UROLOGICAL ONCOLOGY Periprostatic Adiposity Measured on Magnetic Resonance Imaging Correlates with Prostate Cancer Aggressiveness Zhang Qiang,1 Sun Li-jiang,1 Qi Jun,2 Yang Zhi-gang,3 Huang Tao,2 Huo Ri-cha3 1Department of Urology, The Af- filiated Hospital of Qingdao Uni- versity, Qingdao, Shandong 266003, China. 2 Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, S c h o o l o f M e d i c i n e , S h a n g h a i 200092, China. 3Department of Urology, Baotou City Central Hospital, Botou 014040, Inner Mongolia, China. Corresponding Author: Zhang Qiang, MD Department of Urology, The Affili- ated Hospital of Qingdao University Medical College, Qingdao, Shan- dong 266003, China. Tel: +86 474 6955387 Fax: +86 474 6955387 E-mail: zq19825@163.com Received July 2013 Accepted March 2014 Purpose: To evaluate the correlation between aggressiveness of prostate cancer (PCa) and obesity measur- ing the periprostatic fat on magnetic resonance imaging (MRI). Materials and Methods: One hundred eighty-four patients who had undergone radical retropubic prosta- tectomy (RRP) were analyzed retrospectively. The different fat measurements (periprostatic fat area (PFA), the subcutaneous fat thickness, the anterior and posterior abdominal fat thicknesses and anteroposterior diameter) were performed on the slices of MRI and then compared with the clinical and pathologic char- acteristics. Results: The PFA and ratio showed a statistically significant differences (P = .019 and P = .025, respec- tively) among three groups, that is to say, more adipose were distributed in periprostatic area of the high risk patients. Seventy-one patients in clinical stage and 82 patients in Gleason score have the significant dif- ferences between pre-operation and post-operation values. In the clinical stage, the PFA and ratio showed a statistically significant differences (P = .014 and P = .037, respectively). The difference group had more periprostatic adipose than the other one (65.26 ± 9.03 vs. 64.44 ± 9.62; 87.52 ± 3.97 vs. 87.30 ± 3.96). Noth- ing but the “PFA” was significantly different between two groups (P = .017). Logistic regression analysis adjusted for age revealed a statistically significant association between the PFA, the Ratio and the risk of having high-risk disease (P = .031 and P = .024, respectively). Conclusion: The periprostatic adiposity not only affects the PCa aggressiveness, but also has effect in accurate assessment of the tumor stage and grade. We should predict the prognosis of patient with RRP by measuring periprostatic adiposity on pre-operative MRI. Keywords: adipose tissue; body mass index; magnetic resonance imaging; obesity; prostatic neoplasms. 1793 Urological Oncology UROLOGY JOURNAL Vol. 11 No. 04 July - August 2014 1794 Periprostatic Adiposity on MRI and Prostate Cancer Aggressiveness-Qiang et al Figure 2. The anterior abdominal fat thicknesses, posterior abdominal fat thicknesses and anteroposterior diameter on the slices of magnetic resonance imaging (T2 weighted) at the midline section. calculated as the anterior plus posterior abdominal wall fat thickness subtracted from the APD divided by the APD and expressed as per- centage. All measurements were performed in a blinded manner by a single observer (Figure 1). The SFT and the (PFA) were obtained from the images of MRI (T2 weighted) at the transverse section at the level of the femoral head and greater trochanter of the femur (Figure 2). The localization image is on the slice of MRI (T2 weighted) at the midline section. The anterior and posterior abdominal fat thicknesses, and APD were measured in 3 images around the midline and the re- sults were averaged. Statistical Analysis Association between fat measurements and clinical/pathological char- acteristics were analyzed by chi-square test in case of categorical vari- ables and Kruskal-wallis test in case of continuous variables. Logistic regression analysis was applied with adjustment of age to evaluate the independent effect of each variable on the risk of higher-risk disease. INTRODUCTION Prostate cancer (PCa) is the second most common malignant tumor of men worldwide, the incidence of which has also ris-en gradually in China during recent decades.(1,2) Obesity has became a worldwide challenge in the 21st century. Many epidemi- ological studies have found that higher body mass index (BMI) and abdominal obesity were associated with increased risk of several can- cers (kidney, colon, endometrium and breast) including prostate.(3-5) However, the relationship between obesity and PCa aggressiveness is still in controversial. Some studies have found positive correlation,(6-8) whereas others have drawn adverse results.(9,10) The difference of results is considered to be due to the method of measurement. The BMI doesn’t effectively reflect the most metabolic active fat in body, whereas the visceral adipose is a more sophisticated measurement of abdominal obesity than BMI, because it is metabolically active and can produce a large number of hormones and cytokines such as tumor necrosis factor-α, interleukin-6, leptin and adiponectin.(11,12) Magnet- ic Resonance Imaging (MRI) is a direct, quantitative measurement method to characterize the distribution of abdominal adipose tissue in normal status or in pathologic conditions.(13) The aim of this study is to evaluate the correlation between aggressiveness of PCa and obesity by measuring the visceral fat (periprostatic fat) using MRI. MATERIALS AND METHODS From March 2006 to October 2012, one hundred eighty-four patients were histologically diagnosed as localized PCa by prostate needle bi- opsy at Xin Hua hospital affiliated to Shanghai Jiao Tong University School of Medicine before being given radical retropubic prostatecto- my (RRP). In preoperative phase, all patients were evaluated with dig- ital rectal examination (DRE), serum prostate-specific antigen (PSA), transrectal ultrasonography, radionuclide bone scan and X-ray chest film. Magnetic resonance imaging (MRI) was also performed to eval- uate the local extent of disease and the possibility of nodal involve- ment for clinical staging. Pathologic stage is determined by histologic analysis of surgical samples including prostate, seminal vesicles and pelvic lymph nodes. Measurements Height and weight data were recorded before RRP. BMI (kg/m2) was calculated and categorized according to the National Institutes of Health classification of normal weight (< 25 kg/m2), overweight (25- 29 kg/m2) and obese (≥ 30 kg/m2). Only two patients who had a BMI value of < 18.5 kg/m2 were included in the normal weight group. The periprostatic fat area (PFA) (cm2) and the subcutaneous fat thickness (SFT) measurements were performed on the slices of MRI at the trans- verse section, at the level of the femoral head and greater trochanter of the femur (Figure 1); the anterior abdominal fat thicknesses (AAT), posterior abdominal fat thicknesses (PAT) and anteroposterior diam- eter (APD) were measured on the slices of MRI (T2 weighted) of the midline section (Figure 2). The umbilicus, bladder, prostate and ure- thra were identified at the midline section. The ratio of visceral fat was Figure 1. The periprostatic fat area and the subcutaneous fat thickness on the slices of magnetic resonance imaging at the transverse section, at the level of the femoral head and greater trochanter of the femur. .015, P = .041 and P = .042, respectively). Logistic regression analysis which adjusted for age (Table 4) revealed a statistically significant association between the PFA, the ratio and the risk of having higher-risk disease (P = 0.031 and P = 0.024, re- spectively). DISCUSSION In recent years, the relationship between obesity and cancer has drawn significant academic interests. Epidemiological studies have demon- strated that obesity is a risk factor of breast, endometrium, kidney and gallbladder cancers, but its role in PCA etiology remains elusive. (3,5,15). Obesity is often assessed by BMI, which comes from physical measurement or self-reported height and weight. However, the BMI, which is a marker for overall obesity, cannot distinguish between ad- iposity and lean body mass, particularly in men with greater muscle mass, nor does it reflect fat distribution. Therefore, the link between BMI and PCa is controversial in many studies.(16-19) In our research, no association between BMI and PCa risk was revealed, and BMI was not an independent risk factor for PCa aggressiveness. Abdominal adiposity or periprostatic adiposity has been found to pre- cisely reflect the association between obesity and PCa in recent years. (20-22) Although abdominal fat make up only 10% of total body fat, it is metabolically more active than subcutaneous or peripheral fat. Fur- thermore, periprostatic fat is associated with fluctuation in levels of several hormones, including insulin, testosterone, estrogen, sex hor- mone binding globulin, and leptin which play a significant role in the biology of Pca.(23,24) The leptin, a cytokine produced by white adipose tissue, plays a critical role in the regulation of body weight by inhibit- All statistic were performed by the Statistical Package for the Social Science (SPSS Inc, Chicago, Illinois, USA) version 13.0 with statisti- cal significance being defined as P values < .05. RESULTS Baseline Clinical Characteristics and Different Fat Measurements According to Kattan(14) we stratified the patients into three groups. The clinical and pathologic characteristics were summarizes in Table 1. The median age, prostate volume, T-zone volume, bleeding volume and duration of operation had no significant differences among three groups (P > .05). BMI at the time of RRP was 25.51 ± 2.46, 25.83 ± 2.16 and 25.74 ± 2.29 kg/m2, respectively (P = .142). The PFA and the ratio showed statistically significant difference between three groups (P = .019 and P = .025, respectively). Table 2 demonstrates the difference of clinical stage and Gleason score between preoperative and postoperative phase. In clinical stage, the PFA and ratio showed a statistically significant difference (P = .014 and P = .037, respectively). In terms of Gleason score, nothing but PFA was found to have significant difference between two groups (P = .017). Moreover, the prostate volume and T-zone volume have statistically significant difference (P = .049 and P = .020, respective- ly). The difference in bleeding volume and duration of operation are shown in Table 3. During operation, patients with bleeding volume over 450 mL were significantly older (P = .022) and had more dispose in periprostatic area (Ratio: 88.46 ± 3.00 vs. 86.95 ± 4.36, P = .013). The PAT, anteroposterior abdominal fat thickness (APT) and ratio was significantly higher in the group with operation time > 210 min (P = Table 1. Clinical characteristic of study subjects.* Risk Groups Variables Low Intermediate High P Value No. of patients 47 80 57 Age, years 70.10 ± 6.04 69.68 ± 6.39 68.07 ± 5.53 .177 Prostate volume, cm3 40.40 ± 24.22 42.29 ± 22.55 48.02 ± 28.33 .250 T-zone volume, cm3 18.76 ± 15.27 21.49 ± 19.10 25.02 ± 21.46 .242 Initial PSA, ng/mL 6.91 ± 2.87 12.47 ± 4.25 25.15 ± 11.49 .242 BMI, kg/m2 25.51 ± 2.46 25.83 ± 2.16 25.74 ± 2.29 .142 SFT, cm 2.69 ± 0.83 2.78 ± 1.05 2.83 ± 1.03 .773 PFA, cm2 64.44 ± 8.06 64.96 ± 9.75 65.69 ± 9.42 .019 AAT, cm 1.46 ± 0.55 1.42 ± 0.56 1.53 ± 0.67 .533 PAT, cm 0.98 ± 0.48 1.03 ± 0.43 1.03 ± 0.49 .800 APT, cm 19.54 ± 1.67 19.45 ± 1.76 19.87 ± 1.88 .387 Ratio (%) 87.31 ± 4.23 87.52 ± 3.84 87.65 ± 3.99 .025 Bleeding volume, mL 470.85 ± 289.64 452.62 ± 356.57 492.86 ± 463.92 .830 Duration of operation, min 214.77 ± 41.62 215.75 ± 40.09 219.65 ± 62.06 .853 The groups according to Kattan:(14) Low risk, ≤ T2a, Gleason score ≤ 6, iPSA < 10 ng/mL; Intermediate risk, T2b, Gleason score = 7, iPSA = 10-20 ng/mL; High risk, ≥ T2c, Gleason score ≥ 8, iPSA > 20 ng/mL. Abbreviations: BMI, body mass index; SFT, subcutaneous fat thickness; PFA, periprostatic fat area; AAT, anterior abdominal fat thicknesses; PAT, posterior abdominal fat thicknesses; APT, anteroposterior diameter abdominal fat thicknesses; iPSA, initial prostate specific antigen. Ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior dia- meter. * Data are presented as mean ± SD. 1795 Urological Oncology UROLOGY JOURNAL Vol. 11 No. 04 July - August 2014 1796 Clinical Stage Gleason Score Difference No Difference P Value Difference No Difference P Value No. of patients (%) 71 (38.59) 113 (61.41) NS 82 (44.57) 102 (55.43) NS Age, years 68.39 ± 6.37 69.84 ± 5.77 .116 68.96 ± 6.37 68.55 ± 5.84 517 Prostate volume, cm3 44.47 ± 27.02 43.69 ± 23.81 .839 46.83 ± 27.33 39.56 ± 21.08 .049 T-zone volume, cm3 22.09 ± 17.40 22.20 ± 20.31 .971 24.81 ± 22.08 18.25 ± 13.69 .020 Initial PSA, ng/mL 15.22 ± 8.59 14.83 ± 10.97 .800 13.98 ± 9.41 15.78 ± 10.57 .231 BMI, kg/m2 25.13 ± 2.62 24.92 ± 2.37 .451 25.36 ± 3.12 25.41 ± 2.78 .576 SFT, cm 2.77 ± 1.05 2.77 ± 0.96 .997 2.71 ± 0.99 2.82 ± 0.99 .46 PFA, cm2 65.26 ± 9.03 64.44 ± 9.62 .014 65.29 ± 9.57 63.75 ± 8.78 .017 AAT, cm 1.50 ± 0.59 1.43 ± 0.60 .387 1.44 ± 0.58 1.48 ± 0.60 .626 PAT, cm 1.03 ± 0.51 1.03 ± 0.43 .951 0.99 ± 0.46 1.04 ± 0.46 .497 APT, cm 19.73 ± 1.69 19.36 ± 1.89 .169 19.39 ± 1.72 19.77 ± 1.81 .145 Ratio (%) 87.52 ± 3.97 87.30 ± 3.96 .037 87.59 ± 4.15 87.40 ± 3.86 .150 Table 2. The difference in clinical stage and Gleason score between preoperation and postoperation.* Abbreviations: BMI, body mass index; SFT, subcutaneous fat thickness; PFA, periprostatic fat area; AAT, anterior abdominal fat thicknesses; PAT, posterior abdominal fat thicknesses; APT, anteroposterior diameter abdominal fat thicknesses. Ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diam- eter. * Data are presented as mean ± SD. ing food intake and stimulating energy expenditure. In addition, leptin influences cellular differentiation and progression in PCa cells, further increasing PCa risk and stage.(25) The waist circumference (WC) and waist-to-hip ratio (WHR) are commonly used to define the extent of abdominal obesity.(26,27) In a large cohort study among 129,502 men(28) waist circumference and waist-to-hip ratio were positively association with advanced disease among men with a lower BMI. Although WC can be measured easily, it estimates abdominal adipose tissue imprecisely. MRI is an excellent technique to distinguish and quantify subcutaneous and periprostatic fat. The benefits of MRI over other adipose imaging methods are accelerated acquisition, quantita- tive reconstruction and physiologically based threshold, all of which are required for accurate adipose tissue measurements.(13,29) In addi- tion, the patient with PCa should be undergo MRI before surgery in or- der to assess tumor stage, so fat measurement by MRI cannot increase the economic burden of patients. In our study, MRI is proved to be a precise way to measure the periprostatic adiposity. We could clearly distinguish the fat, muscle and bone. By measurement of abdominal adipose distribution, reflecting the periprostatic fat, we have found a close association between periprostatic adiposity (the PFA and ratio) and PCa aggressiveness as well as PCa risk. However, the SFT, PAT Periprostatic Adiposity on MRI and Prostate Cancer Aggressiveness-Qiang et al and AAT, reflecting the peripheral fat, have showed no statistically significant differences. It is important to assess tumor stage and grade more accurately in the preoperative phase, because it would affect the selection of treatment of the localized PCa and evaluation of the patient’s prognosis. The incidence of under staging was 38.6% in our study, which lies between 24% and 60% previously reported in large single institution studies. (30) The incidence of discordance in Gleason score between biopsy and RRP was 44.6%, which was similar to that reported by several researchers.(31) Previous studies have shown that preoperative serum PSA level, the percent of positive systematic prostate biopsies and the interval between biopsy and RRP are the most important predictors of under staging and under grading. In our study, the tumor volume affects the concordance in Gleason score between biopsy and RRP, probably owing to the association between the percentage of positive systematic biopsies and tumor volume.(30,32) Our study is to date only one that analyzed association between periprostatic adiposity and the discordance of staging or grading before and after surgery. These find- ings might be important and may indicate that obese patients require different treatment considerations. Several explanations could be giv- en for the reason. First, the periprostatic fat tissue could affect the Table 3. The difference in bleeding volume and duration of operation.* Bleeding Volume Duration of Operation ≤ 450 mL > 450 mL P Value ≤ 210 min > 210 min P Value No. of patients 118 66 NS 102 82 NS Age, years 68.53 ± 6.31 70.65 ± 5.39 .022 69.29 ± 6.14 69.28 ± 6.02 .988 Prostate volume, cm3 42.35 ± 24.09 45.80 ± 26.43 .368 42.23 ± 26.13 45.27 ± 23.44 .412 T-zone volume, cm3 20.43 ± 17.67 24.50 ± 21.16 .165 20.03 ± 18.60 24.19 ± 19.45 .142 Initial PSA, ng/mL 15.22 ± 10.39 14.55 ± 9.56 .670 14.45 ± 9.62 15.63 ± 10.65 .432 BMI, kg/m2 24.87 ± 2.61 25.08 ± 2.41 .098 25.28 ± 2.26 25.17 ± 2.19 .127 SFT, cm 2.80 ± 1.08 2.73 ± 0.79 .668 2.69 ± 0.91 2.87 ± 1.07 .214 PFA, cm2 65.04 ± 9.61 65.06 ± 8.51 .998 65.12 ± 9.39 64.97 ± 9.03 .916 AAT, cm 1.51 ± 0.67 1.38 ± 0.41 .163 1.40 ± 0.50 1.53 ± 0.68 .125 PAT, cm 1.07 ± 0.48 0.93 ± 0.40 .055 0.94 ± 0.42 1.11 ± 0.50 .015 APT, cm 19.43 ± 1.80 19.90 ± 1.70 .085 19.36 ± 1.77 19.89 ± 1.75 .041 Ratio (%) 86.95 ± 4.36 88.46 ± 3.00 .013 86.82 ± 4.54 88.02 ± 3.40 .042 Abbreviations: BMI, body mass index; SFT, subcutaneous fat thickness; PFA, periprostatic fat area; AAT, anterior abdominal fat thicknesses; PAT, posterior abdominal fat thicknesses; APT, anteroposterior diameter abdominal fat thicknesses; NS, not significant. Ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diam- eter. * Data are presented as mean ± SD. Table 4. Logistic regression analysis of factors predicting high-risk dis- ease.* Variables Odds Ratio (95% CI) P Value Prostate volume, cm3 1.01 (0.97-1.05) .599 T-zone volume, cm3 1.01 (0.96-1.06) .800 BMI, kg/m2 0.98 (0.63-1.58) .485 SFT, cm 0.74 (0.44-1.22) .234 PFA, cm2 1.00 (0.96-1.04) .024 AAT, cm 1.06 (0.96-1.15) .287 PAT, cm 1.08 (1.02-1.21) .261 APT, cm 1.14 (1.02-1.24) .091 Ratio (%) 1.05 (1.03-1.08) .031 Abbreviations: BMI, body mass index; SFT, subcutaneous fat thickness; PFA, peri- prostatic fat area; AAT, anterior abdominal fat thicknesses; PAT, posterior abdominal fat thicknesses; APT, anteroposterior diameter abdominal fat thicknesses; CI, confi- dence interval. Ratio was calculated as: the anterior plus posterior abdominal wall fat thickness sub- tracted from the anteroposterior diameter divided by the anteroposterior diameter. * Data are presented as mean (interquartile range). judgment of extracapsular disease extension, seminal vesicle in va- sion or lymph node metastasis on MRI. Second, the periprostatic fat tissue could influence the positive outcome of systematic prostate bi- opsies. Finally, the periprostatic fat tissue producing cytokine might change the level of preoperative serum PSA, which has been proved to be associated with under staging and under grading in preopera- tive phase. In addition, our study has showed that the periprostatic fat could increase the difficulty and risk of operation (bleeding volume and duration of operation), probably because the periprostatic fat is rich in vascular. The limitations of our study are as follow: first, this is a retrospective review of prospectively maintained database, secondly, our study did not perform other anthropometric measurements such as waist cir- cumference, waist-to-hip ratio and percentage of body fat. Thirdly, different risk group definition could lead to different outcome. The reason why we choose the Kattan,(14) is the treatment and prognosis of the localized PCa assessed according to it in China. Finally, the di- rect measurement of fat area and thickness on preoperative MRI could result in the very small observed difference in the percentage of peri- prostate fat, because it includes muscle, spinal fluid and bowel as well as periprostatic fat within the calculation. Despite these limitations, 1797 Urological Oncology UROLOGY JOURNAL Vol. 11 No. 04 July - August 2014 1798 the result still remained significance. In further study, we should apply quantitative method of MRI to measure the periprostatic fat, in order to precisely reveal the association between periprostatic adiposity and aggressiveness of PCa. In addition, we should perform animal exper- iment, in order to find the mechanism that the periprostate adiposity can influence aggressiveness of PCa. CONCLUSION The periprostatic adiposity can not only affects the aggressiveness, but also has effect in accurate evaluation of stage and grade of PCa. In addition, the periprostate fat could increase the difficulty and risk of RRP. CONFLICT OF INTEREST None declared. REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global can- cer statistics. CA Cancer J Clin. 2011;61:69-90. 2. ZL Tang, J Bai, LN Gu, L Li, D Xue. A Systematic Review: Epidemic Status of Prostate Cancer and Breast Cancer from 2000 to 2010 in China. China Cancer. 2013,4:260-5. 3. Tobias P, Ute N, Heiner B. Obesity and cancer. 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