HCC is the most frequent primary liver malignancy.1 Effective treatment depends on early diagnosis based on current guidelines of the American Association for the Study of Liver Disease (AASLD). However, diagnosis is challenged by the silent course of the disease, fluctuating serum alpha-fetoprotein (AFP) levels2 and inconclusive radiological findings. Factors such as low metabolism,3 physiological liver activity and false positive findings4 restrict the use of positron emission tomography integrated computed tomography (PET/CT) with 18F-FDG. However, it may be a valuable tool for detecting metastatic lymph nodes, distant metastasis and recurrent HCC.5,668Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT is an emerging imaging modality in prostate cancer.7 PSMA expression is also reported for non-prostate malignancies8–11 including HCC.12,13 In this regard the purpose of this study is to evaluate PSMA expression in patients with HCC.
MATERIALS AND METHODS
Nineteen HCC patients (16 men and 3 women; mean age: 57.8, range: 47–69) whom were indicated for 18F-FDG PET by the department of gastroenterology as a part of the restaging procedure, were also performed PSMA PET in a prospective manner. The diagnosis of HCC had already been established at the time of initial presentation, based on radiological imaging findings and AFP levels, based on criteria proposed by AASLD. Accordingly, the diagnosis was confirmed as definite 18 patients whereas biopsy was performed in 1 patient. The institutional ethics committee approved this prospective study, and written informed consent was obtained from all patients.
PET Imaging and Interpretation
PET/CT imaging was performed 60 min after intravenous injection of 18F-FDG (of 2.5 MBq/kg ± 10%) and 68Ga-PSMA (approximately 185 MBq) on a dedicated PET/CT scanner (Biograph TruePoint PET/CT; Siemens Healthcare) on separate days within 1 week. CT portions of PET/CT images were performed without contrast by using careDose 4D (Siemens Healthcare) to minimize radiation exposure.
68Ga-PSMA and 18F-FDG PET/CT images were interpreted by two board-certified nuclear medicine physicians in a binary fashion. Lesions were evaluated for presence or absence of uptake, intensity and pattern of uptake. Intensity of uptake was determined as absent, moderate or high for each tracer based on the visual evaluation and quantitative results. Semiquantitative analysis with determination of SUVmax involved drawing regions of interest around the primary liver lesion and around the metastases, if any. Regions of interest on normal liver tissue were drawn to calculate tumor to background ratios (T/B). Pattern of uptake was evaluated based on a 3-point scale: 1 for homogeneous distribution, 2 for moderately heterogeneous, and 3 for highly heterogeneous.
IBM SPSS 21.0 software was used to perform the statistical analysis. In the descriptive statistics of age, SUVmax and T/B, data were expressed as mean ± SD (standard deviation). Differences in SUVmax and T/B between PSMA and 18F-FDG uptake were assessed using Student’s t test. Pearson correlation test was used to measure the correlation between tracer uptake and time to death.
FDG uptake was present in 15 patients. On visual evaluation, HCC lesions showed high uptake in six patients and moderate uptake in nine patients. HCC uptake of three patients with moderate uptake was identified as highly heterogeneous. FDG distribution in 12 patients was homogeneous. In four patients, there was no FDG uptake but one of the tumors was necrotic. Mean SUVmax of HCC lesions were 8.3 ± 2.3 (range 3–22) and mean T/B was 2.3 ± 1.5.
PSMA expression was positive in 16 patients. Uptake intensity was moderate in 3 patients and high in 13 patients. In one patient with moderate lesion activity, the uptake pattern was highly heterogeneous. In three patients 68Ga-PSMA PET/CT was negative. Mean SUVmax of HCC lesions were 17.4 ± 9 (range 3.8–36.9) and mean T/B was 3.3 ± 2.2.
The metastatic lymph node was detected with both tracers and with SUVmax on FDG and PSMA PET are 9.6 and 4.3, respectively.
Comparison of FDG and PSMA
Two patients showed neither PSMA expression nor 18F-FDG uptake. In four patients, FDG uptake was visually and quantitatively higher than PSMA activity (Fig. 1). One of these patients was PSMA negative. In nine patients, PSMA activity was higher than FDG uptake; however, two of these patients were FDG negative (Figs. 2 and 3). Three patients demonstrated similar uptake levels and were identified as equivalent.
Excluding two patients with no uptake of both tracers, PSMA was negative in one patient and FDG was negative in two patients. One patient was PSMA negative but FDG positive whereas two patients were PSMA positive but FDG negative. Heterogeneous uptake pattern was observed in three patients. In two of these patients only FDG uptake was heterogeneous and in one patient both PSMA activity and FDG uptake were heterogeneous. Visual and quantitative results are summarized in Table 1.
When PSMA and 18F-FDG uptake were compared, there was no statistically significant difference between mean SUVmax and T/B values (P > 0.1). On the other hand, SUVmax of 68Ga-PSMA (P = 0.05) and 18F-FDG (P = 0.012) showed medium strength of correlation with overall survival. The mean survival was 25 months (range: 18–32 months).
Novel tracers are needed due to lack of sensitivity of FDG in HCC and studies have particularly focused on choline PET tracers in this regard.14 However, PSMA which is found in the tumor associated vasculature of non-prostate tumors, is also stained positive in nearly 95% of HCC tumor associated vasculature.15 Similarly, our results demonstrate 68Ga-PSMA uptake in 16 of 19 HCC patients.
Both tumor metabolism as assessed by 18F-FDG uptake and tumor angiogenesis have been reported to have predictive value in the identification of the patients with poor prognosis. Our results further support these findings as PSMA expression and metabolism of the HCC lesions as determined by SUVmax were both correlated with overall survival in this study. While there are studies reporting that 18F-FDG uptake is associated with the degree of angiogenesis, there are also reports that describe a poor association.16 In this regard the role of 18F-FDG PET in predicting tumor angiogenesis is uncertain. Considering PSMA expression as an indication of tumor angiogenesis, our findings represent a similar conflict such that 68Ga-PSMA uptake in nine patients and 18F-FDG uptake in four patients was higher than the other whereas uptake was equivalent in three patients. We observed heterogeneous PSMA (n = 1) and 18F-FDG uptake (n = 3). Intratumoral heterogeneity17–19 as well as the alterations in 18F-FDG biodistribution has been reported for HCC. We believe these findings reflect the heterogeneity of HCC. Heterogeneous PSMA expression is observed in various solid tumors,11 therefore it may also be true for HCC.
To best our knowledge, there is only one study evaluating PSMA PET in seven HCC patients.20 However, there are differences compared to our work. Our cohort includes patients with advanced disease compared to newly diagnosed patients presented by Kesler et al. Regarding uptake, T/B values are comparable, but our cohort includes tumors with no tracer uptake. Comparative results between FDG and PSMA also differ such that in our study FDG and PSMA uptake is correlated. In the study by Kesler et al. the great majority of the lesions are PSMA positive but FDG negative. We believe this dissimilarity is due to patient selection bias. Patients in the other study includes newly diagnosed (six of seven) patients thus FDG negative lesions may be due to well differentiated nature of the HCC and lack of poorly differentiated cells in early stages of disease. Higher than expected FDG positivity in our study may be due to the high proportion of obviously poorly differentiated HCC. In this regard it is possible that sensitivity of PSMA PET in early stages of disease may be superior to FDG PET. Kesler et al. concludes that PSMA PET is superior to FDG PET. Therefore, PSMA seems to be positive in early HCC as well as advanced disease and may have the potential in detecting HCC regardless of disease stage. Unlike Kesler et al. we calculated overall survival which was both correlated with FDG and PSMA activity and no tracer was superior than the other in predicting clinical outcome. On the other hand, PSMA expression as determined by PSMA PET might still be applicable to help with patient-specific treatment options. As angiogenesis inhibitors are an important therapeutic option in HCC21 role of PSMA in regulating angiogenesis22 creates an opportunity for PSMA PET for selecting patients eligible for anti-angiogenic therapy or monitoring response to therapy. In addition, PSMA itself is also a potential target for antiangiogenic therapy23 and PSMA-targeted therapies are also being investigated in this regard (NCT02607553, NCT02067156, NCT01777594). Since treatment options in advanced HCC are limited,24 PSMA targeted radionuclide therapy may also be considered as a palliative therapy when multiple lines of therapy have failed.
The current study has limitations to be disclosed. Firstly, all patients had prior diagnosis of HCC and were not performed biopsy at the time of initial diagnosis. Therefore, it was neither ethically nor technically possible to validate the lesions pathologically. Secondly, the study was not designed to evaluate the diagnostic value of PSMA PET in patients with suspected hepatobiliary malignancies that could yield better statistical results. However, the primary endpoint was to determine PSMA expression by imaging and considering the lack of prior research studies on the topic, the results might still be applicable to help with patient-specific treatment options.
Our results demonstrate evidence of PSMA expression of HCC with 68Ga-PSMA PET encouraging further studies in a larger patient cohort. Currently, selecting patients for PSMA-directed therapies seems to be a more relevant clinical application than diagnosis of HCC. Prospective studies on the utility of PSMA-directed imaging and/or therapy may be useful for patients with limited therapeutic options.
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