This article highlights the major milestones in the development of radioguided reoperative techniques and reviews the recent literature concerning reoperative thyroid and parathyroid surgery.
Radioguided surgery is becoming an increasingly popular modality in surgical practice. Its popularity stems from the need to develop less invasive procedures and to keep pace with a host of improved diagnostic techniques. This trend is no more apparent than in the field of thyroid and parathyroid surgery, where high-resolution ultrasound, scintigraphy, new biochemical assays, and fused positron emission tomography/computed tomography (PET/CT) imaging are aiding in the earlier detection and localization of small foci of persistent and recurrent disease. Minimally invasive radioguided parathyroidectomy (MIRP) is a prime example of how preoperative and intraoperative localization can decrease operating time, complications, and cost. Many centers across the country are offering this technique to patients as the initial surgical treatment of primary hyperparathyroidism. Less commonly, radioguidance is being used in cases of persistent or recurrent hyperparathyroidism after the primary surgery. Similarly, in the field of thyroid surgery, radioguided techniques are offering patients with persistent or recurrent tumors the chance to locate and clear metastatic neck and mediastinal disease with new precision.
This review highlights the major milestones in the development of radioguided reoperative techniques and reviews the recent literature concerning reoperative thyroid and parathyroid surgery.
Nuclear medicine and tumor biology
Radioguided surgery relies on the ability of tumor-avid radiopharmaceuticals to be detected intraoperatively by a handheld radiation detector (probe). The specific radiopharmaceutical used depends on the properties of the tumor. Ideally, it should be tissue specific, safe for the patient and the care providers, and possesses physical properties that are conducive to probe detection. Several radiopharmaceuticals are available that fulfill those criteria to a variable degree ( Table 1 ). The most commonly used radiopharmaceuticals are discussed in the following sections.
| Type of tissue | Radiopharmaceutical |
|---|---|
| Differentiated thyroid carcinoma | 131 I [sodium iodide] |
| 123 I [sodium iodide] | |
| Non–iodine-avid differentiated thyroid carcinoma | 99m Tc sestamibi [ 99m Tc methoxyisobutylisonitrile] |
| 18 F-FDG [ 18 fluorine-fluoro-2-deoxyglucose] | |
| Medullary thyroid carcinoma | 111 In pentetreotide [ 111 indium pentetreotide] |
| 99m Tc(V)-DMSA [ 99m technitium(V) dimercaptosuccinic acid] | |
| Monoclonal antibodies (ie, AES) | |
| 123 I-MIBG [ 123 I metaiodobenzylguanidine] | |
| 131 I-MIBG [ 131 I metaiodobenzylguanidine] | |
| Parathyroid disease | 99m Tc sestamibi [ 99m Tc methoxyisobutylisonitrile] |
| 99m Tc tetrofosmin |
Sodium Iodide
Sodium iodide ( 131 I) is a radioactive isotope of iodine that is used routinely for ablative therapy and total body scanning. It is taken up by normal thyroid tissue and iodine-avid differentiated thyroid carcinomas (DTC). 131 I is used in many radioguided protocols and is readily available. Its main disadvantages are its long half-life (8 days), which increases radiation dose to tissues, and its high gamma energy (364 keV), which is suboptimal for probe detection. Moreover, some differentiated thyroid tumors loose their ability to uptake 131 I; therefore, its use in radioguided surgery is restricted to differentiated iodine-avid thyroid tumors.
123 I is another isotope of iodine that emits a 159-keV gamma photon, which is ideal for probe detection. Its half-life of 13 hours makes it suitable for radioguided surgery. Like 131 I, it is taken up by thyroid tissue that retains its ability to uptake iodine. It has several advantages over the use of 131 I, including physical characteristics that ensure a strong target signal over the following 12 to 24 hours, allowing for scanning and intraoperative detection on the day after administration. 123 I has the additional advantage that it is not associated with a potential stunning effect, which is important for patients who need subsequent ablation. Its main disadvantage is its high cost .
Technetium–99m Sestamibi
Technetium–99m ( 99m Tc) sestamibi (also known as methoxyisobutylisonitrile or MIBI) is a molecule whose uptake is dependent on cellular mitochondrial content and metabolism. It is retained by abnormal parathyroid tissue and thyroid tissue. It washes out relatively quickly from the normal thyroid relative to parathyroid tissue; therefore, it is useful in parathyroid and thyroid cancer localization. 99m Tc sestamibi has also been demonstrated to be highly sensitive for non–iodine-avid dedifferentiated thyroid carcinoma . It has the advantage that it does not require the discontinuation of hormonal therapy before use.
18 Fluorine-Fluoro-2-Deoxyglucose
18 Fluorine-fluoro-2-deoxyglucose ( 18 F-FDG) is a glucose analogue that is taken up by tissues with high aerobic glycoysis (ie, metabolic demand), typical of many tumors. 18 F is a positron emitter that requires PET for imaging. As differentiated iodine-avid thyroid tumors dedifferentiate, they loose their ability to uptake iodine. These non–iodine-avid thyroid tumors are particularly 18 F-FDG avid as they rapidly grow and display high metabolic demand. Uptake in these tumors is associated with increased cellular expression of the glucose transporter, primarily GLUT-1, and hexokinase, primarily hexokinase-2 . While thyroid-stimulating hormone (TSH) suppression can reduce, 18 F-FDG uptake in DTC, endogenous or exogenous TSH stimulation is observed to enhance it . Several investigators are developing probes and protocols to use 18 F-FDG in radioguided thyroid surgery.
Indium–111 Pentetreotide
111 In-Pentetreotide is an analogue of somatostatin. Many endocrine tumors, such as medullary thyroid carcinoma (MTC), have a high density of somatostatin receptors. Therefore, 111 -In-pentetreotide can be used to localize foci of MTC scintigraphically before surgery and with radioguided appraoch intraoperatively .
Antibodies
MTC is known to express high levels of carcinoembryonic antigen (CEA) at its surface, and rising CEA is a marker for detecting MTC recurrence. Antibodies specific to CEA can be labeled with 99m Tc or 111 In and used to target MTC .
Intraoperative handheld probes
Radioguided surgery would not be possible without the advent of compact handheld probes. The first intraoperative use of a handheld gamma probe was reported in 1956 when it was used to locate recurrent thyroid carcinoma . Contemporary commercially available gamma detection probes (GDP) are classified as either scintillation counters or semiconductor probes. Scintillation GDPs use a crystal coupled to a photomultiplier. Ionizing radiation interacts with the crystal and emits light that is converted into an electrical signal registered by the probe. Semiconductor-based GDPs contain an element that produces an electronic charge in the presence of ionizing radiation. In general, scintillation GDPs tend to be more sensitive, whereas semiconductor GDPs have better spatial resolution .
Most intraoperative probes are designed for low-energy gamma photons emitted by isotopes such as 99m Tc (140 keV) or 111 In (170 keV/245 keV). 18 F emits a positron that travels a short distance before meeting an electron, resulting in annihilation of both and an emission of two high-energy (511 keV) gamma photons. The photons can also be detected by a GDP but with much less efficiency because they tend to penetrate the probe’s thin detector. Probes modified for high-energy photons may be more appropriate for 18 F detection. Several studies have recently investigated the use of various modified handheld probes intraoperatively with 18 F-FDG .
An alternative to the use of high-energy GDPs is a beta probe. Beta decay produces positron emission, which can be detected before it is annihilated by an electron; however, there are limitations to detecting positrons directly. Positrons travel only short distances in tissues, and the probe must be within millimeters to detect them. Hybrid technologies are being developed that may overcome this obstacle by combining positron detectors with high-energy gamma detectors .
Although the traditional handheld probe provides for excellent localization, new technologies are being studied, such as handheld miniature gamma cameras. In contrast to nonimaging GDPs, the gamma camera provides a visual representation of the hotspot’s size, shape, and location on an attached laptop computer. Ortega and colleagues reported on its use in minimally invasive parathyroidectomy in a comparative study with the traditional handheld gamma probe. His team concluded that the device could be used to complement or potentially replace the standard probe. Unfortunately, camera probes are far more expensive than traditional probes.
Intraoperative handheld probes
Radioguided surgery would not be possible without the advent of compact handheld probes. The first intraoperative use of a handheld gamma probe was reported in 1956 when it was used to locate recurrent thyroid carcinoma . Contemporary commercially available gamma detection probes (GDP) are classified as either scintillation counters or semiconductor probes. Scintillation GDPs use a crystal coupled to a photomultiplier. Ionizing radiation interacts with the crystal and emits light that is converted into an electrical signal registered by the probe. Semiconductor-based GDPs contain an element that produces an electronic charge in the presence of ionizing radiation. In general, scintillation GDPs tend to be more sensitive, whereas semiconductor GDPs have better spatial resolution .
Most intraoperative probes are designed for low-energy gamma photons emitted by isotopes such as 99m Tc (140 keV) or 111 In (170 keV/245 keV). 18 F emits a positron that travels a short distance before meeting an electron, resulting in annihilation of both and an emission of two high-energy (511 keV) gamma photons. The photons can also be detected by a GDP but with much less efficiency because they tend to penetrate the probe’s thin detector. Probes modified for high-energy photons may be more appropriate for 18 F detection. Several studies have recently investigated the use of various modified handheld probes intraoperatively with 18 F-FDG .
An alternative to the use of high-energy GDPs is a beta probe. Beta decay produces positron emission, which can be detected before it is annihilated by an electron; however, there are limitations to detecting positrons directly. Positrons travel only short distances in tissues, and the probe must be within millimeters to detect them. Hybrid technologies are being developed that may overcome this obstacle by combining positron detectors with high-energy gamma detectors .
Although the traditional handheld probe provides for excellent localization, new technologies are being studied, such as handheld miniature gamma cameras. In contrast to nonimaging GDPs, the gamma camera provides a visual representation of the hotspot’s size, shape, and location on an attached laptop computer. Ortega and colleagues reported on its use in minimally invasive parathyroidectomy in a comparative study with the traditional handheld gamma probe. His team concluded that the device could be used to complement or potentially replace the standard probe. Unfortunately, camera probes are far more expensive than traditional probes.
Radioguided reoperative thyroid surgery
Although the first radioguided thyroid surgery occurred in 1956 , widespread use of radioguided reoperative thyroid surgery is relatively new. Because all thyroid cancers do not share the same biochemical properties, investigators have developed radioguided reoperative thyroid surgery protocols individualized to each type of thyroid cancer.
Differentiated Thyroid Carcinoma
Radioguided surgery for DTC takes advantage of the tumor’s natural ability to uptake radioactive iodine. Several investigators have reported using 131 I or 123 I to locate recurrent or persistent tumor deposits of DTC . Gallowitsch and colleagues were one of the first teams to successfully use 123 I with an intraoperative probe to detect recurrent disease in a patient with papillary thyroid cancer. Later in 1998, Travagli and colleagues used radioguidance and preoperative 131 I total body scintigraphy (TBS) in 54 patients with recurrent disease. Intraoperative scanning assisted in localizing tumors seen on the 131 I TBS and other imaging and found new previously undetectable metastases in 42% of patients.
In 2003, Salvatori and colleagues described the use of radioguided surgery in a series of 10 patients with a history of metastatic DTC after total thyroidectomy and two noncurative 131 I treatments. The study rated surgeon satisfaction with the procedure and concluded that the procedure was decisive (ie, the procedure showed foci not otherwise detected) in two patients, favorable (ie, the procedure showed foci that were already detected by a preoperative diagnostic imaging) in six patients, and irrelevant (ie, the procedure made an unimportant contribution) in two patients. Fifty-three percent of the 78 foci found at histologic examination were only detected intraoperatively using the handheld probe.
Salvatori and colleagues later reported on their experience with 15 patients who had recurrent papillary thyroid cancer. Fifty percent of the 111 lymph node metastases found on histology were found only by using the intraoperative probe with 131 I. Most recently, Rubello and colleagues used 131 I to study 31 patients with a total of 184 foci of recurrent papillary thyroid cancer. Forty-one percent of the foci were found by gamma probe alone, and 5.4% were not seen by either modality.
Non–Iodine-Avid Differentiated Thyroid Cancer
A significant number of patients have recurrent well-differentiated thyroid carcinoma that has lost its ability to uptake iodine. At recurrence, only 50% to 60% of papillary and 64% to 67% of follicular cancers are still iodine avid; the remainder become non–iodine-avid tumors . Absence of radioiodine avidity in these tumors is associated with lower survival rates . Risk factors for non–iodine-avid recurrences include advanced age, aggressive tumors, and poorly differentiated subtypes . Because these tumors do not uptake iodine, 131 I and 123 I are of limited use for intraoperative detection; consequently, different radiopharmaceuticals such as 99m Tc sestamibi or 18 F-FDG must be used.
Boz and colleagues reported the use of 99m Tc sestamibi in a 30-year-old woman who was diagnosed with a non–iodine-avid recurrence of a follicular cell carcinoma. The patient had undergone two prior surgeries as well as ablative 131 I treatment for a well-differentiated follicular cancer before she eventually had a rise in the level of thyroglobulin. A 99m Tc-sestamibi scan revealed the focus of the non–iodine-avid tumor, and radioguidance was used intraoperatively to locate the focus within a bed of scar tissue.
Some clinicians find it helpful to image with 99m Tc sestamibi preoperatively to determine whether there is avid disease and to study how early the tracer is taken up as well as how long it resides in the focus. This information permits proper planning of surgery and radiopharmaceutical injection. Imaging must be coordinated with nuclear medicine staff so that the radiopharmaceutical is administered either right before surgery or intraoperatively in some cases (M. Tulchinsky, personal communication, 2008).
Rubello and colleagues have published multiple studies on using 99m Tc sestamibi intraoperatively to detect non–iodine-avid DTC in patients. His team injected a low dose of 99m Tc sestamibi and used an intraoperative probe to detect the tumor foci during a neck dissection. Six of the eight patients had normalized thyroglobulin levels after the procedure. Rubello and colleagues reported similar success using 99m Tc sestamibi in a larger series of 38 and 58 patients with non–radioiodine-avid DTC.
18 F-FDG is also emerging as an intraoperative tool to detect non–iodine-avid DTC. Kraeber-Bodéré and colleagues were the first to report using preoperative PET scanning and an intraoperative PET probe to resect non–iodine-avid DTC. This technique had been previously reported for metastatic colon cancer and melanoma but had never been used in the setting of thyroid carcinoma . Since then, other researchers have investigated PET probe-guided surgery and have shown that the probe is helpful in localizing difficult to access foci seen on preoperative imaging . To date, 18 F-FDG radioguided surgery has not been able to detect any metastatic deposits that were not already visualized on the preoperative PET scan.
Medullary Thyroid Carcinoma
MTC is a neuroendocrine tumor, and iodine has no direct role in its treatment or detection. Thus, the biochemical properties of these tumors dictate the use of radiopharmaceuticals that are considerably different from those used in DTC. Recurrent or residual MTC disease can dramatically affect long-term survival. Residual MTC may be difficult to detect on CT, MRI, and ultrasound. Fortunately, several radioguided techniques have been developed on the basis of the tumor’s biologic behavior.
One of the earliest studies targeting metastatic recurrent MTC was conducted by Peltier and colleagues in 1993. His team used a two-step radioimmunotargeting protocol consisting of a bispecific anti-CEA/anti-In-DTPA monoclonal antibody and a corresponding 111 In-labeled DTPA dimer (the protocol was later referred to as the affinity enhancement system [AES]). Using an intraoperative probe, this group was able to localize the disease foci in three of five patients. The probe failed to locate the disease in the other two patients. Barbet and colleagues studied AES in a larger series of patients. The technique was considered helpful by the surgeon in 12 patients, including 4 patients in whom it allowed the resection of small, nonpalpable, or visible metastases. More recently, deLabriolle and colleagues used the AES technique to search for occult disease in 13 patients with a history of MTC resection who had high circulating levels of calcitonin and CEA but no abnormalities on physical examination, chest radiograph, cervical and hepatic ultrasound, or CT. The intraoperative gamma probe had a sensitivity of 75% and specificity of 90% when compared with histologic examination.
111 In pentetreotide and technetium 99m(V) dimercaptosuccinic acid [ 99m Tc(V)-DMSA] can be used intraoperatively to detect recurrent MTC foci . In 2001, Adams and colleagues compared intraoperative detection of MTC using both tracers and found that the combined use of these compounds had an overall sensitivity of 97% compared with 65% for surgical palpation.
Iodine 123 metaiodobenzylguanidine ( 123 I-MIBG) and 131 I-MIBG can also localize MTC . Shimotake and colleagues described using 123 I-MIBG to completely resect recurrent MTC in a 7-year-old girl who underwent total thyroidectomy with lymph node dissection and three previous neck surgeries. Unfortunately, this technique is limited by the fact that only 25–30% of MTCs are visualized by 131 I-MIBG .
Indications for Radioguided Thyroid Surgery
Primary thyroid surgery does not typically require radioguidance techniques. Most studies only offer radioguidance to patients who have persistent or recurrent DTC despite total thyroidectomy and two or more 131 I treatments , or as few as one 131 I treatment .
Head and neck surgeons are occasionally asked to complete thyroid tissue resection after subtotal thyroidectomy done elsewhere for presumed low-risk DTC, with pathology revealing a high-risk DTC, such as a tall-cell variant of papillary cancer. Without completion thyroidectomy the radioactive iodine in these cases would mostly be taken up by the normal thyroid tissue without leaving enough radiotracer to localize to regional or distant metastatic disease on TBS. Finding the normal thyroid tissue at reoperation can sometimes be challenging, and tagging that remnant with 123 I and then using the intraoperative gamma probe facilitates rapid detection of the residual thyroid. Typically, 37 MBq of 123 I given the day before the surgery provides an excellent signal for the probe in the operating theater .
Negele and colleagues published a review of radioguided surgery for persistent DTC and discussed two possible indications in the setting of persistent disease: (1) in limited surgical resections in patients who have undergone previous lymphadenectomy for persistent or recurrent disease, or (2) in “recurrent extended operations to check for completeness of resection, particularly in anatomically difficult areas.”
For non–iodine-avid recurrent DTC, Rubello and colleagues adopted strict guidelines including “previous total thyroidectomy, 131 I therapy, increase in serum Tg with a negative 131 I scan, evidence of recurrent on high-resolution CT and 99m Tc-MIBI scan, presence of significant uptake on 99m Tc-MIBI scan, and lack of distant metastases.”
The indications for radioguided surgery in the setting of MTC recurrence are also consistent across studies. Adams and colleagues included patients with previous total thyroidectomies who were “diagnosed with, suspected of having or at risk” of having MTC recurrence. The majority of these patients had also undergone multiple cervical lymph node resections. Peltier and colleagues included patients with a history of MTC and elevated calcitonin after total thyroidectomy and partial or complete local lymphadenectomy. DeLabriolle-Vaylet and colleagues also used elevated calcitonin levels in patients with no detectable disease on conventional imaging modalities.
Protocols for Radioguided Thyroid Surgery
Several radioguided protocols are in use. The ideal protocol reduces exposure, identifies subcentimeter deposits, has sufficient activity in the lesions for the entire surgical procedure, and permits identification even if the focus is deep in surrounding tissue.
Limitations of Radioguided Thyroid Surgery
Radioguided surgery for DTC has several limitations. False-positive 131 I imaging, including uptake by reactive thymus and submandibular salivary glands, may lead to futile surgery . Furthermore, some lymph tissue may harbor foci undetectable by TBS or the intraoperative probe. These false-negative rates range from 5.1% to 11.7% ; therefore, complete resection of all lymph tissue remains the surgical standard in recurrent disease.
Salvatori and colleagues cite additional limitations when using 131 I as opposed to 123 I for radioguided surgery. First, the patient must receive a high dose of radiation not intended for therapy but for diagnosis. Second, 131 I does not provide the best performance when compared with 99m Tc-MIBI or 123 I. Third, most countries do not permit a high dose of 131 I in outpatients. 123 I, if affordable, alleviates these limitations.
Intraoperative localization of MTC with 99m Tc(V)-DMSA has the potential for false-positives secondary to its affinity for sarcoma, osteosarcoma, benign and malignant head and neck tumors, and inflammatory lesions . Additionally, some MTCs may express subtypes of somatostatin receptors with low affinity for [ 111 In-DTPA-D-Phe 1 ]-pentetreotide , and some MTCs may complicate detection by producing endogenous somatostatin .
Novel Techniques
A drawback of most radioguided techniques is that they depend on the tumor’s ability to uptake the tracer. What if the tumor does not easily uptake the radiopharmaceutical, but can be imaged anatomically? Radioguided occult lesion localization involves injecting a small amount of radiotracer into the lesion itself under imaging guidance and then performing the dissection with a gamma probe. The technique was first proposed for detecting nonpalpable nodules in breast surgery. Tükenmez and colleagues modified the technique for thyroid surgery. His team directly injected a radiotracer into suspicious lesions identified on the ultrasound of a patient with recurrent MTC. A handheld gamma probe was used to localize the nonpalpable nodule intraoperatively. Histopathologic examination confirmed thyroid carcinoma.
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