Cost-effective management of thyroid nodules and nodular thyroid goiters. (Featured CME Topic: Thyroid Dysfunction/Disease).

THE PREVALENCE OF THYROID NODULES in the general population has been estimated to be about 5%. Ultrasound and autopsy studies have estimated the prevalence to be as high as 50%, especially in the elderly. Most nodules are impalpable and benign. Only about 10% of nodules are clinically apparent.

The prevalence of thyroid cancer in thyroid nodules is approximately 4% to 6%. Previous studies have indicated a higher prevalence (10% to 30%), probably due to selection bias. A study of surgically resected thyroid tissue indicated the prevalence of occult thyroid cancer to be between 1.5% and 10.0%. (1) Moreover, thyroid cancer accounts for only 0.4% of all cancer deaths. (2) Studies suggest that initially avoiding expensive radiologic studies, combined with early referral to an endocrinologist, is a cost-effective approach. (3) In this review, we discuss an approach that may be adopted in the primary care setting to man age thyroid nodules and multinodular goiters.

CLINICAL EVALUATION OF THYROID NODULES AND NODULAR THYROID GOITER

The clinical assessment of thyroid nodules should include assessment of local symptoms (eg, hoarseness), symptoms of thyroid dysfunction, medical history of thyroid problems/intervention, and family history of thyroid problems. The traditional assumption that growth of nodules suggests cancer has been questioned. A sudden increase in size of a previously noted nodule over a period of a day or more may indicate hemorrhage, whereas cancerous growth is usually progressive over several weeks to months.

A history of head and neck irradiation is especially important to ascertain, since this increases the risk of thyroid cancer. In the 1950s and 1960s, low-dose radiation was given for enlarged tonsils and adenoids, tinea capitis, and thymic enlargement; the incidence of thyroid cancer may approach 50% in these individuals. (4) Interestingly, a high rate of thyroid cancer has been reported in Belarus and the Ukraine because of the Chenobyl nuclear accident. The clinical findings that denote increased risk of malignancy in thyroid nodules are shown in Table 1.

During the clinical evaluation, it is important to consider neck masses arising from nonthyroidal sites. Table 2 lists intrathyroidal and extrathyroidal masses that are included in the differential diagnosis of neck masses. Some masses, such as thyrogiossal cysts, can sometimes be detected by clinical examination (eg, tongue protrusion may make a midline thyroglossal cyst elevate).

While physical examination is an important part of the overall evaluation, its usefulness in detecting malignancy in the early stages is limited. Palpation detects nodules larger than 1 cm and is neither sensitive for detecting thyroid nodules nor a good method for distinguishing benign from malignant nodules.

MULTINODULAR GOITER AND SOLITARY NODULES

Since iodized salt was introduced, the incidence of multinodular goiter has decreased in the United States. In relatively iodine-deficient areas, nodular thyroid disease is widespread.

The presence of compressive symptoms from a large multinodular goiter needs investigation, as outlined in the Figure. The risk of cancer in multinodular goiters has traditionally been assumed to be low. Among nodules identified by ultrasonography, malignancy was noted in 4.7% of solitary nodules and 2.7% of multinodular goiters. (5) A dominant nodule within a multinodular goiter should be evaluated like a solitary nodule. The prevalence of malignancy in cold thyroid nodules of a multinodular goiter may not differ significandy from that of a solitary nodule. (6)

DIAGNOSTIC TESTS IN EVALUATION OF THYROID NODULES AND NODULAR THYROID GOITER

Laboratory Tests

Thyroid function tests should be obtained, though the results of these are usually normal. The thyroid-stimulating hormone (TSH) level is an important determinant of the next step in the investigation, as indicated in the Figure. Thyroid antibody tests may be helpful in the evaluation. Some studies suggest that serum calcitonin levels be obtained. We recommend that this be reserved for patients with higher risk of medullary thyroid cancer. A serum thyroglobulin level can be elevated in both benign and malignant thyroid disease, and is usually of no diagnostic value. It may be useful, however, when the diagnosis of thyroid cancer has been confirmed.

Radiology

A chest film should be obtained. A comparison of the various imaging tests available is given in Table 3. Imaging studies are generally expensive and are not usually not useful in differentiating benign from cancerous lesions.

Thyroid Ultrasonography

High resolution ultrasonography is the imaging method of choice in the evaluation of thyroid gland morphology because it is noninvasive, safe, reliable, portable, relatively inexpensive, and more sensitive than physical examination or other imaging techniques. Thyroid ultrasonography is capable of detecting solid lesions as small as 3 mm in diameter and cystic lesions of approximately i mm in diameter and is able to differentiate between solid (70% of nodules), cystic, or complex nodules. Occult nodules can, therefore, often be detected using this procedure. These are generally benign, and the need for a fine-needle aspiration (FNA) may need to be individualized. High-resolution thyroid ultrasonography shows nodule prevalence of 19% to 46% in the general population (single nodules in about 19.6% and multiple nodules in about 21.5%). (7) Ultrasonography may also have a role in reducing unnecessary further investigation. In one study, thyroid ultrasonography revealed different findings from that of the physica l examination in 63% of patients. (8) Thus, no additional workup may be indicated in the absence of ultrasonographic abnormality Ultrasonography in patients with an apparent solitary thyroid nodule may reveal multiple nodules in 20% to 50% of patients. (9)

Although high-resolution ultrasonography defines thyroid morphology in extensive anatomic detail, in most cases it cannot be used to differentiate benign from malignant disease. Ultrasound-guided FNA is necessary for evaluation of occult thyroid nodules with indeterminate or suspicious ultrasonographic findings. High-resolution ultrasonography may have an added role in patients who refuse FNA or who are on anticoagulants. Moreover, screening ultrasonography in patients with a history of head and neck irradiation is probably justifiable.

Thyroid ultrasonography excels in differentiating solid from cystic masses. High-resolution ultrasonography provides better anatomic delineation, compared with scintigraphic studies of the thyroid. Fifteen percent of solid nodules on ultrasonography may be malignant, whereas in cystic nodules the incidence of malignancy may be closer to 5%. Prevalence of malignancy in cysts measuring less than 4 cm and without solid components is less than 1%, compared with 15% in complex cysts. The ability to follow changes serially (eg, for cystic degeneration) is also a useful feature.

Generally, benign nodules are hyperechoic and have a significant cystic component, a peripheral, eggshell-like calcification, a sonolucent rim, and well-defined margins; whereas malignant nodules are usually hypoechoic, have poorly defined margins, and may contain microcalcifications. Microcalcification within thyroid nodules may be associated with a higher risk of malignancy. The presence of finely stippled calcifications (psammoma bodies) is highly suggestive of papillary thyroid cancer. Patchy calcifications can also be seen in degenerating adenomas and cysts.

Thyroid Scintigraphy

Thyroid scintigraphy is generally more expensive than ultrasonography. Its role in identifying hot nodules and areas of autonomous thyroid function is well established. Hot nodules generally account for less than 10% of clinically evident thyroid nodules. Most hypofunctional cold nodules are benign. Since most thyroid cancers are hypofunctional, scintigraphy is neither sensitive nor specific in differentiating between benign and malignant nodules. Radionuclide studies are generally indicated in the presence of a suppressed TSH level. The study is done with iodine radioisotopes or technetium 99m pertechnetate. Compared with radioiodine, which is taken up and stored as thyroglobulin, pertechnetate is taken up but does not undergo organification and storage. It is, therefore, preferable to perform radioiodine scanning as the initial procedure. Functioning nodules on pertechnetate scans should generally be rescanned using radioiodine. Some clinicians consider using suppression scanning to investigate indetermina te nodules. The TSH level is checked after thyroxine administration. In the presence of a suppressed level of TSH, the persistence of uptake indicates autonomous tissue. An anatomic match of this uptake with the localization of the nodule may be regarded. as evidence of a benign process. Suppression scanning is not advisable in patients with cardiac disease or in the elderly.

Magnetic Resonance Imaging and Computed Tomography

Magnetic resonance imaging (MRI) is superior to ultrasonography in evaluating substernal goiters. Magnetic resonance imaging involves no ionizing radiation; it is noninvasive and easily tolerated but is relatively expensive. Unlike contrast media used with computed tomography (CT), contrast material used in MRI does not influence thyroid function. Computed tomography gives structural information about the thyroid and its relationship to adjacent structures. The high iodine content of the thyroid gives it higher attenuation than the surrounding soft tissue, which is detected by CT and makes CT useful in identifying thyroid extension into the mediastinum. Both MRI and CT have limited roles in thyroid evaluation due to their inability to distinguish benign from malignant thyroid lesions and their relatively high costs.

Fine-needle Aspiration

Fine-needle aspiration of thyroid nodules has emerged as the default diagnostic test. Many have suggested that FNA is a cost-effective initial approach. It has been shown to be superior to ultrasonography in the initial management of thyroid nodules. Fine-needle aspiration of the thyroid is an accurate method to determine the need for surgery in most situations. About 85% of thyroid FNA procedures result in sufficient cellular material for diagnosis. (10) For aspirates considered to be sufficient for diagnosis, the sensitivity and specificity levels are 93% and 96%, respectively, with false-positive and false-negative rates of less than 4%. Fine-needle aspiration results indicate that approximately 60 of thyroid nodules are benign, with 29.5% indeterminate, and 3.4% malignant. (11) To obtain optimal results with FNA, both clinician and cytopathologist experienced in the technique are required. Several passes during the course of the ENA are usually required. A reasonable number of FNAs need to be done annuall y to maintain expertise. There has been no evidence of needle track implantation with the use of FNA.

Ultrasound-guided FNA is an option for occult lesions and is reserved for high-risk groups (those with worrisome imaging, clinical findings, or suspicious history). Transformation of benign nodules into malignant lesions is rare. Although tiny cysts are generally benign, ultrasound-guided FNA can be done in lesions smaller than 1 cm in patients needing diagnostic reassurance. Cyst fluid should always be submitted for cytology. Malignancy is rare in cysts that do not recur after aspiration.

In most patients with occult thyroid nodules, the risk of occult carcinoma is low It may not be advisable to systematically perform ultrasound-guided FNA on all occult nodules unless there is a high index of clinical suspicion. Ultrasound-guided FNA is also useful in evaluating solid hypo-echoic nodules> 1 cm in diameter. (12)

Difficulty may arise in distinguishing benign versus malignant lesions in FNA specimens in the setting of degenerative cysts, follicular, Hurthle cell, and lymphocytic lesions. Fine-needle aspriration of hot nodules, which are generally benign and represent follicular adenomas, may result in indeterminate cytologic findings. This indeterminate category, sometimes referred to as follicular neoplasms, may be reclassified as cancer based on vascular or capsular invasion of tissue obtained at surgery. About 10% to 20% of these lesions turn out to be follicular carcinomas after excision. Cellular and immune markers may prove to be useful in differentiating follicular adenomas from carcinomas. (13,14) Fine-needle aspiration samples can be used for molecular studies to determine the presence of RET oncogenes in inherited thyroid carcinoma. (15) In any event, patients with clinical findings denoting a high likelihood of malignancy may proceed to surgery, independent of the FNA findings.

TREATMENT OF THYROID NODULES AND NODULAR THYROID GOITER

Thyroxine Suppression

The efficacy of thyroxine ([T.sub.4]) in suppressing palpable thyroid nodules has been controversial. Patients with occult thyroid nodules should not be treated with T., suppression therapy unless there is a history of head or neck irradiation. Rapid shrinkage of a nodule after ([T.sub.4]) suppression therapy is generally reassuring; however, shrinkage of a thyroid nodule is not proof of an underlying benign process, since some thyroid cancers also respond by shrinking. (16) A conservative approach may be considered if shrinkage of thyroid nodules is noted after treatment of hypothyroidism. The evidence suggests that T suppressive therapy fails to shrink most nodules, since only 10% to 20% of nodules responded to this treatment. (17) Routine ([T.sub.4]) suppressive therapy is no longer recommended for cytologically benign nodules. Thyroxine suppression can cause or aggravate osteoporosis, especially in postmenopausal women. (18) In elderly patients, suppressive therapy may precipitate thyrotoxicosis. Patents with nodular glands should have their thyroid function monitored for the development of thyrotoxicosis. (19)

Use of Scierosing Agents

Ethanol and tetracycline have been used to treat nodules and cysts. While a reduction in nodule size has been documented using these treatments, they have been less popular in the US due to the potential complications, such as dysphonia, local tissue damage, and fever related to extravasation of these agents.

Radioactive Iodine Treatment

Iodine 131 can be considered for treatment of hot nodules and toxic multinodular goiters. This modality may also have a role in the treatment of compressive symptoms from retrostemal goiters if the patient is not medically fit for surgery. The potential efficacy may be estimated by the extent of uptake on thyroid scintigraphy.

Surgery

Patients with lesions confirmed to be malignant should generally be referred for surgery. Surgery may also be needed if the goiter causes mechanical compression of neck tissues. Endocrinology follow-up with TSH suppression therapy and additional ablation with (131) I may also be needed in cases of differentiated thyroid cancer. Depending on the underlying pathology (eg, lymphoma), there may be a role for chemotherapy and/or radiation. In general, suspicious lesions should also be subjected to surgery.

Many controversies still exist in the management of thyroid nodules. In cases of doubt, endocrinology consultation is advisable.

TABLE 1.

Findings That May Increase Risk of Malignancy in Thyroid Nodules


Solitary, hypoechoic nodule
Cold nodule (hypofunctioning by radioiodine scan)
Cyst >4 cm in diameter or complex cyst
Rapidly enlarging, one nodule is markedly larger
 than the others, or one nodule increasing in
 size despite thyroid hormone treatment
Ipsilateral adenopathy
Irregular, firm, fixed to underlying tissue, poorly
 define margins
Invasion of the capsule or blood vessels, or metastasis
Microcalcifications
Hoarseness with vocal cord paralysis
Age <40 years
Male sex
Female of reproductive age (hormonal factors:
 pregnancy, increased parity)
History of radiation therapy (young age at exposure,
 low-dose radiation, first-degree relative with
 radiation-related tumor)
Inherited tumor syndrome (adenomatous polyposis
 coli, multiple endocrine neopalsia type 2),
 Cowden's disease
TABLE 2

Possible Etiologies of a Thyroid Mass


Extrathyroidal
  Epidermoid cyst
  Lymphadenopathy
  Laryngocele, bronchocele
  Aneurysm
  Branchial cyst
  Cystic hygroma
  Parathyroid adenoma/cyst/carcinoma
  Thyroglossal cyst

Intrathyroidal
  Thyroid adenoma
  Colloid cyst
  Multinodular goiter
  Thyroiditis
  Thyroid carcinoma
  Thyroid hemiagenesis
  Previous surgery
  Previous [I.sup.151] therapy/Marine-Lenhart
   syndrome (tumor recurrence after radioiodine therapy)
  Fibrosis
  Tuberculoma
  Lymphoma
  Metastatic disease
  Amyloidosis
  Hydatid disease
TABLE 3

Comparsion of Diagnostic Tools

Cost($)  Test            Benefits

<250     FNA             Enables definite
                         diagnosis of malignancy
                         Diagnostic accuracy >90%



<250     Thyroid         Guidance for FNA
         ultrasound      Follow size of thyroid
                         nodule
                         Differentiates texture
                         (homogeneous vs
                         heterogeneous, cystic vs
                         solid)
                         Less expensive than other
                         imaging tests




250-750  Thyroid scan    Short half-life (6 hr)
         ([mTc.sup.99])  Low radiation dose
                         Widely available
                         Not stored or organified
                         in thyroid






250-750  Thyroid scan    Less radiation than
         ([I.sup.123])   [I.sup.131]
                         Short half-life (13 hr)
                         Retrosternal
                         visualization
                         Determine foci
                         susceptible to
                         [I.sup.131]









250-750  Thyroid scan    Retrosternal
         (I.sup.131])    visualization
                         8-day half-life allows
                         rescanning days later

















751-950  CT or           Noncontrast study good
         SPECT           for multinodular goiter
                         3-dimensional, good for
                         compressive symptoms
                         Tissue iodine attenuation
                         helps detect deeply
                         positioned metastatic
                         lesions

<950     MRI             As good as CT
                         Good for substernal
                         goiter
                         Gadolinium contrast does
                         not affact thyroid
                         function
                         Nonionizing radiation
                         Noninvasive

Cost($)  Disadvantages

<250     Minor local discomfort
         Less reliable for cystic
         lesions
         Needs experienced surgeon
         and cytopathologist

<250     Operator-dependent
         Very sensitive for
         nodules
         Not good for
         retrosternal,
         intrathoracic goiters
         Does not clearly
         delineate anatomy
         between thyroid and
         adjacent structures
         Cannot diagnose
         malignancy

250-750  Radiation exposure
         Costly
         Difficult with lesions
         in the periphery or
         isthmus
         Normal tissue over
         nonfunctioning nodule
         may mask findings
         Cannot diagnose
         malignancy

250-750  Radiation exposure
         Costly
         Reduced diagnostic value
         (lower percentage uptake
         of labeled iodine related
         to high dietary
         iodine intake from
         widespread use of iodine
         in food preservation)
         Difficult with lesions in
         the periphery or isthmus
         Normal tissue over
         nonfunctioning nodule
         may mask findings
         Cannot diagnose
         malignancy

250-750  High energy gamma
         radiation (image
         quality less than
         that of
         [I.sup.123]
         or [mTc.sup.99])
         Costly
         Reduced diagnostic value
         (lower percentage uptake
         of labeled iodine related
         to high dietary iodine
         widespread use of iodine
         in food preservation)
         Difficult with lesions in
         the periphery or isthmus
         Normal tissue over
         nonfunctioning nodule may
         mask findings
         Cannot diagnose
         malignancy

751-950  Costly
         Cannot diagnose
         malignancy






<950     Expensive
         Cannot diagnose
         malignancy






FNA = Fine-needle aspiration,

CT = comupted tomography,

SPECT = single photon emission computed tomography.

Acknowledgments. We thank Patsy Ellis and Nancy Milligan of the Mountain Home Veterans Affairs Medical Center Library Service.

References

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(13.) Gasbarri A, Martegani MP, Del Prete F, et al: Galectin-3 and CD44v6 isoforms in the preoperative evaluation of thyroid nodules.] Clin Oncol 1999; 17:3494-3502

(14.) Christensen L, Blichert-Toft M, Brandt M, et al: Thyro-peroxidase (TPO) immunostaining of the solitary cold thyroid nodule. Clin Endocrinol (Oxf) 2000; 53:161-169

(15.) Wells SA Jr, Chi DD, Toshima K, et al: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994; 220:237-250

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(19.) Mack E: Management of patients with substernal goiters. Surg Clin North Am 1995; 75:377

From the Mountain Home Veterans Affairs Medical Center and the Department of Medicine, East Tennessee State University, Johnson City.

Reprint requests to Alan N. Peiris, MD, PhD, East Tennessee State University, Department of Medicine, P0 Box 70622, Johnson City, TN 37614.