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Originally published as JCO Early Release 10.1200/JCO.2004.03.132 on December 22 2003 © 2004 American Society of Clinical Oncology. Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical ProstatectomyFrom the Naval Medical Center, San Diego, CA; Walter Reed Army Medical Center, Washington, DC; Madigan Army Medical Center, Tacoma, WA; Naval Medical Center, Portsmouth, VA; Wilford Hall Medical Center; Brooke Army Medical Center, San Antonio, TX; Eisenhower Army Medical Center, Fort Gordon, GA; Center for Prostate Disease Research, Rockville; National Naval Medical Center; Uniformed Services University of the Health Sciences, Bethesda; and Malcolm Grow Medical Center, Andrews Air Force Base, MD. Address reprint requests to Christopher L. Amling, MD, Department of Urology, Naval Medical Center, 34800 Bob Wilson Dr, San Diego, CA 92134-5000; e-mail: clamling{at}nmcsd.med.navy.mil
PURPOSE: To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men.
PATIENTS AND METHODS: A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI RESULTS: Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P < .001) and was associated with a higher risk of biochemical recurrence (P = .027). Blacks had higher BMI (P < .001) and higher recurrence rates (P = .003) than whites. Both BMI (P = .028) and black race (P = .002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P = .021) remained a significant independent predictor of recurrence. CONCLUSION: Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.
Although the precise etiology of prostate cancer (PC) is unknown, several lines of evidence suggest that environmental and/or lifestyle factors may have an important role in the development of clinically significant disease. Men from Western cultures, and especially black men, are known to have significantly higher PC incidence and death rates [1-3]. Asian populations have the lowest PC incidence and mortality rates but attain cancer rates approaching those of US men after migration to this country [4]. Autopsy studies from numerous countries worldwide show similar rates of latent or clinically insignificant PC, despite markedly different PC death rates among these populations [5,6]. These findings suggest that although clinically insignificant PC may be common to all races and ethnic groups, some as yet unknown factor or factors may promote progression of these latent tumors to clinically significant cancers. Obesity is one of several potential factors that might be related to the development of clinically significant PC [7]. Dietary fat intake has been consistently associated with PC risk and some studies suggest that higher consumption of red meat in particular may promote development of more aggressive disease [8-14]. Because body mass appears to influence serum androgen levels and other potential PC growth factors, a relationship between obesity and PC is certainly plausible [15-23]. However, even though lifetime dietary fat consumption and obesity are clearly linked, the association between obesity and PC risk in epidemiologic studies has been inconsistent. Although many case-control and cohort studies show an increased incidence of PC in obese men and some demonstrate that increased body mass may be associated with more advanced disease, an equal number show only minimal or no association [9-12,24-29]. More consistent epidemiologic findings link obesity to increased PC mortality, although only a few studies have assessed the relationship between body mass and PC death rates [30-32]. Taken together, these studies suggest a stronger link between obesity and PC mortality than incidence, and point to obesity as a potential factor in the progression of PC to a potentially lethal form of disease. The racial variability in PC incidence and mortality may also be attributable to an unknown environmental and/or lifestyle factor. As a group, blacks have significantly higher PC incidence and mortality rates than whites, and blacks often present with more advanced disease [3]. Several potential explanations for this difference have been put forth, including genetic susceptibility, socioeconomic factors, and access to medical care [33]. Dietary and/or body composition differences between the races have not been extensively studied as a potential explanation for differences in PC risk. In women with breast cancer, obesity and black race are recognized risk factors that may contribute to more advanced disease and a poorer prognosis, and in many studies, obesity was found to be more prevalent among black than white women with breast cancer [34-36]. A greater consumption of fat from animal sources has also been found to be a more significant risk for PC among blacks than whites [37]. Thus, the higher incidence and clinical aggressiveness of PC among US blacks compared with whites may result from differential effects of animal fat or obesity in these ethnic groups. We performed a retrospective multi-institutional analysis of radical prostatectomy patients treated at geographically diverse equal access medical centers to evaluate the relationship between obesity and PC in patients with clinically localized disease. Our objective was to determine if an association exists between obesity and adverse pathologic features of the cancer, and to assess whether obesity predicts higher recurrence rates after surgical therapy. We also examined racial differences in obesity in this population as a potential explanation for the racial variation in PC risk.
The Center for Prostate Disease Research (CPDR) multicenter longitudinal prostate cancer database was queried to identify men undergoing radical prostatectomy (RP) between January 1987 and August 2002 at nine geographically diverse military medical centers: Naval Medical Center (San Diego, CA), Walter Reed Army Medical Center (Washington, DC), Madigan Army Medical Center (Tacoma, WA), Wilford Hall Medical Center (San Antonio, TX), Brooke Army Medical Center (San Antonio, TX), Malcolm Grow Air Force Medical Center (Andrews Air Force Base, MD), National Naval Medical Center (Bethesda, MD), Naval Medical Center (Portsmouth, VA), and Eisenhower Army Medical Center (Fort Gordon, GA). The CPDR Database is an institutional review board–approved longitudinal database that uses standardized data collection forms to obtain demographic and cancer-specific information from PC patients receiving care in the military healthcare system (military active duty and retiree population). For most patients, data were entered prospectively from the time of prostate cancer diagnosis throughout the follow-up period. In some cases, data were retrieved from the medical and pathologic records with retrospective data entry on men who had previously undergone RP.
Body mass index (BMI) was calculated on all patients in whom height and weight information was known preoperatively. In the majority, patient-reported height and weight data were entered into the database at the time of initial presentation. For some patients, those data were entered retrospectively after review of the medical and anesthesia records. Patient height and weight were used to calculate BMI using the following formula: BMI = weight (kilograms) ÷ height (meters) [2]. BMI was used to categorize patients into three separate BMI groups according to the WHO classification of obesity: obese (BMI For the purposes of this study, clinical, pathologic, and follow-up data were retrieved. Clinical information was determined preoperatively at the time of cancer diagnosis and included patient age, race, height, weight, serum prostate-specific antigen (PSA) level, biopsy cancer grade (Gleason score), and digital rectal examination–determined cancer stage according to the 2002 tumor-node-metastasis system staging system. Data on the pathologic findings (Gleason score, pathologic tumor-node-metastasis system stage, surgical margin, and lymph node status) from the RP specimen were also retrieved. After RP, patients were observed until death for evidence of disease recurrence. In general, patients were seen every 3 months the first year, every 6 months the second and third years, and yearly thereafter unless there was evidence of cancer recurrence, in which case more frequent follow-up was necessary. A serum PSA level was determined at each follow-up appointment. The RP specimens were processed in a similar fashion at each of the nine participating institutions. The surgical specimens were fixed in 10% buffered formalin for 18 to 24 hours and painted with colored tissue inks to determine surgical margin status. The vas deferens and seminal vesicles were amputated and the bladder neck and apical margins transected in a single section parallel to the margin at 0.2 cm in average thickness. The prostate was then serially sectioned at 0.4-cm intervals in a transverse plane perpendicular to the margins. Sections were then divided into right and left sides to accommodate the standard cassette. The final preparation represented 5-µm-thick tissue sections stained with hematoxylin and eosin that demonstrated prostate capsule surfaces and parenchyma. The worst cancer grade was determined using the Gleason grading system. All prostatectomy specimens were pathologically staged according to the tumor-node-metastasis system staging system.
For preliminary statistical analysis, patients were separated into three BMI groups according to the WHO classification of obesity, with normal (BMI Our initial analysis showed a progressively higher proportion of blacks in progressively higher BMI groups. To determine if there were significant differences in BMI between racial groups, mean BMI values for the four ethnic groups (blacks, whites, Hispanics, and Asians) were compared by a one-way analysis of variance followed by multiple comparisons (Scheffé's test). Clinical and pathologic features of PC found in the radical prostatectomy specimen were compared between black and white patients. Recurrence of cancer after RP was defined as a single PSA greater than 0.2 ng/mL or two values at 0.2 ng/mL. PSA recurrence-free survival curves were estimated using the method of Kaplan-Meier and differences in survival between groups were tested using the log-rank test. Both clinical and pathologic factors were tested as univariate predictors of recurrence-free survival using Cox proportional hazards regression. The primary objective of our study was to determine if obesity or race was predictive of disease-free survival after RP, and to gauge whether these demographic factors were independent of well-established pathologic features in predicting disease recurrence. As such, a forward stepwise multivariate analysis was performed using a Cox proportional hazards model. Obesity and race were the initial factors entered into this model, with additional pathologic factors entered in a forward stepwise manner until all factors were entered.
The CPDR database contained data on 4,899 RP patients at the time of this review. A total of 3,162 RP patients (64.5%) had available height and weight data to allow calculation of BMI. Of these, 600 patients (19.0%) were categorized as obese, 1,534 patients (48.5%) were categorized as overweight, and 1,028 patients (32.5%) were categorized as normal according to the BMI determination. At the time of surgery, age was progressively lower in patients with higher degrees of obesity (P < .001). As BMI increased, the percentage of black patients comprising each BMI group also increased (P < .001). Although serum PSA level, transrectal ultrasonography–determined prostate volume, and PSA density were significantly different between the BMI groups, only prostate volume correlated positively with increasing BMI group (P < .001). Prostate biopsy determined Gleason score and percentage of patients with higher Gleason grade tumors (Gleason score  7) was not associated with BMI group (P = .097 and P = .128, respectively). However, clinical stage (determined from preoperative digital rectal examination) was associated with BMI group in that clinical stage distribution was higher in more obese patients (P = .006). Table 1 compares clinical and pathologic factors between black and white patients. In comparison with whites, blacks were more likely to be obese (P < .001), had higher PSA levels (P < .001), and had higher-grade (P = .016) cancers. They were also more likely to have positive surgical margins and involved seminal vesicles at the time of radical prostatectomy. In multiple regression analysis of BMI and black race as predictors of higher Gleason grade cancers, only BMI (P < .001) was an independent predictor, whereas race did not reach significance (P = .068).
Clinical and pathologic factors are compared between the two BMI groups (BMI 30 v BMI < 30 kg/m2) in Table 2. Obese patients had higher PSA levels (P = .027) and significantly higher-grade cancers (P = .003) than those not considered obese. There was a trend toward higher pathologic stage distribution in patients who were more obese, but this did not reach statistical significance (P = .083). However, the incidence of positive surgical margins was significantly higher in obese patients (P = .007). Once again, a significantly higher percentage of blacks was seen in the obese group (P < .001).
The relationship between race and BMI was determined for four racial or ethnic groups: black (n = 626; 20%), white (n = 2,299; 73%), Hispanic (n = 128; 4%), and Asian (n = 109; 3%). A one-way analysis of variance showed an overall difference in ethnic group mean BMI (P < .001). A linear contrast showed which pairs generated this significance. Obesity (BMI 30 kg/m2) was significantly more common (P < .001) in blacks (25.7% of the population) and Hispanics (25.5%) than in either white (17.4%) or Asian (9.2%) patients. Blacks had significantly greater BMI means than whites (P < .001) and Asians (P = .007) but were not different from Hispanics (P = .861). Similarly, BMI means of Hispanics were significantly greater than those of whites (P = .040) and Asians (P = .015). White means were not different from those of Asians (P = .496).
Disease-free survival was estimated using the Kaplan-Meier method and compared among several patient groups. Obese patients (BMI
Although numerous studies show a consistent association between dietary fat intake and PC risk, epidemiologic studies examining the relationship between obesity and the incidence of PC in various populations have been inconsistent. Several studies have shown an increased risk of developing PC in obese men, whereas other studies have found no association [9-12,24-29]. Some of these studies show that BMI may be associated with more advanced PC but the results of these studies have also been inconsistent, possibly because of the limited number of patients in these series with advanced disease [25-27]. However, in studies investigating obesity and PC mortality in large populations, a more consistent association between body mass and PC death has been seen [30-32]. In a study of 135,000 Swedish construction workers observed for an average of 18 years, BMI and weight were both positively associated with the risk of PC, with direct correlation to more aggressive disease [30]. However, a stronger association between BMI and PC mortality than between BMI and PC incidence was seen. In a recent study examining the relationship between BMI and death from PC in two large American Cancer Society cohorts, PC mortality rates were significantly higher among obese (BMI 30 kg/m2) than nonobese (BMI < 25 kg/m2) men in both cohorts [32]. These studies suggest that body mass may be a better predictor of PC aggressiveness than incidence, and support the hypothesis that obesity is associated with higher PC death rates.
To our knowledge, no previous study has investigated the relationship between BMI and recurrence of PC after RP. In our binary analysis comparing the outcomes of obese (BMI The biologic processes underlying the association between PC progression and obesity are unknown, although several potential mechanisms have been proposed. Obesity is associated with several hormonal alterations, including lower levels of sex hormone–binding globulin that may increase the fraction of biologically available testosterone [16-19]. Because androgens have been implicated as a potential cause of PC, these endocrine aberrations may play a role in progression to clinically significant disease. Abdominal obesity is also associated with insulin resistance and hyperinsulinemia [20]. Exposure to elevated blood levels of insulin and insulin growth factors (IGFs) may facilitate PC progression. As with colon and breast cancer, IGF-1 stimulates the growth of both tumor and normal cells of the prostate [21]. A recent prospective investigation of men from the Physicians Health Study showed a positive association between circulating IGF levels and PC risk [22]. Men in the highest quartile of IGF-1 levels had a relative risk of 4.3 compared with men in the lowest quartile independent of baseline PSA level. Leptin is another circulating hormone secreted by adipocytes and positively correlated with body mass [23]. Leptin has been shown to promote angiogenesis, which may predict the ultimate development of metastatic disease in men with PC [39,40]. Our study also addresses the hypothesis that obesity may account, in part, for the racial variability in PC aggressiveness. Consistent with other studies, our data show that black patients present with cancer at younger age and with higher-grade and higher-stage tumors, resulting in higher biochemical recurrence rates after RP, in comparison with white men. Serum PSA levels were also higher in black men. At the same time, black men were significantly more obese than were white patients. Could the more aggressive cancer behavior found in black men be a result of a higher average BMI in this ethnic group? Other studies have shown higher levels of obesity in black compared with white men, particularly in younger age groups. In the recently published National Health and Nutrition Examination Survey assessing the prevalence of obesity among children and adolescents, overweight was significantly more prevalent among non-Hispanic blacks compared with non-Hispanic whites in the 12- to 19-year-old age group [41]. Another recent longitudinal study analyzed the association between age, BMI, and serum hormonal levels in young men during an 8-year period and compared these hormonal levels between black and white male participants [42]. At each examination during this 8-year period, mean BMI was significantly higher in black men than in white men and the increase between years 2 and 10 was significantly greater in blacks than in whites. This study also showed that increasing obesity, particularly central obesity, was associated with decreasing total testosterone and sex hormone–binding globulin levels, and suggested that previously recognized differences in total testosterone between black and white men could be attributed for the most part to racial differences in abdominal obesity. Given that the ultimate development of clinically significant PC may be dependent on body habitus and/or hormonal levels in early life, higher rates of obesity in young black men might predict development of more aggressive disease later in life. Although a greater consumption of animal fat has been linked to an increased risk of PC in both black and white men, some studies suggest that this risk is higher in black men [37]. Racial differences in obesity have also been believed to be important in the racial disparities in breast cancer incidence and mortality. Several studies show that obesity is associated with more aggressive forms of breast cancer and may account for the higher-grade and higher-stage disease seen in black women [34-36]. Thus, although the reason for higher PC incidence and mortality rates in the black population is undoubtedly multifactorial, our findings and those of others suggest that body mass or obesity may have some role in this racial disparity in tumor behavior. There are several limitations to our study. Patient-reported height and weight figures make calculation of BMI for each individual patient imprecise and, as noted in other studies, lean body mass (a measure of muscle mass) may be more relevant than BMI in studies of androgen-dependent disorders such as PC [24]. We did not collect information on whether men had undergone PC screening. If active men with lower BMI were more likely to have undergone screening, reflective of health conscious behavior, earlier or latent cancer may have been detected in this group, which could account for better outcomes in men from lower BMI groups. Because we limited our analysis to RP patients, we cannot assess the relationship between obesity and more advanced stages of PC. Although unlikely, it is also possible that preferential selection for prostatectomy of obese patients with more significant disease (higher stage and grade) might have biased our findings. Pathologic analysis of RP specimens was not centralized, raising the issue whether variation in assessment between institutions might influence consistent reporting of pathologic stage and grade. Despite these limitations, our data show an association between obesity, and adverse pathologic features and higher biochemical recurrence rates in men with PC undergoing RP. They also suggest that obesity may play some role in determining the higher prevalence of advanced disease in black men. Our findings suggest that obesity may induce subtle differences in PC tumor parameters that may not be evident in epidemiologic studies investigating cancer incidence alone. If these findings are confirmed in other studies, lifestyle and dietary changes to limit obesity in men should be recommended to reduce the likelihood of developing clinically significant PC.
Authors' Disclosures of Potential Conflicts of Interest
Supported by the Center for Prostate Disease Research, a Department of Defense program of the Uniformed Services University of the Health Sciences funded by the US Army Medical Research and Materiel Command. The opinions and assertions contained herein are the views of the authors and are not to be construed as reflecting the views of the US Navy, Army, Air Force, or Department of Defense. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
25 kg/m2). For analysis, normal and overweight groups were combined (BMI < 30 kg/m2) and compared with the obese group (BMI 
2 test of contingency was used to assess differences in pathologic cancer grade (Gleason score), tumor stage (tumor-node-metastasis system), surgical margin, and lymph node status determined from the radical prostatectomy specimen. Because obesity and black race were both associated with higher radical prostatectomy Gleason scores, multiple regression analysis was performed to determine which of these factors was an independent predictor of Gleason score. 
