for at least 1 day postoperatively to monitor for late bleeding, airway problems, and tetany

• Admit for high-dose ¹³¹I therapy