Introduction
Contrast media are widely used in multidetector- row computed tomography (CT) to improve visu- alisation of the vascular system and renal tract and to increase lesion-to-tissue contrast. Nevertheless, for patients within the first 6 h of acute stroke, the diagnostic and prognostic ability of conventional CT remains poor. Similarly, despite conventional contrast-enhanced techniques, mass lesions on CT may remain hard to characterize as benign or ma- lignant, both at diagnosis and following cancer therapy. Furthermore, visual assessment of tumor enhancement rarely provides useful prognostic in- formation beyond conventional staging. This pa- per describes how functional CT techniques can maximize the benefits of administering contrast media and so improve the assessment of patients suffering acute stroke or cancer.
Technical Considerations
Quantification for Contrast Enhancement Table 1 compares the information that can be ob- tained using contrast media for anatomical and functional purposes. The additional information from functional CT is obtained by quantifying the amount of contrast medium within a given region or volume element (voxel), usually during a time sequence of CT images [1]. Each CT image displays
the X-ray attenuation values within each voxel of the anatomical slice studied as an X-ray attenua- tion map. Following intravenous administration of contrast medium, the iodine component of the con- trast medium causes a local increase in the X-ray attenuation that is linearly proportional to the io- dine concentration. The amount of attenuation change for a given concentration of contrast medi- um depends upon a range of factors including the CT system used, the tube voltage (kVp), and the body region examined (e.g., chest or abdomen) and can be ascertained with a simple phantom (Fig. 1).
A greater change in attenuation is observed with a lower tube voltage and functional CT protocols may advocate a tube voltage as low as 80 kVp [2].
The concentration of contrast medium at cer- tain time-points following injection can be used to calculate a range of physiological parameters, in- cluding cardiac output and glomerular filtration per gram of renal tissue.At tissue level, it is possible to measure blood flow, blood volume, blood vessel permeability and the size of the extracellular com- partment within each voxel. Absolute quantifica- tion of physiological parameters requires knowl- edge of contrast enhancement within the vascular system as well as the tissue of interest. However, a simple measurement of peak tissue concentration of contrast medium, when combined with the dose of contrast medium administered per kilogram body weight, can be used to calculate the ratio of tissue perfusion to average whole-body perfusion, also known as the Standardized Perfusion Value
IV.2
Functional CT Imaging in Stroke and Oncology
Kenneth A. Miles
Table 1. Comparison of anatomical and functional applications of contrast media
Anatomical Functional
Visualise blood vessels Determine cardiac output
Visualise renal tract Assess renal function
Improve lesion-to-tissue contrast Assess physiology of tissue microcirculation,
e.g., perfusion, vascular permeability
IV.2_Miles 30-06-2005 11:08 Pagina 109110 MDCT: Scanning and Contrast Protocols
(SPV) [3]. Commercial software is now available to calculate many of these parameters and display them as colour-coded functional images. The de- rived values are reproducible and have been vali- dated against reference methods [1].
Image Acquisition
Most patients suffering from acute stroke or cancer presently undergo conventional CT, and the sim- plicity of functional CT means that the necessary images can be readily appended to existing proto- cols. Functional CT is conceptually similar to CT angiography (CTA) but depicts the circulation at the tissue level rather than visualising discrete ves-
sels. Like conventional angiography, some func- tional CT protocols require a rapid series of images without table movement following a bolus of con- trast medium (Table 2, protocols 1 and 2). Such protocols benefit from allowing determination of multiple physiological parameters within one study, but the volume of tissue examined in the cranio-caudal (Z) axis is restricted by the width of the CT detector tract, i.e., 2 cm on modern mutlis- lice systems. Other functional CT protocols mimic CTA in that they comprise a spiral acquisition at a set time after injection of contrast medium, the precise time possibly determined using a small test bolus of contrast medium (Table 2, protocol 3). In either case, a rapid injection of high-concentration contrast medium (at least 370 mg/ml) is favored for Fig. 1. A calibration phantom containing contrast medium at different concentrations (a) can be used to determine the rela- tionship between attenuation and iodine concentration for a range of tube voltages (b)
a b
Table 2. Example acquisition and processing protocols for functional CT
1 2 3
Contrast medium
Concentration
370 mg/ml 370 mg/ml 370 mg/ml
Volume
40 ml 50 ml 50 ml
Injection rate
4–7 ml/s 7–10 ml/s 7–10 ml/s
Slice thickness 2×10 mm 2×10 mm 12 cm spiral
No. images 60 25 1
Image frequency Every 1 s Every 2 s At time of peak enhancement
(determined from test bolus)
Tube current 50–100 mAs 100–200 mAs 100–200 mAs
Analysis method Deconvolution Compartmental Compartmental
modelling modelling
Parameters calculated Perf, BV, MTT, Perf, BV, MTT Perf normalised to cardiac
vascular permeability output
Advantages Good temporal resolution Low image noise Whole-organ imaging Disadvantages Image noise Reduced temporal Perf values only
Limited anatomical resolution
coverage Limited anatomical coverage
(Perf = perfusion, BV = blood volume, MTT = mean transit time)IV.2_Miles 30-06-2005 11:08 Pagina 110
IV.2 • Functional CT Imaging in Stroke and Oncology 111
two reasons. Firstly, a greater quantity of iodine can be administered in a shorter time, thereby maxi- mizing tissue enhancement and improving signal- to-noise ratios. Secondly, a bolus time of 8 s or less, as required for some analysis methods, can be achieved for a given iodine dose more readily with high-concentration media. Tube current and image frequency are selected with regard to analysis methodology and radiation dosimetry. A higher tube current but lower image frequency may be ap- propriate when using compartmental analysis as opposed to deconvolution methods (Table 2). A more detailed discussion of analysis methods and protocols can be found elsewhere [1, 4].
Clinical Applications
Acute Stroke
By demonstrating a regional reduction in perfusion and prolongation of transit time, functional CT en- ables positive diagnosis of acute cerebral ischemia and assessment of prognosis within the first few hours of stroke onset, a time when conventional CT images are typically normal. The size of the is- chemic area provides prognostic information and, in the case of embolic stroke, can influence the tim- ing of anticoagulation therapy, as early anticoagu- lation may be contraindicated unless the infarct is small [5-8]. By comparing perfusion and blood vol- ume images, it is also possible to distinguish re- versible from irreversible changes with results that are comparable to diffusion-weighted magnetic resonance imaging [9, 10]. Areas of reversible is-
chemia demonstrate reduced perfusion but pre- served blood volume, reflecting preservation of vascular autoregulation and hence tissue viability.
Irreversible infarction is characterized by reduced perfusion and blood volume. The term “penumbra”
is given to a region of reversible ischemia sur- rounding an infarct core. Image acquisition with- out table movement is used to identify reversible ischemia because of the need to compare two phys- iological parameters. The demonstration of re- versible ischemia has been proposed as a means to select patients for thrombolysis, but requires fur- ther validation through randomized controlled trials [11].
Oncology
Contrast enhancement in tumors correlates with histological assessments of microvessel density and therefore can be used as an in vivo marker of tu- mor angiogenesis [12, 13]. Measuring peak en- hancement within lung nodules can characterize lesions that are indeterminate on conventional CT;
this is increasingly used for assessment of nodules identified by CT screening protocols [14, 15]
(Fig. 2). Occult hepatic metastases and other tumor sites undetected by conventional CT may be re- vealed on functional CT images. By quantifying contrast enhancement within the liver, it is possible to identify patients at risk of subsequently devel- oping overt metastasis and to predict survival [16- 18]. CT perfusion measurements can also estimate tumor grade in cerebral glioma and lymphoma [1].
Functional CT can demonstrate the effect of cancer treatment on tumor vascularity and may show a re-
a c
b d
Fig. 2a-d Quantifying con- trast enhancement to charac- terize a left-sided lung nodule and obtain a tumour vascu- lar/metabolic profile. a CT pri- or to contrast enhancement.
b Time-attenuation curve in- dicating a peak enhancement of greater than 15 HU at 27 s.
c Standardised Perfusion Val- ue (SPV) image in which the enhancement in each pixel at 27 s has been normalised for patient weight and dose of contrast medium. Enhance- ment of greater than 15 HU and SPV of greater than 1.5 implies malignancy as does fluorodeoxyglucose (FDG)- PET (d). Histology confirmed non-small cell lung cancer.
The Standardised Uptake Val- ue (SUV) for FDG and SPV in- dicate a balanced vascular/
metabolic profile typical of
low-stage lung cancer
IV.2_Miles 30-06-2005 11:08 Pagina 111112 MDCT: Scanning and Contrast Protocols
sponse to drugs that target tumor vessels before any change in tumour size or fluorodeoxyglucose (FDG) uptake is detectable [19]. Measuring a range of physiological parameters within a tumor and as- sessing vascular heterogeneity produces a profile of tumor vascularity. When combined with measure- ments of FDG uptake, for example, during PET/CT, a vascular/metabolic profile can be obtained. Such tumor profiles have the potential to classify tumors in a new way. For example, early studies have shown that low contrast enhancement with high FDG up- take is found more commonly amongst high-stage lung cancers and may represent an aggressive tu- mor type [20].
Conclusions
By exploiting the ability of CT systems to quantify contrast enhancement, functional CT extends the utility of contrast media to include assessment of cardiovascular physiology. Just as Harvey’s discov- ery of the circulation in the seventeenth century significantly advanced medical understanding, so too can functional CT assessments of vascular physiology in ischemic tissue and tumors improve the diagnosis and assessment of patients with stroke or cancer. The variability of clinical course amongst stroke patients with similar clinical pres- entation, and amongst cancer patients with the same tumor stage, has led to a concept of person- alised cancer care in which the patient’s treatment is tailored to individual characteristics of their dis- ease. Functional CT can potentially contribute to the delivery of personalised medicine for stroke pa- tients by identifying reversible ischemia amenable to thrombolytic therapy, and for cancer patients by generating vascular profiles that predict tumor ag- gression, metastatic potential, likely response to ra- diotherapy, and delivery of chemotherapeutic agents.
References
1. Miles KA, Griffiths MR (2003) Perfusion CT: a worthwhile enhancement? Br J Radiol 76:220-231 2. Wintermark M, Maeder P, Verdun FR et al (2000)
Using 80 kVp versus 120 kVp in perfusion CT meas- urement of regional cerebral blood flow. Am J Neu- roradiol 21:1881-1884
3. Miles KA, Griffiths MR, Fuentes MA (2001) Stan- dardized perfusion value: universal CT contrast en- hancement scale that correlates with FDG PET in lung nodules. Radiology 220:548-553
4. Miles KA (2003) Perfusion CT for the assessment of tumour vascularity: which protocol? Br J Radiol 76:S36-42
5. Keith C, Griffiths M, Petersen B et al (2002) Com- puted tomography perfusion imaging in acute stroke. Australas Radiol 46:221-230
6. Wintermark M, Reichhart M, Thiran JP et al (2002) Prognostic accuracy of cerebral blood flow meas- urement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol 51:417-432
7. Mayer TE, Hamann GF, Baranczyk J et al (2000) Dy- namic CT perfusion imaging of acute stroke. Am J Neuroradiol 21:1441-1449
8. Klotz E, König M (1999) Perfusion measurements of the brain: using dynamic CT for the quantitative as- sessment of cerebral ischemia in acute stroke. Eur J Radiol 30:170-184
9. Wintermark M, Reichhart M, Cuisenaire O et al (2002) Comparison of admission perfusion comput- ed tomography and qualitative diffusion- and perfu- sion-weighted magnetic resonance imaging in acute stroke patients. Stroke 33:2025-2031
10. Eastwood JD, Lev MH, Wintermark M et al (2003) Correlation of early dynamic CT perfusion imaging with whole-brain MR diffusion and perfusion imag- ing in acute hemispheric stroke. Am J Neuroradiol 24:1869-1875
11. Latchaw RE, Yonas H, Hunter GJ et al (2003) Coun- cil on Cardiovascular Radiology of the American Heart Association Guidelines and recommenda- tions for perfusion imaging in cerebral ischaemia: a scientific statement for healthcare professionals by the writing group on perfusion imaging, from the Council on Cardiovascular Radiology of the Ameri- can Heart Association. Stroke 34:1084-1104 12. Tateishi U, Nishihara H, Watanabe S et al (2001)
Tumor angiogenesis and dynamic CT in lung ade- nocarcinoma: radiologic-pathologic correlation. J Comput Assist Tomogr 25:23-27
13. Jinzaki M, Tanimoto A, Mukai M et al (2000) Dou- ble-phase helical CT of small renal parenchymal neoplasms: correlation with pathologic findings and tumor angiogenesis. J Comput Assist Tomogr 24:835-842
14. Swensen SJ, Viggiano RW, Midthun DE et al (2000) Lung nodule enhancement at CT: multicenter study.
Radiology 214:73-80
15. Pastorino U, Bellomi M, Landoni C et al (2003) Ear- ly lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year re- sults. Lancet 362:593-597
16. Platt JF, Francis IR, Ellis JH et al (1997) Liver metas- tases: early detection based on abnormal contrast material enhancement at dual-phase helical CT. Ra- diology 205:49-53
17. Dugdale PE, Miles KA (1999) Hepatic metastases:
the value of quantitative assessment of contrast en- hancement on computed tomography. Eur J Radiol 30:206-213
18. Miles KA, Colyvas K, Griffiths MR et al (2004) Colon cancer: risk stratification using perfusion CT. Eur Radiol 14 [Supp 2]:129
19. Willett CG, Boucher Y, Tomaso E di et al (2004) Di- rect evidence that the VEGF-specific antibody beva- cizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147
20. Miles KA, Griffiths MR, Keith CJ (2004) Preliminary investigations into lung tumour flow: metabolism relationships using perfusion CT and FDG-PET. Nu- cl Med Commun 25:407
IV.2_Miles 30-06-2005 11:08 Pagina 112
