Functional Parameters of 18F-FDG PET/CT in Patients with Primary Testicular Diffuse Large B-Cell Lymphoma

Fluorine-18 fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT), a hybrid imaging technique that simultaneously provides functional and anatomical information, has been reported to be useful in lymphoma. The present study was to evaluate the functional parameters of 18F-FDG PET/CT in patients with testicular diffuse large B-cell lymphoma (DLBCL). We retrospectively reviewed medical records of 5095 patients with lymphoma who treated at West China Hospital between March 2003 and January 2017, and selected patients with 18F-FDG PET/CT findings and subsequently biopsy confirmed the invasion of testis with DLBCL. Maximum standardized uptake values (SUVmax), peak standardized uptake values (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the patients were measured. We evaluated the characteristics of 18F-FDG PET/CT in this population. Six patients ranged in age from 37 to 73 years (median age, 58 years) were included in the analysis. The mean SUVmax was 11.09 and varied between 7.20 and 19.75; mean SUVpeak was 9.56 and ranged between 6.79 and 14.39. In addition, mean MTV 42% was 18.4 and varied between 1.3 and 61.6; mean MTV 2.5 was 34.7 and varied significantly between 1.6 and 141.9. With regard to TLG, mean TLG 42% was 168.906 and ranged from 7.514 to 687.004, while mean TLG 2.5 was 253.972 and ranged from 8.400 to 1127.802. In conclusion, 18F-FDG PET/CT scan is a useful tool in patients with testicular DLBCL. SUV, MTV, and TLG may vary a lot in different patients. SUVmax of testicular DLBCL lesion is relatively higher than that of normal testis. Also, we provided a set of MTV and TLG data and firstly showed their significant correlation with overall survival, which indicated a potential prognostic value of MTV and TLG. However, studies with larger population are needed to confirm these findings.


Introduction
Testicular lymphoma is a rare but aggressive form of extranodal lymphoma, accounting for 3-9% of testicular cancers and 1-2% of non-Hodgkin's lymphomas [1,2]. In spite of the low overall incidence, testicular lymphoma is the most common testicular malignancy in men over 60 [2]. Testicular diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype, accounting for about 80% to 98% of all cases [3]. Although radical inguinal orchiectomy is recommended in view of histological evaluation, invasiveness often hinders its wider adoption [4]. Other diagnostic methods include testicular ultrasound, computed tomography (CT), routine blood test, lactate dehydrogenase, bone marrow biopsy, and lumbar puncture [5].
Fluorine-18 fluorodeoxyglucose ( 18 F-FDG) positronemission tomography/computed tomography (PET/CT) is a hybrid imaging technique that simultaneously provides functional and anatomical information. 18 F-FDG PET/CT is important in biomedical research and clinical diagnostics, and its application in lymphoma has already been reported [6,7].
ere are several parameters being repeatedly discussed in recent studies, including maximum standardized uptake values (SUV max ), peak standardized uptake values (SUV peak ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), since they are believed to play important roles in the diagnosis and prognosis of patients with lymphoma [8][9][10]. erefore, the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of 18 F-FDG PET/CT for staging, response evaluation, and prognosis of lymphoma. However, the role of 18 F-FDG PET/CT among patients with testicular DLBCL has still not been well established. In this study, we reported 6 patients with testicular DLBCL who had performed 18 F-FDG PET/CTscan and discussed the role of 18 F-FDG PET/CT in this population at the same time.  18 F-FDG PET/CT was performed using a Gemini GXL PET/CT scanner (Philips, Amsterdam, e Netherlands). Fasting for at least 6 hours was required before the examination, and the blood glucose level was measured immediately before the administration of 18 F-FDG. e PET/CT scan would be rescheduled if the blood glucose level was >150 mg/dL. Approximately 5 MBq of 18 F-FDG per kilogram of body weight was administered intravenously, and the patients rested in a quiet, dark environment for approximately 60 minutes before scanning. After initial low-dose CT (40 mA, 120 kVp), emission images were obtained from the top of the skull to the middle of the thigh, with acquisition times of 2 minutes per bed position in the three-dimensional mode. e PET images were reconstructed iteratively with CTbased attenuation correction (Figures 1 and 2).

Image Analysis.
e image analysis was performed using Compass Viewer software. Circular regions of interest (ROIs) were manually drawn on axial, coronal, or sagittal coregistered PET/CT slices. Within the selected ROI, SUV max , mean standardized uptake values (SUV mean ), SUV peak , MTV, and TLG were measured. SUV max were calculated using the following formula: mean ROI activity (MBq/g)/(injected dose (MBq)/body weight (g)). SUV peak was defined as the mean of SUV max and its 10 neighbors (roughly corresponding to a 0.5 cm ROI). MTV and TLG could be measured by a fixed background SUV cut-off or a fixed percentage of the SUV max . In this study, we calculated SUV mean and MTV based on a fixed threshold of 42% of SUV max (SUV mean 42%, MTV 42%) or based on a fixed background SUV cut-off of 2.5 (SUV mean 2.5, MTV 2.5). TLG was defined as the MTV multiplied with the SUV mean (TLG 42%, TLG 2.5).

Statistical Analysis.
Correlation analysis between the functional parameters of 18 F-FDG PET/CT and overall survival (OS) was conducted, and Spearman's rank coefficients were used to assess the relationship between the functional parameters and outcomes of the patients. Statistical analyses were performed using the SPSS version 22.0 (IBM Corporation, Armonk, NY, USA) at a significance level of p < 0.05.

Results
A total of 34 patients with testicular lymphoma were selected from this population. Eighteen of them had 18 F-FDG PET/CT findings while only 6 had preoperative images. As a result, 6 patients ranging from 37 to 73 years old (median age, 58) were included in the analysis. Patients' characteristics including the histological type, Ann Arbor stage, IPI score, NCCN IPI score, ECOG performance status, B symptom, metastatic sites, and treatment are described in Table 1. All patients had histopathological confirmation of DLBCL. Five (83.3%) out of 6 patients were classified clinically as stage IVB, and 1 (16.7%) as stage IEA according to the Ann Arbor classification. e IPI score of patients were calculated, and the results revealed that 5 patients (83.3%) had a score of 3 while 1 patient (16.7%) had a score of 1. In addition, 1 (16.7%) patient had an ECOG performance status of 1, while 5 patients (83.3%) had an ECOG performance status of 0. Of the 6 patients, 3 (50%) had tumor located on the left side and 1 (16.3%) on the right side, whereas 2 (33.3%) on the bilateral sides. Besides testicular disease, 5 of the patients were identified to have lymph nodes or other distant metastases. All the patients have received treatment, of whom 6 (100%) had orchiectomy and chemotherapy, 2 patients (33.3%) had local radiotherapy, and 4 (66.7%) received prophylactic intrathecal injection in addition to their systemic chemotherapy. Adjunct laboratory and immunohistochemical results of the patients, such as Ki-67, β 2 microglobulin, and LDH, are also shown in Table 1.
Within the selected ROI, SUV max , SUV mean , SUV peak , MTV, and TLG were measured. e mean SUV max was 11.09 and varied between 7.20 and 19.75; mean SUV peak was 9.56 and ranged between 6.79 and 14.39. In addition, mean MTV 42% was 18.4 mL and varied between 1.3 mL and 61.6 mL; mean MTV 2.5 was 34.7 mL and varied significantly between 1.6 mL and 141.9 mL. With regard to TLG, mean TLG 42% was 168.906 and ranged from 7.514 to 687.004, while mean TLG 2.5 was 253.972 and ranged from 8.400 to 1127.802 (Table 2). e result of correlation analysis between functional parameters and survival time indicated that SUV max and SUV peak were not significantly associated with OS of the

18
F-FDG PET/CT is performed in combination with 18 FDG PET and CT scanners. 18 F-FDG PET/CT has been reported to be a very useful tool with high sensitivity and specificity rates in evaluating most lymphoma subtypes, providing both metabolic and morphologic features of diseases [11]. Compared with contrast-enhanced CT (CECT), PET/CT shows a higher diagnostic value with sensitivity of 97% and specificity of 100%, especially for normal-sized lymph nodes and extranodal involvement [12][13][14]. Moreover, with the supplement of other examinations, 18 F-FDG PET/CT can not only make accurate diagnosis but also assess the treatment response as well as predict the outcomes [15][16][17][18]. However, as far as we know, the application of PET/CT in testicular DLBCL patients has not been well studied. In this study, we firstly focused on the use of 18 F-FDG PET/CT in the prognosis and staging of patients with testicular DLBCL and reported their SUV max , SUV mean , SUV peak , MTV, and TLG.
Because of its aggressive clinical biological behavior, patients with testicular lymphoma usually present a poor prognosis. Timely and accurate diagnosis of testicular lymphoma is vital since early diagnosis was reported to be associated with better outcomes [19]. Imaging modalities that may be helpful in diagnosis include ultrasonography, magnetic resonance imaging, and CT, while unfortunately none of these methods shows satisfying specificity [3]. Fine-needle aspiration, testicular biopsy, and orchiectomy have been used for pathological diagnosis of testicular lymphoma. Nevertheless, these pathological diagnostic process may do harm to the testes' physiological functions as well as patients' mental health [3]. PET/CT is now widely used in the diagnosis and initial staging of high-grade lymphoma [20]. In this study, we also demonstrated the value of PET/CT in diagnosis and staging among patients with testicular DLBCL.
SUV max , the most widely used parameter, is a reproducible measurement for disease evaluation in a quantitative way [21]. Previous studies have reported that the normal level of FDG uptake in the testis is relatively high and symmetrical in pattern and declines slightly with age [22]. A study involving 203 men has demonstrated that the normal SUV range from 1.23 to 3.85 with a mean value of 2.44 [23]. In addition, previous study including 53 patients has reported that a SUV max of 3.75 is the optimal cut-off value for differentiating between benign and malignant testicular diseases [24]. As for the testicular lesions of our population, the mean SUV max was 11.09, with a range of 7.20 to 19.75. SUV max of all our patients were larger than 3.75. e results of this study revealed a high FDG uptake in testicular DLBCL patients; therefore, abnormal uptake of FDG in testis warranted further analysis. In addition, the value of SUV peak was also shown in this study. However, to the best of our acknowledgement, no previous studies have reported these indexes of testicular DLBCL patients.
MTV and TLG can be measured by a fixed background SUV cut-off or a fixed percentage of the SUV max [25][26][27]. Both MTV and TLG have been proposed to assess the burden of metabolically active tumors and are assumed to be reliable indicators of the tumor bulk [28]. In this study, we calculated MTV 42%, MTV 2.5, TLG 42%, and TLG 2.5 of each patient. e mean MTV 42% was 18.4 mL while the mean MTV 2.5 was 34.7 mL; meanwhile, both of them showed an apparent change. MTV of tumor burden has been recently found to be a useful prognostic factor in lymphoma [29]. TLG, which combined the volumetric and metabolic information of 18 F-FDG PET, was also calculated in this study. Elevated TLG has also been shown to be associated with poor survival in various types of cancer, but its prognostic value in testicular lymphoma has not been well established [30]. As a result, we demonstrated that MTV and TLG may greatly differ between different patients. e values of MTV and TLG in neither normal testes nor testicular lymphoma have been investigated; thus, further studies  However, further studies are needed to confirm these results. e current study has several limitations. First, this is a retrospective analysis. Second, the number of patients is small. Although we identified 18 testicular DLBCL with PET/CTscan, 12 of them had undergone orchiectomy before PET/CT examination. As a result, testicular disease could not be identified in the scan. ird, population from a single center also limits the conclusions of our study. us, further prospective randomized studies using multicenter data are required to confirm our findings. e strength of this study includes that histological confirmation of testicular DLBCL was obtained in all the patients, and patients' data were complete.

Conclusions
In conclusion, PET/CT scan has the potential in evaluating patients with testicular DLBCL. SUV, MTV, and TLG may vary a lot in different patients. SUV max of testicular DLBCL lesion is relative higher than that of normal testis. Also, we provided a set of MTV and TLG data and firstly showed their significant correlation with OS, which indicated a potential prognostic value of MTV and TLG. However, studies with a larger population are needed to confirm these findings. Metabolic tumor volume TLG:

Abbreviations
Total lesion glycolysis NCCN: National Comprehensive Cancer Network IPI: International Prognostic Index ROI: regions of interest OS: Overall survival.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
e authors declare that they have no conflicts of interest.