Thyroid,Parathyroid,andAdrenalGlandImaging 13

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Thyroid, Parathyroid, and Adrenal Gland Imaging

William H. Martin, Martin P. Sandler, and Milton D. Gross

13.1 The Thyroid

13.1.1 Anatomy

The thyroid is a bilobed structure evolving from the fourth and ﬁfth branchial pouches. It is ini- tially attached to the ventral ﬂoor of the pharynx by the thyroglossal duct. Thyroid tissue may be found anywhere between the base of the tongue and the retrosternal anterior mediastinum (Fig- ure 13.1). The fetal thyroid gland begins to concentrate iodine and synthesize thyroid hormones by approximately 10.5 weeks, which is pertinent when the administration of¹³¹I to fertile women is contemplated. The two ellipsoid lobes of the adult thyroid are joined by a thin isthmus. Each lobe is approximately 2 cm in thickness and width and averages 4–4.5 cm in length. The thyroid gland, averaging approximately 20 grams in weight, resides in the neck at the level of the cricoid cartilage. A pyramidal lobe is present in approximately 30–50%, arising from either the isthmus or the superomedial aspect of either lobe; it under- goes progressive atrophy in adulthood but may be prominent in patients with Graves’ disease.

Although the right lobe tends to be somewhat larger than the left lobe, there is a great deal of variability in both size and shape of the normal gland.

13.1.2 Physiology

An appreciation of thyroid physiology and pathophysiology is essential for the optimal management of thyroid disorders. The function of the thyroid gland includes the concentration of iodine, synthesis of thyroid hormones, storage of these hormones as part of the thyroglobulin (Tg) molecule in the colloid, and their secretion into the circulation as required. Over 99% of circulating thyroid hormones are bound to plasma proteins, primarily thyroxine-binding globulin (TBG). Only the unbound fraction of thyroid hormone is metabolically active and, for this reason, accurate assays of free thyroid hormone, “free T4” and “free T₃”, have been developed.

Dietary sources of iodine include seafood, milk, eggs, and iodized products such as salt and bread.

Approximately one-third of the absorbed dietary iodide is trapped by the thyroid, the remainder being excreted in the urine. Although gastric mucosa, salivary glands, and the lactating breast may also trap iodide, none of these organify it. The concentration of iodide by the thyroid gland, synthesis, and release of thyroid hormones are under the regulatory control of the hypothalamic-pituitary- thyroid axis. Thyroid stimulating hormone (TSH) from the pituitary plays the major role in reg- ulating thyroid function and this, in turn, is

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Figure 13.1. Normal and aberrant locations of thyroid tissue.

under the control of hypothalamic thyrotropin- releasing hormone (TRH) secretion. The present third generation assay for circulating TSH is highly sensitive and represents the most sensitive biochemical indicator of both hypothyroidism and hyperthyroidism; the serum TSH is elevated to above 5 mIU/l with even subclinical primary hypothyroidism and is suppressed usually to undetectable levels with hyperthyroidism. Numer- ous exogenous factors such as systemic illness, nutritional status, thionamides, beta blockers, steroids, iodide, lithium, amiodarone, and anti- convulsants, may affect thyroid hormone secretion and metabolism.

13.1.3 Clinical Applications

Radionuclide imaging and the measurement of thyroid radioactive iodine uptake (RAIU) both

play an important role in the investigation of patients with thyroid disorders, especially those with thyroid nodules. RAIU is discussed in Sec- tion 4.12.

Thyroid Scintigraphy

With the development of ﬁne needle aspiration biopsy (FNA) for evaluation of nodular disease combined with the exquisite anatomic detail provided by sonography, CT, and MRI, the use of thyroid scintigraphy has decreased appropriately.

However, it will continue to play an important role in the functional evaluation of a variety of thyroid disorders as well as the detection of metastatic thyroid cancer. Technetium-99m pertechnetate is the most readily available radionuclide employed for thyroid imaging. Pertechnetate ions (TcO⁻₄) are trapped by the thyroid in the same manner as

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Table 13.1. Thyroid scintigraphy

Radiopharmaceutical [^99mTc]pertechnetate [¹²³I]sodium iodide Activity administered 80–370 MBq (2–10 mCi) 20 MBq (500_µCi)

Intravenous Oral or intravenous

Effective dose equivalent 1–5 mSv (200–400 mrem) 4 mSv (400 mrem) Patient preparation Withdrawal of thyroid medication, avoidance

of foodstuffs with high iodine content

Withdrawal of thyroid medication, avoidance of foodstuffs with high iodine content Collimator Pinhole; low-energy, high-resolution

parallel-hole; low energy converging

Pinhole; low-energy, high-resolution parallel-hole; low energy converging Images acquired Imaging started 15 min post-injection Imaging started 1–2 h post-injection if

intravenous or 24 h if oral Anterior, right and left anterior oblique

views, 600 second exposure per image or 200 kcounts/image

Anterior, right and left anterior oblique views

iodine through an active iodine transporter, but pertechnetate ions are not organiﬁed.¹²³Iodine is both trapped and organiﬁed by the thyroid gland, allowing overall assessment of thyroid function.

Since ¹²³I is cyclotron-produced and has a relatively short half-life of 13.6 hours, it is more expensive and advance notice is necessary for imaging. Because of its inferior image quality and the high thyroid and total body radiation dose from itsβ-emission,¹³¹I is not used for routine thyroid imaging other than for metastatic thyroid cancer assessment. Due primarily to less background activity,¹²³I imaging provides somewhat higher quality images than ^99mTc, but the diagnostic information provided by each is roughly

Figure 13.2. Normal^99mTc thyroid scan. Symmetric, homogeneous uptake with less intense salivary gland uptake and only mild background uptake. The inferior activity is due to a⁵⁷Co marker at the suprasternal notch.

equivalent [1]. ¹²³I imaging is used in speciﬁc situations, such as retrosternal goiter. The protocol for thyroid imaging is given in Table 13.1.

The normal thyroid scintigram is shown in Figure 13.2. High-resolution images are obtained by using a pinhole collimator, thus permitting the detection of nodules as small as 5 mm in diameter.

The oblique views permit detection of small nodules obscured by overlying or underlying physiological activity. Pinhole SPECT has been used to better detect subtle abnormalities. The radionuclide is distributed homogeneously throughout the gland with some increase seen centrally due to physiological thickness of the gland there; activity within the isthmus is variable and must

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Figure 13.3. Subtle cold nodule.^99mTc pertechnetate anterior view a demonstrates a subtle hypofunctioning left lower pole nodule extending into the isthmus, conﬁrmed on a subsequent contrast-enhanced CT b to be a thyroid cyst.

Figure 13.4. Lingual ectopic thyroid. An anterior^99mTc pertechnetate image demonstrates a focus of activity at the base of the tongue in this neonate. Cervical thyroid uptake is absent.

be correlated with physical examination and/or other imaging (Figure 13.3). With pertechnetate, salivary glands, gastric mucosa, esophagus, and blood pool background are seen in addition to thyroid activity. Due to delayed imaging, salivary gland activity is often absent with¹²³I imaging.

In the euthyroid gland, thyroid activity should be greater than that of the salivary glands.

Anatomic variations are relatively frequent and may include agenesis, hemiagenesis, and ectopia (Figure 13.4) as well as mere asymmetry. Ectopia is typically associated with hypothyroidism. Sig- niﬁcant concavity of the lateral margin should be considered suspicious of a hypofunctioning nodule, and exaggerated convexity is often seen with diffuse goiters. The pyramidal lobe, a remnant of the distal thyroglossal duct, is identiﬁed in less than 10% of euthyroid patients, but is visualized in as many as 43% of patients with Graves’ disease (Figure 13.5). Extrathyroidal accumulation of the radiopharmaceutical usually represents ectopic thyroid tissue or metastatic thyroid carcinoma if gastroesophageal and salivary gland activity can be excluded.

Multinodular Goiter

The patient with multinodular goiter (MNG) may present with what seems to be a solitary thyroid nodule, diffuse enlargement of the gland, or hyperthyroidism. Development of MNG is related to cycling periods of stimulation followed by in- volution and may be idiopathic or occur as a result of endemic iodine deﬁciency. Over time the gland enlarges and evolves into an admixture of ﬁbrosis, functional nodules, and non-functioning involuted nodules. Scintigraphically, the MNG

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Figure 13.5. Graves’ disease.^99mTc thyroid scan shows a pyramidal lobe emanating from the medial aspect of the right lobe. Note the convex contour of the gland and the diminished background activity.

is a heterogeneously-appearing, asymmetrically enlarged gland with multiple cold, warm, and hot areas of various sizes (Figure 13.6). The incidence of thyroid carcinoma in MNG is low at 1–6%, but a dominant or enlarging cold nodule should be

biopsied. The differential diagnosis includes autoimmune Hashimoto’s thyroiditis, multiple adenomas, and multifocal carcinoma. Further char- acterization of the gland with ultrasound, CT, or MRI does not appreciably aid clinical diagnosis.

Thyroid Nodules

The management of patients with a solitary thyroid nodule remains controversial, related to the high incidence of nodules, the infrequency of thyroid malignancy, and the relatively low morbidity and mortality associated with differentiated thyroid cancer (DTC) [2]. Thyroid nodules may contain normal thyroid tissue, benign hypofunctioning tissue (solid, cystic, or complex), hyperplastic or autonomously functioning benign tissue, or malignant neoplasm. The evaluation of the patient with a solitary thyroid nodule is di- rected towards differentiating benign from malignant etiologies. Autopsy series have demonstrated a 50% incidence of single or multiple thyroid nodule(s), only 4% of which are malignant. Ul- trasonography detects single or multiple thyroid nodules in 40% of patients with no known thyroid disease. The incidence of thyroid nodules increases with advancing age, and is more frequent

Figure 13.6. Multinodular goiter. An anterior^99mTc pertechnetate view demonstrates asymmetric enlargement of the gland with multiple areas of increased, decreased, and normal activity. The decreased background activity and faint salivary gland activity is compatible with the clinical impression of toxic multinodular goiter.

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in females and in patients with a prior history of neck or facial irradiation.

Hypofunctioning (“cold”) nodules concentrate less radioisotope relative to the remainder of the thyroid gland (see Figure 13.3). Eighty-ﬁve to ninety percent of thyroid nodules are hypofunctioning, but only 10–20% of cold nodules are malignant [2]. The remaining hypofunctioning nodules consist of degenerative nodules, nodular hemorrhage, cysts, thyroiditis, inﬁltrative disorders such as amyloid, and non-thyroid neoplasms.

Clinical features that suggest thyroid cancer include male gender, a prior history of radiation exposure up to 15 Gy (1500 rad), a family history of medullary or papillary thyroid carcinoma, and relative youth. Local ﬁxation of the nodule or palpable adenopathy is also suggestive. Recent rapid enlargement of a nodule is more often related to hemorrhage into a cyst or nodule rather than carcinoma.

Although ultrasound and MRI are sensitive for the detection of thyroid nodules, speciﬁcity for malignancy is poor. Similarly, sensitivity for detection of thyroid cancer is approximately 90%

with scintigraphy, but speciﬁcity is poor at 15–

20%. If extrathyroidal activity is seen in the neck on thyroid scintigraphy in a patient with a solitary thyroid nodule, metastatic thyroid carcinoma is likely. Some investigators have recommended the use of serum thyroglobulin and calcitonin determinations to improve the accuracy of clinical assessment and scintigraphy.

A hot or warm (hyperfunctioning) nodule con- centrates the radioisotope to a greater degree than the normal thyroid gland and represents 10–25%

of palpable nodules in patients. In over 99% of cases, a hot thyroid nodule is benign and biopsy is unnecessary. Although a functioning thyroid nodule in the euthyroid patient may represent hyperplastic (sensitive to TSH stimulation) tissue, most are autonomously functioning thyroid nodules (AFTN) arising independently of TSH stimulation. Biochemical hyperthyroidism, often subclinical, is present in 74% of patients at presentation, although overt hyperthyroidism is less common. Over a period of 3 years after detection, 33% of AFTNs enlarge in patients not re- ceiving deﬁnitive therapy, and 24% of euthyroid patients develop hyperthyroidism [3]. In euthyroid patients, surrounding extranodular thyroid tissue will be visible (Figure 13.7a), thyroid function studies will be normal, and these patients can be followed on an annual basis. If hyperthyroidism

Figure 13.7. Autonomously functioning thyroid nodule. a An anterior ^99mTc thyroid image reveals a focus of increased uptake in the lower pole of the right lobe consistent with a hyperfunctioning nodule. The normal extranodular thyroid ac- tivity is indicative of euthyroidism. b A focus of markedly in- creased activity in the lower pole of the left lobe accompanied by virtual complete suppression of extranodular activity and decreased background and salivary gland activity is consistent with toxic adenoma, subsequently conﬁrmed by an undetectable serum TSH.

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exists, the surrounding normal thyroid tissue will be suppressed, and the TSH level will be undetectable (Figure 13.7b). Spontaneous cystic degeneration occurs in 27%, manifested by central photopenia; there is little concern for malignancy.

Discordant thyroid imaging is a dissociation between trapping and organiﬁcation, measured respectively with ^99mTc pertechnetate and ¹²³I. It occurs in only 2–8% of thyroid nodules and is not speciﬁc for malignant disease. A nodule that traps^99mTc (hot) but is unable to organify iodine (cold) is much more likely to be benign than malignant. If it is assumed that 8% of hot nodules with

99mTc are cold with¹²³I, and if 10% of those are malignant, then less than 1% of hot nodules seen with^99mTc imaging are malignant. Additional radioiodine imaging of hot nodules identiﬁed on a

99mTc scan should probably be reserved for patients deemed at higher risk for malignancy.

Hyperthyroidism

Hyperthyroidism is a clinical syndrome of tachy- cardia, weight loss, and hypermetabolism resulting from supraphysiological circulating levels of thyroid hormones, leading to suppression of TSH secretion. Most cases of hyperthyroidism are due to increased endogenous synthesis and secretion of thyroid hormones from the thyroid.

Other less common etiologies are shown in Table 13.2. Clinical assessment combined with circulating hormone and thyroid autoantibody measurements, thyroid scintigraphy, and RAIU usually al-

Table 13.2. Classiﬁcation of hyperthyroidism

Radioiodine

Etiology uptake

A. Thyroid gland (95%)

Diffuse toxic goiter (Graves’ disease) ↑ Toxic nodule goiter:

multinodular (Plummer’s disease) ↑

solitary nodule ↑

Thyroiditis (subacute/chronic) ↓ B. Exogenous thyroid hormone/iodine (4%)

Iatrogenic ↓

Factitious ↓

Iodine-induced (Jod–Basedow) ↓ C. Rarely encountered causes (1%)

Hypothalamic-pituitary neoplasms ↑

Struma ovarii ↓

Excessive HCG production by trophoblastic ↑ tissue

Metastatic thyroid carcinoma ↓

low identiﬁcation of the various disease processes that may be responsible.

Graves’ disease (autoimmune diffuse toxic goiter) is due to the presence of thyroid-stimulating immunoglobulins and is associated with autoimmune exophthalmos and pretibial myxedema. Al- though it occurs primarily in young women, it may also occur in children and in the elderly.

Radioiodine uptake will usually be elevated at 4 hours and/or 24 hours, and the gland will re- veal diffuse enlargement in most cases with increased thyroid activity and minimal background and salivary gland activity (Figure 13.5). Hyper- plasia of the pyramidal remnant is seen as increased paramedial activity in as many as 43% of Graves’ patients. Occasionally, the gland will ap- pear normal size. The low RAIU (usually≤5%) of hyperthyroid patients with subacute thyroiditis, postpartum thyroiditis, silent thyroiditis, and surreptitious thyroid hormone administration is easily differentiated from the normal RAIU seen in the occasional patient with Graves’ disease (Table 13.2). Although ultrasound demonstrates an enlarged homogeneously hypoechoic gland with prominent vascularity on color-ﬂow Doppler imaging (“thyroid inferno”), it is usually unnecessary for diagnosis clinically. The thyroid scan should easily be able to distinguish toxic nodular goiters from Graves’ disease. The clinical importance of this is that many patients with toxic nodular goiter will require a higher dose of¹³¹I for therapy than will Graves’ disease patients.

Radioiodine Therapy of Hyperthyroidism

Graves’ disease and toxic nodular goiter may be treated successfully with ¹³¹I therapy. Radioio- dine was ﬁrst used for the treatment of hyperthyroidism in 1941 and has since evolved to the treatment modality of choice for the majority of adult patients, particularly in the USA. Antithy- roid drug therapy achieves a permanent remission in only 10–40% of patients, but is used ini- tially in many patients, particularly in Europe and Asia. Although subtotal thyroidectomy is effective and complications are infrequent, thyroidectomy is used only occasionally at present. It is normally limited to patients in whom radioiodine is un- suitable, such as women who may be pregnant, or who have extremely large goiters with compressive symptoms. Radioiodine therapy is effective, prac- tical, inexpensive, and available on an outpatient basis.

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Prior to initiation of therapy, the diagnosis of hyperthyroidism must be confirmed by elevation of thyroid hormone levels and suppression of circulating TSH. An elevated RAIU confirms that endogenous thyroidal secretion is the source of the hyperthyroidism and aids in excluding other etiologies of hyperthyroidism, such as silent thyroiditis, subacute thyroiditis, postpartum thyroiditis, iodine-induced hyperthyroidism, and factitious hyperthyroidism, all of which are associated with a low RAIU (Table 13.2). Rarely, clinical hyperthyroidism with diffuse goiter and elevated RAIU may be related to excessive secretion of human chorionic gonadotropin (HCG) by a trophoblastic tumor or by inappropriate secretion of TSH by a functioning pituitary adenoma. The presence of exophthalmos, pretibial myxedema, and diffuse goiter on physical examination confirms Graves’

disease as the etiology. Otherwise, thyroid scintigraphy is useful to differentiate diffuse involvement due to Graves’ disease from localized disease due to AFTN.

The patient must be counseled prior to therapy regarding the advantages and disadvantages of alternative therapies. Because iodide readily crosses the placenta,¹³¹I may not be administered during pregnancy so a pregnancy test is mandatory prior to administration. Exposure of the fetus to¹³¹I after the 10th week of gestation may result in severe fetal hypothyroidism.

The effectiveness of radioiodine treatment for hyperthyroidism is due to radiation-induced cel- lular damage resulting from high-energy beta emission, the magnitude of which is directly pro- portional to the radiation dose received by the thyroid gland. The major effect of radiation is impairment of the reproductive capacity of follicular cells. The radiation dose to the thyroid is related to (1) the amount of radioiodine administered, (2) the fraction deposited in the gland (uptake), (3) the duration of retention by the thyroid (bio- logic half-life), and (4) the radiosensitivity of the irradiated tissue. Administered dose is usually cal- culated with the goal of administering approximately 70–120 Gy (7000–12 000 rad) to the thyroid gland [4]. Some practitioners have adopted a ﬁxed dose administration, usually approximately 370 MBq (10 mCi) with perhaps 300 MBq (8 mCi) for a small gland and 440–520 MBq (12 to 14 mCi) for a large gland. In the UK, a relatively larger ﬁxed dose of 550 MBq (15 mCi) is given to the majority of adult patients [5]. Other practitioners will calculate a dose of 3–4.4 MBq (80 to 120 µCi)

per gram of thyroid tissue for the usual patient with Graves’ disease. Even higher dosages of up to 7.4 MBq (200 µCi) per gram will be used to produce a more rapid response in patients with severe hyperthyroidism. The calculation is made as follows: administered microcuries= µCi/g de- sired× gland weight (g) × 100 ÷ percent uptake (24 hours). A higher dose may also be required for patients with toxic nodular goiter, in patients previously treated with antithyroid medications, patients with extremely large glands, patients with rapid iodine turnover (a 4 h/24 h RAIU ratio>1), and in patients with renal insufﬁciency. Although estimation of thyroid size is relatively accurate for glands weighing less than 60 grams, the degree of inaccuracy increases in larger glands. Ultrasound may provide an accurate estimation of size, but the increase in accuracy of thyroid radiation dose determination is limited.

The complications of radioiodine therapy include rare exacerbation of hyperthyroidism, pos- sible exacerbation of existing Graves’ orbitopathy, and post-therapeutic hypothyroidism. It is esti- mated that less than 10% of patients require retreatment, and this is rarely undertaken before 3–4 months following therapy. Most practitioners will give at least 20–30% more radioiodine on a second treatment. Pretreatment with antithyroid medications is advisable in elderly patients, in patients with known cardiac disease, and in patients with large thyroid glands, particularly multinodular goiters. These medications should be discon- tinued 48–72 hours prior to administration of

131I, and it is preferable to wait several days before reinitiation of therapy. The administration of beta blockers before or after therapy serves only to ameliorate peripheral manifestations of hyperthyroidism and will not affect therapeutic efﬁcacy of radioiodine.

The incidence of early post-¹³¹I hypothyroidism varies from 10% to 50% according to the dose administered. Subsequently, there is an additional incidence of hypothyroidism at a relatively con- stant rate of 2–3% per year. A similar incidence of hypothyroidism occurs following surgery. Some degree of hypothyroidism may be a natural conse- quence of the autoimmune process of Graves’ disease, since a small percentage of patients treated only with antithyroid medications will become hypothyroid during long-term follow-up after remission.

Although radiation exposure of more than 500 mGy (50 rad) is reported to increase the

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occurrence of leukemia, with a peak incidence at approximately 6 years after exposure, a single¹³¹I treatment delivers only 80–160 mGy (8–16 rad) to the blood and has not been associated with any increased incidence of leukemia, thyroid cancer, infertility, or congenital malformations. Although the desire for subsequent pregnancy is not a con- traindication to radioiodine therapy for hyperthyroidism, patients are usually advised to avoid conception for 6 months in case retreatment is required.

Following radioiodine therapy, the patient should be advised to have serum thyroid hormone and TSH levels checked within 2 to 3 months. Pa- tients may be symptomatically improved within 4 to 6 weeks, but clinically signiﬁcant hypothyroidism rarely occurs before 2 to 3 months. Hy- pothyroidism is only a problem if not adequately treated, and many practitioners will initiate thyroxine replacement therapy at the earliest indica- tion of post-therapy hypothyroidism.

Thyroiditis

Thyroiditis may be classiﬁed as acute, subacute, chronic/autoimmune, and other miscellaneous types; these different types of thyroiditis are un- related to each other (see Further Reading). Acute suppurative thyroiditis is rare and is caused by hematogenous spread of infectious organisms.

This is usually deﬁned clinically and evaluated by

CT and/or sonography; scintigraphy is only rarely performed.

Subacute (de Quervain’s) thyroiditis is a benign, self-limited transient inﬂammatory disease of the thyroid, presumed to be of viral etiology. It may affect the gland diffusely or fo- cally and usually presents as a tender gland in a patient with mild systemic symptoms and an elevated erythrocyte sedimentation rate. Serum thyroglobulin (Tg) is elevated and antithyroid antibodies are only marginally increased. A short- lived destruction-induced thyrotoxicosis is followed by several months of hypothyroidism, usually subclinical. Thyroid scintigraphy will show poor thyroid visualization with increased background activity and an RAIU of <5% (Fig- ure 13.8). Most patients are eventually left with a normal thyroid gland, both histologically and functionally. Symptoms respond to non-steroidal or steroidal anti-inﬂammatory agents and beta blockade.

A second variety of thyrotoxic subacute thyroiditis is termed silent lymphocytic thyroiditis and is similar in presentation to de Quervain’s thyroiditis except for the absence of pain, tenderness, and prodromal systemic symptoms. The etiology is thought to be an exacerbation of underlying autoimmune thyroid disease. Thy- roid autoantibodies are present in high titers, but often diminish as the thyrotoxic phase re- solves. A destruction-induced hyperthyroidism

Figure 13.8. Subacute thyroiditis. An anterior^99mTc image reveals markedly reduced activity in the thyroid bed as compared to background and salivary glands. Serum TSH was undetectable.

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is accompanied by markedly suppressed RAIU and mild thyromegaly, all of which resolve over months. This entity presents more frequently in postpartum women (termed postpartum thyroiditis) and tends to recur with subsequent preg- nancies. Many of these women will eventually develop permanent hypothyroidism.

Chronic Hashimoto’s autoimmune lymphocytic thyroiditis is the most common cause of hypothyroidism in the Western world and usually presents in women with a small to moderately- enlarged ﬁrm goiter, elevated antithyroglobulin and/or antimicrosomal (antiperoxidase) antibodies, and rarely any tenderness. Patients may be euthyroid or hypothyroid and rarely hyperthyroid. Scintigraphy reveals inhomogeneous activity throughout the gland in 50%, though a pattern of multinodular goiter, solitary hot nodule, or solitary cold nodule as well as a normal scan may occur. RAIU may be normal, low, or elevated. Biopsy is rarely necessary for diagnosis, and most patients are treated with thyroid hormone supplementation.

Iodine-induced thyrotoxicosis occurs most frequently in patients with pre-existing thyroid disease via the Jod–Basedow phenomenon. Pa- tients with autonomously functioning thyroid adenoma(s), previously treated Graves’ disease, and colloid goiter are most susceptible. Scintigra- phy usually reveals a pattern of MNG, and RAIU is diminished. On the other hand, the patient with iatrogenic or factitious hyperthyroidism will exhibit only background activity on thyroid scintigraphy and may not have a palpable goiter. RAIU will be very low.

Mediastinal Goiter

The most common neoplasms of the anterior mediastinum are thymomas, lymphomas, and germ cell tumors. Although retrosternal thyroid accounts for only 7–10% of all mediastinal masses, the non-invasive demonstration of radioiodine uptake within a mediastinal mass is useful as it avoids more invasive tissue diagnosis. Retroster- nal thyroid tissue is usually the result of inferior extension of a cervical goiter, but may be related to enlargement of ectopic mediastinal thyroid tissue.

Continuity between the cervical and intrathoracic components of a mediastinal goiter may consist of only a narrow ﬁbrous band and may not be demonstrable by CT or ultrasound. If goiter is considered, thyroid scintigraphy should be performed prior to CT imaging to avoid interference

Figure 13.9. Mediastinal goiter. An anterior¹²³I image demonstrates a relatively normal appearing cervical thyroid accompanied by heterogeneous irregular uptake within the superior mediastinum.

by administration of iodinated contrast media, the most common cause of false negatives.

Due to high background activity related to surrounding blood pool activity, ^99mTc images are suboptimal and difficult to interpret. Iodine-123 is the radionuclide of choice for imaging retrosternal thyroid masses.¹²³I scintigraphy yields high-quality images of thoracic goiters, even when uptake is relatively decreased (Figure 13.9). De- spite the fact that clinically significant thyroid cancer occurs in only 4% of mediastinal goiters, the majority of patients with significant mediastinal goiters eventually undergo surgical resection [6].

However, ¹³¹I treatment, sometimes augmented by administration of recombinant human TSH (rhTSH), can be used to reduce the size of the mass and alleviate tracheal compression in appropriate patients.

Neonatal Hypothyroidism

Congenital hypothyroidism (CHT) has an incidence of 1 per 2500–5000 births, and most infants do not exhibit signs or symptoms of hypothyroidism at birth. A delay in the institution

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of thyroxine replacement therapy beyond 6–8 weeks of life is likely to be associated with mea- surable impairment of intellectual function (cre- tinism). Since the institution of newborn screening programs for CHT by measuring serum TSH and/or T₄ levels, the intellectual impairment of CHT has been eradicated in developed countries.

Thyroid dysgenesis (agenesis, hypoplasia, ectopia) is the most common cause of neonatal hypothyroidism in the industrialized world and USA.^99mTc pertechnetate thyroid scintigraphy is performed immediately after CHT is conﬁrmed.

It can easily detect eutopic and ectopic thyroid tissue as well as assess degree of thyroidal uptake [7]. Using a pinhole collimator, a close-up and a more distant view (to include the face and chest) in the anterior projection as well as a lateral view are acquired 20–30 minutes after intravenous injection of 18 MBq (0.5 mCi). A normal image is seen in cases of false positive screening results. A small focus of relatively faint uptake cephalad to the thyroid cartilage is consistent with ectopia and indicates the need for lifelong thyroxine therapy (see Figure 13.4). A eutopic enlarged gland with increased uptake, usually marked, is most consistent with dyshormonogenesis; a small proportion of these are due to transient immaturity of the iodine organiﬁcation process and will be normal at reassessment after age 3 years. Non-visualization of the thyroid on scintigraphy is due to agenesis in over 90% of cases, the remainder being due to the presence of maternal transmission of TSH- receptor blocking antibodies; these latter patients will be euthyroid at reassessment when these maternal antibodies have cleared. Patients with a non- visualized gland or patients with images suggest- ing dyshormonogenesis are all re-evaluated at age 3–4 years to exclude transient CHT; patients with ectopia are not reassessed.

Therefore, thyroid scintigraphy in the neonate is indispensable in the proper diagnostic work-up of congenital hypothyroidism, because it (1) provides a more speciﬁc diagnosis, (2) is cost-effective for selecting patients for subsequent reassessment to uncover transient CHT and allow discontinua- tion of thyroid hormone replacement therapy, and (3) deﬁnes dyshormonogenesis, which is familial and requires genetic counseling [7].

Detection of Thyroid Carcinoma and Metastatic Thyroid Carcinoma

Thyroid carcinoma accounts for 90% of all endocrine malignancies and 1.5% of all malignan-

cies, with approximately 19 000 new cases occurring annually in the USA; but it constitutes only 1200 cancer deaths per year, resulting in a relatively high prevalence of disease with al- most 200 000 patients living in the USA hav- ing undergone thyroidectomy for thyroid cancer and requiring regular assessment. Although 80% of thyroid malignancies are DTCs (papillary and follicular), medullary carcinomas (7%), lymphomas (5%), and undifferentiated anaplastic carcinomas (<5%) present speciﬁc challenges in imaging.

Differentiated Thyroid Carcinoma

Differentiated thyroid cancers (DTC), which con- stitute 80% of thyroid carcinomas, grow slowly, occur in young people, and are frequently respon- sive to therapy (90% 15-year survival). Eighty percent of DTCs are of the papillary or mixed papillary/follicular histology and the remaining are follicular. The behavior of the two tumor types differs, with papillary typically metasta- sizing to locoregional nodes and the lungs and follicular disseminating hematogenously to the bones. DTC usually maintains the capacity to trap and organify iodine and to synthesize and release Tg. These characteristics of DTC allow post- thyroidectomy treatment of iodine-avid disease with high-dose¹³¹I and the monitoring of therapy using (1) radioiodine scintigraphy and (2) serum Tg. However, dedifferentiation occurs to a variable extent with both types of DTC with loss of the iodide symporter and/or loss of Tg expression, thus presenting challenges for imaging and monitoring these patients. Other less differentiated thyroid malignancies have characteristics (such as calcitonin expression or increased glu- cose metabolism) that permit speciﬁc imaging and post-therapy monitoring.

The traditional methods of follow-up for patients with DTC are whole body radioiodine scintigraphy (RIS) and serum Tg monitoring. Op- timal ¹³¹I uptake by neoplastic tissue is TSH- dependent, so RIS is performed under conditions of TSH stimulation, either endogenous via thyroid hormone withdrawal or by exogenous administration of rhTSH. Adequate endogenous TSH levels of greater than 30 mIU/l can be attained 10–14 days after the discontinuance of exogenous tri- iodothyronine (T3) (liothyronine) or 1–4 weeks after the discontinuance of thyroxine (T₄) therapy [8]. Recombinant human TSH (rhTSH) administration as a method of stimulating RAIU (and Tg

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release) is now available for use in patients main- tained on thyroid hormone therapy.

Thyroglobulin is a complex iodinated glyco- protein synthesized and released by both benign and malignant thyroid cells but no other tissues.

Circulating Tg, normally 1–25 ng/ml, should be undetectable in the absence of functioning thyroid tissue. An elevated serum Tg determination (>2 ng/ml) in post-thyroidectomy patients with DTC after¹³¹I ablation of the normal remnant is a highly sensitive and speciﬁc indicator of residual or metastatic thyroid carcinoma. TSH-stimulated Tg determinations are more sensitive for the detection of metastases than are levels done in patients on suppressive therapy. Traditionally, RIS in combination with TSH-stimulated serum Tg measurements are performed due to reports of recurrent disease occurring in the absence of TSH- stimulated Tg elevation.

Whole body RIS is first performed several weeks after thyroidectomy. Due to its potentially ad- verse effects on a fetus, exclusion of pregnancy is mandatory prior to administering scanning doses of¹³¹I. Following the oral administration of 2–5 mCi of¹³¹I, static whole body images are acquired at 48 to 72 hours. A low iodine diet may signifi- cantly increase RAIU into metastatic lesions. Al- though the specificity of¹³¹I scanning is 95%, one must not confuse the normal physiological activity in the salivary glands, nose, gastric mucosa, urinary bladder, bowel, and lactating breast with metastatic disease. Due to hepatic catabolism of iodothyronines, diffuse liver uptake is seen physi- ologically if there is benign or malignant functioning thyroid tissue present. Typically,¹³¹I uptake is not seen in Hürthle cell, medullary, or anaplastic tumors.

The sensitivity of¹³¹I scintigraphy for the detection of persistent or metastatic thyroid carcinoma is 50–70%, dependent in part on the dose administered. Imaging 3–7 days after a therapeutic dose of 3.7–5.4 GBq (100–200 mCi) of¹³¹I may increase the detection of metastatic lesions by up to 45%

[9]. The combination of RIS and serum Tg determination augments the detection of metastatic disease to 85–100% [10, 11].

A schedule of follow-up examinations at 6–

12 month intervals is recommended until the serum Tg is undetectable and RIS demonstrates no pathologic uptake. Scanning at 2–3 year intervals can then be instituted, remembering that 50%

of DTC recurrences occur more than 5 years after initial treatment.

Stunning is the phenomenon in which the initial diagnostic dose of¹³¹I, 75–185 MBq (2–5 mCi), reduces trapping of the subsequently administered treatment dose. The frequency of this effect and its clinical signiﬁcance is controversial, but quantita- tive uptake studies seem to conﬁrm a 30–50% reduction of therapeutic radioiodine uptake as compared to the diagnostic dose. Many investigators now advocate utilizing¹²³I scintigraphy with 37–

185 MBq (1–5 mCi) partly to avoid¹³¹I-induced stunning but also because of the superior image quality. In most reports, there is little if any differ- ence in the sensitivity for detection of thyroid remnant and metastases using¹²³I versus post-therapy high-dose ¹³¹I imaging, and SPECT acquisitions with or without CT fusion can be performed with diagnostic¹²³I imaging when deemed appropriate [12].

Other DTC-avid radiopharmaceuticals such as ²⁰¹Tl, ^99mTc-MIBI, and ¹⁸FDG (¹⁸F-ﬂuoro- deoxyglucose) are most importantly used in the cohort that is ¹³¹I scan-negative but serum Tg- positive, which constitutes about 10–15% of patients with negative diagnostic RIS. These alternative radiopharmaceuticals should not be used instead of RIS unless the patient is known from earlier studies to be¹³¹I-negative. Although skele- tal metastases of DTC are mostly osteolytic,^99mTc diphosphonate scintigraphy is often positive in patients with bone metastases (64–85%) but may not accurately demonstrate the extent of disease.

Thallium-201 whole body scintigraphy has a sensitivity of 60–90% for the detection of metastatic DTC, including ¹³¹I-negative, Tg- positive metastases, and SPECT may increase the sensitivity for the detection of small metastatic foci. False positive ﬁndings may be seen with non- thyroidal tumors, vascular structures, and salivary glands. ^99mTc-MIBI is highly sensitive for the detection of cervical and mediastinal lymphadenopathy, but is less useful for detection of pulmonary metastases. In a large multicenter trial comprising 222 patients, sensitivity of¹⁸FDG PET was 85% for the patients with negative RIS and was signiﬁcantly higher for¹⁸FDG than for ²⁰¹Tl or

99mTc-MIBI [13]. In a review of 14 studies,¹⁸FDG PET exhibited a consistently high sensitivity for detection of recurrent tumor in patients with elevated serum Tg and negative RIS [14]. The higher the serum Tg, the higher the sensitivity for detection of tumor (50% for Tg 10–20 ng/ml and 93% for Tg >100 ng/ml), but ¹⁸FDG PET re- portedly detects 70% of cervical nodes less than

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1 cm in diameter. Furthermore, there is preliminary evidence that¹⁸FDG PET may have prog- nostic importance with 3-year survival of only 18% in patients with a high volume of ¹⁸FDG- avid disease versus 96% survival in those with less bulky disease [15]. Patients whose metastases are ¹⁸FDG-negative have a good prognosis, and

18FDG-positive lesions tend to be resistant to¹³¹I therapy. There is accumulating evidence that TSH stimulation may increase sensitivity for ¹⁸FDG PET detection of metastatic disease by up to 30%, with a 63% increase in tumor-to-background ratio. Many institutions now perform¹⁸FDG PET for thyroid cancer utilizing rhTSH administration or exogenous hormone withdrawal.

Seventy-ﬁve percent of patients with recurrent DTC will have positive¹³¹I scans. When treated with high-dose¹³¹I therapy, many of the remaining RIS-negative patients demonstrate positive post-therapy scans, indicating that their DTC is to some degree iodine-avid. Although the long-term success of¹³¹I therapy in RIS-negative/Tg-positive patients is controversial in regard to outcome, many do demonstrate a post-therapy reduction in serum Tg. Interestingly, 89% of patients with negative diagnostic RIS and elevated serum Tg but no radiographic evidence of tumor experi- ence a signiﬁcant reduction in serum Tg over prolonged follow-up, 68% down to undetectable levels, without¹³¹I or any other treatment [16].

Therefore, the extent of disease and advisability for surgical management in some of these patients with positive post-therapy scans and elevated serum Tg may better be demonstrated by¹⁸FDG PET combined with conventional cross-sectional imaging. Those patients with elevated serum Tg and negative RIS after ¹³¹I therapy are best evaluated with¹⁸FDG PET, resulting in a change in management in over 50%. In fact, the possi- bility of the coexistence of iodine-negative and iodine-positive lesions and the discordance in localization of iodine-positive and¹⁸FDG-positive lesions are clinical challenges that may further increase the clinical utility of¹⁸FDG PET even in the presence of iodine-positive disease.

In summary, most patients who are RIS negative but serum Tg positive will have RIS performed after a therapeutic dose of¹³¹I. If no metastases are identiﬁed with the post-therapy RIS, the patient will be followed using a combination of conventional imaging including chest X-ray, neck ultrasound, and cross-sectional imaging with or without the use of alternative radiopharmaceuti-

cals.¹⁸FDG PET seems to be the radiopharmaceutical of choice and would be expected to be more sensitive than^99mTc-MIBI or²⁰¹Tl for small volume disease.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC), represent- ing approximately 3–5% of all thyroid cancers, is an intermediate grade malignancy occurring in both a sporadic (80%) and a familial (20%) form.

Nearly 50% of patients have metastatic cervical adenopathy at presentation. Five-year survival is 94% in patients with metastatic lymphadenopathy but only 41% in those with extranodal disease. Typically, MTC does not concentrate iodine, so RIS is not useful and¹³¹I treatment results in no improvement in survival or recurrence rate.

Although numerous scintigraphic modalities including¹²³I/¹³¹I-MIBG,^99mTc-(V)-DMSA,

111In octreotide,²⁰¹Tl and ^99mTc-MIBI imaging have been successfully utilized to a varying degree,

18FDG PET is evolving into the primary modality for detection of MTC with a sensitivity of 73–94%

in patients with MTC and elevated calcitonin levels [17].

Somatostatin receptors are present on the cell surface of medullary carcinomas, and many MTC metastases can be visualized using ¹¹¹In-labeled somatostatin receptor scintigraphy (SRS). In patients with recurrent MTC,¹¹¹In octreotide imag- ing detects 44–65% of metastatic lesions, but it is not sensitive for detection of hepatic involvement due to its physiological liver uptake.

In summary, the early detection of recurrent MTC and the localization of the metastases is important because microdissection offers the chance for long-term remission for up to 40% of patients, improvement in symptomatology, reduction in the occurrence of distant metastases, and possibly the prolongation of survival. No single diagnostic modality is able to reliably demonstrate the full extent of disease in these patients, but the combination of cross-sectional radiography (US, CT, MR) with scintigraphy using¹⁸FDG PET or¹¹¹In octreotide is recommended.

Thyroid Lymphoma and Anaplastic Carcinoma

Primary lymphoma of the thyroid, which accounts for less than 5% of all thyroid malignancies, presents as a rapidly enlarging goiter usually in an elderly patient with preexisting autoimmune lymphocytic thyroiditis.^99mTc and¹³¹I scintigraphy as

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well as¹⁸FDG,²⁰¹Tl, and^99mTc-MIBI imaging are of little utility in differentiating thyroid lymphoma from thyroiditis.¹⁸FDG,²⁰¹Tl, and ^99mTc-MIBI activity is increased in lymphoma, so these modalities may be useful in the detection of extrathyroidal lymphoma and its response to therapy.

The rare undifferentiated or anaplastic carcinoma of the thyroid presents as a rapidly enlarging goiter in an elderly individual; survival is extremely poor.^99mTc and¹²³I scintigraphy will demonstrate non-speciﬁc areas of diminished activity. Preliminary reports indicate that ¹⁸FDG PET,²⁰¹Tl, or^99mTc-MIBI imaging may be useful in evaluating recurrent anaplastic carcinoma, especially if CT/US ﬁndings are equivocal.

13.2 The Parathyroid Glands

13.2.1 Introduction

The diagnosis of hyperparathyroidism is made biochemically by the presence of both hypercalcemia and elevated parathyroid hormone (PTH) levels in the serum. The major contribution of imaging techniques is the localization of the source of abnormal PTH production in patients with hyperparathyroidism. Whereas the use of imaging techniques for localization in individuals

undergoing re-exploration for persistent or recurrent hyperparathyroidism is well accepted, substantial controversy surrounds the efﬁcacy and cost effectiveness of localization procedures used prior to initial surgery.

13.2.2 Anatomy

In most cases, there are four parathyroid glands located posterior to the lateral lobes of the thyroid measuring approximately 5 mm in length and weighing about 35 mg each. Three percent of individuals have only three glands, and in approximately 10–13%, there are a variable number of supernumerary glands, most frequently a ﬁfth gland in a thymic location (Figure 13.10).

The superior parathyroids originate from the fourth branchial pouch and migrate in close association with the posterior portion of the thyroid lobes, so only <10% of superior glands are ectopically placed. The inferior parathyroids arise from the third branchial pouch and descend along with the thymus toward the mediastinum. Vari- able location of the inferior glands is related to their migration, with only approximately 60% of them being found in the region of the inferior poles of the thyroid. Up to 39% may be found in the superior pole of the thymus, 2% in the mediastinum, and another 2% ectopically located

Figure 13.10. Normal and aberrant distribution of the parathyroid glands.

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anywhere from the angle of the jaw to the level of the aortic arch. Intrathyroidal parathyroid adenomas may be found in 2–5% of cases. The arterial and venous anatomy supplying the parathyroid glands are variable depending upon the location of the gland, the presence of vascular variance, and previous neck surgery. Knowledge of the venous drainage is a prerequisite for successful diagnostic venous sampling for PTH.

13.2.3 Pathophysiology

Routine automated screening of the general population for serum calcium has resulted in earlier detection of patients with hyperparathyroidism.

More than 80% of patients now are asymptomatic or have non-speciﬁc symptoms with less than 15%

of patients presenting with renal stones. Primary hyperparathyroidism results from a solitary adenoma in over 80% of cases with multiple adenomas, diffuse hyperplasia, or rarely carcinoma accounting for the rest (Table 13.3). Treatment is usually surgical with a success rate of 90–

95% without preoperative localizing procedures.

Recurrent and persistent hyperparathyroidism is usually related to aberrant or ectopically located glands or recurrent hyperplasia. Re-exploration is technically difﬁcult with a higher morbidity and poorer success rate than initial surgery. Pre- operative non-invasive localization improves the cure rate of second surgery from 50–60% up to 90%. Diffuse hyperplasia accounts for approximately 15% of the cases of primary hyperparathyroidism, and a substantial proportion of these may occur in association with the multiple endocrine neoplasias. Secondary hyperparathyroidism in association with chronic renal failure is also related to diffuse hyperplasia, and may require surgical therapy due to progressive bone disease. To- tal parathyroidectomy plus autotransplantation of remnant tissue into upper extremity musculature is the conventional therapy for this group of patients.

Table 13.3. Pathologic classiﬁcation of parathyroid lesions in patients with primary hyperparathyroidism

Class Type Percentage

Adenomas Single 80

Hyperplasia Chief cell 15 Clear cell 1

Carcinoma 4

13.2.4 Parathyroid Scintigraphy

Both thyroid and parathyroid tissue take up

201Tl, whereas only thyroid tissue will trap^99mTc pertechnetate. Beginning in 1983, this principle was exploited for the localization of parathyroid adenomas in patients with primary hyperparathyroidism using combined^99mTc/²⁰¹Tl subtraction imaging. (Table 13.4). Although this technique has a relatively high sensitivity and speciﬁcity for the detection of parathyroid adenomas, it is not sensitive for the detection of hyperplasia or for smaller adenomas. Patient motion during the acquisition of the two sets of images may cause misregistra- tion of data, resulting in both false positive and false negative interpretations [18].

99mTc-MIBI has been found to accumulate in a wide variety of neoplasms including parathyroid adenomas.^99mTc-MIBI is distributed in proportion to blood ﬂow and is sequestered intracellu- larly within the mitochondria. The large number of mitochondria present in the cells of most parathyroid adenomas, especially oxyphil cells, may be responsible for the avid uptake and slow release of^99mTc-MIBI seen in parathyroid adenomas compared to surrounding thyroid tissue. Phys- iological thyroid ^99mTc-MIBI activity gradually washes out with a half-life of 60 minutes, whereas parathyroid activity is stable over 2 hours, thus explaining the better visualization of parathyroid adenomas at 2–3 hours post-injection. Due to its simplicity and the better imaging characteristics of

99mTc, the detection and localization of parathyroid adenomas with^99mTc-MIBI is now the uni- versally preferred nuclear medicine technique.

Typically^99mTc-MIBI parathyroid scintigraphy is performed as a double-phase study. Follow- ing injection with 740 MBq (20 mCi) ^99mTc- MIBI, two sets of planar images of the neck and mediastinum are obtained using a low-energy high-resolution collimator (Table 13.4). The initial set of images acquired at 10–15 minutes post-injection corresponds to the thyroid phase and a second set acquired at 2–3 hours post- injection to the parathyroid phase. A focus of activity in the neck or mediastinum that either progressively increases over the duration of the study or persists on delayed imaging in contrast to the decreased thyroidal activity on the delayed imaging is interpreted as differential washout consistent with parathyroid adenoma (Figure 13.11).

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Table 13.4. Parathyroid imaging

Radiopharmaceutical ^99mTc pertechnetate and²⁰¹Tl ^99mTc sestamibi Activity administered 80 MBq (2 mCi)²⁰¹Tl;

370 MBq (10 mCi)^99mTc

925 MBq (25 mCi) Effective dose equivalent 4.6 mSv (460 mrem) 5 mSv (500 mrem) Patient preparation As for thyroid scanning None

Collimator Converging or low-energy, high-resolution, parallel-hole

Low-energy, parallel-hole, high-resolution Images acquired Inject Tl ﬁrst and acquire 15-min 100 000 count view of

neck and mediastinum. Then acquire similar Tc images without moving patient. Subtract Tc data from Tl after normalization to equal count densities

Anterior (and oblique) views at 15 min and at 2–3 h; SPECT as needed

This double-phase technique for the detection of abnormal parathyroid glands was reported to be successful in 671 of 803 (84%) patients who had adenomas and was successful in 59 of 93 (63%) patients with multiglandular disease or hyperplasia [19]. Because of the lower sensitivity for detection of very small adenomas and hyperplasia, a “normal”^99mTc-MIBI scan, in the context of hyperparathyroidism, should be interpreted with due caution. The mean sensitivity and specificity of preoperative^99mTc-MIBI imaging for the detection of a solitary adenoma is reported to be 91% and 99% respectively [20]. Al- though the parathyroid pathology is usually best visualized on the delayed images, an adenoma is occasionally best seen on the initial images due to rapid washout from the adenoma (Fig- ure 13.12). As with²⁰¹Tl imaging, thyroid pathology and lymphadenopathy may contribute to false positive findings with ^99mTc-MIBI imaging, although specificity is generally reported to be in the range of 95%. In the patient with known thyroid pathology, a dual radioisotope technique may be preferable;^99mTc pertechnetate or¹²³I subtraction has been used with reported sensitivities of 80–

100% and improved speciﬁcity. SPECT may sometimes detect abnormalities not seen on the planar views, and SPECT/CT fusion imaging is promis- ing for improved localization. Both²⁰¹Tl subtraction imaging and positron emission tomography using¹⁸FDG may sometimes detect a parathyroid adenoma not identiﬁed using^99mTc-MIBI scintigraphy.

There is universal agreement on the need for accurate preoperative imaging for localization in patients undergoing reoperative parathyroid exploration and in patients undergoing parathyroid surgery after previous thyroidectomy. With

accurate preoperative localization, reoperation is successful in over 90% of patients probably due to the fact that ectopia is 3–5 times higher and multiglandular disease is twice as high as in patients undergoing initial surgery. In the evaluation of patients with recurrent or persistent hyperparathyroidism, most surgeons prefer cor- relative imaging with at least two and sometimes three modalities, scintigraphy and at least one cross-sectional technique. Using high-frequency transducers, sonography can reliably detect eutopic enlarged parathyroid glands. Although CT scanning has been used successfully, its use is com- promised by artifacts from metallic clips and the anatomic distortion related to post-surgical scar- ring. Magnetic resonance imaging (MRI) with a variety of echo sequences is highly accurate in the detection of aberrant glands in the neck, thoracic inlet, and mediastinum. Recent reports indicate that MRI is approximately 82–88% sensitive and ^99mTc-MIBI scintigraphy is approximately 79–85% sensitive for the accurate localization of parathyroid pathology in patients with recurrent or persistent hyperparathyroidism [21]. The combination of these two modalities has provided a substantial improvement in the sensitivity and positive predictive value in the range of 89–94% for localizing the offend- ing gland(s) in patients with recurrent/persistent hyperparathyroidism.

13.2.5 Conclusions

In summary, parathyroid imaging may not be necessary in the initial preoperative evaluation of patients with primary hyperparathyroidism. Exceptions to this may be patients

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Figure 13.11. Typical cervical parathyroid adenoma. An anterior immediate^99mTc-MIBI image a demonstrates physiological thyroid activity with some prominence at the left lower pole. The 2-hour delayed image b shows a persistent focus of activity in the left neck after washout of the thyroid activity, consistent with an inferior left adenoma.

with prior thyroid surgery, severe hypercalcemia, or severe concurrent medical problems. How- ever, because of the high sensitivity and speci- ﬁcity of ^99mTc-MIBI scintigraphy, routine preoperative localization is becoming a standard practice. In the assessment of patients with

Figure 13.12. Atypical parathyroid adenoma. An anterior immedi- ate^99mTc-MIBI image a demonstrates a focus of increased activity at the lower pole of the right lobe of the thyroid. A 2-hour delayed im- age b reveals washout of physiological thyroid activity as well as the focal increased activity at the right superior thyroid pole. Despite the atypical ﬁndings, a large 1600 mg inferior right parathyroid adenoma was resected with postoperative resolution of hypercalcemia.

recurrent or persistent hyperparathyroidism, localization procedures prior to re-exploration are mandatory.

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13.3 The Adrenal Glands

13.3.1 Introduction

The evaluation of adrenal disorders has been simpliﬁed by the development of sensitive and speciﬁc biochemical tests and by the availabil- ity of high-resolution CT and MR imaging. On the other hand, the exquisite spatial resolution of these imaging modalities has produced the diagnostic conundrum of the adrenal inciden- taloma. The scintigraphic assessment of disorders of the adrenal cortex, such as Cushing’s syndrome, primary aldosteronism, and adrenal hyperandrogenism, is only infrequently required, whereas the ability to survey the whole body for extra-adrenal disease in patients with pheochromocytoma has resulted in an expanding clinical role for adrenal medullary imaging.

13.3.2 Anatomy

Each adrenal gland lies in the retroperitoneal per- inephric space, weighing approximately 4 grams and with a thickness of<10 mm (Figure 13.13).

The right adrenal is triangular and lies above the upper pole of the right kidney, posterior to the inferior vena cava. The left adrenal is crescent- shaped and lies medial to the kidney above the left renal vein.

13.3.3 Physiology

The adrenal gland has a unique functional and anatomical arrangement. The cortical steroid

Figure 13.13. Axial contrast-enhanced abdominal CT image demonstrates the normal location and contour of the adrenal glands.

hormones are synthesized from a common precursor, cholesterol, and secreted from the three con- centric zones of the adrenal cortex. Aldosterone secretion from the outermost zona glomerulosa is modulated by the renin-angiotensin-aldosterone system whereas cortisol secretion from the zona fasciculata and adrenal androgen secretion from the innermost zona reticularis are under control of the hypothalamic-pituitary-adrenal axis.

The adrenal medulla secretion of the prin- cipal catecholamine, epinephrine (adrenaline), is under central sympathetic nervous system control.

13.3.4 Adrenal Cortical Scintigraphy

131I-6β-Iodomethyl-19-norcholesterol (also known as iodocholesterol or NP-59) is the current radiopharmaceutical of choice for adrenal cortical imaging due to its high avidity for the adrenal cortex. Although iodocholesterol remains inves- tigational in the USA, it is commercially available in Europe and Asia, and¹³¹I-6-iodocholesterol is in clinical trials. The main disadvantage of iodocholesterol scintigraphy is the high radiation dose and it should be used selectively, with other imaging modalities.

The incorporation of these agents into adrenocortical cells is related to the precursor status of cholesterol for adrenal steroid synthesis and to the transport of cholesterol and radiocholesterol by low-density lipoprotein (LDL) [22]. The number of LDL cell surface receptors and their afﬁnity for LDL-cholesterol determine the degree of radiocholesterol uptake by the adrenal cortex. An increase in the serum cholesterol reduces uptake by downregulating LDL receptors. Any increase in circulating ACTH results in increased radiocholesterol uptake. Although radiocholesterol is stored in adrenal cortical cells, it is not esteri- ﬁed and therefore not incorporated into adrenal hormones. Several medications, including glu- cocorticoids, diuretics, spironolactone, ketocona- zole, and cholesterol-lowering agents, may inter- fere with radiocholesterol uptake [22].

Following injection, the uptake of the radio- cholesterols is progressive over several days, and there is prolonged retention within the adrenal cortex, permitting imaging over a period of days to weeks. Although adrenal uptake for all of these agents is≤0.2% per gland, total body exposure is relatively high (Table 13.5).

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Table 13.5. Adrenal imaging

Radiopharmaceutical [¹³¹I]iodocholesterol Activity administered 35 MBq (1 mCi) Effective dose equivalent 105 mSv (10 rem) Patient preparation Thyroid blocked

Collimator High-energy, general purpose, parallel-hole

Images acquired Posterior, lateral, anterior, and obliques of the abdomen.

Images taken at about 4 and 7 days post-injection, 20 min exposure per image

The imaging protocol is presented in Table 13.5.

Emphasis is given to the posterior view of the abdomen, and lateral views may be required to differentiate gallbladder uptake from activity in the right adrenal gland. Due to problems with soft tissue attenuation and relatively high variability of percentage uptake between normal glands, the quantitation of differential uptake is trouble- some. Only when uptakes differ by more than 50%

should they be considered abnormal [22].

Although radiotracer uptake reaches its maxi- mum by 48 hours, imaging is usually delayed to day 4 or 5 to allow clearance of background activity. The right adrenal gland frequently appears more intense than the left due to its more posterior location and the superimposition of hepatic activity (Figure 13.14). Visualization of the liver, colon, and gallbladder is physiological. Gastric and bladder activity due to free iodine will usually clear within 48–72 hours post-injection. Bothersome

gastrointestinal activity related to enterohepatic circulation of radiocholesterol can usually be cleared by the administration of laxatives.

Cushing’s Syndrome

The diagnostic accuracy of iodocholesterol scintigraphy for detecting adrenal hyperplasia, adenoma, or carcinoma as the cause of glucocor- ticoid excess is approximately 95%. However, it is rarely necessary in the evaluation of Cushing’s syndrome. Bilateral symmetrical uptake is seen in ACTH-dependent Cushing’s syndrome related to pituitary hypersecretion (Cushing’s disease) or ectopic ACTH secretion (Figure 13.15). Adrenal uptake is generally≥0.3% of the administered dose per gland and will frequently exceed 1% in cases of ectopic ACTH secretion. However, biochemical testing combined with CT and/or MRI is usually successful in localizing the site of ACTH secretion without scintigraphy, except in occasional cases of ectopic ACTH syndrome.

Although non-functioning adrenal adenomas are not¹⁸FDG-avid, functioning cortical adenomas causing Cushing’s syndrome may be detected by¹⁸FDG PET [23]. Virtually all adrenocortical carcinomas are detected by¹⁸FDG PET and can be accurately staged by PET as well [24].

In patients with recurrent Cushing’s syndrome following prior bilateral adrenalectomy, adrenal scintigraphy may be the most sensitive means of localizing functional adrenal remnants [22]. Despite the use of CT, MRI, venography, arteriography, and selective venous

Figure 13.14. Normal¹³¹I iodocholesterol scan demonstrating normal degree of adrenal symmetry. On the posterior abdominal image (A), the right adrenal appears more intense due to its more posterior (and cephalad) location, whereas on the anterior image (B), the left adrenal appears more intense.

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Figure 13.15. The pattern of¹³¹I iodocholesterol imaging in Cushing’s syndrome. a ACTH-dependent, bilateral hyperplasia. b ACTH- independent,bilateral,nodularhyperplasia.cAdrenocorticaladenoma.dAdrenocorticalcarcinoma.(WithpermissionfromGrossMD,Thompson NW, Beierwaltes WH, et al. Scintigraphic approach to the localization of adrenal lesions causing hypertension. Urol Radiol 1981–82; 3(4):242.)

hormone sampling, many of these remnants are difﬁcult to detect without the use of adrenal scintigraphy.

Primary Aldosteronism

Primary aldosteronism presents with hypertension, hypokalemia, and excessive aldosterone secretion with suppression of plasma renin activity and is generally thought to account for<1% of the hypertensive population. However, recent studies

utilizing the plasma aldosterone/plasma renin activity ratio as a screening test suggest that primary aldosteronism has a prevalence as high as 12% [25]. The differentiation of adenoma from bilateral hyperplasia is difﬁcult with biochemical testing without performing bilateral adrenal vein sampling. Aldosteronomas are typically less than 2 cm in diameter and cannot be differentiated from non-functioning adenomas by CT or MRI; hyperplasia is often inferred by absence of a detectable mass.

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Figure 13.16. Dexamethasone suppression¹³¹I iodocholesterol scintigraphy in primary aldosteronism. A, Day 5 posterior image in a patient with an aldosteronoma; physiological left adrenal activity is faint. B, Day 4 posterior image demonstrates early bilateral symmetric activity in a patient with adrenal hyperplasia. (Reprinted with permission. c American Society of Contemporary Medicine and Surgery. Grekin RJ, Gross MD. Endocrine hypertension. Compr Ther. 1983 Feb;9(2):65–74.)

Aldosterone is not regulated by pituitary ACTH secretion. An adenoma cannot be diagnosed on a baseline scan because both adrenal glands are visualized in all patients with primary aldosteronism, and the degree of asymmetry may be identical in patients with bilateral hyperplasia or adenoma. To increase the speciﬁcity, the dexamethasone suppression scan is necessary [22]. Dexamethasone suppression, 4 mg for 7 days before and contin- ued for 5 to 7 days post-injection, results in scans in which the normal cortex is visualized no earlier than the 5th day after iodocholesterol injection. Unilateral adrenal visualization or “break through” before the 5th day post-injection or marked asymmetrical activity thereafter is consistent with adenoma (Figure 13.16). Bilateral adrenal visualization before the 5th day suggests bilateral adrenal cortical hyperplasia. Bilateral uptake after the 5th day may occur in normal subjects.

Accuracy of the dexamethasone suppression scan exceeds 90%.

Hyperandrogenism

Dexamethasone suppression radiocholesterol scintigraphy has been used successfully to identify an adrenal source of androgen hypersecretion. Because cholesterol is the precursor for synthesis of gonadal steroids, iodocholesterol imaging has successfully localized both neoplastic and non-neoplastic (e.g. hyperthecosis) ovar- ian and testicular sources of excess androgen secretion.

13.3.5 Adrenal Medullary Scintigraphy

Pheochromocytomas are catecholamine-secre- ting neoplasms arising from chromafﬁn cells. Ap- proximately 10% are malignant, 10% are bilateral, 10% occur in children, and 10–20% are extra-adrenal in origin (paragangliomas), usually in the abdomen or pelvis but occasionally in the neck or mediastinum. Bilaterality, extra-adrenal sites, and malignancy are more common in children. Because anatomical imaging studies are non- speciﬁc and may not be sensitive for the presence of extra-adrenal foci, bilaterality, or metastatic disease, adrenal medullary scintigraphy may play a pivotal role in the management of patients with pheochromocytoma, paraganglioma, or even neu- roblastoma (see Section 16.7). This is especially important in view of the several-fold higher peri- operative complication rate associated with reoperation.

Radiopharmaceuticals

Metaiodobenzylguanidine (MIBG) is a guanethi- dine analogue similar to norepinephrine that is taken up by adrenergic tissue via expressed plasma membrane norepinephrine transporters and in- tracellular vesicular monoamine transporters.

Uptake may be inhibited by a variety of phar- maceuticals including sympathomimetics, antide- pressants, and some antihypertensives, especially labetalol. These must be withheld for an appropriate length of time before MIBG administration.