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Pediatric and Reproductive Endocrinology Branch (K.P.), National Institute of Child Health and Human Development; and Clinical Neurocardiology Section (D.S.G., G.E.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
Correspondence: Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc., Unit on Clinical Neuroendocrinology, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive MSC-1583, Bethesda, Maryland 20892-1583. E-mail: karel{at}mail.nih.gov
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 Top Abstract I. IntroductionII. Diagnostic Localization of...III. Future TrendsReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Diagnostic Localization of...III. Future TrendsReferences |
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A. PET principles and radiopharmaceuticals
PET radiopharmaceuticals generate positrons with particular physical characteristics that provide the basis for high-resolution detection and image construction (1, 2). After collision of a positron with an electron, the mass of each is converted to photon energy. Photons, released at 180 degrees from each other, are detected as "coincidences" by detectors in the scanner. The coincidence data are converted into tomographic images, using mathematical reconstruction techniques that correct for attenuation by organs of differing density and for physical decay of the tracer, providing in essence a three-dimensional quantitative map of distribution of the tracer in the body. Two types of scans are generated during a PET imaging session. Emission scans reflect photon emission from inside the body after injection of the imaging agent. Ancillary transmission, or attenuation scans, are like low-resolution computed tomographic scans and are used to correct for photon absorption within organs. Current PET tomographs have a theoretical spatial resolution of 3–4 mm. In clinical practice, this is probably less, i.e., 5–10 mm (3). Lesions smaller than this cannot be imaged confidently.
A PET scanning session can take 20–60 min or more, depending on the number of levels scanned, isotope used, delay between tracer administration and data acquisition, scanner configuration, and nature of data acquisition. Recent developments now offer the ability of blending conventional imaging modalities, such as computed tomography (CT), with PET (4). These PET-CT scanners can serve for both attenuation correction and anatomic registration and will likely improve tumor diagnosis and localization.
The specific cellular targeting of PET agents provides the basis for the excellent diagnostic specificity of PET. 18F can usually be incorporated into a molecule with relatively small effects on the ability of the radiopharmaceutical to bind to receptors, undergo metabolism by enzymes, or enter cells via transporters. Other positron-emitting radionuclides, such as 11C, can be incorporated without changing the molecular structure or characteristics. Because of their short physical half-lives, 11C-, 15O-, and 13N-labeled compounds must be synthesized and administered quickly. In contrast, 18F has a longer half-life, not necessarily requiring on-site isotope production (Table 1
). An advantage of the short half-lives of PET radioisotopes compared with other radiopharmaceuticals is that relatively large radioactive doses can be administered safely to patients. Also, because PET and other radiopharmaceuticals can be synthesized with relatively high specific activity, these compounds can be used at doses that do not produce pharmacological effects.18F-labeled 2-fluoro-deoxy-D-glucose (18FDG) is the most commonly used PET imaging agent (Table 2) (5, 6). 18FDG undergoes active uptake into cells by glucose transporters and is then phosphorylated, but not metabolized, and becomes "trapped" within cells (Fig. 1A). The utility of 18FDG scanning for tumor imaging depends primarily on increased glucose metabolism and, consequently, greater trapping of the agent in the more metabolically active tumor cells than in surrounding tissues. This basis for imaging does not, however, offer high diagnostic specificity. Consequently, interpretation of 18FDG PET images requires experience and skill in recognizing causes of variable physiological uptake, such as may occur with muscle contraction, fasting, inflammation, wound healing, and anatomic or physiological variants (7, 8).
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, B and C) (15, 16, 17). For instance, 6-[18F]fluorodopamine is taken up into pheochromocytoma cells by cell membrane catecholamine transporters and then concentrated in storage vesicles (15, 16). Similarly, [11C]hydroxytryptophan is taken up by carcinoid tumor cells, decarboxylated, and then stored in vesicles as [11C]serotonin (17).
Another basis for visualization of endocrine tumors by PET scanning is binding to receptors (Fig. 1D). Binding of [11C]methylspiperone and [11C]raclopride to dopamine type 2 receptors in pituitary tumors or 68Ga-labeled somatostatin receptor analogs illustrates this type of application (18, 19, 20). Expression of specific nuclear receptors provides another potential target for the development of PET agents.
B. Advantages and limitations of PET scanning
Compared with CT and magnetic resonance imaging (MRI), PET scanning offers the advantage of assessment of physiological and pathophysiological processes—cellular metabolism, tissue perfusion, and DNA and protein synthesis, and, relevant to endocrine oncology, local synthesis, uptake, storage, and receptors for hormones. Functional imaging aids initial preoperative staging, diagnostic evaluation of suspicious lesions, and identification of metastatic or recurrent tumors; in addition, it helps to refine prognosis and to select and predict responses to therapy.
PET scanning offers better resolution than single-photon emission CT due to the relatively intense radioactivity and coincidence detection, which increases signal to noise ratios. The duration of scanning is also relatively short. Thus, PET enables quantitative assessments of amounts of radioactivity in different tissues over time (time-activity curves).
These advantages come with several limitations. First is the cost and limited availability of the technology. Now that health programs have begun to approve reimbursement for PET scanning in cancer diagnosis, the availability of PET scanning is increasing and costs may decline accordingly (21). Medicare now covers 18FDG scanning for many cancers (lung, colorectal, lymphoma, melanoma, esophageal, head and neck, breast), including, most recently, thyroid cancer. A second limitation is the requirement for nearby radioisotope production. The short physical half-lives of PET radioisotopes (Table 1) minimize challenges related to handling of radioactive waste, but geographical and radiation-regulatory issues remain considerations. A third limitation is the theoretical limit of spatial resolution, which is poorer than that of CT or MRI.
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II. Diagnostic Localization of Endocrine Tumors |
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In patients with known thyroid cancer following thyroidectomy, serum thyroglobulin levels, at baseline or after administration of recombinant human TSH, provide useful diagnostic information for detecting recurrence or metastases (36, 37). Some patients with metastatic thyroid cancer have undetectable or uninterpretable thyroglobulin levels, due to circulating thyroglobulin antibodies or minimal thyroglobulin secretion (37). In this setting, radioiodine whole-body scanning and other radiological imaging studies are appropriate.
About 20% of patients with well-differentiated thyroid cancer have postoperative recurrence or cervical metastases. Radioiodine scanning fails to detect one third to one half of such cases due to poor iodine uptake or small tumor size (37, 38). Neck ultrasound (often followed by ultrasound guided biopsy) is therefore usually recommended when a cytological diagnosis is important. Anatomic distortion by prior surgery may obfuscate interpretation of CT and MRI imaging results. If elevated thyroglobulin levels lead to suspicion of recurrence or metastasis, then 18FDG scanning is useful. Given the approximately 90% negative predictive value of thyroglobulin testing in eliminating presence of thyroid cancer, some investigators believe that patients with baseline and TSH-stimulated thyroglobulin levels less than 2 ng/ml need not undergo further scanning, beyond whole-body radioiodine imaging (39). These patients can be followed by serial clinical examination, thyroglobulin levels, and neck ultrasound.
In patients with negative radioiodine scans after thyroidectomy, but with serum thyroglobulin levels above 2 ng/ml, 18FDG scanning can detect metastases in cervical lymph nodes not evident by CT or MRI (22, 24, 40). Thus, thyroid imaging using 18FDG should be restricted to postoperative thyroidectomy patients (Fig. 2A); in such patients, the sensitivity and specificity of 18FDG scanning for detecting residual tumor, recurrence, or metastases are 82–95% and 83–95%, respectively, depending on the site of metastasis (22, 25, 40, 41). 18FDG scanning may also enable detection of Hurthle cell carcinoma, which radioiodine usually fails to visualize (42).
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Other issues relevant to imaging of metastatic thyroid cancer concern the hormone status of the patient. In particular, uptake of 18FDG and image quality may vary with thyroid hormone replacement therapy or TSH suppression therapy. Whether 18FDG uptake is improved when TSH is elevated compared with suppressed is unclear (27, 28, 42, 43, 45). Recombinant TSH-stimulated 18FDG uptake is a new approach to localization and therapy of metastatic thyroid cancer (35A ). Recombinant TSH improves the detectability of occult thyroid metastases using 18FDG PET.
Medullary thyroid cancer is often invasive and progressive over years, with a high potential for metastasis. Because of their hypermetabolic state, 18FDG scanning offers a potential approach to detect such lesions and improve identification of involved lymph nodes, surgical resection of which can result in complete or prolonged remission (46, 47).
Inflamed lymph nodes, thyroiditis, thyroid nodules, brown fat, or physiologically contracted neck muscles can be associated with increased 18FDG uptake (8, 41, 43, 48). Moreover, focal uptake of 18FDG does not reliably distinguish primary thyroid or metastatic cancer from uptake by other nearby tissues. Thyroid "incidentalomas" found on 18FDG scanning appear to have a high rate of malignancy (49) and should be assessed by fine-needle aspiration.
In summary, radioiodine scintigraphy should be used for diagnostic localization of residual, or recurrent well-differentiated cancers of the thyroid gland. 18FDG PET scanning has established its value for detecting recurrence of papillary and follicular thyroid cancer, but this is limited to patients with increased thyroglobulin levels and negative radioiodine scanning. High uptake of 18FDG carries a poor prognosis. PET scanning may also be useful in patients with anaplastic thyroid cancer. Whether 18FDG PET should be performed in patients with elevated TSH levels, during T4 withdrawal, or after TSH administration requires clarification. The role of 18FDG scanning in patients without high thyroglobulin levels but with strongly suspected recurrent or metastatic cancer also requires further study.
PET scanning is likely to be useful in patients with primary or recurrent anaplastic thyroid cancer, although further preliminary studies are warranted. 18FDG scanning also offers a potential imaging approach to detect recurrent or metastatic medullary thyroid cancer.
B. Adrenocortical tumors
Most adrenocortical tumors are discovered as benign incidentalomas, during abdominal imaging, such as CT, done for other reasons. The adrenal gland is also a common site for metastatic spread of many other cancers (50). In the evaluation of adrenocortical tumors, CT and MRI always precede functional imaging.
CT densitometry, computer-generated measurements of the physical density of a tissue, is useful for initial differentiation of adrenal adenomas from metastases (51, 52, 53). A density measurement of less than 10 Hounsfield units (HU) in a homogenous mass by unenhanced CT indicates a lipid-rich adenoma (53). If the mass is inhomogenous or has a density of 10 HU or more, the diagnosis is uncertain. An adenoma remains the most common possibility, but a metastasis or other tumors should be considered. In such situations, if clinical and biochemical information is unrevealing, the next step is to assess washout of contrast material over time from the adrenal gland to distinguish adenomas from other tumors (52, 54). Briefly, standard contrast-enhanced CT images of the adrenal gland are obtained about 60 sec after the injection of contrast material. Adenomas lose enhancement more rapidly than nonadenomas. Thus, in 15 min after injection of contrast material, adrenal masses with an attenuation value of less than 30–40 HU on a contrast-enhanced CT scan or with more than 60% (40% if no unenhanced CT has been performed) of washout of initial enhancement represent adenomas (52, 53, 54).
Chemical-shift MRI can also distinguish adrenal adenomas from metastases (55). This method is based on the detection of different signal intensity for hydrogen atoms in water and lipid molecules. Thus, signal intensity is decreased for tissues containing both water and lipids in comparison with tissue containing no lipids (52, 54). The chemical shift can be detected either visually or by quantitative methods in comparison with reference tissue. MRI is preferable in children or in pregnancy because there is no radiation exposure, but ultrasound may occasionally be considered.
After malignancies are excluded, the clinician should determine the functional characteristics of the adrenal mass. This is most commonly done by biochemical testing. Thereafter, PET scanning and other imaging modalities can be particularly useful for identifying the origin and characterizing the behavior of adrenal lesions. Several PET radiopharmaceuticals are available that can detect increased cellular activity in adrenal hyperfunctional states more specifically than conventional imaging. Independent of secretory activity, PET imaging agents can also target specific adrenal gland enzymes expressed in tumor cells. An example is [11C]metomidate, which binds specifically to 11ß-hydroxylase (Fig. 1C). Additionally, PET scanning can be used to distinguish benign from malignant adrenocortical lesions. 18FDG scanning is remarkably effective in differentiating benign from malignant lesions with high accuracy (56, 57, 58).
[131I]6ß-Iodomethylnorcholesterol (NP-59) scintigraphy is useful for detecting adrenocortical tumor tissue. The agent is specifically bound to low-density lipoproteins and after receptor-mediated uptake, and it is stored in the adrenocortical intracellular lipid droplets. [131I]6ß-Iodomethylnorcholesterol scintigraphy has high specificity (100%) and reasonable sensitivity (
70%) for distinguishing benign functioning adrenal adenomas from other space-occupying adrenal lesions (59, 60). The positive predictive value of [131I]6ß-iodomethylnorcholesterol in differentiating functioning adenomas from other tumors is 100% for lesions at least 2 cm in diameter. The method shows promise for evaluating patients with an incidentally discovered, nonhypersecretory, unilateral adrenal mass (59), but further larger studies are required to confirm this utility. The main limitations of [131I]6ß-iodomethylnorcholesterol scanning are long waiting periods (usually 4–7 d) before attaining optimal tissue-to-background ratios. Other problems are its limited availability, suboptimal image quality, and intestinal secretion that may obscure tumor visualization.
[111In]Octreotide has high sensitivity for detection of adrenal adenomas causing Cushing syndrome (61). High-dose [111In]octreotide scintigraphy may also be useful in localization of tumors causing ectopic ACTH production, when conventional imaging studies prove negative (our unpublished observations). Whether [111In]octreotide scintigraphy or PET scanning is useful for localization of aldosteronomas is unknown, but their small size makes the probability of usefulness of these imaging modalities very low.
[11C]Etomidate and [11C]metomidate represent two PET agents that can be used to distinguish adrenocortical tumor from metastatic cancer based on targeting of specific enzymes expressed in adrenocortical tumors (Fig. 1C) (62, 63). Both bind to 11ß-hydroxylase, a key enzyme in cortisol and aldosterone synthesis. This offers specificity for identifying adrenocortical cells but does not allow differentiation of benign from malignant adrenocortical lesions. The latter can be performed using 18FDG PET scanning, with more than 95% accuracy (57, 58, 64) for distinguishing benign from malignant adrenocortical lesions including secondary adrenocortical tumors.
Adrenocortical cancer carries a poor prognosis due to tumor dissemination in about 80% of cases. Therefore, early diagnosis and localization of metastases are critical (65). Postsurgical changes (e.g., the presence of adhesions, surgical clips, anatomical distortions) in patients with recurrent adrenocortical cancer can occasionally compromise interpretation of anatomic imaging studies. In this setting, 18FDG may identify only hypermetabolic lesions, but studies to date have involved only small numbers of patients. However, virtually all studies show 18FDG scanning to be useful in detection of primary adrenocortical cancer and metastatic lesions (66, 67).
In summary, CT provides the most appropriate initial imaging method to detect a suspected adrenocortical tumor in patients without a history of cancer. CT (using a density measurement or washout technique) can distinguish benign from malignant adrenal lesions. MRI (using a chemical-shift method) is a reasonable alternative in patients with biochemical findings consistent with a benign tumor despite high clinical suspicion of a functioning adenoma or cancer. When results of these imaging studies point to a functioning adenoma or adrenocortical carcinoma, appropriate biochemical assays (e.g., the measurement of cortisol, aldosterone, testosterone) should be done to identify adrenal hyperfunction. Functional imaging using either [131I]6ß-iodomethylnorcholesterol or 18FDG PET may be appropriate to detect malignant adrenal lesions, especially when CT and MRI or biochemical tests do not provide sufficient diagnostic information. If hypersecretion is not found, imaging studies in tumors less than 4–5 cm in diameter should be repeated after 3–6 months to document tumor growth. In patients with no malignancy or lipid-rich adenomas (<10 HU) on CT, no further follow-up is needed.
C. Pheochromocytoma
Pheochromocytomas are chromaffin cell tumors usually arising in the adrenal gland. Those at extraadrenal sites are also called paragangliomas. Diagnosis of pheochromocytoma is usually based on the presence of symptoms and signs of catecholamine excess. CT and MRI are generally accepted for initial localization of these tumors. Sensitivities vary between 75 and 100% depending on location at adrenal or extraadrenal sites and whether the tumor is primary, recurrent, or metastatic (16, 68). Both imaging methods have poor specificity (68). However, MRI is more sensitive than CT in detecting extraadrenal pheochromocytomas (paragangliomas).
Expression of tumor-specific catecholamine transport and storage mechanisms by pheochromocytoma tumor cells provides the basis for [131I]- and [123I]metaiodobenzylguanidine scintigraphy. Several PET agents, including [11C]hydroxyephedrine, [11C]epinephrine, [11C]phenylephrine, and 6-[18F]fluorodopamine take advantage of the same functional characteristics (15, 69, 70, 71). After cellular uptake, the radiopharmaceuticals are concentrated within storage granules (Fig. 1B). Nevertheless, uptake of these radiopharmaceuticals by other cell types, such as salivary glands, heart, liver, pancreas, spleen, gall and urinary bladder, and kidney, may cause difficulties in tumor visualization.
[131I]Metaiodobenzylguanidine scintigraphy has good specificity but limited sensitivity and spatial resolution (72). Single-photon emission scanning with [123I]metaiodobenzylguanidine improves both sensitivity and spatial resolution (72).
Loss of metaiodobenzylguanidine-derived radioactivity from nonadrenergic organs declines slowly, and imaging requires scanning for up to 48 h (69). Metaiodobenzylguanidine does not bind to postsynaptic adrenergic receptors and therefore can be given safely at relatively high doses. Malignant pheochromocytomas take up metaiodobenzylguanidine less avidly than benign tumors, possibly because of decreased expression of norepinephrine transporters by less well-differentiated cells (70). However, less specific [111In]octreotide or 18FDG scanning may improve tumor detection (73). Pentetreotide, as an analog of somatostatin, binds to cell membrane somatostatin receptors, which endocrine tumor cells commonly express. The density of these receptors therefore determines the efficacy of Octreoscan imaging.
PET scanning after injection of [11C]hydroxyephedrine, [11C]epinephrine, 6-[18F]fluorodopamine, or [18F]fluorodihydroxyphenylalanine offers advantages over other nuclear scanning modalities, because tumor visualization can be accomplished within minutes of injection of the imaging agent, and spatial resolution is excellent (15, 16, 69, 70, 74).
In a recent study, all patients with known pheochromocytoma had positive 6-[18F]fluorodopamine PET scanning results that correctly localized tumors (Fig. 2B) (15). Some of these patients had negative [131I]metaiodobenzylguanidine scans. The spatial and temporal resolution of [131I]metaiodobenzylguanidine scintigraphy is inferior to PET scanning. Preparation of 6-[18F]fluorodopamine is, however, currently labor intensive, and has limited availability. The efficacy of 6-[18F]fluorodopamine PET scanning has not yet been compared with that of [123I]metaiodobenzylguanidine single-photon emission CT.
Because tumor visualization using these PET scanning agents for imaging depends on expression of catecholamine uptake and storage systems, it is possible that dedifferentiated tumor cells that lack these systems may not be detected by these techniques. In these cases, [18F]fluorodihydroxyphenylalanine or 18FDG PET scanning may provide alternatives (70, 74, 75). The sensitivity of 18FDG scanning is about 70% for solitary benign or malignant pheochromocytoma (75), and that of [18F]fluorodihydroxyphenylalanine about 100% for detecting solitary tumors (74). The latter reports involved only a small group of patients, none of whom had metastatic pheochromocytoma.
In summary, patients with suspected pheochromocytoma and positive biochemical results should undergo CT or MRI and then functional imaging (e.g., [123I]metaiodobenzylguanidine) to confirm that a tumor is indeed a pheochromocytoma and to rule out metastatic disease before any surgical procedure is considered. Functional imaging is not necessary for epinephrine-secreting small (<5 cm) adrenal tumors. In centers where PET scanning is available, these modalities can offer improved functional imaging. If this fails to visualize a pheochromocytoma but the tumor is still suspected, then 18FDG PET or [111]Inoctreotide scintigraphy may be appropriate (70).
D. Neuroblastoma
Neuroblastomas are tumors derived from neural crest cells of the sympatho-adrenal system. They are the most common solid extracranial tumor in children and are found most often in the abdomen. Early detection of metastatic neuroblastoma by sufficiently specific and sensitive scanning may reveal otherwise unsuspected and still resectable tumors, facilitating staging and prognosis (76). MRI and CT are appropriate for initial localization of neuroblastoma. At present, metaiodobenzylguanidine scintigraphy is considered the most useful functional imaging modality. This is because most primary and metastatic neuroblastomas express tumorspecific catecholamine uptake and storage mechanisms that also rationalize [131I]metaiodobenzylguanidine treatment (77). Radioiodinated metaiodobenzylguanidine scintigraphy has a sensitivity of about 90% for localizing neuroblastoma (77); 18FDG scanning has overall similar sensitivity but may be superior to metaiodobenzylguanidine scintigraphy for locating neuroblastoma in certain tissues or when a tumor becomes less differentiated or loses the noradrenergic transporter system (78, 79). [11C]Hydroxyephedrine represents another PET imaging agent for localization of neuroblastoma (80). Overall, PET scanning should be reserved for situations in which there is high suspicion of neuroblastoma and when metaiodobenzylguanidine scintigraphy is negative.
In summary, MRI and CT remain first-line imaging modalities for diagnostic localization of neuroblastoma. Radioiodinated metaiodobenzylguanidine scintigraphy remains the major functional imaging modality because of the tumor-specific expression of catecholamine uptake and storage mechanisms. The latter rationalizes use of [131I]metaiodobenzylguanidine for treatment of neuroblastoma. PET scanning should be reserved for situations in which there is high suspicion of neuroblastoma but metaiodobenzylguanidine scintigraphy is negative. Accurate tumor staging is crucial for correct medical and surgical treatment decisions.
E. Carcinoids and pancreatic endocrine tumors
Carcinoids are tumors of enterochromaffin cells but can also arise in parenchymal organs outside the gastrointestinal tract. Carcinoid tumors have unique functional characteristics related to synthesis, storage, and release of specific peptides and amines; however, about one third of the tumors are nonfunctional. In patients with metastatic disease, the 5-yr survival is less than 50%.
These tumors often pose a difficult diagnostic challenge because of their small size and multiplicity. Endoscopy and endoscopic ultrasonography provide sensitive tools for visualizing gastric and intestinal carcinoids (81). MRI and CT provide important means to localize thoracic carcinoids or metastases (82, 83).
Pancreatic endocrine tumors include insulinomas (islet cell tumors), gastrinomas, glucagonomas, and somatostatinomas. For localization of pancreatic islet cell tumors, MRI, CT, ultrasound, and endoscopic ultrasound have less than optimal sensitivity (83, 84, 85). Probably the most effective strategy to detect small pancreatic neuroendocrine tumors is intraoperative palpation and intraoperative ultrasound (86).
More than 70% of carcinoids or pancreatic endocrine tumors express somatostatin receptors. Imaging agents for somatostatin receptors, such as [111In]octreotide, provide first-line tests to localize these tumors; diagnostic sensitivity exceeds that of MRI or CT. Many tumors, however, are too small to be detected, and some (especially metastatic lesions) do not express somatostatin receptors (17, 87, 88). One can also attempt using a hand-held intraoperative 
-detecting probe after [111In]octreotide injection to detect very small or even microscopic occult primary tumors or metastases or assess completeness of resection (89). However, use of the -probe is confounded by the high-background uptake of a radiopharmaceutical by the liver, kidney, and spleen.
Metaiodobenzylguanidine scintigraphy for carcinoid tumors has less sensitivity (50%) than does [111In]octreotide scintigraphy (67%), and for pancreatic endocrine tumors also has less sensitivity (9%) than [111In]octreotide scanning (91%) (83). Thus, metaiodobenzylguanidine scintigraphy should be used when other imaging methods fail to localize a tumor, or in patients in whom [131I]metaiodobenzylguanidine is being considered for treatment (83, 90).
Carcinoids characteristically synthesize serotonin. Thus, administration of radioactive serotonin precursors provides an alternative and specific method of tumor visualization. [11C]-5-hydroxytryptophan seems an excellent compound for this purpose—especially in the midgut—with sensitivity exceeding that of CT (17, 91, 92). [18F]Fluorodihydroxyphenylalanine, another amine precursor, can be used to visualize carcinoids (93); its sensitivity exceeds that of 18FDG scanning for primary tumors and lymph node metastases. [11C]Dihydroxyphenylalanine has also successfully localized carcinoids (94).
The above specific, functional approaches may yield false-negative results in detecting undifferentiated carcinoids. Poorly differentiated carcinoids with high proliferative activity usually take up 18FDG; however, 18FDG PET scanning often fails to visualize more common differentiated carcinoids (17, 95, 96). For metastatic carcinoid, 18FDG PET scanning offers little advantage over [111In]octreotide scintigraphy (97, 98).
In summary, the initial approach to hormonally apparent carcinoid is MRI or CT. If these prove negative, both endoscopy and endoscopic ultrasonography are recommended for diagnosing intraluminal tumors; [111In]octreotide scanning is recommended to detect tumors outside the lumen, if endoscopy and endoscopic ultrasonography prove negative. For an insulinoma, intraoperative palpation with intraoperative ultrasound is also very sensitive. For carcinoids not localized by conventional imaging or [111In]octreotide scanning, [123I]- or [131I]metaiodobenzylguanidine scanning or [11C]-5-hydroxytryptophan PET scanning may be helpful. [123I]- or [131I]metaiodobenzylguanidine scanning is also appropriate for patients being considered for [131I]metaiodobenzylguanidine treatment. 18FDG scanning should be reserved for visualizing poorly differentiated tumors not detected by the above methods.
F. Primary hyperparathyroidism
About 90% of primary nonfamilial hyperparathyroidism results from a solitary parathyroid adenoma (99). Less common causes include multiple parathyroid gland disease (hyperplasia or adenoma), seen especially in multiple endocrine neoplasia type 1 and 2A.
In patients without previous neck surgery, identification of parathyroid adenoma by surgical exploration has a sensitivity of about 95% (100). There is increasing interest in less invasive and less expensive procedures, such as unilateral neck exploration or various combinations termed minimally invasive surgery (101). This can be achieved by imaging modalities including preoperative ultrasound, which has the lowest cost and a sensitivity of more than 75% or by CT or MRI with a sensitivity of about 70% (102, 103). Preoperative imaging for localization also decreases surgery and anesthesia time, incision size, tissue trauma, or postoperative scarring and improves detection of parathyroid adenoma in patients with coexisting multinodular goiter or ectopic tumor tissue (103).
Among scintigraphic methods for preoperative localization of parathyroid adenoma, [99mTc]sestamibi is most widely used (101, 104) with sensitivity ranging from 25–98%. The accumulation of [99mTc]sestamibi in parathyroid adenoma is based on both blood flow and its sequestration within the cytoplasm and mitochondria. Because parathyroid adenomas contain a large number of mitochondria in their cells, [99mTc]sestamibi is taken up more avidly in adenomatous tissue than the surrounding thyroid gland (104). Ultrasound combined with [99mTc]sestamibi scanning improves localization of parathyroid adenoma (105).
Radioguided surgery also decreases the extent of neck exploration for single parathyroid adenoma (106). A few hours after [99mTc]sestamibi scintigraphy, the intraoperative -probe technique is used to detect adenoma during surgery. Adding ultrasound to this approach reduces a number of false-positive results, because thyroid nodules can avidly take up [99mTc]sestamibi. In multiple gland disease, [99mTc]-sestamibi scintigraphy rarely identifies all of the tumors (107). The procedure requires an experienced nuclear medicine physician on site to perform the study and for accurate interpretation of the results. Intraoperative PTH monitoring coupled with radioguided surgery is very useful to determine the completeness of this approach.
PET scanning is not currently an established method for detecting and localizing primary parathyroid adenomas (108, 109). [11C]Methionine is a potential PET agent for this purpose (110), with high specificity, but prospective studies are needed.
[99mTc]Sestamibi is the best imaging agent to detect adenoma before surgical reexploration in patients in whom previous surgery failed to locate a parathyroid adenoma. In persistent or recurrent hyperparathyroidism after neck exploration, where various imaging modalities are negative or inconclusive, 18FDG or [11C]methionine PET scanning may be useful (110, 111, 112, 113). Because a combination of ultrasound and [99mTc]sestamibi single-photon emission tomography can usually localize a recurrent parathyroid adenoma, the cost effectiveness of PET for this application seems limited. When results of noninvasive imaging are inconclusive, selective angiography and venous sampling for PTH assay should be considered (114).
In summary, to determine whether a patient with sporadic hyperparathyroidism, who has not had previous neck surgery, is a candidate for minimally invasive parathyroidectomy, [99mTc]sestamibi is the imaging method of choice, followed by ultrasound, CT, or MRI. If preoperative imaging indicates more than one abnormal parathyroid gland, or if there is coexisting thyroid disease, minimally invasive parathyroidectomy is not advised. Intraoperative PTH monitoring can be used to determine the completeness of excision of adenomatous or hyperplastic parathyroid tissue, especially in patients undergoing neck reexploration for recurrent or persistent hyperparathyroidism. Intraoperative parathormone monitoring is also recommended for patients with secondary, tertiary, or familial hyperparathyroidism. In patients with persistent or recurrent sporadic hyperparathyroidism after neck exploration, imaging techniques such as [99mTc]sestamibi scanning can be used to locate parathyroid adenomas; however, none has adequate sensitivity. When conventional imaging techniques fail to localize parathyroid adenomas, PET scanning using 18FDG or [11C]methionine may be attempted before reoperation. Studies comparing these agents with [99mTc]sestamibi are needed. No studies to date have evaluated PET scanning in multipleparathyroid gland disease.
In parathyroid cancer, anecdotal reports have noted positive 18FDG PET scans (101, 115) not detected by other techniques. This very aggressive endocrine tumor with a high metabolic rate traps 18FDG avidly, revealing lesions not detected by other techniques (W. F. Simmonds and S. J. Marx, personal communication).
G. Pituitary tumors
Conventional imaging methods and petrosal sinus sampling in Cushing syndrome remain the tests of choice for localization of pituitary adenomas.
PET ligands used to detect pituitary adenomas include 18FDG for imaging based on glucose metabolism, [11C]methionine and [11C]tyrosine for imaging based on protein synthesis, and [11C]deprenyl, [11C]raclopride, [11C]methylspiperone, and [18F]fluoroethylspiperone for imaging based on expression of receptors (18, 116, 117, 118). Such ligands have been used to visualize different types of pituitary adenomas, differentiate viable neoplastic tissue from fibrosis, necrosis, bleeding, or cystic degeneration, distinguish recurrent tumors from postoperative changes, identify nonfunctioning sellar and parasellar tumors, and assess responses to treatment. None of these approaches, however, has yet had widespread clinical use. MRI remains the method of choice for evaluation of pituitary tumors.
Nevertheless, there are several situations in which PET scanning has the potential to provide valuable clinical information in the assessment of pituitary tumors. One would be to monitor efficacy of treatment in patients with pituitary adenomas, particularly when tumor size seems unchanged or there is a need to decide on the course of a drug regimen. PET ligands targeting specific hormone receptors or intracellular proteins related to hormone synthesis might fulfill these requirements. PET scanning may also prove useful in distinguishing nonfunctioning sellar from parasellar tumors such as craniopharyngiomas.
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III. Future Trends |
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We predict that such coverage will soon extend to endocrine tumors. Already, Medicare covers 18FDG scanning for thyroid cancer under specific circumstances. Cost-benefit analyses of the various applications for endocrine tumors should be performed, as has been done already for PET imaging of other forms of cancer (119). Costs may decrease, based on economies and competition. Reimbursement amounts for 18FDG scanning have already begun to decrease (120). Essential for such analyses will be prospective, controlled studies comparing PET imaging with other techniques for localizing endocrine tumors.
Future applications will increasingly exploit cell type-specific functional characteristics of endocrine tumor cells, to visualize transporters, cell membrane and nuclear receptors, enzymes, and even gene expression. The availability of functionally specific PET agents is presently limited, and most remain investigational. This limited availability largely reflects the more specific clinical applications of these agents, compared with the broader clinical uses of 18FDG. The functionally specific approach is a real, but as yet largely unexploited, strength of PET imaging, which has the potential for localizing endocrine tumors and for characterizing them in terms of cell type, likelihood of recurrence or metastasis, and for planning treatment.
Eventually, PET scanning may also involve "molecular imaging," to visualize gene therapy by identifying and enabling targeting of tumor cells expressing particular mRNAs. In contrast to conventional imaging methods, PET imaging also offers an opportunity to obtain quantitative information in vivo about gene delivery, vector kinetics, gene expression, and efficiency and duration of therapeutic effects (121, 122, 123). A PET reporter probe has already been developed to image herpes simplex virus thymidine kinase expression in tumors (124). Recently, PET imaging of the transcriptional activation of tumor suppressor p53-dependent genes has also been introduced (125).
In summary, functional imaging of endocrine tumors is showing increasing promise. For some tumors, such as thyroid cancer, this approach already is established for diagnostic localization. For others, such as pheochromocytoma and carcinoid, specific PET imaging agents offer excellent visualization, but prospective studies have not yet verified diagnostic efficacy. Finally, for tumors such as parathyroid or pituitary, the diagnostic value of functional imaging remains unproven.
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(v)ß3 integrin expression using 18Flabeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 61:1781–1785
