Efficacy of Pre-operative 18F-FDG PET/CT in Prognostic Prediction in Patients With Renal Cell Carcinoma
1Department of Radiology, Miyako Prefectural Hospital, Okinawa, Japan
2Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3Graduate School of Medical Science, University of the Ryukyus, Department of Urology, Okinawa, Japan
4Department of Radiology, Urasoe General Hospital, Okinawa, Japan
5Graduate School of Medical Science, University of the Ryukyus, Department of Radiology, Okinawa, Japan
18F-fluorodeoxyglucose positron emission tomography/ computed tomography (FDG-PET/CT) is used for the assessment of tumor glucose metabolism, and is widely accepted as a pre-operative tumor staging, postoperative follow up, and monitoring treatment response imaging modality in many patients with malignancy. However, since renal cell carcinoma (RCC) displays limited FDG accumulation due to physiological excretion of FDG by the tumor (1), FDG-PET/CT is not always appropriate for preoperative evaluation of patients with RCC. In clinical practice, the histological diagnosis of RCC, tumor spread, lymph nodes, and distant metastases can be evaluated by dynamic contrast-enhanced CT and MRI in the majority of cases.
Contrary to current practice, some recent studies have demonstrated that pathological nuclear grade and histological subtypes of RCC can be predicted by the maximum standardized uptake value (SUV max) on preoperative FDG-PET/CT (2-4). There is limited research on the power of FDG-PET/CT analysis for prognosis parameter evaluation, such as disease-free survival (DFS), progression-free survival, and overall survival in patients with RCC (5-9). Furthermore, no studies have performed prognostic analysis of cases with surgically resected RCC while accounting for confounding factors. Therefore, if preoperative FDG-PET/CT can be used to evaluate the risk of recurrence or metastasis after surgery, aid tumor staging, and provide pathological information, the clinical relevance of FDG-PET/CT in renal neoplasm diagnosis and prognosis would be increased. Moreover, FDG-PET/CT can provide several metabolic parameters, such as SUV peak, SUV mean, and metabolic tumor volume (MTV) in addition to SUV max. SUV peak represents the average SUV over a small volume of interest centered on the SUV max and its neighboring voxels and is less affected by image noise than SUV max. MTV and SUV mean can evaluate not only metabolic activity but also total tumor burden.
Therefore, we examined whether several functional parameters provided by preoperative FDG-PET/CT were useful for predicting recurrence or metastasis before surgery.
Patients and Methods
We determined the significant predictors that influence prognosis by comparing the two groups according to the presence or absence of recurrence in patients with all RCC and clear cell RCC. Considering the obtained predictor as a confounding factor, multivariate Cox proportional hazard regression models were conducted to evaluate the factors potentially predicting DFS and estimate hazard ratios with 95% confidence intervals, after adjustment for confounding factors.
Finally, we established the optimal cut-off value of SUV parameters by the Youden index, which predicts recurrence in patients with all RCC and clear cell RCC using receiver operating characteristic (ROC) analysis. For each parameter, sensitivity, specificity, and diagnostic accuracy were also calculated. Kaplan–Meier analysis was used to estimate the probability of DFS based on the obtained cut-off value. The DFS was defined as local recurrence, lymph node metastasis, or distant metastasis. The log-rank test was used to assess the resulting DFS curves. A
In all RCC patients, mean age was 61±11 (47 male, 38 female). Fifteen patients had diabetes mellitus, 3 of which used insulin. Median tumor size was 4.1 (IQR=2.6-5.7) cm. T-stage (T1a, T1b, T2a, T2b) was 39, 33, 10, and 3 in all cases, respectively. Median value of SUV max, SUV peak, SUV mean, and MTV were 3.76 (IQR=3.09-5.16), 3.21 (IQR=2.69-4.24), 2.42 (IQR=2.08-3.34), and 11.03 (IQR=4.60-33.6), respectively. Median observation time was 385 (IQR=189-675) days. There were nineteen cases of non-clear cell RCC, including four chromophobe RCC cases, three type 2 papillary RCC, five acquired cystic disease-related RCC, one 6p21translocated RCC, one collecting duct carcinoma, and two unclassified RCC.
Among all RCC cases groups, ROC analysis demonstrated that the optimal cut-off value, sensitivity, specificity, and accuracy in each SUV parameter for predicting DFS were 10.54, 63.6%, 94.6%, and 90.6% for SUV max, 8.90, 54.5%, 97.3%, and 91.8% for SUV peak, 5.70, 63.6%, 93.2%, and 89.4% for SUV mean, respectively.
Among the clear cell RCC cases, the optimal cut-off value, sensitivity, specificity and accuracy in each SUV parameter for predicting DFS were 10.54, 55.6%, 98.2%, and 92.4% for SUV max, 8.73, 55.6%, 98.2%, and 92.4% for SUV peak, 5.70, 55.6%, 98.2%, and 92.4% for SUV mean, respectively. For all indicators, accuracy rate was as high as approximately 90%.
Kaplan–Meier curves between two groups divided by the obtained each cut-off value are shown in
In the two groups, the HR of SUV max, SUV peak, SUV mean by each cut-off value was 12.6 (95%CI=3.523-44.7), 9.62 (95%CI=2.754-33.6), and 11.0 (95%CI=3.059-39.24) among the all RCC group, and 10.2 (95%CI=2.528-40.98), 10.2 (95%CI=2.528-40.98), and 10.2 (95%CI=2.528-40.98) among the clear cell RCC group.
Representative cases of clear cell RCC with high SUV max (
In the current study, FDG-PET/CT was found to be a useful modality for assessing the risk of recurrence. Specifically, the parameters of SUV max, SUV peak, and SUV mean were independent prognostic predictors of local recurrence/ metastasis, regardless of the histologic RCC subtype. Furthermore, the optimal cut-off value, by which it is possible to detect cases of high-risk of recurrence/metastasis, was also demonstrated, with accuracy rate of approximately 90% and a hazard ratio of approximately 10.
Among previous studies that used PET to discriminate tumours based on the Fuhrman grades, Nakajima
Regarding FDG accumulation, past reports demonstrate the correlation between glucose transporter 1 (GLUT1) expression and FDG uptake in tumours derived from organs other than kidney (14,15). In renal cancer, no correlation between FDG uptake and GLUT1 expression has been demonstrated (1,16). In contrast, Chen
In general, patients with RCC have a relatively good prognosis, especially cases where surgery is indicated, with a 5-year survival rate of approximately 70%. Although many patients do not experience recurrence or metastasis for a long period after surgery, recurrence or metastasis sometimes occurs soon after surgery even when pre-operative CT or MRI shows image findings typical of early-stage clear cell carcinoma.
The cut-off values in FDG-PET/CT parameters made it possible to classify those cases preoperatively. Thereby, we were able to estimate a 10 times higher risk of recurrence/ metastasis with high accuracy rate of approximately 90% if a SUV parameter was set at an appropriate threshold. For patients whose risk of recurrence/metastasis is high, careful follow-up after surgery facilitates the speed in implementation of adjuvant therapies, such as molecular-targeted drugs and immune checkpoint inhibitors, immediately after recurrence, resulting in improved prognosis. Furthermore, the cost will be decreased by precluding the need for unnecessary sequential image screenings in patients with low recurrence/metastasis risk. The current study demonstrates that preoperative FDG-PET/CT is useful for evaluating the risk of recurrence/ metastasis, clarifying the role of preoperative imaging modalities. In other words, dynamic CT and MRI can be used to assess the histological subtype, local tumor progression, lymph node metastasis, and distant metastasis. FDG-PET/CT can be used to assess prognosis (
The limitations of the current study are its retrospective nature and the small sample size, especially in the non-clear cell RCC cohort. The reason of sample size was because FDG-PET/CT was introduced at our institute and it applied to urological malignancies only recently. In addition, postoperative follow up was performed at the initial hospital.
In conclusion, preoperative FDG-PET/CT is a useful modality for prognostic assessment of RCC after surgery.
Conflicts of Interest
The Authors have no relevant financial or non-financial interests to disclose regarding this study.
All Authors contributed to the study conception and design. Masafumi Toguchi prepared the first draft of the manuscript, performed data collection and analysis. Kousei Ishigami provided critical revision. Masato Goya and Seiichi Saito provided intellectual clinical advises and contributed to the interpretation of data. Sadayuki Murayama and Akihiro Nishie commented on previous versions. All Authors read and approved the final manuscript.
This work was supported by JSPS KAKENHI Grant Number 19K08124.