Single Photon Emission Computed Tomography (SPECT)

Number: 0376

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses single photon emission computed tomography (SPECT).

1. Medical Necessity

   1. Non-Cardiac Indications

      Aetna considers single photon emission computed tomography (SPECT) medically necessary for any of the following indications:

      1. Assessment of osteomyelitis, to distinguish bone from soft tissue infection; or
      2. Detection of spondylolysis and stress fractures not visible from x-ray; or
      3. Diagnosing and assessing hemangiomas of the liver; or
      4. Diagnosing pulmonary embolism (by means of SPECT ventilation/perfusion scintigraphy); or
      5. Differentiation of necrotic tissue from tumor of the brain; or
      6. Distinguishing Parkinson's disease from essential tremor (e.g., DaTSCAN (Ioflupane I-123 injection); or
      7. Fever of unknown origin, where initial studies (including physical examination) have failed to identify a site of infection; or
      8. Imaging of parathyroids in parathyroid disease; or
      9. Liver metastases or primary liver tumors, before and after hepatic artery chemotherapy infusion or chemoembolization with radioactive spheres; or
      10. Localization of abscess, for suspected or known localized infection or inflammatory process; or
      11. Lymphoma, to distinguish tumor from necrosis; or
      12. Neuroendocrine tumors, diagnosis and staging; or
      13. Pre-surgical ictal detection of seizure focus in members with epilepsy (in place of positron emission tomography (PET)); or
      14. Thyroid cancer, iodine imaging for initial and subsequent staging of thyroid cancers.

      Aetna considers SPECT-CT fusion medically necessary for parathyroid imaging in persons with an enlarged parathyroid gland, parathyroid hyperplasia or suspected parathyroid adenoma or carcinoma, and laboratory evidence of hyperparathyroidism (parathyroid hormone greater than 55 pg/ml and serum calcium greater than 10.2 mg/dL). 

   2. Cardiac Indications

      Aetna considers SPECT medically necessary for the diagnosis of coronary artery disease and for the assessment of prognosis in persons with coronary artery disease except as outlined in "exclusion criteria" below." For medical necessity criteria, see eviCore Healthcare Cardiac Imaging Clinical Guidelines.

      Note: eviCore guidelines undergo a formal review annually; however, eviCore reserves the right to change and update the guidelines without prior notice. Draft guidelines are posted 90 days prior to implementation. Additional clinical guidelines may be developed as needed or may be withdrawn from use.
      
      Tip on accessing eviCore cardiac imaging guidelines: On the eviCore Cardiology & Radiology Clinical Guidelines page, enter Aetna/ Aetna NJ/ Aetna NY as applicable for commercial plans or choose the appropriate Aetna Better Health option for Medicaid plans. Then scroll down and click on “Cardiac imaging Guidelines.” You can search the Cardiac Imaging Guidelines PDF for the specific CPT codes you are interested in. Note: An ID or password is not required to access the eviCore Clinical Guidelines.

2. Experimental, Investigational, or Unproven

   1. Aetna considers SPECT myocardial perfusion imaging experimental, investigational, or unproven for the following indications for which the study is considered “inappropriate” according to appropriateness criteria from the American College of Cardiology (ACC):

      1. As a routine screening evaluation after a percutaneous transluminal coronary angioplasty (PTCA) with or without stenting or coronary artery bypass surgery (CABG) prior to discharge from the acute care setting; or
      2. As a routine screening evaluation after a re-vascularization procedure (PTCA with stenting or  CABG) at an interval of less than 2 years from the procedure if there is no worsening in the members symptomatology and if the member had symptoms prior to the intervention, and there is no history of congestive heart failure.  Note: If there is a history of congestive heart failure and the member is status post re-vascularization, repeat nuclear imaging as frequently as annually may be medically necessary; or
      3. Assessment of vulnerable plaque; or
      4. Evaluation of a member with an acute coronary event and hemodynamic instability, shock, or mechanical complications of the event; or
      5. In the setting of acute chest pain or equivalent symptoms with a high likelihood of being acute coronary syndrome, when there has been a diagnosis of acute myocardial infarction, in the immediate post-thrombolytic period, or when there is a high pre-test likelihood of significant coronary disease as demonstrated by marked ST segment elevation on the ECG; or
      6. Prior to high-riskFootnote3*** surgery when the member is asymptomatic and there was a normal cardiac catheterization, coronary intervention (PTCA, stenting, CABG), or normal nuclear stress test less than 1 year before the surgical date; or
      7. Prior to intermediate-riskFootnote3*** non-cardiac surgery if the member is capable of, and has no contraindication to standard stress testingFootnote2**; or
      8. Prior to low-riskFootnote3*** non-cardiac surgery for risk assessment; or
      9. Re-evaluation of members without chest pain or equivalent symptoms, without known coronary disease, at high-risk for coronary disease (based upon the Framingham score greater than 10)Footnote1*, who have an initial negative radionuclear imaging study, when it has been less than 2 years since the last radionuclear study; or
      10. Re-evaluation of members without chest pain or equivalent symptoms or with stable symptoms, with known coronary disease as determined by prior abnormal catheterization or SPECT cardiac study (but without prior infarction), when it has been less than 1 year since the last radionuclear study.  Note: if the member has worsening symptoms or if the member had silent ischemia, more frequent imaging or other diagnostic testing or interventions may be medically necessary; or
      11. Screening of members with chest pain or chest pain equivalent symptoms when there is a low probability of coronary disease (Framingham score less than 10)Footnote1*, no history of diabetes, and there are no impediments or contraindications to non-nuclear stress testingFootnote2**; or
      12. Screening of members without chest pain or equivalent symptoms when there is a low probability of coronary disease (Framingham score less than 10)Footnote1* and no history of diabetes; or

      Footnote1* A tool for calculating Framingham score is available from the National Heart Lung and Blood Institute at the following website: Framingham Score from National Heart Lung and Blood Institute.

      Footnote2** According to ACC guidelines, the following are impediments or contraindications to non-nuclear stress testing:

      • A history of physical impairments that would preclude physically performing the exercise portion of a stress test; or
      • A history of prior proven ischemic cardiac events; or
      • Proven CAD by past SPECT or coronary catheterization; or
      • The member's ECG would prevent interpretation of a standard stress testing by being “uninterpretable” during the test, i.e., left bundle branch block (LBBB), paced rhythm, Wolf Parkinson White syndrome, left ventricular hypertrophy (LVH) with ST segment depression, or digoxin use.

      Footnote3*** Surgical risk categories.

      • High-risk surgery (risk of cardiac death or myocardial infarction (MI) greater than 5 %): emergent major operations (particularly in the elderly), aortic and peripheral vascular surgery, prolonged surgical procedures associated with large fluid shifts and/or blood loss.
      • Intermediate-risk surgery (risk of cardiac death or MI 1 % to 5 %): carotid endarterectomy, head and neck surgery, surgery of the chest or abdomen, orthopedic surgery, prostate surgery.
      • Low-risk surgery (cardiac death or MI less than 1 %): endoscopic procedures, superficial procedures, cataract surgery, breast surgery.

   2. The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

      1. Freehand SPECT/ultrasonography (US) fusion imaging in persons with thyroid disease
      2. Myocardial sympathetic innervation imaging, with or without SPECT
      3. SPECT for absolute quantitation of myocardial blood flow (AQMBF) 
      4. SPECT for all other cardiac indications 
      5. SPECT-CT fusion imaging for other indications (e.g., detection of metastatic bone disease in malignancies, and quantification of neutrophil uptake in lung cancer)
      6. SPECT for all other non-cardiac indications, including any of the following:
         
         
         1. As an imaging marker of pre-diagnostic Parkinson's disease; or
         2. Assessment of eating disorders; or
         3. Detection of air leak/pneumothorax; or
         4. Diagnosis or assessment of members with attention deficit/hyperactivity disorder; or
         5. Diagnosis or assessment of members with autism; or
         6. Diagnosis or assessment of members with personality disorders (e.g., aggressive and violent behaviors, anti-social personality disorder including psychopathy, schizotypal personality disorder, as well as borderline personality disorder); or
         7. Diagnosis or assessment of members with schizophrenia; or
         8. Diagnosis or assessment of stroke members; or
         9. Diagnosis of lung cancers; or
         10. Diagnosis of ovarian cancer; or
         11. Diagnosis of painful legs and moving toes (PLMT) syndrome; or
         12. Differential diagnosis of Parkinson's disease from other Parkinsonian syndromes; or
         13. Differentiating malignant from benign lung lesions; or
         14. Evaluation of carotid stenosis; or
         15. Evaluation of members with endoleak; or
         16. Evaluation of members with generalized pain or insomnia; or
         17. Evaluation of members with head trauma; or
         18. Evaluation of Merkel cell carcinoma; or
         19. Evaluation of salivary gland dysfunction; or
         20. Initial or differential diagnosis of members with suspected dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia); or
         21. Management of cortico-basal syndrome; or
         22. Management of progressive supranuclear palsy; or
         23. Management of systemic lupus erythematosus; or
         24. Multiple sclerosis; or
         25. Pre-surgical evaluation of members undergoing lung volume reduction surgery; or
         26. Prosthetic graft infection; or
         27. Scanning of internal carotid artery during temporary balloon occlusion; or
         28. Surgical planning in individuals with axial neck and back pain from disc degeneration (spondylosis); or
         29. Vasculitis; or
         30. Work-up of individuals undergoing non-cardiac surgery.

3. Related Policies

   • CPB 0426 - Attention Deficit/Hyperactivity Disorder
   • CPB 0511 - Eating Disorders
   • CPB 0648 - Autism Spectrum Disorders
   • CPB 0716 - Sialolithiasis (Salivary Stones)

Background

Single photon emission computed tomography (SPECT) is a nuclear medicine technique that uses radiopharmaceuticals, a rotating camera (single or multiple-head), and a computer to produce images representing slices through the body in different planes.  Single photon emission computed tomography images are functional in nature rather than being purely anatomical such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI).

SPECT for Myocardial Perfusion Imaging

Single photon emission computed tomography has been applied to the heart for myocardial perfusion imaging.  It is an effective non-invasive diagnostic technology when evaluating patients for clinically significant coronary artery disease (CAD) in the following circumstances: for diagnosing CAD in patients with an abnormal resting electrocardiogram (ECG) and restricted exercise tolerance; or assessing myocardial viability before referral for myocardial re-vascularization.

Single photon emission computed tomography has a far greater sensitivity for detecting silent ischemia than stress ECG.  Pooled data of exercise SPECT studies in over 1,000 patients revealed a 90 % overall sensitivity for detecting CAD.  In assessing myocardial viability, studies indicate that, even in patients with severe irreversible thallium defects on standard exercise-redistribution imaging, thallium re-injection provides information regarding myocardial viability that is comparable to that provided by positron emission tomography (PET).

SPECT for Detection of Neurological Diseases

Single photon emission computed tomography examines cerebral function by documenting regional blood flow and metabolism; SPECT of the brain is a useful alternative to PET for the pre-surgical ictal detection of seizure focus.  Effective surgical treatment of patients with intractable epilepsy is dependent on accurate localization of the epileptic focus and precise delineation of the epileptogenic region.  It is generally agreed that this requires EEG recording with electrocorticography.  This testing is designed to identify the source or sources of the seizures, as well as an assessment of brain function.  The search for non-invasive and cost-effective means of seizure localization has been an important area of research.

Seizures are associated with dramatic increases in blood flow, localized in partial seizures and global during generalized seizures.  Ictal SPECT uses the physiologic increase in regional cerebral blood blow during seizures to potentially localize the epileptogenic region.  Ictal studies, although more difficult logistically, are reported to have a sensitivity of 81 to 93 %.  (Interictal SPECT demonstrates hypo-perfusion and is reported to have a sensitivity ranging from 40 to 75 %).

Other imaging modalities help in localizing abnormal epileptogenic tissue.  Quantitative MRI has a sensitivity of 80 to 90 % for the lateralization of temporal lobe epilepsy.  However, there are instances where ictal SPECT has identified lesions not detected by MRI.  Depth electrocorticography and intra-operative electrocorticography, though accurate in many forms of epilepsy, are both highly invasive.  In cortical developmental disorders, these EEG techniques often fail to localize the epileptogenic area.  Single photon emission computed tomography imaging may offer a safe and accurate alternative.

Ictal SPECT testing requires that seizure activity be provoked through reduction of anti-epileptic medications.  Video EEG monitoring may also be performed.  Due to the nature of ictal SPECT, it should be performed in a hospital setting.

Studies of SPECT in the inter-ictal or post-ictal detection of seizure focus, determination of seizure subtypes and monitoring of drug therapy for epilepsy have not established its efficacy for these indications.

Clinical studies indicate that SPECT is more accurate at detecting acute ischemia than CT scan.  By 8 hours after infarction, about 20 % of CT scans will be positive but nearly 90 % of SPECT scans will be.  Beyond 72 hours, the sensitivities of CT and SPECT are nearly identical.  In addition, the defects noted on SPECT are frequently larger than those noted on CT studies.

Among the treatments of acute ischemic stroke, the use of tissue plasminogen activator (t-PA) has been shown to reduce neurologic impairment if administered within 3 hours of onset.  This is administered when CT is negative for hemorrhage.  Single photon emission computed tomography can not detect hemorrhage in order to rule out use of thrombolysis.  Therefore, while SPECT is more sensitive than CT in detecting ischemia, it has not been shown to be useful in detecting ischemia early enough to play a role in the use of thrombolysis.  Studies using SPECT in the presence of cerebro-vascular accident (CVA) have timed its performance at less than 6 hours to less than 14 days from the time of onset.

Studies have also reported on SPECT's value with regard to the assessment of prognosis after stroke, determination of stroke type, monitoring therapies used post-stroke, diagnosis of vasospasm following subarachnoid hemorrhage and in the diagnosis/prognosis regarding transient ischemic attacks (TIAs).  Single photon emission computed tomography may prove to be helpful in these applications in the future.

Single photon emission computed tomography has proven useful in distinguishing recurrent brain tumor from radiation necrosis.  Radiation necrosis needs to be distinguished from recurrent brain tumor to determine whether chemotherapy is necessary.  Radiation necrosis is more common in brain tumor patients receiving local boost irradiation.  Radiation necrosis and brain tumor may have similar clinical signs and symptoms, and are not reliably distinguished clinically.

Single photon emission computed tomography has been studied in the diagnosis of patients with Alzheimer's disease AD).  At present, the definitive diagnosis of AD can only be made on pathologic examination of brain tissue.  Alzheimer's disease is largely a diagnosis of exclusion.  The diagnostic evaluation of the demented patient is therefore aimed largely at identifying other potentially treatable causes of cognitive impairment.  A technology assessment of SPECT for dementia and AD prepared by the Institute for Clinical Effectiveness and Health Policy (Ferrante, 2004) concluded: "SPECT has not clearly demonstrated its usefulness in assessing patients with dementia, and it has no precise indications for diagnosis, evaluation of prognosis or monitoring response to treatment."

In AD, SPECT shows decreased perfusion in the association cortex of the parietal lobe and the posterior temporal regions.  Frontal association cortex is predominantly affected in some cases, but usually is not involved until late in the course of the disease.  The occipital lobes are less involved and the paracentral cortex is spared.  Although SPECT studies have been reported in over 500 patients with AD, in most cases the diagnosis was made clinically and only in 53 patients it was confirmed by autopsy.  Controlled studies of SPECT in AD have shown a sensitivity of this procedure to vary from 50 % to 95 %.  The best results have been reported in the more recent studies, using higher resolution equipment.  In the 2001 practice parameter on the diagnosis of dementia, the American Academy of Neurology does not recommend SPECT for routine use in either initial or differential diagnosis of dementia (Knopman et al, 2001).

Neuroimaging markers are increasingly important in the early diagnosis of the dementias, not only to detect the rare tumor, but also to differentiate the various types of neurodegenerative dementias.  The potential of MRI and PET as surrogates for disease progression for therapeutic trials is being examined in a large multi-center trial.  However, SPECT has been reported to show specific findings in both fronto-temporal dementia (FTD) and AD and is much more available and less expensive than PET.  McNeil et al (2007) evaluated the diagnostic accuracy of technetium-99–labeled hexamethyl propylene amine oxime SPECT images obtained at initial evaluation in 25 pathologically confirmed cases of FTD and 31 pathologically confirmed cases of AD.  A nuclear medicine physician, blinded to the clinical findings, rated the images.  Except in the case of 1 FTD patient, for whom neuropsychological data were unavailable, the clinical and neuropsychological evaluation was more accurate than SPECT alone in predicting the histological diagnosis.

In a longitudinal, prospective study, Devan and and colleagues (2010) examined the utility of SPECT to predict conversion from mild cognitive impairment (MCI) to AD.  A total of 127 patients with MCI and 59 healthy comparison subjects followed-up for 1 to 9 years were included in this study.  Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, MRI, and brain Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done.  Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (n = 31) from non-converters (n = 96), but the global rating predicted conversion (41.9 % sensitivity and 82.3 % specificity, Fisher's exact test p = 0.013).  Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio [HR]: 2.96, 95 % confidence interval [CI]: 1.16 to 7.53, p = 0.023) and medial temporal regions (HR: 3.12, 95 % CI: 1.14 to 8.56, p = 0.027).  In the 3-year follow-up sample, low parietal (p < 0.05) and medial temporal (p < 0.01) flow predicted conversion to AD, with or without controlling for age, Mini-Mental State Examination, and apolipoprotein E ε4 genotype.  These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal, and entorhinal cortex volumes.  The authors concluded that SPECT visual ratings showed limited utility in predicting MCI conversion to AD.  The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.

Single photon emission computed tomography has also been reported to be used in neoplasms (grading of gliomas), HIV encephalopathy, head trauma, Huntington's chorea, persistent vegetative states and in diagnosing brain death.  Based upon the current evidence, SPECT has not proven to be established in any of these clinical situations.  More study is needed in these areas.

The Food and Drug Administration (FDA) has approved 4 radiopharmaceuticals for imaging of the brain: I-123 isopropyliodoamphetamine (IMP, Spectamine); Tc-99m HMPAO (hexamethyl propylamine oxime, Ceretec); Tc-99m ECD (ethyl cysteinate dimer, Neurolite), and thallium 201 diethyldithiocarbamate (T1-DDC).

SPECT for the Liver

Hemangiomas are the most common benign lesion of the liver.  It is important to differentiate these lesions from others that may be malignant.  Because of the risk of hemorrhage inherent in a percutaneous biopsy of liver hemangiomas, non-invasive modalities have been used for differentiation.  Hepatic hemangiomas are so vascular that their blood pool is easily differentiated from other solid hepatic masses by nuclear scanning with labeled red blood cells (RBCs).  The labeled RBCs are injected intravenously and resolution is markedly improved with SPECT.  Review articles and published studies support SPECT as an appropriate diagnostic modality to differentiate hepatic lesions as hemangiomas.

SPECT for Neuroendocrine Tumors

Carcinoids and other neuroendocrine tumors have somatostatin receptors; therefore, they can be imaged with somatostatin analogs (octreotide, pentetreotide) tagged with an appropriate radioisotope (Khan and Jones, 2005).  Single photon emission computed tomography and subtraction techniques improve detection.  An assessment from the Australian Medical Services Advisory Committee stated that SPECT is often performed in conjunction with antibody imaging (Octreoscan) of neuroendocrine tumors, usually at 24 and occasionally at 48 hours after the injection.  The assessment explained that SPECT is able to differentiate more easily between areas of pathological uptake and physiological uptake in the abdomen.  The assessment explained that SPECT can also help to discriminate between mesenteric and bone lesions.  The assessment noted that extra-planar images may be obtained from areas of specific interest, using longer exposure time for more easily interpreted imaging.

SPECT for Spondylolysis and Stress Fractures

The role of SPECT of the spine has changed in recent years with the wide availability of MRI and especially contrast-enhanced MRI.  Bone scanning with SPECT of the spine may allow for visualization of lesions related to stress fractures or stress reactions in the spine such as spondylolysis.  Single photon emission computed tomography has been accepted as extremely sensitive in detecting incipient spondylolysis and stress/insufficiency fractures (Manaster et al, 2005).  Single photon emission computed tomography shows stress fractures days to weeks earlier than radiographs in many instances, and differentiate between osseous and soft tissue injury as well.  However, in most cases bone scans lack specificity and supplemental imaging may be necessary for conclusive diagnosis or to avoid false positives.  Single photon emission computed tomography continues to be used in back pain, especially in children and adolescents, to detect incipient spondylolysis that may not be detected by conventional imaging.  Because of the sensitivity of SPECT scans, 80 % of all fractures show an abnormality 24 hours post injury and 95 % at 72 hours.  A normal scan generally excludes the diagnosis of stress/insufficiency fracture, and the patient may return to normal activity.

SPECT for the Internal Carotid Artery

Internal carotid artery temporary balloon occlusion (TBO) test is a well-established part of the preoperative evaluation of patients with aneurysm or tumor involving the neck or skull base in whom arterial sacrifice or prolonged temporary occlusion is considered a possible part of the surgical or endovascular therapy.  Temporary balloon occlusion is performed in conjunction with cerebral blood flow analysis to identify those patients who will not tolerate permanent carotid occlusion.  Traditionally, xenon-enhanced CT has been used during TBO to detect signs of ischemia; however, SPECT has recently been reported as a method to detect focal hypo-perfusion during test occlusion.  Several small studies in the published literature report preliminary results that SPECT scanning during TBO is a safe and effective method to assess cerebral blood flow.  However, it is premature to recommend SPECT over the conventional xenon-enhanced CT.

SPECT for the Diagnosis / Assessment of Attention Deficit/Hyperactivity Disorder

Functional neuroimaging such as PET and SPECT has been used to study patients with attention deficit/hyperactivity disorder (ADHD).  Although some studies have shown differences in brain structure or function comparing children with and without ADHD, these findings do not differentiate reliably between children with and without this disorder (i.e., although group means may differ significantly, the overlap in findings among children with and without ADHD results in high rates of false-positives and false-negatives).  As a result, SPECT should not be used as a screening or diagnostic tool for children with ADHD.  The American Academy of Pediatrics' Practice Guideline on “Diagnosis and Evaluation of the Child with Attention-Deficit/Hyperactivity Disorder” does not recommend neuroimaging studies in the diagnosis of ADHD.  An evidence review by McGough and Barkley (2004) stated that there are insufficient scientific data to justify use of laboratory assessment measures, including neuropsychological tests and brain imaging, in diagnosing adult ADHD.

SPECT for the Diagnosis / Assessment of Autism

The American Academy of Neurology (2000) stated that there is no evidence to support a role of neuroimaging modalities such as SPECT in the clinical diagnosis of autism.

SPECT for the Diagnosis of Pulmonary Embolism

In a prospective, observational study, Miles and colleagues (2009) compared SPECT ventilation/perfusion (V/P) scintigraphy with multi-slice CT pulmonary angiography (CTPA) in the diagnosis of pulmonary embolism (PE).  A total of 100 patients who were 50 years of age or older were recruited; 79 underwent both diagnostic 16-detector CTPA, and planar and SPECT V/P scintigraphy.  The agreement between the CTPA and the SPECT V/P scintigraphy for the diagnosis of PE was calculated.  The sensitivity and specificity of blinded SPECT scintigraphy reporting was calculated against a reference diagnosis made by a panel of respiratory physicians that was provided with CTPA and planar V/P scintigraphy reports, clinical information, and 3-month follow-up data.  The observed percentage of agreement between SPECT V/P scintigraphy and CTPA data for the diagnosis of PE was 95 %.  When calculated against the respiratory physicians' reference diagnosis, SPECT V/P scintigraphy had a sensitivity of 83 % and a specificity of 98 %.  The authors concluded that these findings indicated that SPECT V/P scintigraphy is a viable alternative to CTPA for the diagnosis of PE and has potential advantages in that it was feasible in more patients and had fewer contraindications; lower radiation dose; and, arguably, fewer non-diagnostic findings than CTPA.

Gutte et al (2010) evaluated the diagnostic performance of 3-dimensional V/P SPECT in comparison with planar V/P scintigraphy.  Consecutive patients suspected of acute PE were referred to a V/P SPECT, as the first-line imaging procedure.  Patients with positive D-dimer (greater than 0.5 mg/L) or after clinical assessment with a Wells score of more than 2 were included and had a V/P SPECT, low-dose CT, planar V/P scintigraphy, and pulmonary multi-detector CTPA performed the same day.  Ventilation studies were performed using Krypton (Kr).  Patient follow-up was at least 6 months.  A total of 36 patient studies were available for analysis, of which 11 (31 %) had PE.  V/P SPECT had a sensitivity of 100 % and a specificity of 87 %.  Planar V/P scintigraphy had a sensitivity of 64 % and a specificity of 72 %.  The authors concluded that V/P SPECT has a superior diagnostic performance compared with planar V/P scintigraphy and should be preferred when diagnosing PE.

The European Association of Nuclear Medicine (EANM)'s practice guidelines on ventilation/perfusion scintigraphy (Bajc et al, 2009a) stated that PE can only be diagnosed with imaging techniques, which in practice is performed using V/P scintigraphy or multi-detector computed tomography of the pulmonary arteries (MDCT).  The basic principle for the diagnosis of PE based upon V/P scintigraphy is to recognize lung segments or subsegments without perfusion but preserved ventilation, i.e., mismatch.  Ventilation studies are in general performed after inhalation of Kr-labelled or technetium-labelled aerosol of diethylene triamine pentaacetic acid (DTPA) or Technegas.  Perfusion studies are performed after intravenous injection of macro-aggregated human albumin.  Radiation exposure using documented isotope doses is 1.2 to 2 mSv.  Planar and tomographic techniques (Planar V/P and SPECT V/P) are analyzed.  Single photon emission computed tomography V/P has higher sensitivity and specificity than Planar V/P.  The interpretation of either Planar V/P or SPECT V/P should follow holistic principles rather than obsolete probabilistic rules.  Pulmonary embolism should be reported when mis-match of more than 1 subsegment is found.  For the diagnosis of chronic PE, V/P scintigraphy is of value.  The additional diagnostic yield from V/P scintigraphy includes chronic obstructive lung disease (COPD), heart failure and pneumonia.  Single photon emission computed tomography V/P is strongly preferred to Planar V/P as the former permits the accurate diagnosis of PE even in the presence of co-morbid diseases such as COPD and pneumonia.

The EANM's practice guidelines on VP scintigraphy also noted that to reduce the costs, the risks associated with false-negative and false-positive diagnoses, and unnecessary radiation exposure, pre-imaging assessment of clinical probability is recommended.  Diagnostic accuracy is approximately equal for MDCT and Planar V/P and better for SPECT V/P, which is feasible in about 99 % of patients, while MDCT is often contraindicated.  As MDCT is more readily available, access to both techniques is vital for the diagnosis of PE.  Single photon emission computed tomography V/P gives an effective radiation dose of 1.2 to 2 mSv.  For SPECT V/P, the effective dose is about 35 % to 40 % and the absorbed dose to the female breast 4 % of the dose from MDCT performed with a dose-saving protocol.  Thus, SPECT V/P is recommended as a first-line procedure in patients with suspected PE.  It is particularly favored in young patients, especially females, during pregnancy, and for follow-up and research (Bajc et al, 2009b).

Other Indications

Single photon emission computed tomography has proven useful in distinguishing lymphoma from necrosis in the chest and abdomen.  It is also useful in localizing abscesses, and distinguishing abscess from other infectious or inflammatory processes.  Single photon emission computed tomography is also useful in osteomyelitis in distinguishing inflammation of soft tissue from bone.

Guidelines on parathyroid scintigraphy from the Society of Nuclear Medicine (Greenspan et al, 2004) state that there is a developing consensus that SPECT imaging is useful, because, when used in conjunction with planar imaging, SPECT provides increased sensitivity and more precise anatomic localization.  They note that this is particularly true in detecting both primary and recurrent hyperparathyroidism resulting from ectopic adenomas.  In the mediastinum, accurate localization may assist in directing the surgical approach, such as median sternotomy versus left or right thoracotomy.  The Parathyroid Task Group of the EANM (Hindie et al, 2009) stated that the use of SPECT/CT has a major role for obtaining anatomical details on ectopic foci.  However, its use as a routine procedure before target surgery is still investigational.  Preliminary data suggest that SPECT/CT has lower sensitivity in the neck area compared to pinhole imaging.

In a review on neuroimaging in psychopathy (including anti-social personality disorder and violent behavior), Pridmore et al (2005) noted that functional neuroimaging strongly suggests dysfunction of particular frontal and temporal lobe structures in subjects with psychopathy.  However, there are difficulties in selecting homogeneous index cases and appropriate control groups.  These investigators stated that further studies are needed.

An assessment of SPECT for schizophrenia by the Institute for Clinical Effectiveness and Health Policy (Pichon Riviere et al, 2004) found that SPECT has identified increases in dopaminergic activity in the striated body and other areas of the brain during the episodes of schizophrenia exacerbation.  Single photon emission computed tomography has also been able to identify decreases in frontal cortex uptake that are associated with negative symptoms of schizophrenia.  The investigators, however, were unable to find substantial evidence for the role of SPECT scans in therapeutic decision-making in schizophrenia.  They concluded that the use of SPECT scan in schizophrenia remains investigational.

In the recent practice parameter on the diagnosis and prognosis of new onset Parkinson's disease (PD) (an evidence-based review) by the American Academy of Neurology (AAN), Suchowersky et al (2006) stated that SPECT scanning may not be useful in differentiating PD from other parkinsonian syndromes.

In a meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes, Vlaar and colleagues (2007) concluded that SPECT with pre-synaptic radiotracers is relatively accurate to differentiate patients with PD in an early phase from normalcy, patients with PD from those with essential tremor, and PD from vascular parkinsonism.  The accuracy of SPECT with both pre-synaptic and post-synaptic tracers to differentiate between PD and atypical parkinsonian syndrome is relatively low.

The American College of Radiology's "Appropriateness Criteria^® dementia and movement disorders" (Wippold et al, 2010) stated that "[a] diminution of the width of the pars compacta on MRI has been described in PD patients compared to controls, with overlap between groups.  This diminished width probably reflects selective neuronal loss of the pars compacta.  Other authors have found a normal appearance of the substantia nigra on T2-weighted images in a majority of PD patients.  More recently, PET and SPECT tracer studies exploring the presynaptic nigrostriatal terminal function and the postsynaptic dopamine receptors have attempted to classify the various Parkinson syndromes although much of this work remains investigational".

van der Vaart et al (2008) described the current applications of PET and SPECT as a diagnostic tool for vascular disease as relevant to vascular surgeons.  These researchers noted that PET and SPECT may be used to assess plaque vulnerability, biology of aneurysm progression, prosthetic graft infection, and vasculitis.  Moreover, the authors stated that considerable further information will be needed to define whether and where PET or SPECT will fit in a clinical strategy.  The necessary validation studies represent an exciting challenge for the future but also may require the development of inter-disciplinary imaging groups to integrate expertise and optimize nuclear diagnostic potential.

A report by the New Zealand Health Services Assessment Collaboration (Smartt & Campbell-Page, 2009) of combined CT and SPECT (SPECT-CT) scanning in oncology concluded that SPECT-CT imaging in oncology requires further assessment. The report stated that SPECT-CT imaging is being explored in a wide range of cancers for a variety of purposes, and , that there is some evidence of an evolving role in specific areas such as lymph node assessment and mapping and the identification of bone metastases. There is also a growing body of literature comparing the effectiveness and roles of SPECT-CT and PET-CT imaging in oncology which may be expected to mature in the next few years. "However, the quality of the evolving evidence and the cost-effectiveness of combined CT and nuclear imaging systems have yet to be fully assessed." The report stated that there are a number of outstanding questions relating to the clinical and cost- effectiveness of SPECT-CT in oncology. In particular there is a need to compare the clinical utility of hybrid scanners using low performance X-ray scanners with the newer multislice machines to assess the additional benefits of the new generation scanners in clinical practice. The report stated that there is also a need to assess the impact of SPECT-CT on patients’ outcomes and management in specific indications where SPECT imaging/ planar scintigraphy are standard practice e.g. functional imaging of bone (bone scans). Other research needs identified in the report include: 1) research on the cost-effectiveness of SPECT-CT imaging for specific purposes such as lymph-node mapping and sentinel node identification; 2) research to assess the impact of SPECT-CT on patients’ outcomes and management in specific indications where SPECT imaging/ planar scintigraphy are standard practice, e.g. functional imaging of bone (bone scans).

The American College of Radiology’s clinical guideline on “Head trauma” (ACR, 2012) stated that “Advanced imaging techniques (perfusion CT, perfusion MRI, SPECT, and PET) have utility in better understanding selected head-injured patients but are not considered routine clinical practice at this time”.

Jamadar et al (1999) stated that ventilation/perfusion scans with single-photon emission computed tomography (SPECT) were reviewed to determine their usefulness in the evaluation of lung volume reduction surgery (LVRS) candidates, and as a predictor of outcome after surgery.  A total of 50 consecutive planar ventilation (99mTc-DTPA aerosol) and perfusion (99mTc-MAA) scans with perfusion SPET of patients evaluated for LVRS were retrospectively reviewed.  Technical quality and the severity and extent of radiotracer defects in the upper and lower halves of the lungs were scored from visual inspection of planar scans and SPET data separately.  An emphysema index (EI) (extent x severity) for the upper and lower halves of the lung, and an EI ratio for upper to lower lung were calculated for both planar and SPET scans.  The ratios were compared with post-LVRS outcomes, 3, 6 and 12 months after surgery.  All perfusion and SPET images were technically adequate.  Forty-six percent of ventilation scans were not technically adequate due to central airway tracer deposition.  Severity, extent, EI scores and EI ratios between perfusion and SPET were in good agreement (r = 0.52 to 0.68).  The mean perfusion EI ratio was significantly different between the 30 patients undergoing bi-apical LVRS and the 17 patients excluded from LVRS (3.3 +/- 1.8 versus 1.2 +/- 0.7; p < 0.0001), in keeping with the anatomic distribution of emphysema by which patients were selected for surgery by computed tomography (CT).  The perfusion EI ratio correlated moderately with the change in FEV1 at 3 months (r = 0.37, p = 0.04), 6 months (r = 0.36, p = 0.05), and 12 months (r = 0.42, p = 0.03), and the transition dyspnea index at 6 months (r = 0.48, p = 0.014) after LVRS.  The authors concluded that patients selected to undergo LVRS have more severe and extensive apical perfusion deficits than patients not selected for LVRS, based on CT determination.  Moreover, they stated that SPECT after aerosol V/Q imaging does not add significantly to planar perfusion scans.  Aerosol DTPA ventilation scans are not consistently useful.  Perfusion lung scanning may be useful in selecting patients with successful outcomes after LVRS.

Also, an UpToDate review on “Lung volume reduction surgery in COPD” (Martinez, 2014) does not mention the use of SPECT for pre-surgical evaluation.

Nakai et al (2014) reported the case of an 84-year old woman who presented with persistent type II endoleak with sac expansion from 57 mm to 75 mm during 4-year follow-up after endovascular abdominal aortic aneurysm repair.  The patient underwent trans-abdominal embolization with coils and N-butyl cyanoacrylate/ethiodized oil mixture (2.5 ml).  Because of the anticipated embolization artifacts on follow-up computed tomography (CT), technetium-99m-labeled human serum albumin diethylenetriamine pentaacetic acid single-photon emission computed tomography ((99m)Tc-HSAD SPECT) was performed before and after the intervention.  Peri-graft accumulation on (99m)Tc-HSAD SPECT corresponding to the endoleak disappeared after embolization. The authors noted that CT scan performed 12 months after embolization showed no signs of sac expansion; and they stated that (99m)Tc-HSAD SPECT may be useful for evaluating therapeutic effect after embolization for endoleak.

The American College of Radiology Appropriateness Criteria on “Dementia and movement disorders” (ACR, 2014) stated that “An evidence-based review performed by the AAN concluded that SPECT imaging cannot be recommended for either the initial or the differential diagnosis of suspected dementia because it has not demonstrated superiority to clinical criteria.  Also, compared with PET, SPECT has a lower diagnostic accuracy and is inferior in its ability to separate healthy controls from patients with true dementia”.

Freesmeyer et al (2014) reported an initial experience regarding the feasibility and applicability of quasi-integrated freehand SPECT/ultrasonography (US) fusion imaging in patients with thyroid disease.  Local ethics committee approval was obtained, and 34 patients were examined after giving written informed consent.  After intravenous application of 75 MBq of technetium 99m pertechnetate, freehand 3-D SPECT was performed.  Data were reconstructed and transferred to a US system.  The combination of 2 independent positioning systems enabled real-time fusion of metabolic and morphologic information during US examination.  Quality of automatic co-registration was evaluated visually, and deviation was determined by measuring the distance between the center of tracer distribution and the center of the US correlate.  All examinations were technically successful.  For 18 of 34 examinations, the automatic co-registration and image fusion exhibited very good agreement, with no deviation.  Only minor limitations in fusion offset occurred in 16 patients (mean offset ± standard deviation, 0.67 cm ± 0.3; range of 0.2 to 1.0 cm).  SPECT artifacts occurred even in situations of clear thyroid findings (e.g., unifocal autonomy).  The authors concluded that the freehand SPECT/US fusion concept proved feasible and applicable; however, technical improvements are needed.

Ryken et al (2014) determined which imaging techniques most accurately differentiate true tumor progression from pseudo-progression or treatment-related changes in patients with previously diagnosed glioblastoma.  The authors stated that the following recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process:

• Recommendation Level II: Magnetic resonance imaging (MRI) with and without gadolinium enhancement is recommended as the imaging surveillance method to detect the progression of previously diagnosed glioblastoma.
• Recommendation Level II: Magnetic resonance spectroscopy (MRS) is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma.
• Recommendation Level III: The routine use of positron emission tomography (PET) to identify progression of glioblastoma is not recommended.
• Recommendation Level III: Single-photon emission computed tomography (SPECT) imaging is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma.

The National Comprehensive Cancer Network’s clinical practice guideline on “Central nervous system cancers” (Version 2.2014) does not mention SPECT as a management tool.  Furthermore, an UpToDate review on “Management of recurrent high-grade gliomas” (Batchelor et al, 2015) does not mention SPECT as a management tool.

Detection of Fronto-Temporal Dementia

A total of 11 studies (1,117 participants) met inclusion criteria.  These consisted of 6 case-control studies, 2 retrospective cohort studies and 3 prospective cohort studies; 3 studies used single-headed camera SPECT while the remaining 8 used multiple-headed camera SPECT.  Study design and methods varied widely.  Overall, participant selection was not well-described and the studies were judged as having either high or unclear risk of bias.  Often the threshold used to define a positive SPECT result was not pre-defined and the results were reported with knowledge of the reference standard.  Concerns regarding applicability of the studies to the review question were generally low across all 3 domains (participant selection, index test and reference standard).  Sensitivities and specificities for differentiating FTD from non-FTD ranged from 0.73 to 1.00 and from 0.80 to 1.00, respectively, for the 3 multiple-headed camera studies.  Sensitivities were lower for the 2 single-headed camera studies; 1 reported a sensitivity and specificity of 0.40 (95 % CI: 0.05 to 0.85) and 0.95 (95 % CI: 0.90 to 0.98), respectively, and the other a sensitivity and specificity of 0.36 (95 % CI: 0.24 to 0.50) and 0.92 (95 % CI: 0.88 to 0.95), respectively.  Eight of the 11 studies which used SPECT to differentiate FTD from Alzheimer's disease used multiple-headed camera SPECT.  Of these studies, 5 used a case-control design and reported sensitivities of between 0.52 and 1.00, and specificities of between 0.41 and 0.86.  The remaining 3 studies used a cohort design and reported sensitivities of between 0.73 and 1.00, and specificities of between 0.94 and 1.00.  The 3 studies that used single-headed camera SPECT reported sensitivities of between 0.40 and 0.80, and specificities of between 0.61 and 0.97.  The authors concluded that they would not recommend the routine use of rCBF SPECT in clinical practice because there is insufficient evidence from the available literature to support this.  They stated that further research into the use of rCBF SPECT for differentiating FTD from other dementias is needed.  In particular, protocols should be standardized, study populations should be well-described, the threshold for “abnormal” scans pre-defined and clear details given on how scans are analyzed.  The authors stated that more prospective cohort studies that verify the presence or absence of FTD during a period of follow-up should be undertaken.

Detection of Air Leak / Pneumothorax

Ceulemans et al (2012) reported on the case of a 61-year old man with severe chronic obstructive pulmonary disease presented to the authors’ hospital with recurrence of a right-sided spontaneous secondary pneumothorax.  Thoracoscopic abrasion of the parietal pleura was performed, but an important air leak persisted.  Presumed to originate from a bulla in the right upper lobe, bullectomy and pleural decortication were performed, but leakage remained.  Lobectomy was considered, and quantitative ventilation/perfusion SPECT was performed to predict the functional outcome.  Fused high-resolution CT/Tc Technegas images localized leakage not only to a bleb in the right upper lobe but also to the subcutaneous emphysema in the thoracic wall.  The air leak resolved after conservative treatment.

An UpToDate review of “Imaging of pneumothorax” (Stark, 2016) mentions cheat X-ray, CT, and ultrasound for imaging pneumothorax; it does not mention SPECT scan.

Diagnosis of Lung Cancer

In a meta-analysis, Zhang and Liu (2016) examined the value of technetium-99m methoxy isobutyl isonitrile (Tc-MIBI) SPECT in differentiating malignant from benign lung lesions.  The PubMed and Embase databases were comprehensively searched for relevant articles that evaluated lung lesions suspicious for malignancy.  Two reviewers independently extracted the data on study characteristics and examination results, and assessed the quality of each selected study.  The data extracted from the eligible studies were assessed by heterogeneity and threshold effect tests.  Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and areas under the summary receiver-operating characteristic curves (SROC) were also calculated.  A total of 14 studies were included in this meta-analysis.  The pooled sensitivity, specificity, positive and negative likelihood ratio, and DOR of Tc-MIBI scan in detecting malignant lung lesions were 0.84 (95 % CI: 0.81 to 0.87), 0.83 (95 % CI: 0.77 to 0.88), 4.22 (95 % CI: 2.53 to 7.04), 0.20 (95 % CI: 0.12 to 0.31), and 25.71 (95 % CI: 10.67 to 61.96), respectively. The area under the SROC was 0.9062.  Meta-regression analysis showed that the accuracy estimates were significantly influenced by ethnic groups (p < 0.01), but not by image analysis methods, mean lesion size, or year of publication.  Deek funnel plot asymmetry test for the overall analysis did not raise suspicion of publication bias (p = 0.50).  The authors concluded that these findings indicated that Tc-MIBI scan is a promising diagnostic modality in predicting the malignancy of lung lesions.

This meta-analysis had several drawbacks:

1. the studies varied in year of publication, sample size, continuity of patients enrolled, and ethnic groups as well as lesion size.  In addition, 99mTc-MIBI SPECT images were performed under variable conditions, including tracer dose, image analysis methods, the interval time between tracer injection and scanning
2. it is impossible for these researchers to identify all studies of 99mTc-MIBI SPECT for lung cancer diagnosis, especially unpublished studies. Since articles reporting significant results are more likely to be published than those reporting non-significant results, publication bias is a major concern in meta-analysis.  However, the Deek funnel plot asymmetry test for the overall analysis did not raise suspicion of publication bias.  In addition, the authors adopted rigid inclusion criteria and they selected only articles that included at least 10 patients who performed MIBI imaging for lung lesions, which may bring about selection bias, and
3. it was not clear whether SPECT or PET is superior in differentiating malignant from benign lesions.

Two recent published meta-analyses were performed to evaluate the diagnostic accuracy of FDG-PET for detecting lung cancer with a sensitivity of 94 % to 96 % and specificity of 78 % to 86 %.  However, a direct comparison between PET and SPECT is absent.  Only 2 of the studies comparing SPECT with PET were included in this meta-analysis, but the results were generally inconclusive.  According to Santini et al, 99mTc-MIBI SPECT was similar to FDG-PET in the detection of lung malignancies and represents an alternative if PET was not available.

Xing and colleagues (2019) noted that immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer (NSCLC).  Treatment stratification depends on immuno-histochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatio-temporal heterogeneity.  Using a single-domain antibody (sdAb), NM-01, against PD-L1, radiolabeled site-specifically with technetium-99m (99mTc) for SPECT imaging, these researchers evaluated the safety, radiation dosimetry and imaging characteristics of this radio-pharmaceutical and correlated tumor uptake with PD-L1 immunohistochemistry results.  A total of 16 patients (mean age of 61.7 years, 11 men) with NSCLC were recruited.  Primary tumor PD-L1 expression was measured by immunohistochemistry; NM-01 was radio-labeled with [99mTc(OH2)3(CO)3]+ complex binding to its C-terminal hexahistidine tag.  Administered activity was 3.8 to 10.4 MBq/kg, corresponding to 100 µg or 400 µg of NM-01.  Whole body planar and thoracic SPECT/CT scans were performed at 1 and 2 hours post-injection in all patients and 5 patients had additional imaging at 10 mins, 3 and 24 hours for radiation dosimetry calculations.  All patients were monitored for adverse events (AEs).  No drug-related AEs occurred in this study.  The mean effective dose was 8.84×10-3 ± 9.33×10-4 mSv/MBq (3.59 ± 0.74 mSv per patient).  Tracer uptake was observed in the kidneys, spleen, liver and bone marrow.  SPECT primary tumor-blood pool ratios (T:BP) varied from 1.24 to 2.3 (mean = 1.79) at 1 hour and 1.24 to 3.53 (mean = 2.22) at 2 hours (p = 0.005); 2-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r  =0.68, p = 0.014); 2-hour T:BP was lower in tumors with less than or equal to 1 % PD-L1 expression (1.89 versus 2.49, p = 0.048).  Nodal and bone metastases showed tracer uptake.  Heterogeneity (greater than 20 %) between primary tumor and nodal T:BP was present in 4 of 12 patients.  The authors concluded that this first in human study demonstrated that 99mTc-labeled anti-PD-L1-sdAb SPECT/CT imaging was safe and associated with acceptable dosimetry.  Tumor uptake was readily visible against background tissues, particularly at 2 hours when the T:BP ratio correlated with PD-L1 immunohistochemistry results.

Furthermore, National Comprehensive Cancer Network’s clinical practice guidelines on “Non-small cell lung cancer” (Version 3.2019) and “Small cell lung cancer” (Version 1.2019) do not mention SPECT as a diagnostic tool.

Evaluation of Carotid Stenosis

Sato and Matsumoto (2017) stated that multi-phase arterial spin labeling (ASL), which obtains the imaged slices with various post-labeling delays, allows for the non-invasive assessment of cerebral hemodynamics that cannot be adequately acquired by SPECT imaging.  These investigators described the clinical usefulness of multi-phase ASL in a patient with symptomatic carotid stenosis by comparison with SPECT at rest using iodo-amphetamine.  A 75-year old man was referred to the authors’ hospital with severe stenosis of the left internal carotid artery (ICA).  While SPECT showed no significant laterality of CBF, multi-phase ASL demonstrated relatively delayed perfusion in the left ICA territory.  The patient underwent stent placement for the left ICA stenosis.  Post-operatively, while SPECT demonstrated no significant laterality of CBF, multi-phase ASL revealed improved perfusion in the left ICA territory.  The authors concluded that this case showed that multi-phase ASL could accurately evaluate the cerebral hemodynamic status that could not be detected using pre- and post-operative SPECT.

Imaging Marker of Pre-Diagnostic Parkinson's Disease

Noyce and colleagues (2018) examined if pre-diagnostic features of PD were associated with changes in dopamine re-uptake transporter-SPECT and transcranial sonography.  Pre-diagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents.  A total of 46 participants were included in analyses of pre-diagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter-SPECT and nigral hyper-echogenicity on transcranial sonography.  The striatal binding ratio was associated with PD risk estimates (p = 0.040), University of Pennsylvania Smell Identification Test (p = 0.002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (p = 0.024), tapping speed (p = 0.024), and MDS-UPDRS motor scores (p = 0.009).  Remotely collected assessments explained 26 % of variation in the striatal binding ratio.  The inclusion of MDS-UPDRS motor scores did not explain additional variance.  The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (p < 0.001) and MDS-UPDRS scores (p = 0.03) only.  The authors concluded that the dopamine re-uptake transporter-SPECT results correlated with motor and non-motor features of pre-diagnostic PD, supporting its potential use as a marker in the prodromal phase of PD; transcranial sonography results also correlated with risk scores and motor signs.

Work-Up of Individuals Undergoing Non-Cardiac Surgery

Al-Oweidi and colleagues (2017) noted that the prevalence and predictors of myocardial ischemia before non-cardiac surgery are unknown.  In addition the predictive value of myocardial perfusion SPECT before non-cardiac in individual patients is uncertain.  In a retrospective study, these researchers evaluated the prevalence and predictors of myocardial ischemia before non-cardiac surgery, and determined the post-operative cardiac outcome based on results of myocardial perfusion SPECT.  These investigators reviewed the records of adult patients diagnosed with myocardial ischemia by myocardial perfusion SPECT who were undergoing non-cardiac surgery.  Myocardial perfusion SPECT had been performed within 4 weeks prior to non-cardiac surgery requiring general anesthesia.  Main outcome measures included prevalence of abnormal myocardial perfusion SPECT results on pre-operative evaluation; abnormal myocardial perfusion SPECT results as a predictor for post-operative cardiac events such as cardiac death, non-fatal MI, and unstable angina.  Of 131 patients who underwent non-cardiac surgery from February 2015 to April 2016, 84 (64 %) patients were women and the mean (SD) age was 64.1 (13.6) years.  The prevalence of abnormal myocardial perfusion SPECT was 18 % (24 of 131).  Normal myocardial perfusion SPECT was highly predictive (up to 100 %), but a positive myocardial perfusion SPECT had low positive predictive value (PPV; 4 %).  Variables associated with an abnormal myocardial perfusion SPECT included ischemic heart disease, congestive heart failure, American Society of Anesthesiology physical status classification score of 3 or more, limited exercise capacity (less than 4 metabolic equivalents [METs]), male sex, hypercholesterolemia, hypertension, smoking, and abnormal ECG.  In a multi-variable analysis, history of ischemic heart disease and history of smoking were significant predictors of abnormal myocardial perfusion SPECT (p = 0.001, and 0.029, respectively).  The authors concluded that because of the low PPV of myocardial perfusion SPECT, utilization of the technique in the work-up of cardiac patients undergoing non-cardiac surgery has been inappropriate.  They stated that myocardial perfusion SPECT should be restricted to only clearly defined appropriate use criteria.

Chronic Peri-Prosthetic Shoulder Joint Infection

Falstie-Jensen and colleagues (2019) noted that shoulder peri-prosthetic joint infections (PJI) caused by low-virulent bacteria pose a diagnostic challenge.  Combined labeled leukocyte (WBC) and technetium 99m sulfur colloid bone marrow imaging (WBC/BM) is considered the radionuclide imaging gold standard for diagnosing lower limb PJI.  However, it is laborious and expensive to perform, and documentation on shoulder arthroplasties is lacking.  These investigators examined WBC/BM SPECT-CT diagnostic performance in shoulder PJI.  All patients with a failed arthroplasty referred to a highly specialized shoulder department were scheduled for a diagnostic program including a WBC/BM.  If an arthroplasty was revised, biopsy specimens were obtained and cultured for 14 days.  The diagnostic performance of WBC/BM imaging was determined using biopsy specimens as a reference.  Of the 49 patients who underwent a WBC/BM scan, 29 (59 %) were revised.  Infection was present in 11 patients, in whom 2 WBC/BM scans were true-positive.  The WBC/BM scan in 9 patients was false-negative.  The remaining 18 patients all had a true-negative WBC/BM scan; WBC/BM showed a sensitivity 0.18 (95 % CI: 0.00 to 0.41) and specificity 1.00 (95 % CI: 1.00 to 1.00) in detecting shoulder PJI.  The PPV was 1.00 (95 % CI: 1.00 to 1.00), and negative predictive value (NPV) was 0.67 (95 % CI: 0.49 to 0.84).  No patients infected with Cutibacterium (formerly Propionibacterium) acnes resulted in a positive WBC/BM, nor had they pre-operative or peri-operative signs of infection.  The authors concluded that a positive WBC/BM was found only in patients with obvious PJI.  Thus, the scan added nothing to the pre-operative diagnosis.  These investigators stated that the WBC/BM SPECT-CT scan could not be recommended as a screening procedure when evaluating failed shoulder arthroplasties for possible infection.

Cortico-Basal Syndrome and Progressive Supranuclear Palsy

Alster and colleagues (2019) stated that neuroimaging in the context of examining atypical Parkinsonian tauopathies is an evolving matter; PET and SPECT bring tools, which may be reasonable in supplementary examination, however cannot be interpreted as a gold standard for correct diagnosis.  These investigators presented advantages and limitations of tau radiotracers in PET, metabolic PET and perfusion SPECT.  They highlighted the possibilities and boundaries in the supplementary examination of tauopathic Parkinsonian syndromes.  The authors concluded that contemporary medicine is still lacking of not only optimal examination of progressive supranuclear palsy and cortico-basal syndrome.  Advances in neuroimaging based on SPECT and PET showed that available radiotracers lack specificity.  Tau radiotracers have relatively high affinity not only to tau, but also to monoaminoxidase A and B and neuromelanin.  SPECT and the analysis of hypo-perfusion is a tool that can be interpreted as supplementary to clinical examination.  Development of neuroimaging may result in opportunities of earlier introduction of possibly effective treatment such as anti-tau antibodies or microtubule stabilizers.  These researchers stated that further analyses of neuroimaging require longer observations and advances in specificity of accessible tools.

An UpToDate review on “Corticobasal degeneration” (Factor and Tripathi, 2019) states that “There are no established biomarkers for the diagnosis of CBD.  Functional imaging studies cannot reliably distinguish CBD from other atypical parkinsonian syndromes.  DaTscan (i.e., striatal dopamine transporter imaging using 123I-FP-CIT single-photon emission computed tomography [SPECT]) is generally abnormal in CBD in a manner similar to Parkinson disease and other atypical parkinsonian syndromes such as multiple system atrophy and PSP.  Compared with patients who had Parkinson disease, one study reported that FP-CIT binding reduction in patients with CBD was characterized by increased variability, more uniform reduction throughout the striatum (as opposed to greater putaminal loss in Parkinson disease), and greater hemispheric asymmetry.  However, this test cannot be used to definitively differentiate CBD from other atypical parkinsonian syndromes.  SPECT scanning using 99mTc-hexamethylpropylene amine oxime (HMPAO), which measures blood flow through leukocyte labeling, shows regional reductions in HMPAO uptake in the medial frontal, temporoparietal, superior parietal, and lateral frontal regions of both hemispheres in CBD.  In addition, there is bilateral and symmetric reduction in thalamic blood flow in patients with CBD.  These results demonstrated a greater reduction in cerebral cortical blood flow and more asymmetry than those patients with idiopathic Parkinson disease”.

Furthermore, an UpToDate review on “Progressive supranuclear palsy (PSP): Clinical features and diagnosis” (Factor and Esper, 2019) does not mention SPECT as a management tool.

Ovarian Cancer

Verschueren and colleagues (2019) reported a case of a 30-year old woman with a painless palpable nodule in the chest wall, evaluated for osseous involvement by technetium-99m (Tc-99m) bone scintigraphy.  A whole-body scan revealed numerous sites of increased tracer accumulation throughout the thorax, abdomen, and pelvis.  Subsequent SPECT-CT of the abdomen and pelvis showed no abnormal uptake in the bone; however, significant non-osseous tracer accumulation in calcified soft tissue metastases was noted.  Pathology confirmed a high-grade ovarian papillary serous adenocarcinoma.  Extra-osseous uptake of bone-seeking agents in the body was often incidental findings and could be explained by various benign and malignant conditions with soft tissue calcification.  In this case report, this unusual finding on bone scintigraphy was highly suggestive for malignancy, initially not considered during the clinical evaluation of the patient.  It also illustrated the usefulness of additional hybrid SPECT-CT to precisely localize extra-osseous uptake of Tc-99m methylene diphosphonate.

Furthermore, National Comprehensive Cancer Network’s clinical practice guidelines on “Ovarian cancer including fallopian tube cancer and primary peritoneal cancer” (Version 2.2018) does not mention SPECT as a diagnostic tool.

Painful Legs and Moving Toes (PLMT) Syndrome

Nishioka and colleagues (2019) stated that painful legs and moving toes (PLMT) syndrome is a clinical entity characterized by persistent pain in the feet or legs and involuntary movements of 1 or more toes.  The precise patho-mechanisms of PLMT still remain unknown.  In a case-series study, these researchers examined 10 patients clinically identified with PLMT syndrome.  All patients first presented persistent pain prior to the onset of motor symptoms.  Each patient was examined by neurological investigation, neuro-imaging methods including brain MRI and electrophysiological methods.  The brain SPECT images of 8 patients indicated hypo-perfusion of frontal lobes and cerebellum.  The conjunction analysis of brain SPECT imaging data of all 8 patients, using the 3D-SSP program, compared to 34 controls indicated significant hypo-perfusion in the prefrontal cortical, occipital cortical, and cerebellar surfaces, and thalamus, and hyper-perfusion in the surface of the anterior cingulate gyrus and parietal cortices including primary and secondary somatosensory cortices, bilaterally.  These areas reflected on a part of the pain matrix.  Other electrophysiological examinations did not indicate specific abnormalities to explain the patients' symptoms.  On treatment with clonazepam, 4 out of 9 patients could resolve their foot-related motor symptoms, but not the sensory symptoms.  Overall, their pain was an intractable and persistent symptom throughout their clinical course.  The authors concluded that the findings of this study inferred that PLMT syndrome is fundamentally a chronic pain disorder, possibly relating to the central sensitization, involving the region of a part of pain matrix.  These researchers stated that further studies are needed to confirm these findings by adding more patients.

Systemic Lupus Erythematosus

Sahebari and colleagues (2018) noted that systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations.  Cognitive dysfunction is one of the manifestations that could present prior to the emergence of any other neuropsychiatric involvements in SLE.  Cognitive dysfunction is a subtle condition occurring with a high frequency.  However, there are no data on the correlation of cognitive dysfunction with central nervous system (CNS) imaging findings, in particular SPECT and functional MRI.  These investigators carried out a systematic review of brain SPECT and fMRI in SLE patients with cognitive dysfunction.  PubMed, Scopus, and Google Scholar databases were searched until April 2017 with the following keywords: "SLE or systemic lupus erythematous or lupus", and "functional MRI or functional magnetic resonance imaging or fMRI or SPECT or SCAN".  A total of 1,767articles were found; 2 rheumatologists reviewed the articles and finally 14 articles were selected for the final systematic review.  The fMRI and SPECT imaging techniques could provide valuable information regarding the SLE patients with cognitive dysfunction at the early stages of the disease.  The authors concluded that brain SPECT scan and fMRI were used as functional imaging tools in SLE.  Both of these diagnostic modalities were sensitive in reflecting the subtle brain damages in SLE patients with cognitive dysfunction.  The authors concluded that brain fMRI and SPECT scan could be significantly beneficial in the diagnosis and initial management of cognitive dysfunction in SLE.  Moreover, these researchers stated that prospective studies are needed to confirm the application of these diagnostic modalities in the clinical setting.

Furthermore, an UpToDate review on “Diagnosis and differential diagnosis of systemic lupus erythematosus in adults” (Wallace, 2019) does not mention SPECT as a management tool.

Surgical Planning in Individuals with Axial Neck and Back Pain

Brusko and colleagues (2019) stated that hybrid SPECT with CT imaging has been used to aid in elucidating pain generators in patients with axial neck and back pain, identifying potential sites for treatment.  Few studies have examined its role in spine surgery and most literature focuses on its use post-operatively.  These investigators described the largest series to-date of patients with symptomatic spondylosis who underwent pre-operative SPECT imaging for surgical planning.  They carried out a retrospective medical and imaging record review to identify patients who underwent SPECT or SPECT/CT studies between January 2014 and May 2018.  Patients who underwent spine surgical intervention for spondylosis with primary symptoms of axial neck or back pain and who had evidence of hyper-metabolic foci on spinal SPECT imaging were included.  Only those patients who subsequently underwent surgery on a spinal level associated with increased radio-tracer uptake were included in the analysis.  Patient baseline and demographic information, and data pertaining to SPECT imaging, surgical planning, and post-operative care were collected and analyzed.  A total of 23 patients with an average age at surgery of 60.0 ± 11.0 years were included; 15 patients (65.2 %) were men.  A total of 53 spinal levels were treated, with an average of 2.30 levels treated per patient.  All patients underwent fusion surgery, either lumbar (n = 14), with interbody fusion most commonly used (64.2 %); or cervical (n = 9), with anterior cervical discectomy and fusion (66.6 %) being the most common.  The average length of hospital stay was 3.45 ± 2.32 days; 1 patient developed a wound infection post-operatively, requiring re-admission.  At the 3-month follow-up, 18 patients (78.3 %) reported clinical improvement in pain; 11 patients (47.8 %) reported complete symptom resolution at the 6-month follow-up. A t 1 year post-operatively, 19 patients (82.6 %) reported significant relief of their symptoms following surgery.  The authors concluded that this was the largest series to-date describing patients with axial neck and back pain who underwent pre-operative SPECT imaging and subsequent surgical intervention on the affected spinal levels.  The results demonstrated that SPECT imaging may be a useful adjunct to guide surgical planning, resulting in substantial clinical improvement following surgery.

The authors stated that this study had several drawbacks.  First, this series was small, with just 23 patients included.  However, traditional management of axial neck or back pain was non-surgical and thus, this series was the largest one to-date examining surgical outcomes.  Second, a subset of patients had involvement of multiple spinal levels.  Thus, the inability to treat all degenerated levels and the progressive nature of the osteoarthritic disease may be responsible for a lack of clinical improvement in these select patients over time.  Third, biases related to retrospective reviews must be taken into account, and the results of this single-center, single-surgeon series may not be generalizable to other patient populations.

SPECT for Absolute Quantitation of Myocardial Blood Flow (AQMBF)

Shrestha and colleagues (2017) conducted a study to measure myocardial blood flow (MBF) in humans using ^99mTc-tetrofosmin and dynamic single photon emission computed tomography (SPECT). Dynamic SPECT using ^99mTc-tetrofosmin and dynamic positron emission tomography (PET) was performed on a group of 16 patients. The SPECT data were reconstructed using a 4D-spatiotemporal iterative reconstruction method. The data corresponding to 9 patients were used to determine the flow-extraction curve for ^99mTc-tefrofosmin while data from the remaining 7 patients were used for method validation. The nonlinear tracer correction parameters A and B for ^99mTc-tefrofosmin were estimated for the 9 patients by fitting the flow-extraction curve K₁ = F (1 – Aexp (-B/F)) for K₁ values estimated with ^99mTc-tefrofosmin using SPECT and MBF values estimated with ¹³N-NH3 using PET. These parameters were then used to calculate MBF and coronary flow reserve (CFR) in three coronary territories (LAD, RCA, and LCX) using SPECT for an independent cohort of 7 patients. The results were then compared with that estimated with ¹³N-NH3 PET. The flow dependent permeability surface-area product (PS) for ^99mTc-tefrofosmin was also estimated. The estimated flow extraction parameters for ^99mTc-tefrofosmin was found to be A=0.91±0.11, B=0.34±0.20 (R² = 0.49). The range of MBF in LAD, RCA, and LCX was 0.44 ml/min/g to 3.81 ml/min/g. The MBF between PET and SPECT in the group of independent cohort of 7 patients showed statistically significant correlation, r = 0.71 (p < 0.001). However, the corresponding CFR correlation was moderate r = 0.39 yet statistically significant (p = 0.037). The PS for ^99mTc-tefrofosmin was (0.091 ± 0.10) * MBF = (0.32 ± 0.16). The authors concluded that dynamic cardiac SPECT using ^99mTc-tetrofosmin and a clinical two-headed SPECT/CT scanner can be a useful tool for estimation of MBF.

de Souza and colleagues (2022) noted that single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. They further pointed out that gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR), however, evidence of its accuracy is limited, and of its reproducibility is lacking. The authors conducted a study to validate ^99mTc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with ¹³N-ammonial positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. The authors assessed accuracy in 34 participants who underwent dynamic ^99mTc-sestamibi SPECT and ¹³N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 ^99mTc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was carried out. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEMO algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model, and MFR was derived as the stress/rest MBF ratio. SPECT global MBF with splines showed good correlation with ¹³N-ammonia positron emission tomography (r=0.81, p<0.001) and MFR estimates (r=0.74, p<0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61, p<0.001 and r=0.34, p=0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, p<0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68, p<0.001) and MFR correlations (r=0.33, p=0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm (p>0.05 for all). THe authors concluded that MBF and MFR quantification using ^99mTc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with ¹³N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

Wang and colleagues (2023) noted that absolute quantitation of myocardial blood flow (MBF) and myocardial flow reserve (MFR) using single-photon emission computed tomography (SPECT) is clinically feasible, however, there has not been an evaluation of whether flow quantification using NaI(TI) SPECT is superior to commonly performed SPECT myocardial perfusion imaging (MPI) in determining coronary artery disease (CAD). The authors conducted a prospective multi-center study to investigate the diagnostic value of myocardial blood flow (MBF) quantification using Nal(TI)-based single-photon emission computed tomography (SPECT) for determining coronary artery disease (CAD) defined by quantitative coronary angiography (QCA). Patients with suspected or known CAD underwent pharmacological stress/rest dynamic SPECT imaging and routine SPECT MPI followed by QCA. Obstructive disease was defined as ≥ 50% reduction in luminal diameter on QCA. One hundred fifty-four patients (462 vessels) were included in the analysis. Obstructive CAD was detected in 76/154 patients (49.4%) and 112/462 vessels (24.2%). Optimal cut-off values were1.86 mL/min/g for stress MBF and 1.95 for MFR, respectively. Stress MBF and MFR were more sensitive than MPI in both individual patients (stress MBF vs MPI: 81.6% vs 51.3%; MFR vs MPI: 72.4% vs 51.3%)and in coronary vascular regions (stress MBF vs MPI: 78.6% vs 31.3%; MFR vs MPI: 75.9% vs 31.3%; all p < 0.01). In receiver operating characteristic curve analysis, quantification revealed a significantly greater area under the curve than MPI at the patient (stress MBF vs MPI: 0.761 vs 0.641; MFR vs MPI:0.770 vs 0.641) and the vessel (stress MBF vs MPI: 0.745 vs 0.613; MFR vs MPI: 0.756 vs 0.613; all p < 0.05) levels. Integrating quantitative SPECT measures with MPI significantly increased the area under the curve and improved the discriminatory and reclassification capacity. The authors concluded that flow quantification using NaI(Tl) SPECT provides superior sensitivity and discriminatory capacity to MPI in detecting significant stenosis.

SPECT for Assessment of Eating Disorders

Di Gianni and colleagues (2020) carried out a systematic review according to PRISMA guidelines on PubMed, Psychinfo, Medline, Embase to fill the existing literature gap on the effectiveness of PET and SPECT in anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED).  A total of 22 articles were included; 4 studies reported an increased density in 5-hydroxytryptamine receptor (5-HT1A) in fronto-temporo-parietal regions in both affected and recovered AN as well as in BN.  The 5-HT transporter (5-HTT) binding was increased or diminished in different specific cortical areas and in relation to eating disorder (ED) subtypes.  Some evidences of blunted dopamine (DA) release in the putamen in BN patients suggest that their DA function might be impaired as in addictive behaviors.  Studies estimating the regional cerebral blood flow (rCBF) with SPECT demonstrated that temporal areas appeared to play a key role in ED corroborating the hypothesis of a cingulate-temporal cortical dysfunction in AN.  Furthermore, alterations of both parietal and prefrontal cortex provided a possible common neural substrate in AN.  The authors concluded that studies included in this review were heterogeneous preventing robust conclusions; however, these findings added knowledge on some of the neurotransmitters involved in ED.

Furthermore, an UpToDate review on “Eating disorders: Overview of epidemiology, clinical features, and diagnosis” (Yager, 2021) does not mention SPECT as a management tool.

SPECT-CT for Detection of Metastatic Bone Disease in Malignancies

In a prospective study, Mahaletchumy and AbAziz (2017) examined the incremental value of SPECT-CT over planar bone scintigraphy (BS) and SPECT in detecting skeletal lesions in breast cancer patients and its effect on patient management.  This trial was carried out over 1-year duration.  Whole-body planar scintigraphy, SPECT, and SPECT-CT were carried out in 85 breast cancer patients with total of 128 lesions.  Correlative imaging and clinical follow-up were used as the reference standard.  McNemar's multi-step analysis was conducted for each patient and each lesion.  On patient-wise analysis, a total of 47 patients had equivocal diagnosis on planar BS, 28 on SPECT, and 8 on SPECT-CT.  On lesion-wise analysis, there were 72 equivocal lesions on planar BS, 48 on SPECT, and 15 on SPECT-CT.  Overall, SPECT-CT resulted in a significant reduction in the proportion of equivocal diagnosis on both patient-wise (p < 0.004) as well as lesion-wise basis (p < 0.004), irrespective of the skeletal region involved.  The sensitivity on a per-patient basis was 43 %, 58 %, and 78 % for planar BS, SPECT, and SPECT-CT, respectively.  Similarly, the specificity was 85 %, 92 %, and 94 % for planar BS, SPECT, and SPECT-CT, respectively.  Patient management was correctly altered in 32 % of the patients based on SPECT-CT interpretation.  The authors concluded that these findings suggested that adding SPECT-CT to whole-body imaging significantly improved sensitivity and specificity in diagnosing bone metastases and significantly reduced the proportion of equivocal diagnosis in all regions of the skeleton.  The most important outcome was derived from the accurate alteration in patient management clinically by down- and up-staging of patients and a more precise identification of metastatic extent.

The authors stated that the major drawback of this study was that none of the patients imaged had biopsy of the bone lesions; thus, this study lacked any histopathological correlation to confirm the diagnoses of malignant or benign lesion.  Another drawback was the lack of common reference standard in all patients as the decision on which imaging modality to use as the reference standard in some of the patients was left to the referring physician.  These researchers stated that future studies incorporating PET tracers such as 18F fludeoxyglucose (FDG) PET-CT and 18F fluoride FDG PET-CT will prove to be beneficial in choosing the appropriate imaging method for diagnosing skeletal metastasis.

Israel and associates (2019) presented a critical assessment of the relevant literature published on the role of SPECT/CT in a variety of clinical conditions.  It also included an update on the established evidence demonstrating both the advantages and limitations of this modality.  A literature search yielded 104 articles regarding bone SPECT/CT in malignancies, of which 20 were further analyzed.  SPECT/CT was able to characterize most equivocal findings on BS, planar and/or SPECT, in cancer patients.  Despite the heterogeneity of the studies, the results were consistent.  SPECT/CT characterized 66.7 % to 100 % of equivocal findings, for an average rate of 85.3 %, in 826 lesions.  A comparison of sensitivity and specificity of SPECT/CT to other modalities showed its lower performance versus whole-body (WB)-MRI and conflicting results versus 18F-fluoride PET/CT.  A new perspective for skeletal scintigraphy is WB-SPECT/CT substituting for planar BS.  WB-SPECT/CT demonstrated higher sensitivity and similar specificity to WB-planar and 1-field-of-view (FOV)-position-targeted SPECT/CT, but with only limited incremental diagnostic value for 2-FOV versus 1-FOV bone SPECT/CT.  The authors stated  that it appeared reasonable to predict that WB-SPECT/CT will be the future of BS in cancer patients, especially when fast acquisition protocols become widely available.

Rohani and colleagues (2021) noted that skeletal whole-BS (WBS), although widely used as a sensitive tool for detecting metastatic bone disease in oncology cases, has relatively low specificity.  Indeterminate bone lesions (IBLs) detected by WBS cause a diagnostic dilemma, which hampers further management plans.  In the advent of hybrid imaging, SPECT/CT has been gaining popularity as a tool to improve the characterization of IBLs detected by WBS.  As yet, there has not been a systematic review to examine the diagnostic capabilities of SPECT/CT in this area.  These researchers carried out a systematic review of relevant electronic databases up to August 30, 2020.  The outcomes of interest were the reporting of SPECT/CT to identify benign and malignant IBLs and the calculation of the sensitivity and specificity of the index test, based on histopathological examination or clinical and imaging follow-up as the reference standard.  After the risk of bias and eligibility assessment, a total of 12 articles were identified and synthesized in the meta-analysis.  The pooled sensitivity and specificity of SPECT/CT for diagnosing IBLs were 93.0 % [95 % CI: 0.91 to 0.95] and 96.0 % (95 % CI: 0.94 to 0.97), respectively.  There was heterogeneity of the articles due to variable imaging protocols, duration of follow-up and scoring methods for interpreting the SPECT/CT results.  The heterogeneity posed a challenge for accurate interpretation of the true diagnostic capability of SPECT/CT.  The authors concluded that targeted SPECT/CT improved the specificity of diagnosing bone metastases; however, efforts need to be made to standardize the thresholds for SPECT/CT, methodology, as well as harmonizing the reporting and interpretation criteria.  Moreover, these researchers made some recommendations for future works.

Furthermore, an UpToDate review on “Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults” (Yu and Hoffe, 2021) states that “The addition of single-photon tomography (SPECT) to bone scan improves the diagnostic accuracy over bone scan alone but does not improve sensitivity for purely lytic lesions; it is not routinely used”.

SPECT-CT for Quantification of Neutrophil Uptake in Lung Cancer

Farahi and colleagues (2020) stated that neutrophils play an important role in the lung tumor micro-environment.  These researchers hypothesized that radio-labeled neutrophils coupled to SPECT may non-invasively quantify neutrophil uptake in tumors from patients with non-small cell lung cancer (NSCLC).  They demonstrated increased uptake of radio-labeled neutrophils from the blood into tumors compared with non-specific uptake using radio-labeled transferrin.  Moreover, indium-111-neutrophil activity in the tumor biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils.  The authors concluded that these findings supported the use of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.  Moreover, these researchers stated that further studies of in-vivo neutrophil trafficking in NSCLC are needed.

The authors stated that this study had several drawbacks.  First, these findings were drawn from a small sample size (n = 6 patients), and follow-up are needed to confirm the use of neutrophil imaging in NSCLC.  Second, as tumor-associated neutrophils (TANs) exhibit significant heterogeneity, this study could not detect the maturity or activation status of the trafficked cells.  Third, there were reports of increased transferrin receptor expression on lung cancer cells, which could limit the use of radio-labeled transferrin as a negative control.  However, since both radio-labeled transferrin and radio-labeled neutrophils were injected in plasma, this would likely increase the baseline uptake in both cases.

SPECT for Detection of Cardiac Amyloidosis

Wu and Yu (2021) stated that non-invasive myocardial imaging modalities, such as cardiac magnetic resonance (CMR), SPECT, and PET, are well-established and extensively used to detect cardiac amyloid (CA).  In a meta-analysis, these researchers compared CMR, SPECT, and PET scans in the diagnosis of CA, and provided evidence for further scientific research and clinical decision-making.  These investigators searched PubMed, Embase, and Cochrane Library; studies using CMR, SPECT and/or PET for the diagnosis of CA were included.  Pooled sensitivity, specificity, positive and negative likelihood ratio (LR), DOR, their respective 95 % CIs and the area under the SROC curve (AUC) were calculated.  Quality assessment of included studies was conducted.  A total of 31 articles met the inclusion criteria for this meta-analysis.  The pooled sensitivities of CMR, SPECT and PET were 0.84, 0.98 and 0.78, respectively.  Their overall specificities were 0.87, 0.92 and 0.95, respectively.  Subgroup analysis demonstrated that 99mTc-HMDP manifested the highest sensitivity (0.99).  99mTc-PYP had the highest specificity (0.95).  The AUC values of 99mTc-DPD, 99mTc-PYP, 99mTc-HMDP were 0.89, 0.99, and 0.99, respectively.  PET scan with 11C-PIB demonstrated a pooled sensitivity of 0.91 and specificity of 0.97 with an AUC value of 0.98.  The authors concluded that this meta-analysis showed that SEPCT scans present better diagnostic performance for the identification of CA as compared with other 2 modalities.

An UpToDate review on “Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis” (Fontana, 2022) does not mention SPECT as a management option.    

SPECT/CT for the Diagnosis of Aseptic Loosening

In a systematic review and meta-analysis, Peng and colleagues (2021) examined the diagnostic value and clinical applicability of SPECT/ CT in aseptic loosening (AL) of prostheses.  These investigators examined available literature on the diagnostic value of SPECT/CT in AL of prostheses by computer and manual review.  The quality of the included studies was assessed according to the Quality Assessment Diagnostic Accuracy Studies 2.  Pooled sensitivity, specificity, positive LR, negative LR, DOR, and other indicators were calculated, and a forest map and SROC were drawn to calculate the AUC. Meta-regression analysis was carried out to identify the sources of heterogeneity and corresponding subgroup analysis was conducted.  A Fagan plot, LR point plot, and Deek's funnel plot were drawn and analyzed.  A total of 15 studies were included.  The meta-analysis results showed that the pooled sensitivity and specificity of SPECT/CT for the diagnosis of aseptic prosthetic loosening were 0.94 (95 % CI: 0.90 to 0.96) and 0.89 (95% CI: 0.78 to 0.95), respectively, while the pooled positive LR and pooled negative LR were 8.65 (95 % CI: 4.18 to 17.90; and 0.07, 95 % CI: 0.04 to 0.11), respectively.  The pooled DOR was 130.36 (95 % CI: 45.18 to 376.19), and the AUC was 0.97 (95 % CI: 0.95 to 0.98).  The authors concluded that as a diagnostic method for AL, SPECT/CT had high diagnostic sensitivity and specificity as well as high diagnostic efficiency.  It has good clinical application value and should be a primary choice in the diagnosis of AL following joint replacement.

Evaluation of Merkel Cell Carcinoma

Watanabe et al (1998) noted that 131I-MIBG may be useful in the detection of neuroendocrine tumors.  Merkel cell carcinoma (MCC) is a neuroendocrine tumor of the skin.  These investigators examined a patient with MCC using 123I-MIBG single photon emission computed tomography (SPECT) that showed tumor accumulation of the radio-tracer in the right eyelid.  The authors concluded that this finding suggested that 123I-MIBG SPECT may be useful in the evaluation of MCC.  Moreover, these researchers stated that the primary role of 123I-MIBG SPECT is probably not in the detection of MCC, which may be identified in physical examination, and diagnosed on histological examination, but rather to quantify the extent of disease, examine response to therapy, and assess tumor recurrence.

van den Berg et al (2016) examined the feasibility of an intra-operative navigation technology based on pre-operatively acquired SPECT combined with CT (SPECT/CT) images during sentinel node (SN) biopsy in patients with melanoma or MCC.  Patients with a melanoma (n = 4) or MCC (n = 1) of a lower extremity scheduled for wide re-excision of the primary lesion site and SN biopsy were studied.  Following a Tc-nanocolloid injection and lympho-scintigraphy, SPECT/CT images were acquired with a reference target (ReTp) fixed on the leg or the iliac spine.  Intra-operatively, a sterile ReTp was placed at the same site to enable SPECT/CT-based mixed-reality navigation of a gamma ray detection probe also containing a reference target (ReTgp).  The accuracy of the navigation procedure was determined in the coronal plane (x, y-axis) by measuring the discrepancy between standard gamma probe-based SN localization and mixed-reality-based navigation to the SN.  To determine the depth accuracy (z-axis), the depth estimation provided by the navigation system was compared to the skin surface-to-node distance measured in the CT component of the SPECT/CT images.  In 4 of 5 patients, it was possible to navigate towards the pre-operatively defined SN.  The average navigational error was 8.0 mm in the sagittal direction, and 8.5 mm in the coronal direction.  Intra-operative sterile ReTp positioning and tissue movement during surgery exerted a distinct influence on the accuracy of navigation.  The authors concluded that intra-operative navigation during melanoma or MCC surgery was feasible and could provide the surgeon with an interactive 3D road map towards the SN or SNs in the groin.  Moreover, these researchers stated that further technical optimization of the modality is needed before this technology can become routine practice.

Doepker et al (2017) stated that accurate pre-operative lympho-scintigraphy is important in carrying out sentinel lymph node biopsy (SLNB) for cutaneous malignancies.  Potential advantages of SPECT/CT include the ability to readily identify aberrant drainage patterns and provide the surgeon with three-dimensional (3D) anatomic landmarks not observed on conventional planar lymphoscintigraphy (PLS).  In a retrospective study, patients with cutaneous malignancies who underwent SLNB with pre-operative imaging using both SPECT/CT and PLS from 2011 to 2014 were identified.  Both SPECT/CT and PLS were obtained in 351 patients (median age of 69 years; range of 5 to 94 years) with cutaneous malignancies (melanoma = 300, MCC = 33, squamous cell carcinoma [SCC] = 8, other = 10) after intra-dermal injection of 99mtechnetium sulfur colloid (median dose 300 µCi).  A mean of 4.3 hot spots were identified on SPECT/CT compared to 3.0 on PLS (p < 0.001).  A total of 153 patients (43.6 %) had identical findings between SPECT/CT and PLS, while 172 (49 %) had additional hot spots identified on SPECT/CT compared to only 24 (6.8 %) additional on PLS.  SPECT/CT revealed additional nodal basins in 103 patients (29.4 %), compared to only 11 patients (3.1 %) with additional basins on PLS.  The authors concluded that SPECT/CT was a useful adjunct that could aid in localizing sentinel node in challenging cases. It identified additional hot spots not observed on PLS in almost 50 % of patients.  Because PLS identified hot spots not observed on SPECT/CT in 6.8 % of patients, these investigators recommended using both modalities jointly.  Moreover, these researchers stated that long-term follow-up are needed to validate the clinical significance of the additional hot spots identified by SPECT/CT.

The authors stated that the recognized drawbacks of this trial were derived from the inherent flaws of the retrospective design and missing data points for some patients.  The main drawback was not being able to know if all the additional nodes identify on SPECT/CT were SLNs that potentially contained metastatic melanoma or not.  Another drawback was not including a complete cos- analysis.  Currently, additional reimbursement is not provided for SPECT/CT at the authors’ institution because there are no available billing codes.  The patient is charged the cost of PLS with colloid ($2,000 at the authors’ institution) whether or not a SPECT/CT is obtained.  Stoffels et al (2014) examined the cost-effectiveness of SPECT/CT and SLNB or SLNB alone in patients with melanoma.  The authors reported a cost savings of 35 % when SPECT/CT was employed to aid SLNB, which was explained by a significant decrease in operating time (p = 0.002) and hospital length of stay (LOS; p < 0.001).  Moreover, these investigators stated that this study has provided the opportunity to compare patients with cutaneous malignancies who had both a SPECT/CT and PLS.  A future direction is to organize a prospective, multi-center study to compare the 2 imaging modalities to each other, analyzing such variables such as time needed to identify SLNs, placement of incisions, or costs.

An UpToDate review on “Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma” (Tai et al, 2024) does not mention single-photon emission computed tomography / SPECT as a management option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Merkel Cell Carcinoma” (Version 1.2024) does not mention single photon emission computed tomography (SPECT).

References