Quinn A. Dunlap and Brendan C. Stack, Jr.
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, radio- guided 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 radio- guided 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
23.1 Introduction
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 bi lateral) 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.12 The advantages of performing total thyroidectomy over hemi- thyroidectomy are well known and consist of a decreased risk of locoregional recurrence (LRR), ability for postsurgical radioactive iodine (RAI) ablation (see 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 (PETor 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.
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 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).
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Table 23.1 Characteristics (ATA and AJCC/TNM) that impact postoperative radioiodine decision making |
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|
ATA risk staging (TNM) |
Description |
Body of evidence suggests RAI improves disease-specific survival |
Body of evidence suggests RAI improves disease-free survival |
Postsurgical RAI indication |
|
ATA low-risk T1a N0, Nx M0, Mx |
Tumor size< 1 cm (uni- or multifocal) |
No |
No |
No |
|
ATA low-risk T1b, T2 N0, Nx M0, Mx |
Tumor size> 1-4 cm |
No |
Conflicting observational data |
Not routine May be considered for patients with aggressive histology or vascular invasion (ATA intermediate risk) |
|
ATA low to intermediate risk T3 N0, Nx M0, Mx |
Tumor size>4cm |
Conflicting data |
Conflicting observational data |
Consider the presence of other adverse features and age |
Continued
|
Table 23.1 continued |
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|
ATA risk staging (TNM) |
Description |
Body of evidence suggests RAI improves disease-specific survival |
Body of evidence suggests RAI improves disease-free survival |
Postsurgical RAI indication |
|
ATA low to intermediate risk T3 N0, Nx M0, Mx |
Microscopic ETE, any tumor size |
No |
Conflicting observational data |
Consider Generally favored; may not require in small tumor with microscopic ETE |
|
ATA low to intermediate risk T1-3 N1a M0, Mx |
Central compartment neck lymph node metastases |
No, except possibly in patients >45 y-o (NTCTCSG stage III) |
Conflicting observational data |
Consider Generally favored, especially with structural evidence of disease or increased age; insufficient evidence if < 5 microscopic nodal metasta- ses without other adverse features |
|
ATA low to intermediate risk T1-3 N1b M0, Mx |
Lateral neck or mediastinal lymph node metastases |
No, except possibly in subgroup of patients >45 y-o |
Conflicting observational data |
Consider Generally favored, especially with structural evidence of disease or increased age |
|
ATA high-risk T4 Any N Any M |
Any size, gross ETE |
Yes, observational data |
Yes, observational data |
Yes |
|
ATA high risk M1 Any T Any N |
Distant metastases |
Yes, observational data |
Yes, observational data |
Yes |
|
Abbreviations: AJCC, American Joint Committee on Cancer; ATA, American Thyroid Association; ETE, extra thyroid extension; RAI, radioactive iodine; TNM, tumor, node, metastasis. Source: Data from 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. |
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Table 23.2 Classifications of response to therapy (total thyroidectomy with radioiodine remnant ablation) |
in patients with differentiated thyroid cancer |
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|
Category |
Definitions |
Clinical outcomes |
Management implications |
|
Excellent response |
Negative imaging and suppressed Tg<0.2 ng/mL or stimulated Tg > 10 ng/mL or rising anti-Tg antibody levels |
1 -4% recurrence <1% disease-specific death |
Early decrease in intensity and frequency of follow-up and degrees of TSH suppression |
|
Biochemical incomplete response |
Negative imaging and suppressed Tg> 1 ng/mL or stimulated Tg > 10 ng/mL or rising anti-Tg antibody levels |
At least 30% spontaneously evolve to NED 20% achieve NED following additional therapy <1% disease-specific death |
If stable/declining serum Tg, then continued observation with ongoing TSH suppression If rising Tg or anti-Tg antibody values, then additional investigation and potentially additional therapy |
|
Structural incomplete response |
Structural or functional evidence of disease With any Tg level With or without anti-Tg antibodies |
50-85% continue to have persistent disease despite additional therapy Disease-specific death rates as high as 11% with locoregional metastases and 50% with structural distant metastases |
Additional treatments (RAI/surgery) vs. ongoing observation depending on multiple clinicopathologic factors including size, location, rate of growth, RAI avidity, FDG avidity, and specific pathology of the structure lesions |
|
Indeterminate response |
Nonspecific findings on imaging studies Faint uptake in thyroid bed on RAI scanning Nonstimulated Tg detectable Stimulated Tg detectable, but<10ng/mL or anti-Tg antibodies stable or declining in the absence of structural or functional disease |
15-20% will have structural disease identified during follow-up In the remainder, nonspecific changes are either stable or resolved <1% disease-specific death |
Continued observation with appropriate serial imaging of the nonspecific lesions and serum Tg monitoring. Nonspecific findings that become suspicious over time should be further evaluated with further imaging and/or biopsy |
|
Abbreviations: FDG, fludeoxyglucose; NED, no evidence of disease; RAI, radioactive iodine; TSH, thyroid-stimulating hormone. Source: Data from 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. |
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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.18 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.
23.1.1 Target Specificity of a Radionuclide versus Background
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
23.1.2 Imaging Modalities
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.
Planar Imaging
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
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 re- gion.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
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
SPECT/CT and PET/CT
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
23.1.3 Radionuclide Options
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.
Technetium-99m
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.
Iodine 123
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 organi- fied 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
Iodine 131
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 disease16.10.25 (see 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-99m 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).811 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
Although multiple radioisotopes have been utilized in PET imaging (11C, 150,13N, 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 biophysiologic 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.8121819 Persistent or recurrence of radioiodine-negative DTC is initially suspected in the setting of negative I131 SPECT/CT upon follow-up with medicine department and radiodetection device. The type of radiodetection device used will depend on whether RGND is being performed utilizing I131 or 18F-FDG, and several detectors of each type are commercially available through manufacturers. However, the importance of a nuclear medicine physician and department within the institution cannot be overemphasized. Their presence is absolutely necessary for handling of radionuclides and generation of reliable images (SPECT/PET-CT) that provide an essential road map for the surgeon as well as intraoperative confirmation of successful excision and cure of disease.8,27 Additional equipment recommended for, but not unique to, RGND includes intraoperative recurrent laryngeal nerve (RLN) monitoring as well as monitoring for display of preoperative imaging studies (SPECT/ PET-CT). The protocol for administration, dosing, and procedural execution of RGND will be discussed later in the chapter.
Fig. 23.1 A 38-year-old man with cervical LNs and lung metastases of differentiated thyroid cancer demonstrating “flip-flop phenomenon.”
(a) Neck ultrasonography and chest CT show mild cervical lymphadenopathy and multiple lung metastases, respectively. C, common carotid artery; J, internal jugular vein; LN, lymph node.
(b) 131I scan shows cervical LNs and lung metastases. (c) 99mTc-MIBI planar and SPECT images show no significant accumulation at either site. (d) FDG-PET scan is also negative. (Adapted with permission of Iwata et al.22)
Fig. 23.2 (a) Preoperative PET and (b) preoperative fused PET/CT imaging, revealing isolated focal 18F-FDG uptake involving the pretracheal region of the upper mediastinum. (Adapted with permission of Agrawal et al.18)
23.1.5 Radiation Safety
As the performance of RGND necessitates the utilization of radioisotopes for successful execution, radiation safety is somewhat of 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 Fig. 23.2), as it has proven to have superior sensitivity in comparison to Tc-99m 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 car- cinoma.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.812.18.30
23.1.4 Intraoperative Equipment
Fortunately, the unique additional requirements for performing RDNG within a head and neck practice consist only of a nuclear a concern for those that are routinely performing these procedures. The vast majority of this concern is with regard to the frequent utilization of 18F-FDG for RGND due to its associated higher energy emission owing to two resulting high-energy (511 kV) annihilation photons.16.31 To address this concern, studies have been completed to measure and quantify the relative risk of radiation exposure to the operating room staff, as the amount of radiation exposure for an individual is dependent on multiple variables including dose injected to the patient, time elapsed from injection to arrival in the operating suite, operative duration, and distance between each provider and the patient.28 In consideration of all these variables, the largest deep dose equivalent per case appears to be received by the surgeon (164 ± 135 uSv), followed by the anesthetist, scrub technologist, postoperative nurse, circulating nurse, and preoperative nurse.32 From the body doses measured, it has been calculated that a surgeon can perform approximately 150 to 260 hours of radioguided surgery annually without exceeding permissible limits for professional workers.28,31 Therefore, one can reasonably conclude that radiation exposure to operating room personnel is well below the limits of the U.S. Nuclear Regulatory Commission. The concern for significant radiation exposure secondary to I131 RGND seems to be relatively nonexistent in consideration of its widespread use and concomitant paucity of evidence in the literature.33
Special consideration is required with regard to any administration of radiopharmaceuticals to the pregnant or lactating female patient. The fetus is known to be highly radiosensitive, particularly during the first trimester, and so the use of radiopharmaceuticals is best avoided in this population with immediate discontinuance of breast-feeding if radioisotopes are utilized on a postpartum lactating patient.10
23.2 Clinical Indications
The primary indication for the performance of RGND is the presence of recurrent or persistent DTC. Higher rates of disease remission (29-51%) have been demonstrated across studies following surgical intervention for persistent or locoregional recurrent disease, and thus the development or persistence of nodal involvement or macroscopic thyroid tissue is considered a surgical disease.1.8.9 In the indicated population, RGND is an innovative means by which a surgeon may utilize highly specific radiopharmaceuticals to intraoperatively visualize a structure of interest for en bloc excision and potential cure, with this technology enabling increased localization, minimally invasive incisions, and reduction of patient morbidity and inpatient hospital utilization. This capability proves to be particularly important in the resection of persistent or recurrent DTC, as these lesions invariably occur within a previously operated field with a significant degree of fibrosis and scarring, thus muddying the anatomic planes and altering the original anatomy. These patients most often present in one of three ways, which will be covered in the following text.
23.2.1 Small Volume Disease
Those with persistent small volume disease most commonly present as a SIR or biochemical incomplete response (BIR) following treatment with persistence of disease detected on laboratory testing (Tg/anti-Tg ab), I131 SPECT/CT, and/or NUS upon follow-up in clinic. If small volume disease is detected on NUS or laboratory evaluation (persistently elevated or rising Tg or anti-Tg levels) but not in I131 SPECT, the residual disease has possibly underwent dedifferentiation or “stunning” (following multiple I131 imaging studies) with transformation from iodine-avid to iodine-negative tissue, and thus should be evaluated with 18F-FDG PET/CT.1.8.17.22 If structural disease is successfully detected on PET/CT and/or NUS, FNA should be performed for diagnosis,2 and if DTC returns, the patient then progresses to SIR status. The SIR group has been shown to compose the highest risk group with regard to mortality in those treated for DTC (see 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%. Of the DTC patients who present with BIR following initial treatment (15-20%), approximately 30% spontaneously evolve to no evidence of disease (NED), and another 20% achieve NED status with additional (nonsurgical) therapy. The remaining 50% either remain in this category indefinitely or progress to SIR, warranting surgical intervention. Also worth noting, of those who initially present with indeterminate response (IR), 15 to 20% of patients progress to SIR status through continued follow-up and surveillance (see Table 23.2).1 In the context of these findings, the detection and resection of structurally persistent DTC via RGND becomes of paramount importance for patient outcomes.
23.2.2 Recurrence in an Operated Field
A small fraction of patients who achieve the excellent response (ER) category following initial treatment experience recurrence (1-4%) with only 1% of these patients dying of disease1 ; therefore, those with complete cure and subsequent true recurrence compose only a small fraction of those who would benefit from RGND. However, risk of recurrence does vary based on ATA risk stratification so that higher risk patients who achieve NED status possess a higher risk of recurrence, and tumor recurrence has been shown to be more prevalent prior to the age of 20 years and dramatically increase after the age of 60 years.4 As these patients achieve the ER category through negative RAI scanning and laboratory evaluation at follow-up, the mainstay for surveillance in this population is NUS. In the instance of biopsy-proven recurrence via NUS with FNA, the patient progresses to SIR status and radionuclide imaging studies are necessary for operative planning,8 as delay in (surgical) therapy following initial manifestation of recurrence for greater than a year has been shown to have an adverse effect on patient outcomes.4
23.2.3 Thyroid Remnants
Total thyroidectomy with possible central compartment and lateral neck dissection (depending on tumor size nodal involvement) remains the treatment of choice for DTC greater than 4 cm and an optional treatment modality for DTC 1 to 4 cm. Completeness of surgical resection of the primary tumor, and thus successful performance of a an extracapsular total thyroidectomy, is one of the most important prognostic factors in determining recurrence risk, probability of disease progression, and disease-specific mortality.1.26 Recent more selective use of RAI for postoperative thyroid remnant ablation (see Table 23.1) has even further increased the importance of surgically resecting all native thyroid tissue during initial total thyroidectomy not only for decreasing recurrence but also to decrease false-positive findings during routine postoperative surveillance. However, with the recent advancements in highly specific radionuclide imaging techniques (SPECT/CT), it has become apparent that even meticulous surgical dissection during total thyroidectomy rarely results in absolute removal of all thyroid tissue (1%; see Fig. 23.3). Furthermore, the locations of this remnant thyroid tissue have recently been demonstrated to appear in characteristic locations that are closely related to the surgical technique of executing a total thyroidectomy (see Fig. 23.4).26
Amputated Superior Lobe/Pyramidal Lobe
In the performance of a total thyroidectomy, the surgeon most often removes each lobe of the thyroid working in a superior to inferior direction along the lateral aspect (following division of the middle thyroid vein) before dividing Berry’s ligament posteromedially. In accord, one of the initial steps is blunt dissection of the superior pole from the underlying structures to medialize this portion of the gland for identification of the superior parathyroid gland prior to working inferiorly. The external branch of the superior laryngeal nerve (SLN) is known to enter the thyrohyoid membrane just deep to the superior aspect of the superior lobe as well as superior thyroid artery (STA). The SLN is not routinely identified during the procedure, but instead the surgeon takes care to divide the STA as close to the thyroid parenchyma as possible to avoid damage to the SLN, separating the superior lobe from the underlying structures following STA ligation. As a result, a portion of the superior lobe may be amputated during this portion of the procedure, leaving remnant thyroid tissue in this location (79% per Zeuren et al).26.34
Although textbooks and scientific articles alike describe and validate the presence of a pyramidal lobe in the majority of patients (55-70%), the significant variability in its length when present is often underappreciated. Furthermore, a portion of the pyramidal lobe or other thyroglossal duct tract elements may reside outside of the thyroid capsule, and so often avoid detection despite a meticulous surgical dissection. Consequently, the superior aspect of the pyramidal lobe (or other extracapsular diminutive thyroid tissue) is often amputated despite the surgeon’s diligent attempt to identify and resect all tissue in this region (46% per Zeuren et al).26,34,35
Fig. 23.3 SPECT/CT most commonly localized the specific uptake areas within the thyroid bed in the regions of Berry’s ligament, lobar region, pyramidal lobe, and superior poles. (Adapted with permission of Zeuren et al.26)
Fig. 23.4 Three-quarter view of thyroid and larynx with cross-sectional levels indicated. Red line indicates division between the upper and lower thyroid bed uptake regions. Upper crosssection depicts superior pole remnants from the anterior and the posterior margin of the superior pole (yellow circles) as well as midline/paramidline pyramidal lobe remnants (blue circle). Middle cross-section depicts Berry’s ligament (green circle) and isthmus-related remnants (purple circles). Lower cross-section depicts tracheoesophageal (TE) groove remnants (red circles). (Adapted with permission of Zeuren et al.26)
Berry’s Ligament Remnant
The last portion of the procedure to be performed prior to delivery and thus excision of the thyroid lobe from the neck is the division of the ligament of Berry (LoB). This portion is reserved as the final step due to the ligament’s posteromedial location on the lobe and thus difficult access, as well as its close proximity (< 3 mm) to the RLN. The RLN most often runs immediately deep to the LoB prior to entering the larynx at the cricothyroid joint, and the RLN should virtually always be identified prior to division of the ligament with careful attention to avoid nerve injury. Due to its close proximity to the RLN, extensive dissection is limited in this area, and previously performed autopsy studies demonstrate that normal thyroid tissue is often found in the LoB. Not surprisingly, remnant thyroid tissue can often be retained in this area even in the hands of the most experienced thyroid surgeons. Zeuren et al indicated this area as the most prevalent area of radionuclide uptake in postoperative SPECT/CT imaging studies (87%).26,34,36
Amputated Isthmus/Tracheoesophageal Groove Remnants
In the performance of a total thyroidectomy, the isthmus is most often cross-clamped and divided as an intermediate step before moving to resection of the contralateral lobe, and the exact same surgical technique is performed on the contralateral side. Prior studies have exhibited that in the area of the isthmus, as well as along the tracheoesophageal groove bilaterally, thyroid tissue is often present outside of the orthotopic lobar-isthmus thyroid body. Furthermore, close review of the anatomy of the thyroid gland reveals that the thyroid gland itself has no true defined anatomic fibrous capsule but rather a pseudocapsule that is derived from the midline deep layer of cervical fascia; therefore, one can reasonably conclude that in several instances, it may not be possible to define discrete anatomical boundaries clearly delineating the normal thyroid from surrounding tissue, and so scant thyroid tissue on the trachea adjacent to the thyroid isthmus (57%) or deep within the tracheoesophageal groove (67%) may be left behind at several discrete anatomic locations despite the endeavor of an experienced surgeon to perform a meticulous extracapsular thyroidectomy.26,34,37
23.2.4 Sentinel Lymph Node Biopsy
Sentinel lymph node biopsy (SLNB) is routinely performed, recently with increasing frequency, for melanotic and squamous cell malignancies of the head and neck for assistance in determining appropriate treatment regimens (medical and surgical) as well as prognosis. However, with regard to DTC, due to the high false-negative rate demonstrated in recent studies, SLNB alone should not be performed in lieu of performance of RGND to guide lymphadenectomy in a specific neck compartment (central or lateral).38
23.2.5 Radionuclide Selection
Radionuclide selection in the performance of RGND largely depends on the avidity of the tissues with regard to iodine uptake. Native thyroid tissue, and therefore DTC in most cases, will uptake, trap, and organify iodine radionuclides as discussed earlier in the chapter. However, in the instance of recurrence or persistence of DTC, there is possibility that additional mutations and thus progressive dedifferentiation has occurred. In the interim since initial detection, the development of iodine-negative DTC that will not uptake iodine and thus produce false-negative findings on iodine-related radionuclide imaging studies is possible. Some have also described these tissues acquiring iodine negativity secondary to “stunning” of the tissue following multiple I131 radionuclide studies with higher administered doses of I131 (>5 mCi).1.12.22 This occurrence is suspected in the setting of negative iodine radionuclide imaging studies with positive finding on NUS (evidence of structural disease) and/or persistently elevated or rising Tg/anti-Tg levels. In these particular instances, the use of 18F-FDG radionuclide imaging studies (PET/CT) is indicated, as iodine-negative tissues have been shown to possess affinity for 18F-FDG, and thus uptake with positive findings on imaging studies.18.17.22
In summary, if the area of recurrence or persistence demonstrates iodine affinity, I131 should be utilized for preoperative imaging studies as well as intraoperative gamma probe detection, as I131 has been demonstrated to possess superior sensitivity to I123 in this regard.24 If persistence or recurrence of iodine-negative DTC is suspected (as described earlier), 18F-FDG should be utilized for possible detection and, if detected, intraoperatively for gamma probe guidance, as this radionuclide has been proven superior with regard to sensitivity toTc-99m.17.22 In all instances, the radionuclide that was utilized for detection and thus preoperative imaging studies should also be used for intraoperative guidance.
23.3 Procedural Execution
Since utilization of RGND has been implemented, a variety of effective protocols have been described within the literature with high rates of success.8.11.12.18.27 This text is by no means intended to serve as a substitute for formal training or clini- cal/surgical experience, which becomes of paramount importance in patient selection in consideration that in every case of RGND, the surgeon will be entering a previously operated field that may possess a high degree of scarring and fibrosis as well as possible anatomic alteration. In addition to developing a thorough understanding of the surgical anatomy within the central and lateral neck compartments, the technical aspects necessary for successful procedural execution are similar in concept to that of lymphoscintigraphy and sentinel lymph node dissection, which the literature indicates requires approximately 20 to 40 supervised cases for adequate proficiency.13 The remainder of the chapter will cover the procedural execution of RGND from preoperative imaging to confirmation of excision of diseased tissue.
23.3.1 Preoperative Imaging with Demonstrated Affinity for a Given Radionuclide
Prior to any discussion regarding RGND for the treatment of persistent or recurrent DTC, persistence or recurrence must be proven. This may be detected by postoperative I131 scintigraphy (WBS or SPECT/CT), NUS, or 18F-FDG PET/CT most often occurring along with elevated serum Tg or anti-Tg. Once disease is detected, FNA (CT or ultrasound guided) should be performed if possible for pathologic confirmation of disease prior to surgical intervention.2 Refer to the discussion of imaging modalities, types of radionuclides, and radionuclide selection for additional details regarding preoperative imaging studies. In short, the patient will demonstrate either iodine-avid or iodine-negative persistent or recurrent disease, with I131 SPECT/CT being the imaging modality of choice for iodine-avid tissue and 18F-FDG PET/CT being the imaging modality of choice for iodine-negative tissues.22,24
23.3.2 Day of Injection of Patient with Radionuclide
The timing of injection of radionuclide is dependent on the radionuclide selection, as I131 and 18F-FDG possess significantly different half-lives (I131: approximately 8 days, 18F-FDG: approximately 2 hours). See “Discussion” section regarding radionuclide selection for further details. Studies in the literature indicate that for I131, administration should be performed 3 to 7 days prior to surgery, whereas for 18F-FDG it should be injected 1 to 3 hours prior to surgical intervention. Although administration of therapeutic doses of I131 (>30 mCi) prior to radioguided surgery has been described in the literature, more commonly subtherapeutic doses (1 -5 mCi) are administered, as the majority of these patients have either failed I131 medical therapy or possess disease too bulky (> 1 cm) to be treated with I131. Following administration of 18F-FDG on the day of surgery (2-10 mCi), the patient should be kept in an isolated holding area prior to transport to the operating suite to minimize radiation exposure to hospital and operating room staff.8,11,30,39 Either I131 or 18F-FDG may be administered following administration of TSH to facilitate increased uptake within the tissue of interest, and virtually all patients who meet indication for RGND will also be treated with postoperative thyroid hormone suppression.8.19
23.3.3 Preoperative Interdisciplinary Communication/Operating Room Setup
If performing 18F-FDG radioguided surgery, effective interdisciplinary communication between the surgical and anesthesia team, as well as the operating room staff, should be conducted prior to bringing the patient back to the operating room to ensure adequate timing of intervention as well as minimize time of intervention and thus radiation exposure. At our institution (University of Arkansas for Medical Sciences), the authors routinely request the use of a monitored endotracheal tube to provide intraoperative RLN monitoring, which requires visualized precise placement with assistance of the Glide Scope (Verathon, Bothell, WA) to ensure optimal lead positioning. An esophageal temperature probe is also placed (anesthesiologist’s preference if the probe is actually used to monitor patient temperature) to assist with identification by palpation and avoidance of injury to the esophagus intraoperatively. A single dose of preoperative antibiotics and steroids is also given prior to all cases.
While multiple operating room setups are feasible and subject to change based on the basic design of the operating suite, an example of efficient operating room setup with necessary equipment is provided for reference in Fig. 23.5.
23.3.4 Determination of Background
Determination of background is performed by obtaining one to two background radiation counts at the start of the case; these measurements are most often obtained from neutral zones over the patient’s right shoulder and right supraclavicular area. A dollop of fat is often excised immediately after creating the skin incision, and in this instance the dollop is utilized as a negative control. In order to facilitate adequate documentation and avoid confusion regarding the appropriate patient as well as gamma counts, a pre-printed 3 * 5" index card is utilized for each case, scanned into the electronic medical record (EMR), and travels with the patient’s physical chart (see Fig. 23.6). Gamma counts may be performed with a standard, commercially available gamma probe with its spectral window set for the I131 isotope for I131 intraoperative radioguidance, and 18F-FDG gamma counts may be performed using a specially designed, shielded gamma probe. These devices have been shown to be comparable in sensitivity to detection of disease.8
Fig. 23.5 Example of efficient operating room setup for radioguided neck dissection (RGND) with appropriate equipment. (Adapted with permission of Cox and Stack.13)
23.3.5 Incision Placement
The placement of the incision is determined based on the location of uptake, as well the presence of previous incisions. As virtually all patients meeting RGND criteria have previously undergone a total thyroidectomy, the midline neck incision created for performance of this procedure is most often used and simply reopened, provided this incision will enable adequate exposure of the persistent or recurrent disease within the neck. If the patient has previously undergone a selective lateral neck dissection (levels II—VI) for surgical treatment for lateral nodal involvement, this incision may be utilized for exposure. If there is concern that a previous incision will not adequately provide exposure of the diseased tissue, the surgeon may choose to either extend the previous incision to allow appropriate exposure (most common), or simply create another 1 to 2 cm horizontal incision overlying the disease area as determined by preoperative imaging. If a new incision is created, the surgeon should attempt to place this in a skin crease of the neck to minimize appearance of the resultant scar.
Fig. 23.6 Example of layout for 3 x 5" index card stamp or printout for documentation during radioguided neck dissection.
23.3.6 In Situ Identification of Target of Interest
As previously delineated, operative intervention is timed so that the radionuclide being used for intraoperative guidance is maximally sequestered within the persistent or recurrent disease detected on preoperative imaging studies (NUS/PET/ SPECT). However, the surgeon must rely on these preoperative studies in addition to direct visualization, palpation, and scanning of the field with the probe. This can be done in various ways. The skin over the area of maximum uptake may be marked by the nuclear medicine physician in his or her department. This area can be confirmed by scanning over and around the mark during surgery. Alternatively, the probe can be placed in the wound to identify the area of increased radionuclide uptake. By dragging the probe across the field in two passes at right angles to each other, the focus of maximum activity can be identified in two dimensions.8.13.29
23.3.7 Excision of Target of Interest
Once the diseased tissue has been successfully identified, the surgeon should attempt to resect disease tissue en block, rather than “berry-picking,” as studies in the literature have demonstrated that undetected satellite tumors have been identified on pathology from en bloc excision performed with radioguidance, particularly if I131 is the radionuclide of choice.8.11 Once the disease tissue has been excised en bloc, the gamma probe may then be utilized for ex vivo confirmation of radioactivity, which is recorded (see Fig. 23.6). In this manner, the surgeon may determine with a high degree of accuracy that the excised tissue is, in fact, the diseased tissue visualized on preoperative radionuclide imaging studies, as gamma probe readings are a far more accurate predictor of cure rather than size, mass, or cellularity.13.40
23.3.8 Basin Returns to Background
As a secondary means of confirmation of cure in the successful execution of RGND, the remaining wound bed should return to the previously measured background gamma readings (taken from the right shoulder/supraclavicular area) following complete excision of diseased tissue. False-positive readings can be obtained if the probe is directed toward the salivary glands or the heart. In the instance that the remaining wound bed does not return to background following excision despite ex vivo confirmation of excision of diseased tissue, the surgeon should carefully explore the wound bed for additional disease to be excised. Wound bed return to background is indicative of successful complete disease resection, and complete hemostasis should be ensured prior to wound closure. Drain placement is at the discretion of the surgeon and dependent on the extent of dissection and disease resection.
23.3.9 Mitigation of False Positive from Background (Salivary Glands, Heart)
Of fundamental importance in successful procedural execution of RGND and in order to avoid spurious or false-positive counts, due to background radioactivity, measurements of the negative control (fat dollop) and any specimens of interest are performed with the gamma probe held so that it is facing the ceiling. Particularly in the utilization of 18F-FDG, the radionuclide is taken up in area of high glucose uptake, and thus characteristically concentrates in areas such as the salivary gland and heart.
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