Two decades of SPECT/CT – the coming of age of a technology: An updated review of literature evidence

Detection of lymphatic metastatic involvement is important in the staging, prognosis and treatment of various malignancies. Following interstitial radiocolloid injection at the site of the primary tumour, scintigraphy visualizes its lymphatic drainage. The term “sentinel lymph node” (SLN) is used to describe the first lymph node (LN) encountered by lymphatic vessels draining the primary tumour. Lymphatic drainage is complex, and SPECT/CT can achieve accurate pre-surgical SLN mapping, with further implementation into a personalized surgical approach [6].

In breast cancer, where SLN mapping is well validated, a literature search yielded 41 articles on SPECT/CT, 16 of which were retained for analysis (Fig. 1, Online Table 1).

Similarly, SLN mapping has been validated in patients with intermediate-thickness melanoma. A literature search yielded 19 out of 54 articles about SPECT/CT in melanoma that were retained for analysis (Online Table 2).

In early-stage head and neck malignancies, SLN biopsy is increasingly used for treatment stratification, being associated with decreased morbidity and better outcomes as compared to elective neck dissection [7, 8]. The addition of SPECT/CT to dynamic lymphoscintigraphy in oral carcinoma revealed additional SLNs in 22% patients, providing new anatomical information in 3% of patients, for an overall detection rate for the combined approach of 98% [8, 9].

In gynaecological cancers, SLN mapping using SPECT/CT facilitates intraoperative SLN biopsy in cancer of the cervix [10, 11] and vulva [12, 13]. SPECT/CT localization of SLNs was found to be anatomically accurate in 91% of endometrial tumours, a malignancy with a low prevalence of nodal metastases [14]. One prospective study demonstrated the value of SPECT/CT in penile cancer, improving both the LN detection rate and their precise localization in drainage basins [15].

Recent guidelines [16] present the optimal modalities for differentiated thyroid cancer (DTC) management. The selection of patients for post-surgical radioiodine (RAI) ablation is based on clinical and histopathologic risk stratification [17‐20]. RAI whole-body scintigraphy (WBS) at the completion of ablation can change the risk stratification [18]. SPECT/CT provides additional information, mainly by clarifying equivocal planar findings (Fig. 2) [19]. RAI-SPECT/CT has been compared with RAI-WBS at various stages of DTC, including pre- and post-ablation, and after therapy for recurrent or metastatic disease.

Prior to ablation, RAI-SPECT/CT identified unexpected cervical nodal metastases in 30–44% and distant lesions in 4–10% of cases, leading to a change in management in 30–60% of patients, mostly receiving higher RAI treatment doses than initially planned (Online Table 3) [21‐24]. After ablation, SPECT/CT was significantly more specific than WBS with or without SPECT, showing a definite incremental value in 42% of cases [25]. In multiple studies involving large numbers of patients, SPECT/CT correctly characterized over 90% of equivocal RAI foci seen on WBS, and detected additional, cervical LNs or distant metastases in 9–40% of cases. This resulted in modification of the TNM stage on average in 10%, the risk category in 35%, and planned management in up to 15% of patients [26‐39]. Post-ablation RAI-SPECT/CT has also been used for radiation dosimetry estimates [40].

After RAI treatment for recurrent or metastatic DTC, SPECT/CT provided important information in 73.9% of cases and led to a change in management in 47.1% of patients [41]. SPECT/CT detected unexpected nodal neck metastases in 83.1%, lung metastases in 15.5%, and bone lesions in 2.8% of patients [42]. Pretreatment ¹²⁴I-iodide PET/CT and post-therapy SPECT/CT were in agreement in 97% of lesions [43]. A lesion-based comparison of pretreatment [¹⁸F]fluorodeoxyglucose (FDG) PET/CT with pre- and post-treatment RAI-SPECT/CT and WBS showed that pretreatment SPECT/CT performed better than planar WBS or [¹⁸F]FDG PET/CT, while post-therapy SPECT/CT performed better than WBS but worse than [¹⁸F]FDG PET/CT [44]. SPECT/CT had a definite diagnostic impact in an average of 57% of DTC patients (Online Table 4). It detected unexpected sites of cervical LN or distant metastases in about 25% of patients, thus up- or down-staging over 20% and leading to change in planned management in about 25% of patients. [45‐51].

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours originating from single or clustered neuroendocrine cells, located in the gastrointestinal tract (GIT) and lungs and less commonly in the thymus, adrenal medulla, and the pituitary, parathyroid and thyroid glands. Having a nonspecific clinical presentation, NENs represent a diagnostic and therapeutic challenge. The European Neuroendocrine Tumour Society (ENETS) diagnostic and prognostic stratification criteria used in the management decision process are based on histological typing, differentiation, grading, and TNM staging. Imaging plays a fundamental role in the diagnosis, staging, treatment selection, and follow-up of NENs. Specifically, scintigraphy of tumour somatostatin receptor (SSR) expression or catecholamine uptake aims to identify functionally active lesions and has theragnostic potential. SPECT/CT has demonstrated an incremental value for assessment of NENs (Fig. 3), with a literature search yielding a total of 30 articles, 26 of which were retained for further analysis (Online Table 5). Radiolabelled octreotide scintigraphy has been used for assessment of SSR-positive NENs [52‐62] with the addition, in recent years, of PET/CT with ⁶⁸Ga-labelled somatostatin analogues. Catecholamine metabolism is assessed with ¹²³I-metaiodobenzylguanidine (mIBG), ¹⁸F-DOPA, and potentially [¹¹C]5-hydroxytryptophan (5-HTP). While the use of PET/CT is associated with higher diagnostic accuracy, better patient compliance and comfort, and lower radiation exposure, the use of SPECT/CT has a proven incremental value in the assessment of NENs (Online Table 5).

Bone metastases are associated with worse prognosis and decreased survival [63, 64]. Bone scintigraphy (BS) detects metastases in the presence of a reactive increase in bone formation. CT visualizes osseous metastases as a difference in density relative to normal tissue. Literature evidence on the diagnostic accuracy of BS in cancer is of low quality, hampered by the lack of a gold standard. Sensitivity ranges between 85% and 96% [64‐66], limited by spatial resolution of planar and SPECT studies [67]. BS does not detect small osseous metastases unless they exhibit high uptake, such as in prostate cancer. Purely lytic metastases, such as in renal cancer or lymphoma, as well as predominantly lytic lesions in breast cancer, are difficult to detect by BS. These lesions can be detected on the CT component of SPECT/CT, thus enhancing the study sensitivity. Bone metastases can also be efficiently detected using FDG PET/CT, an imaging modality that plays an important role in assessing skeletal involvement in cancer, especially in the case of lesions with a predominantly osteolytic rather than osteoblastic pattern [63]. The specificity of BS for detection of bone metastases is low, since multiple benign conditions show increased radiotracer uptake, thus requiring a differential diagnosis [68]. However, since most benign conditions have a typical appearance on CT, the combined information provided by SPECT/CT adds specificity to BS in the assessment of skeletal involvement in malignant diseases.

A literature search yielded 104 articles about bone SPECT/CT in malignancies, of which 20 were further analysed. SPECT/CT was able to characterize most equivocal findings on BS, planar and/or SPECT, in cancer patients (Fig. 4) [69‐71]. Despite the heterogeneity of the studies, the results are remarkably consistent. SPECT/CT characterized 66.7–100% 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 [69, 71‐78] (Online Table 6) showed its lower performance vs. whole-body (WB)-MRI [69] and conflicting results vs. ¹⁸F-fluoride PET/CT [69, 77]. 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 one-field-of-view (FOV)-position-targeted SPECT/CT [79], but with only limited incremental diagnostic value for 2-FOV vs. 1-FOV bone SPECT/CT [80]. It seems reasonable to predict that WB-SPECT/CT will be the future of BS in cancer patients, in particular when fast acquisition protocols become widely available [81].

The development of PET radioligands directed against the prostate-specific membrane antigen (PSMA) has revolutionized the diagnostic workup of prostate cancer [82, 83]. ^99mTc-labelled PSMA-ligand agents have also recently been developed [84‐88]. SPECT/CT with ^99mTc-MIP 1404 (PSMA-ligand subtype) enabled the detection of small LNs or additional metastases (Fig. 5). SPECT/CT achieved sensitivity of up to 97% for diagnosis of primary prostate cancer [89, 90]. In a group of 225 patients with biochemical relapse, the detection rate correlated with prostate-specific antigen (PSA) levels [91]. PSMA-SPECT/CT also demonstrated higher sensitivity than BS with SPECT/CT and MRI for the detection of skeletal metastases in patients with biochemical recurrence of prostate cancer [92]. However, a small comparative study in 14 patients showed the superiority of ⁶⁸Ga-PSMA-PET/CT over ^99mTc-HYNIC PSMA-SPECT/CT for detection of malignant sites [93].

The liver represents a frequent site of primary cancer and metastatic disease. Transarterial radioembolization (TARE) uses percutaneous intra-arterial techniques to inject micron-sized embolic particles, ⁹⁰Y- or more recently ¹⁶⁶Ho-microspheres, for treatment of malignant liver lesions. Beta irradiation favours destruction of the tumour cells surrounding microvessels with high radioactive particle concentration. The supply of blood to hepatic tumours derives mainly from the arterial circulation, and therefore, delivery of radioactive compounds into the hepatic artery can achieve highly selective tumour uptake. The disadvantages of TARE are related to potential inadvertent delivery or shunting.

A pre-therapy angiographic evaluation combined with scintigraphy following intra-arterial ^99mTc-labelled albumin macroaggregate injection maps the tumour-feeding vessels, quantifies potential liver-to-lung shunting, and can detect the presence of blood reflux to the bowel, stomach, or pancreas. A pre-therapeutic SPECT/CT can better assess intra- and extrahepatic distribution of the radiotracer and can be used as an adjunct to calculate the therapeutic dose. After ⁹⁰Y-microsphere administration, post-therapeutic bremsstrahlung SPECT/CT can verify the sphere distribution and enable post-treatment dosimetry. A literature search yielded 15 of 74 articles, focused mainly on dosimetry, that were retained for analysis (Online Table 7).

^99mTc-methylene diphosphonate (MDP) bone SPECT/CT plays a pivotal role in the assessment of musculoskeletal (MSK) diseases, including in patients with chronic pain or with inconclusive cross-sectional imaging results (Online Table 8), providing functional and localization information and identifying specific structural patterns. SPECT/CT has improved the diagnostic accuracy of BS in trauma and rheumatic diseases such as occult fractures, inflammatory arthritis, and spondyloarthropathies (Fig. 6) [94‐96].

In patients with chronic low back pain (LBP), SPECT/CT has been used to guide therapy [97‐99] and to assess complications following spine surgery [100‐103]. In patients with recurrent pain following lumbar arthrodesis, SPECT/CT was highly sensitive and specific for exclusion of screw loosening [102]. In pelvic girdle pain and sacroiliac joint (SIJ) dysfunction, SPECT/CT diagnosed SIJ incompetence with sensitivity of 95%, specificity of 99%, PPV of 99%, and NPV of 94% [104].

Diagnosis of hand and wrist pain by BS is challenging because of the complex regional anatomy. SPECT/CT can detect post-traumatic bone remodelling in occult fractures, often missed by other imaging tests [105‐107]. SPECT/CT arthrography has been used for assessment of the scapholunate and lunotriquetral ligament or the triangular fibrocartilage complex [108]. In patients with nonspecific regional pain, SPECT/CT has shown a higher lesion detection rate than X-ray and planar BS [109] and higher specificity than MRI [110].

Detecting the source of pain following hip or knee replacement is not straightforward. X-ray is the initial test, often followed by BS to confirm or exclude septic or aseptic loosening. Increased tracer uptake identified on bone SPECT/CT in patients with total hip arthroplasty was shown to correlate significantly with symptoms [111, 112]. While BS is hampered by nonspecific tracer uptake, the CT component of SPECT/CT can identify pain generators such as osteolysis, fracture, calcifications, and joint effusion. SPECT/CT demonstrated higher diagnostic accuracy in evaluating aseptic and septic loosening of hip and knee prostheses as compared with three-phase BS and SPECT [113‐115].

SPECT/CT was used to evaluate bone viability after arthroplasty and was then compared with MRI. The two techniques were complementary in the differentiation between viable and nonviable tissue [116]. In patients following knee replacement, SPECT/CT identified typical patterns in patella-femoral disorders, further improving the management of symptoms [117, 118]. After reconstruction of the anterior cruciate ligament, SPECT/CT identified bone remodelling, graft incorporation, or insufficiency [119, 120]. SPECT/CT has also been useful in the follow-up after realignment treatment, osteotomies, and unloader devices or insoles.

Assessment of foot and ankle pain is challenged by regional anatomical complexity. SPECT/CT has been used in the diagnosis of fractures, infection, pseudoarthrosis, accessory sesamoid bones, tarsal coalition, and osteochondrosis dissecans [121]. SPECT/CT and MRI provided comparable diagnostic yield in painful lesions in the ankle and foot [122]. SPECT/CT of the foot was useful in the assessment of misaligned hindfoot [123] and in characterizing impingement syndromes and soft tissue (ST) pathology in this region [124, 125]. SPECT/CT of the skull was superior to BS for the diagnosis of active condylar hyperplasia [126].

While diagnosis of an infectious process is based on clinical and laboratory data, localization can be difficult. Infection-seeking tracers labelled with single-photon-emitting radionuclides include autologous leukocytes [white blood cells (WBC)] labelled with ^99mTc-hexamethylpropyleneamine oxime (HMPAO) or ¹¹¹In-oxine [127] and, to a lesser extent, radiolabelled antibiotics, antibodies [128, 129], and ^99mTc-ubiquicidin 29-41 [130]. ⁶⁷Ga-citrate is still used in a few scenarios such as osteomyelitis (OM) of the spine or sternum [131‐134]. SPECT/CT enables both early diagnosis of infection and precise localization. Although there has been a recent shift in infection imaging towards [¹⁸F]FDG-PET/CT [135], SPECT/CT is a valid alternative.

SPECT/CT optimizes the diagnosis of clinically suspected MSK infections and localization of known processes. This is useful in cases when bone involvement has to be proven or excluded in the presence of soft tissue infection (STI) or for assessing the extent of OM in a complicated anatomical region such as in post-surgical alterations or close to implanted medical devices. Initial studies including mixed patient populations have reported that SPECT/CT with ¹¹¹In- or ^99mTc-labelled WBCs or ⁶⁷Ga-citrate had high performance indices in one third of cases [128, 131, 136‐138]. A total of 24 papers were retrieved from a literature search and retained for further analysis (Online Table 9).

OM has to be considered in any diabetic patient with chronic non-healing wounds, mainly in the feet. Studies reported that WBC scans confirmed the infection but SPECT/CT detected or excluded OM adjacent to STI in more than 50% of patients with diabetic foot [139‐141], increasing specificity and PPV (Fig. 7) [142, 143]. WBC-SPECT/CT was superior to [¹⁸F]FDG-PET/CT [139] and similar to MRI [143] in the assessment of diabetic foot, with high sensitivity and NPV, but lower specificity and PPV at the end of antibiotic therapy [144, 145].

⁶⁷Ga-citrate SPECT/CT demonstrated high diagnostic accuracy for spondylodiscitis, similar to MRI [132] but inferior to [¹⁸F]FDG-PET/CT [134]. ¹¹¹In-diethylenetriaminepentaaceticacid (DTPA)-biotin SPECT/CT was also used for localization of spinal infection and for tailoring of therapy [146].

Differentiating aseptic loosening of a prosthetic joint from infection defines the treatment strategy. The performance indices of ^99mTc-WBC SPECT/CT reached 93% but were somewhat lower than for ^99mTc-labelled antigranulocyte antibodies [129, 147].

SPECT/CT localized foci of infection to the jaw or other bones in the base of skull [148, 149] and diagnosed OM in cases with malignant otitis externa [150]. Dual-isotope ^99mTc-MDP bone and ¹¹¹In-oxine-WBC SPECT/CT provided high diagnostic confidence for evaluation of infected pelvic pressure sores [151].

STI has nonspecific clinical presentations and requires extensive diagnostic workup [131]. In this setting, SPECT/CT could be useful in vascular graft infection [131, 152‐154], infectious endocarditis [155, 156], infection of cardiac implantable electronic devices [157, 158], and fever of unknown origin [131, 159, 160]. Eleven papers were retrieved from a literature search and retained for further analysis (Online Table 10).

^99mTc-sestamibi (MIBI) SPECT/CT is used in the workup of patients with hyperparathyroidism (HPT). Variable acquisition protocols are used, including single-tracer dual-phase studies and subtraction imaging following ^99mTc-pertechnetate or ¹²³I-iodide administration. Timing of SPECT/CT early, late, or twice during imaging has been described [161‐164].

The recent introduction of minimally invasive surgery for parathyroid adenoma (PTA) underscores the need for precise functional and topographic information provided by SPECT/CT. The main current indication for parathyroid scintigraphy is preoperative localization of PTAs (Online Table 11, Fig. 8). The detectability of PTA by SPECT/CT ranged from 90 to 96% [165, 166], particularly helpful for small lesions less than 10 mm in diameter [54, 166] or weighing less than 210 mg [167]. ^99mTc-MIBI SPECT/CT results were found to correlate with serum parathyroid hormone (PTH) and calcium levels [162, 168]. SPECT/CT improved localization of PTAs in 8–39% patients [169, 170], with a sensitivity range of 83–97%, specificity of 89–96%, PPV of 94–97%, and NPV of 85% [161, 163, 167, 171‐173]. SPECT/CT correctly localized both ectopic PTAs and residual lesions in patients with prior neck surgery [170]. ^99mTc-MIBI SPECT/CT has led to a reduction of up to 50% in the duration of surgery [166, 172, 173]. Positive SPECT/CT is a good criterion for defining patient eligibility for surgery [174] and for surgical procedure planning, particularly in the presence of thyroid disease such as multinodular goitre [172]. ^99mTc-MIBI SPECT/CT localization of a PTA was shown to be superior to both SPECT and ultrasound (US) [54, 165, 167, 171, 173] but not to multiphase 4D CT, which added information, mainly in non-^99mTc-MIBI-avid lesions [175, 176]. In cases resistant to medical treatment, patients with secondary HPT are referred for parathyroidectomy, and preoperative ^99mTc-MIBI SPECT/CT improved surgical outcome [177‐179]. A total of 23 papers retrieved through a literature search were retained for further analysis.

Ventilation and perfusion (V/Q) imaging is routinely used in the workup of patients with suspected pulmonary emboli (PE) [180]. In planar V/Q scans, distinction of anatomical segments is challenging, and it is difficult to determine the extent of embolic involvement [181‐183].

CT pulmonary angiography (CTPA) has gradually replaced V/Q scans for PE, being widely available and having high sensitivity and specificity. Nevertheless, CTPA is limited by technical artefacts, contrast allergy, or poor renal function [184, 185]. V/Q SPECT has improved sensitivity over planar scintigraphy, but has lower specificity than CTPA [185‐191]. V/Q SPECT/CT is typically performed with low-dose CT for purposes of anatomical localization and attenuation correction (AC) [192]. The addition of CT increased specificity (Fig. 9), comparable to CTPA, and characterized abnormalities seen on SPECT in the context of lung comorbidities [189, 193]. In a comparison of V/Q SPECT, SPECT/CT, perfusion-only SPECT/CT, and CTPA for detection of PE, V/Q SPECT/CT achieved sensitivity and specificity of 100% [189, 192].

V/Q SPECT/CT has also been preliminarily described in non-PE applications including preoperative quantification of lung function, defining radiotherapy fields, and assessing regional changes in asthma, emphysema, or interstitial lung disease [192, 194‐207].

Coronary artery disease (CAD) is the number one cause of cardiovascular morbidity and mortality. Current guidelines recommend that patients with low pretest probability for stable CAD undergo cardiac computed tomography angiography (CCTA), which has a high NPV, while patients with high pretest probability should be referred for invasive coronary angiography (ICA). The intermediate-risk group, comprising the majority patients, needs further assessment to define the haemodynamic significance and quantify ischaemia in addition to assessing the degree of stenosis.

Myocardial perfusion imaging (MPI) SPECT using ^99mTc-labelled tracers or ²⁰¹Tl-chloride has been validated for diagnosis, risk stratification, and prognosis of CAD [208]. AC algorithms utilizing CT and iterative image reconstruction techniques have improved the image quality and diagnostic accuracy of SPECT (Fig. 10) [209]. MPI-SPECT with vs. without AC show sensitivity of 89% vs. 87% and specificity of 81% vs. 73%, respectively [210]. SPECT/CT used for AC improved diagnostic confidence in the interpretation of stress-only MPI studies, thus reducing patient radiation exposure following the implementation of this protocol [211].

The CT component of SPECT/CT can be also used for coronary artery calcium score (CAC) measurements without significantly increasing the radiation exposure to the patient. SPECT/CT calcium scanning is becoming a routine part of MPI, with superior diagnostic and prognostic value [212, 213].

CCTA has high diagnostic accuracy for stenosis in native coronary arteries [214‐219]. SPECT/CT systems equipped with components that enable sufficient resolution to perform CCTA are now available. SPECT/CCTA led to similar patient management when compared to ICA [220].

When combining MPI with CT, the patient is exposed to additional radiation varying from 0.5 to 1.0 mSv for CT-AC. Absorbed doses for CAC and CCTA depend on the device and protocol used, estimated to be below 1 mSv for CAC measurements and between 2 and 5 mSv for CCTA, with latest-generation CT scanners even below 1 mSv [221, 222]. A total of 18 papers on cardiac SPECT/CT for AC, CAC measurements, or in combination with CCTA were retrieved by a literature search and retained for further analysis (Online Table 12).

SPECT imaging of brain perfusion is performed in cases of dementia and epilepsy using ^99mTc-HMPAO or ^99mTc-ethyl cysteinate dimer (ECD). The addition of CT to SPECT has not led to a breakthrough in this setting, in part because CT is not the procedure of choice for brain imaging, with MRI being the better tool. In the majority of cases, the diagnostic gain with SPECT/CT is only negligible [223‐233]. Nonetheless, when comparison to age-matched healthy controls is required, such as the examination of the dopamine transporters with ¹²³I-FP CIT in cases of parkinsonism (Fig. 11), CT information helps to obtain a more robust spatial normalization of SPECT data [232‐234]. The use of SPECT/CT in brain tumours with tracers such as ^99mTc-MIBI and ^99mTc-tetrofosmin (Myoview^®) or ^99mTc-bis-methionine-DTPA (MDM) is limited and largely restricted to differentiation between recurrence and radiation necrosis [235].

Active gastrointestinal (GI) bleeding is detected by contrast angiography or endoscopy if present at the time the study is performed. ^99mTc-labelled red blood cell (RBC) scintigraphy is a highly sensitive, non-invasive tool to detect intermittent bleeding. Positive studies identify patients who need immediate treatment if the site of bleeding is localized [236]. SPECT/CT was found to improve bleeding source localization in over 30% of cases [237] and, increased sensitivity from 89% to 93% compared to planar scans, with improved positional accuracy of the bleeding site in 92% vs. 74% of patients [238]. Timing of ^99mTc-RBC SPECT/CT acquisition needs further evaluation. There is also concern that during the relatively long SPECT/CT acquisition, patient motion or bowel artefacts can affect correct localization of the bleeding site [239, 240].