Middle-Aged Woman With Thyroid Nodules

A palpable nodule on the right lobe of the thyroid gland is detected in a 55-year-old woman. The nodule is firm and nontender and moves freely. The lymph nodes in her neck are not enlarged.

HISTORY AND PHYSICAL EXAMINATION
The patient takes a statin for mild hypercholesterolemia and occasionally takes a proton pump inhibitor for heartburn. She has no history of organic heart disease, hypertension, chronic obstructive pulmonary disease, or diabetes; there is no family history of thyroid disease or other endocrinopathy. Except for the thyroid nodule, physical findings are normal.

LABORATORY AND IMAGING RESULTS

Hemogram is normal. Total cholesterol level is 201 mg/dL. Serum calcium level is 9.7 mEq/L; phosphorus, 4.0 mEq/L. The rest of the results of a chemistry panel are normal. Thyroid-stimulating hormone (TSH) level is normal.

Ultrasonography reveals a 2.3-cm solid nodule in the right lobe of the thyroid gland and two 0.5-cm nodules nearby in the same lobe. No microcalcifications or vascular spots are seen. Fine-needle aspiration (FNA) biopsy of the thyroid gland is scheduled.

Which of the following statements about the management of this patient's thyroid nodules is true?A. If FNA biopsy reveals papillary carcinoma, lobectomy is the optimal therapy.
B. If the FNA biopsy specimen is deemed "suspicious," a battery of immunohistochemical stains can reliably differentiate benign from malignant disease.
C. If the FNA biopsy specimen is deemed "suspicious," yearly ultra- sonography is the optimal management strategy.
D. If results of the FNA biopsy are inconclusive, repetition of FNA under ultrasound guidance can reduce the likelihood of a nondiagnostic smear from 15% to less than 5%.CORRECT ANSWER: D
The reported incidence of thyroid nodules, much like that of adrenal nodules, varies widely, depending on which modality is used to identify them. Reported prevalence rates for thyroid nodules identified by palpation are about 4%; for those identified on autopsy in patients without a history of thyroid disease, 50%; and for those identified by ultrasonography, as high as 67%.¹ The Framingham data reveal an estimated annual incidence on palpation of 0.9%, or about 300,000 palpable nodules per year in the United States.¹

Clinical significance of thyroid nodules. Usually, the clinical significance of a thyroid nodule is the possibility that it may be malignant; far less commonly, vocal cord compression (with resultant hoarseness) or cosmetic concerns are issues. Approximately 15% to 20% of thyroid nodules are malignant.

The key maneuvers in the management of thyroid nodules are ultrasonography and FNA biopsy. Ultrasonography is able to detect even nonpalpable nodules and to define the nodular characteristics that are associated with risk of malignancy, such as hypoechoic nature, irregular borders, vascular spots, and microcalcifications.² Ultrasonography is also extremely useful in guiding the needle to an appropriate biopsy site, there-by enhancing the diagnostic yield of FNA.

Indicators of cancer risk. Before proceeding to FNA, certain clinical assessments and an ultrasonographic study, as well as biochemical studies, should be performed. Findings associated with a high suspicion of malignancy include:

• Family history of medullary thyroid cancer or other endocrine neoplasia.
• Rapid tumor growth.
• A very firm or hard nodule.
• Fixation to neck tissues.
• Vocal cord paralysis.
• Regional adenopathy.¹

Nodule size of more than 4 cm in diameter is by itself associated with moderate suspicion of malignancy.¹

The routine biochemical screen is measurement of serum TSH level. A low level suggests hyperthyroidism and the presence of a hyperfunctioning nodule or nodules, which are usually benign. An elevated TSH level--together with positive results of antibody studies--suggests Hashimoto thyroiditis. Almost all patients who have thyroid cancer are euthyroid; however, the incidence of cancer/lymphoma in glands affected by Hashimoto thyroiditis is high enough and FNA complications rare enough that FNA should be offered to patients whose biochemical screening results suggest Hashimoto thyroiditis.

Results of this patient's physical examination, history taking, and ultrasonographic examination reveal no high-risk features. However, her TSH level suggests that she is euthyroid. Thus, the most appropriate initial maneuver is FNA biopsy of the dominant and smaller nodules. It is important to obtain a sufficiently large specimen (defined as 6 or more groups of 10 to 20 well-preserved follicular epithelial cells per group, or at least 2 slides). Smears are interpreted as either benign or malignant in about 85% of patients.¹

Management options for nondiagnostic FNA biopsy results. If a smear is deemed nondiagnostic, repeated FNA biopsy using ultrasound guidance is recommended. As previously stated, by guiding the needle to an appropriate biopsy site, ultrasonography enhances the diagnostic yield of FNA and reduces the likelihood of a nondiagnostic smear from 15% to roughly 3%. Thus, choice D is correct.

What if results remain nondiagnostic or suspicious after FNA has been repeated with ultrasound guidance? This is a difficult situation. Studies have indicated that only about 20% of nodules in such cases prove malignant. Thus, if thyroid surgery is recommended for all such nodules, 80% of the time it will be performed in patients with benign disease. Nonetheless, because there is a roughly 20% incidence of subsequently detected cancers in suspicious nodules, conservative management with repeated ultrasonographic studies (choice C) is not considered adequate.^1,2 In fact, most authorities recommend surgery.

Many strategies to obviate unnecessary surgery in this setting are being investigated. A variety of biochemical and histoimmunologic tests to predict or rule out malignancy have been developed (choice B). The 2 with the best reported results are a test to detect the presence of staining by the human bone marrow endothelial cell (HBME-1), a monoclonal antibody that is directed against human mesothelial cells and that stains thyroid cancer cells, and a test for galectin-3, a protein that is involved in regulation of thyroid physiology and that is expressed only in thyroid cells transformed by malignancy. These tests have achieved diagnostic accuracy rates of 99% in several studies; however, they are not yet accepted or routinely available, and they have not replaced surgery as the procedure of choice in patients with nondiagnostic, suspicious biopsy results.¹

Management of carcinoma of the thyroid gland. When a carcinoma is diagnosed on FNA biopsy, most authorities agree that total thyroidectomy, rather than lobectomy (choice A), is indicated. The reasons for this aggressive approach include:

• The relative safety of this surgery today.
• The need for replacement l-thyroxine therapy in about 50% of patients who undergo lobectomy.
• The definitive, albeit low, incidence of recurrence after lobectomy.^2,3

A recent study of patients with papillary carcinoma demonstrated that in 50% of nodular carcinomatous glands, the tumors were multiclonal (as determined by polymerase chain reaction assay) and thus arose as independent tumors.⁴ These findings further strengthen the case for total thyroidectomy.

Outcome of this case. The patient underwent FNA biopsy, which revealed follicular carcinoma. Results of an evaluation for metastatic disease were negative. A total thyroidectomy was performed without complications. Replacement l-thyroxine was prescribed, which rendered her clinically and biochemically euthyroid. At her 1-year follow-up visit, there was no evidence of recurrence or metastasis.

References:

REFERENCES:

1.

Castro MR, Gharib H. Continuing controversies in the management of thyroid nodules.

Ann Intern Med

. 2005;142:926-931.

2.

Hegedus L. Clinical Practice. The thyroid nodule.

N Engl J Med

. 2004;351: 1764-1771.

3.

Utiger RD. The multiplicity of thyroid nodules and carcinomas.

N Engl J Med

. 2005;352:2376-2378.

4.

Shattuck TM, Westra WH, Ladenson PW, Arnold A. Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma.

N Engl J Med

. 2005;352:2406-2412.