CHEST

Lung cancer perfusion: can we measure pulmonaryand bronchial circulation simultaneously?

Xiaodong Yuan & Jing Zhang & Guokun Ao &

Changbin Quan & Yuan Tian & Hong Li

Received: 16 October 2011 /Revised: 26 December 2011 /Accepted: 4 January 2012 /Published online: 14 March 2012# European Society of Radiology 2012

AbstractObjective To describe a new CT perfusion technique forassessing the dual blood supply in lung cancer and presentthe initial results.Methods This study was approved by the institutional re-view board. A CT protocol was developed, and a dual-inputCT perfusion (DI-CTP) analysis model was applied andevaluated regarding the blood flow fractions in lungtumours. The pulmonary trunk and the descending aortawere selected as the input arteries for the pulmonary circu-lation and the bronchial circulation respectively. Pulmonaryflow (PF), bronchial flow (BF), and a perfusion index (PI, 0PF/ (PF + BF)) were calculated using the maximum slopemethod. After written informed consent was obtained, 13consecutive subjects with primary lung cancer underwentDI-CTP.Results Perfusion results are as follows: PF, 13.45±10.97 ml/min/100 ml; BF, 48.67±28.87 ml/min/100 ml;PI, 21 %±11 %. BF is significantly larger than PF, P<0.001. There is a negative correlation between the tumourvolume and perfusion index (r00.671, P00.012).Conclusion The dual-input CT perfusion analysis methodcan be applied successfully to lung tumours. Initial resultsdemonstrate a dual blood supply in primary lung cancer, inwhich the systemic circulation is dominant, and that the

proportion of the two circulation systems is moderatelydependent on tumour size.Key Points& A new CT perfusion technique can assess lung cancer's

dual blood supply.& A dual blood supply was confirmed with dominant bron-

chial circulation in lung cancer.& The proportion of the two circulations is moderately

dependent on tumour size.& This new technique may benefit the management of lung

cancer.

Keywords Lung cancer . Dual blood supply . Perfusion CT.

Area detector . Computed tomography

Abbreviations

DI-CTP Dual-input CT perfusionPA Pulmonary arteryBA Bronchial arteryTDCs Time density curvesPF Pulmonary flowBF Bronchial flowPI 0 PF/(PF + BF) Perfusion index

Introduction

Recently perfusion CT has become a major imaging tech-nique for assessing tumour angiogenesis and the therapeuticeffect of anti-angiogenic drugs because of the accessibilityof the technology and its ability to provide quantification of

X. Yuan :G. Ao (*) : C. Quan :Y. Tian :H. LiDepartment of Radiology,The 309th Hospital of Chinese People’s Liberation Army,17 Heishanhu Road, Haidian District,Beijing 100091, People’s Republic of Chinae-mail: aoguokun309@163.com

J. ZhangDepartment of Radiology, Tongji Hospital of Tongji University,389 Xincun Road,Shanghai 200065, People’s Republic of China

Eur Radiol (2012) 22:1665–1671DOI 10.1007/s00330-012-2414-5

the haemodynamics of lesions with mass effect [1, 2]. Pre-viously lung cancer CT perfusion analysis was performedusing the single input perfusion model with the input arteryas either the PA or the aorta (as a substitute for BA). There issome debate as to the origin and/or the proportion of bloodsupply in lung cancer [3–7]. If one considers the BA as theonly or dominant blood supply in lung cancer, the aorta willbe chosen as the input artery and vice versa.

In the early 1970s it was discovered through necropsythat lung tumours have a dual vascular supply [8]; howeverin vivo quantification of the dual blood supply in lungcancer with CT perfusion has not been possible due in largepart to the limitations of the technology. The respectiveproportion of the dual blood supply in lung tumours hasnot been previously described with CT perfusion, to ourknowledge. The quantification of the dual blood supply tolung tumours and the relative proportions of each can po-tentially aid in the management of lung cancer.

We developed a new CT perfusion technique for measur-ing the dual blood supply in lung tumours and performedthis technique prospectively in 13 consecutive subjects withbronchogenic carcinoma.

Materials and methods

Dual-input CT perfusion imaging technique

Before the examination, all patients underwent breath train-ing to ensure that they could hold their breath for the entireperfusion process (approximately 30 s). Shallow abdominalbreathing was permitted at the end stage of acquisition incases where the patient was unable to hold their breath forthe entire period of CT data acquisition. Two 20-gaugeintravenous catheters were placed, one in each antecubitalvein.

Before the perfusion CT acquisition, an unenhanced he-lical CT of the entire thorax was performed to determine thelocation of the lesion with mass effect. Dynamic CT perfu-sion was performed using a 320-detector row CT (AquilionONE, Toshiba Medical Systems, Otawara, Japan) with a z-axis coverage of 16 cm. With a dual-head power injector,60 ml of non-ionic contrast medium with an iodine concen-tration of 370 mgI/ml (Iopromide, Bayer Schering, Berlin,Germany) was injected at a flow rate of 8 ml/s (4 ml/s oneach side). Two seconds after the bolus injection, 15 inter-mittent low-dose volume acquisitions were made with 2-sintervals and without table movement (Fig. 1).

The dynamic CT protocol was performed with the fol-lowing parameters: 80-kV tube voltage, 80-mA tube cur-rent, 0.5-s gantry rotation speed and 0.5-mm slice thickness.The 16-cm coverage included both the lung hilum and thelesion with mass effect.

The first two volumes were acquired before contrastmedium arrived in the heart and served as a baseline. Theduration of the breath hold was approximately 30 s. Imagedata sets were reconstructed with 0.5-mm slice thicknessand 0.5-mm spacing, resulting in 320 images per volumeand a total of 4,800 images for the entire perfusion data set.

Data Post-processing and analysis

Post-processing was performed using perfusion softwareavailable on the CT equipment (Body Perfusion, ToshibaMedical Systems, Otawara, Japan). The first step is volumeregistration. The registration is performed to correct formotion between the dynamic volumes and creates a regis-tered volume series. The registered volumes were then load-ed into the body perfusion analysis software.

Rectangular ROIs (mean area 1.0 cm2) were manuallyplaced in the pulmonary artery trunk and the aorta at thelevel of the hilum to generate the TDCs representing the PAinput function and the BA input function respectively. Anelliptical ROI was placed in the left atrium, and the peaktime of the left atrium TDC was used to differentiate pul-monary circulation (before the peak time point) and bron-chial circulation (after the peak time point; Fig. 2). Afreehand ROI was drawn to encompass the lesion with masseffect to generate the TDC of the contrast medium's first-pass attenuation in the tissue of the tumour. The perfusionanalysis range was set from 0 HU to 150 HU to restrict theperfusion analysis to soft tissue regions only and to ignorelung parenchyma and bone. Finally, 512×512 matrixcolour-coded maps of PF, BF, and PI ( PI 0 PF/ (PF +BF)) were produced automatically. For each lesion, meas-urements were repeated on all relevant 5.0-mm axial slicesand then averaged to calculate the final value. Tumourvolume (size) was measured on commercial software (organselection, Vitrea version 6.0, Vital Images, Minnetonka,MN, USA).

Study population

Thirteen consecutive patients were included in the study (9men and 4 women; mean age, 52 years; range, 41–65 years),

Fig. 1 The time sequence display of the perfusion CT with the Aqui-lion ONE system. Two seconds after the start of the bolus injection, 15volume images were acquired with a 2-s interval. The breath-holdduration was approximately 30 s

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all with a solitary pulmonary nodule/mass pathologicallyconfirmed as bronchogenic carcinoma (6 squamous cellcarcinoma, 2 adeno-squamous carcinoma, 3 adenocarcinoma,2 small cell lung carcinoma) through CT-guided puncturebiopsy or bronchoscopy biopsy or surgical resection withinthe 2 weeks before/after the perfusion CT. They were alluntreated before the perfusion CT and enrolled prospectivelyinto the study. The study had institutional review board ap-proval, and written informed consent was obtained from allpatients, which included information about the radiation ex-posure of the CT examinations. Exclusion criteria were preg-nancy, previous reactions to iodinated contrast media anddyspnoea.

The radiation dose of both the dynamic and helical CTwas calculated from the dose–length product (DLP) listed inthe exposure summary sheet generated by the CT equipmentand multiplied by a factor of 0.014 [9].

Statistical analysis

Statistical analysis was performed using commerciallyavailable software (SPSS, V13.0). Paired Student's t-testwas used to compare PF with BF. Tumour size correlatedwith the perfusion index. A P value lower than 0.05 wasconsidered to indicate a significant difference.

Results

Five patients adopted shallow abdominal breathing becauseof hypoxia at the end stage of the perfusion CT. All patientsshowed good compliance with the CT perfusion proceduredespite the relatively high injection rate of contrast agent

and the slightly long breath-hold duration of 30 s. No severeadverse events occurred.

Perfusion parameters were visualised by colour maps andfused onto the original axial CT images. Representativeperfusion colour maps are shown in Figs. 3 and 4. Quanti-tative perfusion parameters of the 13 primary lung cancersderived from DI-CTP are listed in Table 1. Mean tumourvolume was 32.98 cm3, ranging from 5.64 to 69.91 cm3.The dynamic perfusion protocol was identical for all 13cases with the CT dose DLP0324.8 mGy. cm or 4.55 mSv(k00.014).

Discussion

The lungs have a dual vascular blood supply, the pulmonarycirculation and the bronchial circulation. The pulmonarycirculation is dominant in the total blood supply volume.Although the bronchial circulation only accounts for a smallamount of the total blood volume supply in normal lungtissue, it is crucial for maintaining airway and lung function[10]. The bronchial circulation is more transitional underpathological conditions and plays an important role in manylung diseases, especially in lung cancer where there is somedebate regarding its role and importance in terms of thetumour blood supply and therefore tumour growth and bi-ology. Measurement of the two circulations is meaningfulboth physiologically and pathologically.

The new perfusion technique described here is potentiallyvaluable for both differential diagnosis and treatmentplanning:

1. PI as a new parameter derived from DI-CTP has thepotential to differentiate lung cancer from some benign

Fig. 2 Time-density curves(TDCs) of pulmonary artery(PA), bronchial artery (BA), leftatrium and lung tumour. Thevertical dashed line indicatesthe peak enhancement timepoint of the left atrium, which islocated between the two peaksof the PA and the BA; therefore,it is used to distinguish betweenpulmonary and bronchialcirculation. The TDC of thelung tumour had two ascendingslopes representing pulmonaryand bronchial circulationrespectively. The latter wasmuch steeper than the former,which suggests that bronchialcirculation was dominant in thiscase

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lesions such as atelectasis, which has a larger PI phys-iologically (Fig. 3);

2. Of the 13 subjects in the current study the BA is thedominant blood supply with more or less from the PA

Fig. 3 Example 1: Colouredparametric maps in a 45-year-old male patient with a rightinferior lung nodule pathologi-cally confirmed as adenocarci-noma (arrow). Adjacentatelectasis was revealed byabundant pulmonary flow (PF)and a relatively high perfusionindex (PI; arrow head). Thetumour is undersized in ourcohort and demonstrates nearequilibrium between pulmonaryand bronchial circulation at thislevel

Fig. 4 Example 2: Colouredparametric maps in the coronalplane in a 53-year-old male pa-tient with squamous cell carci-noma located in the left inferiorlung. The perfusion is hetero-geneous throughout the tumour.Bronchial circulation is globallydominant even though the pe-ripheral region of the tumour ismainly fed by the PA(arrowhead)

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(Table 1, Fig. 5), which implies that if interventionaltherapy is to be performed on these patients, then trans-pulmonary artery treatment could be considered as wellas trans-bronchial artery treatment, especially for thosewith abundant PF (Fig. 3). Therefore this technique maybenefit the treatment planning of lung cancer. Althoughthe systemic circulation is dominant (accounting formore than half of the total tumour blood supply volume)in every subject in our cohort, PI, which indicates theproportion of the two circulations, varies from subject tosubject. This is partially dependent on tumour volume(Fig. 6); for a few tumours that are of small volume, thePI is close to 50%, suggesting near equilibrium betweenpulmonary and systemic circulation. Tumours that arelarger in size demonstrate a larger proportion of system-ic circulation. From a different perspective, the correla-tion between PI and tumour volume may be hinting thatas bronchogenic carcinoma develops, the systemic cir-culation increases and eventually becomes the dominant

blood supply to the tumour. This gives DI-CTP thepotential to determine disease progression.

In addition to the BA, systemic circulation in the lung canalso originate from intercostal arteries, subclavian arteries,the internal thoracic artery, inferior phrenic artery, etc. Asthey all arise from the aorta, the TDC of the aorta is used asthe input function for systemic circulation when performingDI-CTP analysis in lung tumours. The feeding artery of thesystemic circulation is described as the bronchial artery inthis analysis and its measurements were recorded as BFregardless of the actual origin of the systemic blood supply.

The concept of using two feeding vessels as input func-tions for the maximum slope analysis method to calculatethe dual blood supply in one organ was originally describedby Miles et al. to calculate hepatic perfusion [11]. Theabdominal aorta and the portal vein are selected as thedual-input vessels; the peak time point of the spleen en-hancement is used to differentiate hepatic artery circulationand portal vein circulation. Based on the maximum slopemethod, blood flow by the two vessels can be calculated asthe maximum slopes of the tissue enhancement divided bythe peak values of the two input vessels' enhancement [12].Similarly in our study, PA and BA were selected as the twoinput vessels, the peak enhancement time point of the leftatrium was used to separate the PA and BA circulation.Figure 2 demonstrates this time point located between thetwo peaks of the PA and BA TDCs, so it is an appropriateboundary for differentiating between these two circulations.When the left atrium is not included in the 16-cm coverage,the boundary can be set manually between the two peaks,theoretically with the same results.

Table 1 Perfusion results

Perfusion n Mean SD 95% CI Paired t-test

parameters Lower Upper

PF 13 13.45 10.97 6.83 20.08 t04.997(ml/min/100 mL)

BF 13 48.67 28.87 31.22 66.11 P<0.001(ml/min/100 ml)

PI 13 0.21 0.11 0.14 0.27(100%)

Footnote: pulmonary flow (PF), bronchial flow (BF), perfusion index(PI)

Fig. 5 Box plot of systemic and pulmonary circulation. Systemiccirculation is more dominant than the pulmonary circulation in bron-chogenic carcinoma. Systemic circulation also varies within a widerrange than pulmonary circulation

Fig. 6 Scatter plot of perfusion index and tumour volume. Negativecorrelation between tumour size and perfusion index is revealed:Pearson's correlation coefficient is 0.671 (moderate correlation), whichis significant at the 0.05 level (P00.012)

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Considering the left atrium lies functionally between thepulmonary circulation and the bronchial circulation, its peakenhancement time was chosen to divide the tissue TDC intoa ‘pulmonary part’ and a ‘bronchial part’. This was used inall 13 cases. The software then determined the maximumslope of the ‘pulmonary part’ and the ‘bronchial part’ sep-arately and then calculated the respective blood flow. This isthe key point. In regard to Fig. 2, the tissue TDC showed aclear turning point coinciding with the left atrium peak timethus supporting our choice to use the left atrium peak time.Some cases in our study cohort demonstrated a plateau be-tween slope 2 and slope 1, so there was no obvious turningpoint between them. In these cases the peak of the enhance-ment of the left atrium occurred within the plateau, making it agood point for dividing the two circulations.

When a single input CT perfusion technique was employedin lung cancer perfusion analysis, according to the theory ofthe maximum slope method, the dominant circulation will becalculated and the secondary circulation is ignored. Whenconsidering Fig. 2, for example, slope 2 will be consideredas the circulation of the tumour, while slope 1 will be ignored.That is to say results concerning lung cancer perfusion to datehave effectively only measured that from the bronchial circu-lation. In this sense other studies may have systematicallyunderestimated lung cancer perfusion owing to ignoring thedual blood supply.

The DI-CTP adopted in the present study is based on themaximum slope method, which only takes into account theinitial upslope of the tissue TDC, and the input vessel's peakenhancement value. Therefore the duration of the acquisi-tion can be shorter than when the deconvolution method isused for analysis, which utilises both the ascending and thedescending portions of the TDC. A shorter acquisition timewill result in a lower radiation dose. However, the maximumslope analysis method has the following limitations:

1. The blood volume (BV) and the mean transit time(MTT) cannot be generated directly by the maximumslope method;

2. Contrast agent was injected through bilateral antecubitalveins to achieve a high flow rate, which is required bythe perfusion model hypothesis. Injection rates of be-tween 5 mLl/s and 10 ml/s are required by the maximumslope method owing to its theoretical assumption thatthe tissue maximum slope enhancement is reached be-fore venous drainage begins. For a fixed total contrastagent volume, a higher injection rate means shorterinjection duration, resulting in sharper shapes of theTDCs of the two input arteries, therefore leading to lessoverlap in the phase domain between these two circu-lations (Fig.2) [13]. A large overlap could somewhatundermine the reliability of measurements in DI-CTP,especially for the assessment of systemic circulation due

to residual perfusion from the pulmonary circulation.Besides, a high flow rate may also be of benefit bymaximising tissue enhancement and so improving thesignal-to-noise ratio [14].

Until now, the pulmonary and bronchial circulation inlung cancer tumours has not been assessed simultaneously,which is mainly due to the limited coverage along the z-axisof CT systems with less than 320 detector rows. With theAquilion ONE's 16-cm volume imaging, coverage along thez-axis easily covers more than half of an adult's lung. Thehilum and lesion can usually be included in a single volume.Therefore the PA, the aorta, the left atrium and the lesionstudied are included in one temporally uniform acquisition,which makes the DI-CTP analysis method possible in lungtumours.

An intrinsic limitation of perfusion CT is the radiationexposure, which increases with tube voltage, tube currentand the number of CT volume exposures. In order to keepthe overall radiation dose within the range of clinical utility,we reduced the kV and mA in the perfusion CT so that theoverall dose (including the localisation imaging) equalsapproximately the same dose as a triphasic abdominal im-aging procedure [15, 16]. Additionally, because of itsshorter acquisition time we utilised the maximum slopemethod rather than the deconvolution method to calculatethe perfusion, therefore keeping to the target dose of ourperfusion protocol. Post-processing of volumetric DI-CTPtakes about 5–10 min with volume registration. At present itmay not be suitable for emergency use. In addition, therelatively small sample size and potential heterogeneity oflesions in our study may reduce the clinical significance ofour primary findings. Population-based research is war-ranted to further determine the clinical utility of this method.

In conclusion, a dual-input perfusion analysis techniqueand imaging protocol for lung tumours has been described.It demonstrates two main features: firstly, that there is a dualblood supply pattern in primary lung cancer, of which thesystemic bronchial circulation is usually dominant; second-ly, that the proportion of the two circulations is moderatelydependent on tumour size.

References

1. Goh V, Halligan S, Daley F et al (2008) Colorectal tumor vascu-larity: quantitative assessment with multidetector CT—do tumorperfusion measurements reflect angiogenesis? Radiology 249:510–517

2. Fournier LS, Oudard S, Thiam R et al (2010) Metastatic renalcarcinoma: evaluation of antiangiogenic therapy with dynamiccontrast-enhanced CT. Radiology 256:511–518

3. Tacelli N, Remy-Jardin M, Copin MC et al (2010) Assessment ofnon-small cell lung cancer perfusion: pathologic-CT correlation in15 patients. Radiology 257:863–871

1670 Eur Radiol (2012) 22:1665–1671

4. Milne EN, Zerhouni AE (1987) Blood supply of pulmonary me-tastases. J Thoracic Imaging 2:15–23

5. Kiessling F, Boese J, Corvinus C et al (2004) Perfusion CT in patientswith advanced bronchial carcinomas: a novel chance for character-ization and treatment monitoring? Eur Radiol 14:1226–1233

6. Viamonte M Jr (1965) Angiographic evaluation of lung neo-plasms. Radiol Clin North Am 3:529–542

7. Hellekant C (1979) Bronchial angiography and intraarterial che-motherapy with mitomycin-C in bronchogenic carcinoma: anatomy,technique, complications. Acta Radiol Diagn (Stockh) 20:478–496

8. Milne EN (1967) Circulation of primary and metastatic pulmonaryneoplasms: a postmortem microarteriographic study. Am J Roent-genol Radium Ther Nucl Med 100:603–619

9. Valentin J (2007) Managing patient dose in multi-detector com-puted tomography (MDCT). Ann ICRP 37:1–79

10. McCullagh A, Rosenthal M, Wanner A et al (2010) The bronchialcirculation – worth a closer look: a review of the relationship

between the bronchial vasculature and airway inflammation.Pediatr Pulmonol 45:1–13

11. Miles KA, Hayball MP, Dixon AK (1993) Functional images ofhepatic perfusion obtained with dynamic CT. Radiology 188:405–411

12. Miles KA, Griffiths MR (2003) Perfusion CT: a worthwhile en-hancement? Br J Radiol 76:220–231

13. Bae KT (2003) Peak contrast enhancement in CT and MR angi-ography: when does it occur and why? Pharmacokinetic study in aporcine model. Radiology 227:809–816

14. Miles KA (2003) Perfusion CT for the assessment of tumourvascularity: which protocol? Br J Radiol 76:S36–S42

15. Galanski M, Nagel HD, Stamm G (2007) Results of a federationinquiry 2005/2006: pediatric CT X-ray practice in Germany. Rofo179:1110–1111

16. Tsai HY, Tung CJ, Yu CC, Tyan YS (2007) Survey of computedtomography scanners in Taiwan: dose descriptors, dose guidancelevels, and effective doses. Med Phys 34:1234–1243

Eur Radiol (2012) 22:1665–1671 1671