Spectrum of pheochromocytoma in the 131I-MIBG era.
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3-Iodobenzylguanidine↗
Biomedical subjects
J C Sisson
Publications and source records attributed to J C Sisson.
Scintigraphic detection of regional disruption of adrenergic neurons in the heart.
Experiments were designed to detect regional disruptions of adrenergic neurons in the hearts of living dogs. The neuron disruption was achieved by the application of phenol to the epicardium of the left ventricle. Evidence for denervation was the reduction in endogenous norepinephrine (NE) concentrations in the myocardium beneath the region of phenol treatment and toward the apex. Radiolabeled meta-iodobenzylguanidine (MIBG) acts as an analog of NE and as such is concentrated in adrenergic nerve terminals. Following phenol application, MIBG labeled with 125I was found, 20 hours after injection, to be distributed within myocardium in patterns comparable to those of NE. However, left stellectomy did not alter the distributions of NE or 125I-MIBG in the myocardium and apparently did not disrupt adrenergic innervation. MIBG labeled with 123I enabled scintigraphic images of heart neurons in the living dog 3 and 20 hours after injection; these images portrayed the regions of adrenergic neuron disruption caused by phenol treatment. Concentrations of thallium-201 depicted on scintigraphic image and of triphenyltetrazolium observed on in vitro staining demonstrated no myocardial injury. Thus scintigraphy with 123I-MIBG will display regional adrenergic denervations in the heart.
3-Iodobenzylguanidine↗
Prognostic implications of the tall cell variant of papillary thyroid carcinoma.
The tall cell variant (TCV) of papillary thyroid carcinoma, characterized by a population of tall columnar cells with a height at least twice the width, was analyzed in 12 patients and compared to tumors from 12 patients with the usual type of papillary thyroid carcinoma (UPTC) matched for age, sex, and date of diagnosis to determine if tall cell histology had prognostic significance. Patients with TCV had significantly higher incidences of extrathyroidal disease, recurrent disease, and metastases compared to patients with UPTC. TCV patients also died of their tumors more frequently than UPTC patients (3/12 versus 0/12). There was no significant difference in tumor size or in the incidence of cervical lymph node involvement between the patient groups. These results show that TCV of papillary thyroid carcinoma has a more aggressive clinical course and a worse prognosis than UPTC in patient groups with similar age and sex distribution, length of follow-up, and tumor size.
Adult↗
Scintigraphic portrayal of the syndrome of multiple endocrine neoplasia type-2B.
The scintigraphic appearance of the neoplasms in multiple endocrine neoplasia type 2B (MEN-2B) and the interpretations of the image patterns are described. An 18-year-old male patient with the MEN-2B syndrome underwent TI-201 imaging that showed concentrations of TI-201 in the primary medullary thyroid carcinoma (MTC) tumor and in cervical lymph node metastases. After total thyroidectomy and lymph node dissection, the TI-201 image was normal. Catecholamine levels in the blood and urine were only borderline elevated. Yet, greater than normal concentrations of I-131 metaiodobenzylguanidine (I-131 MIBG) were present in both adrenal glands. Computed tomography of the abdomen showed normal adrenal glands. These results were consistent with the diagnosis of adrenal medullary hyperplasia, a precursor of pheochromocytoma. No operation was indicated to remove the adrenal glands. Imaging with TI-201 appears to be useful in identifying sites of MTC in patients with the MEN-2B syndrome. I-131 MIBG imaging, in conjunction with computed tomography of the adrenal glands and appropriate catecholamine measurements, should be performed in patients with the MEN-2B syndrome to determine the status of the adrenal medullae, which then may be classified as normal, hyperplastic, or tumorous with pheochromocytoma.
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Gastrointestinal iodine-131-meta-iodobenzylguanidine activity.
Radioactivity in the colon during 131-I-meta-iodobenzylguanidine (MIBG) scintigraphy may obscure or be mistaken for tumor uptake. Fecal excretion of radioactivity was examined in eight patients following therapeutic 131-I-MIBG administration (123-218 mCi, 4.551-8.066 GBq) and was found to be 0.02-1.93% of the administered dose. Semiquantitative grading of colonic activity on scintigraphy was inversely related to fecal excretion. An additional patient with marked colonic activity was studied before and after an enema: all visible gut activity was evacuated. We conclude that radioactivity in the colon seen in 131-I-MIBG scintigraphy is due largely to gut excretion of 131-I and is not due to 131-I-MIBG uptake in the autonomic innervation of the gut. Laxatives and enemas are suggested for patients in which such gut radioactivity may lead to difficulties in interpretation.
3-Iodobenzylguanidine↗
Conjugate view gamma camera method for estimating tumor uptake of iodine-131 metaiodobenzylguanidine.
Therapy with [131I]MIBG has produced partial remissions of malignant pheochromocytomas but not all patients respond. Responses correlate with the quantity of radiation delivered. We developed the conjugate-view method of imaging using 131I reference sources of known radioactivity placed on the surface of the patient and standard nuclear medicine equipment (gamma camera and computer), to estimate tumor uptake of [131I]MIBG. Such an estimate is a first step toward calculating radiation absorbed dose. Three different methods of background subtraction were evaluated with an anthropomorphic phantom and in five patients. In phantom results, measured tumor activity decreased exponentially with a half-life in agreement with that of 131I to within 3%. However, in the phantom studies, in which non-tumor activity is zero, no single method of background subtraction is superior. In patients, two background subtraction methods, which take their estimate from regions immediately surrounding or adjacent to the tumor and reference source, are less sensitive to reference source position and appear more accurate than a third method which uses a background region of interest displaced from the tumor. The agreement of the calculated activity concentration (nCi/g) with that measured by counting portions of the excised tumors gives validation to the method.
3-Iodobenzylguanidine↗
Prediction of sudden cardiac death in diabetic autonomic neuropathy.
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3-Iodobenzylguanidine↗
Sodium dependency of uptake of norepinephrine and m-iodobenzylguanidine into cultured human pheochromocytoma cells: evidence for uptake-one.
Radioiodinated m-iodobenzylguanidine (MIBG), a scintigraphic agent used in the detection of human pheochromocytomas, is thought to utilize the same uptake and retention mechanism(s) as norepinephrine (NE). Using primary cultures from 16 human pheochromocytomas, we compared the uptake of MIBG to that of NE. Two different uptake systems were identified. Both NE and MIBG were taken up by a sodium-dependent system that was characterized by: temperature dependency, high affinity, low capacity, saturability, ouabain sensitivity, and desmethylimipramine sensitivity. However, NE and MIBG were also taken up by a temperature-dependent, sodium-independent, apparently unsaturable system. The sodium-dependent uptake system fulfills many of the criteria for Uptake-one while the sodium-independent uptake system is most likely a passive diffusion process. Competitive inhibition studies demonstrated that NE and MIBG share a common uptake system; a concept consistent with the linear correlation between the rate of uptake of 1.0 microM NE and that of 1.0 microM MIBG (r = 0.942). At low concentrations, both NE and MIBG entered the tumor cells primarily by the sodium-dependent uptake system. Differential expression of the sodium-dependent and sodium-independent uptake systems, between different tumor cells, appears to be responsible for the variations of the kinetic parameters for both NE and MIBG. These studies provide the first direct characterization of a NE uptake mechanism in human pheochromocytoma cells.
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Pulmonary function in thyroid carcinoma metastatic to the lung.
Pulmonary testing was carried out in 12 of 35 consecutive cases of differentiated thyroid carcinoma metastatic to the lung, which were identified in a retrospective analysis covering the 22-yr period from 1962-1984. In 7 of the 12 patients, pulmonary function tests showed abnormalities. Impaired pulmonary function was associated with a poor prognosis. Four of the twelve patients died; each had impaired pulmonary function and their ages (12-65 yr) were similar to those still living (13-65 yr). Specific types of functional abnormalities were not associated with pulmonary metastases, and underlying pulmonary disease contributed to the findings in some patients. Four patterns were defined on chest radiographs: macronodular, micronodular, miliary, and normal, but these patterns did not correlate with outcome. Scintiscan patterns varied from normal to diffuse concentration of 131I. Generally, following therapy with radioiodine, fewer abnormalities on chest x-ray and less uptake of 131I in the lungs was noted. However, therapy with radioiodine did not improve pulmonary function. Pulmonary function testing appears to be a better predictor of outcome in patients with thyroid carcinoma metastatic to lung than chest x-ray appearance or scintigraphic scanning.
Adolescent↗
Clonidine-induced suppression of plasma catecholamines in states of adrenal medulla hyperfunction.
To assess adrenal medulla activity in states of hyperfunction, a single 0.3 mg oral dose of clonidine hydrochloride (Catapres) was given to twelve patients with varying evidence of familial adrenal medullary hyperplasia and pheochromocytomas from kindreds with Multiple Endocrine Neoplasia type 2 syndrome (MEN-2), seven patients with sporadic pheochromocytomas and six normal subjects. Mean arterial blood pressure and plasma norepinephrine (NE) levels were lower than baseline values 2 h after clonidine in the normal subjects. Plasma epinephrine (E) rose in one normal but fell in the remainder after clonidine administration. In sporadic pheochromocytoma patients, E fell slightly in 4 and NE fell in 3 while mean arterial blood pressure was not significantly lower than baseline values in 7 patients 2 h after clonidine. In MEN-2, mean arterial blood pressure fell and there was a variable response of plasma E and NE to clonidine, which appears to be related to the presence of detectable anatomic (CT scan) and functional (131I-mlBG scintigraphy) abnormalities of the adrenal medulla. These findings are thus compatible with the spectrum of adrenal medulla dysfunction and the presumed development of pheochromocytoma in this syndrome.
Adolescent↗
Pheochromocytoma, polycythemia, and venous thrombosis.
Polycythemia is rarely associated with pheochromocytoma. A patient with a 22-year history of malignant pheochromocytoma is presented in whom major complications developed as a result of long-standing polycythemia, apparently due to secretion of erythropoietin by the tumors. Despite attempts to reduce tumor burden by surgery, chemotherapy, and large doses of I-131-metaiodobenzylguanidine, polycythemia persisted. Extensive venous thrombosis developed requiring hospitalization and anticoagulation. Thus, polycythemia itself may be a cause of major morbidity in patients with pheochromocytoma, and prophylactic measures may be warranted. Review of the 130 patients with benign and malignant pheochromocytoma studied since the introduction of I-131-metaiodobenzylguanidine in 1980 revealed another six patients with hematocrits over 50 but only one had a hematocrit greater than 55 and required regular phlebotomy. In contrast, anemia (hematocrit less than 35) due to variety of causes was present in 18 cases.
Abdominal Neoplasms↗
QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy.
Alterations in cardiac sympathetic innervation may result in QT interval prolongation and predispose to sudden arrhythmias and death. Sudden cardiac death occurs in diabetic patients who have autonomic neuropathy, but the cause is uncertain. In 30 patients with insulin-dependent diabetes mellitus who had no evidence of ischemic heart disease, cardiac autonomic neuropathy, determined by clinical tests, was found in 17. The corrected QT interval (QTc), measured using Bazett's formula at rest and peak exercise, was prolonged (greater than 440 msec) in 12 of these patients at rest and in 15 at peak exercise. Prolonged QTc intervals were found only in patients who had definite cardiac autonomic neuropathy. As a group, the QTc interval (mean +/- SD) in the diabetic patients with cardiac autonomic neuropathy was prolonged compared to that in patients without cardiac autonomic neuropathy at rest (447 +/- 28 vs. 405 +/- 9 ms; P less than 0.0001) and peak exercise (468 +/- 23 vs. 402 +/- 23 ms; P less than 0.0001). There was a direct linear relationship between the extent of cardiac autonomic neuropathy and the QTc interval (r = 0.71; P less than 0.001). One of the patients with cardiac autonomic neuropathy and prolonged QTc intervals had a nonuniform loss of adrenergic neurons in his heart demonstrated by meta-iodobenzyl-guanidine scintigraphy, indicating sympathetic imbalance; he subsequently died unexpectedly. These data suggest that diabetic cardiac autonomic neuropathy may result in sympathetic imbalance and QTc interval prolongation, predisposing these patients to sudden arrhythmias and death.
Adult↗
Iodine-131 MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma.
Metaiodobenzylguanidine (MIBG) locates most pheochromocytomas and neuroblastomas. The tracer is concentrated in intracellular storage vesicles by an active process. Many other neuroendocrine tumors of the amine precursor uptake and decarboxylation (APUD) series have hormonal storage vesicles and, thus, the potential to take up [131I]MIBG. A variety of neuroendocrine tumors in 57 patients were studied 1, 2, and 3 days after 0.5 mCi [131I]MIBG. Views from skull to pelvis were obtained. Results of MIBG scans were compared with all available imaging modalities (including plain radiography, liver scan, ultrasound, computed tomography, and angiography) and surgical exploration. The neuroendocrine nature of the tumor was determined by histology, immunohistochemistry, electron microscopy, and the assay of appropriate biogenic amines and peptide hormones. Results were (positive/total cases): carcinoids (four of ten), nonsecreting paragangliomas (three of three), sporadic medullary carcinomas of the thyroid (MCT) (one of five), familial MCT (one of 26), chemodectomas (two of five), oat cell carcinomas (zero of four), choriocarcinoma (one of one), atypical schwannoma (with storage granules) (one of one), Merkel cell skin cancer (one of one), islet cell carcinoma (zero of one). We conclude that a wide range of neuroendocrine tumors show [131I]MIBG uptake; tumors other than pheochromocytomas and neuroblastomas are less often seen scintigraphically, but in certain cases (e.g., carcinoid and nonsecreting paragangliomas) scintigraphy may be useful in depicting the extent and location of disease and may indicate therapeutic potential. Iodine-131 MIBG shows promise in the diagnosis and staging of tumors of varied types.
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Iodine-131 MIBG scintigraphy of the extremities in metastatic pheochromocytoma and neuroblastoma.
Iodine-131 MIBG scintigraphy may be used to determine the presence or absence of metastases to the appendicular skeleton in malignant pheochromocytoma and neuroblastoma. Normal bones show no uptake of [131I]MIBG and the joints are seen as photon-deficient areas surrounded by background muscle activity. Discrete concentrations of radioactivity in bone are often seen in patients with malignant pheochromocytoma and neuroblastoma. Bone marrow involvement in neuroblastoma may be indicated by diffuse uptake of [131I]MIBG or focal accumulation at the metaphyses. Uncommonly, bone involvement may not be displayed by the [131I]MIBG images. Since conventional bone scanning agents may also fail to detect these tumors, skeletal scintigraphy with both [131I]MIBG and [99mTc]MDP is necessary to reliably stage malignant pheochromocytoma and neuroblastoma.
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Radiolabeled meta-iodobenzylguanidine and the adrenergic neurons of salivary glands.
The handling of radiolabeled meta-iodobenzylguanidine (MIBG) by salivary glands was evaluated. In the submaxillary glands of rats, the uptake of 125I-MIBG was decreased after 1) nerve injury induced by 6-hydroxydopamine, 2) inhibition of the uptake-1 pathway by desmethylimipramine, and 3) surgical denervation. However, the reduction in 125I-MIGB uptake was less than that of 3H-norepinephrine (3H-NE) and of the endogenous content of NE in the glands. Yet, the sympathomimetic phenylpropanolamine displaced about the same fraction of 125I-MIBG as 3H-NE. These results suggest that 40% or more of 125I-MIBG resides in extraneuronal sites but that at least 30% and possibly more lies in the adrenergic nerve terminals. Fasting and feeding rats produced changes in the rates of disappearance of 125I-MIBG and 3H-NE from the submaxillary gland that were different, and the rates of loss of 125I-MIBG cannot be used as an index of adrenergic nerve activity. In man, the concentrations of 123I-MIBG in the salivary glands, particularly the parotid gland, are readily visible and measureable. Imipramine reduced the uptake of 123I-MIBG into parotid glands little or not at all; some of the 123I-MIBG may enter neurons via an imipramine-insensitive pathway, but a substantial fraction probably arrives in intraneuronal locations. Thus, phenylpropanolamine displaced over 50% of the parotid pool of 123I-MIBG. However, in only the most severe case of generalized autonomic neuropathy was the uptake of 123I-MIBG reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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Metaiodobenzylguanidine as an index of the adrenergic nervous system integrity and function.
The radiopharmaceutical, metaiodobenzylguanidine (MIBG) acts as an analog of norepinephrine (NE). Experiments in rats were carried out to determine how closely the movements of [125I]MIBG in the heart mimicked those of [3H]NE, and if the changes [125I] MIBG concentrations would reflect injury to, and function of, adrenergic neurons in the heart. Injury to adrenergic neurons by 6-hydroxydopamine substantially reduced the uptake of [125I] MIBG into the left ventricle, but the effect was less than that on uptake of [3H]NE uptake and concentration of endogenous NE. Similarly, when desmethylimipramine was given to inhibit the uptake-1 pathway of neurons, the reduction in uptake of [125I]MIBG was statistically significant but less than that of [3H]NE; part of this difference may be attributable to partial uptake of [125I]MIBG into neurons by a diffusion pathway. Substantial fractions of [125I]MIBG and [3H]NE were displaced from the heart by the sympathomimetic drug, phenylpropanolamine. When adrenergic neurons of the heart were stimulated by feeding of rats, the disappearance rates of [3H]NE and [125I]MIBG from the heart were significantly increased. Although not a perfect analog of [3H]NE, [125I]MIBG appears to enter and leave the heart in patterns similar to those of [3H]NE. Thus, movements of [125I]MIBG give indices of adrenergic neuron injury and function in the heart.
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Metaiodobenzylguanidine to map scintigraphically the adrenergic nervous system in man.
Metaiodobenzylguanidine (MIBG) localizes in adrenergic neurons; MIBG labeled with 123I then serves as an analog of norepinephrine, and concentrations of [123I]MIBG reflect sites of adrenergic neurons in organs. Movements of [123I]MIBG into and out of organs were measured by quantitative scintigraphy in man. We perturbed adrenergic neuron function in several ways, and [123I]MIBG concentrations in the heart were subsequently altered in patterns consistent with the concept that [123I]MIBG resides mostly in adrenergic neurons. Uptake of [123I]MIBG into the heart was inhibited by the tricyclic drug, imipramine, and this agent also accelerated the rate of loss of [123I]MIBG. Phenylpropanolamine, a sympathomimetic drug that acts by displacing norepinephrine from neurons, increased the rates of loss of [123I]MIBG from the heart. Exercise was followed by a movement of [123I]MIBG into blood and urine. Generalized autonomic neuropathies were associated with marked diminutions of [123I]MIBG uptake into the heart. We conclude that quantitative scintigraphy in patients will enable determinations of regional disturbances in integrity (by measuring uptake of [123I]MIBG) and function (by measuring rates of loss of [123I]MIBG) of the adrenergic nervous system in the heart.
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Primary extra-adrenal pheochromocytoma: positive I-123 MIBG imaging with negative I-131 MIBG imaging.
I-131 metaiodobenzylguanidine (I-131 MIBG) is a well established imaging agent that reliably detects pheochromocytoma. In some patients, however, I-131 MIBG may fail to localize pheochromocytoma. I-123 MIBG has several potential advantages over I-131 MIBG, and these advantages may enable locating pheochromocytomas which have eluded other techniques, including I-131 MIBG imaging. A patient with primary extra-adrenal pheochromocytoma is described who illustrates the superiority of I-123 MIBG for the imaging of pheochromocytoma.
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