Fundamentals of dual-energy computed tomography and its emerging applications in bladder cancer

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INTRODUCTION

Bladder Cancer

Bladder Cancer (BCa) is the tenth most prevalent malignancy worldwide. Among urogenital tumors, it ranks second, preceded by prostate cancer [1]. It is more frequent in White people, older people (peak incidence at 70 years old), and men (male-to-female ratio of 4:1). Urothelial carcinoma (UC) is the most common type of BCa, which accounts for 90% of cases [2]. It develops from urothelial cells, typical cells lining the urinary system. Multifocality and recurrence are characteristic of this tumor presentation [3, 4].

Tobacco use, some herbs, occupational exposure to aromatic amines (such as β-naphthylamine, benzidine, and 4-aminobiphenyl), history of radiation therapy to the pelvis, chronic bladder problems, and schistosomiasis may increase a person’s risk of developing BCa [5, 6].

The primary presenting symptom that requires prompt investigation is the so-called painless hematuria. It indicates the asymptomatic presence of blood in the urine, which can be macroscopic, if grossly visible, or microscopic, if only detectable under a microscope.

As the urinary system is involved, other symptoms include pollakiuria, pelvic pain, and urinary tract infections. If the tumor is located at the vesicoureteral junction, the patient may complain of a lumbar flank plain, which is due to ureteral obstruction and subsequent hydronephrosis. Systemic symptoms, such as fatigue, fever, and weight loss, are associated with metastatic progression and occur later.

A morphological classification of BCa is based on muscle involvement [7]. The non-muscle invasive BCa (NMIBC), which is a tumor type characterized by its superficiality and usual papillary extension. This type of tumor is present in 70%–80% of patients with BCa. It is superficial because it arises from the epithelium that becomes hyperplastic but remains limited to the mucosa and lamina propria. In only approximately 33% of cases, when the NMIBC is a high-grade tumor (malignant carcinoma in situ), this tumor has a flat appearance, shortly invades the muscle plane, and metastasizes [8, 9].

Muscle-invasive BCa (MIBC) arises in 20%–30% of cases and does not have a papillary presentation. The fast infiltration of all bladder wall layers, passing the latter, and arriving outside the organ, makes this tumor aggressive with a poor prognosis. Distant spread through the lymph nodes starts at a locoregional level and then reaches the common iliac, paracaval, and lumbar–aortic chain. Distant spread via blood most commonly affects the lungs, bone, liver, and adrenal glands [10, 11].

The TNM 8th edition is the current system used for BCa staging, which can be also grouped into grades, resulting in BCa grading [12, 13] (Tables 1 and 2).

 

Table 1. TNM staging (8th edition)
T
Ta	Noninvasive papillary tumor
Tis	In situ (noninvasive flat)
T1	Through the lamina propria into the subepithelial connective tissues
T2	Into the muscularis propria
T2a: invasion of the inner half of the muscle only
T2b: invasion into the outer half of the muscle
T3	Invasion into the perivesical tissues
T3a: Microscopic extravesical invasion
T3b: Invades into the outer half of the muscle
T4	Direct invasion into adjacent structures
T4a: Prostate, seminal vesicles, uterus, and vaginal vault
T4b: Pelvic side wall and/or abdominal wall
N
N0	No nodal involvement
N1	Single node in the true pelvis (hypogastric, obturator, external iliac, or presacral nodes)
N2	Multiple nodes in the true pelvis
N3	Metastasis in a common iliac node
M
M0	No metastases
M1a	Nonregional lymph node involvement
M1b	Other distant metastasis

 

Table. 2. Grading of bladder cancer
Grading
0	Ta or Tis, N0, and M0
I	T1, N0, and M0
II	T2 (a or b), N0, and M0
III	T3 (a or b) or T4a, N0, and M0
IV	T4b, any N, any M or any T, N1-3, and any M

 

Dual-energy computed tomography

Fundamentals

Dual-energy computed tomography (DECT) is an innovative technology that produces various imaging datasets by concurrently operating two X-ray tubes with two different kilovoltages. Its fundamental elements are the same as conventional imaging with X-rays: the power of the X-ray tube, Compton and photoelectric effects, and characteristics of the material.

DECT operates on the premise that materials respond in a specific way to various X-ray photon energies. Therefore, every material with its proper energy-dependent attenuation profiles is obtained with two different energies.

The basis for tissue differentiation on CT and DECT is the attenuation of the photons as they go through and interact with the tissue. The attenuation, expressed in Hounsfield units (HUs), depends on the properties of the material, specifically its atomic number (Z), and electron density. Instead, it is inversely proportional to the radiant energy generated by the tube (kVp): it is greater if low-energy photons are used compared with high-energy ones [14].

At the energy levels used in medical imaging, the interaction between photons and body tissues depends on the photoelectric and Compton effects. The photoelectric effect is energy-dependent and is related to the atomic number (Z), whereas the Compton effect is energy-independent and is related to electron density (mass).

The tissue or contrast material inside the area of interest is characterized by having spectral features, which means that it has an actuation that differs depending on the photon energy. This principle allows DECT to make distinctions between materials.

As a result, materials with a high Z, such as iodine (Z=53), are mainly affected by the photoelectric effect, an interaction that leads to increased attenuation when subjected to a lower energy beam (80–100 kVp), generating a spectral contrast with the biological tissues at DECT. On the contrary, the Compton effect affected mainly materials with low Z, such as oxygen, nitrogen, hydrogen, and carbon (all materials with a Z of 1–8). Calcium is affected nearly equally by the two effects [15].

In summary, each material has a specific Z value and absorption of photons (attenuation) that changes according to the photon energy. In particular, water has a straight line, whereas fat reduces the attenuation values as we approach the lowest energy (40–45 keV) (Fig. 1).

 

Fig. 1. Different attenuation at different energy ranges of iodine, calcium, water, and fat. Iodine has the highest attenuation value for low kEv compared with fat that has the lowest. The attenuation values of water not influenced by different energies. Calcium has an average behavior compared with others.

 

Subsequently, each tissue results from all these variables of each component, as can be water or fat. For example, soft tissue is made up of materials with comparable Z values, and it results in attenuation without discernible differences [14].

Technique

The examinations of cases presented in this narrative review were performed on a single-source scanner with Rapid Kilovoltage Switching (Revolution CT GSI Xtream, GE Healthcare) (Table 3).

 

Table 3. Major characteristics of this single-source dual-energy computed tomography system.
Single-source DECT with Rapid Kilovoltage Switching (SsDECT)
	Schematic illustration of a type of Ss-DECT. Yellow is used to illustrate the low-energy spectrum, whereas blue presents the high-energy spectrum. The detector can rapidly register information from exposure at both energies.
Prospective technique
Single X-ray tube that switches between high (140 kVp) and low (80 kVp) energies in 0.25 ms and within the same gantry rotation.
Reconstruction in the projection space with deep-learning image reconstruction
Full field of view
Slight reduction in temporal resolution due to tube rotation
80 mm GSI collimation; 50 cm GSI FOV; neutral dose, rumor index; hyper drive pitch, 1.531:1; 256 detectors; maximum coverture, 16 cm.

 

The multi-phase acquisition protocol was used. As the first step, an unenhanced scan of the abdomen and pelvis was performed. Then, patients were given furosemide intravenously to delineate the pelvicalyceal system and ureters better and produce more homogenous opacification of the urine bladder.

The post-contrast phases are as follows: corticomedullary phase, obtained 30–40 s after the injection; nephrographic phase, acquired 90–110 s after contrast administration; pyelographic phase, late excretory phase, obtained after 8–12 min from the intravenous administration of the contrast medium (Table 4).

 

Table 4. Schematic protocol with preparation, acquisition phases, Z-axis extension, and scan direction.
PROTOCOL
Preparation	Furosemide: 10–20 mg before the corticomedullary phase
Acquisition Phases	Basal
	Corticomedullary	ROI in the abdominal sopraceliac aorta; threshold HU, 150; after 18–20 s from reaching the bolus-tracking threshold
	Nephrographic	80–100 s from the intravenous injection of the contrast medium
	Excretory	7–10 min from the intravenous injection of the medium contrast
Z-axis extension	From the diaphragmatic cupola to the pubic symphysis for the basal and nephrographic phases.
	From the superior renal pole to the pubic symphysis for the corticomedullary and excretory phases.
Scan direction	Craniocaudal

 

Considering the usefulness of each phase:

• The unenhanced phase allows the detection of calcifications and calcific stones, which appear hyperdense, and hemorrhages, with typical blood density. Moreover, it is useful to measure the attenuation coefficients of a urothelial masses before contrast injection [16–18].
• The corticomedullary phase allows the detection of vascular variations or the presence of arterial enhancements.
• The nephrographic phase allows a better characterization of renal lesions and subsequently their detection [19–20].
• The pyelographic phase allows the detection of urothelium variations with distension, evaluated through the opacification of the urinary system starting from the collecting systems, passing through the ureters until the bladder [21–24].

From the CT, a 3D reconstruction of the urinary tract can be obtained. It represents an evolution of classical urography, and it allows a complete visual of the urinary system, providing information about the morphology and functionality of the kidneys and excretory tract, enhancing malformations, stones, or solid neoformations. It is indicated in the case of hematuria, diagnosis of kidney–ureter–bladder tumors, or stone pain to detect and localize the stone (Fig. 2).

 

Fig. 2. 3D reconstruction obtained from CT urography with a contrast medium, with (a) and without (b) bones in the background in a coronal plane.

 

Reconstructions

Unlike traditional single-energy CT, which yields a single image set, DECT can reconstruct various image types. The following are those used for BCa evaluation [25].

Virtual mono-chromatic images

Virtual mono-chromatic (VMC) images are post-processed images generated by a complex algorithm that generates image quality similar to conventional polychromatic single-energy CT but provides more trustworthy attenuation values.

Two energies applied offer different properties to VMC images. Low energy is responsible for an increased contrast between structures that are near, explained by the high beam attenuation of iodine. In this way, a parietal lesion is easier to evaluate. Meanwhile, high energy is responsible for less noise and artifacts and less contrast between nearby structures.

By using two different kilovoltage sets (high and low energies), from the VMC images, also a spectral attenuation curve, a function of energies is obtained. The latter is attributed to its properties, which is useful to improve lesion characterization.

By acquiring VMC images at different energies, a spectral attenuation curve, which is a function of different energies, is obtained, useful for its properties to improve lesion [14].

Virtual noncontrast images (iodine removed)

Virtual noncontrast (VNC) images are postprocessing images obtained by separating specific materials to create images “without contrast” from scans acquired after contrast administration [26, 27]. Therefore, this postprocessing image has the potential to replace the traditional first scan acquired without contrast during CT [28, 29].

The material suppressed is iodine, and the kind of image obtained is also called “iodine removed.” It means that any iodine uptake identified during DECT multiphasic acquisition is identified and suppressed to generate a VNC scan.

The main advantage of this unique and exclusive imaging technique only referrable to DECT is that it does not require patients to undergo multiple scans, reducing the total amount of radiation dose.

Furthermore, the effort and time required to conduct subsequent investigations can be significantly reduced [30].

Iodine map

Using a complex algorithm, it is possible to select a material with its proper attenuation features and generate a material-specific image. For example, by selecting a high attenuation material such as iodine, an iodine-specific image, known as iodine map, is generated [31].

As the opposite of an iodine-removed image, the iodine map indicates all areas with iodine uptake. Therefore, this kind of postprocessing image enables iodine quantification, expressed in milligrams/milliliter (mg/mL) [14, 32].

Iodine density is then typically overlaid as a color map on traditional CT scans, with voxel values representing iodine concentration in mg/mL. The iodine map can differentiate a vascular from a nonvascular lesion. Quantifying iodine and normalizing it to the amount of iodine present in the aorta is an indirect measure of the vascularity of the region of interest. The optimum thresholds for distinguishing vascular from nonvascular lesions vary from the type of DECT platform, with 0.5 mg/mL for dsDE; 1.3 mg/mL for rsDE, and 0.5 mg/mL for dlDE [31, 33].

Quantifying iodine in the nephrographic phase and normalizing it to the quantity of iodine in the aorta are better: \left|I\right|\ normalized=\left|I\right|\sfrac{lesion}{\left|I\right|}aorta.

Atomic map

An effective atomic number map (Zeff) is used to quantitatively assess material differentiation and evaluate attenuation variations as a function of energy (Fig. 3) [34].

 

Fig. 3. Atomic map with the histograph.

 

Bladder Cancer and Dual-energy computed tomography

In oncologic imaging, CT is essential owing to its accessibility, prompt acquisition time, and high image quality. In patients with suspected BCa, it is the most commonly used technique for the detection and avoidance of misdiagnosis for other potential causes of hematuria. On the contrary, it represents the gold standard for staging to evaluate locoregional and distant extent of disease [7, 35].

The primary limitations of CT are their high radiation dose (25–35 mSv) and the inability to distinguish MIBC and NMIBC BCa [6]. Repeated acquisition phases, particularly in patients with oncologic problems who may require follow-up CTs, raise the issue of ionizing radiation overexposure and frequent injection of iodinated contrast media. In addition to dose reduction, the risk of nephropathy must be also considered in patients with kidney disorders who undergo numerous CT examinations for follow-up. Accordingly, the focus of attention has shifted to new technologies such as DECT, which can provide benefits to both radiologists and patients in tumor diagnosis and monitoring [36].

DECT is a new imaging technique that owing to its technological qualities, it is particularly useful in oncologic imaging. The evident benefits of DECT concern lesion characterization, tumor detection, and lowering the need for additional imaging examinations and biopsies. This is possible thanks to postprocessing reconstruction such as VNC images, VMC images, spectral curves, and iodine maps.

VNC images do not differ considerably from the true unenhanced images, and they can disclose stones, calcifications, and hemorrhages that appear hyperdense in non-contrast CT scans. Moreover, measuring the attenuation coefficients of a mass to compare its value to that obtained in post-enhanced scans is essential [37, 38].

The spectral curve with its properties is useful to improve lesion characterization. For example, a nodular formation of the bladder wall has a curve that goes to the high for lower values of keV (Fig. 4).

 

Fig. 4. Spectral curve that allows the characterization of materials because each material has a different attenuation curve. Using different energies, different materials can be differentiated based on the attenuation of the same at the two energy levels.

 

Lesion extension may be better evaluated, thanks to the use of a VMC image at low-energy kilovoltage that improves the contrast-to-noise ratio. In particular, this image emphasized the suspicious lesion from the surrounding area. The lesions with their appropriate hypo- or hyperenhancement are more viewable than the enhancing background parenchyma. Considering that enhancement is also measurable, VMC images improve lesion detection and characterization (Fig. 5) [39, 40].

 

Fig. 5. Virtual monochromatic images at 40 keV, (a) giving better enhancement of the contrast medium with greater noise; at 140 keV (b) with less contrast, artifacts, and noise.

 

Nakagawa et al. showed that DECT is more effective compared with conventional CT urography to detect small and low-enhanced BCas that might be harder to recognize: The different contrast between BCa and the bladder wall was more evident in the VMC image [41].

By examining the presence and absence of iodine, iodine maps can be used to quantify iodine in each voxel and, in this way, detect slight contrast enhancements to characterize the lesion. Iodine maps can be also used to distinguish vascular and nonvascular lesions, always for lesion characterization. In this case, in the nephrographic phase, iodine quantification must be normalized to the aorta. An iodine concentration threshold of ≥1.0 mg I/mL shows high sensitivity (92%) for urothelial tumors. High specificity (92%) can be reached at a threshold of ≥3.0 mg I/mL (Figs. 6–8) [42].

 

Fig. 6. A patient with hematuria in anticoagulant therapy and suspicion of a clot. (a) Axial plane of an iodine map obtained in the arterial phase. Av = 26.79 represents the mg/mL of iodine concentration with a threshold of 1.3 mg/mL. CT shows that the lesion contains iodine and is therefore highly suspicious for bladder neoformation. The iodine map with color overlay obtained from an arterial phase CT in axial (b) and coronal (c) planes shows the lack of hydroxyapatite content.

 

Fig. 7. A patient with hematuria suspected of bladder lesion. (a) The CT axial plane shows modest bladder wall thickening with significant concentration of iodine, which indicates high suspicion of lesion. AV represents the concentration in mg/mL of iodine, which is 6.7 and 16.48 for the blue circle and yellow marker (threshold value of 1.3 mg/mL), respectively. (b and c) Spectral curve that allows the characterization of materials because each material has a different attenuation curve.

 

Fig. 8. CT image in the nephrographic phase useful for quantifying iodine concentration and normalizing it to the amount of iodine in the aorta. (a) Iodine map showing various solid nodules that adhered to the bladder wall and (b) iodine map with color overlap improves leasion visualization. The average value for the lesion is 1.5 mg/mL, the Av value of the iliac artery is 8.4 mg/mL, and the threshold is 1.3 mg/mL.

 

In summary, the iodine map derived from DECT provides more information than conventional CT because it allows the quantification of iodine content in the lesion and offers a better trustworthy measurement of lesion enhancement. It can be used as a surrogate marker for tissue contrast media uptake, considering that it is not affected by innate tissue attenuation, and does not require evaluation of pre- and post-contrast enhancement of true enhanced image. In the latter case, multiple post-contrast scans, such as the arterial and portal venous scans, must be studied before lesion characterization [14].

DECT may also be useful for staging. Therefore, iodine maps may assess tumor extension both locally to evaluate the infiltration of all bladder wall layers and at a distance to evaluate lymph node involvement and presence of metastases.

Moreover, DECT can be employed not only for lesion characterization and staging but also for treatment planning. In fact, assessing therapy is crucial to understanding BCa extension and assessing the presence of connections with the vascular structure. For this purpose, low-energy VMC images are better postprocessing images and depict with better efficacy the relation between the lesion and surrounding vascular structures. Moreover, as images may be isotropically captured, from the DECT acquisition, maximum intensity projection that can give surgeons a vascular guide can be also reconstructed [14, 43].

Additional DECT advantages may be useful in tumor comorbidities, for example, renal colic, and detection of tumor-related disorders, such as pulmonary embolism or bowel ischemia [44, 45].

However, the current limitations to the use of DECT must be considered, particularly the need for specific equipment and technology, which may only be available in some healthcare facilities. Indeed, it is a high-cost technology that may not be accessible in all healthcare settings, not allowing intra- and interdepartmental comparisons, particularly in the follow-up. Moreover, image scanning and interpretation require qualified and trained staff with advanced training.

CONCLUSION

DECT is a cutting-edge technology that generates various imaging datasets by concurrently operating two X-ray tubes at two distinct kilovoltage levels: one lower and one higher.

The application of DECT in the oncology field is an emergent and revolutionary discovery. In particular, in patients with suspected BCa, postprocessing images provide more information than conventional CT urography to detect the lesion and better characterize it.

Therefore, DECT is analogous to CT considering the image acquisition process; however, postprocessing is exclusive to DECT and allows the production of various other images, such as VNC, VMC, spectral curves, and iodine maps. Each image type can provide more details and knowledge and assist radiologists in making a more certain diagnosis of BCa while benefiting the patient by shortening diagnosis timelines.

DECT may not be limited to the detection of a potentially malignant lesion but also to the staging and treatment planning of tumors such as BCa. In particular, the combination of low-energy images and iodine maps may allow for better depiction and characterization of primary and secondary lesions. Nevertheless, DECT is unavailable in all healthcare settings and requires trained healthcare personnel.

ADDITIONAL INFORMATION

Funding source. This article was not supported by any external sources of funding.

Competing interests. The authors declare that they have no competing interests.

Authors’ contribution. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work. L. Eusebi, F. Masino, G. Guglielmi — work conception and design; V. Ferrara, M. Marcellini, L. Eusebi — data collection; F. Masino, L. Eusebi, M. Montatore, G. Muscatella, R. Gifuni — manuscript writing and editing.

About the authors

Federica Masino

Foggia University School of Medicine

Email: federicamasino@gmail.com
ORCID iD: 0009-0004-4289-3289

MD

Italy, Foggia

Laura Eusebi

“Carlo Urbani” Hospital

Email: lauraeu@virgilio.it
ORCID iD: 0000-0002-4172-5126

MD

Italy, Jesi

Manuela Montatore

Foggia University School of Medicine

Email: manuela.montatore@unifg.it
ORCID iD: 0009-0002-1526-5047

MD

Italy, Foggia

Gianmichele Muscatella

Foggia University School of Medicine

Email: muscatella94@gmail.com
ORCID iD: 0009-0004-3535-5802

MD

Italy, Foggia

Rossella Gifuni

Foggia University School of Medicine

Email: rossella.gifuni@unifg.it
ORCID iD: 0009-0009-9679-3861

MD

Italy, Foggia

Vincenzo Ferrara

“Carlo Urbani” Hospital

Email: vincenzoferrara4@gmail.com
ORCID iD: 0000-0001-8625-4308

MD

Italy, Jesi

Massimo Marcellini

“Senigallia” Hospital

Email: massimo.marcellini@sanita.marche.it
ORCID iD: 0000-0002-5281-7819

MD

Italy, Senigallia

Giuseppe Guglielmi

Foggia University School of Medicine; “Dimiccoli” Hospital; “IRCCS Casa Sollievo della Sofferenza” Hospital

Author for correspondence.
Email: giuseppe.guglielmi@unifg.it
ORCID iD: 0000-0002-4325-8330

MD, Professor

Italy, Foggia; Barletta; San Giovanni Rotondo

References

Supplementary files