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Radioiodine whole-body scintigraphy (WBS), which takes advantage of the high avidity of radioiodine in the functioning thyroid tissues, has been used for detection of differentiated thyroid cancer. Radioiodine is a sensitive marker for detection of thyroid cancer; however, radioiodine uptake is not specific for thyroid tissue. It can also be seen in healthy tissue, including thymus, breast, liver, and gastrointestinal tract, or in benign diseases, such as cysts and inflammation, or in a variety of benign and malignant non-thyroidal tumors, which could be mistaken for thyroid cancer. In order to accurately interpret radioiodine scintigraphy results, one must be familiar with the normal physiologic distribution of the tracer and frequently encountered physiologic and pathologic variants of radioiodine uptake. This article will provide a systematic overview of potential false-positive uptake of radioiodine in the whole body and illustrate how such unexpected findings can be appropriately evaluated.
Differentiated thyroid cancer (DTC) is a favorable malignant tumor, and is associated with a lower risk of death, compared with most other malignancies . Radioiodine has been used for more than five decades for diagnosis and treatment of patients with DTC, with reliance on the fact that trapping, organification, and storage of iodine is more prominent in functioning thyroid tissues than other tissues [2,3]. In particular, on the molecular level, enhanced expression of sodium-iodide symporter (NIS) is a key mechanism of radioiodine uptake in functioning thyroid tissues [4-6]. Radioiodine whole-body scintigraphy (WBS) is an integral part of detection of NIS expression in patients suffering from recurrent or metastatic thyroid cancer and in selection of patients who might benefit from radioiodine therapy [7-9]. Precise interpretation of radioiodine WBS can result in avoidance of futile exposure to high-dose radioiodine and lead patients to optimal management of thyroid cancer, as well as other non-thyroidal disease.
A considerable number of cases of unexpected radioiodine uptake have been reported. Although the mechanism is not fully understood, it can be categorized as follows: 1) functional NIS expression (in normal tissues, including thymus, breast, salivary glands, and gastrointestinal tract, or various benign and malignant tumors), 2) metabolism of radioiodinated thyroid hormone, 3) retention of radioiodinated body fluids (saliva, tears, blood, urine, exudate, transudate, gastric and mucosal secretions, etc.) associated with or without structural change, 4) retention and uptake of radioiodine in inflamed tissue, 5) contamination by physiologic secretions, and 6) unknown. The experienced nuclear medicine physician can differentiate malignant from physiologic radioiodine uptake; however, some findings may remain ambiguous. The first step in evaluation of a patient with suspected residual or recurrent thyroid cancer is correlation of normal or abnormal scintigraphic findings with anatomical imaging, available biochemical data, clinical history, and physical examination. The objectives of this article are to describe the mechanism and distribution of radioiodine uptake, list and discuss normal physiologic variants, list and discuss benign and malignant pathologic causes, and suggest interpretative points for use in differential diagnosis of unusual radioiodine uptake in WBS.
In order to better understand the physiology of radioiodine uptake, a thorough understanding of the relationship between iodine and the thyroid gland is important. Iodine is an element with a high atomic number, 53, and is an essential component of hormones produced by the thyroid gland . The recommended daily intake of iodine is 150 μg. Absorption of almost all ingested iodine (>90%) from occurs rapidly; it is distributed in the extracellular iodine pool, which it leaves via transport into the thyroid gland or by renal excretion (Figure 1) [10,11]. In its organic form, iodine is converted mostly to iodide prior to absorption. Exchange of plasma iodide with iodide in red blood cells occurs rapidly, whereas exchange of iodide between extracellular compartments occurs both rapidly and slowly . The kidneys account for more than 90% of iodide excreted from the body. Iodide is also secreted from the blood into the colon; however, the fecal route contributes only about 1% of total iodide clearance from the body .
The cellular mechanism for iodine uptake in thyroid follicular cells is illustrated in Figure 2. NIS on the apical membrane of enterocytes mediates active iodide uptake. This active, energy-requiring process can lead to concentration of iodide in thyrocytes, some 20-40-fold above its level in the circulation . Within the follicular cells, iodide moves toward the apical membrane to enter into the follicular lumen via pendrin, a membrane iodide-chloride cotransporter; it is then oxidized to iodine by peroxidase [10,11]. Thyroid hormones are produced in the thyroid gland by oxidation, organification, and coupling processes, and are finally released into the blood-stream for their action which is an essential for the regulation of a large number of bodily functions, e.g., energy expenditure and metabolic rate . The majority of thyroid hormones in the thyroid gland and plasma are levothyroxine (T4). Most T4 is converted to triiodothyronine (T3), a more metabolically more active form, by deiodination in liver, skeletal muscle, kidney, brain, and other tissues, while the rest is conjugated with sulfate and glucuronide in the liver, excreted in bile, and partially hydrolyzed in the bowel . This could be a possible reason that diffuse hepatic uptake of radioiodine is frequently observed in WBS.
I-131 is produced in a nuclear reactor by neutron bombardment of natural tellurium (Te-127) and decays by beta emission to xenon-133 (Xe-133), with a half-life of 8.02 days; it also emits gamma emissions (Table 1). It most often (89% of the time) expends its 971 keV of decay energy by transforming into the stable Xe-131, in two steps; gamma decay rapidly following after beta decay. Beta particles with a maximal energy of 606 keV (89% abundance, others 248-807 keV) and 364 keV gamma rays (81% abundance, others 723 keV) are the primary emissions of I-131 decay. I-131 is administered orally with activities of 1-5 mCi or less. As a result of data suggesting that stunning (decreased uptake of the therapeutic dose of I-131 by the residual functioning thyroid tissue or tumor due to cell death or dysfunction caused by the activity administered for diagnostic imaging) is less likely at the lower activity range, many prefer a range of 1-2 mCi. However, a higher rate of detection of iodine concentrating tissues has been reported with higher dosages .
I-123 is produced in a cyclotron by proton irradiation of enriched Xe-124 in a capsule. Decay of I-123 to Te-123 occurs by electron capture, with a half-life of 13.22 hours and gamma radiation is emitted with predominant energies of 159 keV (the gamma ray primarily used for imaging) and 127 keV. Compared with I-131, I-123 is mainly a gamma emitter with a high counting rate, and provides a higher lesion-to-background signal, thereby improving the sensitivity and quality of imaging. With the same administered activity, I-123 delivers an absorbed radiation dose that is approximately one-fifth that of I-131 to the thyroid tissue, thereby lessening the likelihood of stunning from imaging. I-123 is administered orally with activities of 0.4-5.0 mCi, which may allow avoidance of stunning [13,14].
I-124 is a proton-rich isotope of iodine produced in a cyclotron by numerous nuclear reactions; it decays to Te-124 with a half-life of 4.18 days. Its modes of decay include: 74.4% electron capture and 25.6% positron emission. It emits gamma radiation with energies of 511 and 602 keV . I-124 is administered intravenously with activities of 0.5-2.0 mCi for detection of metastatic lesions or assessment of the radiation dose related to I-131 therapy. Compared to radioiodine gamma scintigraphy, significantly greater sensitivity and spatial resolution can be achieved using I-124 positron emission tomography, leading to improved detection of residual or recurrent thyroid cancer. And, it can be used for patient-specific radiation dosimetry for radioiodine treatment .
I-125, which is produced in nuclear reactor by neutron capture in irradiated xenon gas (Xe-124), disintegrates by electron capture via the excited level of 35 keV of Te-125 into the ground state of Te-125. It also emits x-rays and Auger electrons, as well as gamma rays. Because of its relatively long half-life (59.39 days), I-125 is preferred for radioimmunoassay or other in vitro assays, and brachytherapy for several solid tumors, including brain tumor, prostate cancer, and head and neck cancer [17-20]. Owing to its low gamma energy, I-125 is not suitable for whole-body gamma camera imaging. Several authors reported regarding the treatment of hyperthyroidism using I-125 in 1970's, however, this was not the case in clinical practice .
Ectopic thyroid tissue is the result of a failure of migration of the thyroid gland, which begins at embryonic day 24. An endodermal diverticulum from the median plate of the floor of the pharyngeal gut is formed; this diverticulum then descends in the midline, from the foramen cecum to the final location of the thyroid gland, anteriorly to the pre-trachea and larynx . The innate ability to trap iodine and produce thyroglobulin is shared by ectopic thyroid tissues and normal thyroid tissues, observance of ectopic thyroid tissues in radioiodine WBS is a common false-positive finding [10,23,24]. They are frequently found as a lingual, sublingual thyroid, thyroglossal duct cyst, intratracheal and mediastinal thyroid. They can also be located in both supra- and subdiaphragmatic organs, including lung, heart (struma cordis), adrenal glands, gallbladder, duodenum, ovary (struma ovarii), pancreas and intestine . Simultaneous presentation of two ectopic foci, such as lingual and perihyoid, or lingual and porta hepatis can occur [22,25]. Recognition of the location and nature of ectopic thyroid tissue can minimize misinterpretation as metastatic disease.
Although the abilities to trap iodine and produce thyroglobulin are unique features of thyroid tissues, physiological uptake of radioiodine can also be observed in a variety of non-thyroidal tissues (Figure 3 and and4).4). Two main causes of uptake include functional NIS expression and metabolism related to or the retention of excreted iodine. Expression of NIS in salivary and lacrimal glands, stomach, choroid plexus, ciliary body of the eye, skin, placenta, lactating mammary gland, thymus, and, to a lesser extent, the prostate, ovary, adrenal gland, lung, and heart has been demonstrated [4,6]. Liver is regarded as the major organ for metabolism of radioiodinated thyroglobulin released from functioning thyroid tissues . Retention of radioiodine can occur as a result of structural or functional changes in any part of the body located along the route of radioiodine excretion or blood pooling (Table 2).
Breast is the one of major organs expressing NIS. Iodine accumulation in the lactating breast has been recognized for 60 years and is now regarded as a usual finding in postpartum patients . Once the NIS gene was cloned and become available for study, expression of NIS on the basolateral membrane of alveolar cells in mammary glands and marked induction during lactation were demonstrated [28,29]. Bakheet et al.  conducted an analysis of patterns of radioiodine uptake in lactating breasts on 20 radioiodine scintigraphic images. They identified four patterns of uptake: "full" (most common), "focal", "crescent", and "irregular". Uptake was asymmetric in 60% (left > right in 45%, right > left in 15%), symmetric in 25%, and unilateral in 15% of cases. Recognition of those patterns and clinical history is helpful to interpretation of breast uptake on radioiodine scintigraphy (Figure 5). However, breast uptake that presents with an atypical pattern and/or is clinically unexpected may be interpreted as lung metastases.
The significance of radioiodine uptake by the non-lactating breast has also been studied by Hammami et al. . Approximately 6% of all female patients presented with breast uptake unrelated to lactation and the patterns were similar to those observed during breast feeding. Expressible galactorrhea and moderately elevated prolactin levels were observed in 48% and 24% of cases, respectively. According to findings from a recent case report, a 52-year-old female patient presenting with bilateral increased breast uptake was found to have hyperprolactinemia caused by prolactinoma in the pituitary gland . Enhanced NIS expression caused by hyperprolactinemia or individual variations might be a possible mechanism of radioiodine uptake in non-lactating breast.
Hammami et al.  suggested the cautious interpretation of radioiodine uptake in the breast when: (a) A history of breastfeeding is not obtained or occurrence of breast uptake without breastfeeding is not acknowledged, (b) The uptake is irregular or unilateral, (c) There is a coexisting lung (or other) metastasis, (d) There is a coexisting elevated thyroglobulin level but an otherwise unremarkable scan.
Thymic radioiodine uptake is not an unusual finding on radioiodine WBS (Figure 6). In a review of 175 patients, thymic uptake was observed in 1.2% (4/325) of diagnostic scans and 1.5% (3/200) of post-treatment scans in six patients . Patients were females between the ages of 22 and 51 years at the time of diagnosis. Wilson et al. observed that physiological thymic uptake was seldom apparent (with one exception; the youngest) on the scan performed at 3-4 days but was clearly observed on the 7-day scan . The pattern of uptake showed either a diffuse or a dumbbell shape. Overall consensus is that thymic uptake tends to become more evident on delayed imaging, with a therapeutic dose, in younger patients, and with less residual or metastatic thyroid tissues [33-39].
The mechanism of radioiodine uptake by the thymus is not yet fully understood. Autoradiography performed by Verminglio et al.  revealed localization of iodine uptake in the thymus to Hassall’s bodies, which are constituted by epithelial cells resembling keratinocytes. They suggested that this finding reflects the structural similarity between cystic Hassall’s bodies and thyroid follicles. Although a capability of transport and concentration of iodine is weaker in the thymus, compared with that presented in the thyroid gland, the presence of NIS is a proven mechanism of radioiodine uptake in the thymus .
Following findings reported by Michigishi et al.  will be helpful in differentiating physiologic from malignant mediastinal uptake: (a) uptake that becomes more prominent with repeated treatment, (b) requirement of higher than usual iodine doses in order to visualize the area, (c) a young age, (d) a large thymus on CT, and (e) a low serum thyroglobulin level.
Diffuse hepatic uptake of radioiodine is also a common finding on radioiodine WBS. Several authors have suggested that diffuse uptake of radioiodine by the liver is related to residual thyroid tissue or recurrent or persistent metastasis [26,41]. According to Chung et al. , whose study included a large population, because the liver is the major organ for the metabolism of thyroid hormones, this finding was explained by accumulation of radioiodinated thyroid hormones in patients with remnant thyroid tissues. In patients without thyroid remnant, radioiodinated thyroglobulin released from functioning cancer tissue is regarded as the cause of diffuse hepatic uptake of radioiodine.
However, other investigators have stated that diffuse hepatic uptake is a benign finding without clinical importance [42-44]. Tatar et al.  reported no significant association between liver uptake and uptake in the thyroid bed, the dose of radioiodine administered for ablation therapy, thyroglobulin levels, age, stage of disease, presence of local or distant metastases, recurrence, or survival. A more recent study of a larger population conducted by Omur et al  also revealed no correlation of hepatic uptake with serum thyroglobulin levels, thyroid remnant score, and presence of local or distant metastatic foci. Instead, of particular interest, hepatic uptake showed positive correlation with administered doses of RAI, increased hepatic enzymes, and hepatosteatosis. This finding supports the concept that the presence of multiple metabolic factors is related to diffuse hepatic radioiodine uptake. They suggested that associated changes in lipoproteins and hepatic enzymes might have contributed to increased hepatic uptake in patients with hepatosteatosis. The increase of hepatic enzymes is an indication that delayed action of deiodinase may result in delayed excretion of iodine taken up by hepatocytes and consequent higher liver retention. NIS can also contribute to hepatic radioiodine uptake through mediation of active transport in association with iodine in intrahepatic bile ducts.
Studies of physiologic radioiodine uptake in the liver are summarized in Table 3. Obviously, hepatic visualization tends to occur more frequently in post-therapy scanning, compared with diagnostic scanning, and delayed scanning (8-10 days), compared with early scanning (4-5 days). According to our observations, in studies where an early scan was performed, hepatic visualization appears to be associated with functioning thyroid tissues, whereas it was not in studies performed using a delayed scan (Table 3). This discrepancy may be owing to differences in biological characteristics for trapping or excretion of radioiodine in remnant thyroid tissue, metastatic thyroid tissue, and liver with passage of time.
The gestational sac can also be a site of radioiodine accumulation . Although the molecular mechanisms of iodine transport from mother to fetus are not clear, iodide and small amounts of thyroid hormones are transferred through the placenta from mother to fetus. Functional NIS expression in normal human placenta, preferentially in cytotrophoblastic cells, can also be a cause of radioiodine uptake in the gestational sac [46,47].
Physiologic dilatation of the vessel, gut, duct, and ureter, regardless of the presence of obstruction, causes retention of body fluid containing radioiodine. Vascular dilatation of common carotids , thoracic aorta , and greater saphenous vein  have been reported. Displaced blood pool activity associated with pectus excavatum can also be misinterpreted as abnormal radioiodine uptake in the chest . Menstruation history, even in young patients who have not yet reached menarche, should be considered in evaluation of unusual pelvic uptake of radioiodine [52,53]. Retention of tears, saliva, gastric juice, bronchial secretion, bile, intestinal secretion, and urine can be related to a specific disease or clinical situation, such as epiphora, use of aerosol, achalasia, diverticulum, hiatal hernia, gastric volvulus, and ectopic kidney (Figure 7) [48,54-70]. Meckel’s diverticulum has an additional mechanism of radioiodine uptake via NIS, which is originally expressed in gastric mucosa.
Various cystic structures, including the nasolacrimal sac, pleuropericardial, bronchogenic, thymic, breast, hepatic, renal, ovarian, epithelial and sebaceous cysts are also known to show false-positive findings on radioiodine WBS (Figure 8) [71-79]. Entry of radioiodine into cysts occurs via passive diffusion or partially active transport; then, due to the slow exchange of water and chemical elements between the cysts and their surrounding extracellular/extravascular environment, it becomes trapped within the cysts. Although the mechanism is unclear, diffuse radioiodine uptake in bone marrow (bilateral femur and tibia) of patients involved in heavy running activity has also been reported .
External contamination by physiological or pathological body secretions or excretions can result in positive radioiodine uptake, which mimics metastatic involvement of DTC (Table 2) [23,24,27,81-97]. Sweat, breast milk, urine, vomitus and nasal, tracheobronchial, lacrimal, salivary secretions and feces contain radioiodine and their contamination on hair, skin, or clothing can be misinterpreted as metastasis of thyroid cancer (Figure 3 and and9).9). Any focus of radioiodine uptake that cannot be explained by physiological or pathological causation must also be suspected as arising from contamination by secretions. Fortunately, contamination is usually easily recognized by its pattern; acquisition of images should be performed after removal of the contamination using decontaminating procedures or removal of stained clothing. However, unusual patterns of contamination might occur and suspicion of the uptake as contamination would be difficult.
Patients' peculiar physical characteristics or odd habits produce extraordinary patterns of contamination. Careful preparation of patients, including image acquisition in a clean gown after showering, can help to minimize false-positive scanning results due to contamination. Contamination is almost always superficial [23,24], therefore, use of lateral and/or oblique views to give a third dimension to the scan may aid in identification of the contamination. In addition, use of the single photon emission computed tomography (SPECT) image alone or the SPECT image fused with the anatomical image, which provides detailed information on the anatomic location of uptake sites, can be the best way to accurately determine that contamination is the reason for the uptake.
Inflammation, which can be caused by any harmful stimuli, such as infection, trauma, or infarction, is the major cause of non-tumoral pathologic radioiodine uptake (Table 4, Figure 10). Inflamed tissues suffer a cascade of biological events, including increased blood flow and capillary permeability. Increased permeability can result in an abundance of cells in tissue or vessels, and stasis of radioiodinated blood can also occur due to an increase in the concentration of cells within blood.
Mediator molecules also alter blood vessels in order to permit migration of leukocytes outside of the vessels into the tissue. As part of their bactericidal effect, leukocytes are known to induce iodide organification by means of a myeloperoxidase . Therefore, retention of radioiodine in leukocytes of posttraumatic clots or tissues may also explain various reports of false-positive uptake in sites of inflammation (Figure 11) [99,100].
Secretion of mucin containing iodide salts has also been suggested as another possible mechanism of iodine accumulation associated with chronic inflammatory conditions in bronchus, gallbladder, or mucocele [101-106].
Although the mechanism is not fully understood, unexpected radioiodine uptakes in diverse benign tumors having different histopathologic natures has been reported (Table 5). Functional NIS expression in parotid tumors, such as Warthin’s tumor or oncocytoma, breast fibroadenoma (Figure 12), ectopic thyroid tissues, such as struma cordis and struma ovarii, other types of ovarian tumors, and teratoma has been suggested [107-115]. Using immunohistochemical staining, Berger et al.  demonstrated the presence of high levels of functionally active NIS protein not only in normal breast tissue but also in a benign fibroadenoma. However, in a case of cystic mesothelioma , results of immunohistochemical staining did not indicate the presence of NIS expression. It can be speculated that passive diffusion alone might be a mechanism of radioiodine uptake in certain benign tumors.
Because meningioma with or without brain edema [118,119], cavernous angioma , littoral cell angioma , hepatic  and vertebral [123,124] hemangiomas, and osteoid osteoma  share the property that presents high vascularity, it can also be regarded as another mechanism of radioiodine uptake in a variety of benign tumors.
Radioiodine accumulation has been reported in a variety of cancers, either primary or metastasis, involving the following organs: lung (adenocarcinoma, squamous cell carcinoma, large and small cell carcinoma, and bronchioloalveolar cell carcinoma), breast, stomach and cervix (adenocarcinoma), retroperitoneum (malignant fibrous histiocytoma), and liver and bone (metastatic adenocarcinoma) (Table 6).
Expression of NIS is known to occur in more than 80% of breast cancer tissue, although the fraction of tumors that functionally concentrate iodine is likely to be much lower than that in thyroid cancer [29,126]. NIS has also been reported in cancers involving bladder, cervix, oropharynx, colon, lung, pancreas, prostate, skin, stomach, ovary, and endometrium . Of particular interest, absence of NIS was observed in normal lung alveolar tissue, yet positive NIS expression was observed in approximately two thirds of lung adenocarcinomas and squamous cell carcinomas . This suggests that a cellular or subcellular change in iodine affinity as a consequence of malignant transformation leads to accumulation of radioiodine. Tumoral inflammatory response might also play a role in some parts of radioiodine uptake in malignant tumors. Inflammation is a well known microenvironment which is closely related with malignancies .
Almost 10 years have passed since previous researchers summarized extensively scattered reports in the literature involving cases of false-positive radioiodine uptake during surveillance of patients with DTC [23,24]. Despite the incomparable usefulness of radioiodine scintigraphy, a wide variety of pitfalls, which negate its diagnostic confidence, have been consistently reported. By recognition of the exact localization of radioiodine uptake using emerging hybrid imaging, SPECT/CT, we can reduce the incidence of false-positive interpretation in planar WBS . However, availability of SPECT/CT is still limited and some findings may remain ambiguous. Awareness of the nature and characteristics of radioiodine uptake, as described in Table 7, which provides a summarized review of unusual sites of metastasis and non-thyroidal uptake, might aid in differentiation of thyroidal and non-thyroidal, or benign and malignant uptake of radioiodine in the whole body.
In this review, physiology of the thyroid gland and a systemic overview of potential false-positive uptake of radioiodine in the whole body are provided along with illustrations and cases. By integrating the comprehension of physiology and characteristics of radioiodine uptake outlined in this article with anatomical imaging, biochemical data, and clinical findings, physicians can be more confident in establishing proper management for patients with DTC using radioiodine WBS.
This research was financially supported by the Ministry of Knowledge Economy (MKE), Korea Institute for Advancement of Technology (KIAT), and Daegyeong Leading Industry Office through the Leading Industry Development for Economic Region, a Grant from the Nuclear Research & Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science & Technology (MEST), and the Brain Korea 21 Project in 2012.