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Gastrointestinal Imaging |
1 From the Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan (M.H., O.M., T.G.); Department of Radiology, Kouritsu Kaga Chuo Hospital, Kaga, Japan (K.U.); Department of Radiology, Kouseiren Takaoka Hospital, Takaoka, Japan (Y.K.); and Department of Radiology, Shinshu University School of Medicine, Matsumoto, Japan (M.K.). Received July 30, 2001; revision requested September 25; revision received December 19; accepted March 12, 2002. Supported in part by a grant-in-aid for cancer research (10-16) from the Ministry of Health and Welfare of Japan. Address correspondence to M.H.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: One hundred seventy-six borderline lesions seen at computed tomography (CT) during arterial portography (CTAP) and CT during hepatic arteriography (CTHA) were evaluated in 49 patients with cirrhosis who underwent repeated CTAP and/or CTHA but no therapy. On the basis of CTAP findings, nodules were categorized as group A (showing almost the same portal venous supply as the surrounding liver), group B (showing decreased portal venous supply) or group C (showing partially absent portal venous supply); on the basis of CTHA findings, nodules were categorized as group I (showing almost the same arterial supply as the liver), group II (showing decreased arterial supply), or group III (showing partially increased arterial supply).
RESULTS: Progression to classic HCC was observed in 29.4% of group A nodules, 53.9% of group B nodules, and 87.9% of group C nodules within 1,000 days; in 58.6% of group I nodules, 12.9% of group II nodules, and 92.2% of group III nodules within 730 days; and in 0% of nodules in group A and I, 28% of nodules in group B and/or II, and 88.7% of nodules in group C and/or III within 730 days.
CONCLUSION: Evaluation of intranodular blood supply was valuable in predicting the prognosis in borderline lesions, except when only arterial blood supply was evaluated.
© RSNA, 2002
Index terms: Liver, CT, 761.12114, 761.12116 • Liver neoplasms, blood supply, 761.31, 761.323 • Liver neoplasms, diagnosis, 761.31, 761.323 • Liver, nodules, 761.3198
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A dysplastic nodule is defined as a nodular lesion of hepatocytes measuring at least 1 mm in diameter with dysplasia but without definite histologic criteria of malignancy; dysplastic nodules can be further classified into one of two subtypes: low grade and high grade. HCC is defined as a malignant neoplasm composed of cells with hepatocellular differentiation. Two types of hepatocarcinogenesis are now considered to cause HCC (2,8–10). One is de novo carcinogenesis and the other is the multistep development of (a) a dysplastic nodule to (b) a dysplastic nodule with malignant foci to (c) a well-differentiated HCC nodule to (d) definite classic HCC.
Percutaneous biopsy is quite effective for the precise diagnosis of these hepatocellular nodules. However, it is not always possible to perform percutaneous biopsy of these small nodules accurately, and the process of obtaining tissue samples from all multicentric or multifocal nodules is time-consuming and invasive to the patient. Therefore, it would be beneficial to be able to differentiate these nodules at imaging. For this purpose, we previously analyzed the correlation between the intranodular blood supply of these nodules, as evaluated with computed tomography (CT) during intraarterial injection of contrast material, and their histologic grade of malignancy (3,11). We found that the intranodular portal venous supply, as evaluated with CT during arterial portography (CTAP), gradually decreased, whereas the intranodular arterial supply, as evaluated with CT during hepatic arteriography (CTHA), first decreased and then increased in accordance with an increase in the grade of malignancy of the hepatocellular nodule. As a result, it has become possible to estimate, with a high degree of confidence, the histologic grade of malignancy of nodules by evaluating the intranodular blood supply with imaging. However, in clinical practice, it is important to be able to estimate not only the histologic grade of malignancy but also the natural prognosis of the nodules.
Clinically, dysplastic nodules and hypovascular well-differentiated HCC nodules (defined as "borderline lesions" in this study) usually do not show any definite vascular invasion or metastasis to other organs, and therefore do not become life threatening in the absence of associated classic hypervascular HCC. Therefore, predicting the progression of a borderline lesion to hypervascular HCC is clinically important.
The purpose of this study was to analyze the correlation between the intranodular blood supply of borderline lesions, as evaluated with CT during intraarterial injection of contrast material, and their progression to hypervascular HCC in cirrhotic livers.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Repeated CTAP examinations were performed in all 176 nodules and repeated CTHA examinations were performed in 131 nodules. In 99 nodules, both CTAP and CTHA were performed repeatedly. Fifty-seven of 176 nodules were not detected at ultrasonography (US), CT, or magnetic resonance (MR) imaging and were visualized only at CTAP and/or CTHA. The equipment and techniques used in the US, CT, and MR imaging examinations, which were performed not only at our hospital but also at many other referring hospitals, varied; therefore, the rates of detection of these nodules with US, CT, and MR imaging were not analyzed. The observation period was 186–2,167 days (average, 465 days) after CTAP and 186–911 days (average, 450 days) after CTHA. Repeated CTAP and/or CTHA examinations were performed during repeated transcatheter arterial embolization in patients with coexisting classic hypervascular HCC. The interval between each transcatheter arterial embolization session in individual patients varied, ranging from 6 to 20 months (average, 7 months).
CTAP and CTHA were performed in the CT room after hepatic angiography with a digital subtraction angiography system had been completed in the angiography room. For hepatic angiography, about 30 mL of iohexol (350 mg of iodine per milliliter, Omnipaque; Daiichi, Tokyo, Japan) was used. When both CTAP and CTHA were performed, two 4-F catheters were inserted via the ipsilateral common femoral artery with separate punctures.
Conventional CTAP scans were obtained with a 9800 HiLight unit (GE Medical Systems, Milwaukee, Wis) in 10 patients. CTAP was performed in 39 patients with a HiSpeed Advantage unit (GE Medical Systems) with slip-ring technology, 7-mm-thick sections, and 7-mm collimation. The duration of scanning was around 20–25 seconds (during a single breath hold), for a total scanned length of 14–18 cm. Overlapping reconstructions were obtained every 3.5 mm. Helical scanning began 25 seconds after the beginning of an infusion of 60 mL of iohexol (320 mg of iodine per milliliter) at a rate of 1.5 mL/sec.
CTHA scans were obtained with 3-mm-thick sections, 3-mm collimation, and 1.5-mm reconstruction intervals. For CTAP, 20 µg of prostaglandin E1 (Prostandin; Ono, Tokyo, Japan) was injected into the superior mesenteric artery immediately before injection of contrast medium (iohexol, Omnipaque; Daiichi). The CTHA study was divided into two series for scanning the relatively large liver. CTHA scanning began 10 seconds after the start of an injection of iohexol (320 mg of iodine per milliliter) at 1 mL/sec through the 4-F angiographic catheter placed in the common or proper hepatic artery; the infusion was continued throughout scanning.
A diagnosis of hepatocellular nodule was rendered when US, CT, MR imaging, CTAP, and/or CTHA depicted a round distinct nodule larger than 8 mm in widest diameter that was distinguishable from cyst and cavernous hemangioma in cirrhotic livers.
As we reported previously (11), the CTAP findings in the hepatocellular nodules were classified into four groups in which the appearance of a nodule was characterized relative to the appearance of surrounding cirrhotic liver (Fig 1). Group A nodules were not visualized (ie, they were isoattenuating), indicating the presence of almost the same intranodular portal venous blood supply in the nodule as in the liver itself. Group B nodules were visualized as slightly hypoattenuating areas (ie, attenuation in the nodule was higher than that in the intrahepatic inferior vena cava, into which no contrast medium flowed during scanning) relative to the surrounding liver parenchyma, indicating decreased but not absent intranodular portal venous blood flow. Group C nodules were visualized as partially hypoattenuating areas (ie, attenuation in this area was lower than that in the intrahepatic inferior vena cava), indicating a partially absent intranodular portal venous blood supply. In group D nodules, the greater part (more than half) of the nodule was visualized as a markedly hypoattenuating area (ie, entire nodule was more hypoattenuating than the inferior vena cava), indicating an absent intranodular portal venous supply.
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There was a strong tendency that a nodule categorized as a group D nodule at CTAP was categorized as a group IV nodule at CTHA and a group C nodule was categorized as a group III nodule. However, group A nodules were classified as group I or group II without a definite tendency, and group B nodules demonstrated variable types of intranodular portal venous supply (11). The nodules categorized as group D at CTAP and/or group IV at CTHA usually proved to be moderately or poorly differentiated HCC, and, in clinical practice, only these nodules show metastasis and/or definite vascular invasion (ie, are clinically malignant).
Therefore, nodules categorized as group A, B, or C at CTAP and as group I, II, or III at CTHA were defined as borderline lesions in this study. When findings at initial CTAP and/or CTHA changed to those characteristic of group D or IV nodules at repeat CTAP or CTHA, the nodule was considered to have transformed into a clinically malignant nodule (malignant transformation).
The patterns of intranodular blood supply evaluated with CTAP and CTHA were classified into three groups as described in previous paragraphs, and the malignant transformation ratio was compared in each group. The ratio was also analyzed in comparison with combined findings at CTAP and CTHA in the nodules in which both CTAP and CTHA were performed at the same time throughout the series of CT examinations. The groups of CTAP and CTHA findings were retrospectively determined in consensus by three experienced radiologists (M.H., O.M., and K.U.) without knowledge of the final outcome of the nodules.
In each group of CTAP findings, CTHA findings, and the combination of CTAP and CTHA findings, the malignant transformation ratio was calculated with the Kaplan-Meier method and compared. The end point of observation for each nodule was the day of the CTAP or CTHA examination that revealed malignant transformation or the day of the last CTAP or CTHA examination performed. The observation period was defined as the number of days between the first CTAP or CTHA examination and the end point in this study. Differences in the malignant transformation ratio between each group were compared with the log-rank (Mantel-Cox) method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Clinically, almost all HCCs with metastases or vascular invasion are hypervascular relative to the surrounding liver on color Doppler US images and during the arterial-dominant phase of dynamic CT and MR imaging, hepatic arteriography, and CTHA. In addition, almost all HCCs show a definite portal venous perfusion defect at CTAP. On the other hand, hypo- or isovascular well-differentiated HCCs or borderline lesions with intranodular portal venous blood supply usually do not demonstrate any overt metastases or vascular invasion and therefore are considered to be clinically benign. For these reasons, the change of a hypovascular nodule with intranodular portal venous blood supply to a hypervascular nodule with an intranodular portal venous perfusion defect in more than half of the nodule was defined as "malignant transformation."
In terms of CTAP findings, the malignant transformation ratio was lowest in the nodules with almost the same intranodular portal venous blood supply as the surrounding liver (group A), followed by those with decreased but not absent intranodular portal venous blood supply (group B) and those with partially absent intranodular portal venous blood supply (group C). Only 30% of group A nodules showed malignant transformation within 3 years, in contrast to at least 90% of group C nodules. These observations were consistent with our previous results, which revealed the radiologic and histologic correlation that the intranodular portal venous blood supply in hepatocellular nodules gradually decreases in accordance with an increasing grade of malignancy (3,11,12). Therefore, we believe that the usefulness of the evaluation of intranodular portal venous blood supply with imaging in estimating the grade of malignancy of hepatocellular nodules was reconfirmed in this follow-up study.
In terms of CTHA findings, the malignant transformation ratio was higher in nodules with almost the same intranodular arterial blood supply as the surrounding liver (group I) than in those with decreased intranodular arterial blood supply (group II); these two groups showed at least 50% and 20% malignant transformation within 3 years, respectively. As we reported previously, isoattenuation at CTHA (as is demonstrated by group I nodules) can indicate two different conditions—(a) the presence of a large regenerative nodule or low-grade dysplastic nodule in which almost the same arterial supply relative to the surrounding liver is present through a normal hepatic artery or (b) the presence of a high-grade dysplastic nodule or well-differentiated HCC in which an increased abnormal arterial supply compensates for a decreased normal arterial supply (11). We surmise that a relatively large number of more malignant nodules were included among the group I nodules in this study. These results indicate that the evaluation of intranodular arterial blood supply alone is unreliable in predicting the grade of malignancy or the prognosis of group I nodules. On the other hand, all nodules with partially increased arterial blood supply (ie, group III nodules) showed malignant transformation within 3 years.
In terms of the combination of CTAP and CTHA findings, nodules with almost the same intranodular portal venous and arterial blood supply (group A-I) demonstrated no definite malignant transformation, although the number of such nodules was small. On the other hand, at least 30% of the nodules with decreased intranodular portal venous or arterial supply (group B-II) showed malignant transformation within 3 years, as did all of the nodules with partially absent intranodular portal venous supply or partially increased intranodular arterial supply (group C-III). These results were in close agreement with those of our previous radiologic and histologic correlation studies (3,11,12), in which type A-I nodules usually proved to be low-grade dysplastic nodules that were benign in nature.
This study revealed a significant correlation between the intranodular blood supply, as evaluated with CTAP and CTHA, and the prognosis (biologic nature) of hepatocellular nodules associated with liver cirrhosis. Malignant transformation of hepatocellular nodules has been studied in nodules histologically diagnosed at biopsy. Takayama et al (14) reported that nine of 18 biopsy-proved adenomatous hyperplasias transformed to overt HCC within 1–5 years (14). However, to the best of our knowledge, no researchers have yet analyzed the correlation between intranodular blood supply evaluated specifically with CTAP and CTHA and the natural history of a large number of hepatocellular nodules. The results obtained in this study are useful in the clinical management of these nodules, especially when such nodules coexist with overt hypervascular HCC in cirrhotic livers. According to the results obtained in this study, hypovascular hepatocellular nodules with internal portal venous supply can be followed up until an internal focus of hypervascularity appears. However, CTAP and CTHA are invasive examinations; therefore, attempts to visualize intranodular portal venous supply and faint intranodular arterial vascularity with color Doppler US and dynamic CT and MR imaging should be continued. In the future, contrast material–enhanced US (15) and dynamic multisection helical CT will become useful methods for evaluating intranodular arterial and portal venous blood supply. At that time, the findings obtained in this study will be widely applicable to clinical practice.
There were some limitations in this study. One was that there was no pathologic proof for the nodules evaluated in this study. However, one of the major purposes of this study was to define standard criteria for predicting the prognosis of borderline lesions with imaging but without biopsy. Another limitation was the lack of a standard time for follow-up examinations in patients within each of the groups. However, because CTAP and CTHA were performed during transcatheter arterial embolization therapy for coexisting classic HCC, it was impossible to make the period between these examinations standard.
In conclusion, there was a significant correlation between intranodular blood supply evaluated with CT during intraarterial injection of contrast material and prognosis in hepatocellular nodules associated with liver cirrhosis. Almost all of the nodules with partially absent intranodular portal venous blood supply or partially increased intranodular arterial supply transformed to hypervascular classic HCC within 3 years. On the other hand, nodules with almost the same intranodular portal venous and arterial blood supply as the surrounding liver did not show any transformation to hypervascular HCC, and only 30% of nodules with decreased portal venous or arterial blood supply demonstrated malignant transformation. Evaluation of only intranodular arterial blood supply was unreliable in predicting the prognosis of nodules without a hypervascular focus. We believe such information to be clinically useful in the care of cirrhotic patients with such nodules.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, all authors; study concepts, M.H., O.M.; study design, O.M.; literature research, M.H.; clinical studies, all authors; data acquisition and analysis/interpretation, M.H., O.M.; statistical analysis, M.H., Y.K.; manuscript preparation, M.H.; manuscript definition of intellectual content, all authors; manuscript editing, M.H.; manuscript revision/review, O.M.; manuscript final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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