The Thyroid Nodule

The terms cold and hot are commonly used to describe the functional activity of thyroid nodules as revealed by scintigraphy. These descriptors refer to the apparent amount of radionuclide in the lesion relative to that in surrounding normal thyroid tissue. Until recently, this distinction was diagnostically important to identify thyroid cancer. Nearly all malignant tumors in the thyroid concentrate less radioiodine or ^99mTc than the normal gland and therefore appear cold (hypofunctional). However, since many benign tumors and nontumorous nodules are also cold, that characteristic is now of limited clinical use because of the advent of fine-needle biopsy (FNB). Now “hot versus cold” is important in the choice not to do an FNB in patients with a nodule when TSH is low and the nodule is hot; hot nodules are very rarely malignant, and the biopsy may be misleading by incorrectly suggesting malignancy (Fig. 7-2).

The term warm nodule is ambiguous and not helpful in assessing the risk of cancer. The term should not be used. A nodule that is not clearly delineated on a scintiscan may in fact be a cold nodule that is too small or too close to normal activity to be distinguishable from surrounding normal thyroid tissue. In general, a cold nodule must be almost 1 cm or larger in diameter to be detected by pinhole imaging.

Because the great majority of nodules are cold on radioisotope scintiscanning, and such cold nodules may be either benign or malignant, it is not cost effective to obtain a scintiscan as the initial diagnostic test in a euthyroid (normal TSH) patient with a nodule. A fine-needle aspiration (FNA) biopsy is usually performed first. However, when the FNA result indicates sheets of follicular cells that do not look malignant but could be a tumor, scintigraphy may be helpful to identify a hot nodule, thus avoiding surgery.

There are two kinds of hot nodules. The majority of them are reactive to elevated TSH in an otherwise failing thyroid gland and thus are compensatory. These are called hyperplastic nodules. The hot nodules associated with low TSH are autonomous nodules. They function autonomously because the TSH receptor of the thyroid cell has mutated and does not require TSH to stimulate cell activities such as the production of thyroxine or cell replication and nodule growth. The clone of the mutated cells is a benign tumor, which is the nodule, and may grow large enough over time to lead to hyperthyroidism (“toxic” nodule, TAN). When TAN-produced thyroid hormone levels increase, TSH falls, leading to suppression of the normal paranodular tissue in both thyroid lobes.⁵ The chance of malignancy in a hot nodule is less than 1%.¹ Therefore, when TSH is undetectable in a patient with a thyroid nodule, a scintiscan may be the next appropriate test. In some cases, a hyperfunctioning nodule undergoes degeneration or hemorrhage, and therefore part of it, or uncommonly all of it, becomes hypofunctioning or cold. Some of the reported instances of cold areas in a hot nodule are in fact cases of small, coexisting carcinomas in close proximity to a larger, benign hot nodule. Although documented cases have been reported in which the entire hot nodule is malignant, these cases are quite rare.

Occasionally, follicular neoplasms (including follicular adenomas and even some carcinomas) may appear hot on a ^99mTc-pertechnetate image but cold on a radioiodine image, presumably because such tumors are able to trap but do not organify iodine. This type of discordance between ^99mTc and radioiodine images occurs infrequently and must be recognized when ^99mTc is used for thyroid scintiscanning.5–7

In the past, one spoke of a solitary thyroid nodule. We assumed incorrectly that if the rest of the thyroid gland was normal to palpation, it was free of nodules. Examination by ultrasound and correlation with pathology have disclosed that nonpalpable nodules occur commonly when a dominant nodule has been palpated.

Multinodular Goiter

Scintiscanning by itself does not reveal the etiology of a multinodular goiter. Scintiscanning has a role in the diagnostic assessment of multinodular goiter in some patients. When the nodules are discrete and larger than 1 cm in diameter, the scintiscan reveals the functional activity of a particular nodule relative to that of paranodular tissue (Fig. 7-3). When a nodule is clinically dominant—that is, a nodule that on palpation or by ultrasonography is different from the other nodules or is growing faster—the finding on scintiscan that this nodule contains all or most of the functional activity helps to guide management. Such a functioning nodule is unlikely to be malignant. When a multinodular goiter is large and causes symptoms and signs of compression of the trachea or esophagus, scintiscanning may complement other imaging modalities such as MRI or sonography. Either of the latter two methods depicts the extent of the goitrous mass, but only scintiscanning can reveal functioning tissue, information that is often helpful in making therapeutic decisions such as surgery or ¹³¹I therapy.

In a hyperthyroid patient with a nodular goiter, there may be several different patterns on scintigraphy. The image may show many functioning, widely dispersed nodules, generally smaller than 0.5 cm, that have a salt-and-pepper appearance; a coarsely patchy distribution may be evident, or a uniform pattern of uptake not unlike that of Graves’ disease can be seen. In contrast, there may be a cold zone correlating with a nodule that should be evaluated by other means, such as sonography and aspiration biopsy.

In a hypothyroid patient with nodular goiter, the uptake is usually low (unless there is iodine deficiency or dyshormonogenesis), and thus the scintigraphic image shows a “patchy” distribution of radioisotope because of low “counts” that result in poor scan statistics. However, scintigraphy may be of clinical value to identify a reactive, hyperplastic, functional area that is rarely malignant.

Diffuse Goiter Including Graves’ Disease

Assessing the thyroid uptake of radioiodine is diagnostically important to differentiate the low accumulation of the tracer in silent thyroiditis and its high accretion in hyperthyroid Graves’ disease and for precise dosimetry of ¹³¹I therapy. However, thyroid scintiscanning usually is not clinically useful in diffuse goiters. If assessing size is desired, an ultrasonogram offers superior results. Yet, some clinicians order scintiscans for patients with Graves’ disease.

The pattern of isotope accumulation in Graves’ disease usually is uniform, but irregular distribution may occur, especially in a geographic region where goiter is endemic. The heterogeneity should not be misconstrued as reflecting toxic nodular goiter when the clinical setting and serologic tests are more consistent with Graves’ disease. At times, a patient with Graves’ disease may have a palpable thyroid nodule or an unusually firm area, or a nonisotopic neck-imaging procedure might have disclosed an incidentaloma (discussed later) that leads to scintiscanning to assess whether it is cold, in which case sonography and aspiration biopsy might be appropriate. Similarly, a “routine” scintiscan might have revealed a cold area that should be investigated.

Substernal Goiter

A substernal goiter is suspected when chest radiographs or CT reveal an anterior mediastinal mass. A positive radioiodine scintigram definitively identifies such a mass as thyroid tissue. ¹²³I or ¹³¹I is preferred over ^99mTc in such cases because of interference by circulating ^99mTc in the mediastinal blood vessels. SPECT (using ¹²³I) is of particular value in visualizing substernal thyroid tissue and SPECT/CT or MR can precisely localize it to an anatomical structure.

Scintigraphy in Patients With Thyroid Carcinoma

In general, thyroid carcinoma takes up and retains radioiodine much less efficiently than normal thyroid tissue does. Therefore, most thyroid cancers are cold nodules. However, after the thyroid gland has been removed surgically and under the stimulation of elevated TSH levels and iodine deprivation, the uptake in differentiated thyroid carcinoma is often sufficiently high to permit detection by scintigraphy and therapy with ¹³¹I. Thus diagnostic imaging with radioiodine is indicated for patients who have recently undergone thyroid surgery for differentiated thyroid carcinoma. The rationale for imaging in such patients is to identify and quantify uptake in the thyroid remnant and to detect any functioning metastases in the neck or in distant sites. This information helps to determine the amount of ¹³¹I that should be administered to ablate the normal remnant and treat functioning metastases.

To stimulate uptake of radioiodine by malignant thyroid tissue, it is necessary to raise serum TSH levels to 30 mU/L or higher.⁷ In routine practice, levothyroxine therapy is discontinued for 5 to 6 weeks before administration of the diagnostic dose of radioiodine for imaging. To shorten the period of hypothyroidism, liothyronine (triiodothyronine [T₃]) is often given (25 to 50 µg/day in divided doses) for 3 weeks after discontinuation of levothyroxine therapy. T₃ therapy is discontinued 2 weeks before radioiodine administration. Alternatively, it is possible to prepare patients by giving their usual thyroxine dose every other day for 6 weeks, which induces mild hypothyroidism and raises the level of TSH to about 50 mIU/L.

Recently, recombinant human TSH (rhTSH, Thyrogen, Genzyme Corp., Cambridge, MA) has been developed and in clinical trials has been shown to stimulate uptake of ¹³¹I by thyroid remnants and metastases and to raise serum thyroglobulin (Tg) levels in patients who remain euthyroid while taking thyroid hormone therapy.8,9 The Food and Drug Administration has approved the use of rhTSH for radioiodine imaging and serum Tg testing in such patients and for the destruction (ablation) of thyroid tissue that remains after a total thyroidectomy has been performed because of thyroid cancer.

Patients who are scheduled to undergo diagnostic whole-body scintigraphy are advised to follow a low-iodine diet for at least 7 to 10 days before administration of the radioiodine. A simple low-iodine diet has been described.¹⁰ It is even more important to avoid iodine-containing medications and radiographic contrast agents.

Diagnostic administration of ¹³¹I may reduce the uptake of subsequent therapeutic ¹³¹I by normal thyroid remnants or functioning metastases. This phenomenon, which has been termed stunning, seems to involve a sublethal, presumably temporary suppression of iodine uptake (reviewed elsewhere11,12). To avoid stunning, many authors recommend limiting the quantity of ¹³¹I given for diagnostic imaging to 2 mCi (74 MBq)^11,13 or even less.¹⁴ An alternative is to use ¹²³I for whole-body imaging,¹⁵ but the present cost of this radionuclide in millicurie amounts is prohibitive for many centers. While ¹²³I offers superior imaging of deposits of thyroid tumor in the neck when compared to ¹³¹I, its efficiency for deposits deep in the rest of the body remains to be established convincingly.

Physicians who interpret whole-body radioiodine scintigrams must be familiar with the distribution of inorganic iodine in the blood pool and extracellular fluid and its dynamics over time, the normal, nonthyroid sites that accumulate the radioactive iodine tracer, and the behavior of isotope-labeled thyroxine that has been produced in thyroid gland or metastases. The salivary glands, gastric mucosa, kidneys, and lactating breasts concentrate iodide but do not convert it to thyroxine. Nasal secretions, saliva, sweat, urine, stool, and milk may contain high concentrations of inorganic radioiodine and can cause artifacts, depending on the time after isotope administration. Skin and hair are easily contaminated with saliva, urine, or vomitus. Radioiodine-labeled thyroxine is observed later than inorganic iodide and has a different pattern of distribution, including the liver as part of the enterohepatic circulation of thyroxine. Nonthyroid tumors, inflammatory lesions, and cysts may occasionally contain radioiodine as part of their vasculature and result in a false-positive scintigram.11,16

In interpreting ¹³¹I planar whole body scans, there may be atypical or cryptic findings. ¹³¹I SPECT/CT is useful to characterize challenging foci more accurately, differentiate thyroid cancer from physiologic activity or nonthyroid pathology, and reduce false positives. By identifying nonthyroid cancer activity, SPECT/CT can reduce inappropriate treatment with ¹³¹I.

¹³¹I scanning is not 100% sensitive for metastatic thyroid carcinoma. In some series, the rate of false-negative radioiodine scans approaches 35%.¹⁷ When diagnostic ¹³¹I scans are negative and metastases are suspected on the basis of elevated serum Tg levels, some advocate empirical treatment with ¹³¹I. Scans that are done 1 week after ¹³¹I therapy are frequently positive in these cases (reviewed by Clark and Hoelting¹⁸) (Fig. 7-4). Indeed, a routine pre-ablation scan after thyroidectomy for thyroid cancer may not be cost effective. Therefore, many centers employ a protocol of administering a standard therapeutic dose of ¹³¹I without prescanning and perform the whole body scan a week later. This protocol is limited by an inability to do dosimetry for the treatment, which some authorities deem essential, and fails to assess for undetected metastases in the head or spine, which may swell after ¹³¹I and cause neurologic complications.

It is useful in ¹³¹I scan-negative, Tg-positive patients to search for metastases by performing sonography of the neck and, if negative, performing MRI of the neck and chest. Especially if ¹³¹I therapy is anticipated, contrast CT studies are not employed, but noncontrast CT may suffice. The aim is to find metastases that either are surgically accessible or can be treated by external radiotherapy, if appropriate. When the above imaging techniques do not reveal a source of the elevated Tg, scintiscanning with other radiolabeled agents or fluoro-deoxyglucose (FDG)-PET scanning may succeed in localizing ¹³¹I-negative metastases¹⁹ (see Table 7-2).

Thallium (²⁰¹Tl) has been useful in localizing metastases in selected patients (reviewed by Cavalieri¹² and Sisson¹⁹). However, ²⁰¹Tl is concentrated by a variety of benign and malignant lesions other than thyroid carcinoma.

^99mTc-sestamibi (MIBI) is a cationic, lipophilic agent that concentrates in normal and neoplastic thyroid tissue and in a variety of other cancers. Experience indicates that like ²⁰¹Tl, ^99mTc-MIBI can be useful in ¹³¹I-negative patients in whom one has reason to suspect persistent or recurrent tumor.19,20 ^99mTc-MIBI is the agent of choice for imaging Hürthle cell carcinoma, which typically takes up radioiodine poorly.²¹

Other agents that have been shown to concentrate in some metastatic differentiated thyroid tumors are ^99mTc-tetrofosmin, which like MIBI is a myocardial perfusion imaging agent, and ^99mTc-labeled dimercaptosuccinic acid in the pentavalent form (DMSA [V]) (reviewed by Sisson¹⁹). Clinical experience with these agents is still limited. Indium-111-labeled octreotide is used to localize metastatic medullary thyroid carcinoma.²²

¹⁸Fluoro-2-Deoxyglucose Positron Emission Scanning

¹⁸F-fluoro-2-deoxyglucose (¹⁸FDG), a radiolabeled analogue of glucose, is actively concentrated in a variety of malignant tumors, including thyroid carcinoma.^{23 18}FDG uptake tends to be higher in thyroid tumors that are not well differentiated, in contrast to ¹³¹I, which is accumulated by differentiated cancers. For this reason, ¹³¹I-negative tumors are more often positive with ¹⁸FDG, and ¹⁸FDG-negative tumors tend to be positive with ¹³¹I.^{23 18}FDG-PET scans show low background in the chest and liver, which gives this agent a relative advantage over ²⁰¹Tl and ^99mTc-MIBI. Enhanced clinical value of PET images is obtained when they are fused with CT or MRI images. The last section of this chapter, Positron Emission Tomography and Bimodality CT or MRI Fusion Scanning, offers an in-depth discussion of the subject.

Technical Aspects

Sonography uses high-frequency sound waves (ultrasound) in the megahertz range to produce a photographic image of the internal structure of the thyroid gland and its region.24,25 No ionizing radiation is involved, nor is iodinated contrast material given. Sonography is safe; tissue damage has not been reported, and it is less costly than other imaging procedures. Preparation of the patient for the procedure is unnecessary, and it is performed without discontinuing TSH suppressive therapy. To image the thyroid gland and surrounding regions, the patient’s neck is examined in the sagittal, transverse, and oblique planes with a probe called a transducer that both generates the sound energy and receives the reflected signal. The sound enters the body and is transmitted or reflected by interfaces within the tissues. Air does not transmit ultrasound, and calcified areas block its passage. The images are produced quickly and are assembled electronically in “real time.” Each frame of the sonogram shows a static image, and sequential pictures depict motion. Swallowing is used to elevate the thyroid to examine the lower pole of an enlarged lobe, and this maneuver may facilitate identification of the esophagus. With the use of a signal having a frequency of 7.5 to 12 MHz, thyroid nodules and lymphadenopathy as small as 2 to 3 mm are identified in shades of gray. Dynamic information such as blood flow is added by using physics principles called the Doppler effect.²⁶ The signals are translated into colors to differentiate static fluid-filled cystic spaces and blood flowing through the vasculature. Thus the direction and velocity of flow and the degree of vascularity are revealed. Color is assigned to the signal by assuming that venous flow is parallel to, but in the opposite direction to, arterial flow. Arterial signals are made red, and the accompanying venous signals are made blue. The shade of a color is proportional to the direction of flow as it relates to the transducer and flow velocity.

Routine protocols for ultrasound scanning by a technologist are not satisfactory but unfortunately are used too often, degrading the value of the test. Rather, the ultrasound operator must be experienced and aware of the clinical question that has been posed to provide an appropriate answer. Close supervision by a sonographer-physician or endocrinologist who is expert in physical examination and ultrasonography is needed.

It is important to comprehend that the optimal clinical value of sonography depends on the quality of the ultrasound examination, including the maturity of the examiner and the characteristics of the equipment. Grossly misleading results are common with quick, incomplete studies and unsophisticated machines or readouts. Therefore, routine sonography in a medical or radiology office will require proper preparation of the professional and technical staff. Without study, training, and experience, there are likely to be unacceptable results and adverse outcomes.

Sonography of the Normal Thyroid Gland and Environs

With standard gray-scale technique, the normal thyroid gland has a homogeneous appearance like ground glass (Fig. 7-5). The surrounding muscles are of equal or lower echogenicity. Tissue planes are identified. The air-filled trachea, which does not transmit the ultrasound signal, is poorly imaged, and dense echoes represent its calcified tracheal ring anteriorly. The carotid artery and other blood vessels are echo-free unless calcified. Lateral and anterior to the carotid arteries is the jugular vein, which is frequently collapsed and can be identified when it is distended during a Valsalva maneuver. Small blood vessels on the surface of the thyroid and the inferior thyroid artery and vein can sometimes be seen. Color Doppler enhances the identification of blood vessels and flow. The esophagus is sometimes detected behind the thyroid and left of center, anteromedial to the longus colli muscle. It can be observed to distend after the patient swallows a sip of water. Lymph nodes can be seen normally as less than 1 × 3 mm, elliptical, uniform structures with an echo-dense central hilum. The parathyroid glands are not visualized unless they are enlarged. They are less dense to ultrasound than the thyroid gland because of the absence of iodine.

Generally, imaging procedures are not useful in patients whose thyroid gland is normal to palpation unless the patient has a history of exposure to therapeutic irradiation in youth or metastatic thyroid cancer has been discovered and a primary lesion in the gland is being sought. However, in selected circumstances, an ultrasound image may be used to supplement or confirm physical examination findings and identify the size and shape of regional structures accurately and relatively inexpensively. This test is useful when thyroid anatomy is in question but clinical perception is confused by obesity, great muscularity, distortion by abnormal adjacent structures, tortuous blood vessels, a prominent thyroid cartilage, metastatic tumor, lymphadenopathy, prior surgery, or examiner inexperience. On the other hand, the sonogram is so sensitive that many small, nonpalpable thyroid nodules may be detected. Management of these nodules, which are called incidentalomas, requires mature clinical judgment. Objective diagnostic evaluation of all of them is needless and impractical. Selective attention to those found in a patient with a high risk of cancer, those with special characteristics frequently seen in cancers, or those that grow is prudent. Neglecting all of them is inappropriate and occasionally dangerous.

Sonography When There Is Thyroid Enlargement (Goiter)

Enlargement of the thyroid gland is common. In general terms, enlargement may be diffuse and symmetrical, asymmetrical, smooth and uniform, or nodular. It is not generally necessary to obtain a sonogram to confirm thyroid enlargement unless a specific question has attracted clinical concern. Such questions may involve a dominant nodule, a tender spot, focal hardness, or substernal extension. At times, a physician may obtain a sonogram to explain a cryptic finding, such as differentiating goiter from fat or muscle, documenting a controversial observation, estimating the size of the thyroid gland for ¹³¹