Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

12.In vivo Radionuclide Tests and Imaging

I. Ross Mcdougall

The late Ralph Cavalieri was coauthor of this chapter for the sixth through eighth editions of The Thyroid. He is missed enormously. I hope he would have been in support of the additions, edits, and changes that have been made for this edition. The chapter covers the physical characteristics of radionuclides and radiopharmaceuticals that have a clinical role in nuclear imaging of the thyroid. Imaging instruments, including the gamma camera, rectilinear scanner, and positron emission tomographic camera (PET), are described briefly. The method for thyroid uptake measurement and routine scintigraphy for imaging the thyroid are discussed, and the scintigraphic findings in normal and disorders of the thyroid are presented. The role of diagnostic and posttreatment whole-body scintigraphy in patients with thyroid cancer is described. Controversies, including stunning and the role of radiopharmaceuticals for management of patients whose cancers do not trap iodine but secrete thyroglobulin (Tg) (iodine negative/Tg positive), are discussed.

RADIONUCLIDES FOR MEASUREMENT OF THYROID UPTAKE AND SCINTIGRAPHY

In regions with adequate dietary iodine, a normal thyroid traps about 10% to 35% of ingested radioiodine. The trapping mechanism is the sodium-iodide symporter (NIS) (1,2,3). The thyroidal NIS is regulated by thyrotropin (TSH). In contrast, NIS in other tissues such as salivary gland and breast is not under the control of TSH (3). The NIS cannot differentiate radioactive iodine from nonradioactive iodine (127I). Therefore, tracers of radioactive iodine are trapped, organified, and incorporated into thyroid hormones like 127I. There are more than 20 radionuclides of iodine, but only 123I and 131I are in widespread clinical use. 124I and 125I have physical properties that could be beneficial in selected situations, and they could become more important (4). The physical characteristics of these radionuclides are shown in Table 12.1. Because 123I has a relatively short half-life and emits only γ photons, it is preferred for diagnostic testing. It has been used for thyroid uptake and scanning and more recently for whole-body scans in patients with differentiated thyroid cancer. The 159 kev γ photon is almost ideal for scintigraphy with a gamma camera. 123I is the radionuclide of choice for uptake measurements and for routine scintigraphy (5). In contrast, 131I has a half-life of 8 days and emits β particles as well as high-energy γ photons. 131I is therefore suited for therapy, but the γ photons can be imaged, and 131I has a role in diagnostic and posttreatment whole-body scanning in patients with thyroid cancer. The use of131I for routine thyroid scintigraphy is discouraged because the radiation dose is about 100 times greater than that of 123I, although it is legitimate to administer a 5 to 10 µCi tracer of 131I to measure uptake prior to treatment of thyrotoxicosis. However, 123I is preferred. Recently, there has been increasing interest in the use of 123I for whole-body scintigraphy, as discussed in the section on cancer (6,7,8).

TABLE 12.1. RADIONUCLIDES USED FOR IN VIVO THYROID STUDIES


Radionuclide

Half-life

Radioactive Emissions

Prescribed Dose, mCi (MBq)

Radiation to Thyroid, Rads/mCi (cGy/MBq)

Clinical Uses


127I

Nonradioactive

None

 None

Fluorescent scanning

123I

13.2 hr

γ159 kev

0.1–0.4 (3.7–14.8)

12 (0.32)

Routine thyroid scanning

 1–10 (37–370)

Whole-body scanning

131I

8.09 d

γ 364 kev (90%)

1–5 (37–185)

1, 330 (36)

Whole-body scanning

 637 kev β

5–20 (185–740) 30–300 (1.1–11.1 GBq)

Therapy benign and malignant thyroid diseases

124I

4.2 d

β+ positron emitter

890 (24)

Whole-body scanning and dosimetry

125I

60 d

γ 25–35 kev Auger electrons

10–20 mCi (370–740)

790 (21)

In vitro Possibly therapy

 X-rays

Larger doses for cancer (has not been used but theoretically has a role)

 99mTcO4

6 hr

γ 140 kev

1–10 (37–370)

0.23 (0.006)

Widely available, used for routine imaging and uptake


aRadiation exposures, in centiGy (cGy) (= rads) per MBq administered, for radioiodines were calculated using the following assumptions: thyroid gland weight, 20 g (normal adult); maximum uptake, 25% of dose; half-time of uptake, 5 h; and biologic half-life in gland, 65 d. In children, the radiation exposure to the gland is threefold to fivefold higher than in adults. The value for 123I assumes no contamination with other radioiodines. The exposure calculations for radioiodines came from MIRD: Dose estimate report no. 5 (J Nucl Med 1975;16:857) and those for 99mTc from MIRD: Dose estimate report no. 8 (J Nucl Med 1977;17:74).

124I is a positron emitter and, with the recent expansion in experience and availability of PET scanners, there will be increasing interest in this radionuclide. 124I PET scanning, in addition to producing high-resolution images, can be used for volumetric and quantitative measurements (9). 125I has primarily been used for in vitro testing because its low-energy emissions are not suited for imaging with a standard gamma camera. It has been used to treat thyrotoxicosis, and clearly the low-energy Auger electron emissions can deliver sufficient radiation to kill cells (10). In theory, it could be used to treat small pulmonary metastases of functioning thyroid cancer by delivering the radiation at a subcellular level to the cancer cells, yet avoiding radiating the normal lung.

For testing and treatment, the radionuclides of iodine are administered by mouth, although they can be administered intravenously. In routine thyroid testing, uptake measurements are generally made after 24 hours; many physicians also obtain an early measurement after 4 to 6 hours. In patients with thyroid cancer, whole-body scans and uptakes are made after 24 hours when 123I is given, although 48-hour measurements are possible when larger doses are given (185 to 370 MBq) (11,12). When 131I is given, the scan and uptake are obtained after 48 to 72 hours.

123I is not universally available, and many authorities recommend technetium pertechnetate (99mTcO4) for routine thyroid imaging. 99mTcO4 is trapped by the NIS, but it is not organified (13). 99mTcO4 is administered intravenously, and uptake and scan are obtained after 15 to 20 minutes. Some other differences between 99mTcO4 and 123I are discussed later in the chapter. Most nuclear medicine laboratories have 99mTcO4 available. Its availability, plus its low cost, makes it an attractive alternative to 123I.

OTHER RADIONUCLIDES AND RADIOPHARMACEUTICALS

Several noniodide radiopharmaceuticals are used for the evaluation of patients with thyroid disorders. These include thallium-201 (201Tl) (14,15), 99mTc-methoxyisobutylisonitrile (99mTc-sestamibi) (16,17), and 99mTc-tetrafosmin (18,19,20). These agents were introduced for imaging the myocardium, but they are also concentrated by follicular cells—especially cancer cells. 111In-pentreotide, an analogue of somatostatin, has a role in imaging medullary thyroid cancer and differentiated cancers that do not trap iodine (21,22). Pentavalent dimercaptosuccinate acid (99mTc-DMSA) is used in Europe for imaging medullary cancer, but this agent is not approved in the United States (23). One of the minor roles of these radiopharmaceuticals has been to differentiate benign from malignant thyroid nodules. They have also been used in the follow-up of patients who have had treatment for thyroid cancer. The benefits and shortcomings of the cancer-seeking radiopharmaceuticals in these situations are discussed later in this chapter. 18F-fluorodeoxyglucose (18F-FDG) is a positron (β+)-emitting radiopharmaceutical that has gained an important place in the staging and management of several cancers, including lymphoma, non–small-cell lung cancer, melanoma, head and neck cancer, colorectal cancer, and breast cancer (24,25,26). 18F-FDG is useful in patients whose thyroid cancers are unable to trap iodine and has recently been approved in the United States for this purpose (27).

INSTRUMENTS

The simplest instrument for measurement of thyroid uptake, which is discussed later in the chapter, is a probe with a single thallium-activated sodium-iodide crystal. For routine imaging, most nuclear medicine physicians recommend a gamma camera with a pin-hole collimator that has an aperture of < 5 mm. The patient lies supine with the neck extended. The collimator should be at the same distance for all studies, except in the case of a large goiter, which cannot be imaged totally within the field of view. The gamma camera produces images of high quality with either 123I or 99mTcO4, provided 30,000 to 50,000 counts are acquired for 123I images and 100,000 to 200,000 counts are acquired for 99mTcO4 images, or replace imaging is continued for 10 minutes. The patient should be examined at the time of scintigraphy to ensure that a finding such as a nodule is correlated with the scintigraphic finding. A radioactive marker can be placed at the edges of a nodule and an image obtained of the marker superimposed on the thyroid image (Fig. 12.1). Markers can be used to identify anatomic sites such as the manubrium and thyroid cartilage. The gross anatomy can also be demonstrated by placing a source of radiation behind the patient; this produces a transmission scan (Fig. 12.2).

FIGURE 12.1. Left panel: Image of an enlarged thyroid obtained 24 hours after oral administration of 200 µCi (7.4 MBq) of 123I. Right panel: Includes radioactive markers placed by the examiner at the upper and lower poles of the gland. This demonstrates that what is seen on the scintiscan corresponds with what is palpated.

FIGURE 12.2. A transmission scan. The patient has had a thyroidectomy for thyroid cancer. The image is a diagnostic scan after 2 mCi (74 MBq) of 131I. There are two small areas of uptake in the thyroid bed and one in the mediastinum. These would be difficult to position without some anatomic landmarks. This is achieved by putting a source of radiation behind the patient—in this case, a cobalt source used daily for obtaining quality-control images for each gamma camera.

Some clinicians prefer the rectilinear scanner over the gamma camera for imaging the thyroid. The main reason is that the image is life size. However, the resolution of a rectilinear scanner is inferior to a modern gamma camera. In one comparative study the gamma camera had better sensitivity (97% vs. 69%), specificity (90% vs. 86%), and overall accuracy (94% vs. 77%) (28). It is impossible to obtain oblique images with a rectilinear scanner; oblique, or lateral, scintiscans can help define the presence of a nodule and determine its function (29). Tomographic scanning with a gamma camera is important in many aspects of nuclear medicine—for example, in evaluation of myocardial perfusion, cerebral function, and back pain. This technique is called single photon emission computed tomography (SPECT in the United States, or SPET in Europe). The camera head rotates around the patient 180 degrees to 360 degrees. The image is produced by back-projecting the data and using algorithms similar to those used for computed tomography (CT). Coronal, sagittal, and transaxial slices can be obtained. SPECT scanning improves resolution (30). It provides volumetric measurements that can help when the thyroid size is used for dosimetric calculations for treatment. One study found that the thyroid volume determined by SPECT was 108% of the actual size of the surgically removed glands (31). In another study of 25 patients with Graves' disease, planar imaging, SPECT, and ultrasound were compared with magnetic resonance imaging (MRI) in determining the volume of thyroid. MRI was considered to be the gold standard. Volumes calculated from planar images were quite inaccurate, giving an average of 35.2 mL compared with 25 mL by MRI. SPECT gave an average volume of 29.6 mL (32).

Gamma cameras capable of SPECT imaging have been equipped with a pinhole collimator. These instruments produce very high resolution and are able to identify nodules that could not be felt or identified on planar images (33). SPECT does not add information in patients with palpable nodules.

The low photon energies emitted from 125I cannot be imaged by conventional gamma cameras. However, Beekman et al have recently designed a pinhole camera that can detect 125I with a resolution of 0.2 mm for imaging small animals (34). Advances in instrumentation continue and will be translated into clinical use.

In patients with differentiated thyroid cancer who are candidates for 131I treatment, a dual-headed gamma camera capable of whole-body scanning provides anterior and posterior whole-body scans after diagnostic doses of 123I or 131I, and after 131I therapy. Whole-body scans are easier to interpret than multiple spot views. When the radionuclide is 131I, a high-energy collimator is advised because the 364 kev photons of 131I pass through the lead septa of a medium-energy collimator, resulting in images that are badly degraded.

With increased use of positron-emitting radiopharmaceuticals, including 18F-FDG and 124I, a dedicated PET camera provides better resolution than a hybrid PET/gamma camera (35). The reason is that positrons (positive electrons), when emitted from a source, travel a very short distance and interact with electrons in the patient (negative charge). The positive and negative electrons of equal mass annihilate one another. The mass of the two electron particles is transmuted into two photons, each with 511 kev of energy. These photons travel at an angle of 180 degrees. Positron cameras usually have a ring of detectors surrounding the patient and electronics capable of identifying coincident photons, i.e., photons arriving at the same time and detected by opposing detectors. Modern PET scanners have an intrinsic resolution of < 5 to 6 mm. A recent development has been the combination of a PET with a CT scanner. The CT images are used for attenuation correction of the PET images. They also provide anatomic correlation for the functional PET scans (Fig. 12.3).

FIGURE 12.3. This figure shows the format of combined positron emission tomograpy/computed tomography (PET/CT) whole-body camera. The scan was used to evaluate the efficacy of chemotherapy for a nonthyroidal cancer. The central image is the PET scan, completed 1 hour after intravenous injection of 15 mCi (555 MBq) of 18F-fluorodeoxyglucose. It shows physiological uptake in the myocardium, liver, urinary tract, and faintly in the muscles and skeleton. The intense uptake in the thyroid is characteristic of autoimmune thyroid disease, usually Hashimoto's thyroiditis. Left panel: CT which is used for attenuation correction of the PET images and for anatomic correlation. Right panel: Superimposition of the PET and CT images, combining function and anatomy.

Miscellaneous instruments include handheld probes that can be used during surgery to identify focal sites of radioactivity. These instruments are used for sentinel node imaging after local injection of 99mTc sulfur colloid around the cancer. Sentinel node imaging is widely used for breast cancer and melanoma, and has been used in selected patients with thyroid cancer to identify the sentinel node, which, if it does not contain cancer, makes it likely that secondary nodes are also free of cancer (36). Handheld detectors have also been used in patients who have been treated with 131I, and that radionuclide is used as a road map for the surgeon as an aid to determine which tissue should be excised (37).

Fluorescent scanners detect nonradioactive iodine 127I. The scanner has a source of radiation, usually americium (241Am), that emits photons with energies greater than the energy holding the K shell electrons of 127I in their orbits (38). The photon energy of 241Am of 59.6 kev ejects a K shell electron. The vacancy that results from the ejected electron is subsequently filled by an electron from the L shell. There is a difference in binding energy between the L and K electrons of 28.5 kev, and this energy is emitted as a fluorescent X-ray. The fluorescent scanner detects these x-rays and constructs an image that is representative of the quantity of 127I in the gland (39).

THYROID UPTAKE: INDICATIONS AND PRINCIPLES

Measurements of thyroid uptake of radioiodine provide valuable information in the clinical situations listed in Table 12.2 (40). A known amount of tracer is administered orally, and the percentage accumulated at designated times is measured using either a probe or gamma camera. The fractional uptake is a function of the NIS, the rate of binding of iodine within the thyroid, and the rate of release of iodine from the thyroid. The uptake over the first hour reflects trapping. Measurements up to 6 to 8 hours reflect uptake, oxidation, and organification, and later measurements depend on the balance of organification and release of radioiodine from the thyroid. In a hyperthyroid gland, the uptake can be higher at 4 to 6 hours than at 24 hours, but it is unusual to have an abnormal value early and a normal value at 24 hours. It is almost a universal procedure to obtain a 24-hour measurement, but the early 4- to 6-hour measurement allows the clinician to identify a thyroid with rapid turnover. Some authorities obtain only an early measurement and by extrapolation calculate the 24-hour value (41). The uptake is often used in the determination of therapy doses of 131I to treat patients with Graves' thyrotoxicosis or toxic nodular goiter (42). A single early measurement allows for 1-day measurement of uptake and treatment. The author prefers the 24-hour value and finds the benefit of 1-day therapy is balanced by the opportunity to consult twice with the patient to ensure all clinical questions, follow-up arrangements, and legislative requirements related to radiation safety are answered.

TABLE 12.2. INDICATIONS FOR THYROID UPTAKE MEASUREMENT AND IMAGING


Indications for measuring thyroid uptake


To confirm the diagnosis of hyperthyroidism

To distinguish other causes of thyrotoxicosis from hyperthyroidism

To provide data for calculation of a therapeutic dose of 131I

To detect intrathyroidal defects in organification

Indications for thyroid imaging


To compare structure and function of the thyroid

To differentiate different types of thyrotoxicosis

To determine whether a nodule is functioning

To determine whether a cervical or mediastinal mass contains functioning thyroid

To identify ectopic thyroid

To aid in the diagnosis of congenital hypothyroidism

To determine whether functioning metastases from thyroidcarcinoma are present and amenable to 131I therapy

To determine whether a patient with thyroid cancer has been treated successfully


TECHNIQUES AND RESULTS

When patients are referred for uptake and/or scan, it is important to ensure they are not taking thyroid hormone or an antithyroid medication. It is also important that they have not ingested an excess of iodine or been injected with radiographic contrast. It is very important to define that a woman is neither pregnant nor lactating. Please refer to the last paragraph in this chapter. The author prefers to administer the tracer in the morning with the patient fasting. When the patient has had prior studies, it is very helpful to have a copy for direct comparison. The uptake and scan should be interpreted in light of serum thyroid function tests.

For uptake alone, 50 to 100 µCi 123I can be administered in a capsule. For patients who have difficulty swallowing, and children, 123I can be given as a liquid. The dose to be administered is counted in a plastic phantom using the probe that is used for the uptake measurement in the patient. Correction for tissue background is made by counting over the midthigh and subtracting that count from the neck counts. Commercially available thyroid uptake units contain a dedicated computer that calculates the uptake from the standard and patient measurements. It is programmed to correct for the physical decay of 123I. The formula for calculation by hand is

where CPM is counts per minute, R is the ratio of the dose administered to the dose of the standard, and F is the correction for physical decay.

UPTAKE OF 99MTCO4-PERTECHNETATE

Pertechnetate is trapped but not organified. The peak activity in a normal thyroid after intravenous injection occurs at about 15 to 30 minutes (13,43). The peak is earlier in hyperthyroid glands. The range of normal uptake is 0.25% to 3.0% of the injected dose. Therefore, the background activity is high. This has to be subtracted from thyroid counts. 99mTcO4 Is trapped and secreted by salivary glands, and it is important to have the patient drink water to “clear” the esophagus before measuring uptake or scanning. When a probe is used for the uptake measurement, counts over the midthigh are used for this correction. When uptake is measured with a gamma camera, an area adjacent to the thyroid but avoiding the salivary glands can be used for background correction.

Some physicians use a neck-to-thigh ratio. This is rapid, and as little as 10 to 20 µCi 99mTc can be used, thus subjecting the patient and thyroid to very low doses of radiation. This is beneficial for children (44).

FACTORS INFLUENCING THYROID-UPTAKE TESTS

The function of the thyroid is only one of the factors that determine the uptake measurement. The uptake is generally increased in thyrotoxic patients with Graves' disease and toxic nodular goiter. Conversely, the uptake is generally decreased in subacute and silent thyroiditis and hypothyroidism. There are many other factors that influence this result (Table 12.3). The most important nonthyroidal influence is the serum inorganic iodine level, which is dependent on the intake of iodine.

TABLE 12.3. FACTORS THAT INFLUENCE THYROID RADIOIODINE UPTAKE


Causes of increased uptake


Hyperthyroidism

Iodine deficiency

Pregnancy (nuclear medicine tests should not be conducted in pregnant women)

Recovery phase of subacute, silent, or postpartum thyroiditis

Rebound after suppression of thyrotropin

Rebound after withdrawal of antithyroid medication

Lithium carbonate therapy

Some patients with Hashimoto's thyroiditis

Inborn errors of thyroid hormonogenesis apart from trapping defect

Causes of decreased uptake


Primary hypothyroidism

Destructive thyroiditis (subacute thyroiditis, silent thyroiditis, postpartum thyroiditis (ensure patient is not nursing)

After thyroidectomy, or 131I treatment, or external neck radiation

Central hypothyroidism

Thyroid hormone

Excess iodine

Dietary variations

Dietary supplements

Radiological contrast

Amiodarone

Topical iodine

Medications other than those containing iodine

Antithyroid drugs

Perchlorate, thiocyanate

Sulphonamides, sulphonylurea

High-dose glucocorticosteroids


STIMULATION AND SUPPRESSION TESTS

The use of recombinant human thyrotropin (rhTSH) to stimulate uptake of radioiodine in patients with thyroid cancer is described later in the chapter. There is no role for TSH stimulation in differentiating primary from secondary hypothyroidism. Similarly, there are no indications for triiodothyronine (T3)- or thyroxine (T4)-suppression tests. Historically, suppression tests were used to demonstrate that the uptake of the thyroid gland in patients with mild Graves' disease, or a autonomous hyperfunctioning nodule, was not suppressed after the administration of either T3 or T4. The tests were also used in an effort to predict whether a patient with Graves' disease was in remission. Remission was diagnosed when the thyroid uptake could be suppressed by exogenous T4 or T3. The following references are listed for those interested in the history and technical details (45,46). The differentiation of primary from secondary hypothyroidism and the diagnosis of mild thyrotoxicosis can be made by interpreting the scan along with serum thyroid function tests. A single test that can determine when a patient with Graves' disease is in permanent remission is not available.

THYROID SCINTIGRAPHY: NORMAL FINDINGS

The thyroid lies in the anterior cervical area and in adults weighs about 10 to 20 g. There are two lobes and an isthmus. In normal adults in the United States, the 24-hour uptake of oral radioiodine is in the range of 10% to 35% (Fig. 12.4). Therefore, about 1/5 to 1/3 of the administered dose is concentrated in a small superficial organ. This results in images of good quality. Nevertheless, the intrinsic resolution of the nuclear medicine instruments for 123I is about 1 cm for planar images and 5 to 6 mm for tomographic images. Small lesions are not delineated. The pyramidal lobe is occasionally identified, in particular in patients with Graves' disease and less commonly in Hashimoto's thyroiditis (Fig. 12.5)(47).

FIGURE 12.4. A normal thyroid scan obtained 24 hours after an oral dose of 200 µCi (7.4 MBq) of 123I. The lobes are usually minimally asymmetric. The isthmus may not be imaged (as in this scan) when it is thin.

FIGURE 12.5. This image shows an enlarged thyroid with a faint pyramidal lobe is typical of Graves' hyperthyroidism. The early and 24-hour uptake values are usually above normal. This image was obtained at 24 hours after an oral dose of 200 µCi (7.4 MBq) of 123I.

CONGENITAL DEFECTS

Congenital defects include anatomic and inherited disorders (48). Anatomic defects include agenesis and maldescent of the gland, which is positioned along the tract of the thyroglossal duct. Patients with agenesis are clinically and biochemically hypothyroid. Patients with a maldescended thyroid are usually hypothyroid. Imaging is valuable in defining agenesis of the thyroid. The thyroid is not identified, but there is uptake by salivary glands (49). Ectopic thyroid such as lingual thyroid can be identified on scintiscan. Anatomic defects such as hemiagenesis are infrequently identified because they are rare. They are usually identified only if the patient has some disorder such as thyrotoxicosis that results in the thyroid scan being ordered (50).

Pathophysiological defects resulting from inborn errors of synthesis of thyroid hormone can be diagnosed by correlating clinical findings, biochemical results, and uptake, and scintigraphy. Absent trapping due to mutations in NIS also show absence of the thyroid on scan, but in addition there is no trapping by the salivary glands. A defect in thyroid peroxidase can be identified by the combination of active trapping by the thyroid plus a positive perchlorate discharge test. Defects in deiodination can be diagnosed by measuring radioactive monoiodotyrosine and diiodotyrosine in the urine.

THYROTOXICOSIS/HYPERTHYROIDISM

Thyrotoxicosis is the pathophysiological condition resulting from action of excess T4 and T3. Hyperthyroidism refers to an overactive gland, and patients with hyperthyroidism are thyrotoxic. However, not all thyrotoxic patients are hyperthyroid. Table 12.4 lists the more common conditions that result in excess thyroid hormones in the circulation (see Chapter 22 for a complete list). The important differentiation is whether the thyroid is actively trapping an excess of iodine or not. The common causes of hyperthyroidism are Graves' disease (Basedow's disease, diffuse toxic goiter), toxic multinodular goiter, and an autonomous hyperfunctioning nodule. The relative proportion of each varies significantly from country to country. Graves' disease is more common in countries with high intake of iodine, and toxic nodular goiters are more common in iodine-deficient countries. Figure 12.5 shows the typical appearance of Graves' disease on scan. Compared with a normal thyroid, the thyroid lobes are larger in all dimensions, the early and late uptakes are higher, there is less background activity, and the pyramidal lobe is often seen. Thyrotoxicosis as a result of a toxic nodular goiter shows the hyperfunctioning nodule(s), and normal tissue is usually suppressed because there is no TSH stimulation (Fig. 12.6). Figure 12.7 shows the scan of a patient with inflammatory thyroiditis, the uptake was < 1%.

TABLE 12.4. CAUSES OF THYROTOXICOSIS, SEPARATED INTO THOSE WITH HIGH UPTAKE AND THOSE WITH LOW UPTAKE


Thyrotoxicosis with High Uptake

Thyrotoxicosis with Low Uptake


A. Autonomous gland

A. Thyroiditides

Graves' disease

Subacute thyroiditis

Toxic nodular goiter

Silent thyroiditis

Multinodular gland

Postpartum thyroiditis

Single autonomous nodule

B. Gland-stimulated by excess TSH or TSH-like hormone

B. Exogenous thyroid hormone

TSH-secreting pituitary tumor

Factitious thyrotoxicosis

Placental tumors

Thyrotoxicosis medicamentosa

Hydatidiform mole

Choriocarcinoma

Hamburger thyrotoxicosis

C. Ectopic source of hormone secretion

C. Excess iodine exposure

Widespread functioning thyroid cancer (usually follicular cancer)

 Struma ovarii

 


TSH, thyrotropin.

FIGURE 12.6. The image on the right shows a functioning nodule in the right lower pole with partial suppression of uptake in the remainder of the thyroid. The image on the left shows radioactive markers that were placed at the upper and lower edge of the palpable nodule. The patient had mild clinical and biochemical thyrotoxicosis. The images were obtained 24 hours after an oral dose of 200 µCi (7.4 MBq) of 123I.

 

FIGURE 12.7. Thyroid scan of a patient with thyrotoxicosis due to inflammatory thyroiditis. There is no trapping of 123I (200 µCi, 7.4 MBq). This appearance could be due to any of the disorders causing thyrotoxicosis with low uptake, as listed in Table 12.4.

SOLITARY THYROID NODULE

Between 5% and 10% of solitary thyroid nodules are malignant; the main clinical question is whether the nodule is a cancer or not (51,52). Without question the best and most cost-effective test in a euthyroid patient is fine needle aspiration biopsy (53,54,55,56) (see Chapter 73). Many primary care physicians continue to order a thyroid scintiscan to determine whether a nodule is malignant. This is not cost effective. Most cancers are nonfunctioning on scintiscan, and when they are large enough to be detected on scan, they are “cold.” However, most nonfunctioning nodules are benign (57), and benign nodules are much more common than malignant nodules. Figure 12.8 shows a large cold nodule, which was histologically benign. If we accept that 5% of nodules are malignant and 95% are nonfunctioning, the a priori, chance of a nodule being cancerous is 1/20, and after the scan the a posteriori probability is 1/19. To add further confusion, there are occasional disparities when the same nodule is imaged with 123I and 99mTcO4 (58,59).

A nodule that is hot on 99mTcO4 scan and cold on 123I scan has an increased risk of being a cancer. In one study comparing 131I and 99TcO4 in 58 patients, 18 (31%) nodules had disparate results. Of the 18, 14 were malignant, with 12 being follicular and 2 being papillary cancers (59). A review of the literature suggests the disparity is less common than stated above. The difficulty is knowing which 99mTcO4 scan will be disparate by 123I (or 131I) imaging. As a result, those who recommend 99mTcO4 also recommend repeating the scan with 123I in the case of a nodule that is hot on 99mTcO4 scan. Reverse disparity can occur, but rarely. The author prefers 123I. In general, thyroid scintigraphy is not recommended as the first study in euthyroid patients with a solitary thyroid nodule. This is confirmed by the meta-analysis of Ashcraft and Van Herle (51). The positive predictive value of a cold nodule being malignant was 15%, and the specificity, that is, the likelihood that the scan will define the nodule as benign, was 6%.

FIGURE 12.8. Thyroid scan administration of 24 hours after 200 µCi (7.4 MBq) of 123I. There is a large nonfunctioning nodule in the right lobe. The patient, a teenager, had received external radiation therapy in childhood for cancer in the right neck. Because of the history and clinical and scintigraphic findings, the patient was referred for operation. The thyroid nodule was benign.

There are exceptions to the dogma that fine needle aspiration (FNA) should be the first test. In regions of the world that are iodine deficient, there is a higher proportion of functioning nodules, and at a certain percentage it becomes more cost equivalent to obtain the scan. This is because the percentage of microfollicular lesions on biopsy increases with the increasing percentage of functioning nodules. Second, when the patient has thyrotoxicosis, the probability of a functioning nodule increases, although occasionally patients with Graves' disease have a nonfunctioning nodule (60). That nonfunctioning nodule should be biopsied because thyroid cancer can occur in Graves' disease. Some authorities believe thyroid cancer in this setting behaves more aggressively (61,62).

There was hope that a cancer-seeking radiopharmaceutical could differentiate between a benign and malignant nodule. Relevant literature of results using 201Tl, 99mTc-sestamibi, 99mTc-tetrafosmin, and 111In-octreotide are presented later in the chapter. Previous investigators failed to differentiate benign from malignant nodules with 201Tl. Mezosi et al evaluated 59 cold nodules with 99mTc-sestamibi (63). They concluded that it can differentiate degenerative from neoplastic nodules. However, it cannot differentiate adenoma from carcinoma. Demirel et al compared three methods of separating malignant from benign nodules (64). They imaged blood flow into the nodule immediately after injection of 99mTcO4 and 99mTc-sestamibi, and obtained delayed images with each agent. They also conducted Doppler ultrasound. They studied 43 patients who had cold nodules, and all went on to have histological proof of diagnosis. The authors accepted that a hypervascular nodule that demonstrated rapid washout of 99mTcO4 was malignant. When uptake of 99mTc-sestamibi in the nodule was 3+ on either an early or delayed scan, or both, the nodule was judged to be malignant. Radionuclide angiography diagnosed 8 of the 9 cancers and all 34 benign nodules (sensitivity 89%, specificity 100%). These results suggest that radionuclide angiography should be an important test. However, the technique has been available for more than 30 years, and one earlier report found the sensitivity to be 50% (65). 99mTc-sestamibi diagnosed 6 of 9 cancers and 31 of 34 benign nodules (sensitivity 67%, specificity 91%). In a similar study, 99mTc-sestamibi scans were compared with dynamic imaging with 99mTcO4, biopsy, and histology by Sathekge et al (66). They found a sensitivity of 91% and specificity of 77% for 99mTc-sestamibi. The specificity for radionuclide angiography was only 40%. 111In-octreotide has not been shown to be of value in differentiating benign from malignant nodules (67).

Two reports describe the use of 18F-FDG PET to differentiate benign from malignant thyroid nodules. In general, cancers showed high uptake, but there was considerable overlap with benign nodules. Autoimmune thyroid disorders also had high uptake of 18F-FDG, as shown in Figure 12.3 (68,69).

There was then hope that the cancer-seeking radiopharmaceuticals could help in the management of patients with a nodule when biopsy results in indeterminate cytopathology. Lin et al used 10-minute and 3-hour 201Tl images in 27 patients with indeterminate cytopathology and reported a sensitivity of 100% and specificity of 90% (70).

Chen et al concluded this would provide a considerable saving by reducing the number of patients referred for operation who have benign nodules. This was based on the estimated 17,000 to 29,000 indeterminate biopsies done annually in Taiwan (71).

In summary, cancer-seeking radiopharmaceuticals appear to have little role in the routine evaluation of solitary thyroid nodules. The tests are expensive and are not cost effective. The studies cited had an end point of excision of all nodules. The studies also had small numbers of patients and relatively high percentages of cancers. These results cannot be translated into clinical practice where very large numbers of patients are tested and the likelihood of cancer is low. There might be a limited role for imaging when biopsy is indeterminate in a patient who is reluctant to have surgery without compelling evidence the nodule is malignant. However, none of the radiopharmaceuticals are reliable at separating malignant from benign nodules. As a result, a clinician using one or other of these radiopharmaceuticals to determine which patient does not need surgery has to be responsible for follow-up to ensure a cancer is not overlooked. The role of these agents in patients with proven cancer is discussed later in the chapter.

SUBSTERNAL THYROID

When a goiter enlarges, the inferior aspect can enter the thoracic inlet. With time, a higher proportion of, or the entire, gland becomes substernal. This is usually detected on roentgenogram or CT scan done for some other clinical reason. The CT scan findings are occasionally typical and no additional tests are required (72). In many patients, it is not possible to exclude other diagnoses such as lymphoma. Thyroid scintigraphy with 123I confirms that the intrathoracic mass contains functioning thyroid. 99mTcO4 is not recommended because uptake in the goiter is hard to differentiate from activity in the heart and great vessels.

HYPOTHYROIDISM

There is seldom an indication to measure uptake or obtain a scan in an adult with hypothyroidism. Their role in infants was discussed earlier in the chapter.

THYROID CANCER

Introduction

The role of scintigraphy in patients with thyroid cancer involves whole-body scintigraphy after the patient has undergone thyroidectomy. The patient has to have a high serum TSH concentration. In regions where the intake of dietary iodine is high, a low-iodine diet is recommended for 2 weeks prior to imaging and therapy (73). A more detailed diet with recipes is available online at www.thyca.org. A diet for tube-fed patients has been published (74). The high serum TSH value can be obtained by stopping thyroid hormone, T4 is stopped for 4 weeks, and T3 for 2 weeks. Alternatively, thyroid hormone is not prescribed after thyroidectomy, and testing is undertaken after 4 weeks. There is no consensus as to how high the serum TSH value should be, but most accept a value above 25 mU/L. A high level of TSH can be achieved without withdrawing thyroid hormone by administering rhTSH by intramuscular injection (75,76). The most common regime is to inject rhTSH on a Monday and Tuesday, to administer the oral diagnostic dose of 131I (or 123I) on Wednesday, and do a whole-body scan on Friday (or Thursday in the case of 123I). Two multinational trials reported on the value of rhTSH in comparison with standard diagnostic scans (75,77), and several authors have confirmed the value of rhTSH (78,79). The original trials suggested that about 10% of patients had mild transient nausea or headache after injection of rhTSH. In more than 170 studies, the author has found ~40% of patients to have one or the other symptom, but only 1 patient preferred the withdrawal protocol. Serum TSH values 24 hours after the second injection of TSH are in the range of 130 to 140 mU/L, and are inversely related to the mass of the patient.

The scan findings, whether obtained after injection of rhTSH or after withdrawal of thyroid hormone, have to be interpreted in relation to serum thyroglobulin (Tg) values. Knowledge of false positive radioiodine scan findings is important to ensure patients are not diagnosed and treated for nonexisting metastases.

A recent consensus report suggested that whole-body scanning following rhTSH is not necessary in low-risk patients previously treated with thyroidectomy and 131I in whom the serum Tg after rhTSH does not rise to >2 ng/mL (79A).

There are several controversial aspects related to diagnostic whole-body scanning. First, should a diagnostic scan be obtained, or should the patient be treated with 131I after thyroidectomy without obtaining the scan? Second, when a diagnostic scan is obtained, should 131I be used, and if so, what dose should be given? When a decision has been made to give 123I in place of 131I, what is the appropriate dose? Lastly, what is the role of a posttherapy scan?

SHOULD A DIAGNOSTIC SCAN BE OBTAINED?

Some authorities recommend proceeding directly to 131I therapy after surgery without a diagnostic scan. The diagnostic scan gives information about how much thyroid tissue is left and allows for demonstration of metastases once the surgeon has removed most or all of the normal thyroid. Therefore, it provides information on how much 131I to prescribe. When dosimetric calculations are made, it is essential to have a diagnostic scan. The scan also demonstrates potential reasons for not proceeding to 131I, for example, intense uptake in breast tissue in a young woman with good prognostic features.

WHICH RADIONUCLIDE IS BEST FOR WHOLE-BODY IMAGING?

131I, in doses of 1 to 2 mCi (37 to 74 MBq), has been used for diagnostic whole-body scans for several decades. Originally, 131I was the only suitable radionuclide of iodine, and because it was also the radionuclide used for therapy, pretherapy diagnostic scans and uptake measurements were thought to reflect precisely the behavior of the larger therapy dose. It then became apparent that posttherapy scans could show more lesions and demonstrate known lesions better. Therefore, there was a trend to prescribe larger diagnostic doses of 131I (80,81). They were increased to 5 and then 10 mCi (185 to 370 MBq). In contrast, this author found that 2mCi (74 MBq) of 131I seldom underestimated the stage of disease, and other authors confirmed that finding (82). Nevertheless, the popularity of larger diagnostic doses increased, until Park et al described absent or reduced uptake on posttherapy scans in comparison with diagnostic scans (83). The implication was that the diagnostic dose of 131I delivered sufficient radiation to thyroid cells that they were incapable of trapping the therapeutic dose. This has been called “stunning.” Park et al described a linear increase in the frequency of stunning as the diagnostic dose of 131I increased. As a result, some clinicians abandoned diagnostic scans, and others reverted to lower doses of 131I, or changed to 123I. Stunning has become a very controversial topic. Again, this author found it to be rare when 2 mCi (74 MBq) 131I are prescribed (Fig. 12.9). Several other authors have found no evidence of stunning with larger doses of 131I. Cholewinski et al did not encounter this in 122 patients after 5 mCi (185 MBq) (84). Morris et al compared the outcome of 131I therapy in two groups of patients, one treated directly with 131I and the second treated after a diagnostic scan (85). There was no difference in the percentage of patients with a successful outcome after radioiodine therapy. In contrast, several authors strongly support the concept of stunning. Leger et al found that 71% of patients who first had a diagnostic scan with 131I were not successfully ablated, compared with 7% who had 123I diagnostic scans (86). Lees et al also found fewer patients were successfully ablated when given 5 mCi (185 MBq) of 131I (87). Many of these reports require careful evaluation to explain the different conclusions. One disparity is the difference in the diagnostic dose, larger doses being more likely to cause stunning. A second difference is the delay between the diagnostic scan and therapy. The longer the delay, the greater the radiation delivered and the more likely for stunning to occur.

FIGURE 12.9. Whole-body images in a patient who had a thyroidectomy for differentiated thyroid cancer. The left panel shows a scan made 72 hours after 2 mCi (74 MBq) of 131I. The middle panel is a posttherapy scan 1 week after 100 mCi (3.7 GBq) of 131I. The right panel is follow-up scan after 1 year. The diagnostic and posttherapy scans show uptake in the thyroid bed and no evidence of “stunning” or additional lesions. The follow-up scan shows that residual thyroid was successfully ablated.

The concern about stunning has prompted several authorities to administer 123I instead of 131I. However, this author has reported less uptake on posttherapy scans when 123I was the tracer (88). This adds fuel to the concept that the difference in timing of the posttreatment scan compared with the diagnostic scan must be considered. 123I has also been used after stimulation with rhTSH (89).

POSTTHERAPY SCANNING

Posttreatment scans are the most sensitive imaging tests to determine the extent of functioning thyroid cancer. There are several reports of the posttreatment scan showing more lesions than diagnostic 131I scans (80,81). This led to the use of higher doses of 131I for diagnostic whole-body scans, which in turn resulted in the description of stunning. There are differences in when physicians order the posttreatment scan. Some obtain them at the time the patient is discharged from the hospital after treatment. Historically, that was when the retained dose of 131I was < 30 mCi (< 1.1 GBq). Others, including this author, have the patient return for the posttreatment scan after approximately 7 days. This timing also allows for a measurement of emitted radiation to determine whether the patient can be released from the restrictions of their activity intended to protect his or her family and the public. Lesions can be recognized with more certainty on a posttreatment scan in comparison with a diagnostic scan, but the stage of disease is increased in only 3% to 5% of patients (Fig. 12.10). This was confirmed in a study from the Mayo Clinic (90). Because the posttreatment scan can show more lesions, this altered the philosophy of management by some authorities who recommend treatment with 131I when a patient has a negative diagnostic whole-body scan but a high serum Tg level. They describe identification of the site of Tg production on the posttherapy scan (91,92). Alternative methods for finding the thyroid tissue are described later in the chapter.

FIGURE 12.10. The scintiscans on the left are whole-body images made 24 hours after 2 mCi (74 MBq) of 123I. The patient had undergone a thyroidectomy 6 years earlier. The pathology was a follicular adenoma (confirmed on review). She then presented with a mass in her left mandible that was metastatic follicular cancer. The whole-body scan shows lesions in the mandible, left shoulder, left groin and thorax. The images on the right are posttreatment scans acquired 7 days after 200 mCi (7.4 GBq) of 131I showing the same lesions; no additional metastases are recognized. The liver is easily identified on the posttreatment images.

FALSE-POSITIVE RADIOIODINE SCANS

Iodine is trapped not only by thyroid cells, but also by choroid plexus, salivary and mammary glands, and parietal cells. Iodine is also secreted by these glands, and it is cleared through the kidneys into urine. As a result, uptake in these tissues and in the urinary system can be misinterpreted as functioning metastases. There are many benign and malignant conditions that concentrate iodine and can therefore result in a false-positive radioiodine scan (93,94,95) (Table 12.5). It is important for the clinician interpreting the radioiodine scan to determine whether abnormal concentration of radioiodine can reasonably be attributed to thyroid cancer. Knowledge of the natural history and pattern of spread of thyroid cancer is important. In addition, comparison of the scan findings with serum Tg measurements helps determine whether metastases are likely to be present. Figure 12.11 shows abnormal uptake in the left groin area due to contamination of underwear. Repeating the scan with the patient “gowned” demonstrated the uptake was a false-positive.

TABLE 12.5. CAUSES OF A FALSE-POSITIVE WHOLE-BODY RADIOIODINE SCAN THAT CAN BE MISINTERPRETED AS METASTASIS


Physiologic

Pathologic


Salivary glands

Wig

Contamination with saliva

Meningioma

Nasopharynx

Artificial eye

Esophagus

Dacrocystitis

Thymus

Parotid tumor

Breast

Sinusitis

Stomach

Dental caries

Liver (posttherapy scan)

Tracheostomy

Gall bladder

Inflammatory lung disease

Intestine

Carcinoma of lung

Contamination with stool

Pleuropericardial cyst

Urinary tract

Struma cordis

Contamination with urine

Hiatal hernia

 Zenker's diverticulum

 Barrett's esophagus

 Adenocarcinoma of stomach

Renal cyst

 Meckel's diverticulum

 Cystadenoma of ovary


FIGURE 12.11. Whole-body images obtained 7 days after treatment of 100 mCi (3.7 GBq) of 131I in a patient with thyroid cancer treated by surgery. There is uptake in the thyroid bed, salivary glands, liver, and intestine. There is also uptake in the left groin. The patient was not expected to have distant metastases. The pelvic “lesions” were cured by removing the patient's trousers and underwear.

ALTERNATIVE CANCER-SEEKING RADIOPHARMACEUTICALS AND TECHNIQUES

The imaging methods discussed later in the chapter are employed in patients who have negative iodine scans and measurable serum Tg, or in whom the iodine scan is thought to underestimate the extent of disease. Management of patients with a measurable serum Tg value but a negative diagnostic scan with 131I or 123I is controversial. There is evidence that therapeutic doses of 131I can demonstrate lesions and decrease serum Tg (91). Others find that lesions are seldom identified and that the serum Tg does not change (96). Each of the alternative radiopharmaceuticals is discussed briefly, but most authorities agree that PET using 18F-FDG has replaced the other radiopharmaceuticals, including 201Tl, 111In-pentetreotide, 99mTc-sestamibi, and 99mTc-tetrafosmin.

Thallium

201Tl atoms are substantially larger than K atoms. However, both are concentrated in cells through the potassium channel. 201Tl is used for imaging the myocardium, parathyroid adenomas, and several nonthyroidal cancers. The photon emissions are of low energy, and the half-value (the length of tissue that attenuates 50% of the emitted photons) is about 4 cm. Two to four mCi (74 to 148 MBq) injected intravenously and imaging started within 10 to 15 minutes. Because 201Tl can be trapped and washed out of cells at different rates, it is best to image early and after 2 to 3 hours. The quality of 201Tl images is inferior to those of 99mTc compounds and to PET using 18F-FDG. Most authorities no longer recommend this radionuclide for imaging thyroid cancer.

111Indium-Pentetreotide

111In-Pentetreotide is a radiolabeled somatostatin analogue that binds to somatostatin receptors 2, 3, and 5 (97). The radiopharmaceutical is valuable in imaging neuroendocrine cancers such as carcinoids, insulinomas, and some thyroid cancers. Five to six mCi (185 to 222 MBq) is injected intravenously and whole-body and tomographic images obtained at 4 and 24 hours. Most of the published series are of small numbers of patients. In one series of 48 patients, 111In-pentetreotide images positive in 74% of patients (98). Sarlis et al compared this agent with 18F-FDG PET and conventional radiologic studies, including whole-body CT and MRI, ultrasound of the neck, and skeletal surveys (99). The sensitivity of 111In-pentetreotide was 49.5%, and for PET 67.6%; however, some lesions were only detected by the former.

99mTc-Sestamibi and 99mTc-Tetrafosmin

These radiopharmaceuticals are discussed together because they are both technetium-labeled agents used primarily for evaluation of myocardial perfusion. They have also been used to identify parathyroid adenomas. 99mTc-radiopharmaceuticals give excellent resolution, radiation to the patient is low and thyroid hormone need not be withdrawn. Twenty to twenty-five mCi (740 to 925 MBq) are injected intravenously, and whole-body imaging started early, some recommend immediately. In an analysis of 110 patients, 22 of 24 patients with abnormal scans had high serum Tg values (17). Of the 86 who had normal serum Tg values, 83 had negative 99mTc-sestamibi scans. 99mTc-sestamibi has identified local recurrences and metastases in lymph nodes, lung, and skeleton. Not all of the reports have such good sensitivity and specificity. Clinical reports and reviews of 99mTc-tetrafosmin give similar results (100,101,102).

POSITRON EMISSION TOMOGRAPHY WITH 18F-FLUORODEOXYGLUCOSE

This technology is based on the principle that cancers utilize more glucose than normal tissues. There is very little glucose uptake in normal thyroid tissue. Similarly, well-differentiated thyroid cancers trap little 18F-FDG. However, these cancers concentrate radioiodine. When thyroid cancers lose the ability to trap iodine they are less well differentiated, in which case they may concentrate glucose and be imaged by PET scan after intravenous injection of 18F-FDG. The images are made 1 hour after injection of 10 to 15 mCi 18F-FDG (370 to 555 MBq). This technique finds the site of Tg production in 50% to 75% of patients (27,103,104,105,106,107,108,109,110,111,112,113). The scan is more likely to be positive when the serum Tg is higher. Figure 12.12 shows a PET scan in a patient with extensive papillary cancer, a high serum Tg value, and a negative 123I whole-body scan. The author has experience with PET in 80 patients, several of whom have had two or more studies. The images are easy to interpret, the pathology of abnormal sites can be confirmed by directed biopsy, and proven lesions treated by operation or external radiation, depending on their accessibility. Lesions which are FDG avid are usually resistant to 131I therapy.

PET has been used to follow the response of thyroid cancers to retinoid therapy (114). Most of the patients were studied when they were euthyroid or when TSH secretion was suppressed. Recent reports have shown a higher sensitivity for PET when serum TSH values are high (115). This raises the possibility that a negative PET scan in a euthyroid patient should be repeated after stimulation by TSH, either after withdrawal of thyroid hormone or after injection of rhTSH. 18F-FDG scan has a high sensitivity in Hürthle-cell cancer. The author has used it in selected patients with anaplastic cancer to stage the extent of disease with a single imaging procedure. False-positive PET scans can result from inflammatory conditions such as tuberculosis and sarcoidosis. Active muscles use glucose for metabolism, and patients who are tense or shivering can have increased uptake of 18F-FDG in neck muscles that could be misinterpreted as cervical nodal metastases. This can be avoided by reviewing the images on a computer terminal, and scrolling through the tomographic images and following the linear anatomy of muscles. Recently similar uptake of 18F-FDG has been attributed to metabolism in brown fat, and combined PET/CT has confirmed this (Fig. 12.13).

FIGURE 12.12. Coronal images of a positron emission tomograpy (PET) scan made 1 hour after injection of 15 mCi (555 MBq) of 18F-fluorodeoxyglucose (18F-FDG). The patient has had thyroid cancer with recurrences and progression for 50 years. Her serum thyroglobulin concentration is very high. A diagnostic scan showed no uptake of 123I. The PET scan shows intense uptake of 18F-FDG in the mediastinum, lung hila, spine, sternum, and lungs. There is physiological uptake in the brain, myocardium, liver, kidneys, and bladder.

FIGURE 12.13. Coronal images of a positron emission tomograpy/computed tomography (PET/CT) scan made 1 hour after injection of 15 mCi (555 MBq) of 18F-fluorodeoxyglucose (18F-FDG). The patient was being scanned after treatment for Hodgkin's disease. The PET scan is in the middle, CT scan on the left, and fused images are on the right. There is uptake of 18F-FDG in the lateral neck and upper mediastinum. This could be misinterpreted as nodal metastases, but is uptake in brown fat.

INTRAOPERATIVE IMAGING

There are several different approaches to intraoperative imaging. One is to administer a tracer of 125I 24 hours before the operation and use a handheld probe to identify tissue that concentrates the radionuclide. In a study of 64 patients undergoing total thyroidectomy, 43 patients had detectable activity, which could be completely excised in 33. This ensured the thyroidectomy was complete and could eliminate the need for 131I ablation (116).

Schlumberger described a technique in which patients were scanned during surgery several days after a therapeutic dose of 131I, to help the surgeon identify functioning metastases. Potential drawbacks from this approach are that the patient is hypothyroid and the surgeon is exposed to the radioactive patient. The question is whether it is necessary to operate, since 131I alone is a very effective treatment.

Lastly, sentinel node imaging has been described. This is used routinely in patients with breast cancer and melanoma. There are a few reports on the use of sentinel node technique in thyroid carcinoma (36,117,118). Colloidal particles, usually 99cTc-sulfur colloid, is injected in or around the primary cancer. Four hundred to one thousand µCi (15 to 37 MBq) provides sufficient radiation to be detected by a gamma camera and later in the operating room by a handheld probe. There is also a report of this technique using 99mTc-sestamibi as the tracer (119). Whether sentinel node imaging in patients with thyroid cancer will become more widely employed is not certain, since the current approach with thyroidectomy and removal of clinically suspicious nodes produces excellent results.

FLUORESCENT SCANNING

Fluorescent scanners are not widely available, and although they can quantitate the iodine content of the thyroid, they have not gained wide acceptance. The procedure has been used to measure the amount of iodine in the thyroid in different geographic regions. In the United States, the normal range is 5 to 15 mg. In France, the range is 2.5 to 7.5 mg (120). One study found the mean value in Graves' disease to be 36.5 mg, and the result is also high in patients who have received radiographic contrast or who take iodine-rich medications such as amiodarone (39). Because cancers trap less iodine than normal thyroid, it was hoped that fluorescent scanning could differentiate benign from malignant nodules. Unfortunately, the majority of benign nodules contain less iodine than normal thyroid, so the test has little discriminatory power (121).

IMAGING STUDIES FOR MEDULLARY THYROID CARCINOMA

Standard radioiodine scintigraphy is not helpful in patients with medullary thyroid cancer. The usual problem is to find the site of production of calcitonin measurable after total thyroidectomy. Standard radiological studies such as CT, ultrasonography, and MRI can be useful. Nuclear medicine techniques have the advantage of imaging the entire body. 201Tl, 99mTc-sestamibi, and 99mTc-tetrafosmin have been used with some success, ranging from modest to disappointing (20,122). There are reports from Europe of the value of 99mTc-DMSA, but it is not approved in the United States (123). Adalet et al evaluated 34 known lesions with 99mTc-DMSA, 201Tl, and 99mTc-tetrafosmin. 99mTc-DMSA readily detected 30 lesions, whereas 21 and 20 lesions were visualized very faintly with 201Tl or 99mTc-tetrafosmin, respectively. Rhenium-labeled DMSA has been produced for targeted treatment of medullary thyroid cancer (124,125). 131I- and 123I-metaiodobenzylguanidine (MIBG) have been used to image medullary cancer, but the sensitivity is disappointing. 111In-pentetreotide in one study correctly diagnosed 11 of 17 patients (67). In studies comparing 111In-pentetreotide, 201Tl, 99mTc-sestamibi, and 99mTc-DMSA, no single test identified all lesions (22,23). Several investigators have found 18F-FDG PET to be the most sensitive test for identifying medullary cancer (126,127,128,129). In a study comparing PET with 111In-pentetreotide, each procedure found some lesions that were missed by the other (22). There are recent data on the benefit of combined PET/CT imaging (130). This author has had useful results with 18F-FDG PET. However, the test is likely to be negative when the serum calcitonin is < 100 pg/mL.

RADIOACTIVE IODINE AND PREGNANT OR NURSING WOMEN

Pregnant women should not be given radionuclides of iodine. Most patients with thyroid disorders are women of child-bearing potential, and it is important for nuclear medicine personnel to ensure that a pregnant or nursing woman does not receive radioiodine, in particular 131I. This is even more important when larger doses are prescribed for therapy or for whole-body scintigraphy. In the case of patients receiving small tracer doses of 123I, if there is any doubt about the possibility of pregnancy, a serum pregnancy test should be ordered. Because larger doses of 131I can cause ablation of fetal thyroid, a U.S. court has determined that an oral declaration of nonpregnancy is not good enough (131). Urinary pregnancy tests are not sensitive in early pregnancy and do not exclude conception. Therefore, a serum pregnancy test should be obtained in all women who could bear children.

The lactating breast concentrates and secretes iodine. The nursing baby would therefore be exposed to radiation. Because of the small size and increased activity of the thyroid in the newborn, tracer doses of radioiodine given to the mother necessitate cessation of nursing. In the case of a tracer of 123I, we advise complete cessation for 2 to 3 days, and afterward that the radioactivity in an aliquot of milk be measured, to determine whether it is safe to resume nursing. In the case of 131I, because of its half-life and electron emissions, nursing should be stopped completely. There are limited references on this topic (132,133,134).

In the case of a pregnant or nursing patient, the following questions should be answered. Is the study essential? Are there alternative procedures that do not require administration of radionuclides? If not, which radiopharmaceutical will give the lowest radiation dose, and would it be possible to obtain the desired information with a lower dose?

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