13 Thyroid, Parathyroid, and Adrenal Gland Imaging William H. Martin, Martin P. Sandler, and Milton D. Gross

13.1 The Thyroid 13.1.2 Physiology

13.1.1 Anatomy An appreciation of thyroid physiology and patho- physiology is essential for the optimal manage- The thyroid is a bilobed structure evolving from ment of thyroid disorders. The function of the the fourth and fifth branchial pouches. It is ini- thyroid gland includes the concentration of io- tially attached to the ventral floor of the pharynx dine, synthesis of thyroid hormones, storage of by the thyroglossal duct. Thyroid tissue may be these hormones as part of the thyroglobulin (Tg) found anywhere between the base of the tongue molecule in the colloid, and their secretion into and the retrosternal anterior mediastinum (Fig- the circulation as required. Over 99% of circu- ure 13.1). The fetal thyroid gland begins to con- lating thyroid hormones are bound to plasma centrate iodine and synthesize thyroid hormones proteins, primarily thyroxine-binding globulin by approximately 10.5 weeks, which is pertinent (TBG). Only the unbound fraction of thyroid hor- when the administration of 131I to fertile women mone is metabolically active and, for this reason, is contemplated. The two ellipsoid lobes of the accurate assays of free thyroid hormone, “free T4” adult thyroid are joined by a thin isthmus. Each and “free T3”, have been developed. lobe is approximately 2 cm in thickness and Dietary sources of iodine include seafood, milk, width and averages 4–4.5 cm in length. The thy- eggs, and iodized products such as salt and bread. roid gland, averaging approximately 20 grams in Approximately one-third of the absorbed dietary weight, resides in the neck at the level of the cricoid iodide is trapped by the thyroid, the remainder cartilage. A pyramidal lobe is present in approxi- being excreted in the urine. Although gastric mu- mately 30–50%, arising from either the isthmus or cosa, salivary glands, and the lactating breast may the superomedial aspect of either lobe; it under- also trap iodide, none of these organify it. The con- goes progressive atrophy in adulthood but may centration of iodide by the thyroid gland, synthe- be prominent in patients with Graves’ disease. sis, and release of thyroid hormones are under the Although the right lobe tends to be somewhat regulatory control of the hypothalamic-pituitary- larger than the left lobe, there is a great deal of thyroid axis. Thyroid stimulating hormone (TSH) variability in both size and shape of the normal from the pituitary plays the major role in reg- gland. ulating thyroid function and this, in turn, is

247 248 PRACTICAL NUCLEAR MEDICINE

Figure 13.1. Normal and aberrant locations of thyroid tissue. under the control of hypothalamic thyrotropin- play an important role in the investigation of releasing hormone (TRH) secretion. The present patients with thyroid disorders, especially those third generation assay for circulating TSH is highly with thyroid nodules. RAIU is discussed in Sec- sensitive and represents the most sensitive bio- tion 4.12. chemical indicator of both hypothyroidism and hyperthyroidism; the serum TSH is elevated to above 5 mIU/l with even subclinical primary hy- Thyroid Scintigraphy pothyroidism and is suppressed usually to un- With the development of fine needle aspiration detectable levels with hyperthyroidism. Numer- biopsy (FNA) for evaluation of nodular disease ous exogenous factors such as systemic illness, combined with the exquisite anatomic detail pro- nutritional status, thionamides, beta blockers, vided by sonography, CT, and MRI, the use of steroids, iodide, lithium, amiodarone, and anti- thyroid scintigraphy has decreased appropriately. convulsants, may affect thyroid hormone secre- However, it will continue to play an important role tion and metabolism. in the functional evaluation of a variety of thyroid disorders as well as the detection of metastatic thy- 13.1.3 Clinical Applications roid cancer. Technetium-99m pertechnetate is the most readily available radionuclide employed for − Radionuclide imaging and the measurement of thyroid imaging. Pertechnetate ions (TcO4 )are thyroid radioactive iodine uptake (RAIU) both trapped by the thyroid in the same manner as 249 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

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 Withdrawal of thyroid medication, avoidance of of foodstuffs with high iodine content foodstuffs with high iodine content Collimator Pinhole; low-energy, high-resolution Pinhole; low-energy, high-resolution parallel-hole; low energy converging 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 Anterior, right and left anterior oblique views views, 600 second exposure per image or 200 kcounts/image iodine through an active iodine transporter, but equivalent [1]. 123I imaging is used in specific pertechnetate ions are not organified. 123Iodine is situations,suchasretrosternalgoiter.Theprotocol both trapped and organified by the thyroid gland, for thyroid imaging is given in Table 13.1. allowing overall assessment of thyroid function. The normal thyroid scintigram is shown in Since 123I is cyclotron-produced and has a rel- Figure 13.2. High-resolution images are obtained atively short half-life of 13.6 hours, it is more by using a pinhole collimator, thus permitting the expensive and advance notice is necessary for detection of nodules as small as 5 mm in diameter. imaging. Because of its inferior image quality and The oblique views permit detection of small nod- the high thyroid and total body radiation dose ules obscured by overlying or underlying physio- from its β-emission, 131I is not used for routine logical activity. Pinhole SPECT has been used to thyroid imaging other than for metastatic thyroid better detect subtle abnormalities. The radionu- cancer assessment. Due primarily to less back- clide is distributed homogeneously throughout ground activity, 123I imaging provides somewhat the gland with some increase seen centrally due higher quality images than 99mTc, but the diag- to physiological thickness of the gland there; ac- nostic information provided by each is roughly tivity within the isthmus is variable and must

Figure 13.2. Normal 99mTc thyroid scan. Symmetric, homogeneous uptake with less intense salivary gland uptake and only mild back- ground uptake. The inferior activity is due to a 57Co marker at the suprasternal notch. 250 PRACTICAL NUCLEAR MEDICINE

Figure13.3. Subtlecoldnodule. 99mTcpertechnetateanteriorviewademonstratesasubtlehypofunctioningleftlowerpolenoduleextending into the isthmus, confirmed on a subsequent contrast-enhanced CT b to be a thyroid cyst.

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 nod- ule, 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 Figure 13.4. Lingual ectopic thyroid. An anterior 99mTc pertechne- tate image demonstrates a focus of activity at the base of the tongue The patient with multinodular goiter (MNG) may in this neonate. Cervical thyroid uptake is absent. present with what seems to be a solitary thyroid nodule, diffuse enlargement of the gland, or hy- perthyroidism. Development of MNG is related be correlated with physical examination and/or to cycling periods of stimulation followed by in- other imaging (Figure 13.3). With pertechnetate, volution and may be idiopathic or occur as a re- salivary glands, gastric mucosa, esophagus, and sult of endemic iodine deficiency. Over time the blood pool background are seen in addition to gland enlarges and evolves into an admixture of thyroid activity. Due to delayed imaging, salivary fibrosis, functional nodules, and non-functioning gland activity is often absent with 123I imaging. involuted nodules. Scintigraphically, the MNG 251 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

biopsied. The differential diagnosis includes au- toimmune Hashimoto’s thyroiditis, multiple ade- nomas, 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 thy- roid nodule remains controversial, related to the high incidence of nodules, the infrequency of thy- roid malignancy, and the relatively low morbid- ity and mortality associated with differentiated thyroid cancer (DTC) [2]. Thyroid nodules may contain normal thyroid tissue, benign hypofunc- tioning tissue (solid, cystic, or complex), hyper- plastic or autonomously functioning benign tis- Figure13.5. Graves’disease. 99mTcthyroidscanshowsapyramidal sue, or malignant neoplasm. The evaluation of lobe emanating from the medial aspect of the right lobe. Note the the patient with a solitary thyroid nodule is di- convexcontouroftheglandandthediminishedbackgroundactivity. rected towards differentiating benign from malig- nant etiologies. Autopsy series have demonstrated a 50% incidence of single or multiple thyroid is a heterogeneously-appearing, asymmetrically nodule(s), only 4% of which are malignant. Ul- enlarged gland with multiple cold, warm, and hot trasonography detects single or multiple thyroid areas of various sizes (Figure 13.6). The incidence nodules in 40% of patients with no known thy- of thyroid carcinoma in MNG is low at 1–6%, but roid disease. The incidence of thyroid nodules in- a dominant or enlarging cold nodule should be creases 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. 252 PRACTICAL NUCLEAR MEDICINE 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 hypofunc- tioning, but only 10–20% of cold nodules are malignant [2]. The remaining hypofunctioning nodules consist of degenerative nodules, nodular hemorrhage, cysts, thyroiditis, infiltrative disor- ders such as amyloid, and non-thyroid neoplasms. Clinical features that suggest thyroid cancer in- clude male gender, a prior history of radiation exposure up to 15 Gy (1500 rad), a family his- tory 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 re- lated 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 de- tection 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 deter- minations to improve the accuracy of clinical as- sessment 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) tis- sue, most are autonomously functioning thyroid nodules (AFTN) arising independently of TSH Figure 13.7. Autonomously functioning thyroid nodule. a An stimulation. Biochemical hyperthyroidism, often anterior 99mTc thyroid image reveals a focus of increased up- subclinical, is present in 74% of patients at pre- take in the lower pole of the right lobe consistent with a sentation, although overt hyperthyroidism is less hyperfunctioning nodule. The normal extranodular thyroid ac- common. Over a period of 3 years after detec- tivity is indicative of euthyroidism. b A focus of markedly in- tion, 33% of AFTNs enlarge in patients not re- creased activity in the lower pole of the left lobe accompanied ceiving definitive therapy, and 24% of euthyroid by virtual complete suppression of extranodular activity and de- patients develop hyperthyroidism [3]. In euthy- creased background and salivary gland activity is consistent with roid patients, surrounding extranodular thyroid toxic adenoma, subsequently confirmed by an undetectable serum tissue will be visible (Figure 13.7a), thyroid func- TSH. tion studies will be normal, and these patients can be followed on an annual basis. If hyperthyroidism 253 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING exists, the surrounding normal thyroid tissue low identification of the various disease processes will be suppressed, and the TSH level will be that may be responsible. undetectable (Figure 13.7b). Spontaneous cystic Graves’ disease (autoimmune diffuse toxic goi- degeneration occurs in 27%, manifested by central ter) is due to the presence of thyroid-stimulating photopenia; there is little concern for malignancy. immunoglobulins and is associated with autoim- Discordant thyroid imaging is a dissociation be- mune exophthalmos and pretibial myxedema. Al- tween trapping and organification, measured re- though it occurs primarily in young women, it spectively with 99mTc pertechnetate and 123I. It may also occur in children and in the elderly. occurs in only 2–8% of thyroid nodules and is Radioiodine uptake will usually be elevated at 4 not specific for malignant disease. A nodule that hours and/or 24 hours, and the gland will re- traps 99mTc (hot) but is unable to organify iodine veal diffuse enlargement in most cases with in- (cold) is much more likely to be benign than ma- creased thyroid activity and minimal background lignant.Ifitisassumedthat8%ofhotnoduleswith and salivary gland activity (Figure 13.5). Hyper- 99mTc are cold with 123I, and if 10% of those are plasia of the pyramidal remnant is seen as in- malignant, then less than 1% of hot nodules seen creased paramedial activity in as many as 43% of with 99mTc imaging are malignant. Additional ra- Graves’ patients. Occasionally, the gland will ap- dioiodine imaging of hot nodules identified on a pear normal size. The low RAIU (usually ≤5%) 99mTc scan should probably be reserved for pa- of hyperthyroid patients with subacute thyroidi- tients deemed at higher risk for malignancy. tis, postpartum thyroiditis, silent thyroiditis, and surreptitious thyroid hormone administration is Hyperthyroidism easily differentiated from the normal RAIU seen in the occasional patient with Graves’ disease Hyperthyroidism is a clinical syndrome of tachy- (Table 13.2). Although ultrasound demonstrates cardia, weight loss, and hypermetabolism re- an enlarged homogeneously hypoechoic gland sulting from supraphysiological circulating lev- with prominent vascularity on color-flow Doppler els of thyroid hormones, leading to suppression imaging (“thyroid inferno”), it is usually unnec- of TSH secretion. Most cases of hyperthyroidism essary for diagnosis clinically. The thyroid scan are due to increased endogenous synthesis and should easily be able to distinguish toxic nodu- secretion of thyroid hormones from the thyroid. lar goiters from Graves’ disease. The clinical im- Other less common etiologies are shown in Table portance of this is that many patients with toxic 13.2. Clinical assessment combined with circulat- nodular goiter will require a higher dose of 131I for ing hormone and thyroid autoantibody measure- therapy than will Graves’ disease patients. ments, thyroid scintigraphy, and RAIU usually al- Radioiodine Therapy of Hyperthyroidism Table 13.2. Classification of hyperthyroidism Graves’ disease and toxic nodular goiter may be Radioiodine treated successfully with 131I therapy. Radioio- Etiology uptake dine was first used for the treatment of hyper- A. Thyroid gland (95%) thyroidism in 1941 and has since evolved to the Diffuse toxic goiter (Graves’ disease) ↑ treatment modality of choice for the majority of Toxic nodule goiter: ↑ adult patients, particularly in the USA. Antithy- multinodular (Plummer’s disease) roid drug therapy achieves a permanent remis- solitary nodule ↑ Thyroiditis (subacute/chronic) ↓ sion in only 10–40% of patients, but is used ini- B.Exogenousthyroidhormone/iodine(4%) tially in many patients, particularly in Europe and Iatrogenic ↓ Asia. Although subtotal thyroidectomy is effective Factitious ↓ and complications are infrequent, thyroidectomy Iodine-induced (Jod–Basedow) ↓ is used only occasionally at present. It is normally C. Rarely encountered causes (1%) limited to patients in whom radioiodine is un- Hypothalamic-pituitary neoplasms ↑ suitable, such as women who may be pregnant, or Struma ovarii ↓ who have extremely large goiters with compressive ↑ Excessive HCG production by trophoblastic symptoms. Radioiodine therapy is effective, prac- tissue tical, inexpensive, and available on an outpatient Metastatic thyroid carcinoma ↓ basis. 254 PRACTICAL NUCLEAR MEDICINE

Prior to initiation of therapy, the diagnosis of per gram of thyroid tissue for the usual patient hyperthyroidism must be confirmed by elevation with Graves’ disease. Even higher dosages of up of thyroid hormone levels and suppression of cir- to 7.4 MBq (200 µCi) per gram will be used to culating TSH. An elevated RAIU confirms that en- produce a more rapid response in patients with dogenous thyroidal secretion is the source of the severe hyperthyroidism. The calculation is made hyperthyroidism and aids in excluding other eti- as follows: administered microcuries = µCi/g de- ologiesofhyperthyroidism,suchassilentthyroidi- sired × gland weight (g) × 100 ÷ percent uptake tis, subacute thyroiditis, postpartum thyroiditis, (24 hours). A higher dose may also be required iodine-induced hyperthyroidism, and factitious for patients with toxic nodular goiter, in patients hyperthyroidism, all of which are associated with previously treated with antithyroid medications, a low RAIU (Table 13.2). Rarely, clinical hyper- patients with extremely large glands, patients with thyroidism with diffuse goiter and elevated RAIU rapid iodine turnover (a 4 h/24 h RAIU ratio >1), may be related to excessive secretion of human and in patients with renal insufficiency. Although chorionic gonadotropin (HCG) by a trophoblas- estimation of thyroid size is relatively accurate for tic tumor or by inappropriate secretion of TSH glands weighing less than 60 grams, the degree of by a functioning pituitary adenoma. The presence inaccuracy increases in larger glands. Ultrasound of exophthalmos, pretibial myxedema, and diffuse may provide an accurate estimation of size, but goiter on physical examination confirms Graves’ the increase in accuracy of thyroid radiation dose disease as the etiology. Otherwise, thyroid scintig- determination is limited. raphy is useful to differentiate diffuse involvement The complications of radioiodine therapy in- due to Graves’ disease from localized disease due clude rare exacerbation of hyperthyroidism, pos- to AFTN. sible exacerbation of existing Graves’ orbitopathy, The patient must be counseled prior to therapy and post-therapeutic hypothyroidism. It is esti- regarding the advantages and disadvantages of al- mated that less than 10% of patients require re- ternative therapies. Because iodide readily crosses treatment, and this is rarely undertaken before the placenta, 131I may not be administered during 3–4 months following therapy. Most practition- pregnancy so a pregnancy test is mandatory prior ers will give at least 20–30% more radioiodine on to administration. Exposure of the fetus to 131I af- a second treatment. Pretreatment with antithyroid ter the 10th week of gestation may result in severe medications is advisable in elderly patients, in pa- fetal hypothyroidism. tients with known cardiac disease, and in patients The effectiveness of radioiodine treatment for with large thyroid glands, particularly multinodu- hyperthyroidism is due to radiation-induced cel- lar goiters. These medications should be discon- lular damage resulting from high-energy beta tinued 48–72 hours prior to administration of emission, the magnitude of which is directly pro- 131I, and it is preferable to wait several days be- portional to the radiation dose received by the fore reinitiation of therapy. The administration of thyroid gland. The major effect of radiation is im- beta blockers before or after therapy serves only pairment of the reproductive capacity of follicular to ameliorate peripheral manifestations of hyper- cells. The radiation dose to the thyroid is related thyroidism and will not affect therapeutic efficacy to (1) the amount of radioiodine administered, of radioiodine. (2) the fraction deposited in the gland (uptake), The incidence of early post-131Ihypothyroidism (3) the duration of retention by the thyroid (bio- varies from 10% to 50% according to the dose ad- logic half-life), and (4) the radiosensitivity of the ministered. Subsequently, there is an additional irradiated tissue. Administered dose is usually cal- incidence of hypothyroidism at a relatively con- culated with the goal of administering approxi- stant rate of 2–3% per year. A similar incidence of mately 70–120 Gy (7000–12 000 rad) to the thy- hypothyroidism occurs following surgery. Some roid gland [4]. Some practitioners have adopted a degree of hypothyroidism may be a natural conse- fixed dose administration, usually approximately quence of the autoimmune process of Graves’ dis- 370 MBq (10 mCi) with perhaps 300 MBq (8 mCi) ease, since a small percentage of patients treated for a small gland and 440–520 MBq (12 to 14 mCi) only with antithyroid medications will become for a large gland. In the UK, a relatively larger fixed hypothyroid during long-term follow-up after re- dose of 550 MBq (15 mCi) is given to the major- mission. ity of adult patients [5]. Other practitioners will Although radiation exposure of more than calculate a dose of 3–4.4 MBq (80 to 120 µCi) 500 mGy (50 rad) is reported to increase the 255 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING occurrence of leukemia, with a peak incidence at CT and/or sonography; scintigraphy is only rarely approximately 6 years after exposure, a single 131I performed. treatment delivers only 80–160 mGy (8–16 rad) Subacute (de Quervain’s) thyroiditis is a be- to the blood and has not been associated with any nign, self-limited transient inflammatory disease increased incidence of leukemia, thyroid cancer, of the thyroid, presumed to be of viral etiol- infertility, or congenital malformations. Although ogy. It may affect the gland diffusely or fo- the desire for subsequent pregnancy is not a con- cally and usually presents as a tender gland in traindication to radioiodine therapy for hyper- a patient with mild systemic symptoms and an thyroidism, patients are usually advised to avoid elevated erythrocyte sedimentation rate. Serum conception for 6 months in case retreatment is thyroglobulin (Tg) is elevated and antithyroid required. antibodies are only marginally increased. A short- Following radioiodine therapy, the patient lived destruction-induced thyrotoxicosis is fol- should be advised to have serum thyroid hormone lowed by several months of hypothyroidism, usu- and TSH levels checked within 2 to 3 months. Pa- ally subclinical. Thyroid scintigraphy will show tients may be symptomatically improved within poor thyroid visualization with increased back- 4 to 6 weeks, but clinically significant hypothy- ground activity and an RAIU of <5% (Fig- roidism rarely occurs before 2 to 3 months. Hy- ure 13.8). Most patients are eventually left with pothyroidism is only a problem if not adequately a normal thyroid gland, both histologically and treated, and many practitioners will initiate thy- functionally. Symptoms respond to non-steroidal roxine replacement therapy at the earliest indica- or steroidal anti-inflammatory agents and beta tion of post-therapy hypothyroidism. blockade. A second variety of thyrotoxic subacute Thyroiditis thyroiditis is termed silent lymphocytic thyroidi- tis and is similar in presentation to de Quervain’s Thyroiditis may be classified as acute, subacute, thyroiditis except for the absence of pain, ten- chronic/autoimmune, and other miscellaneous derness, and prodromal systemic symptoms. The types; these different types of thyroiditis are un- etiology is thought to be an exacerbation of related to each other (see Further Reading). Acute underlying autoimmune thyroid disease. Thy- suppurative thyroiditis is rare and is caused by roid autoantibodies are present in high titers, hematogenous spread of infectious organisms. but often diminish as the thyrotoxic phase re- This is usually defined clinically and evaluated by 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. 256 PRACTICAL NUCLEAR MEDICINE 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 thy- roiditis) and tends to recur with subsequent preg- nancies. Many of these women will eventually de- velop permanent hypothyroidism. Chronic Hashimoto’s autoimmune lympho- cytic thyroiditis is the most common cause of hy- pothyroidism in the Western world and usually presents in women with a small to moderately- enlarged firm goiter, elevated antithyroglobulin and/or antimicrosomal (antiperoxidase) antibod- ies, and rarely any tenderness. Patients may be euthyroid or hypothyroid and rarely hyperthy- roid. 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 ele- vated. Biopsy is rarely necessary for diagnosis, and most patients are treated with thyroid hormone supplementation. Iodine-induced thyrotoxicosis occurs most fre- quently in patients with pre-existing thyroid disease via the Jod–Basedow phenomenon. Pa- Figure 13.9. Mediastinal goiter. An anterior 123I image demon- tients with autonomously functioning thyroid strates a relatively normal appearing cervical thyroid accompanied adenoma(s), previously treated Graves’ disease, byheterogeneousirregularuptakewithinthesuperiormediastinum. and colloid goiter are most susceptible. Scintigra- phy usually reveals a pattern of MNG, and RAIU is by administration of iodinated contrast media, the diminished. On the other hand, the patient with most common cause of false negatives. iatrogenic or factitious hyperthyroidism will ex- Due to high background activity related to sur- hibit only background activity on thyroid scintig- rounding blood pool activity, 99mTc images are raphy and may not have a palpable goiter. RAIU suboptimal and difficult to interpret. Iodine-123 will be very low. is the radionuclide of choice for imaging ret- rosternal thyroid masses. 123I scintigraphy yields Mediastinal Goiter high-quality images of thoracic goiters, even when uptake is relatively decreased (Figure 13.9). De- The most common neoplasms of the anterior me- spite the fact that clinically significant thyroid can- diastinum are thymomas, lymphomas, and germ cer occurs in only 4% of mediastinal goiters, the cell tumors. Although retrosternal thyroid ac- majority of patients with significant mediastinal counts for only 7–10% of all mediastinal masses, goiters eventually undergo surgical resection [6]. the non-invasive demonstration of radioiodine However, 131I treatment, sometimes augmented uptake within a mediastinal mass is useful as it by administration of recombinant human TSH avoids more invasive tissue diagnosis. Retroster- (rhTSH), can be used to reduce the size of the mass nal thyroid tissue is usually the result of inferior and alleviate tracheal compression in appropriate extension of a cervical goiter, but may be related to patients. enlargement of ectopic mediastinal thyroid tissue. Continuity between the cervical and intrathoracic Neonatal Hypothyroidism components of a mediastinal goiter may consist of only a narrow fibrous band and may not be Congenital hypothyroidism (CHT) has an in- demonstrable by CT or ultrasound. If goiter is cidence of 1 per 2500–5000 births, and most considered, thyroid scintigraphy should be per- infants do not exhibit signs or symptoms of formed prior to CT imaging to avoid interference hypothyroidism at birth. A delay in the institution 257 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING of thyroxine replacement therapy beyond 6–8 cies, with approximately 19 000 new cases oc- weeks of life is likely to be associated with mea- curring annually in the USA; but it constitutes surable impairment of intellectual function (cre- only 1200 cancer deaths per year, resulting in tinism). Since the institution of newborn screen- a relatively high prevalence of disease with al- ing programs for CHT by measuring serum TSH most 200 000 patients living in the USA hav- and/or T4 levels, the intellectual impairment of ing undergone thyroidectomy for thyroid can- CHT has been eradicated in developed countries. cer and requiring regular assessment. Although Thyroid dysgenesis (agenesis, hypoplasia, ec- 80% of thyroid malignancies are DTCs (papil- topia) is the most common cause of neonatal lary and follicular), medullary carcinomas (7%), hypothyroidism in the industrialized world and lymphomas (5%), and undifferentiated anaplastic USA. 99mTc pertechnetate thyroid scintigraphy is carcinomas (<5%) present specific challenges in performed immediately after CHT is confirmed. imaging. 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 Differentiated Thyroid Carcinoma more distant view (to include the face and chest) Differentiated thyroid cancers (DTC), which con- in the anterior projection as well as a lateral view stitute 80% of thyroid carcinomas, grow slowly, are acquired 20–30 minutes after intravenous in- occur in young people, and are frequently respon- jection of 18 MBq (0.5 mCi). A normal image is sive to therapy (90% 15-year survival). Eighty seen in cases of false positive screening results. A percent of DTCs are of the papillary or mixed small focus of relatively faint uptake cephalad to papillary/follicular histology and the remaining the thyroid cartilage is consistent with ectopia and are follicular. The behavior of the two tumor indicates the need for lifelong thyroxine therapy types differs, with papillary typically metasta- (see Figure 13.4). A eutopic enlarged gland with sizing to locoregional nodes and the lungs and increased uptake, usually marked, is most consis- follicular disseminating hematogenously to the tent with dyshormonogenesis; a small proportion bones. DTC usually maintains the capacity to trap of these are due to transient immaturity of the io- and organify iodine and to synthesize and re- dine organification process and will be normal at lease Tg. These characteristics of DTC allow post- reassessment after age 3 years. Non-visualization thyroidectomy treatment of iodine-avid disease of the thyroid on scintigraphy is due to agene- with high-dose 131I and the monitoring of ther- sis in over 90% of cases, the remainder being due apy using (1) radioiodine scintigraphy and (2) to the presence of maternal transmission of TSH- serum Tg. However, dedifferentiation occurs to receptor blocking antibodies; these latter patients a variable extent with both types of DTC with will be euthyroid at reassessment when these ma- loss of the iodide symporter and/or loss of Tg ex- ternalantibodieshavecleared.Patientswithanon- pression, thus presenting challenges for imaging visualized gland or patients with images suggest- and monitoring these patients. Other less differ- ing dyshormonogenesis are all re-evaluated at age entiated thyroid malignancies have characteristics 3–4 years to exclude transient CHT; patients with (such as calcitonin expression or increased glu- ectopia are not reassessed. cose metabolism) that permit specific imaging and Therefore, thyroid scintigraphy in the neonate post-therapy monitoring. is indispensable in the proper diagnostic work-up The traditional methods of follow-up for pa- of congenital hypothyroidism, because it (1) pro- tients with DTC are whole body radioiodine vides a more specific diagnosis, (2) is cost-effective scintigraphy (RIS) and serum Tg monitoring. Op- for selecting patients for subsequent reassessment timal 131I uptake by neoplastic tissue is TSH- to uncover transient CHT and allow discontinua- dependent, so RIS is performed under conditions tion of thyroid hormone replacement therapy, and of TSH stimulation, either endogenous via thyroid (3) defines dyshormonogenesis, which is familial hormone withdrawal or by exogenous administra- and requires genetic counseling [7]. tion of rhTSH. Adequate endogenous TSH levels of greater than 30 mIU/l can be attained 10–14 Detection of Thyroid Carcinoma and Metastatic days after the discontinuance of exogenous tri- Thyroid Carcinoma iodothyronine (T3) (liothyronine) or 1–4 weeks after the discontinuance of thyroxine (T4) therapy Thyroid carcinoma accounts for 90% of all en- [8]. Recombinant human TSH (rhTSH) adminis- docrine malignancies and 1.5% of all malignan- tration as a method of stimulating RAIU (and Tg 258 PRACTICAL NUCLEAR MEDICINE release) is now available for use in patients main- Stunningisthephenomenoninwhichtheinitial tained on thyroid hormone therapy. diagnostic dose of 131I, 75–185 MBq (2–5 mCi), Thyroglobulin is a complex iodinated glyco- reducestrappingofthesubsequentlyadministered protein synthesized and released by both benign treatment dose. The frequency of this effect and its and malignant thyroid cells but no other tissues. clinical significance is controversial, but quantita- Circulating Tg, normally 1–25 ng/ml, should be tive uptake studies seem to confirm a 30–50% re- undetectable in the absence of functioning thy- duction of therapeutic radioiodine uptake as com- roid tissue. An elevated serum Tg determination pared to the diagnostic dose. Many investigators (>2 ng/ml) in post-thyroidectomy patients with now advocate utilizing 123I scintigraphy with 37– DTC after 131I ablation of the normal remnant is a 185 MBq (1–5 mCi) partly to avoid 131I-induced highly sensitive and specific indicator of residual stunning but also because of the superior image or metastatic thyroid carcinoma. TSH-stimulated quality. In most reports, there is little if any differ- Tg determinations are more sensitive for the de- ence in the sensitivity for detection of thyroid rem- tection of metastases than are levels done in pa- nant and metastases using 123I versus post-therapy tients on suppressive therapy. Traditionally, RIS high-dose 131I imaging, and SPECT acquisitions in combination with TSH-stimulated serum Tg with or without CT fusion can be performed with measurements are performed due to reports of re- diagnostic 123I imaging when deemed appropriate current disease occurring in the absence of TSH- [12]. stimulated Tg elevation. Other DTC-avid radiopharmaceuticals such Whole body RIS is first performed several weeks as 201Tl, 99mTc-MIBI, and 18FDG (18F-fluoro- after thyroidectomy. Due to its potentially ad- deoxyglucose) are most importantly used in the verse effects on a fetus, exclusion of pregnancy is cohort that is 131I scan-negative but serum Tg- mandatory prior to administering scanning doses positive, which constitutes about 10–15% of pa- of 131I. Following the oral administration of 2–5 tients with negative diagnostic RIS. These alter- mCi of 131I, static whole body images are acquired native radiopharmaceuticals should not be used at 48 to 72 hours. A low iodine diet may signifi- instead of RIS unless the patient is known from cantly increase RAIU into metastatic lesions. Al- earlier studies to be 131I-negative. Although skele- though the specificity of 131I scanning is 95%, one tal metastases of DTC are mostly osteolytic, 99mTc must not confuse the normal physiological activ- diphosphonate scintigraphy is often positive in pa- ity in the salivary glands, nose, gastric mucosa, tients with bone metastases (64–85%) but may not urinary bladder, bowel, and lactating breast with accurately demonstrate the extent of disease. metastatic disease. Due to hepatic catabolism of Thallium-201 whole body scintigraphy has iodothyronines, diffuse liver uptake is seen physi- a sensitivity of 60–90% for the detection of ologically if there is benign or malignant function- metastatic DTC, including 131I-negative, Tg- ing thyroid tissue present. Typically, 131I uptake is positive metastases, and SPECT may increase the not seen in Hurthle¨ cell, medullary, or anaplastic sensitivity for the detection of small metastatic tumors. foci. False positive findings may be seen with non- The sensitivity of 131I scintigraphy for the detec- thyroidal tumors, vascular structures, and sali- tion of persistent or metastatic thyroid carcinoma vary glands. 99mTc-MIBI is highly sensitive for is 50–70%, dependent in part on the dose admin- the detection of cervical and mediastinal lym- istered. Imaging 3–7 days after a therapeutic dose phadenopathy, but is less useful for detection of of 3.7–5.4 GBq (100–200 mCi) of 131I may increase pulmonary metastases. In a large multicenter trial the detection of metastatic lesions by up to 45% comprising 222 patients, sensitivity of 18FDG PET [9]. The combination of RIS and serum Tg de- was 85% for the patients with negative RIS and was termination augments the detection of metastatic significantly higher for 18FDG than for 201Tl or disease to 85–100% [10, 11]. 99mTc-MIBI [13]. In a review of 14 studies, 18FDG A schedule of follow-up examinations at 6– PET exhibited a consistently high sensitivity for 12 month intervals is recommended until the detection of recurrent tumor in patients with ele- serum Tg is undetectable and RIS demonstrates vated serum Tg and negative RIS [14]. The higher no pathologic uptake. Scanning at 2–3 year inter- the serum Tg, the higher the sensitivity for de- vals can then be instituted, remembering that 50% tection of tumor (50% for Tg 10–20 ng/ml and of DTC recurrences occur more than 5 years after 93% for Tg >100 ng/ml), but 18FDG PET re- initial treatment. portedly detects 70% of cervical nodes less than 259 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

1 cm in diameter. Furthermore, there is prelim- cals. 18FDG PET seems to be the radiopharmaceu- inary evidence that 18FDG PET may have prog- tical of choice and would be expected to be more nostic importance with 3-year survival of only sensitive than 99mTc-MIBI or 201Tl for small vol- 18% in patients with a high volume of 18FDG- ume disease. avid disease versus 96% survival in those with less bulky disease [15]. Patients whose metastases Medullary Thyroid Carcinoma are 18FDG-negative have a good prognosis, and Medullary thyroid carcinoma (MTC), represent- 18FDG-positive lesions tend to be resistant to 131I ing approximately 3–5% of all thyroid cancers, is therapy. There is accumulating evidence that TSH an intermediate grade malignancy occurring in stimulation may increase sensitivity for 18FDG both a sporadic (80%) and a familial (20%) form. PET detection of metastatic disease by up to 30%, Nearly 50% of patients have metastatic cervical with a 63% increase in tumor-to-background ra- adenopathy at presentation. Five-year survival is tio. Many institutions now perform 18FDG PET 94% in patients with metastatic lymphadenopa- for thyroid cancer utilizing rhTSH administration thy but only 41% in those with extranodal dis- or exogenous hormone withdrawal. ease. Typically, MTC does not concentrate iodine, Seventy-five percent of patients with recurrent so RIS is not useful and 131I treatment results in DTC will have positive 131I scans. When treated no improvement in survival or recurrence rate. with high-dose 131I therapy, many of the remain- Although numerous scintigraphic modali- ing RIS-negative patients demonstrate positive ties including 123I/131I-MIBG, 99mTc-(V)-DMSA, post-therapy scans, indicating that their DTC is to 111In octreotide, 201Tl and 99mTc-MIBI imaging some degree iodine-avid. Although the long-term have been successfully utilized to a varying degree, success of 131I therapy in RIS-negative/Tg-positive 18FDG PET is evolving into the primary modality patients is controversial in regard to outcome, for detection of MTC with a sensitivity of 73–94% many do demonstrate a post-therapy reduction in patients with MTC and elevated calcitonin lev- in serum Tg. Interestingly, 89% of patients with els [17]. negative diagnostic RIS and elevated serum Tg Somatostatin receptors are present on the cell but no radiographic evidence of tumor experi- surface of medullary carcinomas, and many MTC ence a significant reduction in serum Tg over metastases can be visualized using 111In-labeled prolonged follow-up, 68% down to undetectable somatostatin receptor scintigraphy (SRS). In pa- levels, without 131I or any other treatment [16]. tients with recurrent MTC, 111In octreotide imag- Therefore, the extent of disease and advisability ing detects 44–65% of metastatic lesions, but it is for surgical management in some of these patients not sensitive for detection of hepatic involvement with positive post-therapy scans and elevated due to its physiological liver uptake. serum Tg may better be demonstrated by 18FDG In summary, the early detection of recurrent PET combined with conventional cross-sectional MTC and the localization of the metastases is im- imaging. Those patients with elevated serum portant because microdissection offers the chance Tg and negative RIS after 131I therapy are best for long-term remission for up to 40% of patients, evaluated with 18FDG PET, resulting in a change improvement in symptomatology, reduction in in management in over 50%. In fact, the possi- the occurrence of distant metastases, and possibly bility of the coexistence of iodine-negative and the prolongation of survival. No single diagnostic iodine-positive lesions and the discordance in lo- modality is able to reliably demonstrate the full calization of iodine-positive and 18FDG-positive extent of disease in these patients, but the com- lesions are clinical challenges that may further bination of cross-sectional radiography (US, CT, increase the clinical utility of 18FDG PET even in MR) with scintigraphy using 18FDG PET or 111In the presence of iodine-positive disease. octreotide is recommended. In summary, most patients who are RIS neg- ative but serum Tg positive will have RIS per- Thyroid Lymphoma and Anaplastic Carcinoma formed after a therapeutic dose of 131I. If no metas- tases are identified with the post-therapy RIS, the Primary lymphoma of the thyroid, which ac- patient will be followed using a combination of counts for less than 5% of all thyroid malignancies, conventional imaging including chest X-ray, neck presents as a rapidly enlarging goiter usually in an ultrasound, and cross-sectional imaging with or elderly patient with preexisting autoimmune lym- without the use of alternative radiopharmaceuti- phocytic thyroiditis. 99mTc and 131I scintigraphy as 260 PRACTICAL NUCLEAR MEDICINE well as 18FDG, 201Tl, and 99mTc-MIBI imaging are undergoing re-exploration for persistent or recur- of little utility in differentiating thyroid lymphoma rent hyperparathyroidism is well accepted, sub- from thyroiditis. 18FDG, 201Tl, and 99mTc-MIBI stantial controversy surrounds the efficacy and activity is increased in lymphoma, so these modal- cost effectiveness of localization procedures used ities may be useful in the detection of extrathy- prior to initial surgery. roidal lymphoma and its response to therapy. The rare undifferentiated or anaplastic carci- noma of the thyroid presents as a rapidly en- 13.2.2 Anatomy larging goiter in an elderly individual; survival is extremely poor. 99mTc and 123I scintigraphy will In most cases, there are four parathyroid glands demonstrate non-specific areas of diminished ac- located posterior to the lateral lobes of the thy- tivity. Preliminary reports indicate that 18FDG roid measuring approximately 5 mm in length PET, 201Tl, or 99mTc-MIBI imaging may be use- and weighing about 35 mg each. Three percent ful in evaluating recurrent anaplastic carcinoma, of individuals have only three glands, and in ap- especially if CT/US findings are equivocal. proximately 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 13.2 The Parathyroid Glands fourth branchial pouch and migrate in close as- sociation with the posterior portion of the thy- 13.2.1 Introduction roid lobes, so only <10% of superior glands are ectopically placed. The inferior parathyroids arise The diagnosis of hyperparathyroidism is made from the third branchial pouch and descend along biochemically by the presence of both hypercal- with the thymus toward the mediastinum. Vari- cemia and elevated parathyroid hormone (PTH) able location of the inferior glands is related to levels in the serum. The major contribution of their migration, with only approximately 60% of imaging techniques is the localization of the them being found in the region of the inferior source of abnormal PTH production in patients poles of the thyroid. Up to 39% may be found with hyperparathyroidism. Whereas the use of in the superior pole of the thymus, 2% in the imaging techniques for localization in individuals mediastinum, and another 2% ectopically located

Figure 13.10. Normal and aberrant distribution of the parathyroid glands. 261 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING anywhere from the angle of the jaw to the level of 13.2.4 Parathyroid Scintigraphy the aortic arch. Intrathyroidal parathyroid adeno- mas may be found in 2–5% of cases. The arterial and venous anatomy supplying the parathyroid Both thyroid and parathyroid tissue take up glands are variable depending upon the location 201Tl, whereas only thyroid tissue will trap 99mTc of the gland, the presence of vascular variance, and pertechnetate. Beginning in 1983, this principle previous neck surgery. Knowledge of the venous was exploited for the localization of parathyroid drainage is a prerequisite for successful diagnostic adenomas in patients with primary hyperparathy- venous sampling for PTH. roidism using combined 99mTc/201Tl subtraction imaging. (Table13.4). Although this technique has 13.2.3 Pathophysiology a relatively high sensitivity and specificity for the detection of parathyroid adenomas, it is not sensi- tive for the detection of hyperplasia or for smaller Routine automated screening of the general pop- adenomas. Patient motion during the acquisition ulation for serum calcium has resulted in earlier of the two sets of images may cause misregistra- detection of patients with hyperparathyroidism. tion of data, resulting in both false positive and More than 80% of patients now are asymptomatic false negative interpretations [18]. or have non-specific symptoms with less than 15% 99mTc-MIBI has been found to accumulate in a of patients presenting with renal stones. Primary wide variety of neoplasms including parathyroid hyperparathyroidism results from a solitary ade- adenomas. 99mTc-MIBI is distributed in propor- noma in over 80% of cases with multiple ade- tion to blood flow and is sequestered intracellu- nomas, diffuse hyperplasia, or rarely carcinoma larly within the mitochondria. The large number accounting for the rest (Table 13.3). Treatment of mitochondria present in the cells of most is usually surgical with a success rate of 90– parathyroid adenomas, especially oxyphil cells, 95% without preoperative localizing procedures. may be responsible for the avid uptake and slow re- Recurrent and persistent hyperparathyroidism is lease of 99mTc-MIBIseeninparathyroidadenomas usually related to aberrant or ectopically located compared to surrounding thyroid tissue. Phys- glands or recurrent hyperplasia. Re-exploration iological thyroid 99mTc-MIBI activity gradually is technically difficult with a higher morbidity washes out with a half-life of 60 minutes, whereas and poorer success rate than initial surgery. Pre- parathyroid activity is stable over 2 hours, thus operative non-invasive localization improves the explaining the better visualization of parathyroid cure rate of second surgery from 50–60% up to adenomas at 2–3 hours post-injection. Due to its 90%. Diffuse hyperplasia accounts for approxi- simplicity and the better imaging characteristics of mately 15% of the cases of primary hyperparathy- 99mTc, the detection and localization of parathy- roidism, and a substantial proportion of these may roid adenomas with 99mTc-MIBI is now the uni- occur in association with the multiple endocrine versally preferred nuclear medicine technique. neoplasias. Secondary hyperparathyroidism in Typically 99mTc-MIBI parathyroid scintigraphy association with chronic renal failure is also is performed as a double-phase study. Follow- related to diffuse hyperplasia, and may require sur- ing injection with 740 MBq (20 mCi) 99mTc- gical therapy due to progressive bone disease. To- MIBI, two sets of planar images of the neck and tal parathyroidectomy plus autotransplantation of mediastinum are obtained using a low-energy remnant tissue into upper extremity musculature high-resolution collimator (Table 13.4). The ini- is the conventional therapy for this group of pa- tial set of images acquired at 10–15 minutes tients. post-injection corresponds to the thyroid phase and a second set acquired at 2–3 hours post- Table 13.3. Pathologic classification of parathyroid lesions in injection to the parathyroid phase. A focus of patients with primary hyperparathyroidism activity in the neck or mediastinum that ei- Class Type Percentage ther progressively increases over the duration of the study or persists on delayed imaging in Adenomas Single 80 contrast to the decreased thyroidal activity on Hyperplasia Chief cell 15 the delayed imaging is interpreted as differen- Clear cell 1 tial washout consistent with parathyroid adenoma Carcinoma 4 (Figure 13.11). 262 PRACTICAL NUCLEAR MEDICINE

Table 13.4. Parathyroid imaging Radiopharmaceutical 99mTc pertechnetate and 201Tl 99mTc sestamibi Activity administered 80 MBq (2 mCi) 201Tl; 925 MBq (25 mCi) 370 MBq (10 mCi) 99mTc 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, Low-energy, parallel-hole, parallel-hole high-resolution Images acquired Inject Tl first and acquire 15-min 100 000 count view of Anterior (and oblique) views at 15 min neck and mediastinum. Then acquire similar Tc and at 2–3 h; SPECT as needed images without moving patient. Subtract Tc data from Tl after normalization to equal count densities

This double-phase technique for the detection accurate preoperative localization, reoperation is of abnormal parathyroid glands was reported to successful in over 90% of patients probably due be successful in 671 of 803 (84%) patients who to the fact that ectopia is 3–5 times higher and had adenomas and was successful in 59 of 93 multiglandular disease is twice as high as in pa- (63%) patients with multiglandular disease or tients undergoing initial surgery. In the eval- hyperplasia [19]. Because of the lower sensitiv- uation of patients with recurrent or persistent ity for detection of very small adenomas and hyperparathyroidism, most surgeons prefer cor- hyperplasia, a “normal” 99mTc-MIBI scan, in the relative imaging with at least two and sometimes context of hyperparathyroidism, should be inter- three modalities, scintigraphy and at least one preted with due caution. The mean sensitivity cross-sectional technique. Using high-frequency and specificity of preoperative 99mTc-MIBI imag- transducers, sonography can reliably detect eu- ing for the detection of a solitary adenoma is re- topic enlarged parathyroid glands. Although CT ported to be 91% and 99% respectively [20]. Al- scanning has been used successfully, its use is com- though the parathyroid pathology is usually best promised by artifacts from metallic clips and the visualized on the delayed images, an adenoma anatomic distortion related to post-surgical scar- is occasionally best seen on the initial images ring. Magnetic resonance imaging (MRI) with due to rapid washout from the adenoma (Fig- a variety of echo sequences is highly accurate ure 13.12). As with 201Tl imaging, thyroid pathol- in the detection of aberrant glands in the neck, ogy and lymphadenopathy may contribute to false thoracic inlet, and mediastinum. Recent reports positive findings with 99mTc-MIBI imaging, al- indicate that MRI is approximately 82–88% sen- though specificity is generally reported to be in the sitive and 99mTc-MIBI scintigraphy is approx- range of 95%. In the patient with known thyroid imately 79–85% sensitive for the accurate lo- pathology, a dual radioisotope technique may be calization of parathyroid pathology in patients preferable; 99mTc pertechnetate or 123Isubtraction with recurrent or persistent hyperparathyroidism has been used with reported sensitivities of 80– [21]. The combination of these two modali- 100% and improved specificity. SPECT may some- ties has provided a substantial improvement in times detect abnormalities not seen on the planar the sensitivity and positive predictive value in views, and SPECT/CT fusion imaging is promis- the range of 89–94% for localizing the offend- ing for improved localization. Both 201Tl subtrac- ing gland(s) in patients with recurrent/persistent tion imaging and positron emission tomography hyperparathyroidism. using 18FDG may sometimes detect a parathyroid adenoma not identified using 99mTc-MIBI scintig- raphy. 13.2.5 Conclusions There is universal agreement on the need for accurate preoperative imaging for localization in In summary, parathyroid imaging may not be patients undergoing reoperative parathyroid ex- necessary in the initial preoperative evalua- ploration and in patients undergoing parathy- tion of patients with primary hyperparathy- roid surgery after previous thyroidectomy. With roidism. Exceptions to this may be patients 263 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

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 Figure 13.12. Atypical parathyroid adenoma. An anterior immedi- delayed image b shows a persistent focus of activity in the left neck ate 99mTc-MIBI image a demonstrates a focus of increased activity at after washout of the thyroid activity, consistent with an inferior left the lower pole of the right lobe of the thyroid. A 2-hour delayed im- adenoma. age b reveals washout of physiological thyroid activity as well as the focal increased activity at the right superior thyroid pole. Despite the atypicalfindings,alarge1600mginferiorrightparathyroidadenoma was resected with postoperative resolution of hypercalcemia. 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 pre- recurrent or persistent hyperparathyroidism, operative localization is becoming a standard localization procedures prior to re-exploration are practice. In the assessment of patients with mandatory. 264 PRACTICAL NUCLEAR MEDICINE

13.3 The Adrenal Glands hormonesaresynthesizedfromacommonprecur- sor, cholesterol, and secreted from the three con- 13.3.1 Introduction centric zones of the adrenal cortex. Aldosterone secretion from the outermost zona glomerulosa is The evaluation of adrenal disorders has been modulated by the renin-angiotensin-aldosterone simplified by the development of sensitive and system whereas cortisol secretion from the zona specific biochemical tests and by the availabil- fasciculata and adrenal androgen secretion from ity of high-resolution CT and MR imaging. On the innermost zona reticularis are under con- the other hand, the exquisite spatial resolution trol of the hypothalamic-pituitary-adrenal axis. of these imaging modalities has produced the The adrenal medulla secretion of the prin- diagnostic conundrum of the adrenal inciden- cipal catecholamine, epinephrine (adrenaline), taloma. The scintigraphic assessment of disorders is under central sympathetic nervous system of the adrenal cortex, such as Cushing’s syndrome, control. primary aldosteronism, and adrenal hyperandro- genism, is only infrequently required, whereas the ability to survey the whole body for extra-adrenal 13.3.4 Adrenal Cortical Scintigraphy disease in patients with pheochromocytoma has 131 β resulted in an expanding clinical role for adrenal I-6 -Iodomethyl-19-norcholesterol (also kno- medullary imaging. wn as iodocholesterol or NP-59) is the current ra- diopharmaceutical of choice for adrenal cortical 13.3.2 Anatomy imaging due to its high avidity for the adrenal cortex. Although iodocholesterol remains inves- tigational in the USA, it is commercially available Each adrenal gland lies in the retroperitoneal per- 131 inephric space, weighing approximately 4 grams in Europe and Asia, and I-6-iodocholesterol is and with a thickness of <10 mm (Figure 13.13). in clinical trials. The main disadvantage of iodoc- The right adrenal is triangular and lies above the holesterol scintigraphy is the high radiation dose upper pole of the right kidney, posterior to the and it should be used selectively, with other imag- inferior vena cava. The left adrenal is crescent- ing modalities. shaped and lies medial to the kidney above the left The incorporation of these agents into adreno- renal vein. cortical cells is related to the precursor status of cholesterol for adrenal steroid synthesis and to the transport of cholesterol and radiocholesterol 13.3.3 Physiology by low-density lipoprotein (LDL) [22]. The num- ber of LDL cell surface receptors and their affinity The adrenal gland has a unique functional and for LDL-cholesterol determine the degree of ra- anatomical arrangement. The cortical steroid diocholesterol 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 radio- cholesterol 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 Figure 13.13. Axial contrast-enhanced abdominal CT image agents is ≤0.2% per gland, total body exposure is demonstratesthenormallocationandcontouroftheadrenalglands. relatively high (Table 13.5). 265 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

Table 13.5. Adrenal imaging gastrointestinal activity related to enterohepatic Radiopharmaceutical [131I]iodocholesterol circulation of radiocholesterol can usually be cleared by the administration of laxatives. Activity administered 35 MBq (1 mCi) Effective dose equivalent 105 mSv (10 rem) Cushing’s Syndrome Patient preparation Thyroid blocked Collimator High-energy, general purpose, The diagnostic accuracy of iodocholesterol parallel-hole scintigraphy for detecting adrenal hyperplasia, Images acquired Posterior, lateral, anterior, and adenoma, or carcinoma as the cause of glucocor- obliques of the abdomen. ticoid excess is approximately 95%. However, it Images taken at about 4 and 7 days post-injection, is rarely necessary in the evaluation of Cushing’s 20 min exposure per image syndrome. Bilateral symmetrical uptake is seen in ACTH-dependent Cushing’s syndrome related to pituitary hypersecretion (Cushing’s disease) or ec- The imaging protocol is presented in Table13.5. topic ACTH secretion (Figure 13.15). Adrenal up- Emphasis is given to the posterior view of the take is generally ≥0.3% of the administered dose abdomen, and lateral views may be required to per gland and will frequently exceed 1% in cases differentiate gallbladder uptake from activity in of ectopic ACTH secretion. However, biochemical the right adrenal gland. Due to problems with testing combined with CT and/or MRI is usually soft tissue attenuation and relatively high variabil- successful in localizing the site of ACTH secretion ity of percentage uptake between normal glands, without scintigraphy, except in occasional cases of the quantitation of differential uptake is trouble- ectopic ACTH syndrome. some. Only when uptakes differ by more than 50% Although non-functioning adrenal adenomas should they be considered abnormal [22]. are not 18FDG-avid, functioning cortical adeno- Although radiotracer uptake reaches its maxi- mas causing Cushing’s syndrome may be detected mum by 48 hours, imaging is usually delayed to by 18FDG PET [23]. Virtually all adrenocortical day 4 or 5 to allow clearance of background ac- carcinomas are detected by 18FDG PET and can tivity. The right adrenal gland frequently appears be accurately staged by PET as well [24]. more intense than the left due to its more posterior In patients with recurrent Cushing’s syn- location and the superimposition of hepatic activ- drome following prior bilateral adrenalectomy, ity (Figure 13.14). Visualization of the liver, colon, adrenal scintigraphy may be the most sen- and gallbladder is physiological. Gastric and blad- sitive means of localizing functional adrenal der activity due to free iodine will usually clear remnants [22]. Despite the use of CT, MRI, within 48–72 hours post-injection. Bothersome venography, arteriography, and selective venous

Figure 13.14. Normal 131I 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. 266 PRACTICAL NUCLEAR MEDICINE

Figure 13.15. The pattern of 131I 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 utilizing the plasma aldosterone/plasma renin ac- difficult to detect without the use of adrenal tivity ratio as a screening test suggest that pri- scintigraphy. mary aldosteronism has a prevalence as high as 12% [25]. The differentiation of adenoma from Primary Aldosteronism bilateral hyperplasia is difficult with biochemical testing without performing bilateral adrenal vein Primary aldosteronism presents with hyperten- sampling. Aldosteronomas are typically less than sion, hypokalemia, and excessive aldosterone se- 2cmindiameterandcannotbedifferentiatedfrom cretion with suppression of plasma renin activity non-functioning adenomas by CT or MRI; hyper- and is generally thought to account for <1% of the plasia is often inferred by absence of a detectable hypertensive population. However, recent studies mass. 267 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

Figure 13.16. Dexamethasone suppression 131I 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 13.3.5 Adrenal Medullary Scintigraphy secretion. An adenoma cannot be diagnosed on a baseline scan because both adrenal glands are visu- Pheochromocytomas are catecholamine-secre- alized in all patients with primary aldosteronism, ting neoplasms arising from chromaffin cells. Ap- and the degree of asymmetry may be identical in proximately 10% are malignant, 10% are bilat- patients with bilateral hyperplasia or adenoma. To eral, 10% occur in children, and 10–20% are increase the specificity, the dexamethasone sup- extra-adrenal in origin (paragangliomas), usually pression scan is necessary [22]. Dexamethasone in the abdomen or pelvis but occasionally in the suppression, 4 mg for 7 days before and contin- neck or mediastinum. Bilaterality, extra-adrenal ued for 5 to 7 days post-injection, results in scans sites, and malignancy are more common in chil- in which the normal cortex is visualized no ear- dren.Becauseanatomicalimagingstudiesarenon- lier than the 5th day after iodocholesterol injec- specific and may not be sensitive for the presence tion. Unilateral adrenal visualization or “break of extra-adrenal foci, bilaterality, or metastatic dis- through” before the 5th day post-injection or ease, adrenal medullary scintigraphy may play a marked asymmetrical activity thereafter is con- pivotal role in the management of patients with sistent with adenoma (Figure 13.16). Bilateral pheochromocytoma,paraganglioma,orevenneu- adrenal visualization before the 5th day suggests roblastoma (see Section 16.7). This is especially bilateral adrenal cortical hyperplasia. Bilateral up- important in view of the several-fold higher peri- takeafterthe5thdaymayoccurinnormalsubjects. operative complication rate associated with reop- Accuracy of the dexamethasone suppression scan eration. exceeds 90%. Radiopharmaceuticals Hyperandrogenism Metaiodobenzylguanidine (MIBG) is a guanethi- Dexamethasone suppression radiocholesterol dine analogue similar to norepinephrine that is scintigraphy has been used successfully to taken up by adrenergic tissue via expressed plasma identify an adrenal source of androgen hyper- membrane norepinephrine transporters and in- secretion. Because cholesterol is the precursor tracellular vesicular monoamine transporters. for synthesis of gonadal steroids, iodocholesterol Uptake may be inhibited by a variety of phar- imaging has successfully localized both neoplastic maceuticals including sympathomimetics, antide- and non-neoplastic (e.g. hyperthecosis) ovar- pressants, and some antihypertensives, especially ian and testicular sources of excess androgen labetalol. These must be withheld for an appro- secretion. priate length of time before MIBG administration. 268 PRACTICAL NUCLEAR MEDICINE

Table 13.6. Pheochromocytoma and sympathomedullary imaging Radiopharmaceutical 123I-MIBG 131I-MIBG Activity administered 400 MBq (10 mCi) 20 MBq (0.5 mCi) Effective dose 6 mSv (600 mrem) 3 mSv (300 mrem) equivalent Patient preparation Lugol’s solution or a saturated solution of Lugol’s solution or a saturated solution of potassium potassium iodide (100 mg twice a day) begun iodide (100 mg twice a day) begun the day prior to the day prior to administration of the administration of the radiopharmaceutical and radiopharmaceutical and continued for 4 days continued for 7 days afterwards afterwards Collimator Low-energy, high-resolution, parallel-hole High-energy, general purpose, parallel-hole Images acquired Whole body images, anterior and posterior, 10 Whole body images, anterior and posterior, 20 minutes per step, at 24 h (and 48 h as needed). minutes per step, at 24 and 48 h (and 72 h as SPECT of abdomen needed)

Although both 131I and 123I have been used to label the image quality is superior (Figure 13.17), sensi- MIBG, 123I is preferable because of its favorable tivity is higher, and SPECT can be routinely used dosimetry and imaging characteristics. Plasma to more accurately localize abnormalities; fusion clearance of MIBG is rapid, with 50–70% of the with CT or MR data is promising. Physiological dose excreted unchanged into the urine within 24 activity is typically seen within the liver, spleen, hours. Due to the release of free radioiodine from bladder, and salivary glands. Faint activity is seen theradiopharmaceutical,theco-administrationof in the normal adrenal medulla in 16% of cases stable iodine to block thyroid uptake is necessary. using 131I-MIBG and in over 25% of cases using 123I-MIBG. Relatively faint activity is also seen in Technique the myocardium and lungs, especially early. Free radioiodine will localize to the gastric mucosa and The imaging protocol is presented in Table 13.6. later in the colon. The uterus may be visualized Although posterior images of the abdomen are during menstruation. Importantly, no skeletal ac- most important, whole body imaging is recom- tivity is normally present. Anatomical variations mended for detection of paragangliomas and in the renal collecting system may lead to false metastatic disease. When 123I-MIBG is utilized, positive imaging results.

Figure 13.17. Anterior and posterior 123I-MIBG images show a unilateral right pheochromocytoma without additional abnormal foci to suggest metastatic disease. Note the physiological distribution of the MIBG and the improved image quality as compared to 131I-MIBG (Figure 13.18). 269 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

Figure13.18. Metastaticpheochromocytoma:48-hourwholebodyposterioraandanteriorb 131I-MIBGimagesdemonstratemultiplenodal and skeletal metastases.

Clinical Applications of proven catecholamine excess due to the low (2%) yield of unsuspected findings [26]. However, The diagnosis of pheochromocytoma is made in patients with suspected pheochromocytoma by the laboratory demonstration of elevated who have negative imaging findings with CT catecholamines in the plasma and/or urine. Since and MRI, MIBG scintigraphy can be very useful, most adrenal pheochromocytomas are larger than especially in view of its high negative predictive 2 cm in diameter, they are readily identified using value. CT or MR imaging. Since adrenal masses occur in Although the sensitivity of CT for the detection approximately 3% of the population, functional of metastatic and extra-adrenal pheochromocy- imaging with MIBG has been recommended to toma is high, CT specificity is relatively poor in the confirm that the mass is a pheochromocytoma post-surgical patient. The evaluation of suspected and to exclude multiple tumors and metastatic recurrent pheochromocytoma requires multiple disease preoperatively (Figures 13.17 and 13.18). modalities and should include whole body MIBG However,somehavenotadvocatedtheuseoffunc- imaging (Figure 13.18). False negative MIBG re- tional imaging in the preoperative assessment of sults in such cases may be related to the pres- patients with a solitary adrenal mass in the context ence of interfering pharmaceuticals or necrotic 270 PRACTICAL NUCLEAR MEDICINE tumor. However, malignant pheochromocytoma may dedifferentiate and thus no longer accumu- late MIBG. In these instances, 18FDG PET imag- ing or 111In octreotide scintigraphy may better demonstrate the extent of metastatic disease (Fig- ure 13.19). Benign pheochromocytoma is also of- ten 18FDG positive although 18FDGismoreof- ten taken up by malignant pheochromocytoma [27]. Dopamine is a better substrate for the nore- pinephrine transporter than other amines, and the use of 18F-fluorodopamine (DA) PET is promising for the determination of metastatic disease extent, especially in patients whose tumor is not MIBG- avid [27]. Most neuroendocrine tumors express so- matostatin receptors, and somatostatin receptor scintigraphy (SRS) using 111In octreotide has been reported to be highly sensitive (>90%) for the de- tection of head and neck paragangliomas. How- ever, SRS has been reported to have a sensitivity as low as 25% for the detection of primary adrenal pheochromocytoma [28]. SRS is at least as sensi- tive as MIBG imaging for detection of metastatic pheochromocytoma (87% versus 57% of lesions) [28].Therefore,SRSisnotrecommendedasafirst- line modality for detection of suspected primary pheochromocytoma. 123I-MIBG imaging may be especially useful in children who more frequently have heredi- tary syndromes (multiple endocrine neoplasia, von Hippel–Lindau, neurofibromatosis, familial pheochromocytoma, and Carney’s triad) and are at higher risk for multifocality, extra-adrenal dis- ease and malignant disease. Bilateral uptake due to medullary hyperplasia may be demonstrated by Figure 13.19. Metastatic pheochromocytoma. A 18FDG PET im- MIBG scintigraphy, but sensitivity is insufficient age demonstrates widespread nodal and parenchymal metastases to exclude contralateral disease [28]. It must be re- in this 39-year-old man who presented with labile hypertension. membered that MIBG imaging, SRS, and 18FDG Biopsy of a hypermetabolic cervical node revealed pheochromo- PET may detect other neuroendocrine tumors cytoma. (With permission from Scanga DR, Martin WH, Delbeke such as medullary thyroid carcinoma, carcinoid, D. Value of FDG PET imaging in the management of patients with and islet cell tumors as well as neuroblastoma and thyroid,neuroendocrine,andneuralcresttumors.ClinNuclMed2004; 29(2):86–90.) small cell lung carcinoma (see Section 16.7). This is especially important in patients with hereditary mary aldosteronism when CT and MR imaging syndromes. Functional imaging with MIBG is es- are equivocal, (2) in the detection of functioning pecially useful in differentiating pheochromocy- adrenal remnant in the patient with recur- toma from neurofibromas in affected individuals. rent/persistent Cushing’s syndrome despite prior bilateral adrenalectomy, and (3) in the charac- 13.3.6 Conclusions terization of ACTH-independent adrenal cortical nodular hyperplasia. In summary, radiocholesterol imaging of the Pheochromocytoma and paragangliomas adrenal cortex is most useful in (1) the differ- are diagnosed by demonstrating circulating entiation of hyperplasia from adenoma in pri- catecholamine excess and are virtually always 271 THYROID, PARATHYROID, AND ADRENAL GLAND IMAGING

localized accurately by CT or MR imaging. MIBG 11. Lupin E, Mechlis-Frish S, Zatz S. Serum thyroglobulin and imaging is complementary to CT/MR and can iodine-131 whole-body scan in the diagnosis and assess- be utilized before initial surgery to confirm that ment of treatment for metastatic differentiated thyroid car- cinoma. J Nucl Med 1994; 35:257–262. the detected mass is a pheochromocytoma and to 12. Alzahrani AS, Bakheet S, Mandil MA, et al. 123I isotope as detect multifocal, extra-adrenal, and metastatic a diagnostic agent in the follow-up of patients with differ- disease. 123I-MIBG is preferable to 131I-MIBG be- entiated thyroid cancer: Comparison with post 131I ther- cause of better dosimetry, higher quality images, apy whole body scanning. J Clin Endocrinol Metab 2001; 86:5294–5300. the ability to use SPECT, and probably higher 13. Grunwald F, Kalicke T, Feine U, et al. Fluorine-18 fluo- sensitivity. 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