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The value of fluorine-18 fluorodeoxyglucose PET in patients with medullary thyroid cancer
Abstract
The early detection of metastases from medullary thyroid cancer (MTC) is important because the only curative therapy consists
in surgical removal of all tumour tissue. There is no single sensitive diagnostic imaging modality for the localization of
all metastases in patients with MTC. Therefore, in many cases several imaging modalities (e.g. ultrasonography, magnetic resonance
imaging, computerized tomography and scintigraphy using pentavalent technetium-99m dimercaptosuccinic acid, thallium-201 chloride,
indium-111 pentetreotide, anti-CEA antibodies or metaiodobenzylguanidine) must be performed consecutively in patients with
elevated calcitonin levels until the tumour is localized. In this prospective study, we investigated the value of fluorine-18
fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in the follow-up of patients with MTC. [18F]FDG PET examinations of the neck and the chest were performed in 20 patients with elevated calcitonin levels or sonographic
abnormalities in the neck. Positive [18F]FDG findings were validated by histology, computerized tomography or selective venous catheterization. [18F]FDG PET detected tumour in 13/17 patients (nine cases were validated by histology, four by computerized tomography). Five
patients showed completely negative PET scans (of these cases, one was true-negative and four false-negative). One patient
with [18F]FDG accumulation in pulmonary lesions from silicosis and one patient with a neck lesion that was not subjected to histological
validation had to be excluded. Considering all validated localizations, [18F]FDG PET detected 12/14 tumour manifestations in the neck, 6/7 mediastinal metastases, 2/2 pulmonary metastases and 2/2 bone
metastases. In two patients with elevated calcitonin levels, no diagnostic modality was able to localize a tumour. The sensitivity
of [18F]FDG PET in the follow-up of MTC was 76% (95% confidence interval 53%–94%); this is encouraging. [18F]FDG PET promises to be a valuable diagnostic method, especially for the detection of lymph node metastases, surgical resection
of which can result in complete remission.
... The sensitivity of 201 Tl chloride, 99m Tc-sestamibi, 99m Tc(V)-DMSA, and 123 I/ 131 I-MIBG have been reported as 63, 47 -83, 68 -95, and 31%, respectively. 111 In-pentetreotid sensitivity was reported to be between 37 and 71% in the literature [3,19,20]. The most successful one of them seems to be 99m Tc (V)-DMSA scintigraphy. ...
The aim of this study was to evaluate the value of fluorine-18 (¹⁸F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the detection of recurrent medullary thyroid carcinoma (MTC) in patients with elevated calcitonin levels.
Thirty-three patients (nine men, 24 women; mean age: 50.3 ± 12 years) who were referred to undergo ¹⁸F-FDG PET/CT for restaging of MTC in patients with high calcitonin levels were included in this study. Five patients also had suspected lymph nodes detected by neck ultrasonography. The results of ¹⁸F-FDG PET/CT and clinical follow-up data were reviewed retrospectively. Histological analysis has been accepted as the gold standard in the confirmation of ¹⁸F-FDG PET/CT results. Patients were followed up for 45.6 ± 4.2 months.
There were 14 negative and 19 positive scans for possible recurrence of MTC. In the positive scans, the possible recurrence sites were neck lymph nodes, thyroid bed, mediastinal lymph nodes, and the lung in 14, two, two, and one patient, respectively. Disease recurrence in 13 patients was confirmed histologically by surgical excision or fine-needle aspiration biopsy. In the remaining six patients, recurrence was excluded as it was reactive as a result of pathological examination. However, one patient had a negative scan, underwent neck lymph node excision after ¹⁸F-FDG PET/CT examination, and lymph node recurrence was detected histologically. According to these results, the sensitivity and specificity of PET/CT were calculated as 93 and 68%, respectively. According to the recommended calcitonin level by the American Thyroid Association (calcitonin levels higher than 150 pg/ml), sensitivity was calculated as 90%. Although the mean maximum standardized uptake values of the true-positive and false-positive groups were calculated as 4.72 ± 2.17 and 4.22 ± 1.02, respectively, the difference between the two groups was not statistically significant (P>0.05).
PET/CT is a sensitive imaging tool in the detection of MTC recurrence, especially in patients with high calcitonin levels, and it gives additional information in one third of all patients on an average by detecting an occult disease or confirming findings of other imaging tools.
The purpose of these guidelines is to provide a broad framework for clinicians considering the use of positron emission tomography (PET) scanning for their patients. PET imaging is a rapidly evolving field, with ongoing developments in imaging technology, radiochemistry, isotope production, animal research and clinical applications.
The optimal treatment for medullary cancer of the thyroid is total thyroidectomy and central nodal lymphadenectomy at a time the primary cancer is small and has not spread. In the three phenotypes of familial medullary cancer, namely, familial medullary cancer and MEN 2A and 2B, screening of families for patients with a mutation in the RET proto-oncogene and a genetic predisposition for the diseases allows surgery at an even earlier stage. Unfortunately, not all patients are treated at the optimal time. Patients with sporadic medullary cancer frequently have extensive local and distant metastases at the time of diagnosis. It is important to define the extent of disease when planning treatment.
The objective of this chapter is to present an overview of the following topics: PET physics and scanners, radiopharmaceutical for PET and indications, imaging technique, normal findings and variations, interpretation of PET-CT scans, false-positive findings, 18F-FDG PET-CT and PET scanning in differentiated thyroid cancer (DTC), role in thyroglobulin (Tg)-positive and iodine-negative patients, prognostic value of 18F-FDG PET scans, and the role of TSH in 18F-FDG PET scanning. The chapter concludes with a brief introduction to 124I PET scanning and other PET-CT radiopharmaceuticals.
Radioactive iodine (RAI; I-131) has been used to destroy thyroid carcinoma tissue postoperatively in patients with and without known residual disease since the mid-twentieth century. By eliminating remaining normal thyroid tissue, RAI ablation facilitates monitoring for persistent or recurrent thyroid carcinoma with thyroglobulin levels and iodine scans. Furthermore, for those patients with invasive cancers, extensive locoregional or distant metastases, many studies demonstrate that RAI treatment improves cause-specific and disease-free survival, but there are many challenges in the thyroid cancer literature to evaluating the benefits of RAI remnant ablation. There is a lack of prospective randomized controlled trials to identify effectiveness of RAI. Moreover, the use of as many as 16 staging systems, pooling of histological subtypes that respond differently to iodine, and lack of agreement of definitions for “low risk” versus “high risk” make it difficult to compare the outcomes for different stages/risks from across studies. In addition, the majority of analyses do not account for ethnic and geographic differences in total incidence and incidence of different histological types of differentiated thyroid cancer (DTC). Furthermore, since recurrence and death from thyroid cancer can be seen many years after the initial diagnosis, attaining significant outcome data depends upon the duration of a study which is, oftentimes, too short to provide meaningful data. Lastly, recent studies use newer methods for detecting recurrence of disease such as with more sensitive thyroglobulin assays and high-resolution ultrasound, making it difficult to compare outcomes from older studies where less sensitive whole-body scanning was performed.
The most frequent forms of thyroid cancer can be divided into two main categories: tumors with follicle cell differentiation and those with C-cell differentiation. Within the category of tumors with follicle cell differentiation, a distinction is made between papillary tumors and follicular tumors. Both undifferentiated and anaplastic tumors are also included in this category, although a clear attribution to an initial cell line is not always possible for anaplastic carcinomas. Within the largest group, the papillary carcinomas, there are several types including encapsulated, minimal invasive, diffuse sclerotic and oncocytic carcinomas. Because of their generally low iodine uptake and their high mito-chondrial content, Hürthle cell carcinomas have a special position, particularly in functional imaging and with respect to therapy options. Carcinomas with C-cell differentiation are partly genetically determined, either as isolated familial medullary carcinoma or in multiple endocrine neoplasia (MEN-2a/MEN-2b). The existence of mixed follicle cell/C-cell differentiated carcinomas should be mentioned, especially in the context of radioiodine therapy, since the latter can certainly offer therapeutic options. We will not discuss the rare forms of thyroid cancer or the further subcategoriza- tion of the tumor entities described above, since this information is currently not relevant to the clinical significance of PET.
In recent years nuclear medicine has contributed to the impressive development of the knowledge of neuroendocrine tumors in terms of biology (receptor scintigraphy), pharmacology (development of new tracers), and therapy (radiometabolic therapy). At present, it is impossible to plan the management of a patient affected by a neuroendocrine tumor without performing nuclear medicine examinations. The contribution of nuclear medicine had affected and improved the management of these patients by offering various important options that are part of the modern diagnosis and treatment protocols. The clinical experience and the literature confirm that, among the wide variety of tracers and nuclear medicine modalities available today, metaiodobenzylguanidine (MIBG) and DTPA-D-Phe-octreotide (pentetreotide) are the radiopharmaceuticals of current clinical use. Several new somatostatin analogues are under investigation. Positron emission tomography (PET) supplies a range of labelled compounds to be used for the visualization of tumor biochemistry. In addition to the first routinely used PET tracer in oncology, F-18-labelled deoxyglucose (FDG), a number of radiopharmaceuticals based on different precursors such as fluorodopamine and 5-hydroxytryptophan (5-HTP) are going to gain a clinical role. Of course, the diagnosis of neuroendocrine tumors has to be based on integrated information derived from different examinations including nuclear medicine studies. The clinical presentation of neuroendocrine tumors is highly variable: sometimes they manifest typical or atypical symptoms but they may also be detected by chance during an X-ray or ultrasound examination carried out for other reasons. At disease presentation nuclear medicine modalities are sometimes able to direct physicians towards the clinical diagnosis thanks to the specificity of their imaging mechanisms. They also play a role in disease staging and restaging, patient follow-up and treatment monitoring. In addition, the biological characterisation of neuroendocrine tissues (receptor status, glucose metabolism, differentiation, etc.) allows the interpretation of radiopharmaceutical uptake as a prognostic parameter and sometimes as a predictor of the response to treatment.
This chapter will consider the role of planar scintigraphy, SPECT and PET in the imaging of skeletal metastatic disease from a miscellaneous group of malignancies, including lung, thyroid and renal carcinomas; multiple myeloma; and neuroendocrine tumours, and will examine how recent technical advances may enhance their effectiveness in this field. Bone scintigraphy using technetium-labelled diphosphonates has for many years been the mainstay of functional imaging of bony metastases, but this technique is of limited value in evaluating myeloma and aggressive osteolytic metastases and also carries the drawback of relatively poor specificity. Single photon emission computed tomography (SPECT), being a tomographic imaging technique, produces three-dimensional images of tracer distribution from multiplanar images. Its application to bone scintigrams in selected cases can greatly improve accurate anatomical localisation and sensitivity in detection of foci of tracer uptake. SPECT can equally be applied to scintigrams using radiotracers which are specific for particular groups of tumours, including somatostatin analogues for neuroendocrine tumours. The advent of combined SPECT/CT systems in recent years has further enhanced the accuracy of SPECT in all these malignancies. Positron emission tomography (PET) detects pairs of gamma rays emitted indirectly by a positron-emitting radiotracer to achieve a higher spatial resolution than single photon imaging. This high resolution and the ability to cover the entire body in a single scan have made it a highly effective technique for the evaluation of skeletal metastatic disease, and it is now a routine combination with CT as PET/CT can provide combined functional and anatomical imaging data in unprecedented clarity and detail. 18F-FDG PET/CT now forms part of routine staging for many carcinomas, such as non-small cell lung carcinomas, and may obviate the need for routine staging scintigraphy in these patients. As uptake of the commonest PET radiotracer, 18F-FDG is dependent on the increased cellular metabolism of most tumours; it may enable earlier detection of metastatic foci than bone scintigraphy, which relies on detecting osteoblastic activity which may be difficult to visualise in the case of small metastases. Another significant advantage of 18F-FDG PET is that it can detect the soft tissue components of metastases. This is particularly important in aggressive osteolytic metastases, where invasion of adjacent connective tissue and muscle is frequent. The effectiveness of 18F-FDG PET is limited in slow-growing tumour types, but 18F-sodium fluoride, a bone radiotracer which can detect very early osteoblastic changes, already shows promise in this area. Bony metastases from many neuroendocrine tumours can be detected with a high degree of specificity by PET using somatostatin analogues. Other novel and often highly specific radiotracers are under evaluation which will further enhance its diagnostic capability. The true potential of PET in this group of malignancies is gradually unfolding; although studied series of patients remain generally small to date, a more detailed evaluation of its role will require the accrual of considerably more data.
Purpose:
The noninvasive imaging of bacterial infections is critical in order to reduce mortality and morbidity caused by these diseases. The recently reported (18)F-FDS ((18)F-2-fluorodeoxy sorbitol) as a PET (positron emission tomography) tracer can be used to image Enterobacteriaceae-specific infections and provides a potential alternative to this problem compared with other probes for imaging infections. In this study, automatic synthesis, validation of (18)F-FDS and a first-in-human study were performed and discussed.
Methods:
A multifunctional synthesis module was employed for the radiosynthesis of (18)F-FDG ((18)F-2-fluorodeoxy glucose) and (18)F-FDS starting from (18)F ion using two-pot three-step fully automated reactions. The behavior of (18)F-FDS as an in vivo imaging probe for infections was evaluated in an Escherichia coli mouse infection model. The first detailed pharmacokinetic and biodistribution parameters were obtained from healthy human volunteers.
Results:
The uptake of (18)F-FDS in an E. coli mouse-myositis infection model was easily differentiated from other organs and normal muscle. Intensive lesion uptake declined after antibiotic treatment. In the pilot human study, no adverse effects due to (18)F-FDS were observed up to 24h post-injection. The radiotracer was rapidly cleared from the circulation and excreted mainly through the urinary system.
Conclusion:
We conclude that (18)F-FDS PET holds great potential for appropriate and effective for the imaging of bacterial infections in vivo. These preliminary results indicate that further clinical studies are warranted.
Purpose:
We aimed to compare the efficacies of gallium-68 (68Ga) DOTATATE PET-computed tomography (CT), fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT and technetium-99m (99mTc)-(V)DMSA scintigraphy in the detection of residual/metastatic medullary thyroid carcinoma (MTC).
Materials and method:
We retrospectively evaluated DOTATATE PET-CT, 18F-FDG PET-CT and (V)DMSA scintigraphy of 22 MTC patients, all taken within a 6-month period in each patient, because of high levels of calcitonin (Ct) and carcinoembryonic antigen (CEA). We investigated the relationships between the results of the imaging modalities and tumour marker levels and the sporadic versus hereditary nature of the disease, as well as the effect of imaging results on patient management.
Results:
The ages of the patients at diagnosis were between 20 and 69 years. The median levels of Ct and CEA were 871.5 pg/ml and 11.2 ng/ml, respectively. In the patient-based analysis, we observed at least one focus of abnormal uptake in 15 of 22 DOTATATE PET-CT (68.2% sensitivity), eight of 18 18F-FDG PET-CT (44.4% sensitivity) and five of 15 (V)DMSA scans (33.3% sensitivity). These data showed a significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P=0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA scintigraphy showed no significant differences (P>0.05). In the lesion-based analysis, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy.
Conclusion:
DOTATATE PET-CT is an efficient imaging modality in MTC patients with increased Ct and CEA (especially >1000 pg/ml and 50 ng/ml, respectively) for localizing recurrent or metastatic disease. 18F-FDG PET-CT can be performed if DOTATATE PET-CT is not available, but (V)DMSA scintigraphy is not recommended.
In this case, we would like to share our experience of a recurrent medullary thyroid cancer patient whose recurrence was detected by Ga-68 DOTATATE PET/CT.
How to cite this article
Soydal C, Ozkan E, Araz M, Kucuk ON, Demirer T. Recurrent Medullary Carcinoma detected by Gallium-68 Positron Emission Tomography. World J Endoc Surg 2013;5(2):59-60.
Purpose
To evaluate the value of [18 F]FDG-PET/CT in the detection of metastatic medullary thyroid cancer.
Methods
From November 2006 to November 2012, 50 medullary thyroid cancer patients (median age 48.7 years old, range 18–76) who had a total thyroidectomy operation underwent whole body [18 F]FDG-PET/CT scans. The diagnostic accuracy of [18 F]FDG-PET/CT was determined through both lesion-based and patient-based analyses. Further pathological tests were performed on all identified lesions or clinically followed for a minimum period of 6 months.
Results
One hundred and forty-four suspicious lesions were identified by organ-based analysis. Of these lesions, [18 F]FDG-PET/CT detected 99 true positive lesions, sensitivity was 73.3%, specificity 66.7%. On the patient-based analysis, the overall sensitivity and specificity was calculated as 65.7% and 92.3%, respectively. Using a cut-off calcitonin value of 1000 pg/ml, in patients with calcitonin lower than this value, sensitivity and specificity were 42.9% and 91.0% respectively. In patients with calcitonin exceeding this value, they raised to 77.3% (X2 = 4.392, P < 0.05))and 100% (X2 = 0.197, P > 0.05), respectively. Compared with conventional imaging modality, PET/CT scans detected more lesions in 10 patients (20.4%) and correctly changed the treatment in 8 patients (16.3%).
Conclusion
[18F] FDG-PET/CT has excellent sensitivity and specificity especially when the calcitonin value is higher than 1000 pg/ml for detecting metastatic medullary thyroid cancer. Compared to conventional morphologic imaging methods it provides additional information for diagnosis
Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and medically challenging malignancy. Even if the extent of initial surgery is deemed adequate, the recurrence rate remains high, up to 50% in most series. Measurement of serum calcitonin is important in the follow-up of patients with MTC, and reliably reflects the existence of the disease.
There is no single sensitive diagnostic imaging method to reveal all MTC recurrences or metastases. Conventional morphologic imaging methods (U/S, CT, and MRI) and several methods of nuclear medicine have been used for this purpose with variable accuracy.
The main role of nuclear medicine imaging is the detection of residual or recurrent tumor in the postoperative follow-up. In this review we present the radiopharmaceuticals used in the diagnosis of MTC recurrence, and comparison among them.
The most used radiopharmaceuticals labelled with γ emitters are: Metaiodobenzylguanidine (MIBG), labelled with (131)I or (123)I, (111)In-pentetreotide (Octreoscan), 99mTc-pentavalent dimercaptosuccinic acid ((99m)Tc(V)-DMSA), and (99m)Tc-EDDA/HYNIC-Tyr3-Octreotide ( Tektrotyd). The radiopharmaceuticals labelled with a positron-emitting radionuclide (β+), suitable for positron emission tomography (PET) imaging are: (18)F-fluorodeoxyglucose ((18)F-FDG), (18)F-fluorodihydroxyphenylalanine (18F-DOPA), and 68Ga-labelled somatostatin analogues (68Ga-DOTATATE or DOTATOC).
Imaging of occupational lung disease, often perceived as a static discipline, continues to evolve with changes in industry and imaging technology. The challenge of accurately identifying an occupational exposure as the cause of lung disease demands a team approach, requiring integration of imaging features with exposure type, time course, and severity. Increasing use of computed tomography has demonstrated that specific occupational exposures can result in a variety of patterns of lung injury. The radiologist must understand the spectrum of expected imaging patterns related to known occupational exposures and must also recognize newly described occupational exposure risks, often related to recent changes in industrial practices. © RSNA, 2014.
Background/aim:
Residual or recurrent medullary thyroid carcinoma (MTC) after thyroidectomy is diagnosed by elevated serum calcitonin (CT) levels. However, in minimal residual MTC or C-cell hyperplasia (CCH), where imaging studies are often negative, basal CT levels are frequently normal and CT stimulation tests are required. We aimed to compare CT stimulation tests with calcium, pentagastrin and their combination in identifying minimal residual MTC and CCH.
Material and methods:
We studied 10 post-thyroidectomy patients with MTC and 20 first-degree relatives of the patients who had no clinically apparent MTC. We performed 54 combined (calcium plus pentagastrin) stimulation tests, 35 calcium stimulation tests and 26 pentagastrin stimulation tests.
Results:
Basal CT levels were abnormal (≥500 pg/ml) in 4 patients with apparent metastatic disease (Group 1A) and in 2 patients with minimal residual disease (Group 1B) but were normal (0-300 pg/ml) in 4 patients with no residual disease (Group 1C) and in the relatives (Group 2). In Groups 1A, 1B and 1C, maximal elevation in CT levels was greater after the combined stimulation test than after calcium or pentagastrin tests. The combined stimulation test induced the greatest increases (920, 700 and 706 pg/ml, respectively) in 3 relatives (Group 2); CCH was confirmed histologically in these patients. Side-effects were mild, short-lasting and of similar intensity and duration during all tests.
Conclusions:
Patients with subclinical MTC (minimal residual or recurrent MTC) or their relatives (with CCH) usually have normal basal CT levels and stimulation tests are necessary. Combined test represents the most sensitive and safe stimulation test for the diagnosis of subclinical hypercalcitonemia.
Patients with differentiated thyroid carcinoma usually have a good prognosis; however, up to 40% of them may develop local recurrence. PET scanning has added new information on disease evaluation. The most appropriate indication to fluorodeoxyglucose (FDG) PET scan is in evaluating patients with high thyroglobulin level when I-131 radioiodine whole-body scans are negative and in patients with medullary thyroid carcinoma when the serum calcitonin level is increased. PET scan is also useful in detecting intrathyroid lesions harboring malignancy when FDG uptake in the thyroid is noted incidentally in patients undergoing PET for another indication.
Positron emission tomography (PET) has evolved into a technique that can accurately determine the distribution of positron-emitting radionuclides. The addition of a coincidence detection mode to a standard dual-head detector system has resulted in the option of single-photon and annihilation coincidence detection. This new device for imaging fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) accumulation in neoplasms became commercially available in 1994. Besides conventional low-energy imaging in the collimated single-photon mode, it offers a relatively inexpensive opportunity to perform uncollimated PET by switching to the coincidence acquisition mode. This review summarises the clinical value of 18F-FDG detection with a dual-head coincidence camera in oncology. The results are compared with the overall results obtained using dedicated PET scanners. With respect to head and neck tumours, 18F-FDG coincidence mode gamma camera imaging (CGI) yields results that are in agreement with those obtained with dedicated PET scanners. With regard to other malignancies, such as lung cancer, lymphoma and brain tumours, data in the literature are too scarce to draw any definite conclusions. In general, the results of 18F-FDG CGI in tumours >15 mm seem to be comparable to those obtained with dedicated PET scanners, whereas in tumours 18F-FDG CGI is approximately 80%. Using attenuation correction, the diagnostic yield of 18F-FDG CGI may increase. However, further clinical investigation is required to definitely establish its value in staging primary disease, therapy monitoring and assessment of tumour recurrence in clinical oncology.
FDG PET can detect thyroid cancer in patients referred for exploration of a different cancer. Because of its lack of specificity, however, this modality is not indicated for examination of thyroid nodules: ultrasonography and fine needle biopsy with cytology allow histological diagnosis, which can be completed by iodine-123 scintigraphy when an autonomous nodule is suspected. No information is currently available about the utility of FDG PET in preoperative staging.
In follow-up of patients undergoing thyroidectomy for adenocarcinoma, FDG PET is useful for detecting recurrence in cases where serum thyroglobulin levels rise and iodine-131 scintigraphy is negative: surgical resection may be appropriate. Nonetheless FDG PET should be performed more widely and earlier: the initial presence of foci positive for FDG is a major predictor of shorter survival, and most cancer lesions take up either iodine or FDG.
In follow-up of medullary carcinoma, FDG PET detects residual tissue better than any other scintigraphic procedures, especially when serum levels of CEA (carcinoembryonic antigen) are rising rapidly.
FDOPA PET seems to have better sensitivity than FDG-PET and may be useful in occult recurrence, as three case reports indicate.
Several studies evaluated the diagnostic performance of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and positron emission tomography/computed tomography (PET/CT) in detecting recurrent medullary thyroid carcinoma (MTC) with conflicting results. Aim of our study is to meta-analyze published data about this topic. A comprehensive computer literature search of studies published in PubMed/MEDLINE, Scopus, and Embase databases through December 2011 and regarding FDG PET or PET/CT in patients with suspected recurrent MTC was carried out. Pooled detection rate (DR) on a per patient-based analysis was calculated to measure the diagnostic performance of FDG PET and PET/CT in this setting. A sub-analysis considering PET device used, serum calcitonin, carcino-embryonic antigen (CEA), calcitonin doubling time (CTDT), and CEA doubling time (CEADT) values was also performed. Twenty-four studies comprising 538 patients with suspected recurrent MTC were included. DR of FDG PET or PET/CT in suspected recurrent MTC on a per patient-based analysis was 59 % (95 % confidence interval: 54–63 %). Heterogeneity between the studies was revealed. DR increased in patients with serum calcitonin > 1,000 ng/L (75 %), CEA > 5 ng/ml (69 %), CTDT <12 months (76 %), and CEADT<24 months (91 %). In patients with suspected recurrent MTC FDG PET and PET/CT are associated with a non-optimal DR since about 40 % of suspected recurrent MTC remain usually unidentified. However, FDG PET and PET/CT could modify the patient management in a certain number of recurrent MTC because these methods are often
performed after negative conventional imaging studies. DR of FDG PET and PET/CT increases in patients with higher calcitonin and CEA values and lower CTDT and CEADT values, suggesting that these imaging methods could be very helpful in patients with more aggressive disease.
Medullary thyroid carcinoma (MTC) metastasizes very early lymphogeneously. It has been shown that the presence of lymph node metastases is associated with a worse outcome. Postoperative biochemical cure, i.e. normalization of posttherapeutical calcitonin levels, has been shown to correlate with a better outcome. The rate of biochemical cure decreases dramatically in the presence of lymph node metastases but can still be achieved in about 30-40% of patients despite the presence of lymph node metastases.
In 2009, the American Thyroid Association (ATA) published guidelines on the management of MTC. Various recommendations in the guidelines are dealing with the extent of lymph node dissection in different clinical settings. This article summarizes and comments on these recommendations.
Positron emission tomography (PET) has many clinical applications in oncology, neurology and cardiology. PET is widely available in developed countries, and has also become available in a number of middle-income countries, including South Africa. Commonly used PET radionuclides include fluorine-18, carbon-11, nitrogen-13 and oxygen-15, which are commonly found in organic chemistry and biochemistry. Undoubtedly the most important radiopharmaceutical used in PET scanning at present is [F-18]-FDG, which accumulates in many tumour cells. FDG PET imaging has some specific uses in the evaluation of patients with endocrine tumours. These include the detection of recurrent differentiated thyroid carcinoma in patients with a rising thyroglobulin level and negative iodine scan, and cases of recurrent medullary thyroid carcinoma with rising calcitonin levels. In parathyroid adenoma, FDG PET appears useful in cases where conventional nuclear medicine imaging is negative. For adrenal masses, FDG PET appears to be a highly accurate tool to distinguish benign from malignant lesions. The role of FDG PET in phaeochromocytomas, carcinoids and endocrine pancreatic tumours is probably limited to those that are less well differentiated and metabolically active. However, a future role for PET imaging in the detection of endocrine tumours, using more specific substrates, appears very promising.
Neuroendocrine tumors (NETs) encompass a wide range of rare and heterogeneous neoplasms arising from the neural crest. Diagnosis of NETs is conventionally done by a combination of common clinical symptoms and biochemical evidence of hormonal excess, which these tumors are known to secrete. After a diagnosis of NET is established, a search for its localization is carried out using common morphologic imaging methods such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). The main problem with structural imaging is, however, its inability to distinguish between endocrine and exocrine lesions. Functional imaging of NETs started with use of iodine-131-meta-iodobenzylguanidine ((131)I-MIBG) and has come a long way since. From accurate demonstration of functioning tumors to detection of small and occult lesions, functional imaging has penetrated almost every aspect of NET management. Procedures such as (131/123)I-MIBG, (111)In-Octreoscan and others are rapidly giving way to use of PET/CT based on the superior resolution of the system and the availability of target-specific positron-emitting radiotracers. The availability of (68)Ga from generator-based radionuclide systems, namely (68)Ge/(68)Ga generators, opened up a new era of molecular imaging for NETs. A multitude of somatostatin analogs can be easily radioliganded with (68)Ga using heterocyclic macromolecular bifunctional chelating systems for targeted diagnosis of somatostatin receptor-expressing tumors, used most effectively to date for detection of NETs. This chapter focuses on our experience at the All India Institute of Medical Sciences, New Delhi regarding the divergent roles of (68)Ga-labeled somatostatin analogs in the workup of patients with NETs.
Purpose. To perform an overview about the role of positron emission tomography (PET) or PET/computed tomography (PET/CT) using different radiopharmaceuticals in recurrent medullary thyroid carcinoma (MTC) based on biochemical findings (increased tumor marker levels after primary surgery). Methods. A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus, and Embase databases through February 2012 regarding PET or PET/CT in patients with recurrent MTC was performed. Results. Twenty-nine studies comprising 714 patients with suspected recurrent MTC were retrieved. Twenty-seven articles evaluated the role of fluorine-18-fluorodeoxyglucose (FDG) PET or PET/CT in recurrent MTC with conflicting results. Diagnostic accuracy of FDG-PET and PET/CT increased in MTC patients with higher calcitonin and carcinoembryonic antigen values, suggesting that these imaging methods could be very useful in patients with more advanced and aggressive disease. Eight articles evaluated the role of fluorine-18-dihydroxyphenylalanine (FDOPA) PET or PET/CT in recurrent MTC reporting promising results. Overall, FDOPA seems to be superior but complementary compared to FDG in detecting recurrent MTC. Few studies evaluating other PET tracers are also discussed. Conclusions. PET radiopharmaceuticals reflect different metabolic pathways in MTC. FDOPA seems to be the most useful PET tracer in detecting recurrent MTC based on rising levels of tumor markers. FDG may complement FDOPA in patients with more aggressive MTC.
Positron emission tomography, PET, is a potent imaging tool in the management of a diverse array of cancers. This chapter
briefly discusses the rationale for PET imaging and describes how it differs from more typical anatomic imaging, reviews the
principles of metabolic targeting with the radiolabeled glucose analogue 18F-fluoro-2-deoxy-d-glucose (FDG), and then describes the clinical results of PET imaging in several types of common cancers. Although there
are detailed descriptions of tumor imaging with other modalities in several areas of this textbook, the discussion here focuses
on the role of PET.
Thyroid cancer can be divided into three main groups: tumors with follicle cell differentiation (differentiated thyroid cancer),
tumors with C-cell differentiation (medullary thyroid cancer), and anaplastic carcinomas. The insular carcinoma takes an intermediate
place between differentiated and anaplastic cancer. Within the category of differentiated cancers, a distinction is made between
papillary and follicular tumors. Papillary tumors are found most frequently and several subtypes are defined referring to
tumor capsule invasion, the extent of invasion, the presence of sclerosis and oncocytic or oxyphil cells. The last subtype
is also called Hürthle-cell carcinoma and is of critical importance because iodine uptake is often low or completely missing.
C-cell cancer can develop spontaneously or be genetically determined as familial medullary cancer or in a multiple endocrine
neoplasia (MEN-2a/ MEN-2b).
Positron emission tomography (PET) is a diagnostic technique that has become an important method in oncology. The basis for
this test is the injection of a positron-emitting radionuclide that localizes in cancers and allows imaging. A positron is
a positive electron, and when emitted, travels a few millimeters before contacting an electron, which has a negative charge.
These particles of equal mass and opposite charges annihilate one another. The mass of the two electrons produces two photons
each with an energy of 511 keV. This is derived from the equation, e = mc2. The photons travel in opposing directions at an angle of 180°. A positron camera usually consists of a ring of detectors
that are designed to identify photons interacting at precisely the same time on opposite positions on the ring (180°).
Clinical thyroid cancer is an uncommon disease, representing only about 1% of all cancers. Microscopic papillary carcinomas,
however, are very common, with an incidence reported as high as 35.6%. The most common site for persistent disease, recurrence,
and lymph node metastases is the neck. Interpretation of PET images of the neck region presents a particular challenge. The
region shows substantial variations in normal uptake that can present difficulties in the identification of pathology. PET-CT
or PET fused with a diagnostic CT is of great help to differentiate between physiologic muscle uptake and pathologic uptake
in tumor or metastatic lymph nodes. FDG PET-CT is an expensive procedure and is probably most useful in patients with more
aggressive thyroid cancer before planned surgery or radiation therapy and to monitor such patients. Neck ultrasound, neck
and chest CT, and 131- or 123-I scanning will normally be the first line imaging modalities. In most studies evaluating PET
as a diagnostic tool in thyroid cancer, the PET examinations have been performed with PET only without integrated CT. Combined
PET-CT is shown to be more accurate than PET alone in the detection and anatomic localization, leading to improved diagnostic
accuracy in most cancers, including suspected recurrent or metastatic well-differentiated thyroid cancer. The role of FDG
PET in the diagnosis and follow-up medullary thyroid cancer is not well defined.
The optimal treatment for medullary thyroid cancer is total thyroidectomy and central nodal lymphadenectomy at presentation
when the primary cancer is small and has not metastasized significantly (1). In the three phenotypes of familial medullary cancer, i.e., familial medullary cancer, multiple endocrine neoplasia (MEN)
IIA, and MENIIB, screening of families for patients with a mutation in the RET proto-oncogene and a genetic predisposition for the diseases allows surgery at an even earlier stage (2–4). Unfortunately, not all patients are treated at the optimal time. Some patients with sporadic medullary cancer have extensive
local and distant metastases at the time of diagnosis. It is important to define the extent of disease when planning treatment.
Other patients who have undergone appropriate surgery are found to have a measurable calcitonin level after the operation.
This implies there is residual disease in the thyroid bed or lymph nodes or distant sites. It is helpful if the site or sites
of calcitonin production can be identified when they are small and amenable to removal at a reoperation.
Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy of combined [(18)F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and February 2011, 59 [(18)F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the 59 [(18)F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient sensitivity of [(18)F]FDG-PET/CT was 44.1%. Using as cut-off point the calcitonin value of 1000 pg/ml, in patients with calcitonin exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [(18)F]FDG-PET/CT was lower (23%) in patients with MEN IIA syndrome. Conclusion. The findings of this paper show that [(18)F]FDG-PET/CT is valuable for the detection of recurrence in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is questionable. Also, there is evidence that the sensitivity of [(18)F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA syndrome.
Neuroendocrine tumours (NETs) are rare, heterogeneous, and often hormonally active neoplasms. Nuclear medicine (NM) imaging using single photon- and positron-emitting radiopharmaceuticals allows sensitive and highly specific molecular imaging of NETs, complementary to anatomy-based techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI). Somatostatin-receptor scintigraphy is a whole-body imaging technique widely used for diagnosis, staging and restaging of NETs. The increasing availability of hybrid single-photon emission CT (SPECT)/CT cameras now offers superior accuracy for localization and functional characterization of NETs compared to traditional planar and SPECT imaging. The potential role of positron-emission tomography (PET) tracers in the functional imaging of NETs is also being increasingly recognized. In addition to 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG), newer positron-emitting radiopharmaceuticals such as (18)F-dihydroxyphenylalanine (DOPA) and (68)Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) peptides, show promise for the future. This article will summarize the role of current and emerging radiopharmaceuticals in NM imaging of this rare but important group of tumours.
To prospectively evaluate the role of Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI-octreotide (Ga-DOTA-NOC) PET-CT in patients with recurrent medullary thyroid carcinoma (MTC) and compare the same with F-fluorodeoxyglucose (F-FDG) PET-CT.
Fifty-two consecutive patients with recurrent MTC based on raised serum calcitonin levels underwent Ga-DOTA-NOC PET-CT. In addition, 41 patients also underwent F-FDG PET-CT. PET-CT images were evaluated by two experienced nuclear medicine physicians both qualitatively and quantitatively (standardized uptake value). Histopathology (when available), correlation with conventional imaging modalities (ultrasonography/CT/MRI) and subsequent clinical/imaging follow-up were used as reference standard. Serum calcitonin levels were correlated with findings of PET-CT.
Overall, Ga-DOTA-NOC PET-CT showed a sensitivity of 80.7% [95% confidence interval (CI) 67.4-90.3] and a positive predictive value of 100% (95% CI 91.5-100) for detecting recurrent MTC. When both were available (n=41), Ga-DOTA-NOC PET-CT proved superior to F-FDG PET-CT with a higher sensitivity (75.61 vs. 63.4%). However, the difference was statistically not significant (P=0.179). Ga-DOTA-NOC PET-CT was superior to F-FDG PET-CT for detecting recurrence in cervical lymph nodes (P<0.001). Both modalities were concordant in 75% of cases. No significant cut-off level of calcitonin could be derived for either Ga-DOTA-NOC or F-FDG PET-CT.
Both Ga-DOTA-NOC PET-CT and F-FDG PET-CT are able to localize disease recurrence in patients with MTC, and their role appears to be complementary for this purpose.
The aim of this study was to investigate diagnostic performance of (18) F-fluorodeoxyglucose position emission tomography (FDG-PET) and PET/computed tomography (PET/CT) for detection of recurrent or metastatic medullary thyroid carcinoma (MTC) in patients after surgery with a meta-analysis. MEDLINE and EMBASE databases were searched for relevant articles. Two investigators independently extracted the data about study characteristics and examination results. Pooled estimates of sensitivity of FDG-PET or FDG-PET/CT were obtained. Fifteen studies met all inclusion criteria. The sensitivity of FDG-PET ranged from 0.47 (95% confidence intervals (CI): 0.21-0.73) to 0.96 (95%CI: 0.86-0.99), the sensitivity of FDG-PET/CT ranger from 0.47 (95% CI: 0.31-0.64) to 0.80 (95% CI: 0.65-0.90). The pooled sensitivities of FDG-PET and PET/CT were 0.68 (95% CI: 0.64-0.72) and 0.69 (95% CI: 0.64-0.74), respectively. There was no statistic significant between FDG-PET and PET/CT. Our results indicate that FDG-PET or FDG-PET/CT has reasonable sensitivity in detecting recurrent or metastatic MTC after primary surgery. However, no single diagnostic technique is able to reliably demonstrate the full extent of disease in patients with recurrent or metastatic MTC, the combination of cross-sectional radiography with FDG-PET or PET/CT is recommended.
To retrospectively evaluate and compare (18)F-FDG, (18)F-DOPA and (68)Ga-somatostatin analogues for PET/CT in patients with residual/recurrent medullary thyroid carcinoma (MTC) suspected on the basis of elevated serum calcitonin levels.
Included in the study were 18 patients with recurrent MTC in whom functional imaging with the three tracers was performed. The PET/CT results were compared on a per-patient basis and on a per-lesion-basis.
At least one focus of abnormal uptake was observed on PET/CT in 13 patients with (18)F-DOPA (72.2% sensitivity), in 6 patients with (68)Ga-somatostatin analogues (33.3%) and in 3 patients with (18)F-FDG (16.7%) (p < 0.01). There was a statistically significant difference in sensitivity between (18)F-DOPA and (18)F-FDG PET/CT (p < 0.01) and between (18)F-DOPA and (68)Ga-somatostatin analogue PET/CT (p = 0.04). Overall, 72 lesions were identified on PET/CT with the three tracers. (18)F-DOPA PET/CT detected 85% of lesions (61 of 72), (68)Ga-somatostatin analogue PET/CT 20% (14 of 72) and (18)F-FDG PET/CT 28% (20 of 72). There was a statistically significant difference in the number of lymph node, liver and bone lesions detected with the three tracers (p < 0.01). In particular, post-hoc tests showed a significant difference in the number of lymph node, liver and bone lesions detected by (18)F-DOPA PET/CT and (18)F-FDG PET/CT (p < 0.01 for all the analyses) and by (18)F-DOPA PET/CT and (68)Ga-somatostatin analogue PET/CT (p < 0.01 for all the analyses). The PET/CT results led to a change in management of eight patients (44%).
(18)F-DOPA PET/CT seems to be the most useful imaging method for detecting recurrent MTC lesions in patients with elevated serum calcitonin levels, performing better than (18)F-FDG and (68)Ga-somatostatin analogue PET/CT. (18)F-FDG may complement (18)F-DOPA in patients with an aggressive tumour.
Medullary thyroid cancer (MTC) arises from parafollicular C cells and is an elusive tumor to image. It occurs as a sporadic neoplasm in 70-80% of cases and is hereditary in 20-30% because of germline mutations of the rearranged during transfection proto-oncogene. Successful disease management relies on accurate staging. Tumor secretory biomarkers are highly sensitive to a disease; however, despite a wide variety of radiopharmaceuticals for molecular imaging that take advantage of hybrid SPECT/CT and PET/CT fusion imaging, imaging of MTC is still problematic. After initial surgical resection, the limited sensitivity of localization of small locoregional disease and the inability to detect early liver metastases hamper the success of later surgical approaches. F-fluorodeoxyglucose PET has been used to detect MTC recurrences with modest success and may be best suited for only a small subset of more biologically aggressive MTCs. Recent developments in PET imaging with novel radiopharmaceuticals targeting specific cellular processes of MTC offer increased sensitivity for identifying recurrence, assessing prognosis, and guiding selection of optimal therapies.
Unlabelled:
Serum calcitonin and carcinoembryonic antigen (CEA) are markers of recurrent or persistent disease in medullary thyroid cancer (MTC). However, conventional imaging often fails to localize metastatic disease. Our aim was to compare fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) and (18)F-FDG PET/CT with multidetector CT (MDCT) and MRI in recurrent or persistent MTC.
Methods:
Nineteen MTC patients with increased calcitonin or CEA on follow-up (mean ± SD, 93 ± 91 mo; range, 4-300 mo) after primary therapy were prospectively imaged with 4 techniques: (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI. Images were analyzed for pathologic lesions, which were surgically removed when possible. The correlation between the detection rate for each method and the calcitonin and CEA concentrations and histopathologic findings was investigated.
Results:
On the basis of histology and follow-up, one or more imaging methods accurately localized metastatic disease in 12 (63%) of 19 patients. The corresponding figures for (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI were 11 (58%) of 19, 10 (53%) of 19, 9 (47%) of 19, and 10 (59%) of 17, respectively. Calcitonin and CEA correlated with (18)F-DOPA PET/CT (P = 0.0007 and P = 0.0263, respectively) and (18)F-FDG PET/CT findings (both P < 0.0001). In patients with an unstable calcitonin doubling time (n = 8), (18)F-DOPA and (18)F-FDG PET/CT were equally sensitive. In contrast, for patients with an unstable CEA doubling time (n = 4), (18)F-FDG PET/CT was more accurate.
Conclusion:
For most MTC patients with occult disease, (18)F-DOPA PET/CT accurately detects metastases. In patients with an unstable calcitonin level, (18)F-DOPA PET/CT and (18)F-FDG PET/CT are complementary. For patients with an unstable CEA doubling time, (18)F-FDG PET/CT may be more feasible. MRI is sensitive but has the highest rate of false-positive results.
Thyroid cancer is the most common endocrine malignancy in adults. The disease is classified into papillary, follicular, medullary and anaplastic types, each with characteristic histology and patterns of biological behavior. Diagnosis of thyroid cancer is usually made by needle aspiration of suspicious thyroid nodules. Disease management of well-differentiated thyroid cancer relies upon characteristic accumulation of radioisotopes of iodine that continues to play a central role in detection and treatment of disease. Recombinant human thyrotropin (rhTSH) is used as an alternative to thyroid hormone withdrawal to provide TSH stimulation necessary for diagnostic radioiodine scintigraphy and preparation for thyroid remnant ablation and cancer therapy. Hybrid SPECT/CT cameras combining functional scintigraphic information with CT anatomy are replacing stand-alone gamma cameras and these devices have been shown to outperform traditional planar and SPECT imaging techniques. Similarly, clinical application of novel radioisotopes like [124I]iodine with PET/CT for thyroid cancer imaging provides improved lesion resolution and direct tumor dosimetry. Alternative tracers such as [18F]fluorodeoxyglucose (FDG) can be used to evaluate well-differentiated thyroid cancers that no longer express the Na+/I- symporter, with a role in staging Hürthle cell, poorly differentiated, and anaplastic thyroid cancers. Medullary thyroid cancer recurrences are often difficult to detect using conventional imaging and traditional radionuclide studies, whereas [18F]FDG and [18F]fluorodihydroxyphenylalanine (DOPA) PET and PET/CT show promise for localizing the often elusive source (s) of elevated calcitonin in these patients.
Positron emission tomography (PET) has seen an increasing clinical utilization in the last decade, such that it is now a standard oncology imaging modality. Its success is based on the detection of altered fluorine-18 fluorodeoxyglucose (18F-FDG) biodistribution, reflecting glucose transport/metabolism in malignant tumor tissues. Integrated PET/computed tomography cameras combine functional and anatomical information in a synergistic manner that improves diagnostic interpretation, and newer positron-emitting radiopharmaceuticals have been developed to expand the application of non-FDG PET imaging. The increasing use of cross-sectional imaging procedures has led to a more frequent detection of incidental adrenal masses. Although conventional imaging modalities such as computed tomography and MRI can characterize the majority of these lesions, 18F-FDG PET has been reported as a useful tool to distinguish benign from malignant etiologies in indeterminate adrenal masses. Although 18F-FDG PET has enjoyed success in staging a wide range of cancers, including detection of adrenal metastases and evaluation of adrenocortical carcinoma, it has had limited impact for the evaluation of neuroendocrine tumors. Positron-emitting amine precursor and somatostatin analogs have been validated in research settings to provide accurate imaging of enterochromaffin and chromaffin neuroendocrine tumors and medullary thyroid cancer. The aim of this review article is to provide an overview of the role of 18F-FDG and newer positron-emitting radiopharmaceuticals in the evaluation of adrenal and neuroendocrine tumors.
The introduction of PET(-CT) has brought about a major paradigm shift in the management of thyroid carcinoma, especially from the diagnostic standpoint. From the viewpoint of patient management, the areas where it has made significant impact include the following: (1) the detection of disease focus in patients with differentiated thyroid carcinoma with elevated Tg levels and negative radioiodine scan. When localized disease is identified with F-18 FDG-PET-CT, surgery or focused radiotherapy could be utilized to eradicate the tumor; (2) the localization of disease in patients of MTC with elevated serum calcitonin levels; (3) the detection of unsuspected focal F-18 FDG uptake in the thyroid in patients undergoing whole body F-18 FDG PET for a different indication. This would prompt a workup to rule out thyroid carcinoma. The use of I-124 is evolving at this time and has been of great promise with regard to (a) its better efficacy of lesion detection and (b) the ability to provide lesion-specific dosimetry. In addition, F-18 FDG PET appears to be of potential value in patients with thyroid lymphoma in making the initial diagnosis, monitoring therapeutic response, and assessing for residual disease and/or recurrence.
Serum calcitonin levels before (S1) and after (S2) surgery were measured in 67 patients with medullary thyroid carcinoma and the patients were followed with serial calcitonin measurements for a mean duration of 7 years. The calcitonin doubling time (T2) was calculated in patients with elevated postoperative calcitonin levels. Assuming that the serum calcitonin level is linearly correlated with tumor weight, the residual tumor weight (W2) is estimated as W1S2/(S1−S2) where W1 is the weight of the resected tumor. The reduction index (α) is defined as W2/(W1+W2)=(1/2)α.α
T
2indicates the expected prolongation in survival (EPS) by surgery. The survival index (β)is defined as the number of doublings of residual tumor until it weighs 1,000 g, which would generally kill the host. The expected duration of survival (EDS) after surgery is estimated as
β
T
2.Death within 3 years after surgery or recurrence within 5 years was best associated with short EPS followed by short T
2 or smallα.S
2had a rather weak correlation and S
1had almost no correlation with the prognosis. The duration of survival in 3 patients who died of the disease was very close to the EDS. T
2indicates growth rate of the tumor,α
indicates degree of radicality of the surgery, EPS indicates the effects of the surgery, and EDS indicates duration of survival after surgery. These parameters allow quantitative judgment of the effect of surgery and quantitative prediction of the prognosis in each patient.
High-frequency, high-resolution sonography was used to detect recurrent thyroid carcinoma in 73 patients with papillary carcinoma, 16 with medullary carcinoma, 10 with follicular carcinoma, and one with small-cell carcinoma. Of the 36 patients with negative sonograms, 35 had no other evidence of recurrence, while one had surgical proof of recurrence. Of 25 patients with positive sonograms, confirmed with surgery or radioactive iodine (I131) scanning (sonographic sensitivity 96%, specificity 83%), palpation was negative in 17 (palpation sensitivity 32%, specificity 100%). Thirty-two patient with positive sonographic findings had no objective clinical proof of recurrence. There were seven false-positive studies. This study suggests that sonography may be the method of choice for earliest detection and localization of recurrent carcinoma of the thyroid.
We evaluated the clinical utility of positive somatostatin receptor scintigraphy in patients with medullary thyroid cancer (MTC).
Twenty-four MTC patients with increased calcitonin levels underwent somatostatin receptor scintigraphy using 111In-pentetreotide (120-200 MBq) with early (4 hr after injection) and delayed (24 hr) whole-body scans and liver SPECT imaging. In Group 1 (12 patients), conventional imaging modalities demonstrated the presence of tumor sites prior to somatostatin receptor scintigraphy; in Group 2 (12 patients), conventional imaging modalities were negative or inconclusive.
Somatostatin receptor scintigraphy had positive results in 9 of 24 patients (37%): of Group 1 patients, 7 of 12 had positive somatostatin receptor scintigraphy results. Of these patients cases, somatostatin receptor scintigraphy demonstrated several involved organs and tumor sites either identical (two patients) or smaller (five patients) in size than conventional imaging modalities. Only two patients in Group 2 had positive somatostatin receptor scintigraphy results which demonstrated significant mediastinal uptake previously classified as indeterminate on conventional imaging modalities. No new tumor site was identified nor were therapeutic options modified by the somatostatin receptor scintigraphy results.
Somatostatin receptor scintigraphy only demonstrates part of tumor sites and cannot visualize small tumor sites (< or = 1 cm). We believe that somatostatin receptor scintigraphy has a limited role in the management of MTC patients.
Scintigraphy using [111In-DTPA-d-Phe1]-pentetreotide or pentavalent technetium-99m-dimercaptosuccinic acid [99mTc(V)-DMSA] has been shown to localize well-differentiated and slowly growing neuroendocrine tumours, whereas increased fluorodeoxyglucose (FDG) uptake is associated with malignancy. The aim of this study was to compare the value of fluorine-18 FDG positron emission tomography (PET) with that of somatostatin receptor scintigraphy (SS-R) and dual-radionuclide scintigraphy [SS-R and 99mTc(V)-DMSA = DNS] in detecting malignant neuroendocrine tumours. Fifteen patients with metastasizing gastroenteropancreatic tumours (GEP tumours; n = 7), medullary thyroid carcinomas (MTCs; n = 8) and elevated tumour markers [GEP tumours: 5-hydroxyindoleacetic acid, insulin; MTCs: calcitonin, carcinoembryonic antigen (CEA)] were studied. Prior to PET, all patients with GEP tumours underwent SS-R. DNS was performed in all patients with MTC. Patients had been fasting for at least 12 h and normal glucose plasma levels were confirmed. Sixty minutes after intravenous administration of 18F-FDG (mean: 374 MBq) whole-body PET and regional scans were performed. In addition, the resected tissues were prepared for immunocytochemistry examination (cell cycle-associated Ki-67 antigen). In two patients with less-differentiated GEP tumours associated with high proliferative activity and increased FDG uptake, SS-R failed to detect any lesion. In comparison, in four patients with well-differentiated GEP tumours showing low proliferative activity, SS-R localized four primary tumours, 22 lymph node metastases and 18 malignant liver lesions, whereas 18F-FDG PET demonstrated normal distribution. In one patient with a metastasizing carcinoid (medium proliferative activity) SS-R localized multiple metastases, whereas PET demonstrated low FDG uptake in all known metastases. In patients with recurrent MTC and rapidly increasing CEA levels DNS detected only three lesions in two patients, whereas PET demonstrated one pulmonary, three osseous, 20 mediastinal, ten locoregional, and four liver metastases in seven patients. Twenty-nine malignant lesions were confirmed by follow-up and nine lymph node metastases could be surgically removed. In conclusion, PET imaging of gastroenteropancreatic tumours revealed increased glucose metabolism only in less-differentiated GEP tumours with high proliferative activity and metastasizing MTC associated with rapidly increasing CEA levels. Therefore, additional 18F-FDG PET should be performed only if SS-R or DNS is negative.
Tumor scintigraphy with flow tracers, such as 201TI-chloride, has an established role in the follow-up of differentiated thyroid cancer. We investigated a new tracer, 99mTc-furifosmin (Technescan Q12, Mallinckrodt Diagnostika, Hennef, Germany), in patients with elevated thyroglobulin levels or sonographic suspicion of lymph node metastases or recurrent disease.
In a prospective study, we examined 20 patients with 99mTc-furifosmin. All patients underwent a 18F-fluorodeoxyglucose (FDG) PET scan of the neck and chest. Positive 99mTc-furifosmin findings were validated by biopsy, (131)I scan, CT or 18F-FDG PET examinations.
In three patients with cervical lymph node metastases detected on a planar 99mTc-furifosmin scan, we found a rapid tracer accumulation in the tumor (maximum < 2 min) and a significant washout in 2 of 3 patients after 4 hr. The visual contrast and the tumor-to-nontumor ratio was rather poor (average 1.2:1). In 3 additional patients, 3 pulmonary and 2 mediastinal lymph node metastases were detected by the 99mTc-furifosmin SPECT scan. Two patients were true-negative, and in 13 of 18 patients, the tumor could be localized by 18F-FDG PET (10 cervical, 6 mediastinal, 4 pulmonary metastases, 1 bone metastasis); 5 patients were false-negative. In 3 of these false-negative cases we could not localize the tumor with other diagnostic methods. Two patients had a true-negative PET examination.
The statistical analysis of our data on 99mTc-furifosmin reveals that the sensitivity and 95% confidence interval of 33% (11%-56%) on a patient-by-patient basis and of 34% (17%-57%) for the lesion-by-lesion analysis is significantly lower than the sensitivity and 95% confidence interval of 72% (50%-89%) on a patient-by-patient basis and of 91% (78%-100%) on lesion-by-lesion basis for 18F-FDG. The sensitivity of 99mTc-furifosmin appears to be poor, even for cervical and mediastinal tumor manifestations where the value of 201TI-chloride is established.
Zusammenfassung
In dieser Studie wurden 24 Patienten mit medullären Schilddrüsenkarzinomen (MTC) und 10 Patienten mit gastro-entero-pankreatischen (GEP-)Tumoren oder Karzinoiden mittels Somatostatinrezeptorszintigraphie untersucht. Als Radio-pharmakon kamen 123I-Tyr3-Oktreotid 19mal, 111In-DTPA-D-Phe1-Oktreotid (Octreoscan®) 25mal und 99mTc-V-DMSA 14mal zur Anwendung. Die MTC-Pati-enten waren durch das Kalzitonin und/oder das CEA, die übrigen durch Tumornachweis auffällig. Die Octreoscan®-Szintigraphie fiel in 68% aller tumorsuspekten Fälle positiv aus, die123I-Tyr3-Oktreotid-Szintigraphie dagegen in nur ca. 11%. 99mTc-V-DMSA-Untersuchungen bei MTC-Patienten fielen in 23% positiv aus. Lebermetastasen ließen sich bei MTC-Patienten (im Gegensatz zu den GEP-Patienten) nicht nachweisen. Die Ergebnisse lassen Octreoscan® überlegen erscheinen.
Between 1977 and 1990 we operated on 33 patients with medullary thyroid carcinoma. We performed total thyroidectomy in 31 patients and central node dissection and/or lateral modified node dissection in 21 patients (63.3%). Two patients underwent radiotherapy after subtotal resection and tracheostomy. No perioperative death occurred. Twenty-five patients were followed (mean follow-up, 63.8 months) and 8 others were unavailable for follow-up. Three patients (1 with multiple endocrine neoplasia type IIB, 2 sporadic with distant metastases) died of their disease at 12, 18 and 36 months after initial operation. Of the remaining 22 patients, 4 with stage II disease were normocalcitoninemic even with pentagastrin stimulation, following total thyroidectomy and bilateral modified neck dissection and central node dissection. Eighteen other patients continued to have elevated calcitonin levels postoperatively. Only 10 patients with known cervical metastatic disease were reoperated upon. We performed extensive node dissection in all. In addition we resected recurrent tumor from the thyroid bed in 4 patients. Despite these extensive reoperations no patient became normocalcitoninemic. At the completion of the study (December 1991), 22 of the 25 patients followed were alive: 4 patients with normal calcitonin levels, baseline and after pentagastrin stimulation, and 18 with persistent mildly elevated calcitonin levels but no other evidence of disease. Our experience supports a very aggressive surgical approach at the time of the first operation for patients with medullary thyroid carcinoma. A lesser operation usually resulted in residual medullary thyroid carcinoma in the neck. We demonstrate the difficulty of achieving a cure by reoperation once the tumor becomes demonstrable by localization studies.
Schilddrsenkarzinome knnen das Mediastinum infiltrieren durch direkte Ausdehnung des Primrtumors oder Metastasierung in die paratrachealen oder retroklavikulr-parajugulren Lymphknoten. Von 1975–1991 wurde bei 47 von 622 Schilddrsenkarzinom-patienten [7,6%, 14 papillary (PTC), 5 follikuldre (FTC), 16 medullre (MTC) und 12 undifferenzierte Karzinome (UTC)] eine transsternale Tumorresektion durchgefhrt. Vier Patienten mit UTC bzw. MTC verstarben 7, 8, 35 und 41 Tage nach der Primrtumorresektion an den Folgen kardialer Vorerkrankungen bzw. am Tumorleiden und, in einem Fall, an einer akuten arteriotrachealen Blutung nach hyperfraktionierter Radiatio; nach transsternaler zervikomediastinaler Lymphadenektomie traten keine letalen Komplikationen auf. 80% der Patienten hatten zum Zeitpunkt der Primroperation ein fortgeschrittenes Tumorstadium (> pT3). 34% (PTC 64%, FTC 40%, MTC 13%, UTC 25%) waren postoperativ bildgebend und laborchemisch tumorfrei. Bei 18 Patienten wurde eine transsternale Mikrodissektion aller vier zervikomediastinalen Lymphknotenkompartimente durchgefhrt. Die histologische Auswertung der entnommenen und tumorbefallenen Lymphknoten ergab bei je 9 Patienten eine unilateral-zervikale und mediastinale oder eine bilateral-zervikale und mediastinale Lymphknotenmetastasierung. Bei unilateral-zervikomediastinaler Lymphknotenmetastasierung konnte bei 2 von 2 Patienten mit papillrem und bei 2 von 6 Patienten mit medullrem Schilddrsenkarzinom Tumorfreiheit erreicht werden. Bei bilateral-zervikomediastinaler Lymphknoten-metastasierung waren 3 von 4 Patienten mit papillrem, jedoch kein Patient mit anderen Karzinomtypen im postoperativen Verlauf tumorfrei. Als bevorzugte Indikationen zur transsternalen zervikomediastinalen Tumor-resektion beim Schilddrsenkarzinom sind somit anzusehen: Primrtumoren mit zervikomediastinaler Ausdehnung ohne Lymphknotenmetastasen und lymphogen metastasierte Schilddrsenkarzinome mit unilateral-zervikomediastinalem Lymphknotenbefall. Bei bilateral-zervikomediastinalen Lymphknotenmetastasen besteht wahrscheinlich nur beim papilldren Karzinomtyp Aussicht, durch eine transsternale Mehrkompartmentektomie Tumorfreiheit zu erreichen.Thyroid carcinoma may invade the mediastinum by direct extension of the primary tumor or metastases to the paratracheal or retroclavicular-parajugular lymph nodes. From 1975 to 1991 in 47 out of 622 thyroid cancer patients (7.6%) [14 papillary (PTC), 5 follicular (FTC), 16 medullary (MTC) and 12 undifferentiated carcinoma (UTC)] transsternal tumor resection has been performed. Four patients (UTC three, MTC one) deceased 7, 8, 35, and 41 days after resection of the primary tumor due to cardiac or tumor disease, and in one patient because of acute arteriotracheal haemorrhage after external irradiation; no patient deceased after transsternal resection as a result of cervicomediastinal lymphadenectomy. At the time of primary operation 80% of patients showed an advanced tumor stage (> pT3). In 34% of patients (PTC 64%, FTC 40%, MTC 13%, UTC 25%) no tumor recurrence was observed neither by imaging nor by biochemical methods. In 18 patients a transsternal microdissection of all four cervico-mediastinal lymph node compartments has been performed. Histological analyses of excised and tumor involved lymph nodes revealed in 9 patients unilateral cervical and mediastinal and in 9 patients bilateral cervical and mediastinal lymph node metastases. In the case of unilateral cervicomediastinal lymph node metastases 2 out of 2 patients with papillary and 2 out of 6 patients with medullary thyroid carcinoma could be cured surgically. In the case of bilateral cervicomediastinal lymph node metastases 3 out of 4 patients with papillary thyroid carcinoma, but no other thyroid cancer patient were free of disease. In conclusion, main indications for transsternal cervicomediastinal resection in thyroid carcinoma are (1) primary tumors extending to the upper mediastinum, but without lymph node metastases, and (2) thyroid carcinomas with unilateral cervicomediastinal lymph node metastases. In the case of bilateral cervicomediastinal lymph node metastases probable only papillary thyroid carcinomas are supposed to be curable by transsternal multicompartmentectomy.
In persistent, clinically inapparent medullary thyroid carcinoma, microsurgical dissection of all lymph node compartments of the neck was performed. Between August 1988 and September 1991, 28 cases (mean age 43.3 years) were treated with 38 surgical interventions. Twenty patients had the sporadic form and eight patients the familial form. Unilateral neck dissection resulted in normalization of serum calcitonin (CT) levels even after pentagastrin stimulation in two patients whereas 16 patients exhibited abnormal CT stimulation tests. Eight of ten patients who had bilateral neck dissections had positive pentagastrin test results after surgery. The main postoperative complications included loss of local cutaneous sensation, generally temporary, and unilateral recurrent laryngeal nerve paralysis.
Recent linkage of the gene for multiple endocrine neoplasia type 2A and 2B to the centromeric region of chromosome 10 has provided new insight into the causes of medullary thyroid carcinoma and has provided tools to diagnose gene carriers status for this syndrome with greater than 90% certainty. This review focuses on how these advances influence the clinical management of both sporadic and hereditary medullary thyroid carcinoma and discusses how tests based on the genetic linkage studies will aid in the early diagnosis and treatment of this syndrome. In addition, the authors have focused on several controversial management questions regarding the type and extent of surgery for this thyroid tumor, the management of the patient with metastatic disease, and the approach to management of other manifestations of multiple endocrine neoplasia types 2A and 2B. This review attempts to provide a balanced overview of these complex issues.
Patients with medullary thyroid carcinomas (MTC) were analyzed according to age, sex, and tumor stage. In addition, the MTC were screened for the predominant histologic pattern, immunocytochemical spectrum (60 tumors), and DNA content (DNA cytophotometry and DNA flow cytometry, 25 tumors). These findings were correlated with follow-up data available for 45 of these patients. Forty-eight percent of the tumors revealed a polygonal cell pattern, whereas 22% showed spindle-cell predominance. All tumors contained cytokeratin, chromogranin A, and calcitonin (CT). Calcitonin gene-related peptide (CGRP) was present in 92%, carcinoembryonic antigen (CEA) in 77%, neuron-specific enolase (NSE) in 75%, and vimentin in 53% of cases. Positivity for neurotensin, somatostatin, neurofilaments, bombesin, and alpha human chorionic gonadotropin (a-hCG) and serotonin ranged between 3% and 27%. All MTC were negative for substance P, adrenocorticotropic hormone (ACTH), thyroglobulin (TG), or S-100 protein. Local recurrences and regional lymph node metastases revealed identical staining patterns as the primaries. Prognosis of MTC was found not to be related to histologic features (dominant architectural pattern, cellular shape, presence of amyloid deposits) or immunocytochemical pattern. Instead, survival was significantly correlated to age, sex, and stage of disease. The best prognosis was seen in women younger than 40 years and revealing an early stage of disease. DNA measurements added valuable information in assessing the prognosis of MTC.
Elevated calcitonin (CT) levels after primary operation of the medullary thyroid carcinoma (MTC) are a reliable marker for persistence or recurrence of MTC, which first metastasizes in the neck or mediastinal region. The reliability of different localisation methods before reoperation in 28 patients with elevated CT levels was tested by comparing their diagnostic results with the actual finding at reoperation. The diagnostic procedures comprised ultrasonography of the neck, CAT-scan of the neck and mediastinum, selective venous catheterization with CT determinations, and fine needle biopsy. Due to the results of these tests 28 patients were reoperated 48 times. Histological evidence confirmed the presence of suspected tumor that had been diagnosed by: palpation 52%, ultrasonography 78%, CAT-scan 70%, selective venous catheterization 75%, fine needle biopsy 81%. Despite the fact that only 2 out of the 28 patients had normal CT levels postoperatively, the 5 year survival rate in reoperated patients (86%) improved compared to patients without reintervention (69%). For precise preoperative staging ultrasonography seems to be the most predictable and reliable method. The prognosis of MTC patients with elevated CT-levels in the follow-up period could be improved by frequent reoperations.
We have investigated the levels of serum calcitonin and calcitonin-gene related peptide (CGRP) in 35 patients with well-documented medullary thyroid carcinoma (MTC). Immunohistochemical investigations for calcitonin and CGRP have been performed on tumour tissue from 9 patients to clarify the cellular pattern of production. In four patients with aggressive disease, serum calcitonin and CGRP values have been monitored in relation to progression of disease after surgery. All 35 patients with MTC have elevated calcitonin and 26 elevated CGRP levels. Generally calcitonin values were found to be higher than those of CGRP, although the ratio of the two peptides varied from patient to patient. The immunohistochemical investigations corresponded with these findings, generally showing diffuse staining for calcitonin in MTC tumour-cells and only a small number of CGRP positive cells. Calcitonin and CGRP are produced by alternative processing of the common precursor gene transcript. Our results suggest that absolute values of either calcitonin or CGRP in serum have no direct relationship to aggressiveness of disease. Thus whilst serum CGRP measurements appear to be a useful additional marker for the disease, they can be considered to be only a useful adjunct to serum calcitonin as a marker for tumour progression.
Magnetic resonance (MR) imaging was used in 32 patients, including eight with benign disease, after partial or total thyroidectomy to determine sensitivity and specificity of MR imaging in the detection of tumor recurrence, to compare signal intensities of scar versus recurrent tumor qualitatively and quantitatively, and to define the extent of recurrent tumor. Findings from surgery (n = 23), needle biopsy (n = 1), or clinical follow-up (n = 8) were used for verification. Of 24 patients with primary thyroid carcinoma, 15 had recurrence and nine had a normal postsurgical thyroid bed. Diagnosis from MR images was correct in 20 cases, but false positive in three and false negative in one. Local recurrence was characterized by low to medium intensity on short repetition time (TR)/short echo time (TE) images and medium to high intensity on long TR/long TE images. Scar in the normal postsurgical thyroid bed showed low intensity on both short and long TR/TE images. Local recurrence of thyroid carcinoma and lymph node metastasis produced positive contrast compared with muscle on short TR/short TE (31 + 19%) and long TR/long TE (85 + 30%) images; fibrosis produced negative contrast, particularly on long TR/long TE (-56, -80%) images. These results indicate the capability of MR imaging in the evaluation of recurrence of thyroid tumors and in the differentiation of abnormal tissue due to tumor recurrence from postoperative fibrosis by means of signal contrast relative to a reference tissue.
Seventy-five patients with medullary thyroid carcinoma (MTC) have been treated at Institut Gustave-Roussy from 1932 to 1979. Of these, 13 patients had distant metastases and received palliative treatment, their median survival was 3 years. Sixty-two patients with MTC limited to the neck received curative treatment; 6 had exclusive external radiotherapy for inoperable disease and 56 were surgically treated: 23 by total thyroidectomy and 33 by partial thyroidectomy. After surgery 29 patients received external radiotherapy for cervical lymph node involvement (25/29) and/or incomplete surgical resection (12/27). The survival rate was 69% at 5 years and 48% at 10 years. It was lower in patients with distant metastases at presentation (p less than 10(-5)), with tumoral infiltration of the posterior tissue planes (p less than 0.025) and in patients in whom surgical excision had not been satisfactory (p less than 0.01). It was not correlated with cervical lymph node involvement probably because those patients with lymph node involvement had been irradiated. The 29 patients who received post-operative cervical radiotherapy had initially more extensive local disease (p less than 0.05) than the 27 patients treated by surgery alone, nevertheless their survival was slightly higher. No difference in survival rate was observed between patients treated by total thyroidectomy or partial thyroidectomy, among whom only 4 local recurrences occurred. Three of the 6 patients treated with external radiotherapy alone experienced long survival (4, 7 and 10 years) and a fourth is still in clinical remission 4 years after treatment. The effectiveness of chemotherapy in patients with metastases was poor, only one patient out of 6 had a partial remission following a treatment by adriamycin. In the familial form and multiple endocrine neoplasia type II, total thyroidectomy appears to be indicated. In the sporadic cases, partial thyroidectomy is usually sufficient. External radiotherapy is effective in MTC and seems to be able to eradicate small foci of residual tumor; it is indicated when surgical excision is impossible or incomplete.
To determine the value of adjunct 131I therapy in medullary carcinoma of the thyroid (MCT), two groups of patients with histologically proved MCT were studied. Group A consisted of 15 patients (6 men and 9 women) treated by surgery, followed by an ablative dose of 131I, and group B included 84 patients (39 men and 45 women) treated by surgery alone. Patients in group A were followed for 1.5-14 yr (median, 53 months), and those in group B were followed for 1-27 hr (median, 75 months). Seven patients (46.6%) from group A and 36 patients (42.9%) from group B developed recurrence or metastasis. The 5- and 10-yr survival rates were 87.5% and 75% for group A and 89% and 74% for group B; the difference was not significant (P greater than 0.05). The changes in serum calcitonin levels in 4 patients of group A were not different from those in patients who did not receive 131I. We conclude that 131I has no value as an adjunct to surgery in the management of MCT.
Somatostatin is secreted from thyroid C-cells and seems to play an important part in the regulation of calcitonin secretion. We therefore evaluated the usefulness of somatostatin receptor scintigraphy in the localization of tumour tissue in patients with persistent medullary thyroid carcinoma.
A prospective clinical study.
The series consisted of 26 patients with elevated calcitonin levels after total thyroidectomy for histologically proven medullary thyroid carcinoma.
Somatostatin receptor scintigraphy using 111In-pentetreotide (Octreoscan) was performed in all patients and the results correlated with histology, ultrasonography, computerized tomography, magnetic resonance imaging, plain radiography, bone scintigraphy and selective venous catheterization. Calcitonin and carcinoembryonic antigen levels were measured.
The sensitivity of somatostatin receptor scintigraphy for localization of persistent medullary thyroid carcinoma was 57% in patients with histologically proven disease. The results depended on tumour mass (low sensitivity (33%) in minimal residual disease) and on the location of metastases (insensitive in detecting liver metastases).
Somatostatin receptor scintigraphy is of value as an additional diagnostic tool in localizing medullary thyroid carcinoma, especially pulmonary metastases. It is of minor importance in detecting minimal residual disease.
A retrospective study of 741 patients with medullary thyroid carcinoma diagnosed between 1967 and 1991 was carried out by members of the German Medullary Thyroid Carcinoma Study Group to evaluate prognostic factors. A total of 559 patients (75%) were considered to have sporadic disease, and 182 (25%) had the familial type. The sex ratio (male to female) was 1:1.4 in sporadic disease patients, and the mean age at diagnosis was 45.9 years (range 5-81 years). For familial disease patients the sex ratio was 1:1.1, and the mean age at diagnosis was 33.4 (range 5-77 years). The follow-up time for 630 patients ranged from 1 month to 20.8 years (mean 13.0 years). The overall adjusted survival rate was 86.7% at 5 years and 64.2% at 10 years. In a univariate analysis the stage of disease at diagnosis, age, sex, and type of disease (sporadic, familial) were relevant prognostic factors, with a better prognosis for young female patients with familial disease and diagnosed at an early stage. In a multivariate proportional hazards analysis, the difference in the survival rate of patients with familial disease versus those with the sporadic form disappeared, while prognostic information provided by age and sex was still significant. The poorer prognosis of patients with sporadic medullary thyroid carcinoma may be related to the patients' older age at detection and more advanced tumor stage at diagnosis. There seems to be no difference in biological behavior between tumors of the sporadic and those of the familial type.
Monoclonal antibodies (Mabs) with tumor specificity and 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) are increasingly being used in cancer imaging. To better understand the mechanism and location of their uptake in tumors, nude mice bearing HTB77 IP3 ovarian cancer xenografts were injected intravenously with 3H-2-fluoro-2-deoxy-D-glucose (3H-DG) or 14C-2-deoxy-D-glucose (14C-DG), with 125I-5G6.4, a Mab that was developed against the HTB77 IP3 cell line (specific Mab) or with 125I-UPC-10 (nonspecific Mab). Tumors were excised at 2 hr or 6 days postinjection and autoradiography was performed. In tumors from animals receiving the Mabs, the grains were concentrated mainly on tumor cells near connective tissue ridges bearing blood vessels at 2 hr postinjection. At 6 days postinjection, further penetration into the tumors was seen, but four times more grains were seen on the viable cancer cells in the tumors receiving the specific Mab than in those receiving the irrelevant Mab. The selective accumulation of 2-DG in viable cancer cells and the negligible concentration of 2-DG in necrotic areas may be preferable to tumor-specific Mabs in assessing the extent of viable tumor and treatment response. Knowledge of the localization of a tracer at the microscopic level is essential to the understanding of the signal depicted on nuclear images using either type of radiotracer.
This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA).
Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions.
The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three.
Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.
This study evaluates the pharmacokinetics, dosimetry, toxicity and therapeutic potential of radiolabeled NP-4 and MN-14 anti-CEA antibodies in medullary thyroid cancer (MTC).
Eighteen patients with advanced MTC entered exploratory clinical studies with therapeutic doses of 131I-labeled NP-4 and MN-14 murine monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). Doses administered ranged from 46 mCi for 131I-MN-14 lgG to 195 mCi for 131I-MN-14 F(ab)2 in patients negative for human anti-mouse antibodies (HAMA).
The radioconjugate blood half-life (T1/2) for the whole lgG was 42.5+/-5.0 hr compared to 18.8+/- 4.1 hr for the bivalent fragments. Tumor doses of 17.5+/-11.0 and 11.4+/-6.3 cGy/mCi were estimated for 131I-MN-14 lgG and F(ab)2, respectively. Tumor/red marrow dose ratios exceeded 3:1 for most lesions. Red marrow doses of up to 350 cGy generally could be delivered with < grade 4 toxicity. Seven of 14 evaluable patients showed evidence of anti-tumor effects lasting up to 26 months, based on physical exam, tumor markers or computed tomography.
This study demonstrates that anti-CEA MAbs may be suitable for radioimmunotherapy of metastatic or recurrent MTC.
Medullary carcinoma of the thyroid gland is a rare tumor. Its prognosis is mainly linked to surgery, because there is no valid alternative therapy to improve patients outcome. In this report, we discuss the recurrence of such a tumor in a 64-year-old female, focusing on magnetic resonance imaging and position emission tomography evaluation of this tumor.
We investigated 5 MTC patients, 3 preoperatively for staging purpose, and 2 after surgery, during the follow-up, because of the persistence of elevated serum tumoral markers. FDG PET results were compared with conventional radiologic (US, CT scan, MRI) and scintigraphic non-invasive techniques (99mTc-MIBI and 99mTc-MDP scans). In all the 3 patients preoperatively studied, PET, as well as the other imaging modalities, detected the primitive tumor and the loco-regional lymphnode metastases. Furthermore, in one case, PET was the only technique that revealed an additional localization to the lungs. One false negative result was recorded with PET, as well as with the conventional imaging, in a MTC patient with a MEN II syndrome and with some liver micrometastases, 2 to 5 mm sized, showed only at laparotomy. PET was the only method capable of early visualizing a mediastinal relapse of the tumor in one of the 2 patients studied during the follow-up. This patient was re-operated and serum calcitonin levels became undetectable. On the basis of our preliminary results on MTC, PET with FDG seems to be an accurate, non-invasive technique, for staging purpose before surgery, and, during the follow-up for visualizing tumoral spread in patients with increased serum tumoral markers.
Imaging of metastatic sites of medullary thyroid carcinoma (MTC) is successful in less than 60% of cases of residual or recurrent disease. Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) takes advantage of the fact that malignant tumors are capable of increased uptake and use of glucose, which is mediated by the members of the glucose transporter family of proteins (GLUT 1 through GLUT 5).
FDG-PET images of 10 patients with recurrent or persistent MTC after primary operation were compared with images by computed tomography or magnetic resonance imaging. Identified metastatic lesions were assessed by intraoperative findings and pathology reports. Expression of GLUT 1 through GLUT 5 was examined by Western blot analysis of tumor tissue from eight of the patients evaluated and an additional panel of 10 MTCs and seven pheochromocytomas.
FDG-PET identified 31 foci of FDG accumulation in 10 patients, and 16 of these metastatic sites were resected and confirmed by histologic analysis. Only 11 foci were demonstrated by computed tomographic or magnetic resonance imaging. None of the glucose transporters examined displayed significant expression. Two pheochromocytomas were successfully imaged by FDG-PET.
FDG-PET imaging can be useful in the localization of cervicomediastinal MTC metastases and pheochromocytoma. The increased glucose uptake in these tumors, as evidenced by FDG-PET, does not appear to be attributable to the expression of the glucose transporter proteins GLUT 1 through GLUT 5.
Normalization of calcitonin levels after surgery has been regarded as the most powerful prognostic factor for medullary thyroid carcinoma (MTC). Although the prognosis of patients with persistent hypercalcitoninemia may be acceptable, the biochemical cure rate can be improved by new microdissection techniques. This raises certain questions: Can extension of locoregional lymphadenectomy (LA) further improve biochemical cure and survival after primary or reoperative MTC surgery? Which factors concerning TNM categories are associated with the possibility of postoperative normalization of calcitonin levels? This study included 64 patients with sporadic MTC operated on from 1986 to 1997. Altogether 27 patients underwent primary surgery, and 37 patients were reoperated, performing a microdissection of all four locoregional compartments (four-compartment lymphadenectomy, or 4CLA). For primary MTC the biochemical cure rate was 100% in node-negative patients and 33% in node-positive patients; the latter could be improved to 45% after 4CLA. In contrast to reoperative MTC, the rate of lymph node metastases (LNMs) with primary MTC correlated with the pT category (pT1 33%, pT2 53%, pT3 100%, pT4 100%) but not with age or sex. Again in contrast to reoperative MTC, mediastinal LNMs in primary MTC were present only in patients with a pT4 tumor. At reoperation, 4CLA was able to cure 22% of node-positive patients, 28% without proved distant metastases. No patient with extrathyroidal tumor involvement or distant metastases was biochemically cured after either primary or reoperative surgery. For all node-positive MTC patients, in addition to cervicocentral LA at least a bilateral cervicolateral LA is recommended. Transsternal mediastinal lymph node dissection is indicated in patients with LNMs in the cervicomediastinal transition, facilitating biochemical cure in up to 45% after the first operation and 22% after reoperative surgery of sporadic MTC.
18-FDG-PET, MRT und CT in der Nachsorge des medullä-ren Schilddrüsenkarzinoms [abstract]
- C Köster
- C Ehrenheim
- W Burchert
- G Oetting
- Hundeshagen
Köster C, Ehrenheim C, Burchert W, Oetting G, Hundeshagen H. 18-FDG-PET, MRT und CT in der Nachsorge des medullä-ren Schilddrüsenkarzinoms [abstract]. Nuklearmedizin 1996; 35: A60.
Metabolic classification and follow-up of thyroid cancer by 18-FDG: clinical results in 150 patients
- Bares R A Bockisch
- R Lietzenmayer
- K Brandt-Mainz
- Feine
Bares R, Bockisch A, Lietzenmayer R, Brandt-Mainz K, Feine U. Metabolic classification and follow-up of thyroid cancer by 18-FDG: clinical results in 150 patients. J Endocrinol Invest (in press).
Somatosta-tin receptor scintigraphy with [ 111 In-DTPA-D-Phe 1 ]-and [ 123 I-Tyr 3 ]-octreotide: the Rotterdam experience with more than 1000 patients
- Krenning Ep
- Kwekkeboom Dj
- Bakker
- Wh
Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatosta-tin receptor scintigraphy with [ 111 In-DTPA-D-Phe 1 ]-and [ 123 I-Tyr 3 ]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20: 716–731.
Müller-Schauenburg W: Fluorine-18-FDG and iodine-131 up-take in thyroid cancer
- U Feine
- R Lietzenmayer
- Jp Hanke
- J Held
- Wöhrle
Feine U, Lietzenmayer R, Hanke JP, Held J, Wöhrle H, Müller-Schauenburg W: Fluorine-18-FDG and iodine-131 up-take in thyroid cancer. J Nucl Med 1996; 37: 1468–1472.
Erfahrungen mit präsymptomatischem Screen-ing bei Patienten mit C-Zell-Carcinom der Schilddrüse
- A Frilling
- Röher Hd
- Ponder Baj
- Goretzki Pe
- R Schlaghecke
Frilling A, Röher HD, Ponder BAJ, Goretzki PE, Schlaghecke R, Reiners C. Erfahrungen mit präsymptomatischem Screen-ing bei Patienten mit C-Zell-Carcinom der Schilddrüse. Chirurg 1993; 64: 28–35.
Postsurgical course of serum cal-citonin levels as a prognostic marker in sporadic medullary thyroid carcinoma
- B Saller
- K Ekrod
- Mann
Saller B, Ekrod K, Mann K. Postsurgical course of serum cal-citonin levels as a prognostic marker in sporadic medullary thyroid carcinoma [abstract]. Endo 1998 (Abstract Volume of the Endocrine Society's 80th Annual Meeting);
Prognostic factors for survival and biochemical cure in medullary thyroid carci-noma: results in 899 patients
- E Modigliani
- Campos R Cohen
- Jm
Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and biochemical cure in medullary thyroid carci-noma: results in 899 patients. Clin Endocrinol (Oxf) 1998; 48: 265–273.
SPECT and pla-nar scintigraphy in diagnostic and follow-up of thyroid cancer
- Reiners C Müller
- Sp
- J Farahati
- Eising
- Eg
Reiners C, Müller SP, Farahati J, Eising EG. SPECT and pla-nar scintigraphy in diagnostic and follow-up of thyroid cancer. Exp Clin Endocrinol 1994; 102: 43–50.
Hexokinase, differenti-ation and growth rates of transplanted rat tumors
- Knox We Jamdar
- Davis Sc
- Pe
Knox WE, Jamdar SC, Davis PE, et al. Hexokinase, differenti-ation and growth rates of transplanted rat tumors. Cancer Res 1970; 30: 2240–2244.