Evaluation of Blood Flow Signal in Small Hepatic Nodules by Color Doppler Ultrasonography

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1 Evaluation of Blood Flow Signal in Small Hepatic Nodules by Color Doppler Ultrasonography Junji Furuse, Masahiko Iwasaki, Masahiro Yoshino, Masaru Konishi, Noriaki Kawano, Taira Kinoshita and Munemasa Ryu Departments of 'Gastrointestinal Medicine and Surgery, National Cancer Center Hospital East, Kashiwa, Chiba Small hepatic nodular lesions are frequently detected by ultrasonography in patients with liver cirrhosis during follow-up. However, hepatocellular carcinomas (s) and non- nodules are difficult to differentiate by ultrasonography because they have a similar appearance. We used color Doppler ultrasonography (CDU) to examine 9 s and 6 non- nodules less than cm in diameter to determine whether CDU can be used to differentiate small hepatic nodules. There were no significant differences between the examined s and non- nodules with regard to ultrasonographic appearance, i.e., hypoechoicity or hyperechoicity. Blood flow signals were detected in a significantly higher percentage of s (3 of 9,.8%) than in non- nodules ( of 6, 7.7%; P< 0.005), although the sensitivity was low. Therefore, we classified nodules as hypoechoic or hyperechoic by B-mode ultrasonography and examined their blood flow signals. Among nodules that were hypoechoic, signals were detected in a significantly higher percentage of s ( of 8, 66.7%) than in non- nodules ( of 3, 5.%; P< 0.005). In contrast, among hyperechoic nodules, signals were detected in only of (9.%) s and in 0 of 3 non- nodules. Our results suggest that examination of blood flow by CDU is useful for differentiating small hepatic nodules, especially hypoechoic nodules. (Jpn J Clin Oncol 6: , 996) Key words: Color Doppler ultrasonography Small hepatic nodule Hepatocellular carcinoma Introduction Hepatocellular carcinoma () is a frequent complication of chronic liver disease, especially liver cirrhosis. " 3 ' Ultrasonography is often used during follow-up in patients with chronic liver disease so that can be diagnosed early. " ' With improvements in ultrasonography, small hepatic nodular lesions are being detected with increasing frequency. However, such small nodules are shown on pathologic examination to be not only s, but also large regenerative nodules and borderline lesions, such as adenomatous hyperplasia and atypical adenomatous hyperplasia. 5-6) Because both s and non- nodules can appear as either Received: February, 996 Accepted: April 7, 996 For reprints and all correspondence: Junji Furuse, Department of Gastrointestinal Medicine, National Cancer Center Hospital East, 5-, Kashiwanoha 6-chome, Kashiwa, Chiba 77 hyperechoic or hypoechoic lesions on ultrasonography, differentiating these two types of nodules is often difficult. 7 ' is generally hypervascular, and diagnosed when hypervascularity or tumor staining is revealed by dynamic computed tomography (CT) or angiography. 8>9) However, both types of examination, especially angiography, are invasive and may require hospitalization. Blood flow in abdominal vessels can now be studied using Doppler ultrasonography. 0 " ' Furthermore, recent improvements in color Doppler flow imaging have enabled blood flow to be examined in greater detail. Therefore, Doppler ultrasonography, especially color Doppler ultrasonography (CDU), is often used in an attempt to differentiate tumor lesions in the liver. 3 " 6 ' Although blood flow signals are detected by CDU in a high percentage of s, 6 " 8 ' they are difficult to detect in small s and it is unclear whether detection of blood flow signals with CDU is useful for the differential diagnosis of small hepatic nodules. Therefore, to determine whether 335 Downloaded from on 8 January 08

2 FURUSE ET AL. Variable Table I. Characteristics of Patients with Small Hepatic Nodules No. of patients No. of nodules Sex Male Female Age (yr) Viral markers HBs Ag( + ), HCV Ab( + ) HBs Ag(-), HCV Ab(+) HBs Ag(-), HCV Ab(-) Associated chronic liver disease Chronic hepatitis Liver cirrhosis Alpha-fetoprotein (ng/ml) ICG R5 (%) ALT QUA) Serum albumin (g/dl) Serum total bilirubin (mg/dl) Nodule size (cm) ± ±0 3 ±9 99± ±0.3.3±0.5.3±0.3 non ± ±9 8 ±3 ± ±0.. ±0.3. ±0. P P<0.05, hepatocellular carcinoma; HBsAg, hepatitis B surface antigen; HCV Ab, hepatitis C antibody; ALT, alanine aminotransferase. CDU is useful for this purpose, we used it to examine blood flow signals in hepatic nodules less than cm in diameter. Materials and Methods Forty-five patients with a total of 55 nodular lesions less than cm in diameter found during follow-up for chronic liver disease were studied between August 99 and September 995. Nodules were diagnosed pathologically by examination of specimens obtained by ultrasonically guided needle biopsy (39 patients, 9 lesions) or hepatic resection (6 patients, 6 lesions). Twenty-nine nodules in 3 patients were s, of which 0 were well differentiated, 7 moderately differentiated, and poorly differentiated. Twenty-six nodules in patients were not ; 9 were normal liver tissue, 3 adenomatous hyperplasia, 3 atypical adenomatous hyperplasia, and was a regenerative nodule. There were no significant differences between patients with and without with regard to sex, age, viral hepatitis markers, associated chronic liver disease, and serum levels of alpha-fetoprotein, ICG R5, alanine aminotransf erase, albumin, and total bilirubin (Table I). With regard to nodule size (mean maximal diameter as measured by B-mode ultrasonography), non- nodules were smaller than s. In this study, hepatic nodules were classified as hypoechoic or hyperechoic by B-mode ultrasonography, and the differences between s and non- nodules were studied retrospectively with reference to blood flow detection by CDU and the pattern of the signals. A CDU system (SSA 70A; Toshiba, Tokyo) with a 3.75-MHz probe and a 3.0- to.5-khz pulse repetition frequency was used. Color Doppler flow imaging and the fast Fourier transform (FFT) algorithm mode were used to search for blood flow signals in nodular lesions. The wave pattern of each lesion's blood flow signal obtained by color Doppler flow imaging was analyzed using the FFT mode. Patterns of signals obtained by CDU were classified as either spotty or linear, and wave forms obtained using the FFT mode were classified as either pulsatile or continuous (Figs. and ). Reappearance signals were sought and then confirmed using the FFT mode to distinguish blood flow signals from noise due to respiration, cardiac stroke, and other processes. Statistical analysis was performed using the x test for comparison of data between groups and Student's t test for comparison of differences in mean values. Differences with P values of less than 0.05 were considered significant. 336 Jpn J Clin Oncol 6(5) 996 Downloaded from on 8 January 08

3 COLOR DOPPLER IN HEPATIC NODULES (b) Fig.. Blood flow signal with linear color flow and continuous wave form by Doppler ultrasonography. a) Right intercostal ultrasonography showing a hypoechoic nodule (arrow),. cm in diameter, in the right hepatic lobe. b) A linear color flow signal (arrowhead) in the nodule detected by color Doppler ultrasonography. c) A continuous wave form obtained using the fast Fourier transform algorithm mode. (b) Fig.. Blood flow signal with spotty color flow and pulsatile wave form by Doppler ultrasonography. a) Right intercostal ultrasonography showing a hypoechoic nodule (arrow),. cm in diameter, in the right hepatic lobe. b) A spotty color flow signal (arrowhead) in the nodule detected by color Doppler ultrasonography. c) A pulsatile wave form obtained using the fast Fourier transform algorithm mode. 337 Downloaded from on 8 January 08

4 FURUSE ET AL. Table II. Ultrasonographic Appearance and Detection of Blood Flow Signals by Color Doppler Ultrasonography in Small Hepatic Nodules Variable No. of nodules Ultrasonographic appearance of nodules Hypoechoic Hyperechoic Blood flow detection by CDU Detected Not detected Blood flow detection by CDU in hypoechoic nodules Detected Not detected Blood flow detection by CDU in hyperechoic nodules Detected Not detected CDU. color Doppler ultrasonography non P P<0.005 P< Results Ultrasonographic Findings and Detection of Blood Flow Signals The differences in ultrasonographic appearance, i.e., hypoechoicity or hyperechoicity, and detection of blood flow signals by CDU between s and non- nodules are indicated in Table II. There were no differences between and non- nodules with regard to ultrasonographic appearance. On the other hand, blood flow signals were detected in a significantly higher percentage of nodules (3 of 9,.8%) than in non- nodules ( of 6, 7.7%, P<0.005). The diagnostic sensitivity, specificity, and accuracy for by detection of blood flow signals in small hepatic nodules were.8%, 9.3%, and 67.3%, respectively. The relationship between detection of blood flow signals and the characteristics of the nodules, i.e. size and echogenicity was then studied (Fig. 3). Blood flow signals were detected in a high percentage of hypoechoic nodules. The signals tended to be detected more frequently in larger nodules than in smaller ones; however, there was no significant correlation between the rate of detection of blood flow signals and nodule size. The detection rate of blood flow signals was low in hypoechoic non- and hyperechoic nodules. Therefore, hepatic nodules were classified as hypoechoic or hyperechoic, and examined for the presence of blood flow signals (Table II). Blood flow signals were detected in a significantly higher percentage of hypoechoic nodules ( of 8, 66.7%) than in hypoechoic non- nodules ( of y s f in isi HxpiKVl j(l nun- in l?l ink iu>auk> of notlule ft 5 i in _ / non- in?) Hypcivchuic IIOUUIL-^ Fig. 3. Detection of Doppler signal in hepatic nodules in relation to nodule size. Solid circles and clear circles indicate nodules with and without Doppler signals, respectively. The vertical bars represent the mean±s.d. 3, 5.%, P<0.005). The diagnostic sensitivity, specificity, and accuracy for using blood flow signal detection in hypoechoic hepatic nodules were 66.7%, 8.6%, and 7.%, respectively. On the other hand, among hyperechoic nodules, blood flow signals were detected in only of (9.%) nodules and 0 of 3 non- nodules. This difference was not significant. The diagnostic sensitivity, specificity, and accuracy for using blood flow signal detection in hyperechoic hepatic nodules were 9.%, 00%, and 58.3%, respectively. Analysis of Blood Flow Signals Among 3 s and non-s showing blood flow signals, the signals were analyzed for color signal pattern and wave form (Table III). In Jpn. Clin Oncol 6(5) 996 Downloaded from on 8 January 08

5 COLOR DOPPLER IN HEPATIC NODULES s, blood flow signals were spotty in 9 nodules and linear in, and wave forms were continuous in 9 and pulsatile in 5 (both types of wave form were detected in nodule). In contrast, non- nodules showed spotty patterns and continuous wave forms. Relationship between Detection of Blood Flow Signals and Pathologic Findings in Hypoechoic s There was no difference in the grade of histologic differentiation between hypoechoic s in which blood flow signals were detected and those in which they were not (Table IV). Table III. Analysis of Blood Flow Signals by Color Doppler Ultrasonography Variable No. of nodules Pattern of color signal Spotty Linear Wave form Continuous Pulsatile 3 *, both types of wave form were detected in one nodule. 9 9* 5* non- 0 0 Discussion s generally receive an abundant blood supply from the hepatic artery and can be detected by the presence of a tumor stain on dynamic CT or angiography. 8 ' 9) In addition, studies evaluating the diagnosis of by Doppler ultrasonographic detection of blood flow have shown that blood flow signals are observed frequently in these lesions. 6 " 8 ' However, many small hepatic nodules found during follow-up in patients with liver cirrhosis are early s and lesions similar to, such as adenomatous hyperplasia, atypical adenomatous hyperplasia, and regenerative nodules. Because early s do not have the characteristic appearance of more mature s, differentiating them from non- nodules by ultrasonography alone is difficult. Furthermore, the rate of detection of blood flow signals in these nodules by Doppler ultrasonography is not high. 7) With recent improvements in CDU, blood flow signals can be detected clearly, and thus early diagnosis of s by detection of tumor blood flow should be theoretically possible. In this study, we examined the ultrasonographic features and blood flow signals visualized by CDU of hepatic nodules less than cm in diameter in patients with chronic liver disease. The majority of such nodules are homogeneous and appear either hypoechoic or hyperechoic on ultrasonography. There was no difference between s and non- nodules with regard to ultrasonographic appearance. On the other hand, blood flow signals were detected by CDU in a significantly higher percentage of s than in non- nodules. However, the sensitivity was low; less than 50%. Therefore, the relationship between detection of blood flow signals and ultrasonographic appearance, i.e. hypoechoicity or hyperechoicity, was studied. Among hypoechoic nodules, blood flow signals were detected in significantly more s (66.7%) than in non- nodules (5.%). Therefore, tumor blood flow in hypoechoic hepatic nodules can be used to diagnose small s. In contrast, Table IV. Relationship between Detection of Blood Flow Signal and Pathologic Findings in Hypoechoic Hepatocellular Carcinoma Blood flow signal Positive Negative n 6 Histologic differentiation Well 7 Moderate Poor among hyperechoic nodules, blood flow signals were observed in only of s and in 0 of 3 non- nodules. Therefore, distinguishing s from non- hyperechoic nodules by CDU is difficult. Areas of fatty change and clear cell formation are reported to show a hyperechoic appearance. 9 ' Ultrasound is weakened by cells showing fatty change, and this pathologic characteristic is thought to be an important factor related to the low rate of detection of blood flow signals with CDU. Furthermore, although the present results suggest that hyperechoic nodules may be less vascular than hypoechoic nodules, the relationship between vascularity and echogenicity of s was not examined pathologically. Tumor vessels and pulsatile waves on CDU are reported to be characteristics of. 6> 7) In this study, linear color signals and pulsatile waves were found only in s, and seemed to be characteristic of small lesions. Therefore, the presence of either feature in a small hepatic nodule is suggestive of. Blood flow signals were detected more frequently by CDU in larger tumors. However, differentiating early s from apparently similar nonmalignant lesions might be difficult with CDU, 339 Downloaded from on 8 January 08

6 FURUSE ET AL. because signals were detected less often in small s. One possible factor related to the failure to detect blood flow signals is the performance of the ultrasonographic apparatus. Present problems include an inability to detect low-velocity blood flow, weakness of the Doppler wave in deep locations, and noise due to respiration, cardiac stroke, and other processes. Another factor may be the characteristics of the tumors themselves. Whether a lesion was hypoechoic or hyperechoic on ultrasonography was thought to be an important factor in s less than cm in diameter. Blood flow signals tended to be detected more frequently in larger nodules; however, signals were also detected in nodules cm in diameter and there was no significant correlation between tumor size and signal detection in small hepatic nodules. In addition, there was no correlation between detection of blood flow signals and the grade of histologic differentiation. Despite the present limitations, we expect that our ability to diagnose early s will improve as CDU techniques are developed, enabling lowvolume and low-velocity blood flow to be detected. Acknowledgments We are grateful to Dr. T. Hasebe for his advice on pathologic examination. References ) Okuda K: Hepatocellular carcinoma: recent progress. Hepatology 5: , 99 ) Shinagawa T, Ohto M, Kimura K, Tsunetomi S, Morita M, Saisho H, Tsuchiya Y, Saotome N, Karasawa E, Miki M, Ueno T, Okuda K: Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of real-time ultrasonography: a study in 5 patients. Gastroenterology 86: 95-50, 98 3) Oka H, Kurioka N, Kim K, Kanno T, Kuroki T, Mizoguchi Y, Kobayashi K: Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology : , 990 ) Sonoda T, Shirabe K, Takenaka K, Kanematsu T, Yasumori K, Sugimachi K: Angiographically undetected small hepatocellular carcinoma: clinicopathological characteristics, follow-up and treatment. Hepatology 0: , 989 5) Sakamoto M, Hirohashi S, Shimosato Y: Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol : 7-78, 99 6) Eguchi A, Nakashima O, Okudaira S, Sugihara S, Kojiro M: Adenomatous hyperplasia in the vicinity of small hepatocellular carcinoma. Hepatology 5: 83-88, 99 7) Takayasu K, Moriyama N, Muramatsu Y, Makuuchi M, Hasegawa H, Okazaki N, Hirohashi S: The diagnosis of small hepatocellular carcinomas: efficacy of various imaging procedures.in 00 patients. AJR 55: 9-5, 990 8) Takayasu K, Shima Y, Muramatsu Y, Goto H, Moriyama N, Yamada T, Makuuchi M, Yamasaki S, Hasegawa H, Okazaki N, Hirohasi S, Kishi K: Angiography of small hepatocellular carcinomas: analysis of 05 resected tumors. AJR 7: 55-59, 986 9) Sumida M, Ohto M, Ebara M, Kimura K, Okuda K, Hirooka N: Accuracy of angiography in the diagnosis of small hepatocellular carcinoma. AJR 7: , 986 0) Mostbeck GH, Wittich GR, Herold C, Vergesslich KA, Walter RM, Frotz S, Sommer G: Hemodynamic significance of the paraumbilical vein in portal hypertension: assessment with duplex US. Radiology 70: 339-3, 989 ) Furuse J, Matsutani S, Yoshikawa M, Ebara M, Saisho H, Tsuchiya Y, Ohto M: Diagnosis of portal vein tumor thrombus by pulsed Doppler ultrasonography. Journal of Clinical Ultrasound 0: 39-6, 99 ) Matsutani S, Furuse J, Ishii H, Mizumoto H, Kimura K, Ohto M: Hemodynamics of the left gastric vein in portal hypertension. Gastroenterology 05: 53-58, 993 3) Taylor KJ, Ramos I, Morse SS, Fortune KL, Hammers L, Taylor CR: Focal liver masses: differential diagnosis with pulsed Doppler US. Radiology 6: 63-67, 987 ) Shimamoto K, Sakuma S, Ishigaki T, Makino N: Intratumoral blood flow: evaluation with color Doppler echography. Radiology 65: , 987 5) Yasuhara K, Kimura K, Ohto M, Matsutani S, Ebara M, Tsuchiya Y, Saisho H: Pulsed Doppler in the diagnosis of small liver tumors. Br J Radiol 6: , 988 6) Tanaka S, Kitamura T, Fujita M, Nakanishi K, Okuda S: Color Doppler flow imaging of liver tumors. AJR 5: 509-5, 990 7) Tanaka S, Kitamura T, Fujita M, Kasugai H, Inoue A, Ishiguro S: Small hepatocellular carcinoma: differentiation from adenomatous hyperplastic nodule with color Doppler flow imaging. Radiology. 8: 6-65, 99 8) Shimamoto K, Sakuma S, Ishigaki T, Ishiguchi T, Itoh S, Fukatsu H: Hepatocellular carcinoma: evaluation with color Doppler US and MRI imaging. Radiology 8: 9-53, 99 9) Nihei T, Ebara M, Ohto M, Kondo F: Study of sonographic findings of small hepatocellular carcinoma based on its pathologic findings. Nippon Shokakibyo Gakkai Zasshi 89: , Jpn J Clin Oncol 6(5) 996 Downloaded from on 8 January 08