23 Radioguided Neck Dissection Abstract Long-term survival for differentiated thyroid cancer (DTC) is greater than 90% with appropriate medical and surgical therapy as well as appropriate follow-up consisting of monitored thyroid-stimulating hormone (TSH)/thyroglobulin (Tg), neck ultrasonography, computed tomography, and radioactive iodine or 18fluoro-fludeoxyglucose (18F-FDG) uptake scanning (SPECT and PET, respectively), when indicated. However, a subset of treated patients experience a structural incomplete response to initial therapy, while an additional subset experience tumor recurrence. While surgery has been proven in the literature to provide the best treatment response in these patients, the presence of significant scarring and fibrosis may hinder the identification and complete excision of diseased tissue. For this reason, radioguided neck dissection has been created and progressively developed to facilitate localization and excision of malignant tissue in a real-time format. Within this chapter, we will cover the concept, clinical indications, methods, and procedural execution of radioguided neck dissection for excision of persistent or recurrent DTC. Keywords: differentiated thyroid cancer, structural incomplete response, radioactive iodine 131, 18fluoro-fludeoxyglucose, single-photon emission computed topography, positron emission topography, neck ultrasonography, computed topography, thyroglobulin, thyroid remnant Total thyroidectomy is indicated for patients who present with thyroid cancer that is greater than 4 cm, demonstrates gross extrathyroidal extension (clinical T3b and T4 disease), clinically apparent nodal metastasis (clinical N1 disease), and/or distant metastasis (clinical M1 disease). In addition, total thyroidectomy (vs. hemithyroidectomy) is still an option for patients presenting with thyroid cancer measuring 1 to 4 cm in size without extrathyroidal extension, nodal metastasis, or distant metastasis.1 Therapeutic bilateral central compartment dissection is indicated in addition to total thyroidectomy if clinically involved central nodes are involved either preoperatively (on imaging) or intraoperatively; prophylactic central neck dissection (ipsilateral or bilateral) should be considered in patients presenting with clinical T3 or T4 disease or clinically involved lateral neck nodes; and therapeutic lateral neck dissection is indicated in patients with biopsy-proven metastatic lateral cervical lymphadenopathy.1,2 The advantages of performing total thyroidectomy over hemithyroidectomy are well known and consist of a decreased risk of locoregional recurrence (LRR), ability for postsurgical radioactive iodine (RAI) ablation (see An aggressive initial management approach with regard to differentiated thyroid carcinoma has been proven to render an approximately 90% long-term survival rate4,5,6 with recent data exhibiting annual death rates less than 2%.7 However, studies also indicate that patients within this population possess LRR rates of up to 30%, depending on the initial treatment modality, and of this population, 30% recur and approximately 30% are never fully eradicated of disease with another 15% dying of disease,5 also producing 10-year cumulative survival rates of 49.1, 89.3, and 32.5% for all patients, patients younger than 45 years, and patients older than 45 years, respectively. In addition, another subset within this population never fully achieves structural eradication of disease, with detected persistence of structural disease at follow-up known as structural incomplete response (SIR). This has been shown to occur in 2 to 6% of American Thyroid Association (ATA) low-risk patients, 19 to 28% of intermediate-risk patients, and 67 to 75% of high-risk patients (see Higher rates of disease remission (29–51%) have been demonstrated across studies following surgical intervention for persistent or LRR disease, and thus the development of nodal recurrence or residual macroscopic thyroid tissue is considered a surgical disease.1,8,9 However, as recurrence or persistence of disease will virtually always present in a previously operated field, the unavoidable presence of significant fibrosis and scarring frequently hinders the surgeon’s capability to identify and excise diseased tissue. For this reason, surgeons have begun using nuclear medicine technology in combination with CT for assistance in intraoperative localization, excision, and confirmation of cure with regard to persistent or recurrent differentiated thyroid cancer (DTC), which is today known as radioguided neck dissection (RGND). To clarify, DTC is the only thyroid malignancy demonstrated to uptake radionuclides, and thus radionuclide imaging studies and RGND cannot be utilized for detection or resection of anaplastic or medullary thyroid cancer. Radioguided surgery can be beneficial intraoperatively, even in cases of DTC which is scan negative because of the sensitivity of operative radiation detection equipment. Nuclear medicine imaging derives its utility from the capability to detect abnormal physiologic function in concordance with and in spite of significant anatomic or morphologic change. Clinical information is derived through the observation of the distribution pattern of a pharmaceutical agent labeled with a radioactive tracer administered to the patient, enabling qualitative and quantitative measurements of radiopharmaceutical distribution that can have a dramatic effect on patient management in diseases of the head and neck.10 Radiopharmaceuticals are designated into two parts: the pharmaceutical portion, which ultimately determines the distribution of the particle, and the radionuclide label, which enables detection of the distribution of the particles. The radionuclide label emits nonparticulate gamma rays that are waves of electromagnetic radiation capable of being detected externally utilizing scintillation camera (s) positioned close to the patient. By way of a complex programed algorithm, separate flashes of light produced by the scintillation camera (s) due to the detection of gamma rays are plotted as dots on a field spatially related to the gamma emissions from the patient. In accord, the higher the rate of gamma emissions from a particular area (i.e., an area with greater amount of radiopharmaceutical), the greater the density of dots present on the formulated spatially related image, thus enabling target specificity due to concentration of a radiopharmaceutical in comparison to the otherwise normal background. Of note, some radionuclides only emit gamma rays (technetium-99 m [Tc-99m], I123) while other possess multiple mechanisms of decay with emission of both beta and gamma emissions (I131, 18F-FDG). It is worth noting and imperative to the successful execution of RGND, these gamma rays can be detected not only by the use of a scintillation camera but also with a “gamma probe,” which is utilized intraoperatively by the surgeon for assistance in identification and verification of successful excision of malignant disease within the neck.8,11,12 In contrast to radioguided parathyroid surgery, in which the gamma probe cannot be utilized for location of the diseased tissue, use of the gamma probe for intraoperative assistance in localization of diseased tissue is one of two fundamental benefits in RGND. The second of these benefits consists of ex vivo confirmation of target excision. In this regard, specimen radioactivity counts may only be meaningfully interpreted when expressed as a proportion of background radioactivity, with gamma probe measurement demonstrating a significant increase in radioactivity of the specimen in comparison to background as a reliable indicator of successful excision.13 Multiple imaging modalities of progressive complexity and utility have been developed over the previous decades for diagnostic, surveillance, and intraoperative use with regard to head and neck pathology. Recently, nuclear medicine imaging has been combined with CT in order to correlate nuclear medicine imaging findings with anatomic location, thus better enabling localization of disease. These imaging modalities and their interrelation will be discussed later. Of importance, one should note that nuclear medicine imaging studies can be performed as either static or dynamic studies. Static studies are obtained after sufficient time has elapsed for the radiopharmaceutical to reach its final biodistribution, while dynamic imaging studies are taken at multiple points in time to assess the changes in biodistribution of radiopharmaceutical over time. While dynamic imaging studies are used for diagnostic and localization purposes within the head and neck (e.g., 4D CT for parathyroid adenoma localization), RGND studies are limited to static (planar or tomographic) imaging studies, and thus the discussion in this chapter will be limited to static scintigraphic nuclear medicine imaging studies. For the performance of planar scintigraphy, images are obtained utilizing a standard low-energy parallel hole collimator, also known as pinhole collimation. As this was the first type of scintigraphic nuclear medicine imaging created, it possesses the most short and simple protocol with the least complex necessary equipment. In accord, the advantages of performing this type of imaging consist of not requiring patients to sit still for long periods without a break, the capability for the imaging to be performed with the use of a basic Anger camera, and the capability of performing in patients in whom SPECT can be challenging, such as obese or claustrophobic patients.14 The advantages come at the expense of decreased sensitivity to what most consider an inadequate degree; therefore, this type of imaging is rarely used currently due to the availability of more sensitive and specific imaging modalities. Single-photon emission computed tomography (SPECT) was developed subsequent to planar imaging as a more complex method for utilizing the same radiopharmaceutical distribution principles as discussed above. Instead of utilizing a single Anger camera, SPECT utilizes two or more multihead Anger cameras that rotate 360 degrees around the patient, thereby enabling three-dimensional reconstruction within the head and neck region.10 While this protocol does require more complex and thus more costly equipment (multihead Anger cameras and software for 3D reconstruction) as well as prolongation of the imaging protocol, it also overcomes the interpretation difficulties associated with the superimposition of tracer activity onto planar images, which in turn provides a significant increase in sensitivity.14 Planar and SPECT imaging are performed utilizing I123, I131, or Tc-99 m radioisotopes, which will be discussed in detail later in the chapter. Positron emission tomography is so named due to the use of pharmaceutical compounds labeled with positron-emitting radioisotopes that function as molecular probes to image and measure biochemical processes in vivo.15 As with SPECT and planar imaging, the amount of radiolabeled material administered is minimal and thus does not disrupt underlying molecular and biochemical processes, but enables the detection of the pharmaceutical’s biodistribution through the utilization of scintigraphy. Unlike planar and SPECT imaging, however, PET utilizes the radiopharmaceutical 18fluoro-fludeoxyglucose (18F-FDG), and is used not only in head and neck imaging but also for the detection of oncologic pathology throughout the entire body.16 PET finds its value in surveillance, perioperative, and intraoperative thyroid imaging in that the mechanism of 18F-FDG uptake differs from that of I131 and I123, thus enabling detection of recurrent or persistent disease in radioiodine-negative DTC patients.12,17,18,19 Following the development of SPECT, PET, and CT, the idea was created to fuse either SPECT or PET with CT in order to enable increased accuracy of localization of detected disease. This addition of anatomic information (CT) to functional information (SPECT/PET) can be achieved either by using a hybrid SPECT/PET-CT scanner capable of the consecutive acquisition of SPECT/PET and multislice CT in one unit, or by software fusion of separately acquired diagnostic CT and SPECT/PET images. If a hybrid SPECT/PET-CT is to be performed, CT is often done in the absence of intravenous (IV) contrast, limiting the radiation dose as well as the diagnostic value of the CT scan. On the other hand, SPECT/PET-CT images (acquired separately) usually consist of CT with IV contrast with an increase in diagnostic value of the CT, but with the expense of a higher radiation dose to the patient as well as cost burden for the institution to fund high-accuracy software fusion of SPECT/PET and CT images. Therefore, in the literature and also clinically, SPECT/PET-CT (hybrid) is often performed and correlated with diagnostic (CT with contrast) images for operative planning.14 In addition, the literature definitively demonstrates that SPECT/PET-CT possesses significantly increased sensitivity, specificity, localization, and lesion characterization than any of these modalities alone, and thus has become the standard of care with regard to surveillance and operative planning of recurrent or persistent DTC.18,19,20,21,22 As previously described, radiopharmaceuticals are composed of two critical components consisting of the pharmaceutical portion and the radionuclide tracer. Several radionuclide tracers have been developed and used in nuclear medicine imaging throughout the years. The primary radionuclide tracers utilized in radioguided thyroid surgery are described below. A number of elements other than iodine are selectively concentrated within the thyroid gland, one of which is technetium. However, technetium is not a naturally occurring element and only exists in radioactive form, with one of these isotopes being Tc-99 m. This radiotracer’s physical characteristics make it an attractive option for use in scintillation scanning (planar or SPECT), particularly with regard to initial evaluation of possible presence of thyroid disease as well as in evaluation of thyroid disease in children. First, the particle is trapped within the thyroid gland but not organified, resulting in a relatively short 6-hour half-life that enables imaging acquisition approximately 15 to 20 minutes following IV administration. Second, the particle produces virtually no beta emissions and moderately low gamma emissions enabling administration with a minimal radiation dose and without local tissue ablation. Last, Tc99-m is readily available as well as inexpensive.10,14,23 However, the necessity of radionuclide evaluation for initial evaluation of thyroid disease has become somewhat rare over the previous decade (i.e., limited to evaluation of thyroid nodule in the setting of hyperthyroid symptoms and a suppressed TSH), and even in necessary situations I123 has become the preferred radionuclide for this particular evaluation.1 As such, Tc-99 m is rarely clinically utilized in radionuclide evaluation, surveillance, or intraoperative guidance in the management of DTC today. Thyroid hormone biosynthesis begins with the trapping of inorganic plasma iodide within the thyroid gland, followed by oxidation to iodide and subsequent organification. As a result, radioactive iodine uptake provides a means to detect and document the presence, size, shape, location, and functional characteristics of thyroid tissue. I123, unlike technetium, is administered orally and subsequently trapped and organified within the thyroid gland, producing a half-life of approximately 13 hours, and results in a delayed but extended optimal imaging window of 4 to 24 hours in comparison to Tc-99 m. I123 has also been proven to produce higher target-to-background images in comparison to Tc-99 m with a consequent increase in sensitivity and accuracy on scintigraphic studies. However, I123 is also less readily available, more expensive, and delivers a higher radiation dose to the patient. In light of the fact that the use of radionuclide imaging for initial evaluation of thyroid nodules in recent years has substantially decreased, I123 has become the study of choice if radionuclide studies do become necessary in the initial workup of a thyroid nodule (s) due to its higher target-to-background imaging characteristics.1,10 Worth noting, neither Tc-99 m nor I123 (SPECT/CT) are routinely utilized in the evaluation of recurrent or persistent DTC due to decreased image quality and thus sensitivity and localization in comparison to I131 SPECT/CT and 18F-FDG PET/CT.14,17,22,24 As with I123, I131 is orally administered with subsequent trapping and organification within the thyroid gland, producing an excellent and highly specific mechanism to obtain information regarding presence, size, shape, and function of thyroid tissue. However, I131 is administered in doses ranging from 30 to 300 mCi in the literature (30–150 mCi in recent ATA guidelines), and is never utilized in initial diagnostic thyroid imaging studies due to its exertion of a significantly higher radiation dose to the patient, longer half-life (> 8 days), and multiple different mechanisms of decay, including release of both beta and gamma emissions. The beta emissions released by I131 irradiates and induces ablation of the immediate local region of tissue in which the radiopharmaceutical concentrates during distribution, making it a valuable tool for therapeutic ablation of remnant thyroid tissue and distant metastatic disease in persistent or recurrent DTC, as well as nonsurgical treatment of Grave’s disease1,6,10,25 (see Although multiple radioisotopes have been utilized in PET imaging (11C, 15O, 13N, 68Ga, 18F), 18F-FDG has by far exerted the most significant clinical impact on PET imaging. The amounts of radiolabeled material administered to the patient are exceedingly small (micrograms—nanograms), and thus produce no pharmacologic effects or risk of toxic radiation dose. In this manner, PET possesses the ability to assess molecular alteration associated with pathology disturbing the underlying biophysio-logic processes. 18F-FDG is a glucose analog, and thus is taken up by glucose transporters in tissues with a significantly increased metabolic demand. As malignant cells maintain a high metabolic rate secondary to unregulated growth and progression through the cell cycle, this radioisotope localizes and concentrates within malignant disease of multiple different types following uptake and trapping within these cells via conversion of FDG to FDG-6-phosphate by hexokinase.28 Consequently, its use is currently widespread for the purposes of surveillance and detection of recurrent or persistent disease throughout the field of oncology.16 Although PET/CT imaging was not initially considered for surveillance or detection of DTC due to the available, highly specific radionuclides already in use, it has proven to be an invaluable tool for surveillance, detection, and intraoperative guidance with regard to iodine-negative DTC thyroid cancer over the previous 15 years.8,12,18,19 Persistent or recurrence of radioiodine-negative DTC is initially suspected in the setting of negative I131 SPECT/CT upon follow-up with persistently elevated or increasing Tg or anti-Tg levels. Further investigation is warranted in such a setting, consisting of neck ultrasonography (NUS) with possible fine needle aspiration (FNA) and 18F-FDG PET/CT (see
23.1 Introduction
Table 23.1), and increased surveillance capability during follow-up through the utilization of Tg, thyroglobulin antibodies (anti-Tg), and RAI whole body scanning (WBS), 18fluoro-fludeoxyglucose (18F-FDG) positron emission tomography (PET), or either of these modalities in combination with computed tomography (PET or SPECT/CT).3 This comes with a potential cost of the risks of postoperative bilateral vocal cord dysfunction (possible tracheotomy) and hypoparathyroidism. Increased sensitivity and specificity of surveillance modalities leads to earlier detection and treatment of recurrence or persistence of disease, and thus improved patient outcomes.
Table 23.1). Within the SIR population, 50 to 85% have been shown to possess persistent disease despite additional therapy with disease-specific death rates as high as 11%. This population has the highest risk with regard to disease-specific mortality of any of the response to therapy categories1 (see 
Table 23.2).
23.1.1 Target Specificity of a Radionuclide versus Background
23.1.2 Imaging Modalities
Planar Imaging
Single-Photon Emission Computed Tomography
Positron Emission Tomography
SPECT/CT and PET/CT
23.1.3 Radionuclide Options
Technetium-99m
Iodine 123
Iodine 131
Table 23.1 for risk stratification and decision making regarding I131 RAI remnant ablation). In addition, since the advent of SPECT/CT the literature has shown that I131 SPECT/CT may be performed at either therapeutic (> 30 mCi) or subtherapeutic (1–5 mCi) levels with increased ability in detection and thus guidance for resection of persistent or recurrent DTC in comparison to Tc-99 m and I123 SPECT/CT in iodine-avid tissues.6,22,24,26 Furthermore, due to the radionuclides emission of gamma particles, it may also be administered preoperatively with subsequent use of a gamma probe. This enables intraoperative confirmation of successful excision of diseased tissue via both ex vivo detection of radioactivity following excision of the specimen as well as in vivo confirmation with return of the wound bed to background in iodine-avid persistence or recurrence of DTC (which will be described in detail later in this chapter).8,11,22,27 Of particular importance, review of the literature demonstrates a known “flip-flop” phenomenon in which radioiodine-avid tissues do not uptake 18F-FDG and thus are not visible on PET/CT imaging with the converse also being true (see 
Fig. 23.1).22
18Fluoro-Fludeoxyglucose
Fig. 23.2), as it has proven to have superior sensitivity in comparison to Tc-99 m SPECT/CT.1,2,17,19,22 As with I131, concentrated areas of 18F-FDG emit gamma rays during decay, which has an approximate half-life of 2 hours (unlike I131), that can be detected with a gamma probe and correlated with preoperative PET/CT. This was first successfully demonstrated in a series of patients with colorectal carcinoma.28,29 Not long afterward, head and neck surgeons began developing and implementing protocols for utilizing TSH-stimulated PET/CT imaging and gamma probe RGND for intraoperative confirmation of successful identification and excision of persistent and recurrent DTC.8,12,18,30
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