BACKGROUND: Metabolic syndrome (MetS) and prostate cancer (PCa) are highly prevalent conditions worldwide. Current evidence suggests the emerging hypothesis that MetS could play a role in the development and progression of several neoplasms. The aims of this study are to evaluate the impact of MetS and MetS factors on PCa incidence, on the risk of high-grade PCa and to analyze the role of MetS and single MetS components on the development of aggressive PCa features.
METHODS: A systematic literature search and analysis on PubMed, EMBASE, Cochrane and Academic One File databases until September 2015 was performed by 2 independent reviewers to evaluate the associations between MetS and PCa incidence, and between MetS and high-grade PCa incidence (bioptical Gleason Score⩾ 8, Prognostic Group 4–5 according to the novel prostate cancer grading system). Also, the association between MetS and individual MetS components with pathological Gleason Score⩾8,extra-capsular extension, seminal vesicle invasion, positive surgical margins and biochemical recurrence (defined as two consecutive PSA values ⩾0.2 ng ml− 1 after radical prostatectomy) was evaluated.
RESULTS: 24 studies were selected including a total of 132 589 participants of whom 17.35% had MetS. There was a slight association between MetS and PCa incidence (odds ratio (OR) = 1.17 (1.00–1.36), P = 0.04) and between high-grade PCa and MetS (OR = 1.89 (1.50–2.38), Po0.0001) but the studies were statistically heterogeneous. No association was found between MetS components and PCa risk except for hypertension. MetS was significantly associated with pathologic Gleason Score ⩾8 (OR = 1.77 (1.34–2.34); Po0.01), extra-capsular extension (OR = 1.13 (1.09–1.18); Po0.01), seminal vesicle invasion (OR = 1.09 (1.07–1.12); Po0.01), positive surgical margins (OR = 1.67 (1.47–1.91); Po0.01) and biochemical recurrence (OR = 1.67 (1.04–2.69); Po0.01).
CONCLUSIONS: The presence of MetS is associated with worse oncologic outcomes in men with PCa, in particular with more aggressive tumor features, and biochemical recurrence.
INTRODUCTION
Prostate cancer (PCa) is the most frequently diagnosed malignancy in industrialized nations1 and the sixth leading cause of cancer death among men worldwide.2 The rate of PCa in western countries is 10–15 times higher than Asian countries and most PCa related deaths occur in developed nations; however, in the last few decades, the incidence of PCa and related mortality in Southeast Asia has seemingly increased as this region has gradually begun embracing the western lifestyle including sedentary habits and a high fat diet.3
Although the pathogenesis of PCa has multiple causes, the only established risk factors are age, race, and family history.4 However, current evidence from epidemiological studies and experimental translational research suggests the emerging hypothesis that metabolic syndrome (MetS) could play a role in the development and progression of several neoplasms.5
MetS is a common clinical condition with a complex etiology, including high-fat intake, sedentary lifestyle and genetic factors. Moreover, MetS is a cluster of risk factors for cardiovascular and metabolic complications, that includes visceral obesity, hyperten- sion, hyperglycemia, low levels of high-density lipoprotein cholesterol (HDL cholesterol), and hypertriglyceridemia.6 MetS has been proposed as one of the leading causes of the variability of geographic incidence and mortality of PCa. In particular, the association between MetS and PCa has been postulated on the basis of the rise of PCa occurrence among Asian migrants, suggesting that westernization is an important risk factor for PCa.7 To this regard, metabolic abnormalities that are typical of the western areas, like diabetes and obesity, can play an important role in the development and progression of PCa.
The underlining mechanisms linking MetS and PCa could be the alteration of insulin and insulin-like growth factor-I (IGF-I),8 the modifications of sex steroid pathways, such as increased serum estradiol levels, sex hormone-binding globulin concentration and decreased free testosterone level.9,10 Moreover, chronic prostatic inflammation as observed in patients with MetS is associated with a milieu enriched in cytokines, inflammatory mediators and growth factors, which may lead to an uncontrolled proliferative response. In fact, increased circulating levels of MetS-related cytokines as well as leptin and adiponectin alterations have been preliminarily associated with PCa carcinogenesis.11
Current preclinical and clinical research on MetS and PCa is still discordant and has failed to determine the real impact of MetS, and/or of its individual component, on PCa incidence and aggressiveness. The aims of this systematic review and meta- analysis are to evaluate the impact of MetS and MetS factors on PCa incidence and risk of high-grade PCa and to analyze their role in the development of the aggressive features of PCa.
MATERIALS AND METHODS
Systematic literature search
This analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.12 We performed a systematic literature search of PubMed, EMBASE, Cochrane, and Academic One File databases using Medical Subject Headings (MeSH) indexes, keyword searches, and publication types until September 2015. The search was limited to English-Language articles. The search terms included 'prostate', 'prostate cancer', 'prostate specific antigen', 'prostate biopsy', 'metabolic syndrome', 'obesity, 'hypertension', 'triglycerides', 'cholesterol', 'recurrence', 'high-grade', 'extra-capsu- lar extension', 'positive margin', 'seminal vesicle invasion', 'Gleason score' and 'prostate biopsy'. Reference lists in relevant articles and reviews were also screened for additional studies.
We defined MetS according to the USA National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III), which requires at least three of the following five components: central obesity (waist circumference 494 cm or body mass index (BMI) ⩾ 30 kg/m2, elevated triglycerides (⩾1.7 mmol l − 1 or 150 mg dl− 1), elevated blood pressure (⩾130/85 mm Hg), elevated fasting glucose (⩾6.1 mmol l − 1 or 110 mg dl− 1) and reduced HDL cholesterol ( o1.03 mmol l − 1 or 40 mg dl− 1). We also included trials based on the MetS criteria proposed by the International Federation of Diabetes and the American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI criteria),13 by The Society of Endocrinology and Metabolism of Turkey metabolic syndrome diagnostic criteria, and by the Chinese Adult Dyslipidemia Prevention Guide,14,15 with the aim to cover all the possible ethnic differences in MetS parameters.
The primary outcome of the meta-analysis was to evaluate the associations between MetS and PCa incidence and between MetS and high-grade PCa (bioptical Gleason Score ⩾ 8, Prognostic Group 4–5 according to the novel prostate cancer grading system16) incidence. The secondary outcomes were the association between MetS and individual MetS components with pathological Gleason Score ⩾ 8, extra-capsular extension, seminal vesicle invasion, positive surgical margins and biochemical recurrence (defined as two consecutive PSA values ⩾ 0.2 ng ml − 1).
Study selection
Two independent reviewers (GIR and AS) revised the studies. Citation lists of retrieved articles were screened manually to ensure accuracy of the search strategy. References of the included papers were hand searched to identify other potentially relevant studies. Data were extracted independently by two reviewers. Discrepancies for inclusion between the investigators were resolved by discussion or further consultation with a third author (MG). The quality of these eligible citations was assessed using Newcastle—Ottawa quality scoring system; two authors scored independently. We created evidence tables reporting study characteristics, outcome measures, MetS definition and study quality. We selected studies that investigated the relationship between MetS and PCa as per our outcomes of interest.
Statistical analysis
For the meta-analysis, the association between MetS and outcome of interest was determined by calculating the Ln (OR). We also estimated the role of each MetS component in this risk among the selected studies. Begg’s and Egger’s methods were used to assess publication bias. Statistical heterogeneity was assessed using the Cochran Q and I2 statistics. A p value ⩽ 0.05 was considered statistically significant. Moreover, a multivariate logistic regression analysis, weighting each study for the number of patients enrolled, was used to verify the independent effect of MetS components on PCa incidence. The analysis was performed using RevMan software v.5.1 (Cochrane Collaboration, Oxford, UK).
RESULTS
Study characteristics
Overall, 327 studies were identified from the databases and relevant references. After evaluating the title and abstract of each study, 24 were identified as eligible for this systematic review, including a total of 132 589 participants: 19 229 (17.35%) with and 93 111 (82.65%) without MetS (Table 1). Figure 1 shows the flow diagram of the search results. The quality assessment score (Newcastle—Ottawa quality scoring system) was 450% in more than half of the studies (20/24).
MetS and PCa incidence/high-grade PCa incidence
As derived from the meta-analysis, the presence of MetS was associated with a 17% increased risk of PCa (pooled odds ratio (OR) = 1.17 (1.00–1.36), Figure 2a). There was a statistically significant heterogeneity in these studies (χ2 = 66.05, I2 = 74%; P o0.01). Moreover, the risk of high-grade PCa (bioptical Gleason Score ⩾ 8) was significantly associated with the presence of MetS (OR = 1.89 (1.50–2.38) (P o0.0001) (Figure 2b). The risk of having PCa was not confirmed by the sub-analysis including exclusively studies that applied NCEP ATP III classification of MetS: OR = 1.09 (95% confidence interval (CI): 0.93–1.27); P = 0.28 (data not shown).
Individual MetS components and PCa risk
The impact of BMI or central obesity (waist circumference) was investigated in 8 studies.15,17–23 There was a statistically significant heterogeneity in these studies (χ2 = 20.38, I2 = 85%, P o0.01). The pooled OR (95% CI) was 1.01 (0.86–1.19, P = 0.91) (Figure 3a).
The role of HDL cholesterol was reported in 8 studies.14,17,18,21–24 There was a statistically significant heterogeneity in these studies (χ2 = 45.57, I2 = 85%, P o0.01). In patients with HDL cholesterol o40 mg dl− 1, the pooled ORs (95% CI) of having PCa was 1.19 (0.89–1.60), thus the overall effect was not statistically significant (P = 0.23; Figure 3b).
The possible association between triglycerides and PCa incidence was investigated in eight studies,14,15,17,18,20–23 which demonstrate significant heterogeneity (χ2 = 44.47, I2 = 84%, P o0.01). In patients with triglycerides ⩾ 150 mg dl− 1, the pooled OR of having PCa was 1.10 (0.89–1.34) (P = 0.38) (Figure 3c).
The role of diabetes on PCa diagnosis was reported in 10 studies,14,15,17–23,25 without significant heterogeneity (χ2 = 42.55, I2 = 81%, P = 0.09). In patients with elevated fasting glucose (⩾6.1 mmol l − 1 or 110 mg dl− 1), or a previous diagnosis of diabetes, the pooled OR (95% CI) of having PCa was not higher (OR = 0.99 (0.84–1.17), P = 0.94) (Figure 3d).
The impact of hypertension was reported in seven studies.15,17–19,21–23 There was not a statistically significant heterogeneity in these studies (χ2 = 1.97, I2 = 0%, P = 0.92). The test of overall effect was statistically significant (P = 0.02). Hence, elevated blood pressure was the only MetS component signifi- cantly associated with a 10% increased risk of PCa OR = 1.10 (1.01–1.19) (Figure 3e).
MetS and PCa aggressiveness
Eight studies26–33 were identified as eligible for PCa aggressive- ness (Figure 1). In the meta-analysis, the presence of MetS was associated with worse oncological outcomes, including pathologic Gleason Score ⩾ 8 (OR = 1.77 (1.34–2.34); P o0.01), extra-capsular extension (OR = 1.13 (1.09–1.18); P o0.01), seminal vesicle inva- sion (OR = 1.09 (1.07–1.12); P o0.01) and positive surgical margins (OR = 1.67 (1.47–1.91); P o0.01). In patients with MetS, the pooled relative risk (RR) (95% CI) of having biochemical recurrence was 1.67 (1.04–2.69); P o0.01, Figure 4).
The impact of each component of MetS on PCa recurrence was investigated in three studies. When considering each component of MetS, obesity RR = 0.9 (95% CI: 0.73–1.16); P = 0.48), low HDL cholesterol (RR = 0.88 (95% CI: 0.70–1.11; P = 0.29), hypertriglycer- idemia (RR = 0.99 (95% CI: 0.78–1.26); P = 0.95) and hypertension (RR = 1.27 (95% CI: 0.61–2.63), P = 0.52) were not associated with an increased risk of biochemical recurrence. Only the presence of hyperglycemia appeared associated with an increased risk of PCa recurrence with a pooled RRs (95% CI) of 1.39 (1.06–1.81); P = 0.02) (Figure 5). No statistical association was found when evaluating other MetS components.
Figure 1. Flow diagram of included studies. MetS, metabolic syndrome; PCa, prostate cancer.
DISCUSSION
In the present comprehensive meta-analysis, we demonstrated that MetS can be considered a possible risk factor for the occurrence PCa, in particular for high-grade PCa (bioptical Gleason score ⩾ 8). Moreover, MetS is associated with worse pathologic outcomes after radical prostatectomy (RP), including pathologic Gleason Score ⩾ 8, extra-capsular extension, seminal vesicle invasion, positive surgical margins and the consequent biochemical recurrence.
Twelve years ago, Laukkanen et al.34 proposed, for the first time, MetS as a composite factor associated with PCa risk: In that prospective population-based study, men with MetS were twofold more likely to develop PCa than those without. In 2007, Hsing demonstrated that the association between obesity, MetS and prostate cancer incidence was inconsistent, even if in some studies obesity was associated with an increased risk of high- grade PCa.3 In 2012, Esposito et al. performed a systematic review and meta-analysis on 14 data sets (4623 P.ts), demonstrating the lack of association between MetS and risk of PCa (RR (95% CI: 1.09 (0.88–1.34), P = 0.438).5 Interestingly, in that paper, a remarkable difference among American (RR (95% CI: 0.79) (0.69–0.91),P = 0.001), Asian (RR (95% CI: 0.98 (0.71–1.36), P = 0.932) and European populations (RR (95% CI: 1.28 (0.89–1.87), P = 0.083) was clearly presented. In addition, several other cohort studies of PCa incidence in European populations have showed a significant positive association,18,34 while analogous studies performed on American cohorts revealed no35 or even a negative association.20 The heterogeneity between these populations may arise from genetic or environmental factors, in addition to different definitions of MetS. In fact, in our review, a sub-analysis of studies based on the more rigorous NCEP ATP III classification failed to reveal a significant link between MetS and PCa incidence. However, considering that the currently used definitions of MetS (WHO, NCEP ATP III, EGIR, IDF) emphasize only single aspects of metabolic disorders, an exclusive classification of MetS should not be used as the gold standard for a meta-analysis including multinational trials.36 Accordingly, in our review we found a slight, but significant, association between MetS and PCa (RR: 1.17); this calculated risk is in line with those reported in current literature.5,37
Figure 2. Association between MetS and overall PCa risk (a) and high-grade PCa risk (b) (⩾8 Gleason Score). CI, confidence interval; MetS, metabolic syndrome; PCa, prostate cancer.
When the relationship between individual MetS components and PCa risk was considered in the meta-analysis, we found only a minimal contribution for hypertension, but not for the other MetS factors. The presence of hypertension could increase the risk of PCa by activating sympathetic nervous system responses (and vice versa), resulting in PCa cell growth.11 However, it is also possible that only the concert of different factors recapitulated in the MetS concept could be deleterious for increasing PCa risk, by activating several pathways including inflammation, insulin resistance, visceral adiposity and hormone changes.11
In our meta-analysis of six trials enrolling more than 3000 patients we demonstrated that men with MetS are nearly 2-fold more at risk to develop a high Gleason (bioptical Gleason Score⩾ 8) PCa as compared to those without MetS. In 2004, Hammarsten first demonstrated that men with high-grade PCa were more often dyslipidemic—that is, higher triglyceride levels and lower HDL cholesterol levels—and showed a higher insulin plasma level than those with low grade PCa.38 In a large Canadian prostate biopsy cohort of 2235 men, MetS was associated with an increased diagnosis of PCa and in particular of high-grade PCa.22 Interestingly, no individual MetS component resulted as being independently associated with PCa outcomes but rather their association. In fact, ⩾ 3 vs 0 MetS components was associated with higher odds (OR: 1.54) of PCa diagnosis.22 In the first meta-analysis on risk of high-grade PCa according to MetS, Xiang et al.37 demonstrated that MetS was associated with an increased risk of high Gleason score PCa. In that meta-analysis, as in the present one based on the contemporary prostate cancer grading system,16 it is interesting to note that almost all the data sets reported a clinically significant, positive correlation between MetS and high Gleason PCa (see also Figure 2b). In the last 3 years, several authors have reported an association between MetS and high risk PCa.32,39 In particular, in the first cohort study in Europe on 349 men treated with RP, MetS was associated with an increased risk of high-grade (OR: 2.0) and locally advanced (pathological stage⩾ pT3a or N1, OR: 2.2) PCa.40 The same data were reported in a large retrospective study in 1016 Asian men, demonstrating that men with MetS presented an increased risk of prostatectomy, Gleason score ⩾ 8 (OR = 1.67), and a 1.5-fold increased risk of pT3- 4 disease (OR = 1.58), as compared to those without MetS.32
In the present study, only diabetes seems to be a potential independent risk factor for biochemical recurrence. Current literature is controversial about the association between diabetes and PCa.
Figure 3. Association between PCa and single components of MetS: waist circumference ⩾ 90 cm (or ⩾ 90 cm for Asians) (a), with HDLo40 mg dl − 1 (b), with triglycerides ⩾ 150 mg dl − 1 (c), in patients with elevated fasting glucose (⩾6.1 mmol l − 1 or 110 mg dl − 1) (d) and in patients with hypertension (e). CI, confidence interval; HDL, high-density lipoprotein; MetS, metabolic syndrome; PCa, prostate cancer.
In particular, trials from the SEARCH database suggest that diabetes was not associated with an increased risk of biochemical recurrence,41,42 while other Asian authors indicate that poor glycemic control was significantly associated with biochemical recurrence and with more aggressive recurrence, after RP.43,44 To critically analyze these data is not an easy task. First of all, the current literature does not report the duration of diabetes: early-onset diabetes has been shown to be associated with an increased risk of PCa diagnosis, whereas late-stage diabetes is associated with a decreased risk.45 Moreover, in most cases information on the treatment of diabetes (metformin, insulin) as well as the effectiveness of glycemic control (hypo, normo or hyper-glycemic) are not available. Finally, diabetes is associated with receiving radiation therapy more frequently than surgery, with high complication rates and treatment failure.46 On the basis of these biases, it is not possible to define the role of a history of diabetes, glycaemia levels and treatment for diabetes in PCa recurrence.
Figure 4. Association between MetS and pathological Gleason score ⩾ 8 (a), extra-capsular extension (b), seminal vesical invasion (c), positive surgical margin (d), and biochemical recurrence (e). CI, confidence interval; MetS, metabolic syndrome.
Intriguing data on inflammation as a potential driver for PCa development and progression has recently emerged.47 The prostate gland is clearly an immunocompetent organ. Besides epithelial and stromal cells, the prostate also contains a small number of immunocompetent cells (lymphocytes, macrophages and granulo- cytes). Stromal prostatic cells are able to secrete several cytokine, chemokine and growth factors, including interleukin-8, CXCL-10 and interleukin-6 not only in response to specific proinflammatory stimuli (that is, tumor necrosis factor-α or the Toll-like receptor-4 agonist lipopolysaccharide), but also to metabolic insults and, in particular, to oxidized low-density lipoprotein and insulin. This suggests the hypothesis that lipids can induce and sustain an nflammatory response and overgrowth in human prostatic cells. Accordingly, several epidemiological studies have demon- strated a tight association between MetS, intraprostatic inflammation and benign prostatic enlargement.13,48,49 In contrast, whether inflammation has a role in the pathogenesis of prostate cancer still remains unclear. Therefore, the association between MetS and more aggressive features of PCa (high grade, clinically advanced, biochemical recurrent neoplasms) must be further investigated with targeted randomized control trials and translational research designed using a holistic approach by urologists, andrologists and endocrinologists.
Figure 5. Association between prostate cancer recurrence and single components of MetS: obesity (BMI ⩾ 30 kg/m2) (a), with HDLo40 mg dl − 1 (b), with triglycerides ⩾ 150 mg dl − 1 (c), in patients with elevated fasting glucose (⩾6.1 mmol l − 1 or 110 mg dl − 1) (d) and in patients with hypertension (e). BMI, body mass index; CI, confidence interval; HDL, high-density lipoprotein; MetS, metabolic syndrome.
The main limitation of this review is the heterogeneity of the studies included (Figure 6): this methodological bias does not allow for the weighting of the overall data or for performing meta- regression analyses. Moreover, several important outcomes, including prostate cancer-specific mortality were not analyzed due to the lack of the data in the randomized control trials included in the meta-analysis. The strength of this manuscript is to have the impact of MetS on both the incidence and aggressive- ness of PCa summarized in a single review. However, it should be recognized that small risk associations (RR o2 or OR o3), such as those observed in the studies included in this meta-analysis, fall below the discriminatory ability of observational studies, and are likely to be attributable to bias rather than causal associations.50 In particular, for our analyses we used Gleason Score 8 (Prognostic Group 4–5) as the cut off point: we believe this is the very first meta-analysis based on this novel five–grade group system, which has proven to achieve the highest prognostic discrimination for all cohorts in both univariable and multivariable analysis.16
Figure 6. Funnel plot to check for the existence of publication bias of the review.
In particular, based on these data, MetS should be investigated within screening protocols, with the aim to increase early detection of more aggressive tumors; moreover, MetS could be included in current clinical nomograms with the aim to improve clinical staging and to personalize the treatment.
CONCLUSIONS
MetS and PCa are two common conditions related to the aging population all over the world: these diseases coexist in an increasing percentage of patients. Men with MetS present a slightly higher incidence of high-grade PCa than those without MetS. The single MetS parameters failed to result as being determinant for the risk of PCa, indicating that only their combined presence increases the risk of PCa development. More importantly, the presence of the MetS construct seems to be associated with adverse postoperative oncologic features, including high Gleason score (⩾ 8), extra-capsular extension or seminal vesicle invasion, positive surgical margins and the consequent biochemical failure. Hence, these data should be carefully assessed in decision-making of treatment and follow up. Further prospective studies are needed to better define interactions between MetS, MetS components and PCa, particularly to evaluate the possible implications for PCa management in patients with MetS and to evaluate the possible effect of MetS treatment on PCa development and progression.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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Written by: M Gacci1, GI Russo2, C De Nunzio3, A Sebastianelli1, M Salvi1, L Vignozzi4, A Tubaro3, G Morgia2 and S Serni1
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A letter from the desk of the editor: Stephan J. Freedland