James C. Sisson

Scintigraphic Localization of Pheochromocytoma

We used a new radiopharmaceutical agent, [131I]meta-iodobenzylguanidine ([131I]MIBG), to produce scintigraphic images of pheochromocytomas in eight patients. One day or more after injection, the only normal organ that displayed distinct concentrations of radioactivity was the urinary bladder. The [131I]MIBG was probably concentrated in adrenergic vesicles; in tissues where vesicles are numerous, such as pheochromocytomas, the radionuclide was retained for days. The spectrum of pheochromocytomas shown the scintigrams was broad: intra-adrenal and extraadrenal in location, benign and malignant in character, 0.2 to 65 g in weight, and with different hormone patterns in secretion. Tumors in four patients were not detected by computed tomography. In one patient, reoperation was undertaken only because the scintigram located the extra-adrenal tumors and thereby directed the surgeons exploration. The method offers hope of safe and reliable localization of pheochromocytomas in their many guises.

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 distributions, length of follow-up, and tumor size.

Radio-iodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors

Radioiodinated meta-iodobenzylguanidine, a recently developed radiopharmaceutical, has been shown to permit safe, noninvasive, sensitive, and specific scintigraphic location of pheochromocytomas of all types. The technique is especially efficacious in the case of extraadrenal primary lesions and locally recurrent and metastatic tumors. In addition to being taken up by pheochromocytomas, meta-iodobenzylguanidine may be used to image neuroblastomas, nonfunctioning paragangliomas, and carcinoid tumors. Lesions with high 131I-meta-iodobenzylguanidine uptake may respond to treatment with large doses of this radiopharmaceutical.

Pilot Study of Iodine-131–Metaiodobenzylguanidine in Combination With Myeloablative Chemotherapy and Autologous Stem-Cell Support for the Treatment of Neuroblastoma

PURPOSE The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.

Radiation Safety in the Treatment of Patients with Thyroid Diseases by Radioiodine 131I: Practice Recommendations of the American Thyroid Association

BACKGROUND Radiation safety is an essential component in the treatment of patients with thyroid diseases by ¹³¹I. The American Thyroid Association created a task force to develop recommendations that would inform medical professionals about attainment of radiation safety for patients, family members, and the public. The task force was constituted so as to obtain advice, experience, and methods from relevant medical specialties and disciplines. METHODS Reviews of Nuclear Regulatory Commission regulations and International Commission on Radiological Protection [corrected] recommendations formed the basic structure of the recommendations. Members of the task force contributed both ideas and methods that are used at their respective institutions to aid groups responsible for treatments and that instruct patients and caregivers in the attainment of radiation safety. There are insufficient data on long-term outcomes to create evidence-based guidelines. RESULTS The information was used to compile delineations of radiation safety. Factors and situations that govern implementation of safety practices are cited and discussed. Examples of the development of tables to ascertain the number of hours or days (24-hour cycles) of radiation precaution appropriate for individual patients treated with ¹³¹I for hyperthyroidism and thyroid cancer have been provided. Reminders in the form of a checklist are presented to assist in assessing patients while taking into account individual circumstances that would bear on radiation safety. Information is presented to supplement the treating physicians advice to patients and caregivers on precautions to be adopted within and outside the home. CONCLUSION Recommendations, complying with Nuclear Regulatory Commission regulations and consistent with guidelines promulgated by the National Council on Radiation Protection and Measurement (NCRP-155), can help physicians and patients maintain radiation safety after treatment with ¹³¹I of patients with thyroid diseases. Both treating physicians and patients must be informed if radiation safety, an integral part of therapy with ¹³¹I, is to be attained. Based on current regulations and understanding of radiation exposures, recommendations have been made to guide physicians and patients in safe practices after treatment with radioactive iodine.

Malignant phaeochromocytoma: clinical, biochemical and scintigraphic characterization.

We have evaluated thirty patients with malignant metastatic phaeochromocytoma with regard to clinical features, indices of catecholamine secretion, histology of lesions and a number of imaging procedures including scintigraphy with the recently developed sympathetic tissue‐seeking radiopharmaceutical 131I‐metaiodobenzylguanidine (131I‐MIBG). The primary tumour was extraadrenal in 13 cases. The commonest site of metastases was the axial skeleton (20 cases), followed by liver (four cases), lymph nodes (four cases), peritoneum (two cases) and lung (three cases). The malignancies were indolent, the mean time following the initial diagnosis was 9·18 years (range 0 to 33 years) and the mean duration of known metastases 3·71 years (range 0 to 18 years). There was a wide range of abnormalities in plasma and urinary catecholamines which did not correlate with the extent of tumour spread, histological pattern (mitotic index, Zellballen pattern, capsular or vascular invasion pleomorphism or necrosis) or 131I‐MIBG uptake by tumour deposits. 131I‐MIBG scintigraphy was found to be a useful technique for determining the extent of metastatic disease in most cases (26 of 30) and in some patients (16 of 30) was more sensitive than other radiological procedures. No false positive scans were encountered.

Spectrum of Pheochromocytoma in Multiple Endocrine Neoplasia: A Scintigraphic Portrayal Using 131I-Metaiodobenzylguanidine

Six patients with multiple endocrine neoplasia (MEN) types 2a and 2b were investigated to determine the spectrum of pheochromocytoma by scintigraphy. Iodine-131-metaiodobenzylguanidine (131I-MIBG), a new imaging agent which concentrates in adrenergic neurotransmitter vesicles, was administered at 0.5 mCi/1.7m2 and scintiscans were taken at 24 and 48 hours. Two normotensive patients with normal plasma and urinary catecholamines had no adrenal tracer uptake. One patient with a modest and intermittent increase only in urinary catecholamine metabolites showed faint adrenal images. Two other patients with increased plasma and urinary catecholamines showed bilateral adrenal imaging patterns. The sixth patient who had increased norepinephrine and epinephrine secretion showed bilateral asymmetrical adrenal images, findings that were corroborated at operation. Functional as well as anatomic evidence of adrenal medullary abnormalities in patients with MEN-2 syndromes are demonstrated by 131I-MIBG scintigraphy. Therefore, the procedure can be used to define the extent of abnormalities of the adrenal medulla in these patients.

Biochemical Diagnosis and Localization of Pheochromocytoma Can We Reach a Consensus

Abstract:  Pheochromocytomas can have a highly variable presentation, making diagnosis challenging. To think of the tumor represents the crucial initial step, but establishing the diagnosis requires biochemical evidence of excessive catecholamine production and imaging studies to localize the source. Currently, however, there exist no generally agreed upon guidelines based on which tests and testing algorithms should be used to confirm and locate or exclude a suspected pheochromocytoma. Choice of biochemical tests and imaging studies instead usually depends on institutional experience. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts and patient representatives discussed current problems and available options for tumor diagnosis and localization and formulated recommendations, which were subsequently agreed upon by those in attendance at the meeting. This article summarizes the discussion and recommendations derived from that session.

Calcitonin, carcinoembryonic antigen and neuron‐specific enolase in medullary thyroid carcinoma. An immunohistochemical study

Calcitonin, carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) were studied in the thyroid glands of patients with multiple endocrine neoplasia (MEN) type 2a, 2b, and with sporadic thyroid carcinomas (MTC). Calcitonin, CEA and NSE were localized in normal C‐cells, hyperplastic C‐cells, and in MTC. While the distribution of calcitonin and CEA was quite similar in most cases, a smaller proportion of cases were positive for NSE. C‐cell hyperplasia was identified in all nine patients with MEN 2a and in four of six patients with MEN 2b. None of the four patients with sporadic MTC had C‐cell hyperplasia. These results indicate that C‐cell hyperplasia is present in patients with MEN 2a and 2b and that NSE in addition to calcitonin and CEA is a useful marker for the thyroid C‐cells.

A Phase II Study of Imatinib in Patients with Advanced Anaplastic Thyroid Cancer

BACKGROUND Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.