Radionuclide imaging of soft tissue neoplasms

Two classes of radiopharmaceuticals may be used for imaging tumors of the musculoskeletal system. The first is comprised of soft tissue or tumor specific agents such as gallium-67, bleomycin, and radionuclide-labeled antibodies, which may be useful for detecting and localizing these tumors. The other class of tracer is comprised of those with avidity for bone. The 99mTc-labeled-phosphate skeletal imaging compounds have been found to localize in a variety of soft tissue lesions, including benign and malignant tumors. In 1972, Enneking began to include bone scans in the preoperative evaluation of soft tissue masses. Later, he and his associates reported that these scans were useful in planning operative treatment of sarcomas by detecting involvement of bone by the tumors. Nearly all malignant soft tissue tumors take up bone-seeking radiopharmaceuticals, and bone involvement was indicated in two-thirds of the scans we reviewed. About half of benign soft tissue lesions had normal scans, but the other half showed uptake within the lesion and a few also showed bone involvement. Careful, thorough imaging technique is essential to proper evaluation. Multiple, high-resolution static gamma camera images in different projections are necessary to adequately demonstrate the presence or absence of soft tissue abnormality and to define the precise relationship of the tumor to the adjacent bone.     

Intracranial meningioma with abnormal localization of bone-seeking radiopharmaceutical: correlation with gross and microscopic pathology

Meningioma is one of the neoplasms in which there may be extraosseous localization of bone-seeking radiopharmaceuticals. Tumor calcification, calvarial erosion, and the formation of reactive bone have been proposed as the cause of this abnormal tracer localization. We present a patient with a frontal meningioma that was evaluated using 99mTc-methylene-diphosphonate bone scintigraphy, head computed tomography, and skull radiography; the homogeneous density seen in the radiographic studies corresponded to the area of bone-seeking-agent localization shown in the scintigram. At autopsy, bony tissue and a few psammoma bodies were found in the meningioma, and apparently accounted for the bone-tracer localization. There was no calvarial erosion and no formation of reactive bone. If skull-radiographic studies show a homogeneous, radio-opaque lesion with no reactive changes in the adjacent skull, a meningioma showing a localization of a bone-seeking radiopharmaceutical may be predicted to have bone-tissue formation with or without psammoma bodies.     

Intracranial meningioma with abnormal localization of bone-seeking radiopharmaceutical: Correlation with gross and microscopic pathology

Meningioma is one of the neoplasms in which there may be extraosseous localization of bone-seeking radiopharmaceuticals. Tumor calcification, calvarial erosion, and the formation of reactive bone have been proposed as the cause of this abnormal tracer localization. We present a patient with a frontal meningioma that was evaluated using ^99mTc-methylene-diphosphonate bone scintigraphy, head computed tomography, and skull radiography; the homogeneous density seen in the radiographic studies corresponded to the area of bone-seeking-agent localization shown in the scitigram. At autopsy, bony tissue and a few psammoma bodies were found in the meningioma, and apparently accounted for the bone-tracer localization. There was no calvarial erosion and no formation of reactive bone. If skull-radiographic studies show a homogeneous, radio-opaque lesion with no reactive changes in the adjacent skull, a meningioma showing a localization of a bone-seeking radiopharmaceutical may be predicted to have bonetissue formation with or without psammoma bodies.     

Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer

Samarium-153 ethylenediaminetetramethylene phosphonic acid ([153Sm]EDTMP) has been proposed to palliate pain resulting from osteoblastic metastatic bone cancer. Encouraging results in dogs with primary malignant bone cancer provided the catalysis for human biodistribution studies in five patients with metastatic skeletal carcinoma. The objective was to assess the preferential localization of [153Sm]EDTMP in bony lesions and compare it to the 99mTc-labeled phosphonates. Blood clearance of [153Sm]EDTMP was rapid with minimal accumulation in nonosseous tissues. Both radiopharmaceuticals showed identical lesion uptake in 23 paired lesions (p greater than 0.05). This indicates that the two radiopharmaceuticals concentrate in metastatic skeletal lesions by the same mechanism and since [153Sm]EDTMP emits beta radiation it may be therapeutically useful in ameliorating metastatic bony cancer pain.     

Technical considerations in in vivo thyroid studies

Radionuclide thyroid studies, although among the oldest of clinical nuclear medicine procedures, continue to show growth and change. In the 7 years since thyroid studies were last reviewed in the Seminars, there have been marked changes in the preferred ways of doing these studies. In the areas of radiopharmaceuticals, 131I remains a useful agent in selected circumstances, but 99mTc-pertechnetate has become the agent of choice for imaging applications. Iodine-123 represents an exciting possibility for the future if problems in cost and radiopurity can be solved. New data on the dosimetry of the various agents allow for more rational choices among them, and useful guidelines can now be given for the use of these radiopharmaceuticals in problem areas such as pregnancy, nursing, and the pediatric age group. The scintillation camera with a pinhole collimator has become the instrument of choice for thyroid imaging, and the use of computers and the availability of systems for fluorescent scanning have added new possibilities for thyroid evaluation. Ancillary techniques such as ultrasound scanning also offer the possibility of improved diagnostic accuracy. These developments are reviewed in the context of clinical studies, together with a discussion of specific clinical applications and a brief look to the future.     

Disappearance of Tc-99m HMDP tumor uptake in oat cell carcinoma after irradiation and chemotherapy

Extraosseous localization of bone-seeking radiopharmaceuticals has been reported in various tumors, presumably on the basis of active calcium deposition in the tumors. We report a case of oat cell carcinoma in which the initial localization of Tc-99m-HMDP in the tumor disappeared after irradiation and chemotherapy. The disappearance of tracer uptake coincided with regression of the mass as seen in the chest radiograph. This finding may have potential application in determining tumor response to anticancer therapy.     

Conventional radionuclide brain imaging in the era of transmission and emission tomography

The clinical applications for conventional radionuclide brain imaging have declined considerably since the introduction of newer imaging modalities (computerized cranial tomography [CCT], nuclear magnetic resonance [NMR]). Currently, conventional brain imaging primarily serves as a complementary test when CCT is negative or equivocal and strong clinical suspicion remains. Selected areas in which radionuclide imaging may be the preferred modality include evaluation of cerebral perfusion in assessment of brain death, detection of early viral encephalitis, evaluation of major venous sinus patency, external marking for localization of intracranial tumor, and in selected cases of suspected subdural hematoma, brain tumor, and cerebrovascular disease. The concept of conventional radionuclide brain imaging will likely undergo considerable change in the near future as newer radiopharmaceuticals are introduced and wider application is made of single photon emission computerized tomography (SPECT) and positron emission tomography (PET) imaging.     

Evaluation of radiopharmaceuticals sequestered by acutely damaged myocardium.

Eighteen radiopharmaceuticals were screened in a small-animal model as potential infarct-localizing agents. Twelve of the 18 compounds were labeled with 99mTc, four with 203Hg, one with 131I, and one with either 203Hg or 125I. The model used heat-induced myocardial lesions in the rat. The absolute concentration within the lesion and also the activity ratios of injured myocardium to normal heart tissue, blood, and muscle were determined for all compounds. Among the 99mTc-labeled agents, two bone-seekers [pyrophosphate (PPi) and 1-hydroxyethylidine-1,1-diphosphonate (HEDP)] showed the most promise; these were followed by 99mTc-tetracycline analogs and 99mTc-glucoheptonaate. The tracer showing the most favorable concentration in the lesion and the best target-to-nontarget ratios was an iodinated derivatives of hydroxymercurifluorescein labeled with either 125I or 203Hg. Consideration of the structure of these compounds suggests that the presence of mercury or of a polycyclic aromatic structure, such as that found is tetracycline and fluorescein, was associated with localization in damaged myocardial tissue. Mercury bound to such an aromatic moiety may produce an additive or even a synergistic effect.     

Clinical applications of PET in oncology

Positron emission tomography (PET) provides metabolic information that has been documented to be useful in patient care. The properties of positron decay permit accurate imaging of the distribution of positron-emitting radiopharmaceuticals. The wide array of positron-emitting radiopharmaceuticals has been used to characterize multiple physiologic and pathologic states. PET is used for characterizing brain disorders such as Alzheimer disease and epilepsy and cardiac disorders such as coronary artery disease and myocardial viability. The neurologic and cardiac applications of PET are not covered in this review. The major utilization of PET clinically is in oncology and consists of imaging the distribution of fluorine 18 fluorodeoxyglucose (FDG). FDG, an analogue of glucose, accumulates in most tumors in a greater amount than it does in normal tissue. FDG PET is being used in diagnosis and follow-up of several malignancies, and the list of articles supporting its use continues to grow. In this review, the physics and instrumentation aspects of PET are described. Many of the clinical applications in oncology are mature and readily covered by third-party payers. Other applications are being used clinically but have not been as carefully evaluated in the literature, and these applications may not be covered by third-party payers. The developing applications of PET are included in this review.     

Cell Irradiation caused by diagnostic nuclear medicine procedures: dose heterogeneity and biological consequences

Most radionuclides used for diagnostic imaging emit Auger electrons (technetium-99m, iodine-123, indium-111, gallium-67 and thallium-201). Their very short range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. This report describes the dosimetric models used to calculate the mean dose absorbed by the cell nucleus from Auger radionuclides. The techniques used to determine the biodistribution of radiopharmaceuticals at the subcellular level are also described and compared. Published examples of cellular dosimetry computations performed with radiotracers are reviewed in various clinical settings.Finally, the biological implications of the subcellular localization of Auger emitters are examined. While a number of efforts have been made to obtain dosimetric models and to estimate subcellular distribution of radioactivity, little is known of the cellular dosimetry of most radiopharmaceuticals used in diagnostic imaging. However, biological examples of selective radiotracer uptake have been shown, leading to extremely strong cell-cell dose heterogeneity. Furthermore, radiobiological experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness greater than 1 compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. This review proposes the most appropriate model for dosimetric computations (cellular or conventional) according to the subcellular distribution of radiotracers. The radionuclide of choice and the general strategy used to design new diagnostic radiopharmaceuticals are also discussed.     

Uncertainties in internal dose calculations for radiopharmaceuticals.

This paper presents a systematic analysis of the inherent uncertainty in internal dose calculations for radiopharmaceuticals. A generic equation for internal dose is presented, and the uncertainty in each of the individual terms is analyzed, with the relative uncertainty of all terms compared. The combined uncertainties in most radiopharmaceutical dose estimates will be typically at least a factor of 2 and may be considerably greater. In therapy applications, if patient-individualized absorbed doses are calculated, with attention being paid to accurate data gathering and analysis and measurement of individual organ volumes, many of the model-based uncertainties can be removed, and the total uncertainty in an individual dose estimate can be reduced to a value of perhaps +/-10%-20%. Radiation dose estimates for different diagnostic radiopharmaceuticals should be appreciated and considered, but small differences in dose estimates between radiopharmaceuticals should not be given too much importance when one is choosing radiopharmaceuticals for general clinical use. Diagnostic accuracy, ease of use, image quality, patient comfort, and other similar factors should predominate in the evaluation, with radiation dose being another issue considered while balancing risks and benefits appropriately.     

Cell irradiation caused by diagnostic nuclear medicine procedures: dose heterogeneity and biological consequences

Most radionuclides used for diagnostic imaging emit Auger electrons (technetium-99m, iodine-123, indium-111, gallium-67 and thallium-201). Their very short range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. This report describes the dosimetric models used to calculate the mean dose absorbed by the cell nucleus from Auger radionuclides. The techniques used to determine the biodistribution of radiopharmaceuticals at the subcellular level are also described and compared. Published examples of cellular dosimetry computations performed with radiotracers are reviewed in various clinical settings. Finally, the biological implications of the subcellular localization of Auger emitters are examined. While a number of efforts have been made to obtain dosimetric models and to estimate subcellular distribution of radioactivity, little is known of the cellular dosimetry of most radiopharmaceuticals used in diagnostic imaging. However, biological examples of selective radiotracer uptake have been shown, leading to extremely strong cell-cell dose heterogeneity. Furthermore, radiobiological experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness greater than 1 compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. This review proposes the most appropriate model for dosimetric computations (cellular or conventional) according to the subcellular distribution of radiotracers. The radionuclide of choice and the general strategy used to design new diagnostic radiopharmaceuticals are also discussed.     

Single photon emission computed tomography (SPECT). Principles and instrumentation

SPECT systems have successfully imaged most major organ systems within the body in conjunction with conventional radiopharmaceuticals. SPECT imaging provides a new three-dimensional perspective with improved lesion detectability resulting from the elimination of overlying and underlying source activity. High-quality, artifact-free images have been obtained from both scanner and camera-based SPECT systems. Novel geometries are currently being investigated to improve system performance. It is anticipated that new developments in instrumentation and radiopharmaceuticals will result in the increased use of SPECT to noninvasively measure important physiologic processes.     

(18)F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in a living system. At present, positron emission tomography/computed tomography (PET/CT) is one the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. Although [(18)F]fluorodeoxyglucose (FDG)-PET/CT imaging provides high specificity and sensitivity in several kinds of cancer and has many applications, it is important to recognize that FDG is not a "specific" radiotracer for imaging malignant disease. Highly "tumor-specific" and "tumor cell signal-specific" PET radiopharmaceuticals are essential to meet the growing demand of radioisotope-based molecular imaging technology. In the last 15 years, many alternative PET tracers have been proposed and evaluated in preclinical and clinical studies to characterize the tumor biology more appropriately. The potential clinical utility of several (18)F-labeled radiotracers (eg, fluoride, FDOPA, FLT, FMISO, FES, and FCH) is being reviewed by several investigators in this issue. An overview of design and development of (18)F-labeled PET radiopharmaceuticals, radiochemistry, and mechanism(s) of tumor cell uptake and localization of radiotracers are presented here. The approval of clinical indications for FDG-PET in the year 2000 by the Food and Drug Administration, based on a review of literature, was a major breakthrough to the rapid incorporation of PET into nuclear medicine practice, particularly in oncology. Approval of a radiopharmaceutical typically involves submission of a "New Drug Application" by a manufacturer or a company clearly documenting 2 major aspects of the drug: (1) manufacturing of PET drug using current good manufacturing practices and (2) the safety and effectiveness of a drug with specific indications. The potential routine clinical utility of (18)F-labeled PET radiopharmaceuticals depends also on regulatory compliance in addition to documentation of potential safety and efficacy by various investigators.     

Needs for radioactivity standards and measurements in the life sciences.

For almost 100 years, radioactivity has been one of the major tools in medicine. Therapeutic applications that began with 226Ra and 222Rn implants have rapidly grown to include about 20 radionuclides with radiations specifically chosen to treat at different depths in tissue--ranging from a few millimeters for intravascular therapy to a few centimeters in the case of large solid tumors. Systemic treatments with radiopharmaceuticals have grown from the traditional 131I to more than ten candidate nuclides which are to be labeled to tumor-specific radiopharmaceuticals. Diagnostic radiopharmaceuticals are used in over 13 million procedures in the United States annually. About 40 nuclides are under investigation for these applications including single photon emitters for SPECT (single photon emission computed tomography) and positron emitters for PET (positron emission tomography). In addition to the mainstays of therapeutic and diagnostic radiology, radionuclides are widely used for in vitro tracers in the life sciences and represent one of the main tools in the field of molecular biology.     

A comparison between the diagnostic efficacy of 99mTc-MDP, 99mTc-DPD and 99mTc-HDP for the detection of bone metastases

We have investigated the clinical efficacy for the detection of bone metastases of two recently marketed bone-seeking radiopharmaceuticals, HDP and DPD, compared with traditionally used MDP. Twenty patients received 15 mCi 99mTc-MDP; after assessment ten of these patients later received 15 mCi 99mTc-DPD and ten other patients of this group were injected with 15 mCi 99mTc-HDP. Scintigraphy took place 3 h after tracer injection. Quantitative analysis included the calculation of normal bone to soft tissue ratios, lesion to soft tissue ratios and lesion to normal bone ratios for all three radiopharmaceuticals. Visual inspection of the scintiphotos revealed the same number of bone lesions at the same localisations. Statistical evaluation of our quantitative data showed that the lesion to normal bone ratio was significantly higher for MDP than for DPD. No further significant differences in the uptake in normal bone or in the metastatic lesions were found between all three radiopharmaceuticals. It is concluded that the new bone-seeking agents DPD and HDP do not possess clinical advantages over MDP for the detection of skeletal metastases.     

Teletherapy and radiopharmaceutical therapy of painful bone metastases

Bone pain from metastatic disease is most common in cancers of the breast, prostate, and lung. Despite the World Health organization algorithm for treating such pain, the outcomes are not often satisfactory. In 2005, there will be 3 radiopharmaceuticals available in the United States that can reduce or relieve bone pain caused by osteoblastic metastases with apparently equal efficacy. Phosphorus-32 as sodium phosphate, strontium-89 ( 89Sr) as the chloride, and samarium-153 lexidronam may all be given intravenously (and 32P also orally) in patients where bone scintigraphy demonstrates a metastatic lesion causing the patient's bone pain. Side effects are usually mild and include pancytopenia with leukocyte and platelet nadirs at approximately 50% of baseline, and a mild-to-moderate, but brief, increase in pain ("flare") in approximately 10% of patients. At least 1 of these radiotracers, 89Sr, has the availability to reduce the incidence of new bone metastases as well, but, given alone, none prolong life. In a few studies in which 89Sr has been combined with chemotherapy, prolongation of patient survival has been demonstrated. Many questions remain as to the optimization of use of this group of radiopharmaceuticals, including whether combinations of radiopharmaceuticals with each other, with bisphosphonates or with chemotherapy can improve the therapeutic outcomes even more.     

Bone scintigraphy in the diagnosis and management of traumatic injury

Imaging with bone-seeking nuclear medicine radiopharmaceuticals has changed dramatically in a span of 10 years. The only indication for bone scintigraphy a decade ago was to detect skeletal metastases in patients with known carcinoma. Improvements in equipment and radiopharmaceuticals have led to the use of nuclear medicine studies for the detection and evaluation of a multitude of benign abnormalities. This article discusses the use of bone-seeking radiopharmaceuticals in traumatic processes involving the skeletal system, connective tissues, and muscles. A review of the subject is included, as well as some new ideas regarding the interpretation and evaluation of scintigraphs with respect to trauma to the bones and soft tissues.     

Scintigraphic studies in adrenal hypertension

Endocrine hypertension secondary to disorders of the adrenal glands is uncommon, but by no means rare. The importance of correct biochemical diagnosis and subsequent localization of the responsible lesion(s) lie in the fact that many of these syndromes occur in younger patients, may exhibit familial patterns of inheritance and are frequently amenable to surgical cure. The radiopharmaceuticals (131)1-6 beta-iodomethyl-19-norcholesterol (NP-59), a marker of adrenocortical cholesterol uptake, and (131)1- and (123)1-metaiodobenzylguanidine (MIBG), a norepinephrine (NE) analog and marker of energy-dependent NE storage vesicle accumulation, can be shown to accurately localize adrenal cortex and sympathoadrenal dysfunction, respectively. In Cushing's syndrome (CS) not only does the pattern of NP-59 uptake depict the adrenal dysfunction and its pathophysiologic basis, but the level of NP-59 accumulation reflects the degree of adrenocortical hyperfunction. Adrenocorticotrophin-independent CS is uniformly and accurately localized, especially in bilateral cortical nodular hyperplasia where even high resolution computed tomography (CT) may fail to depict the often subtle, asymmetric anatomic abnormalities. Dexamethasone suppression NP-59 adrenal scintigraphy has been shown to be highly sensitive and specific, and exceeds the efficacy of CT in the differentiation of adenoma and bilateral hyperplasia in primary aldosteronism. MIBG is useful as a sympathoadrenal imaging agent whose clinical utility has been demonstrated in the localization of pheochromocytoma, especially as a modality to screen the body for multiple and extraadrenal, recurrent, or metastatic lesions. Moreover, the extent of metastatic involvement from neuroblastoma can also be accurately depicted using MIBG. In this review we will examine the role of adrenal scintigraphy in the characterization of hypersecretory disorders of the adrenal cortex, medulla, and related conditions that produce hypertension as part of their symptom(s) complex. This approach, which is complementary to other anatomical modalities of imaging, can be used to advantage in the localization of functioning cortical and medulla adrenal diseases and other neoplasms of adrenergic origin.     

How has the management of medullary thyroid carcinoma changed with the advent of 18F-FDG and non-18F-FDG PET radiopharmaceuticals

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.