Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer Susan E.M

27 Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer Susan E.M. Clarke

Introduction cancer, computed tomography (CT) will detect macroscopic lung metastases, brain and liver metastases, and magnetic resonance imaging Whilst radionuclide imaging of the thyroid has (MRI) has proven sensitivity for detecting long been used in the management of patients marrow involvement. with thyroid cancer, its proven role is the subject Although 131I iodine has been used for over 50 of discussion. 131I iodine has a clearly estab- years to image and treat thyroid cancer, it is in lished place in the imaging and treatment of his- the last 20 years that there has been the devel- tologically proven differentiated papillary and opment of many new radiopharmaceuticals follicular thyroid cancer but the role of radio- that are now being used to image patients with nuclide imaging in diagnosis remains con- thyroid cancer. Whilst many of these remain of troversial. Similarly, in patients with medullary research interest only, 18fluorodeoxyglucose thyroid cancer, radionuclide imaging is utilized (18FDG) is rapidly becoming established as a very variably. It is in the centers where there is valuable agent in patients with 131I iodine scan a close collaboration between the thyroid onco- negative disease. logy service and the nuclear medicine depart- Whilst radionuclide imaging is a comple- ment that the contribution of radionuclide mentary imaging technique to other anatomical imaging is most frequently recognized. imaging methods, it has two main advantages. Diagnostic nuclear medicine techniques may The first is the provision of whole-body infor- be used in the detection of metastatic spread mation that facilitates accurate staging at to the skeleton. The 99mTc diphosphonate bone the time of diagnosis and restaging following scan remains a sensitive method for screening treatment. The second is the potential for for bone metastases and investigating bone therapy with the exchange of a gamma-emitting pain. 99mTc pertechnetate salivary gland imag- radionuclide for a beta or Auger electron ing will identify patients with unilateral or emitter. Uptake of a diagnostic radiopharma- bilateral salivary gland dysfunction including ceutical will identify those patients who may obstruction. benefit from therapy. This is particularly rele- Radionuclide imaging must be considered in vant in patients with recurrent inoperable conjunction with other imaging modalities. In medullary thyroid cancer in whom treatment particular, ultrasound has been demonstrated options are extremely limited with no to be sensitive in detecting cervical lymph significant responses reported to external beam nodes and liver metastases in medullary thyroid radiotherapy or chemotherapy.

341 342 Practical Management of Thyroid Cancer

Radionuclide Imaging some countries, such as the UK, nuclear medicine imaging may only be undertaken with Facilities appropriate certification of facilities and staff. Nuclear medicine diagnostic investigations for the investigation of thyroid cancer require Radiopharmaceuticals appropriate equipment, trained authorized 99mTc Pertechnetate staff, and a supply of appropriate radiopharmaceuticals. 99mTc pertechnetate is the most commonly A gamma camera with tomographic capabil- used radiopharmaceutical for routine thyroid ities is essential if high quality studies with imaging with a 6.4h half-life. It combines the appropriate sensitivity are to be achieved. advantages of good imaging characteristics (140 Studies for small volume recurrent disease will keV), availability, and low cost. Unlike the iso- be nondiagnostic if only planar views are topes of iodine, however, it is trapped but not obtained. High resolution, low, medium and organified by thyroid follicular cells and its bio- high energy collimators will be required if the logical half-life within the thyroid is therefore full range of radionuclide investigations is to significantly shorter than the isotope of iodine be performed. Although gamma cameras with that is used for imaging, 123I (Table 27.1). positron emission tomography (PET) capabili- Imaging is performed 20 minutes after intra- ties are currently used for 18FDG-PET imaging, venous injection. 99mTc pertechnetate is also the dedicated PET systems yield better results taken up by the salivary glands and dynamic with small volume disease. studies of salivary gland function before and Nuclear medicine studies require a team of after stimulation with a sialogogue will identify staff. This should include trained technologists, glands that have been damaged by the radiation medical physicists to ensure that equipment is dose from therapeutic administration of 131I functioning optimally and address radiation sodium iodide and those that are functioning protection issues for patients, staff and the but obstructed. public, appropriately trained doctors and radiopharmacists. 123I Sodium Iodide Many radiopharmaceuticals may be pur- chased directly from the manufacturer but 123I sodium iodide is an alternative agent for some, such as 99mTc(V)-dimercaptosuccinic acid imaging the thyroid. Like 99mTc pertechnetate it (DMSA), must be manufactured in-house, has good imaging characteristics with a gamma requiring an approved radiopharmacy facility energy of 159KeV and a half-life of 13.5h. It is and experienced radiopharmacist. both trapped and organified by the thyroid The legislation covering departments of follicular cells and has a marginally higher sen- nuclear medicine varies across the world but in sitivity for detecting nonfunctioning nodules

Table 27.1 Radiopharmaceuticals used in thyroid disease Radiopharmaceutical Abbreviation Clinical use 99mTc pertechnetate 99mTc Thyroid nodules, goiter, thyrotoxicosis, ectopic thyroid 123I iodide 123I Thyroid nodules, goiter, ectopic thyroid thyrotoxicosis, dyshormonogenesis 131I iodide 131I Carcinoma of the thyroid, diagnosis and treatment 99mTc isonitrile 99mTc-MIBI Thyroid nodules, Ca thyroid MTC 201Thallous chloride 201Tl Thyroid nodules, Ca thyroid, MTC 18Fluorodeoxyglucose 18FDG Ca Thyroid, MTC, Hürthle cell Ca 99mTc (V) dimercaptosuccinic acid 99mTc(V)-DMSA MTC 123I metaiodobenzylguanidine 123/131I-MIBG MTC diagnosis and treatment 111In octreotide 111In Oct MTC, lymphoma, Hürthle cell Ca 67Gallium gitrate 67Ga Lymphoma Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 343 than 99mTc pertechnetate. It is, however, signifi- Table 27.2 Biodistribution of 131I 99m cantly more expensive than Tc pertechnetate Normal sites of 131I and is not routinely available. In combination accumulation Nontumor sites of 131I uptake with perchlorate it can be used to assess the Salivary glands Hepatic cysts organification capabilities of nodules. Saliva in mouth Psoriasis Stomach 124I Sodium Iodide Intestine Bladder 124I sodium iodide is a positron-emitting isotope of iodine and has been used in a limited number of dosimetric studies. With its ultrashort half- life and limited availability, its main use is in nized as a tumor-imaging agent since 1976, dosimetry research as it provides excellent data when Cox et al. [2] first demonstrated 201Tl on functional volumes [1]. uptake in a bronchial carcinoma included inad- vertently in the field of view during a myocar- 201 131I Sodium Iodide dial stress study. Since then, Tl uptake has been described in thyroid and breast carcino- 131I iodine in the form of 131I sodium iodide has mas, lymphomas, osteosarcomas, Ewing’s sarco- been used for over 40 years to diagnose and mas, and esophageal cancers [3]. It has poor treat thyrotoxicosis and differentiated thyroid imaging characteristics, however, and non- carcinoma. It is produced by the fission of specific uptake in the myocardium, liver, and uranium-236 and by the neutron bombardment muscles limits its usefulness outside the neck. of stable tellurium in a nuclear reactor. It decays by emissions of gamma radiations 364keV 99mTc Sestamibi (MIBI) (81%), 337keV (7.3%), and 284keV (6%) with 99m beta radiation of Emax 0.606MeV to stable Tc sestamibi (MIBI) uptake is proportional to xenon-131. 131I iodine has a half-life of 8.04 days. blood flow and mitochondrial concentration. Imaging is performed using a high energy col- Although originally developed as a myocardial limator on the gamma camera. Imaging is per- perfusion imaging agent, its role in tumor formed 24–130 hours after oral administration imaging is well proven, with uptake in parathy- of the radiopharmaceutical, either in liquid roid adenomas, breast tumors, and thyroid form or as a capsule. malignancies. The main advantage of 131I sodium iodide as a diagnostic and therapeutic radiopharmaceuti- 99mTc(V) Dimercaptosuccinic Acid cal is its low cost and availability while its main disadvantage is the high energy gamma emis- 99mTc(V) dimercaptosuccinic acid (DMSA) was sions, which has radiation protection implica- initially developed in Japan as a general tumor- tions for staff, relatives, and other patients. The imaging agent [4]. It rapidly became apparent normal biodistribution includes the salivary that its main clinical use is in patients with glands, stomach, and bladder. The bowel is also medullary thyroid cancer (MTC). Sensitivities visualized on delayed studies (Table 27.2). An ranging from 50% [5] to 80% [6,7] have been awareness of the normal biodistribution is reported in patients with primary and recurrent essential for the accurate interpretation of MTC. Images should be acquired 2–3h after whole-body images. Contamination of the skin injection and uptake may be observed in both and hair with saliva or urine may cause false- soft-tissue and bone metastases. The isomeric positive scans and care must be taken in image mix of 99mTc(V)-DMSA varies when it is pre- interpretation. pared using different commercial kits [8,9]. It is suspected that the poor sensitivity results 201Tl Thallium reported by some workers may be a result of the isomeric composition of their manufactured 201Tl thallium is a potassium analogue and product. A further explanation for some of the crosses the cell membrane via the sodium- poor results reported may be the patient selec- potassium ATPase pump. 201Tl has been recog- tion. There is a well-recognized subset of 344 Practical Management of Thyroid Cancer patients in whom the calcitonin level is elevated 123I/131I Iodine Metaiodobenzylguanidine but stable and in whom no focal disease can be demonstrated for several years. Imaging Following successful imaging of the adrenal with 99mTc(V)-DMSA in this subset will yield medulla by Wieland et al. [14] in 1980, many a significantly lower sensitivity for tumor groups have studied the uptake of the guane- detection. thidine analogue metaiodobenzylguanidine Single photon emission computed tomogra- (MIBG) in neuroectodermally derived tumors phy (SPECT) imaging will increase the sensiti- including MTC. MIBG is commercially available in many countries labeled with either 123I iodine vity of lesion detection and will also define the 131 extent of the primary tumor more accurately or I iodine. Tomographic imaging as well as [10]. planar imaging should be performed to opti- The normal biodistribution of 99mTc( V)- mize sensitivity.Although not routinely used for DMSA is seen at 2h to be in the nasal mucosa diagnostic purposes, a positive scan will indi- and faintly in the skeleton. Breast uptake may cate a possible therapeutic option. A number of be noted in women. Blood pool activity commonly prescribed drugs interfere with the persists at 2h and the blood pool of the uptake of MIBG and should be avoided or dis- heart, liver, and spleen may be identified on continued in patients being considered for diag- whole–body imaging. There is no nonspecific nostic or therapeutic uses of MIBG (Table 27.3). tracer uptake observed in the liver, making 99mTc(V)-DMSA one of the few tumor-imaging 18FDG-PET agents that is able to reliably detect liver metas- 18 tases. Pituitary uptake may be seen in some Radiolabeled fluorodeoxyglucose [ FDG] is the patients. most widely used tracer in PET tumor imaging. A structural analogue of 2-deoxyglucose,FDG is Uptake in sites of MTC ranges from intense to 18 faint, with uptake ratios of greater than 30:1 transported into and trapped by tumor cells. F observed in some patients with neck recur- is a positron emitter with a 20-minute half-life. rence. Uptake in soft-tissue sites appears more The emitted positrons interact with matter with intense than is observed in sites of bone metas- release of two 511KeV gamma photons and it is tases. Image quality is generally good, although these that are imaged. A dedicated PET camera the lack of nonspecific uptake may make local- and appropriate staff are required for imaging ization of an identified lesion difficult. Studies and the short half-life of the tracer together with the high cost of equipment limits availability in using the principle of image registration have 18 permitted the merger of image data from the many areas of the world. FDG accumulation is 99mTc(V)-DMSA image with the data from an a marker of metabolic activity and therefore anatomically precise MRI image. This merged reflects proliferative activity and the number of image gives clinically useful information to the viable tumor cells. surgeon prior to surgery.Image registration also raises the sensitivity of both imaging modalities Monoclonal Antibodies by increasing the confidence with which small lesions may be diagnosed [9]. Several monoclonal antibodies have been used to image patients with MTC. These include 123I-, 131I-, and 111In-CEA [15,16], both whole anti- 111I Indium Octreotide Like many neuroendocrine tumors, MTC Table 27.3 Drugs that interfere with MIBG uptake tumors express somatostatin receptors [11]. Tricyclic antidepressants Somatostatin is a neuropeptide that was dis- Labetalol covered in 1978 [12] and has been found to Reserpine have an inhibitory effect on growth hormone Sympathomimetics receptors. In animals this peptide appears to Antipsychotics Calcium channel blockers inhibit the growth of various malignant tumors Cocaine [13]. Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 345

111 body and fragments, and In-anticalcitonin Technetium Study antibody. These various monoclonal antibodies are currently only available on a research basis.

R Cholecystokinin (CCK)-B/Gastrin I Receptor Imaging G Amiri-Mosavi et al. in 1999 demonstrated that MTC expressed cholecystokinin-B/gastrin re- H ceptors [17]. Behr et al. have demonstrated that T CCK-B/gastrin receptors can be detected in the biopsy specimens of patients with MTC but are not found in normal thyroid tissue [18]. This 1 0 agent is only available on a research basis. c m

Uptake function = 9.03% Normal Range: (0.4 - 4.0) Papillary and Follicular Gland activity (scan time) = 89.3 MBq System sensitivity = 75.0 cps / MBq Thyroid Cancer A Diagnosis The role of imaging in the investigation of patients with suspected thyroid cancer is con- troversial, reflecting the high incidence of nodules in the normal population and low prevalence of thyroid malignancy. In a patient with a palpable nodule in the thyroid, the simple technique of imaging the thyroid using 99mTc pertechnetate will identify whether the palpable nodule is functioning or nonfunctioning. Thyroid cancer typically appears as a hypofunctioning “cold” nodule on 99mTc pertechnetate thyroid imaging but this is a nonspecific finding (Figure 27.1A). Specificity varies with the iodine status of the population B studied. In Austria, prior to iodine supplemen- tation, the incidence of thyroid cancer in cold Figure 27.1 A 99mTc pertechnetate scan of a patient with toxic thyroid nodules was 3.5% [19] compared with diffuse goiter (Graves’ disease). Clinically nonpalpable cold nodule detected which was proven to be papillary thyroid 21% in the iodine-replete USA [20]. 99m In 1978, Tonami et al. [21] described the use cancer on fine-needle aspiration. B Tc pertechnetate scan of of 201Tl in investigating patients with cold a patient with a multinodular goiter diagnosed on palpation. The dominant cold nodule was investigated with fine-needle thyroid nodules. However, Harada et al. [22] aspiration and a colloid nodule was diagnosed. demonstrated that 201Tl could not distinguish between benign and malignant nodules. Alter- native tumor-seeking radiopharmaceuticals such as 99mTc sestamibi, 99mTc tetrofosmin and reduces the number of unnecessary fine-needle 18fluorodeoxyglucose have proved unreliable in aspirations performed on functioning nodules differentiating benign and malignant thyroid and improves sampling accuracy in dominant, nodules. In practice, many centers now proceed nonfunctioning nodules arising from multin- to fine-needle aspiration cytology under ultra- odular glands (Figure 27.1B). sound guidance without prior imaging. A 18FDG-PET has been able to detect thyroid combined scintigraphy/ultrasound approach cancer during studies for other pathologies. An 346 Practical Management of Thyroid Cancer

Figure 27.2 Sixty-two-year-old man undergoing staging investigations for carcinoma of the bronchus with 18FDG-PET.The primary lung lesion was visualized but an additional area of high uptake in the lower left neck was identified.Further investigation confirmed a follicular carcinoma of thyroid. intense area of focal uptake in the thyroid thyroid tissue thereby identifying patients region warrants further evaluation as a number who require 131I ablation therapy. Following of such identified lesions have been proven to successful ablation of remnant thyroid tissue, be thyroid cancer on fine-needle aspiration 131I imaging is routinely used to identify and surgery (Figure 27.2). Uptake of 18FDG in a patients with biochemical evidence of remnant thyroid nodule, however, is not specific for or recurrent tumor and may also be used to thyroid cancer.Adler et al.in a study of 9 thyroid plan the amounts of radioiodine to be nodules demonstrated uptake in 2 of 3 nodules administered. that were malignant but also in 3 out of 4 benign Whilst the use of imaging with tracer doses adenomas [23]. of 131I to establish the presence of remnant Uematsu et al. demonstrated standardized thyroid tissue following surgery for differenti- uptake values (SUVs) greater than 5 in proven ated thyroid carcinoma has been an established cancers, differentiating them from benign practice for many decades, recent concerns that nodules with lower SUVs.A patient with chronic the tracer dose of 131I may influence the efficacy thyroiditis had an SUV of 6.3, however [24]. of the subsequent therapy dose of 131I-iodine have been raised. Management Following Surgery Standard practice has been to undertake an 131I tracer study using administered activities Radionuclide imaging is used following sur- ranging from 74 to 370MBq (2 to 10mCi). The gery to establish the presence of remnant tracer study permits identification of residual Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 347 thyroid tissue and also may identify metastatic Another proposed strategy is to assume that disease.Whole-body imaging plus local views of the majority of patients undergoing total thy- the head and neck area are routinely performed, roidectomy for differentiated thyroid cancer with imaging taking place 48 hours after admin- will have small remnants of thyroid tissue and istration of the tracer dose. As it is essential that patients are therefore treated with an ablation TSH levels are elevated to ensure good uptake of therapy dose of 131I without prior imaging. the tracer dose, imaging should not be per- Whilst this strategy avoids the problem of stun- formed less than 4 weeks after surgery or 4 ning, it prevents therapy dose adjustment on the weeks after discontinuing thyroxine (T4) or 2 weeks after discontinuing triiodothyronine (lio- thyronine, T3). An awareness of the normal biodistribution of 131I is essential in interpreting tracer images, and regions of normal biodistribution are listed in Table 27.2. Artifacts due to urine contamination and saliva must also be recognized. Numerous authors have raised the issue of “stunning” which results in the reduction of uptake of a therapy dose of 131I iodine following a high dose diagnostic tracer scan. The concept of the “stunned” thyroid has raised controversy as to the dose of 131I to be used for these diagnostic studies. Many believe that a large dose is essential, Waxman et al. [25], for example, having shown that identification of an increasing number of remnants was associated with increasing the tracer dose up to 100MBq (30mCi) or more. However, several authors have observed that the uptake of a therapeutic dose may be less than that of a preceding diagnostic dose. Even a dose of 5mCi was found sufficient to reduce the uptake of a therapeutic dose by 54% [26].Various strategies have been proposed to overcome the problem of stunning. These include using low tracer scan doses of 131I A (<185MBq, 5mCi). Whilst data confirms that this strategy reduces the problem of stunning, lower tracer scan doses will reduce the sensitivity of imaging for detecting metastatic disease. Reporting that the induction of the “stunned” thyroid by 370MBq (10mCi) diminished thy- roidal uptake of a 3.7GBq (100mCi) treatment dose, Park et al. [27] recommended that pretherapy scanning should be undertaken with 123I. Murphy et al. [28] have shown that 123I has a sensitivity of 75% compared with 131I if activities of 74MBq (2mCi) are used. If only an estimate of the amount of remaining normal tissue is required, 99mTc can be used B (Figure 27.3A, B)[29], but when, in follow-up studies, identification of possible metastases is Figure 27.3 A 99mTc pertechnetate scan of a patient’s neck after sought, an iodine isotope is essential because of surgical ablation of thyroid for papillary cancer.A small remnant the relatively poor trapping avidity of neoplas- is demonstrated (arrow).B 131I-iodine tracer scan in same patient tic tissue for 131I. showing identical pattern of uptake. 348 Practical Management of Thyroid Cancer basis of the size of the thyroid remnant or dosimetric calculations to be performed. Selection of Ablation Dose Many centers opt for a fixed 131I ablation dose, but others opt for a varied 131I dose based on the size of the thyroid remnant and retention of the tracer dose of 131I. If an 131I tracer study is performed, data may be used to determine an appropriate ablation dose using the following formula. There are few data to suggest that dosimetric calculations improve the first time ablation rate following a first therapy dose. A posttherapy 131I scan should be performed in all patients, particularly those who have not undergone an 131I tracer scan prior to ablation therapy. The posttherapy high activity scan has a higher sensitivity for detecting unsuspected metastatic disease compared with the low activity 131I tracer scan (Figure 27.4). Postablation Management Following the successful ablation of remnant thyroid tissue, the 131I whole-body scan will show no abnormal foci of uptake in the absence of metastatic disease. It is appropriate to monitor these patients subsequently with thyroglobulin measurements and to utilize the 131I tracer scan in patients whose thyroglobulin measurements become elevated. Patients who have metastatic disease at the time of diagnosis will require regular 131I tracer scans between treatments to determine the efficacy of 131I therapy (Figure 27.5A, B, C). Tracer scans with 131I should be undertaken using doses of 185 MBq (5mCi) or less to avoid effects of stunning, although stunning has been only clearly proven as a problem with remnant thyroid tissue. Tracer scans using 131I are not normally performed in less than 6 months following 131I treatment and as the TSH levels must be elevated to optimize the sensitivity of the 131I tracer scan, patients should discontinue thyroid replacement hormone for an appropriate interval or receive human recombinant TSH used to transiently elevate TSH levels [30]. A percentage of patients will be found to have elevated thyroglobulin levels with negative Figure 27.4 131I iodine postablation scan in a patient demon- iodine tracer scans. This is a particular issue in strating unsuspected widespread metastases from papillary patients with Hürthle cell carcinomas in whom thyroid cancer. only 10% of tumors are iodine avid. Patients LUT 1 FRONT Scale: 1000 LUT 1 POST Scale: 1000

R L I E G F H T T

ANTERIOR POSTERIOR B

Figure 27.5 A 131I-iodine posttherapy scan in a patient with metastatic papillary thyroid cancer. B 99mTc diphosphonate bone scan in same patient demonstrating lower sensitivity for detecting bone metastases than 131I-iodine scan. C 131I-iodine scan in same patient following two therapies with 5.5GBq of radioiodine. Significant resolution of many metastatic sites is demonstrated. ANTERIOR POSTERIOR C 350 Practical Management of Thyroid Cancer with papillary and follicular carcinomas in 74% for detecting the sites of recurrence in whom dedifferentiation occurs may also con- patients with 131I scan negative disease [37]. tinue to have raised thyroglobulin levels, but Preliminary reports suggest a role for 111In become iodine tracer scan negative as a feature octreotide in this setting [38]. 18FDG-PET has of dedifferentiation. Various strategies have proved useful in detecting cervical nodes and been proposed in patients in whom dedifferen- can direct surgical intervention. It can also be tiation is suspected. These include a proposal to used to identify metastases in the mediastinum, use to retinoic acid to cause tumor redifferenti- thorax, and skeleton. The main value of 18FDG- ation and restoration of tumor iodine uptake PET in the management of thyroid carcinoma capabilities. A number of studies have been patients, like that of the other methods above, published confirming that retinoids will cause lies in its ability to demonstrate metastatic redifferentiation in approximately 30% of sites after negative iodine scanning. Its accuracy patients but the duration of this redifferentia- is high, particularly for cervical lymph nodes tion appears short and the longer-term benefit where it has proved particularly helpful for of retinoid treatment remains unclear. directing surgical management. It can also iden- Alternative imaging agents may also be used tify metastases in the mediastinum, thorax, and to identify the location of recurrent disease in bone. Studies on patients with thyroglobulin 131I scan negative patients to determine oper- positive and iodine scan negative disease gave ability. The sensitivities of 201Tl and 99mTc tet ro- sensitivities of between 70% and 90% for detect- fosmin are comparable with that of 131I for ing iodine negative disease [39,40]. A multi- detecting distant metastases (0.85, 0.85, 0.78), center study compared the sensitivity of although 131I is more sensitive than the other 18FDG-PET, 201Tl,and 99mTc-MIBI in 131I scan neg- two for detecting postsurgical residual thyroid ative disease. The 90% sensitivity of 18FDG-PET tissue [31]. Scintigraphic imaging with 201Tl has was significantly higher than that of the other been thought to reflect the abnormal DNA char- scanning agents [41]. The increased metabolic acteristic of poor prognosis in differentiated activity of dedifferentiating, aggressive tumors thyroid carcinoma [32]. would explain the high 18FDG uptake compared MIBI has been proved to be clinically more with much lower uptake seen in iodine avid useful than 201Tl in detecting lung, lymph tumors. The 3-year survival of patients with node, and bone metastases from differentiated 18FDG positive scans is markedly reduced com- thyroid carcinoma, as image quality was better. pared with patients whose scans are negative The overall sensitivity of the two techniques is [42]. not, however, significantly different [33]. The Recently, the importance of TSH stimulation superiority of MIBI in detecting lymph node in the uptake of 18FDG has been appreciated. In disease before initial 131I treatment has also been a number of studies, patients have been imaged described by Ng et al. [34], who noted that MIBI whilst on TSH suppressive dose of thyroxine is not as sensitive as 131I scanning for thyroid and when off thyroxine with a high endoge- remnants or lung metastases. nous TSH. Several studies have confirmed Both MIBI and 201Tl yield high specificity and the increased sensitivity of tumor detection in positive predictive value for residual thyroid patients off thyroxine [43]. A recent study by cancer in patients with negative 131I scans who Petrich et al. [44] has confirmed that the use of have an increased risk of recurrence after 131I recombinant human TSH prior to imaging with therapy. Both imaging agents have been shown 18FDG increases imaging sensitivity. to detect residual cancer and cause a change in In patients with iodine negative, thyroglobu- management in more than half the patients in lin positive disease,these studies,in conjunction whom conventional imaging techniques were with anatomical imaging, will assist in patient unreliable [35]. management decisions by identifying whether Another myocardial imaging agent, 99mTc the recurrence is operable or inoperable due to tetrofosmin, has a high sensitivity in detecting location or multifocality. 18FDG-PET scanning metastases and recurrences of thyroid cancer has the highest sensitivity for detecting dedif- [36]. 99mTc tetrofosmin is both sensitive (86%) ferentiating recurrent disease, particularly with and specific for detecting recurrence in patients the patient off thyroxine or after recombinant taking thyroxine and also has a sensitivity of TSH administration. Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 351

Hürthle Cell Cancer nonfunctioning nodules on the 99mTc pertechnetate thyroid scan raises the possibility of MTC The Hürthle cell variant of follicular thyroid associated with familial MTC (FMTC), multiple cancer is characterized by oxyphilic follicular endocrine neoplasia type 2A (MEN2A), or cells. They are more aggressive than follicular MEN2B [54]. Parthasarathy et al. [55] first described the carcinomas and metastasize more frequently. 201 Unlike standard follicular cancers, only 10% of accumulation of Tl in an MTC primary lesion, and subsequently uptake has been reported in Hürthle cell cancers take up iodine and this fact, 56–58 together with their aggressive behavior, results both primary and recurrent lesions with in a 20-year survival of 65% compared with 81% sensitivities of up to 91% and specificities of 100% reported. The poor imaging characteris- for follicular cancers. 201 Imaging Hürthle cell cancers has been tics of Tl are not a problem in visualizing neck attempted with a variety of radiopharmaceuti- recurrence, but limit the value of this agent in cals. Yen et al. [45] have explored the role of detecting distant metastases. The nonspecific 99mTc-MIBI in diagnosing metastatic disease uptake of this tracer in the liver and lungs and and shown a significantly better sensitivity its uptake in the myocardium reduce its sensi- 131 tivity in detecting liver and lung metastases. than with I. Vergara et al. [46] have studied 99m 99mTc(V)-DMSA in Hürthle cell tumors and The main role for Tc(V)-DMSA imaging is in the follow-up of patients after surgery [56]. have shown that although uptake is seen in 99m some tumors, the sensitivity is not adequate for In primary MTC, Tc(V)-DMSA can confirm a clinical purposes. 111I indium octreotide uptake clinical suspicion of MTC while the calcitonin results are awaited. Papillary and follicular has been demonstrated in some Hürthle cell 99m tumors but, again, the uptake is not reliably sen- tumors of the thyroid do not take up Tc( V)- DMSA and positive uptake in a cold nodule on sitive for routine clinical use [47]. 99m 18 a Tc pertechnetate scan is strongly suggestive The role of FDG-PET has been explored 99m in a number of studies. Intense uptake in sites of MTC. Tc(V)-DMSA whole-body imaging is of recurrent disease has been demonstrated, also useful when planning surgery to stage the changing management in 50% of the patients disease. It is probably the most effective imaging who were so studied [48,49]. agent for demonstrating soft-tissue and bone metastases. Immediately following surgery, 99mTc( V)- Insular Carcinoma DMSA imaging may be useful in determining whether residual tumor is present (Figure This rare variant of follicular cancer is poorly 27.6A). It is essential that the patient is imaged differentiated and highly aggressive. Local inva- prior to surgery when there is bulky disease in sion and distant metastases at the time of order to assess whether the primary tumor diagnosis are common. Poor results have been takes up the agent. In longer-term follow-up, 99m observed with most radionuclide imaging Tc(V)-DMSA imaging can be used to deter- methods including 131I, 111In octreotide [50], mine the site of recurrence in patients in whom 99mTc-MIBI [51], and 99mTc(V)-DMSA [52]. the postoperative calcitonin levels start to rise. The aggressive nature of insular carcinomas Again SPECT imaging will increase the sensi- with negative 131I uptake makes it probable that tivity of lesion detection, particularly in pati- 18FDG-PET uptake will be seen and this has ents with small-volume recurrent mediastinal been confirmed by Diehl et al. [53] in a retro- deposits. spective study of five patients. (V)-DMSA may also be labeled with rhenium-186 [57]. Clinical experience with this radiopharmaceutical confirms that its Medullary Thyroid Cancer biodistribution resembles that of 99mTc( V)- DMSA, although renal retention is greater [58]. Diagnosis and Follow-Up Limited therapy experience is available The availability of 186Re is limited,however. 188Re pro- In a patient undergoing investigation for duced from a generator is now available and thyroid nodules, the identification of bilateral studies using 188 Re (V)-DMSA are in progress. 352 Practical Management of Thyroid Cancer

MTC and demonstrated that 99mTc-MIBI is more sensitive than CT for detecting recurrence in the head, neck, and chest, but CT was more sensitive for detecting disease in the liver. The 99mTc bone scan was more sensitive for detecting bone metastases than 99mTc-MIBI. Ugur et al. [60] compared the sensitivities of 99mTc-MIBI, 201Tl, and 99mTc(V)-DMSA and showed them to be 47%, 19%, and 95%, respectively. These data confirm that at present 99mTc(V)-DMSA is the most sensitive radionuclide imaging agent available. Juweid et al. have used 99mTc- MIBI to explore the multidrug resistance of MTC [61]. Following successful imaging of the adrenal medulla by Wieland et al. [14] in 1980, the role of 123/131I-MIBG in MTC has been investigated in MTC. Nakajo et al. [62] in 1983 studied a number of patients with neuroectodermal A tumors, including one patient with MTC. They reported no uptake in MTC. The first positive case of 131I-MIBG uptake in a patient with MEN2A was reported by Endo et al. [63] in 1984. Uptake in both the primary MTC and the coex- istent pheochromocytoma was observed. In the same year Connell et al. [64] also described 131I- MIBG uptake in a primary tumor of a patient with familial MTC. The first report of uptake in metastatic MTC was made by Sone et al. [65] in 1985, who studied a nonfamilial case of MTC with bone and liver metastases. Uptake was seen in all sites of known disease. Following the publication of these case reports a number of series of cases have been reported. Poston et al. [66] in 1985 studied six patients, three with sporadic MTC, two with MEN2A, and one with MEN2B. Although all patients studied were postoperative with calcitonin evidence of recurrence, only one patient had a positive study. The results of many series B of MTC patients studied with MIBG have been 99m published [5,67–71]. The later series have been Figure 27.6 A Tc(V)-DMSA whole-body scan following 123 surgery for medullary thyroid cancer demonstrating residual performed with I-MIBG that has increased tumor in lower left neck. B 111I indium octreotide scan in same resolution, but none of the studies have utilized patient showing lower uptake in remnant tumor. SPECT. In most studies a sensitivity of 30% is reported, and this is confirmed when the cumu- lative experience is reviewed. Several studies have been undertaken to compare the sensitivities of different radiophar- The role of 99mTc-MIBI has been investigated maceuticals in MTC. Clarke et al. [72] in 1988 as an imaging agent in patients with recurrent compared the uptake of 99mTc(V)-DMSA, 131I- MTC. Learoyd et al. [59] compared the uptake of MIBG, and 99mTc-MDP in patients with MTC and 99mTc-MIBI with CT in patients with recurrent showed that 99mTc(V)-DMSA was the most sen- Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 353 sitive agent for detecting sites of MTC. Verga The importance of detecting recurrent dis- et al. [5] in 1989 compared 99mTc(V)-DMSA and ease to facilitate surgery and prolong symptom- 123I- or 131I-MIBG and again confirmed that free survival has been emphasized earlier. 99mTc(V)-DMSA was the more sensitive agent. Numerous studies have been undertaken with The technical aspects of 123I- or 131I-MIBG 18FDG in patients with calcitonin elevations imaging in MTC need to be considered. In indicating the site of recurrent MTC (Figure patients with primary disease or suspected 27.8). A multicenter study by Diehl et al. [80] neck recurrence who have not undergone total concluded that 18FDG is sensitive in detecting thyroidectomy, it is essential to block the recurrent disease and compares favorably thyroid prior to administration of MIBG. Unless with other radionuclide and non-radionuclide adequate blockade with potassium iodate is imaging techniques. Other studies have sug- achieved, interpretation of uptake in the neck gested that 18FDG-PET imaging is more sensi- will be extremely difficult. Whole-body images tive in patients with rapidly progressive disease at 4 and 24 hours should be acquired, and than in patients with slowly rising calcitonin SPECT imaging of the neck and liver at 24 hours levels [81]. will increase lesion detection in patients imaged Results from imaging with monoclonal anti- with 123I-MIBG. The role for 131I-MIBG in diag- bodies have been varied, ranging from 0% nostic imaging is debated. The slow tumor accu- with anticalcitonin antibody to 78% with 131I- mulation of MIBG may indicate that the later anti-CEA antibody. The results of imaging with imaging possible with 131I-MIBG compared with monoclonal antibodies in patients with MTC 123I-MIBG may increase the sensitivity of lesion have been compared with imaging with other detection. radiopharmaceuticals by a number of groups. Although 131I- and 123I-MIBG have been Cabezas et al. [16] compared imaging with 131I- shown to have an unacceptably low sensitivity anti-CEA antibody and 131I-MIBG and showed for diagnostic imaging, the therapeutic potential of 131I-MIBG in those patients in whom good uptake is demonstrated should be recognized. A number of patients with MTC have now 131 R L been treated with I-MIBG and a palliative I E G F response has been achieved in about 50% of H T patients so treated [73]. Partial response has T been observed in a further 25% of patients, with response times lasting up to 18 months [74,75] (Figure 27.7). 111In octreotide is also used to detect recurrence in patients with rising calcitonin levels indicating recurrent MTC. SPECT imaging will enhance lesion detection in the neck and liver. Sensitivities of 65% have been reported in detecting MTC lesions, although the sensitivity is lower in the liver as a result of nonspecific uptake (Figure 27.6B) [76]. Since some therapeutic responses in MTC have been reported using a somatostatin analogue [77], the ability to demonstrate which MTC patients may respond to this agent should prove of great benefit given the high cost of treatment. Therapy has been undertaken with high doses of 111In octreotide utilizing the radiation effect of Auger electrons [78]. Various 90 Y-labeled compounds have been evaluated Figure 27.7 131I-MIBG posttherapy scan in a patient with although some studies have reported renal tox- metastatic medullary thyroid cancer. Good uptake of therapy icity as a dose limiting factor [79]. dose at metastatic sites is identified. 354 Practical Management of Thyroid Cancer

TRANSAXIAL

ANTERIOR CORONAL SAGITTAL

Figure 27.8 18FDG-PET scan in patient with history of medullary thyroid cancer and a rising calcitonin.Other imaging investigations failed to identify the location of recurrence but the 18FDG-PET scan demonstrated uptake in bihilar nodes. As recurrence was inoperable, patient was referred for chemotherapy. significantly higher lesion detection with the Juweid et al. [84] explored high dose 131I-MN- antibody. They also compared the relative sen- 14F(ab)(2) anti-CEA antibody and autologous sitivity of CT imaging with the two radionuclide hemopoietic stem cell rescue in patients with techniques and showed that CT imaging was rapidly progressive disease, with all patients also inferior to 131I-anti-CEA imaging. Sandrock achieving disease stabilization and some et al. [71] compared the results of imaging with showing tumor regression. The same group has 131I-MIBG, 201Tl, and 111In-anti-CEA antibody also undertaken animal studies using combina- and also concluded that imaging with the anti- tions of 90Y-labeled CEA antibody with doxoru- body yielded the best results. Troncone et al. bicin and Taxol. The efficacy of the combined [70] evaluated 99mTc(V)-DMSA, 131I-MIBG, and treatments was greater than either treatment 131I-anti-CEA antibody and showed that the given alone [85]. sensitivity of imaging with 99mTc(V)-DMSA and Imaging studies in patients with MTC using 131I-anti-CEA antibody was far superior to 111In diethylenetriamine pentaacetic acid- imaging with MIBG. As the target to back- Dglu(1)-minigastrin have demonstrated a 91% ground ratio of anti-CEA antibody is low, the sensitivity for detecting tumor, even in patients Marseille group have developed a two-step tar- with occult disease. Dose escalation studies are geting technique of a bispecific antibody. The now being undertaken to assess the efficacy first arm (Fab fragment) recognizes the CEA and toxicity of 90Y-minigastrin in patients with tumor expression and the second arm (Fab advanced metastatic disease. Initial results are fragment) is specific for the bivalent di- reported as promising although nephrotoxicity DTPA–indium hapten. In the first step of the is a major concern [22]. A summary of the process the non-labeled antibody is injected advantages and disadvantages of the various and binds to the tumor cells expressing CEA, radiopharmaceuticals used to image patients Four to 5 days later, the bivalent hapten which is with MTC is given in Table 27.1. radiolabeled is injected and binds to the anti- hapten arm of the antibody. In the interval before injection of the radiolabeled compound Conclusion bispecific antibody is gradually degraded by normal tissues [82]. Preliminary studies have Nuclear medicine imaging continues to have an been encouraging in a French multicenter study established role in the management of patients in patients with MTC and preliminary results of with papillary and follicular thyroid cancers, a phase I/II clinical trial been published [83]. with 131I scanning remaining the routine Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 355 imaging technique for localizing remnant and 13. Lamberts SWJ, Koper JW, Reubi JC. Potential role of the recurrent disease. The development of recombi- somatostatin analogues in the treatment of cancer. Eur J Clin Invest 1987; 17:281–287. nant human TSH offers increased flexibility for 14. Wieland DM, Win JL, Brown LE. Radiolabelled adrener- imaging and treatment, whilst reducing the side gic neuroblocking agents: adrenomedullary imaging effects of thyroxine withdrawal. The newer with Iodine-131 meta iodobenzylguanidine. J Nucl Med radionuclide imaging techniques remain under- 1980; 21:349–353. utilized, despite good evidence for their sensi- 15. Reiners C, Eilles C, Spiegel W, Becker W, Boerner W. Immunoscintigraphy in MTC using 123I or 111In labelled tivity in detecting tumor recurrence. The monoclonal anti CEA antibody fragment. J Nucl Med development of new agents continues with 1986; 25:227–231. the potential for new therapeutic agents. The 16. Cabezas RC, Berna L, Estorch M, Carrio I, Garcia- importance of the development of evidence- Ameijeiras A. Localisation of metastases from medullary thyroid carcinoma using different methods. based strategies for the optimal integration of Henry Ford Hosp Med J 1989; 37:169–172. radionuclide imaging in the diagnosis and 17. Amiri-Mosavi A, Ahlman H, Tisell LE, Wangberg B, follow-up of patients with thyroid cancers needs Kolby L, Forsell-Aronsson E. Expression of cholecys- to be recognized. tokinin–B/gastrin receptors in MTC. Eur J Surg 1999; 165:628–631. 18. Behr TM, Behe MP.Cholecystokinin–B/gastrin receptor targeting peptides for staging and therapy of MTC and other cholecystokinin-B receptor expressing malignancies. Sem Nucl Med 2002; 32:97–109. References 19. Ricabonna G. In: Thyroid cancer. Berlin: Springer, 1987: 8. 1. Flower MA, al-Saadi D, Harmer CL, McCready VR, Ott 20. Oberdisse K, Klein E, Reinwein D. Die Krankheiten der RJ. Dose response study on thyrotoxic patients under- Schilddrusse. Stuttgart: Thieme, 1980. going positron emission tomography and radioiodine 21. Tonami N, Bunko H, Mishigishi T, Kuwajima A, Hisada therapy. Eur J Nucl Med 1994; 21:531–536. K. Clinical application of 201Tl scintigraphy in patients 2. Cox PH, Belfer AJ, Van der Pompe WB. Thallium 201 with cold thyroid nodules. Clin Nucl Med 1978; 3:217– uptake in tumours, a possible complication in heart 221. scintigraphy. Br J Radiol 1976; 49:767–768. 22. Harada T, Ito Y, Shimaoka K, Taniguchi T, Matsudo A, 3. Hisada K, Tonami N, Miyamae T, et al. Clinical evalua- Senoo T. Clinical evaluation of 201Tl-chloride scan for tion of tumour imaging with 201-Tl chloride. Radiology thyroid nodule. Eur J Nucl Med 1980; 5:125–130. 1978; 129:497–500. 23. Adler LP, Bloom AD. Positron emission tomography of 4. Ohta H, Yamamoto K, Endo K. A new imaging agent for thyroid nodules. Thyroid 1993; 3:195–200. medullary thyroid cancer. J Nucl Med 1984; 25:323–325. 24. Uematsu H, Sadat N, Ohtsubu T. Fluorine-18 fluoro- 5. Verga V, Muratori F, Sacco G, Ban F, Libroia A. Role of deoxyglucose PET versus thallium-201 scintigraphy 131iodine MIBG and 99mTc (V)DMSA in the diagnostic evaluation of thyroid tumours. J Nucl Med 1998; 39:453– value of MTC. Henry Ford Hosp Med J 1989; 37:175– 459. 177. 25. Waxman A, Ramanna L, Chapman N, et al. The 6. Clarke SEM, Fogelman I, Lazarus CR, Edwards S, Maisey significance of I-131 scan dose in patients with thyroid MN. A comparison of 131iodine-MIBG and 99mTc- cancer: determination of ablation (concise communica- pentavalent-DMSA for imaging patients with medullary tion). J Nucl Med 1981; 22:861–865. carcinoma of the thyroid. In: Schmidt HAE, Emrich D 26. Jeevanram RK, Shah DH, Sharma SM, Ganatra RD. (eds) Nuklearmedizin – nuclear medicine in research Influence of initial large dose on subsequent uptake of and practice. Stuttgart: Schattauer, 1987: 375–378. therapeutic radioiodine in thyroid cancer patients. Nucl 7. Guerra UP,Pizzocara C, Terzi A. New tracers for imaging Med Biol 1986; 13:277–279. MTC. Nucl Med Comm 1989; 10:285–295. 27. Park HM, Perkins OW,Edmonson JW,Schnute RB, Man- 8. Blower P, Singh J, Clarke SEM, Bisnnaden M, Went M. atunga A. Influence of diagnostic radioiodines on the Pentavalent 186rhenium DMSA: a possible tumour uptake of ablative doses of iodine 131. Thyroid 1994; 4: therapy agent. J Nucl Med 1990; 31:768–770. 49–54. 9. Blower PJ, Singh J, Clarke SEM. The chemical identity of 28. Murphy EJ, Almeida F, Lull R, et al. 123I scanning pentavalent technetium 99m-dimercaptosuccinic acid. for follow-up of thyroid cancer. J Invest Med 2000; 70A. J Nucl Med 1991; 32:845–849. 29. Blake G. 10. Chaudhuri AR, Lewis MK, Bingham JB, Clarke SEM. 30. rTSH scans. Registration of MR and SPECT images in medullary 31. Ünal S, Menda Y, Adalet I, Boztepe H. Ozbey N, et al. thyroid carcinoma. Nucl Med Comm 1993; 14:256. Thallium-201,technetium-99m-tetrofosmin and iodine- 11. O’Brien DS, DeLellis RA, Wolfe HJ, Tashjian AH, Reichlin 131 in detecting differentiated thyroid carcinoma S. Somatostatin immunoreactivity in human C-cell metastases. J Nucl Med 1998; 39:1897–1902. hyperplasia and medullary thyroid carcinoma. J Lab 32. Nakada K, Katoh C, Morita K, et al. Relationship among Clin Med 1987; 109:320–326. 201Tl uptake, nuclear DNA content and clinical behavior 12. Guillemin R. Peptides in the brain: the new endocrino- in metastatic thyroid carcinoma. J Nucl Med 1999; 40: logy of the neuron. Science 1978; 202:390–402. 963–967. 356 Practical Management of Thyroid Cancer

33. Miyamoto S, Kasagi K, Misaki T, Alam MS, Konshi J. 48. Lowe VJ, Mullan BP, Hay ID, McIver B, Kasperbauer JL. Evaluation of technetium-99m-MIBI scintigraphy in 18F FDG PET of patients with Hurthle cell Ca. J Nucl Med metastatic differentiated thyroid carcinoma. J Nucl Med 2003; 44:1402–1406. 1997; 38:352–356. 49. Plotkin M, Hautzel H, Krause BJ, et al. Implication of 18F 34. Ng DCE, Sundram FX, Sin AE. 99mTc-Sestamibi and 131I FDG PET in the follow up of Hurthle cell thyroid cancer, whole-body scintigraphy and initial serum thyroglobu- Thyroid 2002; 12:155–161. lin in the management of differentiated thyroid carci- 50. Tenenbaum, FR, Lumbroso J, Schlumberger M, et al. noma. J Nucl Med 2000; 41:631–635. Radioloabelled somatostatin scintigraphy in differenti- 35. Seabold JE, Gurll N, Schurrer ME, Aktay R, Kirchner PT. ated thyroid cancer. J Nucl Med 1999; 36:807–810. Comparison of 99mTc-methoxyisobutyl isonitrile and 51. Zak IT,Seabold JE,Robinson RA,et al. 99mTc MIBI.Scinti- 201Tl scintigraphy for detection of residual thyroid graphic detection of metastatic insular thyroid cancer. cancer after 131I ablative therapy. J Nucl Med 1999; 40: Clin Nucl Med 1995; 20:31–36. 1434–1440. 52. Yen TC, King KL, Yang AH, et al. Comparative radionu- 36. Gallowitsch H-J, Mikosch P,Kresnik E, et al. Thyroglob- clide imaging of metastatic insular carcinoma of the ulin and low-dose iodine-131 and technetium-99m- thyroid: value of 99mTc(V)-DMSA. J Nucl Med 1996; 37: tetrofosmin whole-body scintigraphy in differentiated 78–80. thyroid carcinoma. J Nucl Med 1998; 39:870–875. 53. Diehl M, Graichen S, Menzel C, Lindhorst C, Grunwald 37. Lind P,Gallowitsch H-J, Langsteger W,et al. Technetium- F. 18F FDG PET in insular thyroid cancer. Clin Nucl Med 99m-tetrofosmin whole-body scintigraphy in the 2003; 28:728–731. follow-up of differentiated thyroid carcinoma. J Nucl 54. Anderson RJ, Sizemore GW, Wahner HW. Thyroid Med 1997; 38:348–352. scintigraphy in familial medullary carcinoma of the 38. Baudin E, Schlumberger M, Lumbroso J, et al. Octreotide thyroid gland. Clin Nucl Med 1978; 3:148. scintigraphy in patients with differentiated thyroid car- 55. Parthasarathy KL, Shimaoka K, Bakshi SP, Razack MS. cinoma: contribution for patients with negative radio- Radiotracer uptake in medullary carcinoma of the iodine scan. J Clin Endocrinol Metab 1996; 81:2541– thyroid. Clin Nucl Med 1980; 5:45–48. 2544. 56. Clarke SEM, Lazarus CR, Maisey MN. Experience in 39. Chung J-K, So Y, Lee JS, et al. Value of FDG PET in pap- imaging medullary thyroid carcinoma using 99mTc (V) illary thyroid carcinoma with negative 131I whole-body dimercaptosuccinic acid (DMSA). Henry Ford Hosp scan. J Nucl Med 1999; 40:986–992. Med J 1989; 37:167–168. 40. Wang W. [18F]-2-Fluoro-2-deoxy-D-glucose positron 57. Singh J, Powell AK, Clarke SEM, Blower PJ. Crystal struc- emission tomography localizes residual thyroid cancer ture and isomerism of a tumour targetting radiophar- in patients with negative diagnostic 131I whole body maceutical: [ReO(DMSA)2] - (H2DMSA = meso-2, scans and elevated serum thyroglobulin levels. J Clin 3-dimercapto succinic acid). J Chem Soc Chem Endocrinol Metab 1999; 84:2291–2302. Commun 1991; 16:1115. 41. Grunwald F, Kalicke T, Feine U, et al. Fluorine-18 58. Allen S, Blake GM, McKenney DB, et al. 186Re-V-DMSA: fluorodeoxyglucose positron emission tomography in dosimetry of a new radiopharmaceutical for therapy of thyroid cancer: results of a multicentre study. Eur J Nucl medullary carcinoma of the thyroid.Nucl Med Commun Med 1999; 26:1547–1552. 1990; 11:220–221. 42. Wang W, Larson SM, Fazzari M. Prognostic value of 59. Learoyd LA, Roach PJ, Briggs GM, Delbridge LW, 18FDG PET scanning in patients with thyroid cancer. J Wilmshurst EG, Robinson BG. 99mTc-sestamibi scan- Clin Endocrinol Metab 2000; 85:1107–1113. ning in recurrent MTC. J Nucl Med 1997; 38:227–230. 43. van Tol KM, Jager PL, Piers DA, et al. Better yield of 18- 60. Ugur O,Kostakoglu L,Guler N,et al.Comparison of 99mTc fluoro deoxyglucose positron emission tomography in (v) DMSA, 201Thallium, and 99mTc MIBI imaging in the patients with metastatic differentiated thyroid carci- follow up of patients with MTC. Eur J Nucl Med 1996; noma during thyrotropin stimulation. Thyroid 2002; 12: 23:1367–1371. 381–387. 61. Juweid M, Blumenthal RD, Hajjar G, Yeldell D, Stein R, 44. Petrich T, Borner AR, Otto D, et al. Influence of rhTSH Goldenberg DM. Use of 99(m) Tc-Sestamibi for imaging on 18-F fluorodeoxyglucose uptake by differentiated and assessment of multidrug resistance (MDR) of MTC. thyroid cancer. J Nucl Med Mol Imaging 2002; 29: Eur J Nucl Med 1999; 26:OS 172. 641–647. 62. Nakajo M, Shapiro B, Copp J. The normal and abnormal 45. Yen TC, Lin HD, Lee CH, Chang SL, Yeh SH. The role of distribution of the adrenomedullary imaging agent 99mTc MIBI whole body scans in diagnosing metastatic M-[I-131] re Meta [I-131] iodobenzylguanidine in Hurthle cell carcinoma of the thyroid gland after total man: evaluation by scintigraphy. J Nucl Med 1983; 24: thyroidectomy: a comparison with 131I iodine and 201Tl 672. thallium whole body scans. Eur J Nucl Med 1994; 21: 63. Endo K, Shiomi K, Kasagi K, et al. Imaging of medullary 980–983. thyroid carcinoma with 131iodine-MIBG. Lancet 1984; 46. Vergara E, Lastoria S, Varella P, Lapenta L, Salvatore M. ii:233–235. Technetium-99m pentavalent dimercaptosuccinic acid 64. Connell JMC, Hilditch TE, Elliott A, Semple PF. 131I- uptake in Hurthle cell tumour of the thyroid, J Nucl Biol MIBG and medullary carcinoma of the thyroid. Lancet Med 1993; 37:67–68. 1984; ii:1273–1274. 47. Forsell-Aronsson EB, Nilsson O, Bejegard SA, et al. 111I 65. Sone T, Fukunaga M, Otsuka N, et al. Metastatic Indium–DTPA-D-Phe1-octreotide binding and somato- medullary thyroid cancer: localization with 131iodine statin receptor subtypes in thyroid tumours. J Nucl Med metaiodobenzylguanidine. J Nucl Med 1985; 26:604– 2000; 41:636–642. 608. Diagnostic Nuclear Medicine Investigations in the Management of Thyroid Cancer 357

66. Poston GJ, Thomas AM, Macdonald DW, et al. Imaging 77. Libroia A,Verga U, Di Sacco G, Piolini M, Muratori F.Use of the medullary carcinoma of the thyroid with 131iodine of somatostatin analog SMS 201–995 in MTC. Henry metaiodobenzylguanidine. Nucl Med Commun 1986; Ford Hosp Med J 1989; 37:151–153. 7:215–221. 78. Krenning EP,Valkeme R, Kooij PPM, et al. Radionuclide 67. Hoefnagel CA,deKraker J,Marcuse HR,Voûte PA.Detec- therapy with 111In-DTPA-octreotide. Eur J Nucl Med tion and treatment of neural crest tumours using 131I 1996; 29:1118. MIBG. Eur J Nucl Med 1985; 11:A73. 79. Waldherr C, Schumacher T, Pless M, Crazzolara A, 68. Hilditch TE, Connell JMC, Elliot AT, Murray T, Reed NS. Maecke HR, Nitzsche EU. Radiopeptide transmitted Poor results with 99mTc-V-DMS and 131iodine MIBG in internal irradiation of non-iodophil thyroid cancer and the imaging of medullary thyroid carcinoma.J Nucl Med conventionally untreatable MTC using [Y-90]-DOTA-D- 1986; 27:1150–1153. Phe(1)-Tyr(3)-octreotide: a pilot study. Nucl Med 69. Clarke SEM, Lazarus CR, Edwards S. Scintigraphy and Comm 2001; 22:673–678. treatment of MTC with 131iodine MIBG.J Nucl Med 1987; 80. Diehl M, Risse JH, Brandt-Mainz K, Dietlin M, Bohuslav- 28:1820–1825. izki KH, Matheja P.Fluorine-18 fluorodeoxyglucose PET 70. Troncone L, Rufni V,De Rosa G, Testa A. Diagnostic and in MTC: results of a multicentre study Eur J Nucl Med therapeutic potential of new radiopharmaceutical 2001; 28:1671–1676. agents in medullary thyroid carcinoma. Henry Ford 81. Brandt-Mainz K, Muller SP,Gorges R, Saller B, Bockisch Hosp Med J 1989; 37:178–184. A. The value of fluorine-18 fluorodeoxyglucose PET in 71. Sandrock D, Blossey HC, Bessler MJ, Steinroder M, patients with medullary thyroid cancer Eur J Nucl Med Muntz D. Contribution of different scintigraphic tech- 2000; 27:490–496. niques to the management of MTC. Henry Ford Hosp 82. Peltier P, Curtet C, Chatal JF, et al. Radioimmunodetec- Med J 1989; 37:173–174. tion of MTC using a bispecific antiCEA/anti indium- 72. Clarke SEM, Lazarus CR, Wraight P,Sampson C, Maisey DTPA antibody and an 111Indium labeled DTPA dimer. J MN. Pentavalent 99mTc DMSA, 131I MIBG, and 99mTc MDP Nucl Med 1993; 34:1267–1273. – an evaluation of three imaging techniques in patients 83. Kraeber-Bodere F, Bardet S, Hoefnagel CA, et al. with medullary carcinoma of the thyroid. J Nucl Med Radioimmunotherapy in MYC using bispecific antibody 1988; 29:33–38. and iodine 131-labeled bivalent hapten: Preliminary 73. Clarke SEM. 131I Meta iodobenzylguanidine therapy in results of Phase I/II clinical trial. Clin Cancer Res 1999; MTC: Guy’s Hospital experience. J Nucl Med Biol 1991; 5:3190S–198S. 35:323–327. 84. Juweid ME, Hajjar G, Stein R, Sharkey RM, Herskovic T, 74. Hoefnagel CA, Delprat CC, Valdes Olmes RA. Role of Swayne LC. Initial experience with high dose radioim- metaiodobenzylguanidine therapy in MTC. J Nucl Med munotherapy of metastatic MTC using I-131-MN- Biol 1991; 35:334–336. 14F(ab)(2)anti- CEA antigen Mab and AHSCR. J Nucl 75. Proceedings of Fourth International Workshop on 131 I Med 2000; 41:93–103. MIBG Therapy. Barcelona, 2000 (in press). 85. Stein R, Juweid M, Zhang CH, Goldenberg DM. Assess- 76. Krenning EP, Lamberts SWJ, Reubi JC, et al. Somato- ment of combined radioimmunotherapy and chemo- statin receptor imaging in medullary thyroid carci- therapy for the treatment of MTC Clin Cancer Res 1999; noma. Thyroid 1991; 1(Suppl 1):564. 5:199S–206S.