Diagnostic accuracy of 18F-methylcholine positron emission tomography/computed tomography for intra- and extrahepatic hepatocellular carcinoma
Departments of Surgery, Academic Medical Center, the Netherlands
Address reprint requests to: Matthanja Bieze, M.D., Ph.D., Department of Surgery, Academic Medical Center, IWO 1-A1-132, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: M.Bieze@amc.uva.nl; fax: +31 20 6976621.
Potential conflict of interest: Nothing to report.
This article was presented at The Annual Congress of SNM in Miami 2012, The Congress of the IHPBA in Paris 2012, and The Congress of the E-AHPBA in Belgrade 2013.
Diagnosis of hepatocellular carcinoma (HCC) primarily involves imaging. The aim of this study was to assess the accuracy of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) for detection of HCC and evaluation of extent of disease. Patients with HCC >1 cm were included between 2009 and July 2011, and follow-up closed in February 2013. Diagnosis was based on American Association for the Study of Liver Diseases criteria, and all patients underwent 18F-FCH PET/computed tomography (CT) at baseline before treatment, 6 underwent a second PET/CT posttreatment, and 1 a third during follow-up. Whole-body PET and low-dose CT imaging were performed 15 minutes after 18F-FCH injection. Evaluation of imaging was done with standardized uptake value (SUV) ratios: SUV maximum of the lesion divided by the SUV mean of surrounding tissue. Statistical analyses included descriptive analyses, receiver operating characteristic curve, McNemar's test, and Kaplan-Meier's test at 5% level of significance. Twenty-nine patients revealed 53 intrahepatic lesions. In 48 of 53 lesions, 18F-FCH PET was positive (SUVratio, 1.95 ± 0.66; sensitivity, 88%; specificity, 100%). PET/CT showed uptake in 18 extrahepatic lesions and no uptake in 3 lesions affirmed non-HCC lesions; all lesions were confirmed with additional investigation (accuracy, 100%). In 17 of 29 patients, additional lesions were found on PET/CT imaging, with implications for treatment in 15 patients. Posttreatment PET/CT showed identical results, compared with standard treatment evaluation. Conclusion: This study shows additional value of 18F-FCH PET/CT for patients with HCC. 18F-FCH PET/CT has implications for staging, management, and treatment evaluation because of accurate assessment of extrahepatic disease. (Hepatology 2014;59:996–1006)
American Association for the Study of Liver Diseases
Barcelona Clinic Liver Cancer
field of view
gamma glutamyl transpeptidase
magnetic resonance imaging
negative predictive value
positron emission tomography
positive predictive value
receiver operating characteristic
standardized uptake value
Hepatocellular carcinoma (HCC) is the sixth-most common malignancy worldwide[1, 2] and varies greatly in geographic occurrence. Incidence of HCC in Eastern Asia and Middle Africa is at least 10 times higher as in Europe and the United States, although the incidence is increasing with the prospect of the rate noted in recent data from developed countries in Asia. The strongest correlation between underlying disease and HCC development is the cirrhotic liver, in which 80% of HCCs occur4; also, viral hepatitis, storage diseases, and nonalcoholic steatohepatitis can lead to HCC. The Barcelona Clinic Liver Cancer (BCLC) classification is generally used as the standard classification for HCC and was endorsed by the European Association for the Study of the Liver and American Association for the Study of Liver Diseases (AASLD; Fig. 1).[5, 6] This classification offers a correlation between the tumors' stage, underlying disease, treatment strategy, and prognosis.
In a (cirrhotic) liver, diagnosis of HCC is based on one multiphase computed tomography (CT) or dynamic magnetic resonance imaging (MRI) imaging study, if definitively characteristic for HCC. Only when imaging modalities are inconclusive is histological confirmation recommended. Metastatic disease also relies on assessment with MRI or CT imaging of the abdomen and thorax. Metastatic disease also relies on assessment with MRI or CT imaging of the abdomen and thorax. Finally, during treatment evaluation of HCC, accurate staging is necessary for selecting the best follow-up treatment for the patient.
However, imaging results are complicated by interfering effects of treatment, including necrosis, local inflammation, and fibrosis. This makes detection and distinction of viable tumor tissue difficult and, possibly, unreliable with CT and MRI. Even after many technical improvements in imaging modalities used for diagnosing HCC, detection and characterization of small (<2 cm) lesions remain difficult in the cirrhotic liver.
To maximize patients' treatment options, early and accurate detection of (metastatic) HCC is crucial in diagnostic work-up and in follow-up of patients.[5, 11] The 18F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET)/CT scan is used in oncological work-up and response-adapted treatment of certain tumor types, including esophagus and ovarian carcinomas. Also, for high-risk patients with breast cancer, there is increasing evidence that the FDG PET/CT scan can be used to modify staging and management as well as to evaluate treatment, including neoadjuvant chemotherapy. The diagnostic work-up for HCC does not include standard FDG PET/CT imaging, because diagnostic accuracy is limited, especially in well-differentiated HCC. FDG PET/CT has no additional value to conventional imaging in detection of HCC, and therefore PET/CT imaging is not implemented in guidelines for diagnostic work-up of HCC. Different radioactive tracers have been evaluated for HCC. In a study by Talbot et al., 18F-methylcholine (FCH) showed a sensitivity of 88%, compared to FDG (with 68%), and was found to be useful for detection and follow-up of patients with HCC. In a recent study by Cheung et al., the investigators strongly suggest the use of dual-tracer PET/CT (FDG and 11C-acetate) in staging liver transplant patients because this modality has a higher sensitivity and specificity than contrast-enhanced CT alone.
Bone scintigraphy is only advised as preoperative staging preceding liver transplantation, and no routine bone scan is necessary to detect asymptomatic bone metastases in patients with resectable HCC. Some data are available on cases in previously published studies and uptake of choline tracer in HCC bone metastases.[15, 20] Early detection of (extrahepatic) HCC is of clinical importance.[21, 22] The 18F-FCH PET/CT is a promising additional diagnostic tool, which might be useful in the diagnostic work-up of HCC, including assessment of metastatic disease and follow-up to assess treatment effectiveness, recurrence, and disease progression.
The aims of this study were to (1) assess the sensitivity of 18F-FCH PET/CT for detection of intrahepatic and metastatic HCC and (2) determine the role of 18F-FCH PET/CT in patient management and determine whether 18F-FCH PET/CT is accurate for evaluation of tumor response to treatment.
Materials and Methods
This study is a prospective, single-center, investigator-driven study for diagnostic accuracy. The study was approved by the local medical ethics committee, and written informed consent was obtained from all patients. Patients with suspicion of HCC were presented at multidisciplinary meetings and screened for potential inclusion for the study. Patients were eligible if primary or recurrent intrahepatic HCC larger than 2 cm was present, and patients were 18 years of age or older. Patient inclusion depended on availability of the 18F-FCH tracer in regard to the fast-track treatment plan as well as on mobility of the patient and his or her proximity to the hospital (over 30 minutes of traveling time were considered unethical for the severely ill patient). Only if PET imaging could be combined with other necessary investigations were these patients asked to participate in the study. After patient inclusion, laboratory tests were assessed for alpha-fetoprotein (AFP) and serum liver tests (aspartate aminotransferase [AST] normal: <40 U/L; alanine aminotransferase [ALT] normal: <45 U/L; alkaline phosphatase [ALP] normal: <120 U/L; gamma-glutamyl transpeptidase [GGT] normal: <60 U/L). History of hepatitis, Gaucher's disease, hemochromatosis, and other preexisting hepatic conditions were noted.
Thirty nonconsecutive patients (median age: 63 years; range, 18-84) were included between 2008 and July 2011, and follow-up closed in February 2013. Table 1 summarizes patient characteristics. In 3 patients, lesion(s) were incidentally found on imaging performed for general check-up or other unrelated indications. In 12 patients, lesion(s) were found during follow-up of high-risk underlying parenchymal disease, and in 15 the presenting symptoms were consistent with HCC on imaging.
18F-FCH has a half-life of 110 minutes, the kidney is the dose-critical organ, and 18F-FCH reaches a steady distribution in the liver within 10 minutes. Through choline transporter(s) or facilitated diffusion, choline is transported into the cell. Three major metabolic pathways of choline are known (Fig. 2), with radiolabeled phosphocholine as the major metabolite in cancers responsible for choline uptake in PET imaging.[26, 27] 18F-FCH was synthesized as previously described by Degrado et al. This resulted in 18F-FCH with a 98% or more radiochemical purity. PET/CT was performed using a Philips Gemini TF-16 PET/CT scanner (Philips Medical Systems, Eindhoven, the Netherlands), with spatial resolution near the field-of-view (FOV) center of 4.8 mm in transverse and axial directions. PET images were acquired at 2 minutes per bed position (FOV). An average of 10 bed positions were acquired. FOV overlap is 50%. Total acquisition time, including CT, is 25 minutes. A whole-body, low-dose CT scan in the supine position was acquired, encompassing the body from skull base to mid-thigh. The 12-channel helical CT scanning parameters were as follows: 120 kVp; 50 mA/slice; rotation time of 0.75 seconds; and slice thickness/interval of 5.0 mm. No intravenous (IV) contrast was used. At 15 minutes after IV injection of 150 MBq of 18F-FCH, whole-body emission scans were acquired from mid-thigh to skull base.
Image reconstruction employed a list-mode version of a maximum likelihood expectation maximization algorithm with a time-of-flight kernel applied in both the forward- and back-projection operations. CT data were used for attenuation correction. PET images were analyzed by a nuclear radiologist (15 years of experience in nuclear medicine and a 2-year abdominal radiology fellowship training) and the low-dose CT images by a radiologist experienced in abdominal radiology (12 years of experience in liver and abdominal radiology). Both readers were blinded for patient history, previous imaging, and pathology reports, but were aware of the differential diagnosis of HCC. PET/CT images were evaluated on a workstation (Hermes Medical Solutions, Stockholm, Sweden). HCC often presents in the background of a cirrhotic liver. This leads to inhomogeneous uptake of the 18F-FCH tracer in the liver surrounding the HCC lesion. Therefore, we decided to use a ratio to evaluate uptake of the tracer: This made comparison between patients possible, because every patient is his or her own control. The maximum standardized uptake value (SUV) of the lesion(s) and the mean SUV of nonaffected (liver) tissue were determined. The SUVmean of the liver was determined in part of the liver without tumor load using a circle region of interest of 50 pixels. The SUV ratio was calculated by dividing the maximum SUV of the lesion (SUVmax lesion) by the mean SUV of the nonaffected liver (SUVmean liver). In the case of extrahepatic localization of 18F-FCH uptake in the surrounding or contralateral mesenterial, bone or lung tissue was used as the mean reference, depending on the location of the lesion (SUVmean tissue):
Response to treatment was assessed on standard imaging in the following manner: Compared to imaging before treatment, tumor size, intensity of arterial enhancement on dynamic imaging of the primary lesion, and extent of disease was evaluated on imaging (dynamic CT and/or MRI). PET imaging was assessed for intensity (SUVratio) of the lesion, compared to primary imaging, as well as size of the lesion, and extent of disease.
Standard of Reference
Diagnosis, staging, and treatment selection was made according to the AASLD criteria.[5, 6, 29] The primary diagnosis was based on one or two imaging modalities consistent with HCC: MRI with gadolinium contrast or with additional hepatobiliary contrast ethoxybenzyl diethylenetriamine pentaacetic acid (Primovist; Bayer, Berlin, Germany) were used to confirm diagnosis. MRI was performed with a 1.5T MRI scanner (Avanto; Siemens Medical System, Erlangen, Germany). MRI series consisted of conventional in- and opposed-phase imaging, coronal T2-weighted fat-saturated images, diffusion-weighted echo planar imaging, T2-weighted HASTE, and pre- and postcontrast T1-weighted fat-saturated images. Hepatobiliary phase images, if used, were made at 20 minutes postinjection. Images were evaluated on characteristic morphology of the lesion. Hyperintensity on the arterial T1-weighted series with subsequent loss of signal intensity (washout) on the portal T1-weighted series was diagnostic for HCC. As a secondary imaging modality, multiphase CT imaging was used. CT images consisted of precontrast, arterial, portal/venous, and late series. Characteristics of HCC included hyperintensity on the arterial phase and subsequent washout during the portal or late phase of imaging. Whenever histopathology was obtained, this was used as the final standard of reference. The histological specimen was obtained by biopsy or resection. In 1 patient (18 years of age), the 4 hepatic lesions were primarily diagnosed as HCC and after resection diagnosed as hepatic blastomas. The 18F-FCH PET/CT imaging data from this patient were excluded from analyses.
Staging and extent of the disease were assessed with the standard of care using CT thorax and abdomen. Size, location, and additional hepatic lesions were noted. Abdominal lymph nodes and lung nodules larger than 1 cm in short axis were considered enlarged in patients without underlying inflammatory hepatic disease and larger than 2 cm in patients with inflammatory hepatic disease. No radiological screening for bone lesions was performed as part of the standard of care. Results of 18F-FCH PET/CT imaging were always checked on primary imaging, additional investigation, or close follow-up, especially when treatment might be altered based on the results (see flow chart of the study; Fig. 3).
Statistical analysis was performed using SPSS 20 (IBM Corporation, Armonk, NY). Descriptive statistics were used to assess study population. A Kaplan-Meier estimator plot of cumulative survival was made. A receiver operating characteristic (ROC) curve was performed to assess the cutoff for the SUVratio. Mann-Whitney's test was used to assess continuous factors. Pearson's chi square and Fisher's exact correlation tests were used for categorical data analyses. Sensitivity and specificity were based on McNemar's test. The positive (PPV) and negative predictive value (NPV) of the test was calculated and the confidence interval of the proportions was based on Wilson's procedure without correction for continuity. All statistical tests were evaluated at the 5% level of significance.
Diagnosis in the 29 patients with HCC was confirmed with histopathology in 17 (14 resection specimen and 3 biopsy specimens). In 12 patients, diagnosis was based on imaging. Curative treatment was performed in 13 patients with resection and 1 with radiofrequency ablation (RFA). Palliative care was performed in 15 patients: 6 with transarterial chemoembolization (TACE) and 9 with sorafenib (with or without local treatment with RFA and/or TACE). One patient died of other causes and was excluded from survival analyses. Eleven patients died as a result of spread of the disease. Seventeen patients were alive in February 2013 when follow-up closed. The cumulative survival is shown in Fig. 4.
Baseline 18F-FCH PET/CT
In all, 29 patients with 81 lesions on baseline 18F-FCH PET/CT were evaluated: 53 intrahepatic HCC and 28 extrahepatic lesions. Results are shown in the flow chart and online (Supporting Table I). The ROC of SUVratio on baseline PET/CT imaging was performed (with Fig. 5), resulting in an SUVratio cutoff of 1.12 (sensitivity, 0.912; specificity, 1.0).
Thirty-five of fifty-three (66%) intrahepatic lesions were typical HCC on standard imaging and 18 of 53 (34%) lesions were missed, atypical, or non-HCC on standard imaging (Supporting Table I). The additional findings were found correct on imaging, additional investigation, or by means of follow-up (Supporting Table I). Extrahepatic lesions were found on standard imaging in 4 of 28 (14%) lesions. Eighteen of twenty-eight (64%) lesions were missed, atypical, or non-HCC on standard imaging and found correct on standard imaging, additional investigation, or by means of follow-up (Supporting Table 1). The remaining 6 lesions (4 patients) did not have a reference on standard imaging or additional investigation; however, if lesions were found positive, this would not have changed treatment in 3 of 4 patients, therefore no additional investigation needed to be performed. In 1 of 4 patients, there was no thorax imaging to corroborate additional lung and lymph node lesions detected on 18F-FCH PET/CT. This might have changed the treatment strategy from local therapy (TACE) to sorafenib. Future follow-up will have to determine the extent of disease. These 6 lesions were excluded from 18F-FCH PET/CT SUVratio evaluation for extrahepatic disease.
AFP was not significant for increased SUVratio or SUVmax of the lesion (0.941 and P = 0.825, respectively). AFP was significant for overall survival: Patients with AFP >30 had worse survival, compared to patients with normal AFP levels (P = 0.003).
With intra- and extrahepatic lesions combined, a total of 36 additional lesions on 18F-FCH PET/CT imaging were found in 17 of 29 (59%) patients. This led to change in 15 of 29 (52%) patients (flow chart 2). In 1 of 30 patients, the intrahepatic lesion was photopenic on 18F-FCH PET/CT, but typical HCC on standard imaging. Final histopathology of the resection specimen showed moderately differentiated HCC.
Baseline 18F-FCH PET/CT imaging for intrahepatic HCC showed a sensitivity of 88% (Table 2), with median SUVratio of 1.95 ± 0.66 (range, 1.14-4.24) for positive lesions. Baseline 18F-FCH PET/CT imaging for extrahepatic lesions showed a sensitivity of 100%, with median SUVratio of 4.41 ± 3.62 (range, 2.48-13.80) for positive lesions (Table 2).
Table 2. Sensitivity and Specificity of Baseline FCH PET/CT
Sensitivity and specificity are based on the McNemar's test. NPV is calculated for HCC lesions, with only 1 non-HCC lesion. Therefore, this NPV cannot be used to conclude on non-HCC lesions, which are supposed to be negative for 18F-FCH PET/CT.
Two intrahepatic lesions were excluded from analyses because no reference for diagnosis was available.
Seven extrahepatic lesions were excluded from analyses because no reference for diagnosis was available.
In 6 patients, treatment evaluation 18F-FCH PET/CT was performed. Results are shown in the flow chart and online (Supporting Table II). In 4 of 6 patients, evaluation of treatment was possible with 18F-FCH PET/CT and showed identical results as standard imaging: no recurrence in 1 patient and progressive disease in 3. Progressive disease presented as increase of SUVratio (Supporting Table II, indicated under PET/CT with ↑) and/or presence of new (extrahepatic) lesions on 18F-FCH PET/CT (Fig. 6C). Additional findings were made with the 18F-FCH PET/CT: In one of six treatment evaluations, 18F-FCH PET/CT showed extrahepatic disease (lung and adrenal gland), whereas standard imaging of the patient showed no new disease or recurrence because the findings were outside the imaging field. Finally, 1 patient showed progressive disease on 18F-FCH PET/CT imaging and standard imaging, by increased size and number of lesions. However, treatment evaluation and additional follow-up 18F-FCH PET/CT showed a decrease in SUVratio.
This study showed that 18F-FCH PET/CT can depict intrahepatic HCC with 88% accuracy. In addition, extrahepatic disease was detected on 18F-FCH PET/CT, which was not visible on standard imaging. Finally, the results suggest the option for a potential novel way to evaluate biological response to treatment.
In case HCC shows no extrahepatic spread of disease, ablative local regional treatment is possible. However, extrahepatic metastases are not uncommon, and treatment of these patients is restricted to palliative systemic treatment with poor prognosis. Therefore, accurate pretreatment staging of HCC is crucial. Our study shows that in over half of the included patients, additional lesions were found on 18F-FCH PET/CT imaging, with treatment implications in 50% of patients. The additional value of 18F-FCH PET/CT lies in accurate whole-body assessment with regard to extent of disease, which has direct implications for staging and treatment decisions. Sensitivity for 18F-FCH PET/CT for hepatic HCC was 89%, and for extrahepatic HCC sensitivity was 100%.
In this study, 6 patients underwent posttreatment 18F-FCH PET/CT imaging, and based on 18F-FCH PET/CT, treatment evaluation was accurate, compared to standard imaging. Local effects after TACE, RFA, or sorafenib, including necrosis in the lesion, were shown as a decrease in SUVratio as an indication of altered tumor metabolism. Also, recurrence of HCC after RFA and TACE or detection of new (extrahepatic) lesions were shown on 18F-FCH PET/CT and could be used for follow-up of HCC patients. Song et al. used SUVratio (SUVmax/ SUVmean liver) as a method to evaluate HCC lesions with FDG PET/CT. The investigators concluded that with this method, tumor progression can be predicted. The use of SUVratio is especially useful with underlying parenchymal disease such as the cirrhotic liver, which affects the tracers' uptake. The patient is his or her own control because the surrounding liver is used as the reference, and in this way, the SUVratio better represents tumor metabolism in light of underlying disease. Hypothesis generating 18F-FCH PET/CT imaging could be used in the future for “modified response evaluation criteria in solid tumors” for HCC.
One patient, who underwent a total of three 18F-FCH PET/CT studies, showed results that differed from the expected result: The first two 18F-FCH PET/CT studies showed positive hepatic disease with extrahepatic spread with progression, both in size and in SUVratio. The final 18F-FCH PET/CT study, after several months of sorafenib use, showed decrease in SUVratio of the hepatic lesion (extrahepatic disease positive). The size of hepatic involvement did increase, as well as serum AFP, and the number of extrahepatic lesions. This decrease in SUVratio could be explained by dedifferentiation of the hepatic lesion during the course of the disease, resulting in no uptake of 18F-FCH. Studies show that 18F-FCH is most sensitive in well- and moderately differentiated HCC and less in poorly differentiated hepatic HCC lesions.
When patients present with typical HCC and a history of another malignancy, lung lesions, for example, are difficult to characterize on imaging as one or the other. 18F-FCH PET/CT imaging in this study was sensitive in differentiating extrahepatic HCC lesions from renal cell and urothelial carcinomas. A study by Talbot et al. suggests that 18F-FCH PET/CT imaging does not show uptake in colorectal liver metastases. However, further study will have to determine whether colorectal lung metastases do show up on 18F-FCH PET/CT imaging and could differentiate between both entities. The SUVratio might also have prognostic value, as was shown by Morris et al. for breast cancer and by Lee et al. for HCC.
MRI is the most sensitive imaging modality for (small) HCC lesions, as it has the potential to combine dynamic evaluation of the lesion (in and out phase) and diffusion images. The latter is useful for detection of very small lesions (1-2 cm), and this method increases detection of possible HCC lesions. Therefore, the additional value of 18FCH-PET/CT does not lie in detection of intrahepatic lesions, but in detection of extrahepatic lesions to evaluate metastatic disease.
This study has some limitations. The inclusion of patients was not consecutive because of logistics, and evaluation of 18F-FCH PET/CT images was performed by one experienced nuclear medicine physician. Logistics of 18F-FCH PET/CT imaging might impair its use because synthesis of the 18F-FCH tracer and the possibility of PET/CT imaging are not available in every medical center. Finally, PET/CT imaging is costly when implemented in pretreatment workup for patients with HCC. However, accurate pretreatment staging will prevent unnecessary interventions, including expensive surgery, TACE, and experimental local treatment. This study has a limited number of patients, and therefore further investigation in a larger cohort is warranted to confirm our findings and determine, in more detail, at what time point FCH PET/CT is most valuable for the individual patient. A study with prospective design, including consecutive patients with HCC confirmed on imaging, is preferable. Nuclear medicine physician(s) should be blinded for outcomes of standard imaging, and abdominal radiologist(s) evaluating standard imaging should be blinded for outcome of PET/CT imaging. If possible, results should be discussed in a multidisciplinary team to discus outcomes of both imaging modalities to maximize treatment options and evaluation.
This study shows additional value of 18F-FCH PET/CT to conventional imaging in the assessment of extent of intra- and extrahepatic disease in patients with HCC. 18F-FCH PET/CT has additional value in an accurate assessment of extrahepatic disease. 18F-FCH PET/CT has the potential to be considered in patients who are in the workup for curative treatment, especially in patients with high hepatic tumor load. The role of 18F-FCH PET/CT in evaluation of treatment needs to be confirmed in additional studies.
The authors acknowledge the support of Dr. A.D. Windhorst and the Radionuclide Center at the Free Univeristy of Amsterdam for synthesis of FCH.