59 THYROID NODULES AND CANCER
Robert C. McIntyre Jr., M.D.

1. What is the prevalence of thyroid nodules and cancer?

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Thyroid nodules increase throughout life. Nodules are four times more common in females than in males, and 50% of 50-year-old women have a palpable nodule. After exposure to radiation, nodules develop at approximately 2% annually, reaching a peak at 25 years. Nodules are 10 times more frequent in glands examined by ultrasound, at surgery, or at autopsy. Fewer than 50% of thyroid nodules that appear solitary on physical examination are truly solitary.
Each year in the United States, there are approximately 15,000 new cases and 1000 deaths due to thyroid cancer. Up to 35% of thyroid glands examined at autopsy contain occult papillary cancer (< 1.0 cm).

2. What is the importance of the distinction between solitary and multiple thyroid nodules?

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Traditionally, multiple thyroid nodules were considered benign and solitary thyroid nodules malignant. However, multiple series suggest that a dominant nodule in a multinodular gland carries the same risk of cancer as a solitary nodule (5%).

3. What is the differential diagnosis of thyroid nodules?

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* Adenoma
o Macrofollicular (colloid)
o Microfollicular
o Embryonal
o Hurthle cell
* Carcinoma
o Papillary
o Follicular
o Medullary
o Anaplastic
o Lymphoma
o Metastatic
* Cyst
* Nodular goiter with a dominant nodule
* Other
o Inflammatory diseases (e.g., Hashimoto’s thyroiditis)
o Developmental abnormalities

4. What features of the history and physical examination indicate a higher risk of cancer?

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Nodules occurring at the extremes of age are more likely to be cancerous, particularly in males. Rapid growth and local invasion raise the possibility of malignancy, but associated symptoms (e.g., hoarseness, dysphagia) are uncommon. A history of radiation exposure increases the frequency of both benign and malignant nodules. A family history of medullary or papillary thyroid cancer or Gardner’s syndrome (i.e., familial polyposis) increases the risk of cancer.
Cancer is more often found in patients with firm, solitary nodules. Fixation to adjacent structures, vocal cord paralysis, and enlarged lymph nodes also are associated with an increased risk of malignancy.

5. What is the proper laboratory evaluation of a patient with a thyroid nodule?

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The only biochemical test that is routinely needed is a serum thyroid-stimulating hormone (TSH) concentration to identify patients with unsuspected hyperthyroidism. In patients with suspected medullary thyroid carcinoma (MTC), serum calcitonin should be measured. In patients with known medullary carcinoma, serum calcium levels and 24-hour urine collection for assessment of catecholamines and their metabolic products should be done to exclude multiple endocrine neoplasia (MEN II) before thyroidectomy. Patients with MTC should have lymphocyte-derived DNA analysis for ret proto-oncogene mutations.

6. Which single test best predicts the need for surgical intervention?

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The single best test to predict the need for surgery is fine-needle aspiration (FNA). If an adequate specimen is obtained, the three possible results are benign (70%), suspicious (15%), and malignant (5%). FNA is most reliable for the diagnosis of papillary carcinoma and in patients with medullary and anaplastic cancer. It is least reliable in distinguishing benign from malignant follicular and Hurthle cell neoplasms. The overall accuracy exceeds 95% in experienced hands. When FNA reveals cancer, it is 97% correct (3% false-positive rate); when it indicates a benign nodule, cancer is present in 4% of cases (4% false-negative rate). When the FNA is suspicious, 30% of nodules are malignant.

7. What other tests may be useful in the evaluation of a thyroid nodule?

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Thyroid radionuclide studies with isotopes of either iodine (most common) or technetium often are performed but cannot reliably differentiate malignant from benign nodules. Scans may be useful in patients with indeterminate FNA results and TSH < 1.5 μIU/mL because hyperfunctioning nodules are almost always benign.
Ultrasound categorizes nodules as cystic, solid, or mixed and is the best measure of the size of a nodule. Ultrasound can be used to determine the presence of other nodules in a patient with a solitary nodule on physical examination. It is particularly useful to follow the size of a nodule. Similar to radionuclide scans, ultrasound cannot distinguish malignant from benign nodules; thus, it is not routinely used in the evaluation of a nodule.

8. Should a solitary thyroid nodule be suppressed with thyroxine for 3-6 months to determine whether it is benign or malignant?

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Most nodules change very little over the short term. In one series, 13% of nodules decreased in size, 22% disappeared, 46% did not change, and 19% enlarged. Studies of thyroxine therapy suggest that drug treatment is not superior to placebo in patients with solitary nodules. Most nodules do not change in size, 30% decrease in size, and a few increase in size. Thus, the response to thyroxine is not a reliable indicator of malignancy.

9. What are the types and distribution of thyroid cancer?

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Papillary	70%
Follicular	20%
Medullary	5%
Anaplastic and lymphoma	5%

10. What are the axioms of thyroid surgery?

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* A meticulously dry operative field must be maintained.
* Tissue in the region of the recurrent laryngeal nerve should not be cut or clamped until the nerve is definitively identified.
* Every parathyroid gland should be treated as if it were the last functioning gland.
* If malignancy is suspected, the entire operation should be done as if the lesion were cancer.

KEY POINTS: THYROID NODULES

1. Thyroid nodules are more common in females than in males.
2. The only biochemical test that is routinely needed is a serum thyroid-stimulating hormone concentration to identify patients with unsuspected hyperthyroidism.
3. The single best test to predict the need for surgery is fine-needle aspiration.
4. Thyroid carcinoma should be treated by near-total or total thyroidectomy except in young patients with small, well-differentiated tumors (≤ 1 cm) and no evidence of lymph node or extrathyroidal disease. In such cases lobectomy and isthmusectomy are adequate therapy.

11. What is the minimal extent of thyroidectomy for a solitary thyroid nodule?

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The goal of surgery is to remove all foci of neoplastic tissue and any palpable cervical adenopathy. With the exception of small lesions in the thyroid isthmus, the minimal procedure for suspected malignancy should be lobectomy, including the isthmus (as a diagnostic biopsy). Enucleation is to be avoided. Frozen section is accurate for papillary, medullary, and anaplastic carcinoma. Frozen section is no more accurate than FNA for follicular and Hurthle cell carcinoma. Functioning “toxic” nodules may be resected by a partial lobectomy because they are usually benign. If the lesion is large, a lobectomy is preferred.

12. What is the most common form of thyroiditis in nodules?

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Hashimoto’s thyroiditis, subacute thyroiditis, and Reidel struma (rare). These conditions usually do not require surgery. Thyroidectomy is indicated for compressive symptoms or when cancer cannot be excluded.

13. What is the surgical therapy for thyroid carcinoma?

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Thyroid carcinoma should be treated by near-total or total thyroidectomy except in young patients with small, well-differentiated tumors (≤ 1 cm) and no evidence of lymph node or extrathyroidal disease. In such cases, lobectomy with resection of the isthmus is adequate therapy. Near-total thyroidectomy eliminates multifocal cancer in the thyroid, allows postoperative radioiodine for the diagnosis and therapy of metastatic disease, decreases the risk of local-regional recurrence, and improves the accuracy of serum thyroglobulin as a marker for persistent or recurrent disease. Enlarged cervical lymph nodes should be removed and examined by frozen section. If metastatic cancer is identified, a neck dissection is performed. “Berry picking” results in an increased rate of regional recurrence and should be avoided in favor of anatomic dissections.
Because medullary thyroid cancer is not responsive to radioiodine or levothyroxine, a total thyroidectomy should be performed. A central neck dissection is mandatory to evaluate metastatic disease. If the central nodes are positive for cancer on frozen section, an ipsilateral modified neck dissection is performed. The contralateral neck may be observed.
Surgery for anaplastic carcinoma is palliative and usually is limited to debulking and tracheostomy for relief of compressive symptoms.

14. Describe the arterial supply and venous drainage of the thyroid.

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The blood supply to the thyroid gland comes from the superior and inferior thyroid arteries. Occasionally, a midline thyroid imma artery arises from the aortic arch. The superior thyroid artery is the first branch of the external carotid artery. The inferior thyroid artery arises from the thyrocervical trunk.
The three major veins are the superior, middle, and inferior thyroid veins. The superior and middle thyroid veins drain into the internal jugular vein, and the inferior vein drains into the innominate vein.

15. Describe the anatomy of the recurrent laryngeal nerves.

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The right recurrent laryngeal nerve (RLN) arises from the vagus and loops around the right subclavian artery. The left vagus nerve gives off the left RLN and loops around the aorta. The RLNs run obliquely through the neck, usually in the tracheoesophageal groove. Low in the neck, the nerves are more lateral and course medially as they ascend. The right nerve runs more obliquely than the left. Occasionally, the RLN may branch before entering the larynx, usually on the left side. The motor fibers are usually in the most medial branch. In 1% of cases, the right RLN is not recurrent and enters the neck from a lateral and superior direction.

16. What defect results from injury to the RLN?

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Injury to a single RLN results in a paralyzed vocal cord, which causes a weak, hoarse voice. Patients also have abnormal swallowing and problems with aspiration. Injury to both nerves causes paralysis of both cords and obstruction of airflow. This situation necessitates a tracheostomy. RLN injury occurs in 1% of thyroidectomies.

17. Describe the anatomy of the superior laryngeal nerve and the defect that occurs with its injury.

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The superior laryngeal nerve gives off the external laryngeal nerve, which runs medial to the superior pole vessels to enter the cricothyroid muscle. This motor nerve (i.e., Amelita Galli-Curci nerve) increases tension of the vocal cords, allowing for high notes. The internal laryngeal nerve provides the sensory innervation to the posterior pharynx. It lies superior to the thyroid cartilage. Injury to the nerve leads to a weak, low voice that lacks resonance. Patients may also have problems with aspiration.

18. What is the other major complication of thyroidectomy?

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Permanent hypoparathyroidism occurs in 1% of patients who have had thyroidectomies.

19. What is the postoperative therapy for well-differentiated thyroid carcinoma?

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Patients with risk factors should be treated with postoperative radioiodine (I-131). Risk factors include older age (> 45 years old), male gender, tumor size, direct local invasion, nodal spread, and distant disease. All patients with well-differentiated thyroid cancer should be treated with levothyroxine (Synthroid) to suppress serum levels of TSH (0.2-0.5 μU/mL). This three-component therapy (i.e., surgery, I-131, levothyroxine) results in the lowest recurrence rate.

20. How should a patient be followed after therapy for well-differentiated thyroid carcinoma?

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In young, low-risk patients, physical examination of the neck is done every 6 months for 2 years and then yearly thereafter. In high-risk patients, close follow-up includes repeat neck examination in addition to assessment of serum thyroglobulin (Tg) levels, diagnostic radioiodine scans, and cervical ultrasound. Assessment of the serum Tg and scanning depends on the state of the serum TSH. In order to fully evaluate for recurrent disease, the patient should be taken off thyroxine or given recombinent TSH (Thyrogen).
Patients with recurrent cervical disease by palpation or ultrasound should have repeat surgery if the procedure can be performed with low morbidity. After removal of gross disease, patients should be treated with radioiodine. Distant disease should be treated with radioiodine if the metastases take up iodine.

References
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