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1 Department of Radiology, Thomas Jefferson University Hospital, 132 S. 10th
St., 1096 Main Bldg., Philadelphia, PA 19107.
2 Present address: Department of Diagnostic Radiology, Chonnam National
University Medical School, 8 Hackdong, Dongku, Kwangju, South Korea.
3 Present address: Department of Radiology, Hokkaido University School of
Medicine, North-15, West-7, Kita-Ku, 0608638, Sapporo, Japan.
Received August 3, 2001;
accepted after revision December 12, 2001.
Address correspondence to D. G. Mitchell.
Abstract
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MATERIALS AND METHODS. Our review of radiology reports yielded 68 nodules in 40 patients with cirrhosis that showed no hyperintensity on T2-weighted MR images but had rapid enhancement during arterial phase MR imaging after administration of a gadolinium contrast agent. Thirty-four patients (60 nodules) had multiple follow-up MR imaging examinations (range of length of follow-up, 1-72 months; average length of follow-up, 15 months 2 weeks). The final diagnosis of the nodule was determined by pathology reports or after at least 2 years of follow-up to ensure nodule stability and, therefore, benignity. Two radiologists independently reviewed MR images of the nodules, noting the size, signal intensity on T1- or T2-weighted images, and homogeneity of contrast enhancement.
RESULTS. Nine (13%) of the 68 nodules were hepatocellular carcinomas (HCCs). The size of nodules on the first MR examination was between 4 and 20 mm (mean size, 9.5 mm). No significant correlation between the diagnosis of HCC and nodule signal intensity (p = 0.48) or contrast enhancement homogeneity (p = 0.56) on first MR examination was found. Positive predictive value (PPV) and negative predictive value (NPV) for diagnosing HCC on the basis of nodule growth were 100% and 98%, respectively. For diagnosing HCC on the basis of a change in nodule signal intensity, the PPV was 60% and the NPV was 91%. For diagnosing HCC on the basis of a change of enhancement homogeneity, the PPV was 63%, and the NPV was 94%.
CONCLUSION. A finding of growth in small, early-enhancing nodules in patients with cirrhosis is highly predictive of HCC. When small nodules are observed on a single examination, close follow-up of the patient appears appropriate.
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For inclusion in our study, a patient had to have cirrhosis that was confirmed by pathology or by imaging criteria [10] and had to have a small (<20 mm) nodule that enhanced during the early phase at the patient's first dynamic MR examination but did not show hyperintensity on T2-weighted MR images (because this finding strongly indicates malignancy). Sixty-four patients were selected using this criteria. Patients were excluded from the study if they had undergone chemoembolization or ablation therapy (n = 6). In these patients, small nodules might be satellite metastases. In addition, patients (n = 15) that were lost to follow-up or did not have an adequate arterial-predominant phase (n = 3) were excluded. The criteria of adequate arterial-predominant enhancement required for inclusion were a minimal enhancement of the liver, no enhancement of the hepatic veins, intense enhancement of the pancreas and renal cortex, a minimal enhancement of renal pyramids, and a serpiginous enhancement of spleen.
Consequently, the study population included 40 patients with 68 nodules. The group included 29 men and 11 women, whose ages ranged from 31 to 78 years (mean age, 52 years), with cirrhosis caused by viral infection (hepatitis B [n = 18], hepatitis C [n = 12], combined hepatitis B and C [n = 1]), alcoholic hepatitis (n = 4), hemochromotosis (n = 1), autoimmune hepatitis (n = 1), or an unknown entity (n = 3). Twenty-five patients had one nodule, nine patients had two nodules, three patients had three nodules, one patient had four nodules, one patient had five nodules, and one patient had seven nodules.
Six patients (eight nodules) had only one MR examination. Thirty-four patients (60 nodules) had multiple follow-up MR examinations (range of length of follow-up, 1-72 months; average length of follow-up, 15 months 2 weeks). The number of measurements of nodule growth in the intervals between examinations that we had available was two measurements for 18 patients, three measurements for six patients, and four or more measurements for 10 patients. Nine patients with 10 nodules had a follow-up MR examination less than 3 months after the initial baseline examination, but confirmation of benign disease required a lack of growth in or disappearance of the nodules on follow-up imaging for at least 2 years.
Diagnosis was confirmed in 14 patients by liver explantation, in 13 patients by percutaneous biopsy, in one patient by hepatectomy, and in 20 patients by clinical means (three of these after biopsy). Three patients underwent both liver transplantation and percutaneous biopsy. The time interval between transplantation and final MR examination ranged from 12 to 390 days (mean, 112 days). Explanted livers were cut sequentially into 10-mm sections that corresponded as closely as possible to the MR imaging planes. HCC and dysplastic nodules were identified grossly as those that were distinct from the surrounding regenerative nodules in terms of size, texture, color, or degree of bulging beyond the cut surface of the liver [11]. Clinical confirmation consisted of imaging and clinical follow-up of at least 2 years; a nodule was considered benign if the size of the mass did not change during a sufficiently long follow-up period [12]. Five patients underwent biopsy and had clinical confirmation of their diagnoses.
All HCCs were pathologically confirmed by either liver transplantation (four nodules in three patients), biopsy (four nodules in four patients), or hepatectomy (one nodule in one patient). One patient with one nodule on MR imaging had one HCC with three dysplastic nodules confirmed at liver transplantation.
Of the 68 nodules, 59 were proven benign. Eleven patients with 22 nodules visible on MR images showed no corresponding lesion at explantation (of which four nodules in three patients were also confirmed as benign at biopsy). Nine patients with 14 nodules had only benign tissue confirmed at sonographically guided biopsy, including one patient with a dysplastic nodule. In 20 patients with 33 benign nodules (of which six nodules in three patients were also confirmed as benign by biopsy), follow-up imaging showed a lack of growth in (n = 5) or disappearance of (n = 28) the nodules. Six of these 20 patients (with nine of these 33 benign lesions) had had prior negative results at biopsy (three patients) or at subsequent liver explantation (three patients).
MR Imaging Technique
MR imaging was performed with a 1.5-T system (Signa; General Electric
Medical Systems, Milwaukee, WI). A standard whole-body coil was used for the
early examinations, but a phased array coil was used as the receiver coil in
most studies performed after 1995. All patients underwent axial T1- and
T2-weighted MR imaging. T1-weighted imaging included at least one of the
following sequences: conventional spin-echo imaging (TR range/TE, 400-600/12)
with or without fat suppression; in-phase gradient-echo imaging
(80-210/4.0-4.8; flip angle, 70-90°); and opposed-phase gradient-echo
imaging (80-210/2.3-2.7; flip angle, 60-90°). T2-weighted imaging included
conventional spin-echo imaging (1500-3000/50, 90, or 100);
respiratory-triggered fast spin-echo imaging (TR range/TEeff range,
3000-4000/80-102) with fat suppression; and single-shot fast spin-echo imaging
(TR/TEeff, infinite/100). The imaging matrix used was 256 x
256, 160, or 192 pixels for the spin-echo and gradient-echo images and 256
x 256 pixels for respiratory-triggered fast spin-echo images. A
rectangular field of view was usually used to reduce the number of
phase-encoding acquisitions. The section thickness was 7-10 mm, with an
intersection gap of 1-2 mm or smaller.
Dynamic contrast-enhanced MR imaging was performed before and after administration of gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ). Dynamic imaging was performed with one of two sequences—either fast multiplanar spoiled gradient-recalled echo breath-hold imaging (70-160/2.2-2.6; flip angle, 90°) without presaturation pulse or three-dimensional spoiled gradient-echo imaging (7-9/2-3; flip angle, 15°) with spectral fat saturation. The contrast material dose was 0.1 mmol/kg of body weight administered as a rapid IV bolus, followed by a 20 mL flush of normal saline. After unenhanced imaging, arterial phase images were obtained during the 15-20 sec after the start of IV bolus administration [12]. Second and third sets of images were obtained after allowing the patient to take another breath, approximately 45 sec and 90 sec, respectively. The imaging matrix was 256 x 192 pixels. The section thickness was 7-10 mm, with an intersection gap of 1-2 mm or smaller. The time at which three-dimensional spoiled gradient-echo contrast-enhanced imaging was initiated had been determined by a prior timing-bolus technique [13]. Three-dimensional spoiled gradient-echo contrast-enhanced imaging was performed three times within seconds of previous acquisition to obtain multiphasic images (arterial, early portal, and late portal phases) for each of 18 patients. The imaging matrix was 256 x 128-160 pixels, and the acquired slice thickness was 5-7 mm, with zero fill interpolation in the section encoding axis to yield images at 2.5-3.5 mm increments.
Image Analysis
We reviewed the MR images, noting the size, signal intensity, and contrast
enhancement pattern of nodules. One radiologist measured the nodule size. The
average size was calculated from the greatest two dimensions in the left to
right and anterior to posterior axes (measured from axial images), as
described by Havelaar et al.
[14]. To test reproducibility
of the data, subsequent measurements of tumor diameter were repeated
successively three times on one patient during one of his follow-up
studies.
The growth rate of HCC was expressed as tumor volume doubling time, as proposed by Collins et al. [15], and the following formula developed by Schwartz [16] was used for calculation: Tumor volume doubling time = time interval between measurements x log (2)/3 x log (tumor diameter at last measurement/tumor diameter at first measurement). We estimated the doubling time, applying the best fitting regression line derived from all of the data available for a given patient.
Two radiologists independently evaluated the signal intensity (hyperintense, isointense, or hypointense relative to liver parenchyma), contrast enhancement pattern (homogeneous or inhomogeneous), and site of visible nodules. A change of signal intensity in nodules on T2-weighted images was defined as an intensity that initially was isointense and became hypo- or hyperintense. When disagreement in the assessments was encountered, the two radiologists reached a consensus. The chi-square test was used to determine significant differences between the imaging features and a diagnosis of HCC.
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Nodule size ranged between 4 and 20 mm (mean, 9.5 mm) at the first examination. Forty-two nodules were smaller than 10 mm, and 26 were 10 mm or larger. Three (7%) of the 42 nodules smaller than 10 mm and six (23%) of the 26 nodules larger than 10 mm were HCC. Fifty-two of 68 nodules were isointense on T1-weighted images. Eight of nine HCCs were isointense on T1-weighted images. Fifty-six of 68 nodules had homogenous enhancement. Twelve nodules had inhomogenous enhancement. Eight of nine HCCs had homogeneous enhancement. No significant correlation existed between HCC and signal intensity (p = 0.48) or enhancement pattern (p = 0.56).
In patients with follow-up images, eight of the 60 nodules were HCCs, and 52 were benign. Follow-up MR findings for HCCs are summarized in Table 2. The range of length of follow-up periods was from 2-24 months (average length, 10 months 2 weeks). On serial follow-up MR images, the size of seven nodules increased, 24 remained stable, and 29 were no longer visible. All nodules with interval growth were HCCs (Figs. 1A,1B,1C,1D,1E,1F and 2A,2B,2C,2D,2E,2F). One HCC, diagnosed by surgical resection, was stable for 2 months, but all other stable nodules or nodules not detected on follow-up examinations were benign (Fig. 3A,3B,3C,3D,3E,3F).
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The doubling time in the seven HCCs with interval nodule growth had a log-normal distribution. The mean doubling time was 2 months 2 weeks (Fig. 4). The positive predictive value (PPV) and negative predictive value (NPV) of the interval growth of nodules for diagnosis of HCC were 100% and 98%, respectively.
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On T2-weighted images, the signal intensity of five nodules changed during the follow-up period. Three nodules with a change in signal intensity were HCCs (Fig. 2A,2B,2C,2D,2E,2F). In the two benign nodules with a change in signal intensity, a lesion was not identified at liver transplantation or biopsy. Fifty of 55 nodules with no change in signal intensity were benign nodules. For diagnosis of HCC, a change in signal intensity had a PPV of 60% and a NPV of 91%. A change of enhancement pattern was found in eight nodules. Five of these nodules were HCCs. There was no change of enhancement pattern in 52 nodules. Forty-nine of these nodules were benign nodules. For diagnosis of HCC, a change of enhancement pattern had a PPV of 63% and a NPV of 94%.
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Early enhancement of a nodule on arterial phase CT or MR imaging is suggestive of HCC [6,7,8]. With improved MR imaging technique (that is, use of a timing bolus and thin contiguous or overlapping selections), detection of tiny, enhancing foci has become more common [5]. However, clinical treatment of patients with cirrhosis who had small nodules detected on arterial phase imaging may be problematic. First, characterization of small nodules is more difficult in patients with cirrhotic livers than in patients with normal livers because of the severely disturbed liver architecture and altered portal hemodynamics caused by cirrhosis [19]. An early-enhancing mass may also be a benign lesion such as pseudolesion, hemangioma, or dysplastic nodule [2, 20,21,22]. The cause of early enhancement is benign solid lesions has been suggested to be derangement in vascular flow or neoplastic angiogenesis in the cirrhotic liver [20, 23, 24]. Second, the small size and the well-differentiated nature of early HCC account for the frequent failure to establish definite diagnosis using imaging or biopsy [25]. Sonographically guided biopsy is often useful in obtaining tissue from these small nodules, but many small nodules shown on MR images may not be visible on sonography used to perform of percutaneous biopsy, especially if the nodule is seen only on arterial phase contrast-enhanced images. Additionally, a needle biopsy specimen is often not sufficient for definitive histologic diagnosis because of the multicompartmental nature of HCC and, in many cases, the similarity between the cirrhotic liver and a well-differentiated HCC.
The finding of small, enhancing nodules in patients with cirrhosis raises questions regarding management. Although the biological behavior of precancerous nodules associated with cirrhosis is uncertain, they appear to have low potential for malignancy and rarely cause metastasis or vascular invasion [26, 27]. In our study, only 13% (9/68) of small, early-enhancing nodules were HCC. We only considered nodules that were not hyperintense to the liver on T2-weighted images; it is more difficult to diagnose these lesions than those that are hyperintense on T2-weighted images because the latter lesions are highly likely to be malignant. We cannot contribute data explaining the reason that HCCs are isointense to the liver, but we can speculate that it may be related to the histologic similarity of a well-differentiated HCC to the liver parenchyma or to the increased signal intensity of the surrounding damaged and inflamed liver.
It has long been hoped that MR imaging could aid in distinguishing HCC from nonmalignant regenerative and dysplastic nodules on the basis of signal characteristics [4, 9, 28, 29]. Generally, regenerative nodules are isointense on T1-weighted images and iso- or hypointense on T2-weighted images. Dysplastic nodules are usually hyperintense on T1-weighted images and iso- or hypointense on T2-weighted images. Overt HCC may be hypoiso-, or hyperintense on T1-weighted images and hyperintense on T2-weighted images, but it has recently become clear that isointensity, or even hypointensity, of HCC on T2-weighted images is not uncommon [4, 8, 9, 28, 30]. Kelekis et al. [31] reported that 235 (66%) of 354 HCCs were hyperintense on T2-weighted images and 106 (30%) were isointense. Thus, the signal intensity of a dysplastic nodule and a small overt HCC overlaps considerably.
The results of previous MR imaging studies have shown the importance of imaging during the hepatic arterial phase, especially for detection of small HCCs, because these may be occult at other pulse sequences and on portal venous and delayed phase images [5,6,7]. Small tumors measuring less than or equal to 1.5 cm are frequently isointense on both T1- and T2-weighted images and may be detected only on hepatic arterial phase images as diffuse homogeneously enhancing tumors [31]. Peterson et al. [32] reported that 16% were prospectively detected on dynamic MR images but not on spin-echo MR images. Our series included nine HCCs that were isointense on T2-weighted images at the first examination and intensely enhancing on hepatic arterial phase images.
Krinsky et al. [33] studied 71 patients with cirrhosis with explantation correlation using MR imaging. Fifteen lesions in 10 patients were incorrectly diagnosed as HCC. Four of these lesions were seen only during the hepatic arterial phase and appeared to be well-circumscribed masses measuring 5-21 mm. A correlating lesion could not be identified at pathologic examination. In our study, 22 early-enhancing nodules could not be identified at explanation. Eighteen patients had 28 nodules that were not visible on follow-up MR imaging. Possibly, some of these early-enhancing foci represented transient vascular phenomena such as arteriovenous shunting.
Our study showed that for diagnosis of HCC, the PPV of interval growth of nodules on follow-up MR images was 100%. The PPVs of changed signal intensity and changed enhancement pattern were 60% and 63%, respectively. Little is known of the growth rate of small HCCs [34, 35] because small, early-enhancing nodules are often treated by chemoembolization or ablation therapy when first discovered [18, 36]. Sheu et al. [34] reported a mean doubling time of 3 months 2 weeks with HCC; a suitable screening interval for its early detection was 4 to 5 months. In our series, all nodules with interval growth were HCCs. The mean doubling time of HCC was 2 months 2 weeks and less than 5 months in all cases. All but one of the nodules that were stable or not visible on follow-up images proved to be benign. Therefore, interval serial scanning may be a practical way to eventually arrive at the correct diagnosis of early-enhancing nodules that are not hyperintense on T2-weighted images.
Our study had several limitations. First, because they were not visible when reexamined, many lesions in our series were diagnosed during follow-up. Stability in the size of a solid nodule on cross-sectional images for more than 2 years has been generally accepted as an indicator of benignity [12]. Second, our study was retrospective, and consequently, parameters used in the MR imaging varied. Because the T1 of liver has been recorded as slightly less than 500 msec at 1.5 T, variations in TR, even as a TR as low as 1500 msec, should not cause great differences of T1 contrast of subtle lesions on the T2-weighted images. The greatest deficiency of this intermediate TR is in depicting fluid, which was not relevant in our study. T2-weighted imaging was sometimes performed with fat suppression and sometimes without. Nodules in cirrhotic livers may have slightly different signal intensities with these sequences. Third, our calculations of size are based on linear measurements of the diameter of the visualized lesions. Some error (in millimeters) is introduced because the exact center of the small lesions might not be bisected in each scan, despite the careful use of a measuring technique [37]. However, we were able to establish a reliable trend in tumor growth because of the acquisition of multiple scans in some patients over an extended period. Finally, the overall number of pathologically confirmed cases of HCC was small because the inclusion criteria in our study were isointense nodules on T2-weighted images that showed early increased enhancement relative to the remainder of the liver, an atypical appearance for HCC.
In conclusion, signal intensity and contrast enhancement patterns could not be used for definitive diagnosis of HCC in small, hepatic arterial phase—enhancing nodules in cirrhotic patients. However, interval nodule growth is highly predictive of HCC, irrespective of the homogeneity of enhancement. When a small, hepatic arterial phase—enhancing nodule is observed on a single examination, close follow-up of the patient appears appropriate.
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