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DOI: 10.1148/radiol.2372041634
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(Radiology 2005;237:529-534.)
© RSNA, 2005

Gastrointestinal Imaging

Neoangiogenesis and Sinusoidal Capillarization in Hepatocellular Carcinoma: Correlation between Dynamic CT and Density of Tumor Microvessels1

Chan Kyo Kim, MD, Jae Hoon Lim, MD, Cheol Keun Park, MD, Dongil Choi, MD, Hyo Keun Lim, MD and Won Jae Lee, MD

1 From the Departments of Radiology (C.K.K., J.H.L., D.C., H.K.L., W.J.L.) and Pathology (C.K.P.), Samsung Medical Center, Sungkyunkwan University College of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul, Korea 135-710. Received September 23, 2004; revision requested November 26; revision received December 20; accepted January 21, 2005. Address correspondence to C.K.P. (e-mail: ckpark{at}smc.samsung.co.kr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To retrospectively evaluate the correlation between the degree of contrast enhancement on dynamic computed tomographic (CT) scans and the degree of neoangiogenesis and sinusoidal capillarization in hepatocellular carcinoma (HCC).

MATERIALS AND METHODS: The institutional review board did not require approval or informed patient's consent for the review of medical records or images. Dynamic CT scans of 97 nodular HCCs in 97 patients (79 men, 18 women; age range, 29–73 years; mean age, 54 years) were evaluated in terms of the attenuation change in the arterial, portal venous, and delayed phases, and the results were correlated with the number of unpaired arteries and the degree of sinusoidal capillarization at histopathologic examination. The mean attenuation value of the nodular HCCs on triple-phase helical CT scans was correlated with the number of unpaired arteries and the degree of sinusoidal capillarization. Statistical analysis was performed with the Spearman rank correlation test.

RESULTS: The number of unpaired arteries in the nodular HCCs was found to correlate with the degree of contrast enhancement in the arterial phase (r = 0.225, P = .027), but did not correlate with the degree of contrast enhancement in the portal and delayed phases. The degree of sinusoidal capillarization did not correlate linearly with the mean attenuation of the nodular HCCs in any phase of contrast enhancement.

CONCLUSION: The degree of contrast enhancement of the nodular HCCs in the arterial phase tended to correlate with the number of unpaired arteries, but no correlation was evident between the degree of contrast enhancement and sinusoidal capillarization in any phase of CT imaging.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The enhancement pattern of hepatocellular carcinoma (HCC) on dynamic computed tomographic (CT) scans is well documented and has been observed by many researchers. Generally, nodular HCCs manifest as hyperattenuated lesions against a background of minimally enhanced liver parenchyma in the arterial phase, because the tumor is supplied by the hepatic artery and is hypervascular. On delayed phase images, these nodular HCCs become low attenuating compared with the surrounding liver parenchyma, generally owing to early washout (1–3).

In terms of hepatocarcinogenesis, the number of unpaired arteries and the degree of sinusoidal capillarization are substantially greater in HCCs than in cirrhotic nodules or low-or high-grade dysplastic nodules (4–6). CT enhancement may reflect the status of intratumoral angiogenesis, since the degree of contrast enhancement is predicated on the basis of both the number of blood vessels and the permeability of the microvasculature within the tumors (7–10). We hypothesized that the degree of contrast enhancement depends on both the number of unpaired arteries in the arterial phase and the degree of sinusoidal capillarization in the delayed phase. The aim of this study, therefore, was to retrospectively evaluate the correlation between the degree of contrast enhancement on dynamic CT scans and the degree of neoangiogenesis and sinusoidal capillarization in HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
Between March 2000 and June 2004, 454 patients underwent hepatic resection, and 504 HCC nodules were confirmed pathologically. Among these patients, 433 underwent dynamic CT at our hospital as a preoperative evaluation for hepatic resection. The remaining 21 patients who underwent dynamic CT at outside hospitals were excluded because we were not able to measure the mean attenuation value of their tumors. Of the 433 included patients, 253 who had HCCs larger than 3 cm in diameter were also excluded because large tumors may contain necrotic portions or large vessels, making it prohibitively difficult to correlate tumor nodules attenuation profiles at CT and at histopathologic examination. We also excluded 43 patients with two or more nodules, five patients with apparent fatty liver, 25 patients who had undergone transarterial chemoembolization, and 10 patients who had undergone radiofrequency ablation. Therefore, the final study group consisted of 97 patients (79 men, age range of 31–74 years, mean age of 51 years ± 10.3; 18 women, age range of 29–67 years, mean age of 51 years ± 12.1), each exhibiting single nodules. There were no significant differences in age distribution between the male and female patients (P > .05). The institutional review board of our hospital required neither its approval nor patient informed consent for the review of medical records or imaging. Of 97 patients, 90 patients had chronic hepatitis B, five patients had chronic hepatitis C, and the remaining two patients had alcoholic liver disease. All patients underwent tumor resection 1–52 days (mean, 18 days) after triple-phase helical CT.

Triple-Phase Helical CT Imaging
All 97 patients with HCC underwent triple-phase helical CT. Seventy-two patients underwent multi–detector row CT, 43 with a four–detector row scanner (LightSpeed QX/i; GE Medical Systems, Milwaukee, Wis), 16 with an eight–detector row scanner (Lightspeed Ultra; GE Medical Systems), and 13 with a 16–detector row scanner (Lightspeed 16; GE Medical Systems). The scanning parameters were 5-mm section thickness, 15.0 mm/sec table speed (pitch of 0.75) for the four–detector row scanner, 17.5 mm/sec (pitch of 0.875) table speed for the eight–detector row scanner, and 18.75 mm/sec table speed (pitch of 0.938) for the 16–detector row scanner during a single breath-hold helical acquisition of 7.7–10.5 seconds (depending on liver size). Images were obtained in the craniocaudal direction and were reconstructed every 5 mm to provide contiguous sections. With a bolus-triggered technique, the arterial phase of scanning commenced 20–35 seconds after the beginning of an intravenous injection of 120 mL of nonionic iodinated contrast material (iopamidol [Iopamiro 300], Bracco, Milano, Italy; or iopromide [Ultravist 300], Schering, Berlin, Germany) via the antecubital vein at a rate of 3–4 mL/sec. The portal venous phase of scanning commenced 70 seconds after the beginning of contrast material injection. The delayed phase of scanning commenced 180 seconds after the beginning of contrast material injection.

The remaining 25 patients underwent helical CT (HiSpeed Advantage; GE Medical Systems). The scans were obtained through the liver in a craniocaudal direction with 7-mm collimation and 7-mm/sec table speed (pitch, 1.0) during a single breath-hold helical acquisition of 25–30 seconds, depending on the size of the liver, and a 7-mm reconstruction interval. For triple-phase helical CT, the arterial, portal venous, and delayed phases commenced 30, 60, and 180 seconds, respectively, after the beginning of the injection of 120 mL of nonionic iodinated contrast material (iopamidol or iopromide) via the antecubital vein at a rate of 3 mL/sec by using a power injector.

Image Analysis
The mean attenuation value of tumors and the adjacent normal liver parenchyma on images obtained in the hepatic arterial, portal venous, and delayed phases was measured by one radiologist (C.K.K.) with 3.5 years of experience in liver CT. The lesions were objectively assessed by using a circular region of interest (ROI). The mean attenuation value within the tumor was measured in Hounsfield units. The ROI cursor was located in the homogeneous area for the heterogeneously enhancing lesions. The size range of tumor ROIs was 10–45 mm2 (mean, 31 mm2± 4). The ROIs were drawn three times in each location, and the mean values were then recorded. The mean attenuation value of the normal liver parenchyma adjacent to the tumors was also measured at the same segment as the tumor, about 1 cm apart from the tumor, avoiding vessels and artifacts. The ROIs were drawn electronically and ranged from 20 to 50 mm2 (mean, 38 mm2± 5). The mean attenuation values were read on a 2000 x 2000 picture archiving and communication systems monitor (GE Medical Systems Integrated Imaging Solutions, Mt Prospect, Ill). At each reading, the window settings were largely fixed on the abdominal soft-tissue window (window width, 310 HU; window level, 60 HU) or the liver window (window width, 230 HU; window level, 85 HU), and the optimal window setting in each case could be adjusted as needed. The ROI cursors were located in the same site for each triple-phase helical CT scan (Fig 1).



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  		Figure 1a. Transverse CT images of the liver obtained at the same level in (a) arterial, (b) portal venous, and (c) delayed phases in a 65-year-old man with HCC in liver segment 8. ROI measurements were obtained from the tumor and the adjacent hepatic parenchyma at identical anatomic locations.

 


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  		Figure 1b. Transverse CT images of the liver obtained at the same level in (a) arterial, (b) portal venous, and (c) delayed phases in a 65-year-old man with HCC in liver segment 8. ROI measurements were obtained from the tumor and the adjacent hepatic parenchyma at identical anatomic locations.

 


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  		Figure 1c. Transverse CT images of the liver obtained at the same level in (a) arterial, (b) portal venous, and (c) delayed phases in a 65-year-old man with HCC in liver segment 8. ROI measurements were obtained from the tumor and the adjacent hepatic parenchyma at identical anatomic locations.

 
Histopathologic Analysis
Formalin-fixed paraffin-embedded tissues, including both the HCC and adjacent nontumorous liver, were sectioned at a thickness of 4 µm. Hematoxylin-eosin staining was performed to verify the morphologic diagnosis of HCC. Immunohistochemical studies were performed by using the streptavidin-biotin complex method, with an automated staining system (TechMate 1000; DakoChemmate, Glostrup, Denmark). Deparaffinized sections were treated with 3% hydrogen peroxide in methanol for 10 minutes to inhibit the activity of endogenous peroxidase. The sections were then incubated with primary antibodies for 30 minutes at room temperature. The primary antibodies used were mouse monoclonal antibody against {alpha}–smooth muscle actin (DakoChemmate) at 1:1000 dilution and mouse monoclonal antibody against CD34 (DakoChemmate) at 1:100 dilution. Each section was treated sequentially with biotinylated secondary antibody and streptavidin-peroxidase complex (DakoChemmate). 3,3'-diaminobenzidine tetrahydrochloride was used as a chromogen, and Mayer's hematoxylin counterstain was applied. Negative controls (omission of primary antibody) were run simultaneously.

A liver pathologist (C.K.P.) with 18 years of experience evaluated the number of unpaired arteries and the extent of sinusoidal capillarization of nodular HCCs. Arteries in neoangiogenesis were defined as thick-walled vessels that stained positively for anti-{alpha}–smooth muscle actin in their thick tunica media and exhibited a medial layer thickness to external diameter ratio of more than 1:10, excluding venous structures, which were located in the tumor parenchyma and were not accompanied by fibrous tissue or bile ducts, the so-called "unpaired arteries" (11). The number of unpaired arteries was counted in five fields of view at higher (x200) magnification within the mostly neovascularized area ("hot spot"), and the numbers of arteries were grouped arbitrarily as follows: group 1, 20 or fewer; group 2, 21–40; group 3, 41–60; group 4, 61–80; and group 5, 81 or more.

CD34 expression of sinusoidal endothelial cells was evaluated and grouped arbitrarily as follows: group 1, staining of endothelial cells occupying 20% or less of the sinusoidal liver surface; group 2, staining of endothelial cells occupying 21%–40% of the sinusoidal liver surface; group 3, staining of endothelial cells occupying 41%–60% of the sinusoidal liver surface; group 4, staining of endothelial cells occupying 61%–80% of the sinusoidal liver surface; and group 5, staining of endothelial cells occupying 81% or more of the sinusoidal liver surface.

Each group was correlated with the mean attenuation values of tumors in the arterial, portal venous, and delayed phases for the number of unpaired arteries and the degree of sinusoidal capillarization.

Statistical Analysis
All statistical calculations were performed by using software (SPSS for windows, release 12.0.0; SPSS, Chicago, Ill). Correlation between the parameters (ie, the degree of contrast enhancement, the number of unpaired arteries, and the degree of sinusoidal capillarization) was evaluated with the Spearman rank correlation test. P < .05 was considered to indicate a significant difference. To evaluate the polynomial relationship between the degree of sinusoidal capillarization and the mean attenuation values of HCCs, we calculated the polynomial regression by using software (8.2 Proc Reg; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The mean attenuation values of the tumor and the adjacent normal liver parenchyma at triple-phase helical CT in comparison to the groups classified according to the number of unpaired arteries are shown in Table 1. As the number of unpaired arteries in the HCCs increased from group 1 to group 5, the mean attenuation values in the arterial phase tended to increase (Fig 2). This tendency was found to be significant (P = .027). There appeared to be no correlation between the groups of unpaired arteries and the mean attenuation values of tumors in the portal venous and delayed phases.


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  		TABLE 1. Correlation between Number of Unpaired Arteries and Degree of Contrast Enhancement at Triple-Phase Helical CT in HCCs

 


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  		Figure 2. Scatterplot shows relationship between mean attenuation value and number of unpaired arteries in HCCs during the arterial phase. The mean attenuation value increases as number of unpaired arteries increases (r = 0.225, P = .027).

 
The mean attenuation values of the tumor and the adjacent normal liver parenchyma on triple-phase helical CT scans in comparison to the groups classified according to the degree of sinusoidal capillarization are shown in Table 2. There appeared to be no linear correlation between the degree of sinusoidal capillarization and the mean attenuation value of a tumor in any phase of triple-phase imaging (Fig 3). The correlation coefficient of the second-order polynomial regression equation was –0.00771, and the P value was .019, which is significant.


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  		TABLE 2. Correlation between the Degree of Sinusoidal Capillarization and Contrast Enhancement at Triple-Phase Helical CT in HCCs

 


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  		Figure 3. Scatterplot shows relationship between mean attenuation value and degree of sinusoidal capillarization in HCCs during the delayed phase. Although there is no significant linear correlation (r = 0.17, P = .097), there is somewhat of a second-order polynomial correlation.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Neoangiogenesis refers to the formation of new blood vessels within tumors, which is crucial to tumor growth and metastasis (12). In the hepatic nodules, the development of unpaired arteries is closely related to the development of malignancy in a nodule (4,13,14). The number of unpaired arteries is substantially different for cirrhotic or dysplastic nodules, with a gradual increase from cirrhotic nodules (lowest) to low- and high-grade dysplastic nodules and with the greatest numbers in HCC and particularly in HCCs smaller than 3 cm in diameter, which exhibit the highest number of unpaired arteries. Park et al (14) reported that 12 of 17 small HCCs manifested more than 50 unpaired arteries per 10 fields x100, while eight of 21 advanced HCCs greater than 3 cm in diameter possessed fewer than six unpaired arteries per 10 fields x100.

Currently, microvessel density and vascular endothelial growth factor have been used as indicators for tumor angiogenetic activity (15–18). However, these markers have only been studied immunohistochemically in vitro by using biopsy or surgical tissues. Modern imaging modalities including Doppler ultrasonography, magnetic resonance (MR) imaging, or CT can depict hemodynamic characteristics such as blood flow and can reflect the hemodynamic changes (19–23).

Knowledge of the angiogenetic process is important for understanding the way in which tumors are enhanced on CT scans and can also be helpful in the characterization of focal liver disease. The development of new vessels results in physiologic changes, specifically, increased blood flow, blood volume, and capillary permeability, which alter the contrast enhancement of tumors on CT scans (7–9,19,23,24). The magnitude of contrast enhancement tends to be determined by the intensity of neovascularization associated with that particular tumor. Changes in contrast enhancement will be greatest at the tumor periphery, where angiogenesis is typically most intense. Because the tumor grows, the central portions become relatively hypovascular and eventually necrotic (25,26).

To evaluate angiogenesis more precisely, the development of dedicated CT techniques is necessary for the assessment of perfusion, blood volume, and permeability (27,28). Dynamic CT is helpful in evaluating neovascularity of HCCs. Chen et al (23) reported that the enhancement features associated with HCCs at dynamic spiral CT can be correlated with tumor microvessel density and reflect the intratumoral distribution characteristics of tumor microvessels. Our study findings showed that the mean attenuation value compared with the degree of the number of unpaired arteries in HCCs tended to correlate in the arterial phase. This correlation was clearly significant (P = .027).

Sinusoidal capillarization accompanies the evolution of cirrhosis and HCC. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries, coupled with collagenization of the extravascular spaces of Disse and deposition of basement membranes near the endothelial cells and hepatocytes (29). In cases of chronic liver disease, sinusoidal capillarization modifies both the transit time and the distribution volume for small and large molecules, as has been previously demonstrated in multiple indicator dilution studies (30,31). Sinusoidal capillarization may be an aspect of hepatocarcinogenesis in which the lesions convert to the predominantly arterial blood supply associated with HCC (32,33). However, it remains unknown as to how sinusoidal capillarization in HCC might affect CT enhancement patterns. We attempted to ascertain how the degree of sinusoidal capillarization in HCC might affect contrast enhancement on triple-phase helical CT scans. Our results indicate that there exists no real linear correlation between the degree of sinusoidal capillarization and contrast enhancement occurring in any phase of triple-phase imaging.

There was a limitation in this study. We did not evaluate other factors such as permeability, blood volume, and the extent of extracellular space, which may influence contrast enhancement of HCC. In particular, vascular endothelial growth factor, which is similar to vascular permeability factor, might play an important role in the development of HCC (14,34).

On the basis of our results, we believe that the number of unpaired arteries in HCC may have some influence primarily on the degree of contrast enhancement in the arterial phase, but the extent of sinusoidal capillarization exhibits no positive correlation. Other factors such as permeability and the extent of extracellular space probably play major roles in the contrast enhancement observed on the delayed phase images (7,10). Further studies regarding sinusoidal capillarization are required.

Functional imaging, such as functional CT or MR imaging, which can be used to measure perfusion, permeability, and blood volume, can provide us with valuable information regarding how angiogenesis affects contrast enhancement. Although it involves some relatively complex image analysis, functional imaging can also be used as a diagnostic tool, providing information that is impossible to obtain from the mere visual inspection of contrast material–enhanced images. In the future, molecular imaging will play a fundamental role in the evaluation of angiogenesis. By studying the physiologic counterparts of the microanatomical changes associated with tumor angiogenesis, quantitative contrast enhancement analysis can provide useful diagnostic and prognostic information regarding patients with HCCs.


   ACKNOWLEDGMENTS
 
The authors thank Masamichi Kojiro, MD, Department of Pathology, Kurume University School of Medicine, Kurume, Japan for the invaluable help in the discussion regarding neoangiogenesis and sinusoidal capillarization of hepatocellular carcinoma, and Seonwoo Kim, PhD, in Samsung Biomedical Research Institute, Samsung Medical Center, Korea for her help in statistical consultation.


   FOOTNOTES
 

Abbreviations: HCC = hepatocellular carcinoma • ROI = region of interest

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, C.K.K., J.H.L., C.K.P.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, C.K.K., J.H.L., H.K.L.; clinical studies, C.K.P., D.C., W.J.L.; statistical analysis, C.K.K., D.C.; and manuscript editing, C.K.K., J.H.L., C.K.P.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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