DOI: 10.1148/rg.275065729
RadioGraphics 2007;27:1355-1369
© RSNA, 2007
Scintigraphic Imaging of Body Neuroendocrine Tumors1
Charles M. Intenzo, MD,
Serge Jabbour, MD,
Henry C. Lin, MD,
Jeffrey L. Miller, MD,
Sung M. Kim, MD,
David M. Capuzzi, MD, and
Edith P. Mitchell, MD
1 From the Departments of Radiology (C.M.I., S.M.K.) and Medicine (S.J., J.L.M., E.P.M.), Thomas Jefferson University School of Medicine, 132 S 10th St, Philadelphia, PA 19107; the Department of Radiology, St Vincent’s Hospital, New York, NY (H.C.L.); and the Lankenau Institute for Medical Research, Wynnewood, Pa (D.M.C.). Received August 31, 2006; revision requested October 24 and received December 20; accepted January 15, 2007. All authors have no financial relationships to disclose.
Address correspondence to C.M.I. (e-mail: charles.intenzo{at}jefferson.edu).
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Abstract
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Radionuclide imaging is often used in the diagnosis and work-up of a wide range of neoplasms, on the basis of the biologic behavior of the tumor. Neuroendocrine tumors are a subgroup of neoplasms that are generally small and slow growing, and consequently their identification with conventional anatomic imaging can be difficult. Depending on the physiologic properties of the tumor, functional images obtained with radionuclides are often complementary to anatomic images, not only in the localization of the tumor and its metastases, but also in the assessment of prognosis and response to therapy. Familiarity with the choice of the appropriate radiopharmaceutical, proper imaging protocols, and the wide range of imaging patterns will enable the radiologist to guide the clinician in case management.
© RSNA, 2007
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LEARNING OBJECTIVES FOR TEST 4
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After reading this article and taking the test, the reader will be able to:- List the three radiopharmaceuticals most commonly used in neuroendocrine tumor imaging and describe the appropriate patient preparation.
- Discuss the relative advantages and limitations of scintigraphy and anatomic imaging in the work-up of patients with neuroendocrine tumors.
- Identify cases in which the use of FDG PET is appropriate.
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Introduction
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Neuroendocrine tumors are derived from embryonic neural crest tissue found in the hypothalamus, pituitary gland, thyroid gland, adrenal medulla, and gastrointestinal tract. They develop the capacity to initially synthesize amines from precursor molecules, then decarboxylate the amines, thereby producing polypeptide hormones. The cells were originally referred to as APUD (amine precursor uptake and decarboxylose) cells (1). APUD cells produce amines and peptides that function as neurotransmitters and hormones. Tumors derived from these cells were consequently named APUDomas. Later, as it became apparent that the peptides and hormones produced by the APUD cells were found in both the central nervous system and the endocrine system, the terms neuroendocrine cells and neuroendocrine tumors replaced the terms APUD cells and APUDomas, respectively.
In this article, we review the radiopharmaceuticals (somatostatin analogs, guanethidine analogs, glucose analog) and imaging techniques used for scintigraphy of neuroendocrine tumors. In addition, we discuss and illustrate the scintigraphic findings in the neuroendocrine tumors of the thorax, abdomen, and pelvis that are most commonly encountered in clinical practice, namely, entero-pancreatic tumors (carcinoid tumors, gastrinoma, glucagonoma, vasoactive intestinal peptide [VIP]–related tumors [VIPomas], poorly differentiated neuroendocrine tumors), sympathoadrenal tumors (pheochromocytoma [PHEO], paraganglioma), multiple endocrine neoplasia (MEN) syndromes (type 1 MEN, type 2 MEN), and medullary thyroid carcinoma (MTC). We also describe potential pitfalls in the imaging of these disorders.
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Radiopharmaceuticals
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By releasing biologically active peptides and hormones, neuroendocrine tumors can potentially create a significant symptom complex. The radio-pharmaceuticals used for imaging neuroendocrine tumors are either similar in molecular structure to the hormones that the tumors synthesize or incorporated into various metabolic and cellular processes of the tumor cells.
Somatostatin Analogs
Peptide and hormone synthesis by neuroendocrine cells is inhibited by a hormone known as somatostatin, a 14–amino acid peptide that can be considered an "antigrowth" hormone because it inhibits the release of anterior pituitary hormones (adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone) (2). Subsequently, it was shown that somatostatin inhibits the release of certain intestinal and pancreatic peptides such as insulin, glucagon, gastrin, VIP, gastric inhibitory polypeptide, secretin, motilin, and cholecystokinin. Theoretically, radionuclide-labeled somatostatin could bind to neuroendocrine tumors that contain somatostatin receptors, thereby facilitating the identification and imaging of the tumor and, potentially, of tumor metastases. Moreover, as an inhibitory substance, somatostatin can be given therapeutically to decrease the release of biologically active peptides and hormones overproduced by the neuroendocrine tumor, thereby helping to control or reduce tumor growth. The use of radiolabeled somatostatin in itself is not practical, however, owing to the molecular structure of somatostatin. Because of its 14–amino acid chain, the somatostatin molecule consists of numerous covalent bonds that are readily disrupted by various circulating plasma enzymes. Consequently, somatostatin has a biological half-life in the circulation of only 2–4 minutes, which compromises its efficacy in diagnostic imaging. To circumvent this limitation, an eight–amino acid analog of somatostatin called octreotide was developed whose plasma half-life is nearly 2 hours. Octreotide is more commonly known by its trade name, Sandostatin (Novartis, Basel, Switzerland).
The next step was to label octreotide with a radioisotope for the purpose of tumor imaging. This labeling was achieved with indium-111, which decays by electron capture with a physical half-life of 68 hours and principal gamma emissions of approximately 171 and 245 keV. The In-111 is chelated to the octreotide molecule by diethylenetriaminepentaacetic acid. The resulting radiopharmaceutical is called In-111 pentetreotide, often referred to by its trade name, Octreoscan (Tyco Healthcare, St Louis, Mo). In-111 pentetreotide binds to somatostatin receptors on the cell surface, and the sensitivity of In-111 pentetreotide depends on the receptor subtype. There are five somatostatin receptor subtypes, all of which avidly bind somatostatin, although only subtypes 2 and 5 bind the somatostatin analog, In-111 pentetreotide. However, because 80% of enteropancreatic neuroendocrine tumors express subtype 2 receptors, a majority of abdominal neuroendocrine tumors will be In-111 pentetreotide avid (3).
Guanethidine Analogs
The radioiodinated derivatives of guanethidine, I-131 metaiodobenzylguanidine (MIBG) and I-123 MIBG, are incorporated into cell membranes by means of active transport, a process referred to as the type I uptake mechanism. Guanethidine and its analogs are stored in vesicles within the cells of the sympathomedullary system. Consequently, MIBG will concentrate in catecholamine-producing adrenal medullary tumors—both intraadrenal (PHEOs) and extraadrenal (paragangliomas)—and chromaffin cell tumors (4), with an imaging sensitivity of approximately 77%–100% (5). In addition, MIBG-negative paragangliomas will sometimes concentrate In-111 pentetreotide (6).
Glucose Analog
2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) enters tumor cells and is phosphorylated to FDG-6-phosphate. This substrate undergoes no further metabolism and accumulates in the cell. Because glucose metabolism is accelerated in rapidly growing tumors, such tumors will concentrate FDG to a greater extent than will nonmalignant tissue, thereby permitting localization. However, because most neuroendocrine tumors are well differentiated and slow growing, they have lower metabolic and proliferative rates than do many other solid organ tumors. Consequently, their relatively lower glucose utilization results in a lower sensitivity for their detection at FDG imaging (7). Pasquali et al (8) performed FDG imaging in 16 patients with histologically proved neuroendocrine tumors. FDG uptake was seen in only eight of these patients, namely, those with rapidly growing tumors or with aggressive tumors with distant metastases. In contrast, the remaining eight patients had well-differentiated, slow-growing neuroendocrine tumors that would not be expected to have increased glucose metabolism. The scans obtained in these patients were FDG negative. However, the less aggressive, well-differentiated neuroendocrine tumors are more likely to express somatostatin receptors and to concentrate In-111 pentetreotide than are the rapidly growing, poorly differentiated tumors. Six of the eight FDG-negative patients underwent In-111 pentetreotide imaging, with radiotracer uptake being seen in four patients. Therefore, FDG positron emission tomography (PET) is useful only in patients who are suspected of having aggressive neuroendocrine tumors that escaped detection at somatostatin receptor imaging or conventional anatomic imaging.
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Scintigraphic Technique
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In-111 pentetreotide imaging involves obtaining two sets of images with 5–6 mCi (185–222 MBq) of radiotracer. The first imaging session consists of single photon emission computed tomography (SPECT) of the area of interest 4 hours after intravenous injection. The second imaging session takes place on the following day, 18–24 hours after injection. This session consists of repeat SPECT of the same anatomic region that was imaged the previous day, followed by whole-body imaging. The rationale for the early SPECT is to avoid physiologic biliary radiotracer excretion, which could potentially obscure lesion visualization in the small and large bowel. This radiotracer excretion is sometimes seen 24 hours after injection but rarely at 4 hours (Fig 1). The SPECT images are acquired with a dual-head camera at 180° rotation and using a 128 x 128 matrix and a Hanning-Nyquist filter. Planar whole-body In-111 pentetreotide imaging is performed with the same camera at a speed of 6.77 cm per minute at the In-111 photopeaks of 171 and 245 keV, using large-field-of-view medium-energy collimators. Patient preparation for In-111 pentetreotide imaging consists of the administration of an oral laxative the evening after injection to ensure optimal bowel clearance for the next day’s imaging. However, laxative administration is not necessary for certain patients with carcinoid tumors who have diarrhea as part of the symptom complex. In addition, if the patient is undergoing octreotide therapy, this therapy must be discontinued 72 hours before injection because octreotide and In-111 pentetreotide competitively bind to somatostatin receptors, thereby decreasing the sensitivity of imaging with the latter (3). Although the plasma half-life of octreotide is only 2–4 minutes, it is uncertain as to how long the drug remains bound to the receptors, which justifies the manufacturer’s recommendation of waiting 72 hours before injecting In-111 pentetreotide.
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Figure 1a. Carcinoid tumor in a 77-year-old woman with debilitating abdominal pain, diarrhea, and dehydration. Endoscopy revealed a duodenal mass, which proved to be a carcinoid tumor at biopsy. (a, b) Abdominal SPECT images obtained 4 (a) and 24 (b) hours after radiotracer injection demonstrate the tumor (arrow). Note the absence of physiologic radiotracer excretion into bowel in a. (c) Anterior (left) and posterior (right) whole-body In-111 pentetreotide images obtained 24 hours after radiotracer injection show the tumor (arrow) without evidence of metastases. The tumor was resected, and the patient’s symptoms resolved. (d) On an abdominal SPECT image obtained following tumor resection, In-111 pentetreotide uptake is normal.
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Figure 1b. Carcinoid tumor in a 77-year-old woman with debilitating abdominal pain, diarrhea, and dehydration. Endoscopy revealed a duodenal mass, which proved to be a carcinoid tumor at biopsy. (a, b) Abdominal SPECT images obtained 4 (a) and 24 (b) hours after radiotracer injection demonstrate the tumor (arrow). Note the absence of physiologic radiotracer excretion into bowel in a. (c) Anterior (left) and posterior (right) whole-body In-111 pentetreotide images obtained 24 hours after radiotracer injection show the tumor (arrow) without evidence of metastases. The tumor was resected, and the patient’s symptoms resolved. (d) On an abdominal SPECT image obtained following tumor resection, In-111 pentetreotide uptake is normal.
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Figure 1c. Carcinoid tumor in a 77-year-old woman with debilitating abdominal pain, diarrhea, and dehydration. Endoscopy revealed a duodenal mass, which proved to be a carcinoid tumor at biopsy. (a, b) Abdominal SPECT images obtained 4 (a) and 24 (b) hours after radiotracer injection demonstrate the tumor (arrow). Note the absence of physiologic radiotracer excretion into bowel in a. (c) Anterior (left) and posterior (right) whole-body In-111 pentetreotide images obtained 24 hours after radiotracer injection show the tumor (arrow) without evidence of metastases. The tumor was resected, and the patient’s symptoms resolved. (d) On an abdominal SPECT image obtained following tumor resection, In-111 pentetreotide uptake is normal.
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Figure 1d. Carcinoid tumor in a 77-year-old woman with debilitating abdominal pain, diarrhea, and dehydration. Endoscopy revealed a duodenal mass, which proved to be a carcinoid tumor at biopsy. (a, b) Abdominal SPECT images obtained 4 (a) and 24 (b) hours after radiotracer injection demonstrate the tumor (arrow). Note the absence of physiologic radiotracer excretion into bowel in a. (c) Anterior (left) and posterior (right) whole-body In-111 pentetreotide images obtained 24 hours after radiotracer injection show the tumor (arrow) without evidence of metastases. The tumor was resected, and the patient’s symptoms resolved. (d) On an abdominal SPECT image obtained following tumor resection, In-111 pentetreotide uptake is normal.
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I-123 MIBG scans are obtained 24 hours after the intravenous administration of 5–10 mCi (185–370 MBq) of radiotracer, using the same continuous whole-body imaging acquisition protocol as that used for In-111 pentetreotide imaging, including SPECT if necessary. Unlike with In-111 pentetreotide, however, the energy photo-peak for I-123 (159 keV) is used. I-131 MIBG scintigraphy is performed 48–72 hours after the intravenous administration of 0.5–1 mCi (18.5–37 MBq) of radiotracer. A 72-hour delay is preferable, since the target-to-background activity level is higher at 72 hours than at 48 hours. Because any unbound I-131 and I-123 is concentrated by the thyroid gland and would potentially deliver a high radiation dose to the gland, either Lugol solution or a supersaturated solution of potassium iodide should be given orally as directed on the package insert. Planar static images of the thorax, abdomen, and pelvis are obtained for 20 minutes each (total of 60 minutes per imaging session) with a large-field-of-view dual-head camera, a high-energy collimator, and a 20% window centered at the 364-keV photopeak for I-131. These "spot" images are preferred over the whole-body continuous gamma camera acquisition protocol due to the relatively low count rate of 0.5–1 mCi (18.5–37 MBq) of I-131 (the maximum permissible dosage), compared with 10 mCi (370 MBq) of I-123. With the longer acquisition time, spot imaging allows better image resolution. SPECT with I-131 MIBG is in most cases not feasible due to the low count rate and the need for high-energy SPECT collimators.
I-123 MIBG scintigraphy is preferable to I-131 MIBG scintigraphy because (a) it provides higher-quality images (159 keV vs 364 keV); (b) the lower radiation burden of I-123 allows a higher permissible dosage (10 mCi [370 MBq] vs 1 mCi [37 MBq]), resulting in a higher count rate; (c) SPECT can more feasibly be performed with I-123; (d) a high-energy collimator is required for I-131 MIBG scintigraphy; and (e) less time elapses between injection and imaging with I-123 MIBG scintigraphy (24 hours) than with I-131 MIBG scintigraphy (48–72 hours). As of this writing, the only disadvantage of I-123 MIBG is that it is substantially more costly than I-131 MIBG. Regardless of the radioisotope used, MIBG uptake and retention can be decreased or inhibited by drugs that inhibit the type I transport mechanism, such as sympathomimetics, reserpine, calcium channel blockers, tricyclic antidepressants, and labetalol (9). Therefore, the patient must discontinue these medications for at least 3–4 days prior to MIBG administration.
FDG PET scans were acquired with a Philips Allegro scanner (Philips Medical Systems, Milpitas, Calif). Patients were injected intravenously with 10–12 mCi (370–444 MBq) of FDG and were scanned 1 hour later at 3 minutes per bed position (eight or nine bed positions per session). Images were reconstructed using a three-dimensional RAMLA (row action maximum likelihood algorithm) reconstruction algorithm with a section thickness of 4 mm. The images were reconstructed with 4-mm pixels, interpolated to smaller pixels on magnified images. Each image set consisted of transaxial, coronal, and sagittal images, including a rotating maximum-intensity-projection image.
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Enteropancreatic Tumors
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Carcinoid Tumors
Carcinoid tumor cells secrete excessive amounts of vasoactive substances and neuropeptides, including serotonin, histamine, bradykinin, substance P, and neurokinin-A. Most carcinoid tumors originate from the gastrointestinal tract (73%–85% of cases), followed by the broncho-pulmonary system (10%–29%) and, rarely, organs such as the kidney, thymus, larynx, ovary, or skin (10). Carcinoid tumors are relatively slow growing; however, about 40% of patients have metastases at the time of presentation (11). The clinical presentation depends on the location and extent of disease, the presence of metastases, and the hormones or peptides produced by the tumor. Signs and symptoms of gastrointestinal tumors include abdominal pain, bowel obstruction, flushing, and diarrhea, all resulting from an excess of serotonin and other vasoactive peptides. The so-called carcinoid syndrome classically consists of flushing, diarrhea, abdominal discomfort, bronchial constriction, and, sometimes, right-sided heart failure. However, most patients will not have all of the aforementioned signs and symptoms. In fact, only about one-third of patients will present with the typical carcinoid syndrome (12). Moreover, because many patients experience few or vague symptoms early on, the actual diagnosis of the tumor is often delayed. Patients with the full syndrome usually have multiple liver metastases (Fig 2). The theory behind this concept is that not only do the metastases produce the causative peptides and hormones, but the space they occupy in the liver results in fewer normal liver cells, which normally inactivate the offending peptides, amines, and hormones released into the portal circulation (12).
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Figure 2. Malignant carcinoid tumor in a 63-year-old woman. Anterior whole-body In-111 pentetreotide image shows a carcinoid tumor of the ileum (arrow) with metastases to a left supraclavicular lymph node (arrowhead), the lungs, and the liver. The patient responded only minimally to octreotide therapy and did not survive.
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Most lung carcinoid tumors are incidentally diagnosed at conventional radiography. The actual compound causing the bronchial constriction is unknown but is presumed to consist of tachykinins and bradykinins (12). Laboratory testing in carcinoid tumors includes serum measurements of a glycoprotein produced by the tumor cells known as chromogranin-A, the most common tumor marker. Serotonin, the major metabolic product of most carcinoid tumors, is degraded to 5–hydroxyindoleacetic acid (HIAA), which is excreted in the urine, and urinary measurements of 5-HIAA are used in the diagnosis of carcinoid tumors (13).
Diagnostic imaging methods used to localize the primary tumors and their metastases include endoscopy, barium enema examination, CT, magnetic resonance (MR) imaging, and angiography. Because the primary tumor is usually small and difficult to localize with traditional anatomic imaging (eg, CT, MR imaging, barium studies), somatostatin receptor scintigraphy has increasingly played a key role in this clinical setting. Between 80% and 100% of carcinoid tumors contain somatostatin receptors (14), of which (as mentioned earlier) there are five receptor subtypes. In-111 pentetreotide binds to two of these subtypes, with an overall imaging sensitivity of 80%–90% in patients with carcinoid tumors (12). Consequently, In-111 pentetreotide imaging is considerably more sensitive than conventional anatomic imaging in diagnosing carcinoid tumors. Because of its high sensitivity and whole-body imaging capability, In-111 pentetreotide imaging should be the initial procedure of choice for the localization and staging of carcinoid tumor.
MIBG scintigraphy can also be used for carcinoid tumors. Like many other neuroendocrine tumors, carcinoid tumors are capable of incorporating and storing guanethidine, by means of the type I uptake mechanism. Therefore, catecholamine-synthesizing enzymes are present in many carcinoid tumors, allowing the cells to accumulate norepinephrine and to synthesize and secrete catecholamines. Consequently, carcinoid tumor patients theoretically have increased urinary catecholamines (15) and MIBG accumulation in tumors and metastases (16). However, the sensitivity of I-123 or I-131 MIBG scintigraphy in carcinoid tumors ranges from 55% to 70%, compared with the 80%–90% sensitivity of In-111 pentetreotide imaging (17), so that the latter procedure is preferred.
Gastrinoma
Initially described by Zollinger and Ellison 5 decades ago (18), gastrinoma is a pancreatic islet cell tumor that produces excessive amounts of gastrin, which in turn results in an overproduction of gastric acid. This overproduction invariably leads to peptic ulcer disease with its associated signs and symptoms and is referred to as Zollinger-Ellison syndrome. Most gastrinomas arise from the pancreas (Fig 3), with the remainder arising from the duodenum. Approximately 25% of gastrinomas are associated with type 1 MEN syndrome. Approximately 50%–60% of gastrinomas are malignant (ie, have metastases at the time of diagnosis). However, patients with Zollinger-Ellison syndrome generally enjoy prolonged survival, despite the fact that there is usually a delay in diagnosis because the tumors are often slow growing (12). The signs and symptoms of gastrinoma are identical to those of peptic ulcer disease and its sequelae and include abdominal pain, gastrointestinal bleeding, gastric perforation, and so on (19). Diarrhea is not uncommon and is caused by fat malabsorption secondary to the breakdown of pancreatic lipase from excessive gastric acid. The diagnosis of gastrinoma is established on the basis of elevated fasting serum gastrin levels. Localization of small tumors with CT and MR imaging can be challenging. However, In-111 pentetreotide imaging has a sensitivity of 75%–93% (20,21) and is the nuclear imaging procedure of choice.
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Figure 3. Gastrinoma in a 68-year-old woman with Zollinger-Ellison syndrome. The patient had a serum gastrin level of 158 pg/mL (normal, 8–47 pg/mL). Anterior In-111 pentetreotide image shows focal radio-tracer uptake within the pancreatic head (arrow), a finding that represents the primary tumor. Note the presence of multiple liver metastases.
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Glucagonoma
Glucagon, a peptide hormone produced by the alpha cells of the pancreatic islets, counteracts the effects of insulin on glucose metabolism, resulting in glucose intolerance. Tumors that overproduce glucagon arise almost exclusively in the pancreas, usually in the body or tail (Fig 4). Metastases to liver or lymph nodes are present at the time of presentation in over 50% of cases. The clinical syndrome resulting from glucagonoma is referred to as the "four Ds, " namely, diabetes, dermatitis, deep venous thrombosis, and depression. Nearly all patients have a skin rash at presentation that is characterized by erythema, typically begins at the groin and lower extremities, is highly pruritic, and migrates. This rash is known as necrolytic migratory erythema (22). Its exact cause is unknown, although it usually resolves when the serum glucagon level returns to normal once the patient is treated. Because necrolytic migratory erythema is a true deficiency dermatitis, the presumption is that the elevated glucagon levels result in multiple nutrient and vitamin B deficiencies (23). The cause of the deep venous thrombosis is also unknown. The diagnosis of glucagonoma is established on the basis of the presence of a pancreatic mass and elevated glucagon levels. Like most neuroendocrine enteropancreatic tumors, glucagonomas express the subtype 2 somatostatin receptor and theoretically could be imaged with somatostatin receptor scintigraphy. However, because of the low prevalence of glucagonomas, to our knowledge there have been no studies of a sufficient number of glucagonoma patients evaluated with In-111 pentetreotide imaging to establish the sensitivity or specificity of this modality. Instead, only isolated reports are available. In-111 pentetreotide imaging was significantly positive in both patients in a study by Gregianin et al (24). In a series of patients with enteropancreatic tumors in Rotterdam described by Krenning et al (20), all five patients with glucogonoma had positive scans.
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Figure 4a. Glucagonoma in a 69-year-old man in whom the tumor had been diagnosed previously at another institution. The patient presented with type II diabetes and an erythematous rash and was referred for In-111 pentetreotide imaging as part of a work-up for metastases prior to surgical resection. Results of In-111 pentetreotide imaging were negative. (a, b) Transverse abdominal CT (a) and FDG PET (b) scans reveal intense metabolic activity with a pancreatic tail mass (arrow). (c) PET-CT fusion image. No metastases were seen at whole-body FDG PET.
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Figure 4b. Glucagonoma in a 69-year-old man in whom the tumor had been diagnosed previously at another institution. The patient presented with type II diabetes and an erythematous rash and was referred for In-111 pentetreotide imaging as part of a work-up for metastases prior to surgical resection. Results of In-111 pentetreotide imaging were negative. (a, b) Transverse abdominal CT (a) and FDG PET (b) scans reveal intense metabolic activity with a pancreatic tail mass (arrow). (c) PET-CT fusion image. No metastases were seen at whole-body FDG PET.
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Figure 4c. Glucagonoma in a 69-year-old man in whom the tumor had been diagnosed previously at another institution. The patient presented with type II diabetes and an erythematous rash and was referred for In-111 pentetreotide imaging as part of a work-up for metastases prior to surgical resection. Results of In-111 pentetreotide imaging were negative. (a, b) Transverse abdominal CT (a) and FDG PET (b) scans reveal intense metabolic activity with a pancreatic tail mass (arrow). (c) PET-CT fusion image. No metastases were seen at whole-body FDG PET.
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VIPoma
VIP is a neuropeptide in the central and peripheral nervous system. In the latter, VIP is stored in neurons located near the blood vessels within the splanchnic viscera involving the small and large intestine and the exocrine pancreas. The primary action of VIP is vasodilation, and its overproduction results in severe, watery diarrhea, even during fasting. This condition in turn leads to hypokalemia. The clinical syndrome is referred to as WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria) or Verner-Morrison syndrome (25). The achlorhydria arises from the direct inhibition of gastric acid secretion by VIP. Flushing occurs in some patients from peripheral vasodilatation, mimicking carcinoid syndrome (26). However, the neoplasm that overproduces VIP, known as vasoactive peptideoma or VIPoma, is easily distinguished from carcinoid tumor on the basis of the elevated serum levels of VIP. About 90% of these neoplasms arise from the pancreas, and 60% of all VIPomas will have metastasized at the time of diagnosis (Fig 5) (27). VIPoma is diagnosed on the basis of elevated serum VIP levels, watery diarrhea, and a pancreatic islet cell tumor. In-111 pentetreotide imaging of VIPomas has a sensitivity of 88% and is considered the nuclear imaging procedure of choice in this setting.
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Figure 5. VIPoma in a 43-year-old man with intractable watery diarrhea. Anterior whole-body In-111 pentetreotide image demonstrates liver metastases (white arrowhead indicates the largest metastatic lesion), focal uptake in the left lower quadrant (arrow), and numerous abdominal lymph node metastases (black arrowheads). Results of exploratory laparotomy confirmed the liver metastases and mesenteric adenopathy, the frozen sections of which revealed metastatic neuroendocrine carcinoma. There was also a 3-cm palpable mass in the uncinate process of the pancreas corresponding to the In-111 pentetreotide–avid focus in the left lower quadrant. Immunohistochemical staining of the biopsy specimen was positive for VIP.
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Poorly Differentiated Neuroendocrine Tumors
The World Health Organization defines poorly differentiated neuroendocrine tumors (sometimes referred to as nonfunctional neuroendocrine tumors) as neuroendocrine tumors that have small, poorly granular cells and demonstrate a high proliferation rate and vascular invasion. These tumors can arise anywhere along the gastrointestinal tract, usually from the pancreas. Unlike well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine tumors do not give rise to a clinical syndrome; instead, they usually develop from a mass effect within the abdomen, similar to ductal adenocarcinoma of the pancreas (28). Poorly differentiated neuroendocrine tumors are aggressive tumors with high proliferative and metabolic activity and low cellular differentiation. They metastasize early and are rarely resectable for cure. Poorly differentiated neuroendocrine tumors are diagnosed at histologic analysis performed with immunohistochemical staining, with positive reactivity for chromogranin-A and neuron-specific enolase—findings that are characteristic of neuroendocrine tumors—but with negative reactivity for insulin, glucagon, and somatostatin (29). These tumors are highly malignant with a poor prognosis.
Another feature of poorly differentiated neuroendocrine tumors is the absence or loss of somatostatin receptor activity, so that these tumors cannot be reliably imaged with In-111 pentetreotide. However, their poor differentiation and high proliferative rate are associated with increased glucose utilization, which makes FDG PET a highly accurate imaging method not only for localization of metastases, but also for the assessment of prognosis (the greater the degree of uptake, the worse the prognosis) (8,30). Therefore, FDG PET is the preferred procedure in the work-up and management of poorly differentiated neuroendocrine tumors (Fig 6).
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Figure 6a. Poorly differentiated neuroendocrine tumor in a 73-year-old man with weight loss, abdominal pain, a pancreatic mass, and bone metastases. The presumptive diagnosis was pancreatic adenocarcinoma. Biopsy revealed a poorly differentiated tumor of neural crest origin. Immuno-histochemical staining was negative for somatostatin but positive for neuron-specific enolase, findings that are characteristic of poorly differentiated neuroendocrine tumor. Anterior (a) and sagittal (b) FDG PET scans demonstrate the primary tumor (arrow in a) and abdominal lymphadenopathy (black arrowheads in a). Pulmonary metastases as well as skeletal metastases (white arrowheads in a) are evident.
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Figure 6b. Poorly differentiated neuroendocrine tumor in a 73-year-old man with weight loss, abdominal pain, a pancreatic mass, and bone metastases. The presumptive diagnosis was pancreatic adenocarcinoma. Biopsy revealed a poorly differentiated tumor of neural crest origin. Immuno-histochemical staining was negative for somatostatin but positive for neuron-specific enolase, findings that are characteristic of poorly differentiated neuroendocrine tumor. Anterior (a) and sagittal (b) FDG PET scans demonstrate the primary tumor (arrow in a) and abdominal lymphadenopathy (black arrowheads in a). Pulmonary metastases as well as skeletal metastases (white arrowheads in a) are evident.
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Sympathoadrenal Tumors
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Pheochromocytoma
PHEOs derive from the primary chromaffin cells of the adrenal medulla known as pheochromocytes. These tumors secrete excess catecholamines into the circulation, resulting in adverse physiologic effects such as hypertension, cardiac arrhythmias, myocardial infarction, and so on. Approximately 10% of PHEOs are bilateral and about 10% are malignant. Therefore, diagnosis and localization of PHEOs are crucial. The laboratory diagnosis of PHEO is established by measuring plasma levels of catecholamines and their metabolites and by obtaining a 24-hour collection of total urinary levels of catecholamines and their metabolites (31). The primary catecholamine metabolite is metanephrine, and this is the reason that plasma-free metanephrines are considered the diagnostic test of choice. Another metabolite measured in the urine is vanillymandelic acid (VMA). The 24-hour urine sampling is sometimes more sensitive than serum sampling, since the secretion of catecholamines by PHEO is intermittent rather than constant. In addition, the fact that catecholamines have a relatively short plasma half-life could result in a falsely low serum level, depending on when the sample was drawn (32).
For PHEO localization, both anatomic and functional imaging are useful in detecting the primary tumor, recurrence, and metastatic disease. CT and MR imaging are highly sensitive but not very specific for PHEO localization. The sensitivity of CT for adrenal PHEO varies between 85% and 94%, whereas that for extraadrenal, metastatic, or recurrent PHEO is about 90% before surgery (33). After surgery, however, its sensitivity decreases due to postoperative changes. If CT performed in a patient with clinical and laboratory evidence of PHEO is negative or equivocal, MR imaging is performed, with a sensitivity of 90%–100% (33). However, the specificity of MR imaging is limited due to the fact that PHEO appears similar to other adrenal lesions, with 65% of PHEOs being correctly diagnosed but 35% being misinterpreted as representing malignancy or benign adenomas (34).
Functional (nuclear) imaging helps confirm that a lesion detected at CT or MR imaging is a PHEO. The vast majority of adrenal lesions are benign, with only about 6.5% being PHEOs (35). In effect, owing to its higher specificity, functional imaging is complementary to anatomic imaging. In addition, with its whole-body imaging capability, nuclear imaging can help localize multifocal and metastatic disease.
The sensitivity of I-123 MIBG scintigraphy (83%–100%) is higher than that of I-131 MIBG scintigraphy (approximately 77%–90%) due to the superior imaging characteristics of I-123. Another advantage of I-123 MIBG over I-131 MIBG is that SPECT is possible with I-123 MIBG. However, the specificities of I-123 MIBG scintigraphy and I-131 MIBG scintigraphy are identical (95%–100%) (5). In general, a positive I-123 MIBG scan reliably confirms the presence of a PHEO, and a negative scan reliably excludes PHEO. MIBG uptake in PHEO is compromised by the presence of drugs or compounds that inhibit its transport into adrenergic tissues. These substances include certain antihypertensives such as calcium-channel blockers, labetalol and reserpine, tricyclic antidepressants, antipsychotic drugs, and sympathomimetics such as amphetamines and certain nasal decongestants. To avoid a potential false-negative MIBG scan, these drugs should be discontinued 3 days prior to MIBG injection (33).
For benign adrenal PHEO, In-111 pentetreotide imaging is less sensitive than MIBG scintigraphy due to the prominent physiologic renal uptake of In-111 pentetreotide, resulting in a high false-negative rate of 66%–75% despite a positive MIBG scan (5). However, the sensitivity of In-111 pentetreotide imaging increases to 87% for malignant and metastatic PHEO, since tumor dedifferentiation could decrease cell membrane norepinephrine transporter expression without affecting somatostatin receptor expression. Consequently, In-111 pentetreotide imaging becomes more sensitive than MIBG scintigraphy in this setting (5). Similarly, FDG accumulates in malignant PHEO to a greater extent than in benign PHEO (sensitivity, 88% vs 58%), since the benign tumors require less glucose consumption (36). The PHEO shown in Figure 7 concentrated both MIBG and FDG. Although pathologic analysis indicated a benign tumor, close follow-up was deemed appropriate in this case, particularly since PHEO tumors larger than 5 cm have a higher potential for malignancy (33).
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Figure 7a. Malignant PHEO in a 78-year-old man with recent onset of labile hypertension and arrhythmias. The patient underwent a work-up for PHEO, which revealed a plasma norepinephrine level of over 2000 pg/mL, along with urine levels of norepinephrine, dopamine, and metanephrine of 591, 1132, and 9375 µg/L, respectively (all of these levels are elevated). (a) Abdominal MR image shows a 7.5 x 6.9-cm left adrenal mass (arrow). (b) On an anterior abdominal I-123 MIBG scan (spot view), the mass avidly concentrates radiotracer. PET was performed as a second whole-body survey for metastases. (c) Anterior FDG PET scan shows strongly positive uptake. FDG accumulates in malignant PHEO (sensitivity of 88%) to a greater extent than in benign PHEO (58%).
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Figure 7b. Malignant PHEO in a 78-year-old man with recent onset of labile hypertension and arrhythmias. The patient underwent a work-up for PHEO, which revealed a plasma norepinephrine level of over 2000 pg/mL, along with urine levels of norepinephrine, dopamine, and metanephrine of 591, 1132, and 9375 µg/L, respectively (all of these levels are elevated). (a) Abdominal MR image shows a 7.5 x 6.9-cm left adrenal mass (arrow). (b) On an anterior abdominal I-123 MIBG scan (spot view), the mass avidly concentrates radiotracer. PET was performed as a second whole-body survey for metastases. (c) Anterior FDG PET scan shows strongly positive uptake. FDG accumulates in malignant PHEO (sensitivity of 88%) to a greater extent than in benign PHEO (58%).
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Figure 7c. Malignant PHEO in a 78-year-old man with recent onset of labile hypertension and arrhythmias. The patient underwent a work-up for PHEO, which revealed a plasma norepinephrine level of over 2000 pg/mL, along with urine levels of norepinephrine, dopamine, and metanephrine of 591, 1132, and 9375 µg/L, respectively (all of these levels are elevated). (a) Abdominal MR image shows a 7.5 x 6.9-cm left adrenal mass (arrow). (b) On an anterior abdominal I-123 MIBG scan (spot view), the mass avidly concentrates radiotracer. PET was performed as a second whole-body survey for metastases. (c) Anterior FDG PET scan shows strongly positive uptake. FDG accumulates in malignant PHEO (sensitivity of 88%) to a greater extent than in benign PHEO (58%).
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With a sensitivity of 83%–100% for benign PHEO, I-123 MIBG scintigraphy is the imaging procedure of choice. For malignant PHEO, the sensitivities of In-111 pentetreotide imaging and FDG imaging are similar (87% and 88%, respectively) and both are superior to I-123 MIBG scintigraphy. Because In-111 pentetreotide imaging is less expensive than FDG PET, it should be the initial imaging procedure in cases of suspected malignant PHEO.
Paraganglioma
Paragangliomas are extraadrenal PHEOs arising from paraganglion cells, which are derived from neural crest cells that migrate in utero in close association with the autonomic nervous system from the neck to the pelvis. Paraganglion cells contain chromaffin and are capable of producing catacholamines. The clinical manifestation of paragangliomas is the same as that of intraadrenal tumors, although the former neoplasms are believed to have a higher malignant potential. Paragangliomas are multiple in 3%–5% of patients, and 38% of patients have a positive family history of the tumor (37). Hereditary paragangliomas of the neck are termed glomus tumors (Fig 8). In-111 pentetreotide is considered the radionuclide of choice for imaging paraganglioma, with an imaging sensitivity of 94% (38). MIBG scintigraphy is less sensitive and specific, since MIBG concentrates only in functioning paragangliomas.
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Figure 8a. Carotid body paraganglioma (glomus tumor) in a 50-year-old man with a palpable neck mass, progressive dyspnea, and intermittent episodes of supraventricular tachycardia. Abdominal CT revealed only a 2-cm left adrenal nodule, which was thought to be an incidental finding. (a) Anterior whole-body In-111 pentetreotide image shows the neck mass (arrow) and anterior mediastinal uptake (arrowhead). (b, c) Anterior I-131 MIBG scans of the head (b) and chest (c) show the neck mass (white arrow in b), mediastinal uptake (black arrow in b and c), and a faint focus inferior to the mass (arrowhead). No abnormal uptake was seen in the abdomen and pelvis, including the suprarenal area. At surgery, the neck mass proved to be a paraganglioma at the carotid bifurcation, with a small satellite lesion adjacent to the trachea corresponding to the faint focus. Mediastinal uptake on all three images represented normal thymic tissue.
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Figure 8b. Carotid body paraganglioma (glomus tumor) in a 50-year-old man with a palpable neck mass, progressive dyspnea, and intermittent episodes of supraventricular tachycardia. Abdominal CT revealed only a 2-cm left adrenal nodule, which was thought to be an incidental finding. (a) Anterior whole-body In-111 pentetreotide image shows the neck mass (arrow) and anterior mediastinal uptake (arrowhead). (b, c) Anterior I-131 MIBG scans of the head (b) and chest (c) show the neck mass (white arrow in b), mediastinal uptake (black arrow in b and c), and a faint focus inferior to the mass (arrowhead). No abnormal uptake was seen in the abdomen and pelvis, including the suprarenal area. At surgery, the neck mass proved to be a paraganglioma at the carotid bifurcation, with a small satellite lesion adjacent to the trachea corresponding to the faint focus. Mediastinal uptake on all three images represented normal thymic tissue.
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Figure 8c. Carotid body paraganglioma (glomus tumor) in a 50-year-old man with a palpable neck mass, progressive dyspnea, and intermittent episodes of supraventricular tachycardia. Abdominal CT revealed only a 2-cm left adrenal nodule, which was thought to be an incidental finding. (a) Anterior whole-body In-111 pentetreotide image shows the neck mass (arrow) and anterior mediastinal uptake (arrowhead). (b, c) Anterior I-131 MIBG scans of the head (b) and chest (c) show the neck mass (white arrow in b), mediastinal uptake (black arrow in b and c), and a faint focus inferior to the mass (arrowhead). No abnormal uptake was seen in the abdomen and pelvis, including the suprarenal area. At surgery, the neck mass proved to be a paraganglioma at the carotid bifurcation, with a small satellite lesion adjacent to the trachea corresponding to the faint focus. Mediastinal uptake on all three images represented normal thymic tissue.
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MEN Syndromes
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Type 1 MEN
MEN is a genetic disorder characterized by two or more endocrine tumors resulting in malignancy or increased glandular function. There are two major forms of MEN: type 1 MEN and type 2 MEN. Type 1 MEN is autosomal dominant, with the defect on chromosome 11 (38), and is most often associated with parathyroid, pancreatic, and pituitary tumors. In about 95% of patients, primary hyperparathyroidism is the presenting disorder (39). Usually, all four parathyroid glands are affected, with the disease manifesting primarily as hyperplasia; parathyroid adenoma is also encountered. Figure 9 illustrates a case of diffuse four-gland parathyroid hyperplasia, although only two of the glands concentrated sestamibi at parathyroid scintigraphy.
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Figure 9a. Type 1 MEN syndrome in a 41-year-old woman who presented with abdominal pain, diarrhea, and hypercalcemia. A diagnosis of MEN had been made 10 years earlier, and the patient had undergone partial pituitary resection and partial pancreatectomy. CT revealed gastric and duodenal masses. (a) Whole-body In-111 pentetreotide image demonstrates uptake in the stomach and small bowel with no metastases. Endoscopic biopsy revealed type II carcinoid tumors in the stomach and duodenum, findings that are often associated with type 1 MEN. Work-up for hypercalcemia demonstrated a parathyroid hormone level of 141 pg/mL. (b) Technetium-99m sestamibi parathyroid scan obtained 3 hours after radiotracer injection reveals bilateral focal radiotracer retention (arrows), a finding that suggests the presence of parathyroid lesions. The lesions were surgically removed, and final pathologic analysis revealed hypercellularity of the right inferior and left superior glands, a finding that indicated parathyroid gland hyperplasia.
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Figure 9b. Type 1 MEN syndrome in a 41-year-old woman who presented with abdominal pain, diarrhea, and hypercalcemia. A diagnosis of MEN had been made 10 years earlier, and the patient had undergone partial pituitary resection and partial pancreatectomy. CT revealed gastric and duodenal masses. (a) Whole-body In-111 pentetreotide image demonstrates uptake in the stomach and small bowel with no metastases. Endoscopic biopsy revealed type II carcinoid tumors in the stomach and duodenum, findings that are often associated with type 1 MEN. Work-up for hypercalcemia demonstrated a parathyroid hormone level of 141 pg/mL. (b) Technetium-99m sestamibi parathyroid scan obtained 3 hours after radiotracer injection reveals bilateral focal radiotracer retention (arrows), a finding that suggests the presence of parathyroid lesions. The lesions were surgically removed, and final pathologic analysis revealed hypercellularity of the right inferior and left superior glands, a finding that indicated parathyroid gland hyperplasia.
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The pancreatic tumors in type 1 MEN are hyperfunctioning, usually nonmalignant tumors. About 60% of these tumors are gastrinomas, and patients sometimes present with Zollinger-Ellison syndrome. Another 30% of patients have insulinomas (40). Carcinoid tumors are found in only 2%–5% of patients with type 1 MEN, and up to 4% of patients with carcinoid tumor also have type 1 MEN (41). Occasionally in type 1 MEN, a gastrinoma and gastric carcinoid tumor will coexist.
Type 2 MEN
An autosomal dominant syndrome located on chromosome 10, type 2 MEN is further subclassified into type 2A MEN and type 2B MEN. Type 2A MEN consists of MTC, hyperparathyroidism, and PHEO (Fig 10). Type 2B MEN includes MTC and PHEO, but unlike type 2A MEN is characterized by mucosal neuromas instead of parathyroid disease.
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Figure 10a. Documented type 2A MEN in a 46-year-old woman who had previously undergone thyroidectomy for medullary carcinoma and bilateral adrenalectomy for bilateral PHEO. Because of tremors, anxiety, and blood pressure lability, a work-up for PHEO was undertaken and revealed elevated plasma catecholamine levels (eg, the plasma norepinephrine level was 1584 pg/mL). PET scan (a) and PET-CT fusion image (b) show a left adrenal mass (arrow) that is MIBG negative but markedly FDG positive. Histopathologic analysis revealed a 4-cm recurrent PHEO. The tumor was removed, after which the patient’s symptoms improved and the plasma catecholamine levels returned to normal.
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Figure 10b. Documented type 2A MEN in a 46-year-old woman who had previously undergone thyroidectomy for medullary carcinoma and bilateral adrenalectomy for bilateral PHEO. Because of tremors, anxiety, and blood pressure lability, a work-up for PHEO was undertaken and revealed elevated plasma catecholamine levels (eg, the plasma norepinephrine level was 1584 pg/mL). PET scan (a) and PET-CT fusion image (b) show a left adrenal mass (arrow) that is MIBG negative but markedly FDG positive. Histopathologic analysis revealed a 4-cm recurrent PHEO. The tumor was removed, after which the patient’s symptoms improved and the plasma catecholamine levels returned to normal.
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Medullary Thyroid Carcinoma
MTC is a neoplasm of the parafollicular C cells of the thyroid gland. The C cells are derived from the neural crest and secrete calcitonin and other polypeptides, including VIP, carcinoembryonic antigen, and somatostatin. Eighty percent of MTC cases are sporadic, and the remaining (familial) cases are a part of type 2 MEN (42). Metastatic cervical and mediastinal adenopathy is seen at the time of presentation in about 50% of cases, and distant metastases to lung, liver, and bone occur in 15%–25% (Fig 11) (43). Calcitonin is the primary tumor marker used for follow-up, followed by carcinoembryonic antigen. At the time of diagnosis, anatomic imaging with ultrasonography, CT, or MR imaging as well as functional imaging with In-111 pentetreotide are often used for metastatic work-up, although none of these modalities is particularly sensitive. However, because MTC is a relatively aggressive tumor whose cells are actively metabolizing, FDG PET is a reliable tool, especially with rising calcitonin levels (44). In a recent prospective study of 26 patients by de Groot et al (45), FDG PET demonstrated a sensitivity of 96%, whereas the sensitivity of In-111 pentetreotide imaging was only 41%. Presumably, the low sensitivity of the latter is a reflection of the loss of somatostatin receptor expression as the tumor proliferates and aggressively metastasizes. Nonetheless, In-111 pentetreotide imaging should be the initial scintigraphic procedure for staging of MTC. If In-111 pentetreotide imaging is either negative or inconsistent with anatomic imaging findings, FDG PET should be performed.
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Figure 11. MTC in a 58-year-old man who presented with lung metastases and rising calcitonin levels. The diagnosis of MTC had been made 2 years earlier, and the patient had undergone a total thyroidectomy followed by chemotherapy. Whole-body In-111 pentetreotide image demonstrates a right supraclavicular lymph node (white arrow), a metastasis to the right femur (black arrow), and lung metastases (arrowhead). The image was intentionally darkened for better visualization of the supraclavicular node and lung metastases.
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Summary
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Neuroendocrine tumor may pose a diagnostic challenge to the clinician. Symptoms may vary and sometimes overlap among tumor subtypes, the diagnosis is often unavoidably delayed until these slow-growing tumors are detected, and both the primary tumor and its metastases are difficult to localize with diagnostic imaging. At this time, no single imaging modality is considered the procedure of choice for neuroendocrine tumor evaluation. Although functional imaging with radionuclides does not provide the fine structural detail that anatomic imaging provides, it does have potential advantages. First, as a physiologic reflection of tumor activity, radionuclide imaging provides detail regarding tumor viability, recurrence, response to therapy, and, in certain instances, prognosis, thereby supplementing the information already provided by anatomic imaging. Second, owing to its whole-body imaging capability, scintigraphy is an excellent tool in the surveillance of metastatic activity. Moreover, it is sometimes difficult or impossible to distinguish benign from malignant neuroendocrine tumor microscopically. In general, however, a neuroendocrine tumor is considered to be malignant if metastases are present. Consequently, scintigraphy, as a detector of metastatic disease, often helps assess for neuroendocrine tumor malignancy.
Pitfalls in scan interpretation must be avoided. False-negative In-111 pentetreotide imaging results can be seen in patients currently undergoing octreotide therapy and also in small PHEOs, in which tumor activity is obscured by physiologic radiotracer uptake in the kidney. In addition, the biliary excretion of In-111 pentetreotide into bowel could obscure lesion detection, a pitfall that can be circumvented with early SPECT. A potential false-positive scan may also result from biliary excretion; the gallbladder can usually be visualized on 24-hour images, sometimes mimicking a liver metastatic lesion. False-negative MIBG scintigraphy occurs when patients are taking certain medications. Finally, both In-111 pentetreotide and MIBG could lose their ability to concentrate in a neuroendocrine tumor that begins to dedifferentiate and no longer maintains certain physiologic properties, such as somatostatin receptor expression or the capacity to produce catecholamines. Under these circumstances, however, a dedifferentiating and aggressive tumor will increase its metabolic rate and glucose consumption, thereby facilitating detection with FDG PET. There are other neuroendocrine tumors that are either very rare or not easily imaged with any radioisotope. For example, insulinoma is a neuroendocrine tumor that arises from the islet cells in the pancreas and overproduces insulin. The sensitivity of In-111 pentetreotide imaging in detecting this tumor is no more than 50%–60% (46). Of the few patients with suspected insulinoma who were referred to our laboratory for In-111 pentetreotide imaging over the past decade, none had an abnormal scan.
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Footnotes
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Abbreviations: APUD = amine precursor uptake and decarboxylose, FDG = 2-[fluorine-18]fluoro-2-deoxy-D-glucose, HIAA = hydroxyindoleacetic acid, MEN = multiple endocrine neoplasia, MIBG = metaiodobenzylguanidine, MTC = medullary thyroid carcinoma, PHEO = pheochromocytoma, VIP = vasoactive intestinal peptide
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References
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- Pearse AG. The APUD concept and hormone production. Clin Endocrinol Metab 1980;9:211–222.[Medline]
- Kvols LK. Somatostatin-receptor imaging of human malignancies: a new era in the localization, staging, and treatment of tumors. Gastroenterology 1993;105:1909–1911.[Medline]
- de Herder WW, Hofland LJ, van der Lely AJ, Lamberts SW. Somatostatin receptor in gastroentero-pancreatic neuroendocrine tumours. Endocr Relat Cancer 2003;10:451–458.[Abstract]
- Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB. Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours. Eur J Endocrinol 2004;151:15–27.[Abstract]
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