Use of F-18 FDG PET/CT Through Delayed Diuretic Imaging for Preoperative Evaluation of Upper Urinary Tract-Occupying Lesions

Purpose To evaluate the value of F-18 FDG PET/CT in the differentiation of malignant and benign upper urinary tract-occupying lesions. Patients and Methods 64 patients with upper urinary tract-occupying lesions underwent F-18 FDG PET/CT at RenJi Hospital from January 2015 to February 2019 in this retrospective study. Of the 64 patients, 50 patients received nephroureterectomy or partial ureterectomy; 14 patients received ureteroscopy and biopsy. The comparisons of PET/CT parameters and clinical characteristics between malignant and benign upper urinary tract-occupying lesions were investigated. Results Of the 64 patients, 49 were found to have malignant tumors. Receiver operating characteristic analysis determined the lesion SUVmax value of 6.75 as the threshold for predicting malignant tumors. There were significant associations between malignant and benign upper urinary tract-occupying lesions and SUVmax of lesion (P<0.001), lesion size (P<0.001), and patient age (P=0.011). Multivariate analysis showed that SUVmax of lesion (P=0.042) and patient age (P=0.009) as independent predictors for differentiation of malignant from benign upper urinary tract-occupying lesions. There was a significant difference in tumor size between the positive (SUVmax >6.75) and negative (SUVmax ≤6.75) PET groups in 38 of the 49 patients with malignant tumors. Conclusion The SUVmax of lesion and patient age is associated with the nature of upper urinary tract-occupying lesions. F-18 FDG PET/CT may be useful to distinguish between malignant and benign upper urinary tract-occupying lesions and determine a suitable therapeutic strategy.


INTRODUCTION
Lesions occupying the upper urinary tract are a commonly encountered problem in the urinary system and can be caused by several diseases. Identifying the cause of upper urinary tractoccupying lesions is often critical for optimal management and prognostication. Urine cytology is often used to diagnose upper urinary tract-occupying lesions (1,2). However, its sensitivity for detection of upper urinary tract occupying-lesions is not very high (3)(4)(5). Owing to miniaturization and increased scope flexibility, ureteroscopy demonstrates more accurate diagnosis (6)(7)(8). However, the accuracy of ureteroscopic biopsy is still inherently limited (8,9). Further cause for concern is the invasive nature of the procedure. Thus, alternative noninvasive strategies that can distinguish malignant from benign upper urinary tractoccupying lesions are needed. Though computed tomography urography (CTU) has been widely used for diagnosis of upper urinary tract carcinoma, benign diseases could mimic upper urinary tract carcinoma.
F-18 FDG PET was often used to differentiate between benign lesions and malignant tumors (10,11). However, use of F-18 FDG PET/CT in urinary system has developed slowly due to the uptake of F-18 FDG in urine. Though previous studies showed that delayed diuretic PET/CT could be used in the diagnosis of bladder cancer (12)(13)(14), only few studies investigated the value of F-18 FDG PET/CT in upper urinary tract-occupying lesions. Though the diagnostic sensitivity of F-18 FDG PET/CT for detecting metastasis was superior to CT in upper urinary tract carcinoma, it was not feasible to detect the primary tumor because of the radiotracer in the urine (15). The aim of our study was to investigate the value of F-18 FDG PET/CT through delayed diuretic imaging in determining the cause of upper urinary tract-occupying lesions.

Patient Demographics
In Renji Hospital delayed diuretic F-18 FDG PET/CT were routinely performed in patients with upper urinary tractoccupying lesions. 64 patients with upper urinary tractoccupying lesions who underwent F-18 FDG PET/CT were included at RenJi Hospital from January 2015 to February 2019 in this retrospective study. Before F-18 FDG PET/CT, 53 patients underwent contrast-enhanced CT, 7 patients underwent magnetic resonance, 2 patients underwent ultrasound and 2 patients underwent ureteroscopy. Despite the presence of upper urinary tract-occupying lesions on imaging (CT, magnetic resonance, and ultrasound) and ureteroscopy, the nature of the lesion were unclear. F-18 FDG PET/CT was undertaken to clarify the nature of the lesion and total-body condition. The inclusion criteria were: a) the consecutive patients who presented with an upper tract lesion underwent F-18 FDG PET/CT between January 2015 and February 2019; b) the lesions were subsequently histologically diagnosed; c) patients information including gender, age, primary site laterality, lesion site and pathological information were available. Of the 64 patients, 50 patients received nephroureterectomy or partial ureterectomy; 14 patients received ureteroscopy and biopsy. For the 49 had malignant lesions, radical resection was used for patients without metastatic disease and palliative nephroureterectomy was used for patients with metastatic disease. For the 15 patients had benign lesions, 7 patients received biopsy and 8 patients received surgical operation. All lesions were confirmed by pathological diagnosis. The tumor originated in the renal pelvis and the ureter in 31 (48.4%) and 33 (51.6%) patients, respectively. Patient characteristics are listed in Table 1. The institutional review board of RenJi Hospital approved this study. The informed consent was waived because it was a retrospective study.

F-18 FDG PET/CT Imaging
Blood glucose levels should be less than <140 mg/dL. After a minimum fasting and resting period of 6 h and 1 h, respectively, F-18 FDG was injected for every patient at the dose of 3.7 MBq/ kg. F-18 FDG PET/CT scanning was performed using a wholebody scanner (Biograph mCT; Siemens) (early PET/CT imaging). Delayed PET/CT imaging was performed after 120 min of early PET/CT imaging. Patients received intravenous furosemide (20 mg) and oral intake of at least 500 mL water. Delayed imaging covered a range of 1-2 bed positions centered at the location of the lesion. The response of delayed PET/CT imaging was uniform for all patients.
The PET/CT images were evaluated by two experienced nuclear medicine physicians (Yiping Shi and Ruohua Chen). They evaluated the images independently and were blinded to patients' information. For patients with metastatic disease, the SUVmax of urinary tract lesions were measured. When discrepancies occurred, they reached a consensus. There was perfect agreement between them (k coefficient = 0.96).

Statistical Analysis
The data are shown as mean ± SD. Statistically significant differences between groups were compared using the chisquare test, Fisher's exact test, or Mann-Whitney U test where applicable. P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS, version 13.0.

Differences Between Malignant and Benign Upper Urinary Tract Lesions
The relationship between patients' characteristics and malignant or benign upper urinary tract lesions were shown in Table 2. No significant differences were observed in lesion site, primary site laterality. However, there were significant differences in SUVmax, age, and lesion size. Malignant lesions showed

The Association Between Patient Characteristics and PET/CT In Patients Treated With Ureterectomy or Nephrectomy
Of the 49 patients with malignant tumors, 38 were treated with nephroureterectomy or partial ureterectomy. We investigated the relationship between patient characteristics and PET/CT parameters in the 38 patients ( Table 5). The patients were classified into two groups based on the SUVmax of malignant lesions: positive PET group (SUVmax > 6.75) and negative PET group (SUVmax ≤ 6.75). There were no significant difference between age, sex, tumor laterality, tumor site, T stage, N stage and positive/negative group. However, the positive PET group had larger tumor size than the negative PET group (30.8 ± 17.2 vs. 11.3 ± 4.7; P < 0.001).

DISCUSSION
F-18 FDG PET/CT is commonly used for diagnosis of many malignant tumors (16)(17)(18). However, FDG is not widely used in urology due to its urinary elimination (13). In this study, the value of F-18 FDG PET/CT for diagnosing upper urinary tractoccupying lesions was investigated. This study was the first to evaluate whether F-18 FDG PET/CT could be used for differentiating benign from malignant upper urinary tractoccupying lesions.  Upper urinary tract-occupying lesions are known to occur due to various diseases such as urothelial carcinomas or inflammatory hyperplasia (7). Although ureteroscopy and biopsy are commonly used for the diagnosis of benign and malignant lesions, its accuracy for upper urinary tract occupying-lesions is limited; furthermore, ureteroscopy is an invasive procedure that carries the risk of infection (19,20). In this study, we found that F-18 FDG PET/CT could be used to differentiate malignant from benign upper urinary tract-occupying lesions. The ROC analysis indicated that SUVmax can be used for predicting whether the lesion is benign or malignant. Multivariate analysis revealed that both the SUVmax of the lesion and age were independent predictors of the nature of the lesion. This is the first study to indicate that the SUVmax of upper urinary tract-occupying lesions could differentiate between benign and malignant lesions. When SUVmax was 6.75, the sensitivity and specificity for predicting malignant lesions were 75.5% (37/49) and 86.7% (13/15), respectively. In addition, we also found that patient age were significant predictors for predicting malignant lesions, which was consistent with previous studies.
We categorized patients with upper urinary tract-occupying lesions into high-potential, moderate-potential, and low-potential groups based on their potential for having malignant lesions, as indicated by SUVmax and age. The chance of having malignant lesions detected in 97.0% of the patients in the highpotential group, but only in 18.2% of the patients in the lowpotential group. These data suggest that the possibility of malignancy is very high in patients classified to the highpotential group; these findings merit further attention.
In this study, we also investigated the relationships between SUVmax of tumors and clinicopathologic features in 38 patients with malignant lesions. Our findings suggest that upper urinary tract urothelial carcinomas with high FDG accumulation are likely larger tumors. Therefore, when using SUVmax to distinguish malignant from benign lesions, the tumor size should also be considered. However, tumor size was not the independent predictor for malignant tumors in patients with ureteral occupying.
Our study had several limitations because it was a retrospective study and had small samples. In our study 14 patients were confirmed only by ureteroscopy and biopsy, and they have limitations in upper tract disease. Previous studies showed that micropapillary and sarcomatoid variants were associated with poorer oncological outcomes, and molecular markers such as human epidermal growth factor receptor−2 (HER2) is considered to be a potential prognostic and therapeutic marker in patients with upper tract urothelial carcinoma (21,22). In our study, no patients with micropapillary and sarcomatoid variants were found. They might be because our sample was small. In addition, molecular markers were not detected in our study, so the relationship between molecular markers and prognosis were not analyzed. Further prospective studies with large samples and molecular markers are needed to confirm our results.

CONCLUSIONS
Our study was the first to investigate the diagnostic value of F-18 FDG PET/CT in the upper urinary tract system and demonstrated that F-18 FDG PET/CT through delayed diuretic imaging could be used for differentiating malignant from benign upper urinary tract-occupying lesions. Our study may advance the development of noninvasive strategies to predict the cause of upper urinary tract-occupying lesions.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Renji Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.