Cumali Aktolun • Umut Elboga • Muammer Urhan
Thyroid cancer, the most common endocrine malignancy, accounts for approximately 1% to 3% of all human malignancies, and its incidence has been increasing in the past three decades.1 Although differentiated thyroid cancers are generally slow growing tumors with a 10-year survival of 85%, metastatic spread, especially metastasis to regional lymph nodes is seen in approximately 20% of patients in the first 10 years following initial diagnosis. In approximately 5% of patients, the tumor develops aggressive behavior and does not respond to radioiodine therapy; these patients die from this disease, accounting for 0.5% of all cancer deaths.
In the fetal period, thyroid cells may fail to complete the emigration process, and are trapped at various sites between the base of the tongue and the anterior mediastinum causing thyroid ectopia.2 These sites may also develop thyroid cancer. Therefore, ectopic thyroid neoplasm may theoretically arise at any site in mouth, neck, or mediastinum.
The lymphatics of the thyroid usually follows the branches of the superior and inferior thyroid arteries and drain into the deep and superficial lymphatic chains of the neck. Cervical lymph nodes located at levels IV, V, and VI are most likely invaded by thyroid cancer, but lymph nodes located below or above these levels can also be involved in metastatic spread.
There are two groups of hormone-producing cells within the thyroid gland; follicular cells called thyrocytes that secrete triiodothyronine (T3) and thyroxine (T4); parafollicular cells called C cells that produce calcitonin. Although both groups of hormones are secreted from the thyroid gland, traditionally, only the hormones (T3 and T4) produced by thyrocytes are called “thyroid hormones.” The principle units of thyroid gland secreting T3 and T4 are the follicles: small pools of colliod lined with a single layer of thyrocytes (follicular cells).
Iodine is an essential component of thyroid hormones. Iodide, as iodide ion rapidly absorbed in the upper gastrointestinal tract and enters the circulation. The main route of iodine excretion is the kidney; and only about one-fifth of the circulating iodine is taken up by the thyroid gland. The first step of thyroid hormone production is the trapping of the iodine by follicular cells of the thyroid gland. Iodine is transported against an electrochemical gradient by a protein transporter system called the sodium–iodide symporter (NIS) located on the basolateral membrane of the follicular cells. The NIS gene is encoded on chromosome IX and is also expressed in non-thyroidal organs including salivary glands, stomach, kidney, placenta, and thymus accounting for the uptake of radioactive iodine in extrathyroideal tissues.
When iodine is trapped by the follicular cells, it is enzymatically linked to the amino acid tyrosine in the presence of thyroid peroxidase (thyroperoxidase or TPO), hydrogen peroxide, and thyroglobulin (Tg). TPO catalyzes the iodination of tyrosine-producing monoiodotyrosine (MIT) and diiodotyrosine (DIT) (the process is also called organification of iodine). Two molecules of DIT are coupled to produce T4; one molecule of DIT and MIT produce T3. Iodine as a component of the thyroid hormones as well as non-hormonal compounds (e.g., reverse T3, MIT, and DIT) is bound by Tg and stored within the colloid for about 100 days. Tg, one of the largest biologic molecules (660K daltons), is produced in the follicular cells. Increasing serum Tg after thyroidectomy and radioactive iodine ablation in a patient with differentiated thyroid cancer suggests the development of recurrence and/or metastasis. Hence, Tg is a valuable clinical tool as a tumor biomarker and it is commonly used in the follow-up and management of the patients with follicular and papillary thyroid cancers (PTC).
The production and secretion of thyroid hormones is modulated by thyroid stimulating hormone (TSH), a two-polypeptide glycoprotein chain (α and β). It is secreted by the anterior pituitary and controlled positively by thyrotropin-releasing hormone (TRH) which is produced in the hypothalamus and controlled negatively by thyroid hormones. The β-subunit confers the major biologic and immunologic function of TSH. The TSH receptor is located on base of the follicular cells. The colloid lined with a single layer of thyrocytes containing thyroid hormones and Tg is taken back into the follicular cells from the pool by endocytosis through the apical margin of the follicular cells. Inside the cytoplasm, colloid droplets fuse with intracellular lysosomes containing proteolytic and deiodinase (dehalogenase) enzymes. T4 and T3 are subsequently released into the circulation and then they are transported by the serum proteins such as thyroxin-binding globulin (TBG), transthyretin, and pre-albumin. Serum T3 is 99.7% protein bound and 0.3% is free whereas only 0.03% of T4 is free. T4 and T3 are metabolized (deiodination) with a specific enzyme “5’-deiodinase” which is found in the liver, kidney, muscle, white blood cells, brain, and pituitary. The liver can be visualized on post-therapy scans in patients with thyroid cancer because of metabolism of iodine incorporated in the thyroid hormone in the liver through conjugation with glucuronide or sulfate, deamination, and decarboxylation of the amino terminal of the molecule.
Calcitonin, a 32-amino acid peptide, is produced and secreted by parafollicular C cells that are scattered among the thyroid follicular cells. Increased serum calcitonin after thyroidectomy in a patient with medullary thyroid cancer (MTC) suggests recurrence or metastasis. Thus calcitonin is a unique tumor biomarker in these patients.
THYROID CANCER PATHOLOGY
Thyroid cancer is a group of tumors with different histologic and biologic features. The majority of thyroid cancers originate from follicular cells (papillary, follicular, Hürthle cell, and anaplastic carcinomas), parafollicular C cells (medullary carcinoma) and to a lesser extent, from the connective and lymphoid tissues of the thyroid (sarcoma, lymphoma, and germ cell tumor). Of these cancers, about 85% are differentiated thyroid cancers (DTC) (papillary and follicular thyroid cancers), of which 90% is papillary. Based on histo pathologic features of PTC, several variants and subtypes have been recognized including classic type, follicular variant, mixed type, and tall cell, diffuse sclerosing, and columnar variants. The last three variants (tall cell, diffuse sclerosing, and columnar variants) require special clinical attention because they are associated with lack of or diminished uptake of 131I or other radioisotopes of iodine and tend to develop aggressive clinical behavior resulting in less favorable response to 131I therapy and also more frequent local recurrence and metastasis. The simultaneous presence of two tumors of different cellular origins such as papillary carcinoma and medullary carcinoma in the thyroid gland in a single patient can be seen. This rare, interesting condition is called “collision tumor” and requires treatment of both tumors with different modalities and protocols.
Genetic alterations in thyroid cancers, particularly the BRAF (V600E) mutation has recently attracted interest as a link between genetic mutations and the clinical and pathologic features of these tumors has been discovered. Nevertheless, there have been no studies that resulted in modification of current therapeutic protocol.
PTC tends to metastasize to regional lymph nodes but axillary, pulmonary, and disseminated distant metastases are also seen.3 In about 45% of PTC, the tumor is multifocal. Regional spread to the cervical and mediastinal lymph nodes is a common feature at initial diagnosis. Unlike papillary cancers, hematogenous spread to the bone marrow, lungs, brain, liver, skin, and bladder are frequent in patients with follicular thyroid carcinoma (FTC) which has a less favorable prognosis than PTC, particularly if distant metastasis occurs or capsular or vascular invasion is present.4
Hürthle cell carcinoma (HCC) contains oncocytic cells which are rich in mitochondria. This tumor is associated with an increased incidence of regional and distant metastasis compared to other differentiated thyroid cancers.5Anaplastic thyroid carcinoma (ATC), the most aggressive subtype of thyroid cancer, is seen most often in the elderly and in patients with long-standing nodular goiter. The 10-year survival rate is less than 20% in patients with advanced disease. Patients usually present with distant metastasis most commonly in the lungs, bone marrow, brain, and liver.6 Both HCC and ATC do not accumulate 131I excluding the possibility of using 131I in diagnosis and therapy.
Medullary thyroid carcinoma (MTC) originates from calcitonin-secreting parafollicular C cells and accounts for about 20% of all thyroid cancer deaths. MTC may be either sporadic or familial (associated with other neoplasms and exhibits distinctive biochemical and genetic features). Most of the patients with MTC (80%) have a sporadic (non-familial) form of the disease. The remaining 20% inherit the autosomal dominant trait resulting in one of the multiple endocrine neoplasm syndromes (in MEN 2A and 2B). Familial MTC is accepted as a phenotypic variant of MEN 2A with decreased penetrance for pheochromocytoma and primary hyperparathyroidism rather than a distinct pathologic and clinical entity. The disease may spread to the neck musculature, local cervical lymph nodes, and to distant organs including the lungs, liver, bone marrow, and adrenal glands. When metastasized, the overall prognosis is poor. In patients with good prognostic factors including early diagnosis, young age at initial diagnosis, female gender, and absence of thyroid capsule invasion, the survival rate might be as high as 80%.7
Lymphoma is a rare malignancy of the thyroid gland and accounts for only 2% of all extranodal lymphomas. Most lymphomas involving the thyroid are non-Hodgkin lymphomas and frequently occur in the setting of Hashimoto thyroiditis.8
Risk stratification is important to choose the right therapeutic tool, especially the optimal amount of 131I activity for thyroid cancer therapy. Examining the detailed histopathologic report of surgically removed tissue is thus a prerequisite to determine the correct dose of radiation to be delivered to the region. The presence of malignancy in the surgical border, metastatic involvement of regional lymph nodes, multiple foci of tumor within the thyroid gland, extension of tumor tissue to surrounding structures, invasion of lymphatic channels, veins, and tumor and thyroid capsules are associated with higher risk of recurrence and metastasis. The prognosis of thyroid malignancy is poorer in patients younger than 20 or older than 60 years. Differentiated thyroid cancer behaves more aggressively in men, but, more commonly affects women.
Although for the past 60 years, nuclear medicine has been at the heart of diagnosis and treatment of patients with thyroid cancers, radionuclide imaging, except for general use of thyroid scintigraphy, has limited role for the initial diagnosis of the primary tumor in patients with thyroid cancer. Imaging techniques have been refined to find the optimal protocols for therapy. Currently, almost all of radionuclide techniques used in thyroid cancer are thus treatment-related procedures including detection of metastases before or after therapy, prognostication, ablation of residual thyroid tissue, therapy of metastatic disease, and assessment of response to therapy.
RADIOPHARMACEUTICALS USED FOR THYROID CANCER MANAGEMENT
The principal mechanism for radionuclide thyroid imaging is the “trapping” of the radionuclide in the thyroid follicular cells and the concentration inside the colloidal pool for a certain time sufficient to be visualized by dedicated imaging systems. Although thyroid scintigraphy is a “functional picture” of the gland, the structural information about the location, shape, and global size of the thyroid lobes are clinically useful in selected patients. Although diminished or absence of uptake in any nodule (hypoactive nodule) is associated with higher risk of malignancy, there is no definite scintigraphic pattern of thyroid cancer.
The principal mechanism for radionuclide thyroid imaging is the “trapping” of the radionuclide in the thyroid follicular cells and the concentration inside the colloidal pool for a time sufficient to be visualized by dedicated imaging systems. Although thyroid scintigraphy is a “functional picture” of the gland, the structural information about the location, shape, and global size of the thyroid lobes are clinically useful in selected patients. Although diminished or absence of uptake in any nodule (hypoactive cold nodule) is associated with higher risk of malignancy, there is no definite scintigraphic pattern of thyroid cancer.
131I is an isotope of stable iodine with a physical half-life of 8.1 days. It decays to 131Xe by emitting a negatively charged β-particle of 0.610 MeV. After ingestion, iodine is absorbed from the gastrointestinal tract and approximately 90% of the radionuclide ingested reaches the thyroid follicular cells within a couple of hours but images are taken after 24 to 72 hours post-ingestion to obtain better tissue–background contrast. Use of 131I requires high-energy collimators for its 364-keV γ-emission. Poor image quality and long physical half-life which result in high radiation exposure to the thyroid by its β-particle emission are the main disadvantages of 131I as an imaging agent for diagnostic thyroid scintigraphy. 131I is no longer used for routine thyroid scan except for the evaluation of retrosternal goiter. 131I is commonly used in thyroid cancer management for the thyroid uptake test, whole body scan (WBS), ablation and therapy of thyroid cancer.
123I is another isotope of iodine with a physical half-life of 13.3 hours. Physiologically, it is almost an ideal agent for thyroid scintigraphy in many respects: a single γ-ray of 159 keV ideal for modern γ-cameras equipped with thin NaI crystal. The radiation exposure to the thyroid is substantially lower than 131I because of the shorter half-life, lack of particle radiation, and a relatively lower γ-photon energy of 123I. Despite unique advantages offered by 123I,9–11its use has been limited because of its high cost and the necessity for an onsite or nearby cyclotron. In North America, 123I is frequently used for diagnostic thyroid scintigraphy and less frequently for whole body imaging.
Technetium 99m Pertechnetate (99mTcO4)
99mTcO4 is a non-iodine alternative tracer for thyroid scintigraphy. It is the most commonly used agent because of its availability in almost every nuclear medicine department as a generator-produced radionuclide. 99mTcO4 is trapped by the NIS mechanism, but it is not organified. The relatively short physical half-life (6 hours) and the (140-keV) γ-photon emitted is optimal for γ-camera imaging. Except its use for postoperative scan to demonstrate remaining thyroid tissue (“remnant scan”), 99mTcO4 thyroid scintigraphy has no role in thyroid cancer management.
124I is a novel positron-emitting iodine isotope that provides useful information in patients with differentiated thyroid cancer. It has a physical half-life of 4.2 days and a decay scheme characterized by 22% of the disintegrations producing positrons of relatively high energies (1,532 and 2,135 keV). With dedicated positron emission tomography (PET) systems, it provides three dimensional high-resolution images of functioning thyroid tissue along with quantitative data. Initial studies confirmed the feasibility and precision of 124I PET for tumor dosimetry in the 131I ablation and therapy of thyroid cancer. Although its diagnostic potential as an imaging agent has not been fully exploited because of the cost and, in general, lack of availability, 124I PET/CT is a valuable research tool (Fig. 3.1).12
18F-fluorodeoxyglucose (18F-FDG) PET/CT provides information that differentiates between benign and malignant thyroid nodules by revealing the increased glucose metabolism in thyroid cancer cells, but, focal FDG accumulation can also be seen in benign lesions including hyperplastic thyroid nodules. There is increasing evidence of a high rate of malignancy in thyroid nodules showing incidental 18F-FDG uptake (incidentaloma) in patients who were imaged for other reasons.13 18F-FDG PET/CT imaging is currently used for the management of ATC, MTC, and persistent, recurrent, and metastatic differentiated thyroid cancer, especially in patients with negative radioiodine whole body scan and elevated serum Tg.14 Although clinical experience in a large number of patients is not available yet, indications of 18F-FDG PET/CT imaging in thyroid cancer management will likely expand.14
FIGURE 3.1. A: Several foci of radioiodine uptake on anterior post-therapy 131I whole body image suggesting disseminated functional metastases in a patient with differentiated thyroid carcinoma. B: Many additional radioiodine avid foci were detected on 124I PET/CT maximum intensity projection (MIP) image. (Reproduced with permission from the article by Van Nostrand D, Moreau S, Bandaru VV, et al. (124I) positron emission tomography versus (131I) planar imaging in the identification of residual thyroid tissue and/or metastasis in patients who have well-differentiated thyroid cancer. Thyroid. 2010;20(8):879–883.)
TREATMENT OF THYROID CANCER
Standard treatment guidelines in DTCs include total thyroidectomy followed by radioactive iodine and TSH suppression. Thyroid cancers with aggressive behavior and disseminated metastases as well as MTCs require a different therapeutic approach.
When the diagnosis of differentiated thyroid cancer is established with fine-needle cytology, the treatment of choice is the surgery. Total thyroidectomy coupled with cervicocentral lymph node sampling is the standard procedure, because of the necessity to remove all thyroid tissue before consequent 131I treatment.15,16 Even in the hands of experienced thyroid surgeons, it is quite common that some residual thyroid tissue will remain in the thyroid bed.
Remnant scan: Thyroid scan using 123I or 99mTcO4 can be used in the presence of elevated TSH to determine the amount of residual thyroid tissue in the thyroid bed after thyroidectomy. If a significant amount of residual thyroid tissue is detected on remnant scan, reoperation and removal of the remaining thyroid parenchyma is usually recommended and to minimize the chance of complications during remnant ablation and to increase the effectiveness of subsequent high dose 131I therapy on metastatic foci.
Sentinel Lymph Node Detection, Imaging, and Biopsy
Selective dissections of lymph nodes may lessen the possibility of locoregional relapse and complications. Sentinel lymph node (SLN) detection is well known to guide selective lymph node dissection in breast carcinoma and melanoma. Initial reports describing its application in thyroid cancers are encouraging.17–21 Following the injection of radiolabeled material into the nodule or thyroid tissue surrounding the nodule with malignant tissue detected with fine-needle aspiration biopsy, γ-probes can be used for intraoperative SLN identification as an alternative to central or lateral neck dissection. Mobile dedicated γ-cameras can also be used for lymph node imaging either in the nuclear medicine department or in surgical theatre. Identification of sentinal lymph nodes that lie outside the central compartment is also possible with this technique. SLN imaging may be further useful in malignant Hürthle cell tumors and well-differentiated follicular carcinomas which are difficult to identify cytologically on fine-needle aspiration; identifying SLNs with metastasis can guide SLNBx in such cases establishing the diagnoses before surgery.18
Lymphoscintigraphy of the SLN: A practical technique has been described that involves a lymphoscintigraphy performed prior to surgery following a single intratumoral injection of 99mTc nanocolloid. Immediately after peritumoral radiotracer injection, a sequential scintigraphic acquisition is performed using a low-energy, high-resolution collimator. Multiple images are collected at 120 seconds per frame in anterior and oblique positions, followed by multiple static images until there is clear visualization of sentinel node(s). The last image at 90 minutes after injection includes the neck and body. In this image, the activity in all nodes visualized is determined and background corrected. Addition of single photon emission computed tomography and computed tomography (SPECT/CT) allows preoperative identification of lymph nodes, especially in the lateral neck compartment. It may reduce surgical time and improves surgical planning.21
Gamma Probe Detection of SLN: Intraoperative SLN localization can be performed using a handheld γ-probe. Before incision, the handheld γ-probe is placed in a sterile surgical wrap, and slowly moved from the injection site to the cervical regions to identify a focus with the highest count rate. Following thyroidectomy (removal of thyroid gland as the main source of radioactivity), the central compartment is also scanned. The node with the most counts as well as nodes with count rates greater than 10% of the hottest node are removed. On the basis of lymphoscintigraphic mapping prior to surgery by lymphoscintigraphy, the lateral compartment of the neck can be scanned also with a γ-probe; nodes with a count rate at least 10% of the hottest node are removed. Colloid labeled with 99mTcO4 yielded higher SLN detection rate compared with those using the blue dye technique for SLN detection.20
Radioiodine Ablation and Therapy
Although differentiated thyroid carcinoma expresses NIS, the uptake of iodine and radioiodine is less vigorous than normal tissue. Currently, 131I is the only radionuclide used to ablate residual normal thyroid tissue after thyroidectomy and to treat recurrent and metastatic thyroid cancer. In ablation, the goal is to “ablate” the remaining healthy thyroid tissue. Ablation of thyroid remnants after surgery is usually recommended for almost all patients except for non-iodine avid thyroid cancers (e.g., medullary, oncocytic, and ATCs). In “curative treatment,” the aim is to destroy tumor cells in both residual, otherwise normal tissue as well as in the metastatic foci.
Determination of the Amount of Radioiodine
The term “dose” properly refers to the radiation absorbed by or delivered to the individual tissue whereas the term “activity” refers to the amount of radioactive substance administered to the patient. Despite this clear distinction, it is not unusual for “dose” to be used for both of these situations. There are two important areas of debate in nuclear medicine and endocrinology experts: amount of activity to use (low versus high) and the method of selection of the activity (fixed activity versus dosimetric determination of the activity to be ingested).
131I Activity for Ablation: The appropriate radiation dose for thyroid remnant ablation is a source of continuing controversy in cumulative literature. Although some clinical practitioners still prefer a fixed activity of 3.7 GBq (100 mCi) or higher amount of 131I for patients with non-metastatic, non-recurrent, low- to medium-risk thyroid cancer,22 other experts challenge this approach and propose a low dose ablation with activities as low as 1,110 GBq (30 mCi) of 131I.23,24 Defenders of high dose ablation have reported higher ablation rate with single ingestion and equally low complication rates. Those who prefer lower amounts of 131I in low-risk patients refer to the reports of equally high ablation rate at a reduced radiation burden to the patient and family. There is no consensus on this issue, but, reducing radiation dose in younger individuals with low-risk thyroid cancer during childbearing ages and who also have a long life expectancy during which potential tumorigenic effects may be seen sounds reasonable. Nevertheless, there is a need to validate the efficacy of lower amounts of 131I in terms of preventing recurrent disease requiring additional treatment with more 131I activity or possibly even death caused by recurrent thyroid carcinoma due to insufficient treatment.
COMMONLY USED FIXED AMOUNTS OF ACTIVITY OF 131I FOR THYROID CANCER MANAGEMENT
131I Activity for Therapy: The recurrent and the metastatic thyroid cancer may be evident at the time of initial diagnosis and/or surgery or may become evident any time during the follow-up period. The overall risk of recurrence in patients with thyroid cancer is related to the age at diagnosis, size of the primary tumor, extent of the primary disease, and presence of metastasis at initial diagnosis. 131I treatment of functioning recurrent or metastatic thyroid cancer is similar to thyroid remnant ablation in many aspects, but the activity used is higher than the 131I activity used to ablate remnant thyroid tissue. High amount of 131I is usually recommended if there exists local persistent or distant metastatic disease or the tumor mass is large as the destructive effect of 131I inversely correlates with the tumor mass. Bony and pulmonary metastases may require repeated high amounts of 131I to destroy functioning tumor cells (Table 3.1). An important feature of treating metastatic disease with high amount of 131I is to be observant for complications because of toxicity (especially to bone marrow, liver, and kidneys) caused by high amount of radiation, swelling of metastatic focus, and also local and systemic comorbidities caused by metastatic disease. Airway obstruction in metastatic involvement of the neck and upper mediastinum may require emergency interventions. Brain edema that may occur after high dose 131I treatment of intracranial metastases is a potentially fatal complication.
There are several approaches to selecting the amount of 131I for the treatment of residual or metastatic DTC. The most common practice is to administer a fixed dose of 131I. Although this is an “empirical” method, several variables are considered in this choice; that is, risk stratification based on clinical findings and histopathologic features of the primary tumor. These include tumor size, subtype, features indicating the degree of de-differentiation, necrosis, capsule invasion, genetic mutations, invasion of surrounding structures, and multicentricity. Additional features include the patient’s age, the number of local and distant metastases, and comorbidities. Patients are classified as low, medium, or high risk based on these pathologic and clinical features.
Dosimetry provides, before the ingestion of therapeutic activity of 131I, calculation of 131I radiation dose to be absorbed by the tumor, the whole body and some individual, critical organs and tissues including the salivary glands, liver, bone marrow, and the blood. Tumor dosimetry allows the treating physician to decide on the precise amount of 131I activity to deliver sufficient radiation dose to the tumor tissue whereas the whole body dosimetry provide data about the radiation absorbed dose to the critical organs and tissues to predict the possible complications which actually limit the amount of 131I to be ingested.
In patients with disseminated disease, the physician cannot adjust the administered amount for each tumor site, and thus a high amount of activity is preferred after it is determined that it can be given “safely.” The first determinant of “safety” is the radiation absorbed dose to the bone marrow; the limit selected is 200 cGy although the data shows that close to 300 cGy can often be tolerated by the bone marrow but, there are often other confounding variables including age, prior therapy, and comorbidities.
Dose-Limiting Toxicity (DLT): Radiation injury to any critical organ or tissue will limit the amount of therapeutic 131I activity to be ingested. In many departments, dosimetric information about the radiation absorbed dose to the bone marrow is taken as the most important dose-limiting criterion. An important consideration at doses >150 mCi and even below is the secondary organ toxicity, which frequently limits the amount of 131I activity when whole body dosimetry in terms of radiation dose absorbed by the bone marrow would allow the use of higher amount of activity. One of the most important secondary organ toxicities seen in patients who have ingested high amount of therapeutic 131I activity is the radiation injury to salivary glands.
123I, 124I, and 131I have been used for dosimetric studies. There are different methods of dosimetric calculations for thyroid cancer therapy with 131I.25 Although 131I is the most widely studied radionuclide for dosimetric studies using γ-camera technology, recent efforts with 124I and PET imaging have provided greater accuracy based on improved quantitation using PET technology.
Most of the dosimetric data have been obtained from studies which utilized the basic formula of the Medical Internal Dose Committee (MIRD) of the Society of Nuclear Medicine. MIRD formula is based on the specific S values of radionuclides defined as the “mean absorbed dose” to a target organ per radioactive decay. It provides mean absorbed dose only to organs. No data is available for tumor dosimetry as the absorbed dose would vary with location and other variables. In addition, the data provided by these determinations does not take into account the nonuniform source distribution within the target organ. Dosimetric calculation at the voxel level has been introduced to solve these problems in MIRD Pamphlet No.17.26 Voxel-based dosimetry with tomographic slices using SPECT or PET provide three-dimensional data. Studies with 124I PET dosimetry have been attempted to select a patient-specific 131I dose.
Since the imaging data is attenuation corrected, 124I PET provides high-resolution images with quantitative information, which can be used to estimate the functional volume of thyroid tissue. With this added advantage of 124I PET, more accurate tumor dosimetry becomes available possibly leading to improving management of the patient with thyroid cancer. 124I PET is also helpful in volume estimations with an imprecision of approximately 20%. This is superior to information from 131I WBS in detecting recurrent or metastatic disease foci, and localizing and differentiating between the thyroid remnant and cervical lymph node metastases.27,28
Voxel S values that are necessary for voxel-based dosimetry can be calculated for each radionuclide and voxel dimension through direct Monte Carlo transport simulation.29 Recent efforts to refine voxel-based dosimetry in nonuniform activity distributions provide a practical solution by avoiding the calculation of the S values at the voxel level.30 Simplified and highly refined three-dimensional methods are now available for absorbed dose calculations to both the tumor lesions and critical organs. The biggest problem with dosimetric calculations reported in the literature is that none of these methods has been validated in a clinical setting in a large number of patients and multicenter trials.
Evaluation of Serum TSH
Ablative or therapeutic doses of 131I are usually administered 4 to 6 weeks after thyroidectomy. If the patient has not been treated with replacement thyroid hormone, serum TSH at that time will exceed 30 mU/L to stimulate 131I uptake by thyroid cancer cells.31 There are two methods to elevate serum TSH prior to 131I diagnostic procedures or treatment: withdrawal of thyroid hormone or injection of recombinant human TSH (rhTSH).
Following near-total or total thyroidectomy, T4 replacement is withheld for 4 to 6 weeks to increase endogenous secretion of TSH to stimulate 131I uptake by functioning remnant tissue and metastases. If the patient has been placed on thyroid hormone replacement after thyroid surgery to promote wound healing and avoid post-surgical complications, thyroid hormone replacement is changed from T4 to triiodothyronine (25 μg) for 2 weeks after which all thyroid hormone replacement is stopped before radioiodine treatment. During the withdrawal period, the patient is asked to comply with low iodine diet and avoid food and beverages rich in iodine. Nevertheless, in a subset of patients, withdrawal of thyroid hormones may fail to elevate serum TSH because of production of thyroid hormones by functioning remnant tissue and metastatic foci. rhTSH administration is therefore necessary to augment uptake. In addition, there may be clinical contraindications to withdrawal of thyroid hormone in patients with serious cardiopulmonary disease. Finally, patients who for one reason or another have non-functioning pituitary glands will be unable to augment their TSH level. This too provides justification for the use of rhTSH even in locations where the expense of the material precludes the routine use of rhTSH to prepare patients in this category for 131I diagnostic procedures, remnant ablation or therapy of metastatic disease.
In many parts of the United States and in some locations in Europe, rhTSH is available for routine use in the various situations in which it is essential to assure 131I uptake of residual thyroid tissue or tumor. It has been demonstrated that follow-up imaging in patients receiving rhTSH after having undergone thyroidectomy is equivalent to thyroid hormone withdrawal. Although originally, introduced only for diagnostic purposes, it was subsequently demonstrated that ablation of remnant thyroid tissue can be achieved with the same degree of success as thyroid hormone withdrawal. Finally, there is also cumulative experience substantiating the the use of rhTSH to prepare patients for 131I treatment of metastatic disease.
Low Iodine Diet
Prior to 131I ingestion for diagnostic whole body scanning, a low iodine diet for 2 to 3 weeks is recommended to increase the radioiodine uptake by functioning healthy thyrocytes and recurrent and metastatic tumor cells. Iodine intake through foods and beverages should be restricted to stimulate radioiodine uptake in healthy thyrocytes and thyroid cancer cells before the ingestion of therapeutic radioactive iodine. Each department has its own protocols to diminish the daily iodine intake of the patients. The major source of iodine is the food containing iodinated salt and seafood. There is no consensus on the time interval for low iodine diet, however many departments initiate iodine deficient diet at least 2 weeks before radioiodine treatment. Iodinated contrast agents commonly used in radiologic procedures and use of amiodarone, an antiarrhythmic agent, also interfere with 131I uptake for about 1 year.
Administration of 131I
Nuclear medicine physician has the medicolegal responsibility to take the record of the negative pregnancy test (preferably measuring serum level of β-human chorionic gonadotropin, β-HCG) within the last 24 hours before the ingestion of radioiodine in the reproductive age because radioiodine ingestion is contraindicated during pregnancy. In addition, the treating physician should inform the patient about the radiation protection instructions and the presence of fecal and urinal incontinence should be addressed clearly.
Although it is not a common practice in the USA, many departments in other parts of the world require that the patient should fast at least 6 hours to avoid interference with the gastrointestinal absorption of radioiodine. Many departments prefer a single oral capsule; however, others still use liquid form of 131I because of lower cost. Liquid form is less expensive but it is associated with potentially higher radiation exposure to the medical staff and supposedly to the patient’s mouth and esophagus. The patients should be hydrated orally or intravenously if oral route is not available before 131I treatment to facilitate urinary excretion of the radioiodine to minimize the radiation exposure to blood and salivary gland.
Pretreatment administration of steroids is recommended if metastatic involvement of any critical organ is detected before radioiodine therapy. Thus, some precautions can be taken to avoid serious side effects caused by inflammatory changes and edema that may happen following administration of high amount of 131I in patients with brain metastasis.
In 24 hours following radioiodine administration, liberal oral hydration and the use of lemon juice or sour candy or chewing gum increases salivary flow and reduces radiation exposure of the salivary glands. It is not evident whether lemon juice may be even more effective 24 hours after than immediately after radioiodine administration.32 Recently, it was also reported that salivary stimulation may result in higher radiation burden to salivary glands.33
Hospitalization Versus Outpatient Protocol
The maximum activity allowed for outpatient use and the release criteria after the ingestion of therapeutic activity differ greatly in many countries. The laws and regulations that control patient discharge after ingestion of therapeutic dose of 131I are more strict in Japan and Europe than North America. In many countries, ingestion of 131I activity greater than 30 mCi requires hospitalization in a specially shielded room under strict isolation rules. In the USA and Canada, the regulations have been amended to allow practitioners to administer higher amounts of 131I provided that they can demonstrate that no member of the public, including family, will receive more than an allowable exposure. In some locations, it has become permissible to treat patients with up to 250 mCi and release the patient to a proper environment if the accommodation otherwise fulfills the requirement. Despite these modifications, the main criterion for discharge is the dose rate as determined by official bodies in each country.
Side Effects of Therapeutic 131I
To reduce radiation-induced side effects and avoid unexpected consequences, treating nuclear physician must be aware of the potential side effects which can be seen immediately after radioiodine administration and during the period that follows. Early side effects include nausea and vomiting in the first 5 to 7 days following 131I ingestion. Swelling and pain in the thyroid remnant is not rare and respond well to common analgesics such as paracetamol and aspirin. If swelling gets severe, corticosteroids are effective medications in most of the patients, but airway obstruction caused by swelling of large amount of thyroid remnant after high amount of 131I activity requires emergency intervention for tracheostomy.
Damage to the salivary glands because of 131I therapy results in sialadenitis and xerostomia (dryness of the mouth). Among all salivary glands, parotid glands are more frequently affected. The risk of sialadenitis and xerostomia, seen in approximately 4% of the patients, is dose dependent; the risk increases with higher amount of 131I activity. Sialadenitis can be avoided by stimulation of salivary glands by lemon juice or chewing gums although otherwise is also reported about the benefits of salivary stimulation.
Hematologic abnormalities such as thrombo/leucopenia may occur in approximately 5% of the patients, and depending on the total administered activity of 131I, bone marrow aplasia and leukemia may develop in 0.2% to 2% of the patients.
Pulmonary fibrosis, a severe side effect of 131I therapy in patients with thyroid cancer may occur in patients with diffuse lung metastases.34 Nasolacrimal duct obstruction, dacryocystitis, and epiphora are rare adverse effects that can be seen after 131I therapy in patients with thyroid cancer.
Post-therapy Whole Body 131I Scan (PTS)
Post-therapy whole body images obtained 7 to 10 days after discharge is useful for the assessment of the distribution of 131I within patient’s body and its localization in the thyroid remnant tissue and functional metastatic foci. Small metastatic deposits, particularly those in the lungs can been seen only on post-therapy images (Fig. 3.2). Both American and European guidelines recommend routine use of post-therapy scan.35,36 The time for performing post-therapy whole body scan after 131I therapy varies from 3 to 10 days,37 although the optimal time for performing the PTS still remains controversial. It is generally believed that the longer the time elapsed before imaging, the greater the target-to-background ratio, but, recent data surprisingly suggest that earlier imaging at 72 to 96 hours may be preferred for the detection of metastatic disease.37 Because the therapeutic dose of 131I is much greater than the low dose of 131I used for routine follow-up whole body scan, the PTS can reveal additional unexpected sites of uptake, such as pulmonary or skeletal lesions, which may alter staging, follow-up strategy, and prognosis in some patients.16,38 As a result, the PTS can change patient management by leading to immediate additional imaging studies, prompting an earlier follow-up time frame or altering plans for subsequent WBS and additional 131I therapy.39–41
FIGURE 3.2. 131I post-therapy whole body scan in a patient with papillary thyroid cancer treated with 200 mCi of radioiodine. Anterior (A) and posterior (B) images show high uptake in the functioning residual thyroid tissue (arrows) and diffuse uptake in the miliary metastases in both lungs (arrowheads).
Compared with low dose 131I WBS routinely performed after 48 to 72 hours of ingestion of 131I activity, PTS which provides a greater target-to-background ratio can be more sensitive than the WBS for detection of thyroid remnant and metastatic disease, because, in addition to the high amount of 131I activity deposited within the body after the ingestion of therapeutic activity, it is typically acquired several days after therapy allowing excretion of circulating activity reducing background uptake.40
123I Whole Body Scan
Although 131I is a readily available in most departments, it has certain disadvantages as an imaging agent for use before ablation or therapy. Moreover, the efficiency of the consequent 131I treatment is claimed to decrease because of the stunning effect on functioning thyroid tumor tissue possibly caused by even small amount of β-particle radiation emitted by diagnostic dose of 131I.42–44 123I may be an alternative radionuclide as it emits low-energy γ-rays which are ideal for imaging with standard γ-cameras and has neither particle radiation nor stunning effect theoretically. It was shown that 123I whole body was comparable to those of high dose posttreatment 131I whole body images.45 The short half-life of 123I and its high cost however limit the worldwide use of this agent for imaging in the diagnostic workup of thyroid cancer.
131I SPECT/CT Imaging
SPECT/CT is feasible in both low dose 131I whole body scan and also for high dose post-therapy 131I whole body imaging. Sensitivities ranging between 45% and 75% have been reported in the literature for diagnostic 131I planar whole body scan in detecting recurrences or metastases from DTC.46–51 Lack of anatomical landmarks and the nonspecific uptake of the tracer in other pathologic conditions or normal tissues somewhat complicate the interpretation of the 131I planar whole body images. SPECT/CT provides valuable information about precise location of increased uptake in the neck and other areas of interest by coronal, sagittal, and transaxial slices. Several studies have demonstrated that SPECT/CT images are significantly more accurate for the diagnosis of recurrence and metastasis, staging of thyroid cancer, and distinguishing between benign and malignant foci of radioiodine accumulation more efficiently than conventional γ-camera imaging.52–53 Thus, 131I SPECT/CT is a useful clinical tool for the evaluation of DTC patients with its superior technical ability of three-dimensional imaging.
A recent retrospective analysis showed that SPECT/CT improved the performance of 131I imaging for the diagnosis, staging, and follow-up of patients with DTC.52 Wakabayashi et al.52 reported that SPECT/CT improved image interpretation, showing higher confidence levels of both benign and malignant lesions, and more precise localization of the true lesions as compared with 131I WBS image.50 In a study by Ciappuccini et al.,53 the sensitivity and specificity of 131I SPECT/CT for postablation scintigraphy were 78% and 100%, respectively. In another study, the sensitivity of 131I SPECT/CT and planar imaging were both 62%, and the overall specificity of imaging increased from 78% to 98% with the addition of 131I SPECT/CT.51 Recent studies showed that SPECT/CT improved the diagnosis in 47.6% to 88% of patients and modified therapeutic strategies in 23.5% to 25%.50,52,53
In low-risk and intermediate/high-risk subjects, the risk stratification can be further refined by ongoing assessment within the first 2 years.51,54 Avram et al.55 concluded that risk stratification and staging of patients should not be based solely on clinical and histopathologic criteria, but should include specific imaging, in particular 131I SPECT/CT imaging, to identify regional and distant metastases. Post-therapy 131I SPECT/CT provided new information for nodal staging in 35% to 36.4% of patients and resulted in a new risk stratification in 6.4% to 25%.56–58
Menges et al.59 reported that incremental diagnostic value is higher with 131I SPECT/CT in lesions outside the neck than in those in the neck and absent in patients without iodine-positive foci on 131I WBS imaging. Chen et al.60conducted 37 SPECT/CT studies in 23 patients with inconclusive foci on WBS and reported a change in management in 34.7%8,23 of the patients with the addition of SPECT/CT. In follow-up studies comparing planar and tomographic techniques, 131I SPECT/CT images had greater diagnostic value in 57.7% to 73.9% of DTC patients based on precise localization and characterization of foci accumulating 131I.59–60 SPECT/CT in long-term follow-up changes the management of patients contributes to change in the management of patients with DTC, including surgical management, 131I and external radiation therapy.
131I Whole Body Scan Versus Tg Measurement and Neck Ultrasonography
Tg is exclusively produced by functional thyroid tissue and follicular cell-derived differentiated thyroid cancer cells. Stimulated serum Tg measurement provides a reliable method for detecting the presence of recurrent disease and monitoring the response to 131I treatment. The sensitivity of serum Tg measurement is about 80% to 90% in the absence of anti-Tg antibodies after withdrawal of thyroid hormone replacement. Some studies suggest that, especially for low-risk patients, radioiodine scanning is of low sensitivity, and thus can be replaced with neck ultrasound and stimulated serum Tg determination as a false positive radioiodine scan because of physiologic radioiodine accumulation in some organs (i.e., salivary glands, pharynx, stomach, colon, urinary bladder, etc.) and at areas of inflammation may lead to an unnecessary high dose 131I treatment.61
Thyroglobulin-Positive, Iodine-Negative Patients (TENIS Syndrome)
Increasing number of papers report discrepancy between serum Tg measurement and low dose 131I whole body imaging in some patients with DTC. In these patients, serum Tg is high while 131I WBS fails to localize any focus of increased iodine uptake (TENIS syndrome). Serum Tg provides no diagnostic information for localizing the site of recurrent or metastatic disease secreting Tg, therefore patients with a negative radioiodine scanning and elevated serum Tg pose a diagnostic challenge. 18F-FDG PET/CT is able to demonstrate tumor foci in a significant portion of these patients (Fig. 3.3). Thus, one of the indications of 18F-FDG PET/CT in thyroid cancer is the demonstration of iodine-negative tumors secreting Tg because treatment with high amount of 131I activity (“blind treatment”) seems to be the unique available radionuclide therapeutic technique before proceeding to systemic chemotherapy with novel agents. In some patients with disseminated disease, some of the metastatic lesions are iodine avid and thus can be demonstrated on 131I whole body scan whereas additional foci can be shown by 18F-FDG PET/CT (Fig. 3.4). This advantage of 18F-FDG PET/CT may have some therapeutic implications in the management of thyroid cancer.
Stimulation with Recombinant Human TSH: Its Implications on Serum Thyroglobulin Measurement, 131I Whole Body Scan, and Ablation
For patients who are at risk of serious health hazards because of severe hypothyroidism (elderly patients with cardiovascular insufficiency, poorly controlled hypertension, and renal insufficiency), exogenous stimulation by rhTSH injections can be used to obtain prompt increase of serum TSH before follow-up WBS.62
FIGURE 3.3. Invasion of the esophageal wall by papillary thyroid carcinoma in a patient with increasing serum thyroglobulin (Tg: 39 ng/dL). The post-therapy scan obtained following 200-mCi 131I ingestion failed to demonstrate any focus of increased uptake on anterior (A) and posterior (B) images. 18F-FDG PET/CT images (C: MIP image, D: transaxial PET scan, E: transaxial CT scan, F: transaxial PET/CT fusion scan) showed an FDG-avid metastatic lesion in the esophageal wall (arrow).
With the use of rhTSH, the sensitivity of Tg measurement to detect recurrent disease during the follow-up of DTC patients is enhanced. Indeed, many studies consistently have shown that rhTSH-stimulated Tg measurement has a good diagnostic accuracy.63–65 Pacini et al.63 showed that 88% of patients with undetectable serum Tg under rhTSH-stimulation also had a negative Tg result under hypothyroidism. In the remaining 12% of patients with positive Tg only under hypothyroidism, diagnostic whole body scan was either negative (83% of patients) or showed a faint uptake in the thyroid bed. Mazzaferri and Kloos64 reported that 11 of 11 patients with locoregional or distant metastases had an rhTSH-stimulated Tg >2 ng/mL. In another study, Kloos and Mazzaferri65 confirmed the good sensitivity of rhTSH in predicting persistent tumor, whereas a single rhTSH Tg <0.5 ng/mL had 98% likelihood of identifying patients completely free of tumor.
However, the levels of serum Tg after rhTSH stimulation are lower by a factor of two to four compared to the hypothyroid state.66–68 Consequently, the American consensus on the management of DTC sets a threshold as low as 2 ng/mL, above which an empiric trial of 131I therapy might be considered.69 To respond to the concerns that were raised as to whether rhTSH-stimulated Tg measurement could be as accurate as Tg measurement in the hypothyroid state during thyroid hormone withdrawal in the detection of residual or recurrent DTC, Eustatia-Rutten et al.70 performed a meta-analysis on more than 9,000 patients with DTC and concluded that, with the use of appropriate thresholds, rhTSH-stimulated Tg has a sensitivity comparable to that under hormone withdrawal, although specificity is lower.
Although the clinical role of TSH stimulation by rhTSH injections expands gradually to include Tg measurement and 131I thyroid ablation and therapy, thyroid hormone withdrawal is still the most widely used method for 131I whole body imaging performed for evaluation prior to 131I ablation, and low dose 131I whole body scanning coupled with serum Tg/anti-Tg measurement to localize recurrent and metastatic disease during follow-up.71 Because of the side effects of hormone withdrawal, 131I WBS during follow-up period has been progressively abandoned by many departments. More frequent use of TSH stimulation with rhTSH injections may potentially result in reinventing the merits of routine follow-up 131I whole body scan. In locales where rhTSH is available, it is being used simply to evaluate if the Tg levels rise in response to the rhTSH to a level suggestive of recurrence. A randomized international study, demonstrated comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3,700 MBq by either administering rhTSH or thyroid hormone withdrawal.72 However, Pacini et al.73 suggests that an activity of 30 mCi does not provide a satisfactory thyroid ablation rate when rhTSH is preferred for TSH stimulation. In Europe, and more recently in the United States, the use of rhTSH for post-surgical remnant ablation is approved for low-risk patients receiving an ablative 131I dose of 3,700 MBq (100 mCi). Pilli et al.74 reported that the rate of successful ablation after rhTSH administration is high with 1,850 MBq (50 mCi) and that the procedure can be used even in patients with lymph node metastases. It should be noted that the number of patients with nodal disease in this study is quite small and the follow-up period is short. In fact, although rhTSH has proven to be almost as good as withdrawal-induced endogenous stimulation for the ablation of normal thyroid tissue, long-term follow-up data is not yet available compare the efficacy rates in terms of preventing recurrences. Although some reports suggest that high-risk patients should undergo post-surgical initial 131I therapy with thyroid hormone withdrawal to maximize radioiodine uptake by residual cancer tissue and to optimize the early detection of occult distant metastases,75 it is widely accepted in the United States and some countries in Europe that rhTSH is as effective as withdrawal in high-risk patients, too.
FIGURE 3.4. Low dose (5 mCi) and post-therapy 131I whole body scans compared with 18F-FDG PET/CT in a patient with papillary thyroid cancer and increased thyroglobulin level (209 ng/dL). Focal radioiodine accumulation is seen on low dose 131I scan in the upper part of the right lung (arrowheads, A: anterior and B: posterior), and additional lesions (arrowheads, lung lesions previously seen on low dose 131I scan) were noted on post-therapy whole body scan following 200-mCi 131I ingestion in the right lung (arrows, C: anterior and D: posterior), and more lesions in the lungs not detected on 131I images were clearly depicted on 18F-FDG PET/CT images (arrows, E: MIP image, F:transaxial CT scan, G: transaxial fusion PET/CT scan).
rhTSH Stimulation Before 131I Therapy of in Patients with Metastatic Differentiated Thyroid Cancer
Functioning metastatic foci can secrete sufficient amount of thyroid hormone to suppress TSH. One of the most important applications of rhTSH stimulation is its use prior to the treatment of residual or metastatic cancer in patients in whom elevation of TSH after thyroid hormone withdrawal is difficult to achieve and/or contraindicated. It is clinically well tolerated, even in elderly and frail patients who could be negatively affected by hypothyroidism. The use of rhTSH avoids long period of hypothyroidism necessary to achieve high endogenous TSH serum levels. rhTSH enhances 131I uptake into metastatic lesions and prolongs the tumoral and thyroid tissue retention of the 131I, but the respective efficacy of rhTSH and hypothyroid stimulation in this group of patients have not been compared in randomized trials. From retrospective analysis of the literature, complete remission in metastatic DTC is achieved in about 33% to 50% of patients treated in the hypothyroid state whereas this figure is about 2% in the case of rhTSH-aided treatment. It must be underlined that these populations are hardly comparable, as rhTSH has often been used on a compassionate basis in frail patients and in those with a more advanced disease. There are few case reports, however, when direct intrapatient comparison was available, suggesting that rhTSH may be less effective than hormone withdrawal to treat metastatic lesions.76,77 Pötzi et al.78 studied the time course of radioiodine specifically in metastatic tissue in four patients by comparing results in the hypothyroid state induced by thyroid hormone withdrawal with those after rhTSH administration. All patients had lesser uptake of radioiodine under rhTSH stimulation than after hormone withdrawal (median uptake dose in percent in tumor tissue: 0.05 versus 0.08). The median half-life in tumor tissue was also shorter under rhTSH (21.9 hours versus 39.8 hours). The authors concluded that when cancerous tissue is stimulated by rhTSH, higher radioiodine activities would be required to achieve the same therapeutic effect. However, the radiation absorbed dose to the tumor is also influenced by the biologic half-life of the localized 131I.
It is thus expected that rhTSH may be used for the treatment of patients with metastatic DTC in whom hormone withdrawal is medically contraindicated or in whom adequate endogenous TSH levels cannot be obtained because of reduced pituitary reserve or continued T4 production by metastatic tissue.
PET/CT IMAGING IN THYROID CANCER
Glucose transporters (GLUT 1 to 5), which are essential to transport glucose into cells, are expressed in aggressive thyroid carcinomas. TSH stimulation increases GLUT 1 expression and glucose metabolism in thyroid cells.79–81TSH stimulation can be achieved by T4 withdrawal (endogenous TSH stimulation) or exogenous administration of human recombinant TSH. Increased TSH levels therefore can improve the sensitivity of 18F-FDG PET/CT to identify residual normal thyroid as well as malignant thyroid tissue.131I FDG PET/CT imaging has become useful in thyroid cancer management (Table 3.2). Patients with larger volumes of 18F-FDG avid disease or higher SUVs are less likely to respond to radioiodine therapy. They have a higher mortality over a 3-year follow-up compared with patients whose tumors do not demonstrate 18FDG uptake.82 Conversely, tumors that take up 131I are less likely to yield positive 18F-FDG PET scans.83
WIDELY ACCEPTED CLINICAL INDICATIONS FOR 18F-FDG PET/CT IMAGING IN THYROID CANCER MANAGEMENT
18F-FDG PET/CT in TENIS Syndrome
DTC cells expressing the NIS concentrate radioiodine and the patient will also have elevated Tg, indicating the presence of persistent, recurrent, or metastatic disease. When the NIS protein expression is low (dedifferentiation, more aggressive disease), the thyroid tumor cells lose their iodine trapping capacity, rendering the whole body iodine scan negative. 18F-FDG PET/CT imaging has become an established imaging modality in DTC patients with elevated Tg level but negative whole body iodine scans (TENIS syndrome) to identify nonfunctioning metastases. False positive Tg (i.e., mild-to-moderately elevated Tg) can be encountered in certain non-thyroidal malignancies like histiocytic lymphoma, Hodgkin lymphoma, breast and alveolar lung carcinoma, laryngeal malignancies, spindle cell, and Kaposi sarcomas.84
The prognosis of patients with 131I-negative DTC metastases, the so-called nonfunctioning metastases, is significantly worse. In these patients, early diagnosis of nonfunctioning metastasis and their surgical extirpation if possible is the optimal therapeutic approach. At that stage there is an activation of cellular glucose metabolism, promoting 18F-FDG uptake in these dedifferentiated cells. The whole body iodine and the 18F-FDG PET/CT scans are therefore complementary in this clinical scenario. Most often, a tumor lesion will take up either only radioiodine or 18F-FDG, but some patients can have both radioiodine and 18F-FDG avid lesions because of varying grades of differentiation among various lesions.83,85,86 Whole body 18F-FDG PET/CT is a dependable imaging tool in assessing patients with TENIS syndrome with a reported sensitivity of 70% to 95%.85 The optimal goal here is to identify surgically resectable lesions to render a patient disease free. Shammas et al.87 found that, in patients with negative 131I whole body scan, 18F-FDG PET/CT improved diagnostic accuracy and changed therapeutic management regardless of the Tg level. They reported an overall sensitivity, specificity, and accuracy of 18F-FDG PET/CT in localizing recurrent or metastatic disease to be 68.4%, 82.4%, and 73.8%, respectively.
Comparatively, the sensitivity of 18F-FDG PET/CT in clinical applications is typically limited to lymph nodes with a cross-sectional diameter of 8 to 9 mm. Depending on the degree of hypermetabolism, smaller lesions are likely to be missed. It is generally felt that the higher the Tg value, the greater the sensitivity of 18F-FDG PET studies. Clinically, it would be a good strategy to perform 18F-FDG PET/CT studies in TENIS patients with more than 10 ng/mL serum Tg levels especially if the neck ultrasonography fails to identify any locoregional disease.
Pulmonary metastases are the most common distant metastases in DTC and can be responsible for many of DTCs presenting as TENIS syndrome.88 18F-FDG PET/CT has a high detection rate in these cases. However, one must bear in mind that 18F-FDG PET shows almost negligible or no uptake and thus has decreased sensitivity to identify miliary pulmonary metastases as a stand-alone 18F-FDG PET study.89 Thus, a high-resolution thorax CT is mandatory when performing an 18F-FDG PET study.
Beyond its diagnostic utility, 18F-FDG PET/CT also provides prognostic information in TENIS syndrome. Wang et al.82 have shown that in 125 patients with thyroid cancer (93 papillary, 18 follicular, 12 Hürthle cell, and 2 anaplastic carcinomas) with TENIS syndrome using multivariate analysis, the volume of 18F-FDG avid disease was the single strongest predictor of survival. The 3-year survival probability of patients with 18F-FDG avid tumor volumes of 125 mL or less was 0.96 (95% confidence interval 0.91, 1) compared with 0.18 (95% confidence interval 0.04, 0.85) in patients with 18F-FDG volume greater than 125 mL.
More recently the same investigators showed strong inverse correlation between the SUV in metastatic lesions and survival in thyroid cancer patients. Intensity of 18F-FDG uptake is correlated with progressive dedifferentiation. They quantified 18F-FDG uptake by SUV and found that an intense 18F-FDG uptake with the concomitant loss of 131I uptake indicates progression of disease. Patients with an initially high SUV had an unfavorable clinical course whereas decreasing 18F-FDG uptake together with persistent 131I uptake was associated with a good prognosis. Apart from age, the number of 18F-FDG avid lesions and higher SUV (especially more than 13) has been found to have a negative impact in the prognosis of TENIS syndrome patients.82
Surgery is considered as the first-line therapy in 131I-negative patients with gross nodal or recurrent neck disease whereas most patients with disseminated metastatic disease will need systemic therapy. 18F-FDG avid, iodine-negative tumors are accepted as good candidates for systemic treatment. Symptomatic patients with metastatic thyroid cancer or progressive disease who are radioiodine nonresponsive can be considered for investigational therapies with novel agents including angiogenesis inhibitors and tyrosine–kinase inhibitors.
18F-FDG PET/CT in the Evaluation of Hürthle Cell Carcinoma
Hürthle cell variant of DTC attract special attention because they, as a group, have low radioiodine avidity and are more likely to be falsely negative on a whole body iodine scan.90 Recurrence is a strong possibility in these patients with high Tg despite negative whole body iodine scan. Thus, they need to be further worked out by imaging with 18F-FDG PET/CT.
Normally patients with Hürthle cell thyroid carcinoma are usually monitored with sequential serum Tg measurements, because more than 80% of these patients have non-iodine avid tumor and the clinical utility of radioiodine imaging is limited in this population. This subset of thyroid malignancy also carries a worse prognosis and a greater risk of distant metastases. 18F-FDG PET/CT has thus a potential role to play in identifying locoregional disease and distant metastases.36,90 Pryma et al.91 showed that 18F-FDG PET/CT is the imaging modality of choice with a high sensitivity and specificity (95% each) for immediate thyroidectomy risk stratification and also in Hürthle cell carcinoma patients with detectable Tg and negative conventional 131I imaging. SUVmax provided a dependable prognostication in high-risk patients. Each increase in intensity by one SUVmax unit was associated with a 6% increase in mortality in this study. The 5-year overall survival in patients with SUVmax less than 10 was 92%, but declined to 64% in those with SUVmax of more than 10.
18F-FDG PET/CT in Poorly Differentiated and Anaplastic Thyroid Carcinoma
Poorly differentiated thyroid carcinomas (PDTC) and ATC comprise of highly undifferentiated thyroid cells and do not accumulate radioiodine but overexpress GLUT 1 receptors making 18F-FDG PET/CT the imaging method of choice. These lesions show high 18F-FDG avidity, a sign of aggressive clinical behavior of tumors, and poor prognosis doubling its volume in 7 days.92
Poisson et al.93 evaluated 20 consecutive ATC patients with 18F-FDG PET/CT and contrast-enhanced total-body CT for initial staging, prognostic assessment, therapeutic monitoring, and follow-up. A total of 265 lesions in 63 organs were demonstrated in 18 patients. Thirty-five percent of involved organs were visualized only with 18F-FDG PET/CT and one with CT only. In three patients, 18F-FDG PET/CT also demonstrated unknown sites of metastases. Initial treatment modalities were modified by PET/CT findings in 25% of cases. The volume of 18F-FDG uptake (≥300 mL) and the intensity of 18F-FDG uptake (SUVmax ≥18) were significant prognostic factors for survival. 18F-FDG PET/CT permitted an earlier assessment of tumor response to treatment than CT in four of the eleven patients in whom both examinations were performed. After chemoradiation, only two patients with a negative PET/CT had complete remission at 14 and 38 months; whereas eight patients who had persistent 18F-FDG avid lesions during treatment had a clinical recurrence and expired in 6 months. The authors concluded that 18F-FDG PET/CT appears to be the reference imaging modality for ATC at initial staging and seems promising in the early evaluation of treatment response and follow-up.93
18F-FDG PET/CT in Preoperative Staging and Postoperative Follow-Up of MTC
MTCs do not accumulate radioiodine. Routine preoperative 18F-FDG PET/CT imaging is not indicated in MTCs. 18F-FDG PET/CT imaging is a valuable clinical tool when conventional imaging techniques are either negative or inconclusive or if there is a persistent elevated serum calcitonin level (more than 150 pg/mL 3 months post-thyroidectomy) or carcinoembryonic antigen (CEA) beyond 30 ng/mL.94 CEA levels greater than 30 ng/mL suggest central and lateral (ipsilateral) lymph node metastases, whereas CEA levels greater than 100 ng/mL signify lateral (contralateral) lymph node metastases and distant metastasis.95
Considerable overlap exists with results of conventional imaging modalities (neck ultrasonography, chest CT, MRI abdomen) and 18F-FDG PET/CT imaging in the detection of locoregional (neck) and distant metastases. In general, there is a correlation between the calcitonin doubling time and 18F-FDG PET/CT positivity. It is believed that the shorter the doubling time the higher the sensitivity for 18F-FDG PET/CT which is especially recommended for patients with calcitonin higher than 150 to 500 pg/mL.36
Other PET tracers that may be potentially useful in detecting recurrence of metastatic disease in MTC patients include somatostatin receptor analogs and dihydroxyphenylalanine (DOPA). The sensitivity of 18F-DOPA PET/CT was found to be 94% whereas the corresponding value for 18F-FDG PET/CT was 62%.96,97
Correlation of anti-Tg Antibody and 18F-FDG PET/CT
Kingpetch et al.98 studied 22 consecutive DTC patients with elevated anti-Tg antibodies. 18F-FDG PET/CT findings were correlated with histopathology, follow-up imaging, or clinical follow-up. Twelve patients had positive findings on 18F-FDG PET/CT, six were true positives, and six were false positives. 18F-FDG PET/CT results were true negative in 10 patients and the authors found no false negative patients. The overall sensitivity, specificity, and accuracy of 18F-FDG PET/CT were 100%, 62.5%, and 72.7%, respectively. They concluded that those patients with negative whole body iodine scan and anti-TgAb levels equal to or higher than 414.6 IU/mL should undergo 18F-FDG PET/CT scan. They demonstrated that 18F-FDG PET/CT results were highly positive if SUVmax value is equal or greater than 4.5.
Another recent study by Ozkan et al.99 have retrospectively investigated the clinical value of 18F-FDG PET/CT in detecting the recurrence of disease with negative 131I whole body scans, undetectable Tg, and increased anti-Tg antibody levels taking the clinical follow-up and histologic results as the reference standard in 27 women and 4 men, with average age of 50.2 years. Time from thyroidectomy to 18F-FDG PET/CT scan was 30 months on average. All patients had undetectable serum Tg and increased anti-Tg antibody levels. The authors calculated the performance characteristics of 18F-FDG PET/CT for the detection of recurrent DTC and found the sensitivity 75%, specificity 76%, negative predictive value 86%, positive predictive value 75%, and accuracy 80%. They concluded that 18F-FDG PET/CT can be useful in patients with suspected DTC recurrence, whose Tg levels are undetectable because of high anti-Tg antibodies.
18F-FDG PET/CT for Prognostication and Determination of Disease Extent in High-Risk Group
Although not a standard practice yet, several studies have shown that 18F-FDG PET/CT correlates with overall survival.100 The SUVmax, the number of lesions, and the location are essential for an effective patient management to determine the need for additional systemic treatment or if the metastases are refractory/resistant to 131I or if they have achieved the maximum benefit from the treatment. Robbins et al.101 hypothesized that the metabolic activity of metastatic lesions, as defined by retention of FDG, would correlate with prognosis. They studied the age, serum Tg, American Joint Committee on Cancer (AJCC) stage, histology, radioiodine avidity, 18F-FDG PET positivity, number of FDG avid lesions, the glycolytic rate of the most active lesion, and PET/CT outcomes in all patients correlated with survival by univariate analysis. However, only age and PET results continued to be the strong predictors of survival under multivariate analysis. The initial AJCC stage was not a significant predictor of survival by multivariate analysis. There were significant inverse relationships between survival and both the glycolytic rate of the most active lesion and the number of 18F-FDG avid lesions. Metastatic thyroid deposits with negative iodine avidity are found to have higher positive 18F-FDG rate and higher SUVmax than the lesions with iodine avidity. Survival was reduced in patients having distant metastatic lesions with negative iodine, positive 18F-FDG scans, and high Tg level. Volume of metastatic disease identified by anatomical imaging had the strongest influence of any variable on survival. The study found that tumors that did not concentrate 18F-FDG had a significantly better prognosis (after a median follow-up of about 8 years) than tumors that avidly concentrated 18F-FDG.
Evaluation of Incidental 18F-FDG Uptake in Thyroid Gland: Thyroid Incidentalomas
Focal or diffusely increased 18F-FDG uptake in the thyroid gland in a patient with no past medical history of thyroid disease is defined as an incidental thyroid lesion. Prevalence of incidental 18F-FDG uptake in thyroid gland, either focal or diffuse, is approximately 2% to 3% and prevalence of focal versus diffuse 18F-FDG uptake is found to be almost equal.13,101,102 The incidence of 18F-FDG uptake in thyroid is yet much lower than the percentage of thyroid abnormalities detected during a routine neck ultrasound but, the risk of a malignant process in an 18F-FDG avid thyroid lesion is much higher than ultrasound abnormality suggesting a higher clinical significance of 18F-FDG-positive thyroid lesion (Fig. 3.5).102–104 It is observed that 18F-FDG uptake in a completely normal thyroid gland is rare, and either a focal or diffuse 18F-FDG uptake is viewed with high suspicion of an occult thyroid disorder. Diffuse 18F-FDG uptake is almost always benign and is usually caused by autoimmune (Hashimoto) thyroiditis. Another common cause for the diffuse 18F-FDG uptake is Graves disease. Malignancy as a cause of diffuse uptake is very rare.
Focal uptake on the other hand significantly points to a nodule and possibly a thyroid malignancy. Estimated risk of malignancy in a focal 18F-FDG-positive thyroid lesion is as high as 30% to 50% (versus 4% to 13% risk of malignancy in ultrasound detected nodules).103,104 Most of these cases are primary thyroid malignancy, particularly papillary type. In patients with a mixed uptake pattern (focal and diffuse), the risk is estimated to be as equal to the focal 18F-FDG uptake.
Although diffuse 18F-FDG uptake points to a more precise benign etiology, a focus of 18F-FDG uptake in the thyroid may not always be malignant. Value of SUVs in the differentiation of benign from malignant lesion is controversial in thyroid incidentalomas. Hürthle cell adenoma or autonomous adenomas, although benign, have been found to have higher SUVs. Generally, it is found that hypothyroid status is associated with higher FDG uptake than euthyroid status.
Although highly differentiated thyroid malignant lesions can have low or no FDG uptake, high FDG uptake in malignant thyroid lesions always point to a higher degree of malignancy, aggressive behavior, and poor prognosis. Tall cell variant, sclerosing papillary, insular, and Hürthle variants of DTC are expected to have higher 18F-FDG uptake. Extrathyroidal extension at presentation has been especially observed in most of patients with tall cell variant if SUV is considerably high. Undifferentiated thyroid malignancies tend to show higher SUVs than the DTC varieties. Experience in patients with thyroid incidentalomas on 18F-FDG PET/CT scan showed that (a) there is higher chance of incidence of malignancy with focal 18F-FDG uptake; (b) incidentally detected thyroid malignancies with higher 18F-FDG uptake demonstrate a high rate of unfavorable prognosis, and may represent an aggressive variant of thyroid carcinoma; (c) there is less than 1% chance for a focal 18F-FDG uptake to be representing a secondary metastatic deposit in thyroid gland.104
18F-FDG PET/CT Indeterminate/Inconclusive Thyroid Nodules on Fine-Needle Aspiration Cytology
Ten to fifteen percent of thyroid nodules are classified as “indeterminate” on fine-needle aspiration cytology (FNA) suggesting uncertain cellular etiology and/or failure to differentiate between benign and malignant cells (i.e., follicular or Hürthle cell lesion). Based on their acquired capacity of cancerous cells to concentrate more glucose, it may be feasible to use 18F-FDG PET/CT in the preoperative assessment of cytologically indeterminate thyroid lesions, thereby avoiding unnecessary “diagnostic” thyroidectomies.105,106 A recent study by Deandries et al.107 however demonstrated that adding 18F-FDG PET/CT findings to neck ultrasound in patients with indeterminate thyroid nodules provided no additional diagnostic benefit. The sensitivity and specificity of 18F-FDG PET/CT in the presurgical evaluation of indeterminate thyroid nodules is too low to recommend its use routinely.
FIGURE 3.5. Thyroid incidentaloma. A large thyroid nodule with a peripheral hypermetabolic rim and central hypometabolism (necrosis) was detected in the left lower lobe of the thyroid gland on 18F-FDG PET/CT scan (arrows) in a 62-year-old man with laryngeal carcinoma who was being investigated for mediastinal lymphadenopathy detected on previous CT images of the chest (A: MIP image; B: transaxial FDG PET; C: transaxial CT; D: transaxial fusion PET/CT scan). The cytologic findings obtained from the nodule through fine-needle aspiration biopsy were indeterminate for thyroid malignancy. The patient underwent thyroidectomy and poorly differentiated thyroid cancer was histopathologically confirmed on surgical specimen.
RADIONUCLIDE IMAGING IN MEDULLARY THYROID CANCER
MTC exhibits similar features of other neuroendocrine tumors such as carcinoid and islet cell tumors. The surgical intervention is the only option for a potential cure when distant organ metastasis is excluded. Following surgery, differentiation between postoperative changes and recurrent tumor in the neck poses a diagnostic challenge. Nuclear medicine modalities are less affected by postoperative changes and permit whole body scanning for distant metastases.
There is no radiopharmaceutical yet that is universally accepted and can be used in all patients with MTC whereas each agent described below shows reasonable success in the patient population reported in the literature. Some of the agents used for radionuclide imaging of MTC such as 201Tl chloride and 99mTc MIBI are nonspecific tumor-seeking radiopharmaceuticals but others such as 123/131I metaiodobenzylguanidine (MIBG) and gallium-68 (68Ga) DOTA complexes are are highly specific agents and thus can be used in the management of neuroendocrine tumors.
The sensitivity of radionuclide imaging with 99mTc MIBI and 201Tl chloride, somatostatin receptor compounds, 99mTc labeled pentavalent dimercaptosuccinic acid (99mTc-DMSA[V]), and MIBG labeled with either 131I/123I ranges from 25% to 95%. Among them, 99mTc MIBI and 201Tl chloride were sensitive in the diagnosis of MTC, particularly in cases with basal calcitonin level greater than 1,000 pg/mL. 201Tl chloride has the same characteristics with isonitriles; therefore it exhibits similar sensitivity as with 99mTc MIBI.108,109 DMSA(V) labeled with 99mTc has a valance of (+5) resembling the phosphate ion. The mechanism of uptake still remains unknown.99mTc DMSA(V) was found to be useful for localizing the MTC lesions; however false negative results on 99mTc DMSA(V) scan were frequent particularly in patients with mildly elevated serum calcitonin levels, most probably because of low tumor burden.109–111
The parafollicular C cells from which MTC originates are derived from neuroectodermal tissues like adrenal medulla. MIBG is similar to the adrenergic neuron blocker guanethidine and the neurotransmitter noradrenalin. MIBG labeled with either 131 or 123 is localized in neurosecreting granules of tumors including pheochromocytoma of the adrenal medulla, neuroblastoma, carcinoid tumors, nonsecreting paragangliomas, and MTC. Radioiodine labeled MIBG has been found to be less sensitive than sestamibi, 201Tl chloride, and DMSA(V) imaging, however it is highly specific and thus can be used in conjunction with other localization modalities.112–114
It was reported that 18F-FDG-PET/CT could be useful for preoperative staging and postoperative follow-up particularly in patients with elevated serum calcitonin levels. de Groot et al.115 reported that 18F-FDG PET detects more lesions than 99mTc DMSA(V) and indium-111 (111In) labeled Octreotide, as well as bone scintigraphy combined with morphologic imaging such as ultrasonography, CT, or MRI. The performance of 18F-FDG-PET/CT has been superior to the conventional nuclear medicine. The performance of 18F-FDG-PET/CT in identifying lymph node metastasis was also assessed and the reported results were comparable to those of anatomical imaging modalities. Szakall et al.116 reported that 18F-FDG-PET/CT detected more cervical, supraclavicular, and mediastinal lesions than structural imaging methods did. 18F-FDG-PET/CT failed to localize subcentimetric hepatic and pulmonary lesions which were detected by CT and MR imaging because of their superior spatial resolution. 18F-FDG-PET/CT whole body imaging has the advantage of detecting local persistent disease in the thyroid bed and neck, and distant organ metastasis leading to a potential complete cure by cervical dissection.
Despite the ability of 18F-FDG PET/CT to detect more malignant lesions than other nuclear medicine imaging tools, a more specific agent is needed to work up neuroendocrine tumors including MTC. Somatostatin receptors are present on cell surface of MTC cells. The persistent or metastatic tumor can be visualized with somatostatin receptor scintigraphy (SRS). Somatostatin receptor analogs are labeled with technetium compounds via hydrazino nicotinamide (HYNIC) to take advantage of using a readily available agent and reduce the cost. The sensitivity, specificity, and the accuracy of imaging with 99mTc EDDA/HYNIC-Tyr3-octreotide (99mTc TOC), another somatostatin receptor analog labeled with 99mTc was reported to be 88.4%, 92.3%, and 89.3%, respectively.117 SRS is less sensitive in detecting hepatic lesions because of the presence of physiologic hepatic uptake. The contribution of the novel agents such as radiolabeled anti-CEA antibodies and gastrin receptor scintigraphy was reported to be limited in the diagnostic work-up of patients with MTC118,119
Because of poor physical characteristics of 111In as an imaging agent, which has been widely used in the past to label somatostatin receptor analog octreotide, recent studies have focused on somatostatin receptor analogs labeled with various positron emitters such as 68Ga.120,121 Imaging is principally based on binding to the somatostatin receptors which are found on many different malignant cells including thyroid medullary cancer. 68Ga is a generator-produced radionuclide that can be chelated with DOTA to form stable complexes including 68Ga DOTATOC, 68Ga DOTANOC, and 68Ga DOTATATE.120,121 Initial limited experience with PET/CT using 68Ga DOTA complexes are promising but clinical validation of these highly selective radiopharmaceuticals in the management of MTC is required in large number of patients (Fig. 3.6). If initial results are confirmed in multicenter trials, DOTA complexes labeled with 177Lu or 90Y can open a new era in the therapy of these interesting neuroendocrine tumors.
FIGURE 3.6. 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT in medullary thyroid carcinoma. A 65-year-old man with surgically removed medullary thyroid carcinoma underwent 18F-FDG PET/CT for the investigation of elevated serum calcitonin (1967 pg/mL) and CEA (71.8 ng/mL) during follow-up. 18FDG PET/CT MIP image (A) demonstrates multiple foci of benign reactive uptake in the spine (arrows) and a focal uptake in the right shoulder joint (thick arrow), but no other focus of pathologic uptake. In an ongoing trial, 68Ga-DOTATATE PET/CT (B) was performed to assess the eligibility of this patient for experimental peptide receptor radionuclide therapy revealing focal uptake in the left retropharyngeal, upper mediastinal, and paratracheal lymph nodes (arrows) suggestive of metastases which showed high 177Lutetium-DOTATATE uptake on post-therapy scan (image not provided). The patient responded to 177Lutetium-DOTATATE therapy with dramatic decrease in both calcitonin and CEA levels within 3 months. (Images courtesy of Serkan Kuyumcu, MD, Department of Nuclear Medicine, School of Medicine, University of Istanbul).
6-(18F-)fluoro-L-dihydroxyphenylalanine 18F-DOPA, and 18F- fluorodopamine have also been studied in recent clinical trials,122,123 but none of these agent have yet been clinically validated in large number of patients with MTC.
Early detection of the recurrent disease and localizing the tumor site is important in patients with MTC as microdissection in the neck and thyroid bed may offer the chance for a long-term remission or for a potential complete cure in some patients. So far, no single diagnostic modality has been reliable and satisfactory in the initial staging or demonstration of the full extent of the disease. The combination of anatomical (US, CT, and MRI) and functional nuclear imaging has proved to be useful and most likely offer reliable information for the detection and removal of the metastatic tumor.
Therapy of confirmed thyroid cancer frequently involves administration of 131I after surgery to ablate remnant tissue. In the follow-up of thyroid cancer patients, increased Tg levels often requires performing 131I whole body radioiodine imaging in search for recurrent or metastatic disease. 18F-FDG PET/CT is also useful in patients with increased Tg but negative radioiodine whole body scan TENIS syndrome, patients with aggressive thyroid cancer, and patients with differentiated cancer where histologic transformation to dedifferentiation is suspected.
In rare types of thyroid cancer, such as MTC, PET/CT imaging using 18F-FDG and 68Ga labeled somatostatin receptor binding agents may have an important clinical role in selected patients if initial results are confirmed subsequently confirmed in future studies.
In a majority of patients, the fixed activity-based approach for the treatment of thyroid cancer is widely preferred because of its simplicity. In most cases, this therapy regime stays well below any toxicity limits. The main disadvantage in using this approach is the failure to consider the individuality of the patient care. Dosimetric approach for determining the precise activity needed to ablate the functioning thyroid tissue is thus likely to find its place in clinical setting, at least in selected patients. 124I PET dosimetry has strong potential in patients with DTC.
Consensus is needed on standard activities of 131I to be used for remnant ablation, local recurrence, locoregional lymph node metastasis, and distant metastasis. Further evidence obtained from studies performed on larger groups of patients is necessary to justify low dose 131I protocols for thyroid bed ablation.
Standard clinical approaches should be modified to offer a more efficient therapeutic option to patients with Tg-positive, iodine scan–negative DTC and aggressive variants of papillary and follicular cancers as the number of reports describing genetic and clinical aspects of these subgroups of patients is increasing rapidly. Better understanding of tumor angiogenesis and discovery of genetic mutations are expected to result in new therapeutic and diagnostic perspectives in radioiodine-negative DTC and MTC leading to novel systemic therapies and new radionuclide techniques in future. 124I PET/CT is likely to be an alternative diagnostic imaging tool to compete with 131I whole body scan in DTC. Clinical trials involving larger number of patients should be given priority to investigate the emerging role of 68Ga DOTA complexes in the diagnosis and therapy of MTC, in which current nuclear medicine techniques have limited role.
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