Maximum standardized uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography improves outcome prediction in retroperitoneal liposarcoma

While 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been investigated in extremity sarcomas, there is no evidence on its usefulness in retroperitoneal sarcoma. This study was designed to evaluate the usefulness of 18F-FDG PET/CT in predicting aggressiveness of retroperitoneal liposarcoma. Patients experienced surgery for retroperitoneal liposarcoma from November 2007 to February 2018 and underwent preoperative 18F-FDG PET/CT were included. Preoperative maximum standardized uptake value (SUVmax) was calculated. To evaluate the predictability of SUVmax for Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3, receiver operating characteristics (ROC) curve analysis was performed. To analyze whether SUVmax can be a risk factor for prognosis, multivariable Cox regression was performed including potential risk factors regarding operation and histopathology. A total of 133 patients were included. ROC curve showed area under the curve of 0.877 (P < 0.001), with a cut-off point of 4.5 SUVmax showing 85.7% sensitivity and 78.3% specificity. Cox analyses showed that SUVmax > 4.5 was a significant factor for recurrence-free survival (HR = 2.148, CI 1.301–3.546, P = 0.003) and overall survival (HR = 5.052, CI 1.854–13.766, P = 0.002). SUVmax is highly predictive of FNCLCC grade 3 and SUVmax > 4.5 can be used as a prognostic factor before obtaining the histopathology.

www.nature.com/scientificreports www.nature.com/scientificreports/ proliferation 15 . Several studies have reported correlations of hypermetabolic STSs with histopathologic characteristics and their clinical implications for prognosis 18,19 . However, these previous studies only included limb sarcoma. Since retroperitoneal STSs locate in the deepest region of the abdomen and cause minimum symptoms, they are often discovered incidentally and have an even poorer prognosis than extremity STS. Their close anatomical relationship to vital retroperitoneal structures makes complete surgical resection difficult and has a major impact on survival. Nonetheless, despite the different disease course of retroperitoneal STS compared with extremity STS, the biological characteristics are the same. Therefore, we designed this study to evaluate the usefulness of 18 F-FDG PET/CT in predicting tumor aggressiveness in retroperitoneal LPS and whether it has clinical implications for prognosis.

Methods
Patients. Data on patients who underwent surgery for retroperitoneal LPS from November 2007 to February 2018 were reviewed from the center's sarcoma database. Among these patients, those who underwent 18 F-FDG PET/CT before surgery and were proven to have a histopathology of LPS were considered eligible for inclusion. Patients whose FNCLCC grades were unclassifiable were included. Patients who had STS other than LPS were excluded from the study.
Data collection. Demographic data, treatment history, preoperative CT and 18 F-FDG PET/CT, operative data, postoperative course, histopathology, and follow-up data regarding recurrence and death were collected. A detailed review of 18 F-FDG PET/CT images was performed by a nuclear medicine specialist and the preoperative maximum standardized uptake value (SUV max ) of the tumor was re-evaluated for this study. Medical records were thoroughly reviewed to obtain data on surgical procedures. 18 F-FDG PET/CT imaging and measurement of maximum SUV. All patients fasted for at least 6 hours before the PET/CT study. Blood glucose levels were required to be less than 200 mg/dL. Whole-body PET and unenhanced CT images were acquired using a PET/CT scanner (Discovery STE, GE Healthcare, Waukesha, WI, USA). Whole-body CT was performed using a 16-slice helical CT with 30 to 170 mAs adjusted to the patient's body weight at a 140-kVp and 3.75-mm section width. After the CT scan, an emission scan was performed from the thigh to the basal skull for 2.5 min per frame in three-dimensional mode 60 minutes after intravenous injection of 18 F-FDG (5.0 MBq/kg). PET images were reconstructed using CT for attenuation correction with the ordered subsets expectation maximization algorithm (20 subsets, 2 iterations) with matrix of 128 × 128 and voxel size of 3.9 × 3.9 × 3.3 mm. Standardized uptake value (SUV max ) was normalized to patient body weight.
For measurement of SUV max , we placed a spherical volume of interest of 3 cm in diameter at a location where the LPS tissue had highest metabolic activity on PET using the volume viewer software on a GE Advantage Workstation 4.4. Data analysis. The study was designed for analysis of two main outcomes. First, we analyzed whether preoperative SUV max can be predictive of FNCLCC grade, which is representative of tumor aggressiveness and has been proven to be related to the prognosis of STS. Second, we analyzed whether a high SUV max can be predictive of the prognosis of the patient.
We performed receiver operating characteristics (ROC) curve analysis for medical diagnostic test evaluation using SUV max of the tumor to predict FNCLCC grade 3 LPS. We also calculated the cut-off point based on the maximum Youden index.
Median SUV max was compared between different histopathologic categories (FNCLCC grade, tumor differentiation, mitotic count, and necrosis) using the Kruskal Wallis test.
To analyze whether the cut-off point of SUV max can be a risk factor for prognosis, survival analyses were performed including data from the first set of PET/CT scans, operation procedures, and histopathology of patients with non-metastatic LPS. Recurrence-free survival and overall survival were analyzed using Kaplan-Meier survival analysis. Potential risk factors for recurrence and death were analyzed using a multivariable Cox proportional hazard model including the cut-off point of SUV max . We designed three survival models based on different time points of evaluation. Model 1 contains preoperative variables including the SUV max . Model 2 includes operative variables such as specific details of the surgery together with SUV max and other preoperative variables. Model 3 includes the histopathology of the tumor and does not include SUV max .
All statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL). This study was approved by the institutional review board of Samsung Medical (IRB No. 2018-05-047). The need for informed consent was waived by the institutional review board of Samsung Medical Center due to the retrospective nature of the study. The data can be available on individual investigator's request.

Results
A total of 133 patients met the inclusion criteria of available SUV max data from 18 F-FDG PET/CT scan, subsequent surgery, and histopathology of LPS. One hundred and nine patients had single data set of PET/CT scans, while 23 patients had two data sets of PET/CT scans after recurrence and 1 patient had three data sets of PET/CT scans after two recurrent episodes. Among these patients, 158 sets of data on PET/CT scan, operation, and histopathology were reviewed. Table 1 shows the baseline characteristics of the study population. There were 73 males and 60 females with a mean age of 55.9 ± 11.8 years at the initial presentation. Nearly half of the patients (n = 74, 46.8%) had primary LPS while 10.8% and 41.8% had remnant LPS from a previous operation and recurred LPS, respectively. The median SUV max was 3.3 with an interquartile range (IQR) of 4.4. The SUV max of the entire patient population ranged from 0.4 to 41.3. Nearly two-thirds (n = 106, 67.1%) of the PET/CT scans showed a SUV max less than 5. Regarding disease aggressiveness, 40 (25.3%), 80 (50.6%), and 35 (22.2%) patients were classified as FNCLCC grade 1, 2, and 3 respectively. Regarding histology, 37 (23.4%), 113 (71.5%), 7 (4.4%), and 1 (0.6%) patients had well-differentiated LPS (WDLPS), dedifferentiated LPS (DDLPS), myxoid/round cell LPS, and pleomorphic LPS,
ROC curve of SUV max predicting FNCLCC grade 3. Figure 1 shows the ROC curve of SUV max predicting FNCLCC grade 3. The area under the curve (AUC) was calculated to be 0.877 (confidence interval [CI] 0.813-0.940, P < 0.001). By setting the cut-off point as SUV max of 4.5, sensitivity and specificity were calculated to be 85.7% and 78.3%, respectively. Table 2 shows the comparisons of characteristics between the SUV max ≤ 4.5 group and SUV max > 4.5 group. There were no differences in sex (P = 0.623), age (P = 0.362), disease status (P = 0.920), and median tumor size (P = 0.514). However, linear-by-linear association analysis showed a significant difference in the distribution of cases according to FNCLCC grade (P < 0.001). There were only five cases with FNCLCC grade 3 in the SUV max ≤ 4.5 group whereas more than half (n = 30, 53.6%) of the SUV max > 4.5 group were FNCLCC grade 3 and there were no grade 1 cases. Differentiation (P < 0.001), mitosis (P < 0.001), and necrosis (P < 0.001) were significantly unfavorable in the SUV max > 4.5 group.
SUV max > 4.5 as a prognostic factor of recurrence-free survival. Survival analyses were based on the first surgical procedure performed in our center for each patient. The 1-, 3-, and 5-year recurrence-free survivals were 64.9%, 43.2%, and 28.1%, respectively. Multivariable Cox regression analyses were performed for three different models. Potential risk factors for recurrence in the univariable analyses were used for multivariable adjusted models. (Table 3) Model 1 was composed of preoperative variables including SUV max > 4.5. Multivariable Cox analysis showed that SUV max  SUVmax > 4.5 as a prognostic factor of overall survival. The 1-, 3-, and 5-year overall survival rates were 95.5%, 80.9%, and 75.2%, respectively. Multivariable Cox regression analyses were performed for three different models following the principle described above (Table 4).

Discussion
This study analyzed the usefulness of 18 F-FDG PET/CT in predicting tumor aggressiveness represented by FNCLCC grade and yielded promising results. To date, there are only a few studies evaluating 18 F-FDG PET/CT for extremity STS 16,[20][21][22] . Furthermore, these studies had a heterogeneous background through inclusion of various STSs. Our study focused only on retroperitoneal LPS, which is the most common STS in the retroperitoneum, and showed a high predictability of SUV max for FNCLCC grade 3 and a significant relationship to recurrence and survival when using a cut-off point of SUV max 4.5.
In our sarcoma center, the goal of surgery is to perform gross complete resection for the purpose of obtaining a negative margin. To achieve this goal, we perform radical nephrectomy in cases with a tumor invading or abutting the perirenal fat. Other organs are resected only when tumor invasion is evident and combined resection is inevitable. Previously, we reported the importance of achieving gross complete resection and performing radical nephrectomy when the tumor is abutting perirenal fat 8,23 . The patients undergo 18 F-FDG PET/CT preoperatively for metastasis work-up, but it also gives information on the metabolic status of the tumor.  www.nature.com/scientificreports www.nature.com/scientificreports/ The 18 F-FDG PET/CT scan showed a variable range of SUV max with a median value of 3.3 (range 0.4-41.3). ROC curve analysis showed an AUC of 0.877, and SUV max > 4.5 showed 85.7% sensitivity and 78.3% specificity. Nearly one-third (36.1%) of cases were above 4.5 SUV max , and there were no differences in the baseline characteristics except for tumor histopathology between cases above or below 4.5 SUV max . Therefore, setting a cut-off point of 4.5 seems appropriate not only due to the high SUV but also based on the data distribution.
In particular, in multivariable Cox regression analyses SUV max > 4.5 showed a significant relationship to poor recurrence-free survival and overall survival. In analysis using three models, SUV max > 4.5 showed usefulness as a prognostic factor comparable to FNCLCC grade. These results might be useful as they allow surgical oncologists to predict tumor aggressiveness by SUV max even before the surgery. The information can be crucial in planning the extent of resection. Surgical oncologists can plan radical resection with combined organ resection when a tumor is predicted to be aggressive. However, a well-designed study is required for making a conclusion on the topic.
The usefulness of 18 Table 3. Three separate multivariable Cox proportional hazard models analyzing risk factors for recurrencefree survival. *Model 1 is modeled based on preoperative variables while model 2 and 3 added operative variables and tumor histopathology to model 1, respectively. Age >60 (P = 0.954), multiplicity (P = 0.635), size >20 cm (P = 0.272), nephrectomy (P = 0.052) and resection of three or more organs (P = 0.424) were excluded from multivariable adjusted modeling due to an insignificant relationship in the univariable analysis.  Table 4. Three separate multivariable Cox proportional hazard models analyzing risk factors for overall survival. *Model 1 is modeled based on preoperative variables while model 2 and 3 added operative variables and tumor histopathology to model 1, respectively. Age >60 (P = 0.738), remnant or recurrent (P = 0.114), suspected invasion (P = 0.078), multiplicity (P = 0.540), size >20 cm (P = 0.717), perinephric location (P = 0.258), resection of three or more organs (P = 0.073), and differentiation (P = 0.377) were excluded from the multivariable adjusted modeling due to insignificant relationship in the univariable analysis.
www.nature.com/scientificreports www.nature.com/scientificreports/ in the abdomen or retroperitoneum, and LPS accounted for 18% (n = 13) of patients. However, no previous study focused on retroperitoneal STS, especially LPS.
There are some limitations that must be overcome in future studies. The study only included retroperitoneal LPS and therefore our results cannot be generalized to the other types of STS. However, retroperitoneal LPS can be distinguished by radiologic findings when evaluated by a radiologist specialized in STS. When a retroperitoneal tumor is suspected to be LPS, the 18 F-FDG PET/CT scan can add valuable information on the aggressiveness of the tumor.
We only used SUV max as a prognostic tool, although SUV avg or metabolic tumor volume (MTV) were also evaluated for practicality. LPSs are usually giant tumors and there is heterogeneity within the tumor mass regarding aggressiveness. Even if a mass is composed of mainly WDLPS, a single solid portion can be DDLPS with high grade. Consequently, the patient may possess a small but high-grade tumor content. These characteristics are in accordance with 18 F-FDG PET/CT findings that the most fat-containing portion shows low SUV uptake while a single solid portion can be hypermetabolic. Adjusting SUV avg in a giant tumor can deviate the result because grade, not size, is the most important prognostic factor. Therefore, we concluded that SUV max better reflects the clinical situation. Figure 3 shows an example of different aggressiveness within a mass. A 56-year old male patient underwent mass excision for retroperitoneal LPS. Preoperatively, the patient had a LPS with a solid portion that showed hypermetabolic features (SUV max = 5.0) and a fatty mass on the medial side with small FDG uptake (SUV = 1.8). During the first operation the solid mass was completely removed and histopathology revealed DDLPS with FNCLCC grade 2. However, the 1-week postoperative CT scan showed that a mass similar to normal fat remained on the medial side near the inferior vena cava. After the second operation, the fatty mass was found to be WDLPS with FNCLCC grade 1. Unfortunately, on the 8-month postoperative CT scan the patient was discovered to have a peritoneal carcinomatosis with several solid masses in the entire abdomen. The patient died 4 months later. This is a typical case that shows the heterogeneous characteristics of a mass in a single patient showing a spectrum from low-grade to high-grade tumor. The small but high FDG-uptake spot that showed SUV max of 5.0 can represent the patient's prognosis more precisely than the bulk WDLPS with no uptake. For this reason, we consider SUV max to be the key indicator of prognosis in patients with retroperitoneal LPS. www.nature.com/scientificreports www.nature.com/scientificreports/ In cases similar to Fig. 3, the clinical significance of preoperative needle biopsy can be limited. In a huge mass, a single site biopsy cannot represent the tumor's aggressiveness properly. Measuring the SUV max can give valuable information in those cases.