Nuclear endocrinology as a monitoring tool

Nuclear Endocrinology as a Monitoring Tool Yodphat Krausz Malignant endocrine disorders have been an enigma over the last few decades, from genetic, clinical, and imaging perspectives. The detection of the primary tumor and the identification of recurrent disease have been essentially based on various anatomic techniques, w i t h localization procedures extensively developed for staging, follow-up, radio-guided surgery, and therapy. Frequently, the lesions are too small to cause anatomic alterations, or they are obscured by the changes in anatomic planes that occur after initial surgery, Small lesions, however, are the ones that can potentially be cured. Thus, every attempt should be made to localize these sites before further growth and dissemination occur beyond the scope of cure. Since the advent of iodine-131 for staging and follow-up of patients w i t h differentiated thyroid carcinoma, the search has led to the use of radioiodinated metaiodo-

benzylguanidine (MIBG) for recurrent pheochromocytoma and neuroblastoma, to the development of antibodies to carcinoembryonic antigen for the staging and treatment of medullary thyroid carcinoma, and to the characterization of peptide receptors on neuroendocrine tumors. Additionally, there has been a breakthrough w i t h the use of positron emitters in nuclear oncology, including F-18-fluorodeoxyglucose, for 1-131-negative metastases of differentiated thyroid carcinoma, recurrent medullary thyroid carcinoma, malignant pheochromocytoma, and adrenocortical carcinoma. Undoubtedly, optimal care of the patient requires both the expertise of the treating endocrinologist and the use of various imaging techniques in the diagnosis, staging, and follow-up of these diseases. Copyright 9 2001 b y W.B. Saunders Company

HIS ARTICLE deals with the management of patients with endocrine tumors after initial surgery, including thyroid carcinoma, malignant tumors of the adrenal gland, and endocrine tumors of the gastrointestinal tract.

Serum Tg, produced only by thyroid follicular cells, serves as a sensitive tumor marker and as a prognostic indicator. ~ It occasionally discloses the presence of metastatic disease even before the WBS. Rising levels of serum Tg under adequate thyroxine suppression indicate the recurrence of DTC, whereas serially undetectable levels significantly reduce the need for a follow-up radioiodine diagnostic WBS. 2'3 The sensitivity of Tg testing increases with a rise in thyroid stimulating hormone (TSH), but its use is limited when anti-Tg autoantibodies, which interfere with the Tg assay, are present. The use of iodine-131 in the monitoring of patients with differentiated thyroid cancer has been well established over the last 50 years, and it is the most important and highly specific imaging technique used to visualize the tumor tissue. The uptake of radioactive iodine permits the detection of metastatic disease after initial surgery and ablation of the thyroid remnant. It may indicate the extent and site of tumor suitable for additional surgery or for radioiodine therapy. Any recurrence should be considered for surgical excision if feasible, preferably after precise localization of the iodine-131-avid site by the use of gamma cameramounted x-ray tomography. 4 Alternatively, the WBS may disclose multiple foci or diffuse metastatic disease for radioiodine treatment. It can even show the metastases before visualization by conventional techniques, such as CT, at a stage in which patients may be more likely to respond to a high dose of radioiodine therapy (Fig 1).

T

THYROID CANCER

Differentiated Thyroid Cancer Most patients with well-differentiated thyroid cancer (DTC) have a normal life expectancy. Fifteen percent of patients, however, may develop recurrence, with up to 50% recurrence more than 5 years after initial surgery. Thus, there is a need for optimal long-term surveillance and therapy, applied particularly to patients with poor prognostic factors at diagnosis. These patients are closely monitored for local recurrence and distant metastases by periodic whole-body radioiodine scanning (WBS) and by serum thyroglobulin (Tg) determination. These tests can detect the recurrent disease at a stage when it is not visible on radiograph, computed tomography (CT), or ultrasound (US). The use of both techniques together is superior to using either one alone. From the Department of Medical Biophysics and Nuclear Medicine, Hadassah University Hospital, Jerusalem, Israel. Address reprint requests to Yodphat Krausz, MD, Department of Nuclear Medicine, Hadassah University Hospital, PO Box 12000, Jerusalem, 91120 Israel. Copyright 9 2001 by W.B. Saunders Company 0001-2998/01/3103-0007535. 00/0 doi: 10.1053/snuc.2001.23530

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Seminars in Nuclear Medicine, Vol XXXl, No 3 (July), 2001: pp 238-250

239

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Fig 1. Diffuse pulmonary metastases of papillary thyroid carcinoma. Whole-body 1-131 scan in a 41-year-old man 1 month after total thyroidectomy and modified right neck dissection (left). The scan shows radioiodine uptake in the thyroid remnant and diffuse metastatic process in the lungs (the latter not visualized on CT). After a cumulative dose of 600 mCi of 1o131, given in 3 doses (July 1996, May 1997, and February 1998), WBS became negative (right) and serum Tg decreased from 107 pg/L off-thyroxine to 8.4 IJg/L (4.4 and <0.5 pg/L on-thyroxine, respectively).

The frequency of follow-up WBS varies depending on the size and extent of the primary tumor and on serum Tg. They are usually performed during the first few years after initial surgery. At the time of radioiodine WBS, a high TSH level is required for stimulation of iodine uptake and also improves the sensitivity of Tg testing. An increase in TSH can be achieved either by thyroxine withdrawal for 4 weeks s or by administration of recombinant human TSH (rTSH).6 The periodic withdrawal of thyroid hormone may lead to a significant decrease in quality of life and an increased risk of tumor progression. Furthermore, some patients cannot surmount a sufficient endogenous TSH rise. These limitations, however, have been overcome by the recent introduction of rTSH into clinical practice, rTSH was found to stimulate the uptake of radioiodine by residual and cancerous tissue and to increase the sensitivity of Tg determination in patients maintained on thyroid hormone therapy. Furthermore, it spares the debilitating effects of prolonged hypothyroid state induced by thyroxine withdrawal. Three clinical

trials have compared rTSH-stimulated testing with conventional withdrawal of thyroid hormone suppressive therapy in a total of 385 patients with DTC. 6-8 In a preliminary phase I/II trial of 19 patients, 6 the quality of 1-131 scans and the number of abnormal foci were similar after rTSH and after thyroid hormone withdrawal in 12 patients (63%), with additional sites of uptake in 3 patients (16%) only after rTSH, and in 3 patients (16%) only after T3 withdrawal. In the first phase III trial of 127 patients, a WBS was performed after rTSH was given daily in a dose of 0.9 mg intramuscularly for 2 days, and it was compared with a withdrawal scan. Both scans were performed 48 hours after administration of 2 to 4 mCi (74 to 148 MBq) of I-131. The rTSH and withdrawal scans were concordant in 41 of 62 patients with positive scans, superior after rTSH in 3 patients (5%), and superior after withdrawal in 18 patients (29%). 7 The superior sensitivity of the withdrawal scan may have been due to the marked reduction of iodine clearance with increased bioavailability of 1-131, as compared with euthyroid patients receiving rTSH. In a second phase III trial of 229 patients, the scan classification criteria were rationalized to identify only clinically important differences in scan findings. There were no significant differences between the number of superior rTSH and withdrawal scans (8 [4%] versus 17 [8%], respectively; P = . 108) among the 220 patients with scans that could be evaluated. 8 These studies also showed that the sensitivity of rTSH-stimulated Tg determination for the detection of residual thyroid tissue or cancer is superior to that of Tg assay on continued thyroid hormone therapy (74% v 43%, respectively). 9 Furthermore, measurement of serum Tg together with WBS after rTSH greatly improved the detection of remnant tissue or cancer, with identification of 100% of metastatic disease and 93% of patients with uptake limited to the thyroid bed. 8 Currently, rTSH is suggested for patients who do not respond to hormone withdrawal or cannot tolerate hypothyroidism. For patients with a low risk of tumor recurrence, rTSH-stimulated testing may be used for the first cycle of scanning and Tg measurement 6 to 12 months after postoperative 1-131 ablation. In high-risk patients, one set of negative I-131 scan and Tg test results after hormone withdrawal are recommended before using rTSH testing, because of a greater sensitivity of the

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withdrawal scan and because rTSH is not currently approved for subsequent I-131 therapy often indicated in these patients. 9 Despite the excellent diagnostic capabilities of the WBS, only 70% to 80% of residual or metastatic disease would concentrate 1-131. A falsenegative scan may be caused by iodine contamination, inadequate TSH stimulation, or the inability to concentrate iodine after the loss of sodium-iodide human symport expression.I~ Falsepositive scans can be accounted for by artifacts, anatomic variants, and nonthyroidal diseasesJ 1 If a diagnostic WBS is negative and if Tg is not related to the presence of thyroid remnant tissue, a complete work over is indicated, including US of the neck, CT of the chest, magnetic resonance imaging (MRI) of the brain, and isotopic bone scan. Alternatively, radionuclide imaging procedures using T1-201, Tc-99m MIBI, somatostatin receptor scintigraphy, and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) have been suggested. 12-15 The use of T1-201, whose uptake is based on tumor viability and malignancy grade, has decreased over the last decade, mainly with the introduction of Tc-99m-labeled analogues and FDG-PET. Tc-99m MIBI is taken up by cells rich in mitochondria and is thus more contributory to patients with Htirthle cell carcinoma. 16 Somatostatin receptor scintigraphy (SRS), with the use of labeled octreotide, may guide imaging modalities in patients with negative 1-131 WBS or in patients who cannot tolerate thyroxine withdrawal. 14 FDGPET also contributes to the detection of metastases of DTC. Using FDG-PET, Chung et al found a sensitivity of 93.9% compared with that of thyroglobulin (54.5%) in 33 patients with metastases, and a specificity of 95.2% and 76.1%, respectively, in 21 patients in remission. In their patients, FDG-PET was found to be superior to 1-131 WBS and serum Tg mainly for the detection of metastases to cervical lymph nodes, with impact on their surgical managementJ 5 Feine et al found the combined sensitivity of FDG and 1-131 in the range of 95%. The uptake of 1-131 and FDG alternated in the metastases in 90% of their patients: 1-131 trapping metastases with no FDG uptake and FDG trapping metastases with no I-131 uptake, with the latter representing poor functional differentiation. 17 Griinwald et al compared the FDG-PET with 1-131 and Tc-99m MIBI scintigra-

YODPHAT KRAUSZ

phy. They found discordant FDG results with I-131 WBS in most cases with recurrence and/or metastases, reflecting the different proliferative activity. Eleven tumor sites were FDG true-positive/ WB-negative, 8 were WB true-positive/FDGnegative, and 10 sites were found concordant in 7 patients. FDG correlated better with MIBI, with concordant positive results in 13 sites. In 5 cases, FDG was superior to MIBI, including 3 patients with distant metastases, whereas 2 tumors were FDG-negative/MIBI-positive (1 WBS-positive, 1 WBS-negative). As far as grading could be obtained, FDG-PET seemed more sensitive in highgrade tumors, whereas WBS was positive predominantly in low-grade carcinomas. 13 Some metastases that are too small to be visualized with diagnostic doses of radioiodine used for WBS can be seen with larger doses, diagnostic or therapeutic. The use of diagnostic doses as high as 10 mCi (370 MBq) has been discouraged because of the stunning effect induced by radiation damage even after 5 mCi, with resultant reduction of the actual dose delivered to the patient on subsequent radioiodine therapy. 18 Occasionally, some diagnostic scans do not show visible uptake, but larger therapeutic doses of radioiodine do concentrate in areas of known or suspected metastases with beneficial effect, even in the choroid. 19 In fact, radioiodine therapy has been suggested for patients with negative WBS and elevated serum Tg, if the metastatic lesions are nonresectable. 2~ An empiric therapeutic trial of 1-131 100 mCi (3,700 MBq) is performed and followed by a posttherapy scan. Treatment is then repeated until the posttherapy scan becomes negative, if originally positive. 1 After radioiodine ablation or treatment, WBS is crucial to confirm the uptake of 1-131 and to identify additional occult 1-131-avid sites of disease. The posttherapy scan may show new areas of radioiodine uptake not seen on the diagnostic scan, as documented in 10% 21 and in 15% of cases. 2 The amount of I-131 administered for ablation or therapy is based either on a fixed standard dose or on a maximum safe amount, with 30,000 rad (300 Gy) required for ablation and 8,500 rad (85 Gy) for treatment of residual or metastatic disease. 22 The maximum dose is restricted by bone marrow exposure to an upper limit of 200 rad (2 Gy) and/or by 80 mCi (2,960 MBq) of retained activity at 48 hours in patients with diffuse meta-

NUCLEAR ENDOCRINOLOGY

static lung disease. A significant uptake in metastases may not be observed, however, and external radiation therapy may be required. 2"3 If the projected dose to the tumor from an amount of 1-131 that would deliver 200 rad (2 Gy) to the whole blood is less than 4,000 rad (40 Gy), surgery or external-beam therapy is recommended. 23 In summary, radioiodine WBS and serum Tg determination are the essence of follow-up of patients with differentiated thyroid carcinoma, with amelioration of the thyroxine withdrawal symptoms by the use of rTSH. In case of a negative radioiodine WBS, alternative imaging techniques have been suggested, or a therapeutic trial with 1-131.

Medullary Thyroid Carcinoma Medullary thyroid carcinomas (MTC) account for 3% to 10% of all thyroid carcinomas. This neuroendocrine tumor is associated with early local spread to cervical and mediastinal lymph nodes, whereas distant metastases to the lungs, liver, and bone generally occur in an advanced stage of the disease. Surgery is the first line of treatment for cure or prolongation of survival, with meticulous total thyroidectomy and central neck dissection suggested. 24-26 When no distant metastases are present and localization 27 with microdissection 24 of tumor recurrence is feasible, surgery should be performed. MTC mostly expresses calcitonin and carcinoembryonic antigen (CEA), and the elevation of these tumor markers suggests the existence of residual or metastatic disease. Localization of pathologic foci is difficult, however, even with MRI that only facilitates planning of surgery for macroscopic metastases. 28 Occult MTC can be localized by selective venous catheterization in 89% of patients, by CT in 38%, and by US in 28%. At present, selective venous catheterization is the most reliable procedure for localization of MTC tissue. 29 Scintigraphic studies using T1-201,3~ Tc-99m dimercaptosuccinic acid (DMSA), 31 1-131-metaiodobenzylguanidine (MIBG), 32 Tc-99m MIBI single photon emission computed tomography (SPECT), 33 labeled anticalcitonin, 34 anti-CEA antibody, 35 and In-I 11diethylenetriaminepentaacetic acid (DTPA)octreotide 36 have been also suggested. These techniques, however, have limited sensitivity except for DMSA, 37"38 or inadequate specificity, although anti-CEA antibody labeled with I- 131 has been used

241

for radioimmunotherapy. In- 111-DTPA-octreotide is superior to MRI in localizing occult recurrence, a8 It enables tumor localization with lesion detection rates ranging from 29% to at least one lesion in 100% of patients with minimal residual disease. 27'37"39-42 This variable sensitivity of SRS in detecting MTC foci, compared with other neuroendocrine tumors, may be due to insufficient number and density of somatostatin receptors with high affinity for octreotide, 43 or to somatostatin production by the tumor. 44 Tumors initially visualized with the labeled octreotide may lose receptors during dedifferentiation, causing differential tracer uptake even in the same patient. 4~'45 The degree of tumor dedifferentiation was found to be inversely correlated with somatostatin receptor expression. In patients with occult disease, SRS was able to localize at least one lesion with higher tumor-tobackground ratio than that observed by anti-CEA immunoscintigraphy, whereas in patients with rapidly progressive disease or distant metastases, the labeled octreotide did not target any tumor, and immunoscintigraphy showed a high tumor-tobackground ratio. 46 Thus, scintigraphic visualization of MTC allows for lesion localization and for prediction of prognosis. Cervicomediastinal metastases of MTC can also be localized by FDG-PET imaging even when the lesions are not demonstrable on CT or MRI. The glucose uptake in these tumors, however, was not found to be related to the expression of glucose transporter proteins GLUT1 through GLUT5. 47 Based on the outstanding diagnostic accuracy of the pentagastrin test in detecting the persistence or recurrence of malignant C cells, Reubi and Waser used in vitro autoradiography to document the presence of cholecystokinin-B (CCK-B)/gastrin receptors in 92% of medullary thyroid cancers, with their absence in nonmedullary thyroid cancer and in normal thyroid tissue. 4s Behr et al showed the feasibility of radiolabeled gastrin derivatives to target CCK-B receptor-expressing MTC tumors in nude mice bearing subcutaneous xenografts of human MTC cell line, in a patient with metastatic MTC, 49 and in a patient with multiple endocrine neoplasia type liB and normal In-I 11 octreotide distribution. 42 In summary, multiple scintigraphic techniques have been developed for the early detection of minimal residual and metastatic disease in patients with MTC, when curative surgery is still feasible.

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The recent identification of receptors to CCK-B/ gastrin tumor growth factors may have future diagnostic and therapeutic implications. ADRENAL TUMORS

Pheochromocytoma and Neuroblastoma Pheochromocytomas and neuroblastomas are the most common tumors that originate in the adrenergic nervous system. Pheochromocytomas arise from chromaffin cells that are found in the adrenal medulla, sympathetic ganglia, organ of Zuckerkandl, and the aortic and carotid chemoreceptors. These tumors follow the "rule of 10": 10% are malignant, 10% are bilateral, 10% occur in pediatric patients, and 10% are extra-adrenal. Extra-adrenal lesions occur in 10% of adults (malignant in 30% to 40% of patients) and in 30% of children (malignant only in 2%). Localization of pheochromocytoma is based mostly on CT, MRI, and radioiodinated MIBG. CT or MRI scans are more sensitive (100%) in detecting the primary tumors of the adrenal glands. Their sensitivity is 75% and 83%, respectively, for extraadrenal or malignant tumors. In contrast, MIBG scintigraphy contributes mainly to the delineation of extra-adrenal disease and metastatic spread, 5~ with an overall sensitivity of 86% and specificity of 99%, 51 although unusual sites of uptake have occasionally been documented. 52 The ligand MIBG structurally resembles norepinephrine and guanethidine. It is absorbed by the energy-requiring, sodium-dependent (active transport) type 1 amine uptake mechanism and also by the nonenergy-dependent diffuse mechanism (type II). 53 Once inside the cell, MIBG is concentrated in the intracellular storage vesicles by an energydependent, reserpine-sensitive mechanism, with uptake being proportional to the number of neurosecretory granules within the tumor. MIBG does not bind to postsynaptic adrenergic receptors, nor does it undergo enzymatic degradation. In light of the uptake mechanism, all medications that interfere with MIBG concentrating in adrenergic tissues should be avoided, and stable iodine should be administered to reduce thyroid exposure to radioiodine. MIBG scintigraphy has become essential for staging and following the course of pheochromocytoma. It may disclose local recurrence or distant metastases, which would require surgical resection (if feasible) or I- 131 MIBG therapy when

sufficient tracer uptake and retention in the tumor sites are observed. 1-131 MIBG therapy has been less successful for malignant pheochromocytoma than for neuroblastoma, and it is currently aimed only at the reduction of tumor function with effective palliation of symptoms. 54 Somatostatin receptor scintigraphy has been suggested for localization of malignant pheochromocytomas only when MIBG is negative, because of the lower uptake intensity and number of sites detected by the labeled octreotide when compared with MIBG. 55 FDG-PET can also detect the majority of pheochromocytomas (Fig 2). Although it is concentrated in both malignant and benign tumors, a greater percentage of the malignant ones are scan-positive. The uptake of FDG and MIBG in metastatic disease is similar to that in the primary tumor, but FDG-PET has a limited sensitivity and lower specificity compared with that of MIBG. Shulkin et al compared 35 FDG-PET scans with the 35 MIBG scans of 29 patients with proven pheochromocytoma, and they quantified the tumor uptake on positive PET scans. Among the 12 benign tumors, uptake of FDG was seen in 7 (58%), with uptake of MIBG in 10 (83%). Among the 17 patients with malignant pheochromocytoma, tumors in 14 (82%) concentrated FDG and tumors in 15 (88%) concentrated MIBG. MIBG images ranked better in 6 patients, and FDG ranked better in 1 of 12 patients with tumors taking up both radiopharmaceuticals. Semiquantitative analysis did not distinguish benign from malignant pheochromocytomas, with standardized uptake value ranging from 2.6 to 13.4, and from 1.6 to 13.3, respectively. The authors concluded that FDG is especially useful in defining the distribution of pheochromocytomas that fail to concentrate MIBG. 56 Alternatively, PET using C-11-hydroxy ephedrine that concentrates in adrenergic nerve terminals has been applied to patients with pheochromocytoma. This radioligand allows for the visualization of both primary and metastatic deposits (90% sensitivity) within minutes of tracer injection, and a tumor-to-background ratio greater than that of 1-123 MIBG. 57 PET has also been successfully used to predict the radiation dose achieved by therapy levels of 1-131 MIBG, when one uses the uptake of 1-124 MIBG in metastatic pheochromocytoma.5s Neuroblastoma (NB), the third most common malignancy of childhood, constitutes 10% of pedi-

NUCLEAR ENDOCRINOLOGY

243

Fig 2. Multiple metastases of malignant pheochromocytoma. (A) Whole-body dedicated FDG-PET scan in a 23-year-old man, 20 months after left adrenalectomy for malignant pheochromocytoma that had Invaded the left renal tissue. Local recurrence was identified 18 months after initial surgery, with negative MIBG performed before reoperation. The FOG-PET scan (projection image, left panel; coronal sections, middle and right) shows increased metabolic activity in the para-aortic nodes (arrow, middle panel) and in the left lower abdomen, at the level of the lilac crest (arrow, right panel). Parts B and C show the coincidence detection images (second panel from left), x-rey (far left), and fusion Images (third panel from left) by using a gamma camera-mounted anatomic x-ray tomograph. In part B, the pare-aortic nodes are shown, and in part C, the metabelically active focus, precisely located behind the left psoas muscle.

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YODPHAT KRAUSZ

Fig 2 (cont'd).

attic tumors and accounts for about 15% of cancer deaths in children. Factors affecting the prognosis are the stage of disease, the patient's age, the site of the primary tumor, the pattern and rate of catecholamine excretion, serum fertitin level, tumor histology, and genetic parameters, such as amplification of the N-myc oncogene and deletion of chromosome lp36. The prognosis and treatment of recurrent or progressive NB depend on the site, extent, and progression of the recurrence, and on previous therapy. In contrast with pheochromocytoma, the NB cells are poor in granules, and they retain the MIBG by rapid reuptake of the ligand that has escaped the cell via nonvesicular binding within the cytoplasm. 59 In this disease, MIBG scintigraphy is used for the diagnosis of the primary lesion (when inaccessible to biopsy), for staging, and for the evaluation of prognosis and response to therapy. The sensitivity of MIBG in detecting NB is about 87%, and the specificity is 94% to 96% 53,60 with an accuracy of - 9 0 % . This technique is particularly sensitive in the detection of early recurrence after treatment and may be used for radio-guided surgery in children undergoing

relaparotomy. 61 Whole-body MIBG scintigraphy also depicts lesions in the bone (sensitivity, 91% to 97%), soft tissue, and in the bone marrow; 1-123 MIBG SPECT improves the delineation of tumor deposits, occasionally with an increase in the number of lesions detected. 62 Shulkin et al documented the concordance of MIBG and Tc-99m methylene diphosphonate (MDP) bone scans for the presence or absence of skeletal disease, although 10% to 40% more lesions were depicted by MIBG, which showed more widespread disease, as reflected also in one of our patients (Fig 3). However, in no patient with a negative bone scan did the MIBG study indicate bone involvement. 63 Patients with residual, recurrent, or progressive disease during or after conventional therapy are selected for therapy with I-131 MIBG, 64 occasionally with myeloablative chemotherapy and stem cell rescue to improve the outcome in advanced NB. 65 Scans are performed after treatment, along with a repeat diagnostic MIBG scan at 3- to 12-month intervals in patients with NB and yearly in patients with pheochromocytoma. False-negative MIBG studies are caused by limitations in spatial resolution, tumor heterogeneity

NUCLEAR ENDOCRINOLOGY

Tc99m-MDP

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i! Fig 3. Multiple metastases of neuroblastoma. Tc-99m MOP scan (left) and whole-body 1-123 MIBG scan (right) in a 17-year-old patient 1 year after initial diagnosis of NB, stemming from the right adrenal gland. The MIBG scan shows multiple metastases in the bone and in the soft tissues, whereas the MDP scan shows only irregular uptake along both thighs.

with loss of uptake or rapid washout of MIBG from the storage pool, or poor uptake after chemotherapy or radiotherapy. When MIBG fails to concentrate in neuroblastomas, then In-111-pentetreotide 66 and FDG-PET 67 may be used. The labeled octreotide was found to be less sensitive than I- 131 MIBG for the detection of active neuroblastomas. 66 In contrast, FDG accumulates in most neuroblastomas and can help define the distribution of tumors that fail to concentrate MIBG. 67 On the whole, MIBG scintigraphy is currently the most effective indicator of neuroblastoma. It plays an important role in staging and restaging after treatment, in the search for postsurgical residual tumor in the early diagnosis of recurrence, and in monitoring the effect of treatment. Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare tumor affecting only 1 to 2 people per million. It usually occurs in adults, with a median age at diagnosis of

44 years. The disease has a poor prognosis, with frequent metastases to the peritoneum, lung, liver, and bone. Local recurrence and selected cases of metastatic disease can sometimes be palliated by surgery, whereas an unresectable or widely disseminated tumor requires antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. Currently, there is no convincing evidence that systemic therapy improves the survival duration of patients with adrenal cancer. Present emphasis in adrenocortical disease has shifted to high-resolution, anatomic imaging with CT and MRI, 68"69 but occasionally metastases in unusual sites were documented. 7~ Adrenocortical scintigraphy, with the use of cholesterol-based radiopharmaceuticals, has great clinical use in the evaluation of adrenocortical disease, such as Cushing's disease, and in distinguishing benign from malignant incidentaloma. This technique plays an important role at initial diagnosis and may rarely be used for follow-up, such as for recurrent Cushing's syndrome after bilateral adrenalectomy with adrenal reimplantation (Fig 4). Recently, inhibitors of adrenal steroid hormone synthesis, such as C-11 etomidate and C-11 metomidate, have shown promise for PET imaging of the normal adrenal glands and for differentiation of adrenocortical tumors from noncortical lesions. 71"72 FDG-PET may help characterize an adrenal mass, whether benign or malignant, in patients with cancer. 73 It may also help differentiate an isolated metastasis to the adrenal gland from disseminated disease for the selection of patients for adrenalectomy. 74 In addition, FDGPET may disclose the presence of metastatic ACC, with impact on the management of these patients. The first case presentation of metastatic ACC studied with FDG-PET is of a 13-year-old boy with a solitary liver metastasis that had been removed at initial surgery. FDG-PET, performed a month later, before adjuvant therapy with mitotane, showed increased glucose utilization in a paravertebral mass, histologically verified after surgical resection to be a metastasis of the same tumor. 75 Subsequently, Becherer et al studied 10 patients with ACC and found increased FDG-PET uptake in all known sites of disease, with a change in tumor stage in 3 patients. 76 Thus, FDG-PET may help delineate the metastases of ACC. Despite the current limitations and the poor prognosis,

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YODPHAT KRAUSZ

Fig 4. Functioning adrenal implant. Planar view of the abdomen, pelvis, and thighs, with the use of Se-75selenocholesterol, shows the adrenal tissue (arrow) that had been implanted at the time of bilateral adrenalectomy in a patient with Cushing's disease.

patients with ACC should be studied for early detection of recurrent disease. NEUROENDOCRINE TUMORS OF THE GASTROINTESTINAL TRACT

Neuroendocrine tumors of the gastrointestinal tract include carcinoid and islet cell tumors and are collectively referred to as gastroenteropancreatic tumors. Carcinoid and islet cell tumors constitute approximately 2% of all malignant tumors of the gastrointestinal system and are clinically detected in 5 and 3 cases per million, respectively. These tumors have a variable malignant potential, but they run an indolent clinical course and may remain undetected for years despite the associated peptide hypersecretion. Surgery is the main treatment for localized disease, whether primary or metastatic. Localization is difficult, however, with

detection rates of radiologic procedures ranging from 13% to 85%, depending on type, site, size of tumor, and the technique used. 77 In most of these tumors, there is an overexpression of certain receptors for regulatory peptides, with binding of the peptide to the extracellular domain of the receptor. Internalization of the ligand-receptor complex is followed either by degradation or by recycling of the internalized receptor to the cell surface. For radiolabeled peptide scintigraphy and/or therapy, this internalization process leads to accumulation of the radionuclide within the cell, thus enhancing the scintigraphic signal and/or the therapeutic effect. The overexpression of dense, high-affinity somatostatin receptors type II and V on membrane homogenates and tissue sections of gastroenteropancreatic t u m o r s 36'78 led to the use of radiolabeled somatostatin analogues for in vitro autoradiography, 79 in vivo scintigraphy, 8~ and for intraoperative probe detection 81 of these tumors. The scintigraphic technique, using In- 111-DTPA-octreotide, detects tumor uptake with a sensitivity ranging from 82% to 9 5 % , 77'82-86 and it has successfully revealed additional metastases not visualized on conventional imaging in about one third 86 to one half 85 of various neuroendocrine tumors. After initial surgery, SRS aids in the visualization of local recurrence or metastatic spread to the liver and mesentery not visualized on CT. The whole-body screening can occasionally expose multiple soft tissue and bony lesions (Fig 5), with sparing of unnecessary surgery. 87'8s This technique also identifies the receptor status of metastases for octreotide treatment, with high correlation to the ability of long-acting somatostatin analogues to inhibit in vivo hormone secretionfl 9'90 Carcinoid patients may manifest excellent symptomatic relief in response to somatostatin analog therapy, but the beneficial effect on tumor growth per se is questionableY '91-93 One of our patients with glucagonoma experienced transient regression of receptor-positive liver metastases over a 2-year period, and a carcinoid patient had no progression of hepatic involvement during a 7-year follow-up period, both on octreotide therapy. 89 The ability of certain tumors to bind labeled octreotide for imaging, as shown on scintigraphy (Fig 5), is also reflected in the response to high radiation dose delivered by Y-90- or In-11 l-octreotide when used for the treatment of receptor-positive me-

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tumors are typically s l o w - g r o w i n g and are only m i n i m a l l y responsive to systemic chemotherapy, the techniques discussed here should be used to assist the surgical r e m o v a l o f local recurrence or distant metastasis. If metastatic spread is evident, differentiated tumors may benefit f r o m physiologic uptake o f a labeled ligand, with radioguided therapy. M a n y years of e x p e r i e n c e h a v e established the use o f 1-131 for localization and treatment o f metastatic differentiated thyroid carcinoma. In contrast, there is no a g r e e m e n t yet as to w h i c h radiopharmaceutical should be used in noniodine concentrating endocrine cancer, including undifferentiated thyroid carcinoma, medullary thyroid cancer, and other n e u r o e n d o c r i n e tumors; h o w e v e r , more specific radiopharmaceuticals m a y be d e v e l o p e d in the future. G i v e n the different diagnostic and therapeutic modalities available, the particular m e t h o d used must be carefully chosen and tailored to the individual patient.

ACKNOWLEDGMENT

The author wishes to express her deep gratitude to Benjamin Glaser, MD, for his judicious remarks and great help in editing this manuscript, and to Hava Lester, PhD, for her help in editing the manuscript and for her exquisite contribution to the preparation of the figures. The author also wishes to thank Dr. MUller, of Basel, Switzerland, for the Y-90-DOTA-octreotide administered to our carcinoid patient. REFERENCES

POST

RNT

Fig 5. Multiple metastases of carcinoid tumor. Whole-body scan, after intravenous administration of In-111-penfetreotide, was performed in a 48-year-old man after tissue diagnosis of a liver metastasis (top). The scan shows multiple metastases with high density of somatostatin receptors in the dorsal spine, liver, pare.aortic nodes, sacrum, left sacroiliac joint, left ileum, and right pararectal area. The patient was referred for treatment with 4 escalating doses of Y-90-DOTA-octreotide. Several months after the last treatment, the patient experienced bone pain. On repeat scan (bottom), the liver metastases have regressed, as confirmed by CT, but multiple bone lesions, with fainter tracer uptake compared with the previous scan, are shown.

tastases. 94'95 In contrast, nonvisualization o f k n o w n metastatic spread by S R S suggests t u m o r dedifferentiation and requires aggressive chemotherapy. In summary, the surveillance o f patients with m a l i g n a n t e n d o c r i n e tumors requires the optimal c h o i c e o f the diagnostic modality. B e c a u s e the

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