Nuclear Medicine is a medical speciality that uses the nuclear properties of elements (mainly radioactive but occasionally stable) in diagnosis or therapy of diseases. The most visible component of this is in the use of gamma-ray emitting radioisotopes to produce images (scans). There is also extensive use of in-vivo non-imaging diagnostic methods (eg breath tests) which use either stable or radioactive elements, a declining use of in-vitro diagnostic tests (eg radioimmunoassay), and use of elements decaying with gamma, beta and alpha radiation producing higher radiation doses as therapeutic agents
Because many of these radionuclides are delivered to their intended site by linking them to complex organic or biological molecules, and because of the change in the emotion generated by the word “Nuclear” in the 60 years of the specialty’s existence, the term “Molecular Imaging” is becoming more widespread in journals and special society titles.
Nuclear Medicine relies on the “tracer” principle, where the distribution of a substance depends on physical or chemical processes. The tracer material is itself, or is labelled with a radioactive material. The combination is usually referred to as a radiopharmaceutical. The most commonly used radioactive material used in conventional nuclear medicine is technetium 99m (99mTc), the chemistry of which allows its attachment to many molecules, allowing, in turn, concentration in multiple organs or processes (eg bone, heart, liver, kidney, lung etc). It has an ideal g-ray energy for imaging, a half life long enough to allow preparations to last a working day, but short enough to minimise patient radiation exposure (typically similar to an X-ray of the corresponding region) by decaying to negligible amounts shortly after the end of the diagnostic process. For diagnostic (not therapeutic) doses of radiopharmaceuticals in the patient, there is no need for the surgeon to delay operating, as the radiation dose arising from the patient will be negligible.
Radioactivity is a property of the nucleus of the element in which the ratio
of protons and neutrons in the element is such that an adjustment has to
be made for the nucleus to be at the lowest energy state. This can be done
by the release of an alpha particle (2 protons and 2 neutrons, a heavy, charged
particle, which gives a large radiation dose, and travels less than a millimetre
within soft tissue, and cannot be detected from outside the intact body.
Alpha (
) emitters
are therefore of potential use in therapy, but are of little use in diagnostic
applications. Many heavy or natural radioisotopes (Uranium, Radium) are alpha
emitters. Beta (ß) emission occurs from many of the
frequently used radionuclides, and accompanies the transmutation of a neutron
to a proton (ß-) from radioactive isotopes
produced in a nuclear reactor, or positrons (ß+)
from isotopes produced in cyclotrons. These latter tracers are more usually
used in positron emission tomography (PET). ß- travel
several mm in tissue, again causing a radiation dose to tissue, but not readily
detected at the surface.
The radiotherapeutic effects of many radionuclides (eg 131Iodine) are caused by their ß emissions.
Gamma (
) rays
are electromagnetic waves physically undisguisable from X-rays and pass relatively
freely through tissue, and causing least radiation effect of these radiations.
As they will exit the body and are relatively easily detected, they are of
most use in non-invasive imaging using gamma cameras.
The time-activity relationship of uptake or transit of tracer in or through an organ may be determined with dynamic studies (eg gastric emptying). Nuclear medicine particularly lends itself to quantitative studies. Frequently, the distribution of tracer in the process of interest at one time point “static image” is all that is required (eg presence or absence of a tumour). Computed Tomography is very commonly performed in nuclear medicine. This is commonly performed with conventional tracers SPECT, Single Photon Emission Computed Tomography, or PET, Positron Emission (computed) Tomography. When looking at nuclear images, it should be remembered that they are not “shadows” but images of radioactive organs. The display, therefore is as if the observer were “viewing” “luminous” organs, and therefore in an anterior image, the patient’s left is on the observer’s right, but from posterior right is on right.
Diagnostic nuclear medicine interacts with many medical specialties.
Most frequently, the radiopharmaceutical will either localise in the organ of interest, and so diagnosis is based on disturbance in the anatomy or dynamics of the organ, or it will localise in the pathological process of interest (eg cancer, infection).
The following topics are arranged in organ systems preceded by the relevant radiopharmaceutical
Radiopharmaceutical: Tc99m bisphosphonate
(adsorbed to actively mineralising bone)
Uptake: local blood flow, mass of bone, and metabolic
activity
Primary or metastatic malignancies usually have bony remodelling at periphery - increased uptake. MRI shows soft-tissue component, particularly in primary. Some benign lesions show increased uptake on the bone scan, (eg the classically painful and difficult to diagnose osteoid osteoma is very “hot” on the bone scan).
Paraneoplastic phenomena, such as hypertrophic pulmonary osteoarthropathy, or the results of malignant hypercalcemia (lung, stomach and increased bone uptake), may also manifest on the bone scan.
Radiopharmaceuticals:
99mTc-DTPA - cleared by glomerular filtration
99mTc-MAG3 - cleared by glomerular filtration and tubular excretion
- more useful if renal function is impaired or in children.
99mTc-DMSA - accumulates in renal tubules, gives map of functioning
renal tissue, useful in cortical masses or scarring.
| May be recognised by its effect on the inflow into and subsequent reduced function of the affected kidney. This is enhanced by prior administration of Angiotensin Converting Enzyme inhibitor (Fig 6). The technique is useful for screening, but also monitoring the effect of revascularisation surgery. Functional results of renal artery stenosis are shown by changes in size or function, rather than the anatomical lesions shown by conventional imaging, which may not be associated with significant functional change. | |
| Particularly in paediatric patients, localised functional disturbance in renal parenchyma with prognostic significance (often a prelude to scarring in children with reflux) may be demonstrated with 99mTc-DMSA scanning (Fig 7) and prompt decisions regarding intervention. Reflux in children may be assessed by direct (activity introduced into the bladder via catheter) or indirect (99mTc MAG3 excreted by kidney) cystography. This has a radiation dose advantage on the x-ray techniques. |
| Dilated renal collecting systems may not be “obstructed” (normal function, good prognosis) Interventional decisions may be assisted by the diuretic renogram which uses a rapidly cleared radiopharmaceutical to fill, then “stress” the dilated system with diuretic. The dilated, but not obstructed system, clears promptly (typically half –clearance time < 13min. See Fig 8 and movie 1). The differential renal function is also important to confirm loss if present. | |
Radiopharmaceuticals:
99m-Tc colloid (reticulo-endothelial function)
99m-Tc red cells (acute GI bleeding, hepatic haemangiomata)
99m-Tc heat-damaged red cells (splenunculi)
99m-Tc-IDA derivative (excreted in bile)
Na99m-TcO4 (Meckel’s Diverticulum)
99m-Tc –colloid or 111In labelled leucocytes
(inflammatory bowel disease)
Labelled anti-CEA antibodies (colon cancer)
| The traditional colloid liver scan (depending on phagocytosis of particles in liver Kupffer cells and splenic sinusoids) is obsolete other than for confirming focal nodular hyperplasia (Fig 9). Depending on the radiopharmaceutical, masses may have more uptake (“hot”) or less (“cold” Fig 10) than the surrounding liver, or be invisible. For some common patterns see table 1. Haemangiomata are common and have typical appearances on ultrasound and CT scans (biopsy being unhelpful and contraindicated). If atypical, and if not thrombosed, they may be shown to slowly fill their vascular spaces if scanned with labelled red cells (Fig 11). For these and most lesions, a diameter of >1.5cm is needed for confidence. SPECT improves the contrast. Very few other lesions (vascular haemangiosarcomata) show similar activity. | ||
Table 1
|
Colloid |
Red Cells |
IDA derivatives |
Octreotide |
MIBG |
Labelled anti-CEA antibody |
FDG |
|
|
Hepatocellular carcinoma |
- |
- |
- |
+/- |
- |
- |
++ |
|
Adenoma |
- |
- |
+/- |
- |
- |
- |
+ |
|
Haemangioma |
- |
++ |
- |
- |
- |
- |
- |
|
Focal nodular hyperplasia |
+ |
+ |
+ |
+ |
- |
- |
+ |
|
Metastasis |
- |
- |
- |
++* |
+/- |
++ (colorectal) |
++* |
|
Cyst |
- |
- |
- |
- |
- |
- |
- |
|
Neuroendocrine tumour |
- |
- |
- |
++* |
+/- |
- |
+/- |
|
Splenic tissue (splenuculus) |
++ |
++ (heat-damaged) |
- |
+ |
- |
- |
- |
| 99mTc IDA –derivatives are useful in assessing biliary tract disease. Visualisation of the gall bladder an hour after injection (enhanced by 2mg iv morphine to cause sphincter of Oddi contraction if indicated) virtually excludes acute cholecystitis (Fig 12). Quantitative studies may be useful in patients in whom biliary dyskinesia is a problem (gall-bladder ejection fraction following fatty meal or iv cholecystokinin is normally >40%). Post-traumatic and post surgical biliary leaks are readily assessed (Fig 13, movie 2). Following liver transplantation. Scanning after administration of a 99mTc IDA derivative can demonstrate adequacy of perfusion, uptake by liver parenchyma, excretory function and patency of biliary channels. Serial imaging is particularly useful. |
| Autologous red cells labelled with 99mTc and damaged by heating to 49°C for 20 minutes are taken up very avidly by splenic tissue Following relapse of conditions treated by splenectomy, (spherocytosis, ITP), regenerating splenic rests or splenunculi are often to blame. This is the procedure of choice to localise these splenic rests (Fig 14). | |
Apart from the exclusion of splenic infarction (wedge–shaped defects often in an enlarged spleen), most indications for splenic colloid imaging are obsolete. It has no part to play in trauma.
| Radionuclide tests lend themselves to quantitation, and assessment of GI motility is an ideal indication Pharyngeal clearance studies are seldom performed, but may be useful indications for oesophageal clearance studies include anatomical (stricture, hiatus hernia but not suspected malignancy) neuromuscular (spasm, achalasia) or reflux. Quantitative oesophageal clearance (Fig 15) studies often displayed as functional images where the vertical position of the radionuclide is plotted against time, which gives a image of the clearance of activity from the oesophagus. Slowing of transit, sites of hold-up, or reflux are easily demonstrated. | |
|
|
|
Small
bowel transit (most simply mouth-caecum transit time) is readily studied
by radionuclide techniques, although the indications for this are limited.
Colonic transit studies are much more frequently performed in the assessment
of constipation, giving a readily quantifiable assessment of bowel transit,
and the site of hold-up. The agent of choice is 67Gallium citrate
because of its half-life. Daily scans are performed, with the centroid of
activity plotted, and the rate of clearance measured. Obstructed defaecation
is readily distinguished from more generalised motility disturbances (fig
17).
In obscure anaemia, the faecal excretion of 57Cr autologous red cells gives precision of better than 1ml/day (the same technique can measure menstrual loss if this is a differential). This has no localising ability.
| If the bleeding is acute and rapid, then localisation of the bleeding site is feasible. Autologous erythrocytes are labelled with 99mTc and reinjected. Bleeding rates of 0.5-1 ml/ min should be identifiable in the GI tract. It is important that images are taken serially (at short intervals of no more than a few minutes movie 4) to localise the bleeding (Fig 18) If the patient is imaged only several hours after beginning, then the extravasated activity will have moved distally, and redundantly confirm that the patient was bleeding. In the paediatric or young adult population, if Meckel’s diverticulum is considered then Na99mTc04 may be used. It is taken up by excretory epithelium, (particularly gastric mucosa) and will localise within a few minutes in native and ectopic gastric mucosa, adjacent to which is the ulcer causing bleeding. | |
| May be difficult to assess in activity or extent by conventional techniques.
Leucocytes (mixed or granulocytes) localise at sites of active bowel
inflammation and are shed into the lumen. Imaging (fig 20) and counting
excreta can both localise and score disease activity.
Non imaging nuclear techniques may be used in the investigation of absorption: The Schilling test (vitamin B12) is affected both by gastric (intrinsic factor) or terminal ileal (specific receptors) disease, either medical or post surgical. Breath testing for malabsorption of fat (triglycerides, triolein) is also well established. 99mTc-monoclonal antibody (CEA_Scan) has been shown to be useful in the localisation of recurrent and metastatic colon cancer. It is less accurate than 18FDG PET. |
| These share many pathophysiological pathways, and no absolutely specific agent exists. Nevertheless, labelled granulocytes in particular appear to accumulate in areas of acute inflammation, and help localise this if there is acute leucocytic infiltration. Chronic inflammation (infection) is less likely to have leucocytic infiltration, and therefore labelled leucocytes may not reveal these. Particular use has been made in determining infection in “violated” bone, and inflammatory bowel disease, but the technique is useful in localising acute inflammation anywhere Abscesses are readily seen (Fig 21), and acute appendicitis is readily visualised (fig 22), although anatomical imaging is usually used first. Pyrexia of unknown origin without suspected focal sepsis has a poor yield with these investigations. | ||
| Nuclear techniques remain relevant in the assessment of thyroid structure and function. Although ultrasound and fine needle aspiration are most frequently used to determine the nature of palpable nodules, assessment of global thyroid uptake (most conveniently with Na99mTc04 may give useful information about the function of nodules). Malignancy is less common in functioning than “cold” nodules (fig 23), and prior to surgery for hyperthyroidism, the exclusion of an autonomously functioning “hot” thyroid nodule, or the lack of uptake in viral or drug induced thyroiditis may be worthwhile (fig 24). Whole body iodine scanning (most usually 131I) is indicated in the follow up of follicular and papillary thyroid cancer after radionuclide ablative treatment (Fig 25). Medullary thyroid cancer arises from a different cell line and is not iodine avid. Despite these thyroid cancers having less uptake than normal thyroid, they have far more uptake than other tissues, and will concentrate radioiodine for diagnostic or therapeutic purposes. Use in recurrence of thyroid cancer tends to be complementary to thyroglobulin assay. | ||
| Although open surgery is very effective in locating and treating hyperparathyroidism, it may fail in 5-10% of operations. Minimally invasive parathyroid surgery is also becoming more common. Both of these are indications for pr-operative parathyroid imaging. The sensitivity of CT, MR, ultrasound and MIBI scanning is similar (70%-90%) The nuclear scan is particularly useful in demonstrating mediastinal lesions and in the post –surgical situation, where conventional imaging is difficult because of scarring. Both the thyroid and parathyroid will take up the current agent of choice, MIBI but the parathyroid lacks the P-Glycoprotein mechanism which clears sestamibi from the thyroid, hence parathyroid tissue retains activity for several hours. Some thyroid nodules also lose this mechanism, and therefore they may be a differential diagnosis for focal uptake in the neck (Fig 26). |
| MIBG-usually labelled with 123I is a catecholamine precursor, which is taken up in phaeochromocytoma (faintly in normal adrenal medulla and adrenergic nerve endings), and some other malignancies (eg carcinoid, neuroblastoma). It may be used in the confirmation of the nature of incidentally found lesions, as well as detecting those in hypertensive patients with appropriately abnormal biochemistry (Fig 27). Functioning metastases are also localisable. | |
| Octreotide (a somatostatin analogue usually labelled with 111In) is frequently taken up in primary and metastatic carcinoid tumours (Fig 28) and other neuroendocrine tumours such as gastrinomas and pituitary neoplasms. | |
Many radiopharmaceuticals will localise within tumours as a result of their intrinsic biodistribution. 99mTc-MIBI is initially distributed by blood flow and metabolic activity. It has been shown to be useful in the diagnosis of primary and recurrent breast cancer, particularly in mammographically dense breasts (Fig 29). The technique is not sensitive enough for local staging. Uptake has also been shown in sarcomata and lung cancers. 99mTcDMSA(V) is also a non-specific tumour scanning agent, shown to be useful in medullary thyroid cancer (Fig 30), and may detect recurrences indicated by calcitonin increases. 201Thallium whole body scans may detect iodine non-avid metastatic thyroid malignancy, sarcomas and brain tumours. Nevertheless it is likely that 18FDG PET scanning is of equal or better utility in most of these indications. |
| Soluble or fine colloidal materials injected interstitially will be taken up into lymphatic vessels and subsequently particulate material will be taken up into draining lymph nodes, mimicking the presumed behaviour of micrometastases. | |
| Sentinel lymph nodes are nodes receiving direct drainage from the tumour, and are regarded as those most likely to be involved with (micro) metastases and predictive of the status of the entire nodal basin. The technique has found most use in cutaneous melanoma (Fig 31) and breast tumour (Fig 32), although head and neck (movie 5), vulval and internal cancers (injected endoscopically) have been studied by this technique. When staging the axilla in breast cancer, many studies have shown concordance between the sentinel node and axillary status of better than 95%. Localisation of lymph nodes is best performed with a combination of radioactive tracers and blue dyes. | |
| Pulmonary embolism is a frequent post operative complication, and confirmation has important therapeutic implications. The ventilation-perfusion (V/Q) scan has been a mainstay of diagnosis for many years, and continues to have a very high predictive value with normal or scans with mismatch (Fig 33). Its specificity is reduced if there are chest-x-ray abnormalities, and in this situation, CT pulmonary angiography will likely give more information, but has a number of contra-indications. | |
Differentiated thyroid malignancy was the original condition treated by radioisotopes, which remain a mainstay of treatment. Metastatic disease is treated by at least two doses of radioiodine (131I). The first dose is needed to ablate the normal thyroid, rests which remain no matter how extensive the surgery. The metastases are usually less avid than normal thyroid tissue. Scanning should be performed after therapeutic doses, as sensitivity for thyroid metastases (Fig 25) is greater. The patient should have an elevated TSH at the time of iodine administration (cease thyroid hormone therapy or administer synthetic TSH).
For hyperthyroidism as an alternative to medical or surgical therapy, the larger the dose of radioiodine administered, the more rapidly control is reached. Ultimately most patients will become hypothyroid. Debate continues regarding the role of radioiodine in the therapy of multinodular goitre.
Neuro-endocrine tumours, may be treated with 131I-MIBG (particularly phaeochromocytoma and neuroblastoma. Octreotide derivatives labelled with 111In, 90Y or other radionuclides have shown some effectiveness in avid tumours. 32P is a therapeutic alternative to reduce the re-accumulation of malignant pleural effusion or ascites.
| Metastatic disease in the liver is supplied mainly by the hepatic artery (predominant portal flow for normal liver), therefore radiopharmaceuticals which will embolise a capillary circulation will preferentially localise in metastatic disease after injection into the hepatic artery. 90Y labelled ceramic microspheres (SIR-Spheres), Fig 34 have has some success in this indication (movie 6), and similarly 131I-labelled lipiodol in hepatocellular carcinoma. Painful bony metastases will localise other bone-seeking radiopharmaceuticals using the same mechanism as bone-scanning agents. 153Sm EDTMP and 89Sr have been shown to be useful in palliation. Labelled monoclonal antibodies are effective in treating certain lymphomas and specific antibodies are being developed for other indications. |
Radiopharmaceuticals:
Perfusion scanning
201Thallous chloride
99mTc Sestamibi
99mTc tetrofosmin
Gated Blood Pool Scanning
99mTc labelled Red Cells
Myocardial infarct scanning
99mTc Imidiodiphosphate
Cardiac Shunt studies
Left-Right
99mTc labelled Red Cells
Right-Left
99mTc-MAA
Nuclear cardiology is one of the main indications for nuclear medicine
studies. The major areas of study include assessment of blood flow to the
heart muscle itself (perfusion scanning), the contractile function of the
heart muscle, and occasionally the determination of whether a myocardial
infarct has occurred recently.
If a patient has typical symptoms of angina, and intervention to improve
blood-flow to the heart is planned, then generally a coronary angiogram will
be performed. This is an invasive test which usually involves the passage
of a catheter.
In some general departments, this may account for half the workload. Although different techniques may be used, the general principle involves the comparison of the myocardial distribution of a tracer under conditions of stress (hyperaemia) with the distribution at rest. The differences in these images might suggest :
The stressors used are typically:
Each of these stressors is associated with a small risk, and patient informed consent is important.
Myocardial perfusion scanning is used usually to:
The images obtained are usually tomographic (slices) displayed in a standardised
orientation (not anatomical) related to the long axis of the left ventricle
which is >80% of myocardial bulk. These may also be related to typical
distribution of coronary artery territory, but anomalous vessels cannot be
recognised on these studies. Displays may be enhanced by “bullseye” images,
which display the entire myocardium in one picture of concentric slices,
apex to the centre.
The images below give some examples of these.
NOTE: The usual jargon used for defects is “reperfusing” ie
changes between rest and stress implying relatively ischaemic but viable
tissue, and “fixed” implying myocardial scar.
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Fig 35. Normal SPECT images demonstrating slice orientation,
typical appearance and "bullseye" dispaly
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Fig 36 Normal gated images - slices and 3D |
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Figs 37-39: Reversible
myocardial ischaemia in LAD, circumflex artery and RCA territory
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| Fig 40: A polar map, to quantify inferior ischaemia |
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By acquiring images synchronised with the heart beat (ECG), sufficient radioactive counts may be collected to produce an image of a typical cardiac cycle. This principle was seen above in the myocardial perfusion scanning section, where the movement of the myocardium itself was monitored. Although those images may be used to estimate an ejection fraction, this depends on a number of geometric assumptions, which may be incorrect, particularly in disease, and therefore the precision of ejection fractions obtained from perfusion scans is not high, particularly if they are to be used to monitor the progress of a patient.
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Fig 42: Normal GBPS scan and curves |
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Fig 43: Low LVEF with dyskinesia and apical aneurism |
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Fig 44: LV filling curve |
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| Several radiopharmaceuticals, most notably the bone seeking radiopharmaceutical, 99mTc imidodiphosphate, localise in recently necrotic myocardium. If the standard ECG or biochemical tests of myocardial necrosis are not helpful, an IDP scan 2 hr ± 6 days after the acute event may help confirm recent infarction. |
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Confirmation of shunting from the left to the right side of the circulation (eg atrial septal defect), and quantification of this may be simply done in a study taking a few minutes. Rapid frames are taken following IV injection of tracer. Early recirculation to the lungs implies shunting of blood. The ratio of blood flow through the systemic to pulmonary circulation (QP/QS) may be calculated.
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Fig 46: QP/QS curve.
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If the shunt is in the opposite direction (venous to arterial side, reversal in VSD, AV shunting in the lungs), then 99mTc MAA, used in lung scanning, will bypass the pulmonary circulation, and lodge in the next capillary bed (brain and kidneys in particular at rest). The proportion shunted may be easily calculated.
| Fig 47: R-L shunt. |