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Clinical Investigations |
1 Department of Nuclear Medicine and PET, Hong Kong Sanatorium and Hospital, Hong Kong, China
2 Department of Radiology, University of Hong Kong, Hong Kong, China
3 Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, Hong Kong, China
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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3 (32 patients; 55 lesions; mean size ± SD, 3.5 ± 1.9 cm), the sensitivity of detection by 11C-acetate is 87.3% (11C-acetate maximum SUV [SUVmax] = 7.32 ± 2.02, with a lesion-to-normal liver ratio of 1.96 ± 0.63), whereas the sensitivity of detection by 18F-FDG is only 47.3%, and 34% lesions show uptake of both tracers. None of the lesions was negative for both tracers (100% sensitivity using both tracers). In some lesions and in the subgroup of HCC patients (n = 7) with multifocal or diffuse disease, dual-tracer uptake by different parts of the tumor is demonstrated. Histopathologic correlation suggests that the well-differentiated HCC tumors are detected by 11C-acetate and the poorly differentiated types are detected by 18F-FDG. All 16 non-HCC malignant (cholangiocarcinoma and metastatic) liver lesions do not show abnormal 11C-acetate metabolism. Of the benign liver lesions, only FNH shows mildly increased 11C-acetate activities (11C-acetate SUVmax = 3.59, with a lesion-to-normal liver ratio of 1.25). Conclusion: 11C-Acetate has a high sensitivity and specificity as a radiotracer complementary to 18F-FDG in PET imaging of HCC and evaluation of other liver masses.
Key Words: 11C-acetate • PET • hepatocellular carcinoma
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-fetoprotein concentration. The conventional method of detection for HCC is by structural imaging, most commonly and economically by sonography, followed by contrast CT and MRI (2–4). In the past decades, the use of PET, with 18F-FDG as the functional probe, has been found to be successful in the evaluation of many forms of solid malignancies. However, it is well known that 18F-FDG is far from being a universal tracer on the basis of the understanding that tumor kinetics may vary and increased glycolysis may not be the preferred kinetic pathway in some tumors. It is understood that HCC is one of the known tumors that may exhibit a net glycolysis similar to or even lower than that of normal liver parenchyma and therefore may escape detection (5–13). The average reported false-negative rate using 18F-FDG PET in HCC approaches 40%–50% (6,10,11,14). In countries where this tumor is prevalent, this low sensitivity has been a major weakness of 18F-FDG PET in the evaluation of liver masses. Several research studies in the recent years have demonstrated that 11C-acetate may be a useful tracer for urologic tumors (15,16). Because there are no data in the literature regarding the use of this tracer in liver masses, this study was designed to evaluate prospectively the characteristics of 11C-acetate metabolism in HCC and some selective liver pathology. Its potential use as a radiotracer complementary to 18F-FDG in the detection of HCC was investigated. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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11C-Acetate Synthesis, Injection, and Imaging
11C-Acetate was prepared by modifying the methodology and setup proposed by Norenberg et al. (17). A dose of 555 MBq (15 mCi) 11C-acetate was administered intravenously, and regional imaging of the upper abdomen in 2 positions was performed at 10 min after injection using an ECAT EXACT 47 PET scanner (model 921; CTI/Siemens, Inc., Knoxville, TN). The axial field of view was 16.2 cm. Both transmission and emission scans were obtained with a total of 10-min acquisition time for each position. Attenuation correction was performed with the standardized ordered-subsets expectation maximization technique. Reconstructed transaxial spatial resolution was about 4.4 mm. These images were compared with the anatomic images (CT or MRI).
18F-FDG Synthesis, Injection, and Imaging
18F-FDG synthesis was based on the standard technique of Hamacher et al. (18) (CTI Corp. chemical synthesizer). A dose of 37–555 MBq (10–15 mCi) 18F-FDG was injected intravenously. For those patients undergoing the same-day protocol, 18F-FDG was injected at 10–15 min after 11C-acetate imaging (40–45 min after initial 11C-acetate injection). Regional imaging of the upper abdomen of the same patient began at 45–60 min after 18F-FDG administration. This allowed a total of 85–105 min after the initial injection of 11C-acetate—thus, >4–5 decay half-lives of 11C (20 min). For the first few cases with positive 11C-acetate uptake in the tumor lesions, imaging at 85–100 min before 18F-FDG injection was performed to confirm little or no significant residual activities before this technique was adopted for all subsequent patients (the most intense pancreatic uptake of 11C-acetate was not seen on all 18F-FDG PET images). Instrumentation, imaging, reconstruction, and semiquantitative analysis were similar to the specifications as stated above.
Interpretation Criteria and Statistical Analysis
The hepatic masses were referred to the CT or MR images for lesion-to-lesion comparison. A lesion was regarded as positive for 18F-FDG or 11C-acetate on the basis of visual judgment of the degree of increased metabolism, supported by calculation of the standardized uptake value (SUV). A lesion was considered negative for the PET tracer (18F-FDG or 11C-acetate) when it was isointense with nontumor tissue by visual inspection, supported by a lesion-to-liver SUV ratio of <1.20. Both maximum and average values were calculated. The region of interest (ROI) was drawn automatically at 75% threshold of the maximum lesion count around the tumor. The same ROI was used to evaluate the SUV of nontumor liver tissue in the same patient. For those patients whose lesion was seen with only 1 type of PET tracer, the same ROI was applied at the same level on the transaxial images of the other PET tracer after direct visual alignment of both sets of images. For the subgroup of patients with multifocal or diffuse disease, the ROI was drawn either automatically or manually around the representative lesions or areas. In some of these patients with advanced or infiltrative disease, semiquantitative evaluation was not possible or was possible only in some lesions, and nontumor tissue could be defined only as liver tissue with no apparent tumor on CT or MRI and on PET imaging. The biopsy sites were identified if biopsies were performed before PET imaging. Statistical analysis with an unpaired Student t test was performed on (a) the 11C-acetate-positive HCC lesions to check for any significant difference with the benign lesions, (b) the non-HCC malignant lesions with normal liver tissue, and (c) the average lesion-to-liver ratios among the HCC patients with 3 tumor lesions (group Ia, as defined below) according to cellular differentiation. Partial-volume effect correction was not performed because only 3 lesions in this study were between 1.7 and 2.0 cm in size.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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3 lesions and disease was confined within the hepatic parenchyma; and group Ib (n = 7), those patients with >3 lesions, including those with diffusely infiltrating or multifocal disease, vascular invasion, and extrahepatic metastasis. In group Ia, there were 32 patients with a total of 55 hepatic lesions. Of these 55 HCC lesions, 29 were positive only for 11C-acetate (Fig. 1A), 7 were positive only for 18F-FDG (Fig. 1B), and 19 were positive for both (Fig. 1C). Lesion size ranged from 1.7 to 11.1 cm (mean size, 3.5 ± 1.9 cm). On the basis of this subgroup statistics, the sensitivity for detection of HCC by 11C-acetate was 87.3% (lesions positive only for 11C-acetate plus lesions positive for both 11C-acetate and 18F-FDG; n = 48). Whereas for 18F-FDG, the sensitivity for detection of HCC was only 47.3% (lesions positive only for 18F-FDG plus lesions positive for both; n = 26). Results are summarized in Table 1. About 34.5% (n = 19) of these HCC lesions showed increased metabolism of both radiotracers, and some lesions appeared to be complementary (different tracer uptake in different parts of the same tumor lesion, as shown in a patient in Fig. 2). The average 11C-acetate maximum SUV [SUVmax] in group Ia HCC lesions was 7.32 ± 2.02 (mean ± SD; range, 4.11–13.28), with an average lesion-to-liver ratio of 1.96 ± 0.63 (SE = 0.11 at t0.025).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-fetoprotein concentration), the radiologic diagnosis of HCC is usually not difficult to make. It is related partly to the fact that today the incidence of benign hepatic lesions such as FNH and adenoma is rather low, and, in fact, FNH is frequently an entity diagnosed by exclusion because of the concern of biopsy sampling error. However, various trials and combinations of techniques regarding different imaging methods exist in the literature in an attempt to increase the accuracy of detecting and diagnosing atypical lesions and tumors of <2-cm size (19–25). This is particularly true in patients with a low or intermediate likelihood of having the disease (negative status of hepatitis B surface antigen, borderline or normal -fetoprotein concentration). Cirrhosis is another known variable that causes confounding degrees of contrast-enhanced appearances on both conventional and helical CT (26–28), primarily related to the coexistence of regenerating and dysplastic nodules. Peterson and Baron (27) reported a low detection accuracy of 37%–45% based on recent screening studies on large cirrhotic populations. In those patients with cirrhotic livers and small lesions, the diagnosis of HCC can be difficult to make.
The role of 18F-FDG PET in the detection and diagnosis of HCC is well known to be very limited. Okazumi et al. (11) proposed that HCC may be classified into 3 "metabolic" types according to the avidity of the tumor cells for 18F-FDG. The net accumulation of 18F-FDG-6-phosphate is determined both by the phosphorylation kinase activity (reflected by the kinetic rate constant k3) and by the abundance of the glucose-6-phosphatase activity (k4). In many forms of tumor tissue, 18F-FDG is "metabolically trapped" because 18F-FDG-6-phosphate can neither pass on to the next step of glycolysis nor back diffuse to the circulation because of the low concentration of glucose-6-phosphatase enzyme (k4 approaches zero). In normal liver parenchyma, the concentration of glucose-6-phosphatase is relatively high (nonzero k4). This actually may account for the fact that the intensity of normal liver is only mild on 18F-FDG PET imaging (SUV usually 
2.0), contrary to its role as the powerhouse of the human body. Okazumi et al. found that the type 1 hepatocellular carcinoma cells have a lower k4/k3 ratio and may show increased uptake on 18F-FDG PET imaging like many other forms of malignancy. Type 2 hepatocellular carcinoma cells have a k4/k3 ratio similar to that of normal hepatocytes and therefore may be isointense on 18F-FDG PET imaging. Type 3 tumor cells have a higher k4/k3 ratio and are actually hypointense. The combination of type 2 and type 3 tumors constitutes about a 43% false-negative rate in Okazumi’s group. In our study, the false-negative rate by account of tumor lesions is 52.7%, slightly higher than their reported value as well as those by others (6,10).
In fact, the degree and nature of tumor cell differentiation are known to affect the amount of 18F-FDG accumulation in cells, as suggested by other investigators with smaller samples in their studies (8,12,14). Early research on rat hepatomas had suggested that the patterns of glycolytic enzymes might reflect hepatoma cell growth, function, and graded dedifferentiation (29). Because well-differentiated hepatocellular carcinoma cells are histologically closer to the normal liver cells than to the undifferentiated types, the abundance of glucose-6-phosphatase enzyme may render these tumors undetectable. This relationship is strongly suggested by data in this study. Figure 5 shows that there is a statistically significant relationship of cellular differentiation with the tumor’s avidity for 18F-FDG and 11C-acetate metabolism in terms of the lesion-to-liver SUV ratio. The well-differentiated and well-to-moderately differentiated types tend to be negative for 18F-FDG; whereas the poorly differentiated and moderate-to-poorly differentiated types show increased 18F-FDG metabolism.
The use of 11C-acetate in tumor imaging has been suggested recently in urologic malignancies (15,16). Possible biochemical paths of acetate incorporation or accumulation include (a) entering the Krebs cycle from acetyl coenzyme A (acetyl CoA) or as an intermediate metabolite, (b) esterification to form acetyl CoA as a major precursor in ß-oxidation for fatty acid synthesis, (c) combining with glycine in heme synthesis, and (d) through citrate for cholesterol synthesis. Of all of these possible metabolic pathways, participation in free fatty acid (lipid) synthesis is believed to be the dominant method of incorporation in tumors. Yoshimoto et al. (30) suggested that this mechanism of tumor uptake was different from that of myocardium, in which 11C-acetate was channeled mainly to the Krebs cycle. The results of this study suggest that 11C-acetate is able to detect the entire proportion of HCC lesions that are negative on 18F-FDG imaging. In those tumors that are both 11C-acetate and 18F-FDG positive (the moderately differentiated type), some cases suggest that these tracers are taken up by different parts of the tumor (Figs. 2 and 3). Therefore, mixed metabolic constituents and kinetics are likely to be present within the same tumor at variable degrees. These 2 tracers are probably complementary to each other in the detection of HCC. The lesion-to-liver SUV ratios for 11C-acetate and 18F-FDG have a statistically significant relationship to each other in tumor cellular differentiation (Fig. 5). In the detection of individual tumor lesions (partial or whole tumor), the overall ability of 11C-acetate is better than that of 18F-FDG, with a detection sensitivity of 87.3% versus 47.3% using 18F-FDG. This relative accuracy appears to be highly dependent on tumor cellular differentiation. For HCC with 3 tumor lesions, tumor cells show a variable degree of differentiation with 60%–70% in the well- and moderately differentiated category. As tumor cells become more aggressive in later or advanced stages, cellular kinetic also change. The poor- or less well-differentiated tumor cells begin to retain 18F-FDG. In our study, all of the group Ib patients showed more 18F-FDG accumulation in their primary liver tumors and metastases, including vascular, nodal and distant metastases (except 1 case with a surgically confirmed moderately differentiated brain metastasis, as depicted in Fig. 4). Furthermore, the finding of a strong complementary relationship of 11C-acetate and 18F-FDG in the evaluation of HCC appears to be very important to the use of PET imaging in the monitoring of therapy in patients with this tumor.
The other interesting observation is that 11C-acetate may be quite specific for HCC in the evaluation of liver lesions. Our study showed that 11C-acetate is negative in hemangioma; cholangiocarcinoma (pure primary adenocarcinoma of liver without HCC components); secondary carcinomas from colon, breast, and lung; as well as carcinoid tumors. This specificity can be highly useful in the preliminary evaluation of unknown liver masses. When both tracers are positive or positive only for 11C-acetate, the likelihood for the tumor mass to be HCC is very high. On the other hand, when a liver mass is positive only for 18F-FDG but is negative for 11C-acetate, the possibility of non-HCC malignancy or poorly differentiated HCC should be considered. In case both tracers are negative, benign pathology is more likely. Two cases of FNH showed only mildly increased 11C-acetate metabolism. The lesion with the higher lesion-to-liver SUV ratio showed a value of 1.25, statistically lower than the average value of all of the 11C-acetate-positive HCC cases in this study (1.96 ± 0.63; P < 0.001).
It is not possible to include all other liver lesions in a single study; therefore, we studied only 2 FNH cases and 1 case of adenoma. In addition, other pathology such as fibrolamellar HCC and liver abscess have not yet been studied. In the next stage of evaluation, patients with smaller HCC lesions of <2-cm size and more severely cirrhotic livers may be investigated. The findings reported here and concurrent work on the kinetic modeling of 11C-acetate in HCC may add to the understanding of the molecular basis of this tumor. A reliable diagnostic PET radiopharmaceutical is important for formulating and monitoring therapeutic treatment of this tumor.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Chi-Lai Ho, MBBS, Department of Nuclear Medicine and PET, Hong Kong Sanatorium and Hospital, 2 Village Rd., Happy Valley, Hong Kong, China.
E-mail: garrettho{at}hksh.org.hk
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| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
, 11C-acetate; •, 18F-FDG. Values are sorted in descending order of 11C-acetate SUV ratios in each group.