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1 Institut de Diagnòstic per la Imatge, Hospital Universitari de
Bellvitge, L'Hospitalet de Llobregat, Autovia de Castelldefels, Barcelona
08907, Spain.
2 Department of Surgery, Hospital Princeps d'Espanya, Barcelona, Spain.
3 Department of Pathology, Hospital Princeps d'Espanya, Barcelona, Spain.
Received July 7, 2003;
accepted after revision October 7, 2003.
Address correspondence to C. Valls
(carlosvalls{at}csub.scs.es).
Abstract
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SUBJECTS AND METHODS. Eighty-five patients with cirrhosis were studied preoperatively with biphasic helical CT. Arterial, portal, and equilibrium phase images were obtained after injection of 170 mL of contrast material at 5 mL/sec. The prospective CT interpretation was compared with pathologic results on a lesion-by-lesion basis.
RESULTS. Pathologic examination found 85 cases of HCC in 51 patients. Helical CT enabled a correct diagnosis of HCC in 67 of 85 lesions for a sensitivity of 78.8%. HCC nodules were hypervascular in the arterial phase and hypovascular in the equilibrium phase in 63.5% (54/85) of patients. The false-negative rate was 21% (n = 18), and the positive predictive value was 88%. We had nine false-positive findings (11.8%) related to hemangiomas, transient hepatic attenuation differences, and regenerative nodules. Helical CT detected 61% (23/38) of lesions smaller than 2 cm and 93.6% (44/47) of lesions 2 cm or larger.
CONCLUSION. Helical CT is a useful preoperative imaging technique in cirrhotic patients who are candidates for orthotopic liver transplantation, although it is relatively insensitive for detection of small lesions (< 2 cm).
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Surgery is still the best treatment option with a reported 5-year survival rate ranging between 35% and 51% for hepatic resection and between 58% and 75% for orthotopic liver transplantation [5]. However, accurate tumor staging in patients with HCC is critical to provide a potentially curative treatment. Reports on selected groups of patients show that similar results can be achieved in terms of survival after orthotopic liver transplantation (63% vs 68%, 5-year survival) both in cirrhotic patients with HCC and in cirrhotic patients without HCC [6]. Therefore, orthotopic liver transplantation arises as the optimal treatment for patients with HCC and limited disease, although only a limited number of patients will actually benefit from this treatment.
Preoperative staging of HCC is important because it allows more accurate defining of the intrahepatic extension of HCC and, therefore, it may be useful in selecting optimal candidates for liver transplantation.
The objectives of our study were twofold: to determine the sensitivity and positive predictive value of helical CT in the detection and characterization of HCC in cirrhotic patients undergoing orthotopic liver transplantation and to assess the efficacy of helical CT in the preoperative staging of candidates for orthotopic liver transplantation.
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Our final study group consisted of 85 patients who underwent helical CT before chemoembolization and orthotopic liver transplantation. There were 55 men and 30 women with a mean age of 55 years (range, 32–70 years; standard deviation [SD], 8.2). All the patients had chronic liver disease. Fifty-two of these patients had chronic hepatitis C virus infection, six had chronic hepatitis B virus infection, 23 had alcohol-induced cirrhosis, one had primary biliary cirrhosis, one had primary sclerosing cholangitis, and in two patients the cause of cirrhosis was cryptogenetic. Preoperative determination of serum ß1-fetoprotein levels was performed in 50 patients with values ranging from 1 to 1721 ng/mL (mean, 73.2 [SD, 259] ng/mL). Increased levels of ß1-fetoprotein (> 400 ng/mL) suggestive of HCC were observed in 2.4% patients (2/85).
The time interval between helical CT and orthotopic liver transplantation was 1–18 months (mean, 6.6 months). In 53 patients, CT was performed between 1 and 6 months before surgery, whereas in 32 patients, CT was performed more than 6 months before surgery.
CT Technique
Preoperative evaluation was performed in all patients with helical CT with
5-mm collimation and a 1:1.5 pitch, and subsequently the images were
reconstructed at a 4- or 5-mm interval. Helical CT was performed with a
ProSpeed Plus system (General Electric Medical Systems). Contrast material
(170 mL) was injected at 5 mL/sec with an automated power injector (MCT,
Medrad) and a large (18-gauge) venous catheter. The helical acquisition
started at 20–25 sec for the arterial phase and 60–70 sec for the
portal phase. In addition, we also routinely obtained equilibrium phase images
5–10 min after the administration of contrast material because most HCC
is hypodense relative to the liver parenchyma during this phase.
Image Interpretation and Analysis
Helical CT images were prospectively evaluated before liver transplantation
by at least two of three experienced abdominal radiologists in consensus.
Arterial, portal, and equilibrium phase images were interpreted conjointly.
All imaging findings were recorded in an electronic database. Preoperative
assessment included number, location, and size of all lesions as well as their
enhancement features.
The diagnostic criteria for HCC were classified in contrast enhancement features and morphologic signs.
Contrast Enhancement Features
Contrast enhancement signs included transient brisk hyperenhancement on the
arterial phase imaging, hypo- or isodensity of the lesion relative to the
normal liver parenchyma on portal phase imaging, and hypodensity relative to
normal liver parenchyma on delayed imaging.
Morphologic Signs
Morphologic signs included mosaic pattern, peritumoral capsule, and fatty
infiltration. Mosaic pattern was defined as an internal tumoral structure with
nodules and septa of different attenuations and different degrees of contrast
enhancement. Peritumoral capsule was defined as a thin, sharply marginated rim
of tissue that surrounds an expansive tumor. Fatty infiltration was defined as
a gross fatty attenuation area within the tumor.
HCC was defined as a hypervascular lesion (focal lesion hyperattenuated relative to the adjacent liver parenchyma) in the arterial phase that was hypoattenuating in the portal or equilibrium phase. Additionally, hypervascular lesions in the arterial phase without imaging features suggestive of hemangioma or transient hepatic attenuation differences were considered to be HCC. Hemangioma was defined as a homogeneous hyperenhacing lesion in arterial, portal, and equilibrium phases. Transient hepatic attenuation differences were defined as subcapsular, wedge-shaped hypervascular lesions in the arterial phase with a straight border and no hypoattenuation in portal or equilibrium phase.
Hypodense lesions in any phase of enhancement with mosaic pattern, peritumoral capsule, or fatty metamorphosis were also considered to be HCC.
The findings on pathologic examination were compared with the helical CT results and stored in the database. Liver lesions recorded in the database as HCC and detected at histologic study in the same location and with similar size were considered true-positive. HCC nodules detected on histologic examination and missed on helical CT were considered false-negative. Benign hepatic lesions at histologic examination that were misclassified as HCC by helical CT were considered false-positive. Lesions considered as HCC by helical CT that were not identified after thorough histopathologic examination were also considered false-positive.
Sensitivity was defined as the number of HCC nodules correctly detected by helical CT divided by the number of HCC lesions identified at pathologic examination. The false-positive ratio was defined as the number of false-positive lesions detected by helical CT divided by the total number of lesions (true-positive + false-positive). The positive predictive value was defined as the number of HCC nodules correctly detected by imaging divided by the total number of lesions considered to be HCC by CT.
Preoperative Staging
At our institution, patients with limited HCC are considered suitable
candidates for orthotopic liver transplantation. Current indication criteria
for liver transplantation in patients with HCC at our institution include
single tumors of less than 5 cm in diameter or fewer than three nodules, all
less than 3 cm, and absence of macroscopic tumoral vein invasion or
extrahepatic disease, as has been previously reported in the literature
[7]. However, these indication
criteria were not absolute, and selected patients in our series (n =
6) underwent transplantation surgery even though preoperative imaging
disclosed slightly more advanced tumoral disease.
In addition, suitable candidates should not have macroscopic portal vein invasion, lymph node spread, or distant metastasis.
We considered that explanted livers with single HCC nodules with a maximum diameter of 5 cm or fewer than three nodules, all less than 3 cm, had been adequately staged to determine the ability of helical CT to perform preoperative staging of HCC.
Explanted livers with single lesions larger than 5 cm, more than three nodules, macroscopic vascular invasion, or gross extrahepatic disease were considered as understaged. Patients who were known preoperatively to have more advanced disease but still considered candidates were not considered understaged.
Histopathologic Review
All explanted livers were serially sliced at 5- to 10-mm intervals and were
carefully inspected to detect focal lesions.
The size and location of all visible nodules were recorded at gross inspection. All suspicious macroscopic nodules were examined microscopically. Each focal lesion described at preoperative CT was directly correlated with the histopathologic examination.
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Eighty-five HCC nodules were detected at histologic study in 51 patients. The size of the lesions ranged from 0.3 to 9 cm (mean, 1.9 cm). Helical CT correctly detected 67 HCC lesions. The number of HCC nodules in each patient ranged from one to five (mean, 1.7). The overall detection rate of HCC lesions on helical CT was 78.8% (67/85), and the positive predictive value was 88% (67/76).
The sensitivity of helical CT for lesions 2 cm or larger was 93.6% (44/47). The sensitivity of helical CT for lesions smaller than 2 cm was 61% (23/38). The false-positive rate was 11.8% (9/76).
Lesion Characterization
Lesion enhancement and morphologic features are summarized in
Table 1. Eighty-eight percent
(59/67) of HCC nodules were hyperenhancing in the arterial phase (Fig.
1A,
1B,
1C,
1D). In 80.6% (54/67) of the
patients, HCC nodules were hyperenhancing in the arterial phase and
hypoenhancing in the equilibrium phase. Only 8.9% (6/67) of all HCC nodules
were hypoenhancing in both the arterial and the equilibrium phases.
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Nineteen HCC nodules (28.4%) were isoenhancing in the portal phase and hypoenhancing in the equilibrium phase, whereas only four (5.9%) were hypoenhancing in the portal phase and isoenhancing in the equilibrium phase.
Therefore, the positive predictive value for HCC of focal liver lesions hyperenhancing in the arterial phase was 72.8% (59/81). The positive predictive value for HCC of hepatic nodules hyperenhancing in the arterial phase and hypoenhancing in the equilibrium was 93.1% (54/58). Finally, the positive predictive value of hypoenhancing lesions in the arterial and equilibrium phases was 33.3% (6/18).
Peritumoral capsule was observed in only 13.4% (9/67) of all HCC nodules. The positive predictive value of peritumoral capsule for HCC was 90% (9/10). Mosaic pattern and fatty infiltration were extremely infrequent in our series (one nodule and none, respectively) and did not have any diagnostic value.
False-Positive Lesions
Nine false-positive lesions were detected in seven patients (Fig.
2A,
2B,
2C). The false-positive
findings were hypervascular lesions in five patients (one hemangioma, two
regenerative nodules, one dysplastic nodule, and one transient hepatic
attenuation difference) and hypovascular lesions in four (two regenerative
nodules, one necrotic nodule, and one hemangioma).
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In two of these patients with false-positive findings, there was no HCC, and histologic examination disclosed a necrotic nodule in one patient and a hemangioma in the other.
The overall false-positive rate in our series was 11.8% (9/76) on a lesion-by-lesion basis. On a patient-by-patient basis, considering only patients with false-positive findings and no HCC nodules, the false-positive rate was 3.9% (2/51).
False-Negative Lesions
Helical CT found 18 false-negative lesions in 12 patients. The size of
these missed lesions ranged from 0.3 to 2.8 cm (mean, 1.2 cm). In all
patients, the lesions were not seen on CT. Sixteen of these lesions were 2 cm
or less (range, 0.3–2 cm), whereas two were larger than 2 cm (range,
2.5–2.8 cm). In 10 patients, true-positive findings for HCC were also
detected.
Preoperative Staging
Preoperative staging with helical CT disclosed single tumors less than 5 cm
or three tumors less than 3 cm in 88.2% (45/51) of the patients. The remaining
six patients had slightly more advanced tumor on CT but no macroscopic portal
vein invasion. Radiologic–pathologic correlation after orthotopic liver
transplantation showed good correlation between preoperative radiologic
staging and postoperative pathologic staging in 92.2% (47/51). Understaging of
HCC occurred in 7.8% of patients (4/51). The causes of understaging were as
follows: extrahepatic disease with diaphragmatic crus infiltration in one
patient (Fig. 3A,
3B), presence of more than
three nodules (n = 5) less than 3 cm in two patients, and presence of
more than three nodules (n = 5), including one larger than 5 cm.
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Follow-Up and Clinical Outcome
The mean follow-up of patients with HCC was 25.9 months (SD, 21.1 months;
range, 1–88 months) with a median of 22 months.
By the end of the study, 7.8% (4/51) of the patients had experienced tumor recurrence. Two of these patients had understaging of the disease: one had extrahepatic disease and the other had more than three HCC nodules (n = 5), one of which was larger than 5 cm. The third patient was correctly staged preoperatively, and helical CT showed three HCC nodules less than 3 cm that were confirmed at histologic examination. However, the patient had an ß1-fetoprotein level of 1,710 ng/mL, and tumoral recurrence was detected 6 months after orthotopic liver transplantation. The patient with extrahepatic disease and the patient with increased ß1-fetoprotein levels died with massive hepatic and lymph node recurrence and peritoneal recurrence, respectively. The patient with more than three HCC nodules is still alive with hepatic pulmonary and osseous recurrence.
The fourth patient had a single 2-cm nodule correctly staged on CT. The patient developed tumoral recurrence in the liver and bone 5 years after transplantation, and he is still alive.
With a median follow-up of 25.9 months (range, 1–88 months), 1-, 3-, and 5-year survival rates were 86%, 80%, and 70%, respectively. The subgroup of patients (n = 10) with single lesions greater than 5 cm or more than three nodules had a 5-year survival rate of 65%.
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The advent of helical CT over recent years has dramatically improved our ability to detect and stage HCC [9, 10]. However, a recent review article reports conflicting detection rates of CT for HCC from different authors ranging between 50% and 84% [11]. In older series with nonhelical CT, Miller et al. [12] reported a sensitivity of 68% for the detection of HCC [12]. More recent studies with up-to-date imaging technology have shown better results. Noguchi et al. [13] found a sensitivity of 98% for lesions larger than 2 cm. However, the sensitivity dropped to 50.3% for lesions smaller than 2 cm, and the global sensitivity was 66%. In another series, Lim et al. [14] report a global sensitivity of helical CT in the detection of HCC of 71% (15/21). In that series, the detection rate for HCC larger than 2 cm was 82%, whereas the detection rate for lesions of less than 2 cm was only 60%.
The results of imaging techniques, therefore, seem to depend largely on the size of the lesions. However, lesion detection is a critical point if preoperative imaging is used to select patients with cirrhosis and HCC for transplantation. Published data on preoperative staging of HCC before orthotopic liver transplantation are relatively scant. Krinsky et al. [15] studied 71 patients with chronic liver disease and without known HCC on MRI before liver transplantation. These authors found a sensitivity of 50% (5/10) for the detection of HCC. In this study, all patients had very advanced hepatic cirrhosis and patients with known HCC were excluded to avoid positive bias. Therefore, this study has a strong negative bias and does not represent the usual clinical scenario, in which patients with known HCC are also imaged, not only for diagnosis but also for staging. In this series, a large number of false-positive findings were seen (15 lesions in 10 patients). Those false-positive findings were related to hypervascular dysplastic nodules and nodular forms of transient hepatic attenuation differences related to arterioportal shunts.
Lim et al. [14] studied 41 patients with biphasic helical CT before orthotopic liver transplantation. The global sensitivity of helical CT in the detection of HCC on a lesion-by-lesion basis was 71% (15/21), whereas patient sensitivity was 80% (12/15). That series is limited by the relatively low number of patients with HCC. In another series, Zacherl et al. [16] reported a sensitivity of 75% and a positive predictive value of 72% in a series of 23 patients who underwent biphasic helical CT before liver transplantation. In that series, the authors report a surprisingly high false-positive rate for helical CT of 27.7% (15/54) but unfortunately do not specify the causes of these false-positive findings.
In our series, the results in terms of lesion detection are slightly better than those in previous studies even though our patients were studied with single-detector helical CT. The use of large volumes of contrast material (170 mL), high injection rate (5 mL/sec), and the routine addition of delayed images may account for these differences. In addition, even if approximately 20% of the lesions were missed, from a clinical standpoint preoperative staging was excellent because 90% of the patients were adequately staged. Another important point is that none of our patients had macroscopic portal invasion at pathologic examination. This is critical because portal vein invasion is the only independent variable associated with a worse prognosis [17, 18].
Recent studies have shown that results after orthotopic liver transplantation in cirrhotic patients in terms of survival are very good even if lesions larger than those in our inclusion criteria are included [19], and many surgical teams believe that patients with more extensive HCC can be safely treated. In the series of Yao et al. [19], transplantation patients with solitary lesions less than 6.5 cm or fewer than three nodules smaller than 4.5 cm had a survival rate of 90% at 1 year, whereas patients with macroscopic vein invasion had only a 33% survival rate. In fact, in our series, 10 patients underwent transplantation with lesions greater than 5 cm or more than three lesions less than 3 cm without concomitant portal vein invasion. Six of these patients knowingly underwent transplantation, whereas four were understaged on helical CT. Yet the recurrence rate in our series was only 7.8%, and the survival rate at 5 years was 70%. Specifically, this small subset of patients with "more advanced disease" had a survival rate at 5 years of 65%. Therefore, it is possible that the inclusion criteria for transplantation may be expanded in selected patients, and perhaps the main goal of imaging should be to exclude patients with macroscopic venous invasion or diffuse disease. However, further studies are probably needed.
In a recent study, Bhartia et al. [20] reported a series of 14 cirrhotic patients who underwent double-contrast (iron oxide particles with superparamagnetic properties and gadolinium) MRI and subsequently underwent transplantation. The overall sensitivity of double-contrast MRI on a lesion-by-lesion basis was 78% (25/32). In addition, Bhartia et al. reported 14 false-positive lesions giving a false-positive ratio of 35.8% (14/39) and a positive predictive value of 63.8%. These results are not different from those in our series or other previous series with helical CT in terms of sensitivity; however, the positive predictive value of helical CT seems to be much higher (88%) in our series. The use of two contrast agents significantly increases the cost and time of the diagnostic examinations, and according to the reported results, these expensive and time-consuming procedures add little information if high-quality helical CT is performed.
In addition, we prospectively assessed the ability of helical CT to perform accurate preoperative staging of HCC before liver transplantation. Staging systems for HCC is a widely discussed issue, and currently no agreement on the best staging method has been reached [4]. The TNM system [21] has been previously used in surgery [22], but it has been shown to be a poor predictor of the outcome of HCC patients. The new TNM staging [17] better reflects the major prognostic factors of resected tumors. However, this staging system is not designed to be performed preoperatively because microscopic vascular invasion and hepatic fibrosis cannot be assessed by imaging techniques. Therefore, in our study we only evaluated the ability of HCC to be a preoperative identifer for optimal candidates for orthotopic liver transplantation in terms of tumor stage—that is, single tumors less than 5 cm or up to three nodules less than 3 cm as has been previously reported in various surgical series [7].
In our series, pathologic correlation after transplantation showed good agreement between preoperative radiologic staging and postoperative pathologic staging in 92.2% (47/51), and understaging of HCC occurred in only 7.8% (4/51) of the patients.
Our study had several limitations. We used single-detector CT to perform our biphasic study. The use of MDCT would allow thinner collimation and probably would have resulted in increased conspicuity of small lesions. However, previous reports suggest that 5- and 2.5-mm slices do not have a significant impact on the detection of hypervascular HCC [23]. In addition, in our series, the mean interval between helical CT and orthotopic liver transplantation was 6.6 months. This long delay may account for discrepancies between imaging and histologic findings due to tumor progression.
In summary, our results show that helical CT is useful for detecting HCC nodules larger than 2 cm with a sensitivity of 93.6%, although it is limited in lesions smaller than 2 cm with a sensitivity of 61%. However, in our experience, helical CT is useful in the preoperative staging of HCC in candidates for orthotopic liver transplantation with a global sensitivity of 78.8% and a positive predictive value of 88%. In addition, helical CT allows adequate staging before transplantation in 92% of patients.
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