The role of nuclear medicine in clinical investigationBMJ 1998; 316 doi: http://dx.doi.org/10.1136/bmj.316.7138.1140 (Published 11 April 1998) Cite this as: BMJ 1998;316:1140
- E M Prvulovich (), consultant, nuclear medicine,
- J B Bomanji, consultant, nuclear medicine
- Correspondence to: Dr Prvulovich
- Accepted 20 November 1997
Nuclear medicine uses radioactive isotopes for the diagnosis and treatment of patients. Whereas radiology provides data mostly on structure, nuclear medicine provides complementary information about function. Limited undergraduate teaching, together with regional differences in the provision of nuclear medicine services, means that many clinicians know little about how radionuclide techniques can help in the management of patients. Consequently, patients who would benefit from such a procedure are not referred. This review highlights how nuclear medicine techniques can be used in the investigation of patients presenting with such common conditions as ischaemic chest pain, malignancy, and suspected pulmonary embolism. Many promising new tracers are being developed, particularly for the investigation of patients with malignancy and suspected infection, and readers will be directed elsewhere for information.
Myocardial perfusion imaging has strong prognostic value
Lung scintigraphy is a simple non-invasive method for detecting pulmonary embolism
Bone scans are useful in assessing benign and malignant bone lesions
Radioisotope renal imaging is useful for detecting renal outflow obstruction, cortical scarring, and renovascular dysfunction
Imaging with radiolabelled white cells can detect occult infection and monitor inflammatory bowel disease
Thyroid scintigraphy is most commonly used to assess the nature of a thyroid nodule
Nuclear medicine techniques in oncology can localise primary tumours, delineate extent of disease, and monitor response to treatment
Radionuclide treatment is used in hyperthyroidism, thyroid cancer, palliation of bone pain, and neural crest tumours
The published articles reviewed here were chosen primarily for the clarity and simplicity with which they describe the role of nuclear medicine techniques in specific fields. Six short texts commissioned by the British Nuclear Medicine Society provide detailed reviews of the clinical utility of nuclear medicine in an eminently readable and digestible format.1-6
Myocardial perfusion imaging is the only non-invasive method of assessing myocardial perfusion. This technique relies on the radiotracer being distributed throughout the myocardium in proportion to regional blood flow. Typically two sets of images are acquired, one set reflecting perfusion at peak stress and the other set reflecting perfusion at rest. Either dynamic exercise or pharmacological stress is used in conjunction with thallium-201 or tracers labelled with technetium-99m. In areas supplied by functionally significant coronary stenoses, the stress defect may improve when imaging is performed with the patient at rest (reversible defect) (fig 1). Stress defects that fail to improve on rest imaging (fixed defects) generally represent infarcted areas.
Myocardial perfusion imaging has higher diagnostic sensitivity and specificity than exercise electrocardiography (80% and 92% v 64% and 82% respectively) for coronary artery disease.7 Because of its higher cost and the patient radiation burden, however, myocardial perfusion imaging is largely reserved for diagnosis of coronary artery disease when an exercise test is unhelpful or leaves doubt. In clinical practice this may occur when resting electrocardiographic abnormalities such as left bundle branch block exist, equivocal ST segment changes occur with exercise, exercise testing is normal despite a high pretest likelihood of disease, abnormal ST segment changes are seen despite a low pretest likelihood of disease, or only submaximal exercise is achieved (in these patients pharmacological stress is preferable).
The evidence that myocardial perfusion imaging has strong prognostic value is overwhelming.8 A normal stress perfusion study predicts a favourable prognosis (risk of cardiac death and myocardial infarction less than 1% annually) even where there is angiographic evidence of coronary artery disease. Conversely, severe and extensive reversible ischaemia predicts an adverse prognosis (fig 1).
Myocardial perfusion imaging is also used for assessing the functional importance of known coronary stenoses, risk stratification before major non-cardiac surgery, monitoring the effects of intervention such as angioplasty and bypass grafting, and detecting hibernating myocardium in patients with ischaemic left ventricular dysfunction. 1 9-11 Positron emission tomography is regarded as optimal for detecting hibernating myocardium, but it is expensive and not widely available.
Radionuclide ventriculography, performed using red blood cells labelled with 99mTc-pertechnetate, provides accurate and reproducible information regarding left ventricular function. The widespread availability of echocardiography limits the use of radionuclide ventriculography to cardiac patients for whom an adequate echocardiographic window cannot be achieved, and for serial monitoring of patients in cardiac failure and patients undergoing cardiotoxic chemotherapy.
When pulmonary embolism is suspected the goal of diagnostic imaging is to direct and validate treatment, be it anticoagulation or thrombolysis, which has appreciable morbidity and mortality. Ventilation-perfusion lung scanning is a non-invasive method of evaluating patients for pulmonary embolism, but accurate interpretation requires comparison with a chest radiograph taken within 24 hours. Ventilation images are acquired using xenon-133, krypton-81m, or 99mTc radiolabelled aerosols; perfusion images are obtained using 99mTc macroaggregates.
Lung scans are typically interpreted as being normal or having low probability, intermediate (indeterminate) probability, or high probability for pulmonary embolism. Interpretation criteria for these are complex and require integrating clinical, radiological, and physiological data. 12 13 A normal lung scan excludes clinically important pulmonary embolism, whereas a scintigraphic study showing multiple, wedge shaped perfusion defects with normal ventilation and a chest radiograph that is clear in the corresponding areas suggest high probability for pulmonary embolism (fig 2). Patients with normal or very low probability scans do not require treatment for pulmonary embolism, whereas those with a high probability scan do. Interpretation of intermediate probability scans requires more expertise, and consultation with the specialist in nuclear medicine is essential. Usually these patients should be treated according to whether they have cardiorespiratory disease, and further investigation with serial duplex ultrasonography or tailored spiral computed tomography may be required.14 Finally, in patients at high risk for recurrent pulmonary embolism, ventilation-perfusion imaging repeated after three months of anticoagulation provides a baseline against which to assess new symptoms.15
Gallium-67 citrate imaging is useful in patients with sarcoidosis. It is used to map the extent of disease and monitor response to treatment.
Radionuclide bone scanning is performed using radiolabelled diphosphonates such as 99mTc methylene diphosphonate (99mTc-MDP). Bone scanning is commonly used to detect metastases from tumours that are likely to metastasise to bone. The technique is sensitive and allows visualisation of the whole skeleton in a short time. Bone scintigraphy is used to stage the disease and to evaluate the efficacy of treatment (fig 3).16 Bone scans are more sensitive than x rays, since lesions generally cannot be seen on radiographs until 50% of bone mineral matrix has been lost. When solitary bone lesions present a diagnostic dilemma, magnetic resonance imaging may help to corroborate the bone scan findings.
In primary bone tumours, the major roles of bone scintigraphy are to detect distal bone metastases, evaluate the response to neoadjuvant chemotherapy, and restage the disease. In benign bone disease, bone scintigraphy is used to diagnose sports injuries (such as stress fractures and shin splints) (fig 4), show avascular necrosis of the hips and knees, differentiate between loosening and infection of joint prostheses, diagnose metabolic bone disease, perform a joint survey in arthritis, and investigate patients with bone pain of unknown origin. 2 17 Tomographic imaging, with its improved sensitivity over planar imaging, is particularly beneficial in the investigation of low back pain.
Nuclear medicine plays an important role in the diagnosis and management of patients with diseases that cause loss of bone mineral, particularly osteoporosis. Bone densitometry (using single or dual photon absorptiometry—DXA) is the only objective method available for accurate measurement of bone mass.
Glomerular filtration rate can be measured in vitro by using chromium-51 ethylenediaminetetraacetate (51Cr-EDTA). The simplicity, accuracy, and reproducibility of this technique make it ideal for serial monitoring of renal function. Importantly, the non-renal factors that limit the accuracy of measurements of serum creatinine and creatinine clearance do not compromise this method of measuring glomerular filtration rate.
Dynamic renal scanning can be performed with either 99mTc-mercaptoacetyltriglycine (99mTc-MAG3), which is mainly eliminated via tubular secretion, or 99mTc-diethylenetriamine pentaacetic acid (99mTc-DTPA), which is cleared by glomerular filtration. When renal function is preserved, either tracer can be used, but when renal function is impaired 99mTc-MAG3 provides images of higher quality. Dynamic renography provides information about vascular supply and tracer extraction and excretion, as well as divided renal function.
Patients with suspected urinary tract obstruction generally undergo one or more of abdominal ultrasonography, intravenous urography, and computed tomography. All three techniques can be used to confirm a dilated collecting system, but none can provide information about divided function or degree of obstruction. In contrast, dynamic renography is an excellent non-invasive means of differentiating obstructed and non-obstructed dilated collected systems (fig 5). A normal dynamic renogram excludes obstruction, whereas impaired or absent tracer excretion after frusemide generally indicates obstructive nephropathy. Rarely, false positive results are obtained if the renal pelvis is very large or renal function is very poor.18 Dynamic renography is particularly useful for detecting recurrent obstruction and monitoring changes in renal function after pyeloplasty or insertion of a stent.
Dynamic renography is also commonly used to detect vesicorenal reflux in patients with urinary tract infection and for the serial evaluation of renal transplant function.3 Captopril renography is indicated in patients with suspected renovascular hypertension.19
Reflux nephropathy, in which parenchymal scarring occurs in the context of lower urinary tract abnormalities and infection, is responsible for hypertension and renal impairment and contributes to end stage renal failure. The identification of renal scarring is therefore of diagnostic and prognostic importance as well as being crucial for management. 99mTc-dimercaptosuccinic acid (99mTc-DMSA) is extracted by tubular cells and is used to define parenchymal structure and divided function.
99mTc-DMSA scanning has higher diagnostic sensitivity and specificity for the detection of renal scars than intravenous urography (96% and 98% v 86% and 92% respectively)20 or abdominal ultrasound, and is regarded as the gold standard (fig 6).
Infection and inflammation
In many patients with fever, a diagnosis of active infection is obvious from clinical history and physical examination in conjunction with structural imaging techniques. However, after surgery or the insertion of a joint prosthesis, diagnosing active infection using structural imaging techniques may be difficult because of disrupted anatomy. By contrast, nuclear medicine techniques image inflammatory activity, irrespective of the causative factor, and can be used to identify active infection even where anatomy is distorted.21-23
In patients with fever of unknown origin, nuclear medicine provides whole body images after a single injection of tracer. Structural imaging techniques that concentrate on one area of the body have limited application in these patients as there are no localising signs or symptoms to direct the investigation.
For routine clinical use, the choice of radiotracer lies between 67Ga-citrate and autologous leukocytes labelled with 99mTc-hexamethylpropylenamine oxime (99Tc-HMPAO) or indium-111 oxine. 67Ga-citrate is preferred if chronic infection is suspected or the patient is HIV positive and leukocyte labelling is undesirable.
Only a few of the radionuclide investigations used to study the gastrointestinal tract 4 25 are reviewed here. Motility tests can assess oesophageal, gastric, and small and large bowel motility. Gastric emptying is one of the more common tests and is used to investigate suspected gastroparesis in diabetic patients and patients after gastric surgery or when taking medication which affects gastric motility.
In vitro tests include the carbon-14 urea breath test for Helicobacter pylori infection, the modified Schilling test to differentiate between vitamin B-12 malabsorption secondary to intrinsic factor deficiency (pernicious anaemia) and ileal malabsorption, and the selenium-75 homotaurocholate (SEHCAT) test, which is used to detect malabsorption of bile acid.
Although endoscopy is often used to localise gastrointestinal bleeding, it can be unhelpful, particularly if the bleeding is intermittent or very heavy and the mucosa is obscured. In such cases, imaging of radiolabelled autologous red blood cells may be of help. Bleeding can be detected for 24 hours after radiotracer is given, and positive results may obviate the need for angiography. Red blood cell imaging is well tolerated, is easy to perform in acutely ill patients, and has a high sensitivity, even at low bleeding rates (0.5-1.25 ml/minute). Where Meckel's diverticulum is suspected, 99mTc-pertechnetate should be used, and scintigraphy has a sensitivity of greater than 80% for detecting ectopic gastric mucosa (fig 8).
Biliary scintigraphy using 99mTc-iminodiacetic acid derivatives is used to assess hepatobiliary function. These derivatives are taken up the hepatocytes and excreted in the bile, with accumulation in the gall bladder and excretion into the small bowel. Indications include cholecystitis, cholestasis, assessment of surgical or endoscopic intervention for obstruction, detection of bile leakage after surgery or trauma, and assessment after hepatic transplantation.
Neurological and psychiatric disease
The most common forms of radionuclide brain imaging are cerebral blood flow studies with 99mTc-HMPAO and positron emission tomography studies with fluorine-18-fluorodeoxyglucose (18F-FDG). Both techniques can be used to locate the focus of the seizure before surgery in patients with intractable temporal lobe epilepsy. 5 26 In HIV positive patients, nuclear medicine studies can help to determine when space occupying lesions are due to Toxoplasma gondii abscess or lymphoma. Finally, radionuclide cerebral blood flow studies are a useful adjunct in the differential diagnosis of dementia. 5 26
In thyroid disease, the most common reason for scintigraphy, which can be performed with either 99mTc-pertechnetate or iodine-123, is to determine which nodules require needle biopsy (fig 9). Functional nodules are unlikely to be malignant, whereas “cold” nodules—either solitary nodules or those that are a dominant part of a multinodular goitre—require biopsy.27
Thyroid scintigraphy is also used to differentiate between Graves' disease and Plummer's disease,28 to investigate patients with suspected thyroiditis (particularly Hashimoto's thyroiditis), to confirm a non-suppressed thyroid trap, and to calculate the optimal therapeutic dose of radioactive iodine. In young patients, scintigraphy is used for the differential diagnosis of anterior neck masses: apart from sublingual thyroid tissue, all anterior neck masses, including thyroglossal cysts, do not appear as functional tissue on scintigraphy.
Metaiodobenzylguanidine (MIBG) is an analogue of guanethidine which concentrates in sympathoadrenal tissue. Its radiolabelled form has high sensitivity for neural crest tumours (88% for phaeochromocytoma, 89% for paraganglioma, 92% for neuroblastoma, 71% for carcinoid, and 35% for medullary thyroid cancer)29 and is complementary to structural imaging in detection, staging, and follow up. Scintigraphic evaluation is an integral part of assessment for possible treatment with 131I-MIBG (fig 10).
Scintigraphy is helpful to localise residual hyperparathyroid tissue before surgery for recurrent or persistent hyperparathyroidism. Dual phase imaging with 99mTc-sestamibi has high sensitivity (89%) and specificity (94%) for detecting adenomas, but its accuracy is lower in cases of hyperplastic glands (sensitivity 55%), especially when these are multiple.30
Selenium-75 selenomethyl-19-norcholesterol concentrates in the tissues that secrete steroid hormones and can therefore be used to image the adrenal cortex. It is used predominantly in assessing incidentally discovered adrenal masses.
The most commonly performed nuclear medicine investigation in patients with malignancy is a bone scan for tumour staging. A broad range of techniques is used to detect primary tumours and recurrences, and after treatment to differentiate residual viable tumour from fibrosis. 6 31 32
In lymphoma,67 Ga-citrate imaging is superior to both computed tomography and magnetic resonance imaging in the evaluation of mediastinal masses after radiotherapy. High dose 67Ga-citrate tomography has a sensitivity of 82-92% for residual tumour. 33 34 In vitro measurement of red cell mass and plasma volume can distinguish polycythaemia rubra vera from pseudo-polycythaemia.
In patients with thyroid cancer, regular measurement of thyroglobulin concentrations, together with whole body 131I imaging, is used to detect the site and extent of residual or recurrent disease (fig 11).
Many tumours express somatostatin receptors and can be imaged using a radiolabelled somatostatin analogue, 111In-pentetreotide.29 This analogue allows whole body imaging, detects primary tumours or metastases as small as 1 cm in diameter, and can be used to monitor treatment. 111In-pentetreotide scintigraphy is most commonly used in the assessment of patients with carcinoid (sensitivity about 85%) (fig 12). It can also be used to image the rarer gastroendocrine tumours, including glucogonomas and VIPomas. Positive uptake is regarded as a prelude to treatment with radiolabelled octreotide.
Screening mammography has relatively poor specificity for breast cancer in radiologically dense breasts. In contrast, scintimammography (99mTc-sestamibi) has a negative predictive value for breast cancer of 97%35; its use reduces the number of unnecessary biopsies. It is also useful in the detection of local recurrences.
Nuclear medicine has an important role in assessing local and nodal spread in cutaneous melanoma, head and neck tumours, and breast cancer.36
Radioimmunoscintigraphy is used to detect recurrent or occult sites from colorectal, ovarian, and prostate cancers. Monoclonal antibodies radiolabelled with 111In or 99mTc, which bind to the tumour cells, are used for imaging.
Radionuclide therapy works on the principle of internal targeting and is used most often to treat thyrotoxicosis. 131I has become the treatment of choice for hyperthyroidism, especially Graves' disease in adults and more recently in children and adolescents.37 Treatment is generally on an outpatient basis and aims to control thyrotoxic symptoms and biochemistry over a few months, the time depending on the patient's initial toxic status. Side effects are minimal and the most common effect is hypothyroidism.
In treating differentiated thyroid cancer, 131I has two distinct therapeutic roles: the ablation of residual thyroid tissue after surgery and the treatment of recurrent disease. Side effects are generally limited to an early and short lived sialitis.
Bone metastases are the commonest cause of pain in cancer patients. The systemic administration of radionuclides can be effective in treating symptomatic bone metastases. Strontium-89, a calcium analogue administered by intravenous injection, preferentially localises in tumour and is effective in treating painful bone metastases. Pain is relieved in 75% of patients, most typically 1-3 weeks after treatment, and relief may continue for several months.38 The current trend is to complement 89Sr therapy with local external beam radiotherapy to achieve optimal palliation of symptoms.
131I-MIBG therapy is often used for neural crest tumours: clinical indications include inoperable disease, control of tumour progression, and palliation of symptoms. Patients selected for treatment should have a relatively high uptake of 123I-MIBG on the diagnostic scan and a life expectancy of more than one year, since the response to treatment is slow. The most commonly treated tumours include malignant phaeochromocytoma, malignant carcinoid, neuroblastomas (mainly stage IV), and medullary carcinoma of the thyroid. Complete or partial responses have been reported in 20% of patients and a palliative response in at least 58%.29 These results should be viewed against a background of widespread metastatic disease that shows little or no response to other forms of treatment. Radiolabelled octreotide is yet to be licensed for therapy.
We are grateful to Dr Sveto Gacinovic of the Institute of Nuclear Medicine, University College London Medical School, for his help in providing images.
Conflict of interest: None.