BERKELEY, CA (UroToday.com) - There is a general opinion that inflammatory diseases are frequently associated with an increased risk of prostate cancer (PCa), one of the most common cancers. Proliferative inflammatory atrophy (PIA) lesions are strictly related to chronic prostatic inflammation, and histological cellular transitions have been noted between areas of PIA and high-grade prostate intraepithelial neoplasia (HGPIN), and, additionally, between PIA and PCa. A key role of the PIA lesion is the presence of leukocyte infiltration, with the majority of cells belonging to the monocyte-macrophages lineage.
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Tumor-associated macrophages (TAMs) are a significant component of the inflammatory cell infiltrates in prostate cancer. TAMs may have both tumor stimulatory and/or inhibitory properties, probably because they can differentiate into either cytotoxic (M1) or tumor growth promoting (M2) states. Inflammation has been thoroughly described as a key player in PCa, and among various inflammatory cell populations, macrophages have been recognized as one of the major components. A strong association has been demonstrated between chronic prostatic inflammation, pre-malignant, and malignant changes in the prostatic epithelium.
In our paper we investigated the causal connection between M1 and M2 phenotype macrophages occurrence with PCa, and evaluated their correlation with commonly used clinico-pathological variables and survival in 93 patients with stage cT2b-c PCa undergoing radical prostatectomy (RP). All patients received anterograde RP according to our previously published technique. Macrophages were quantified by systematically screening the entire carcinoma area at low magnification using a 2,5X or 5X lens and selecting the areas with highest density of macrophages and by counting them. M1 and M2 were distinguished by two different primary antibodies: anti-CD163 (for M2) and anti-CD68 (for M1) and two different chromogens: chromogen diaminobenzidine (DAB) for CD163 (M2) and chromogen FAST RED for CD68 (M1). We systematically screened the entire carcinoma area at low magnification, and in this way we selected the areas rich with macrophages (called “hot spots”). After that, both M1 and M2 macrophages were manually counted at high magnification. Finally, the mean of both the number of M1 macrophages and M2 macrophages in these 3 hot spots was obtained.
Our patients presented with median preoperative PSA of 7.6 and a prevalence of biopsy GS 6 (53.8%). Biochemical recurrence (BCR) occurred in 24.7% of patients with a mean (SD) follow-up period of 26.3 (25.2) months. 35.5% of patients presented organ confined disease (OC), while in 64.5% of patients there was extracapsular extension (ECE). Positive surgical margins were found in 11.8%. In 36.6% of patients, a higher prevalence of M1 was found, while in 63.4% there was a higher prevalence of M2. M1 occurred more frequently in OC PCa, especially with GS 6 to 7 (mean number 18.6, median 11.6), while M2 resulted more frequently in PCa with ECE and GS 7 to 8-10 (mean number 20.2, median 10). When we correlated M1-M2 ratio to GS, biopsy cores, stage, and BCR at Student t test and Pearson χ2 test, we found statistical correlation only with stage (p=0.004). Moreover at univariate analysis for ECE, pathological GS and M2 phenotype were statistically correlated to ECE (0.029, 0.0001, and 0.0079, respectively). On the contrary, we did not find any statistical correlation between BCR and M1-M2 ratio, even if patients with higher prevalence of M1 phenotype presented better results. At logistic regression analysis, only specimen GS and M1-M2 ratio were confirmed to be statistically correlated to ECE (p=0.05, RR 10.65, 95% CI 1.11-102.26 and p=0.03, RR 0.295, 95% CI 0.09-0.89, respectively). Moreover, at univariate analysis biopsy, GS, pathological GS, pTNM, positive surgical margins, and high density of macrophages in 3 hot spots proved to be independently predictive of BCR (p=0.0009, 0.0006 and 0.0147, respectively), while sub-stratification in M1 and M2 did not achieve statistical significance. At Cox multivariable analysis, only pathologic GS and stage were independent predictors of BCR (r = 19.146, p = 0.02 and r = 3.43, p = 0.05, respectively).
At Kaplan-Meier survival analysis, the 36 and 60 months BR-free survival rate for the global population was 84.6% and 72.5%, respectively. According to macrophage density, BCR-free survival curves at the Kaplan-Meier analysis were 94.4 vs 74.0 and 85.1 vs 62.2 at 36 and 60 months, respectively, with a statistically significant difference among the curves (p=0.05). Moreover when we stratified our patients for M1 and M2 macrophage phenotype, we didn’t find any statistical difference among BCR-free survival curves (log rank p=ns), although we observed that patients with prevalence of M2-macrophages showed a trend toward worst BCR-free survival rates at 36 and 60 months compared to patients with M1 prevalence (78.2 vs 94.1 and 71.0 vs 77.4, respectively). When we analyzed survival curves for the category of patients with only ECE, among them stratification for M1 and M2-macrophage phenotype did not allow us to establish a significative correlation with prognosis, although even in this instance, patients with M2 phenotype prevalence were confirmed to have a slightly worse prognosis.
We observed that a higher density of macrophages was statistically associated with poorer prognosis (p=0.02). M2 population had a greater percentage of PCa with ECE (p=0.0079) and GS 7 to 8-10, pT3a stage and BCR (p=ns). According to previous data published in the literature, TAMs generally exhibit an M2 phenotype known to promote angiogenesis, tumor growth, and metastasis. We noticed a slight higher incidence of extracapsular disease and GS 7, certainly due to our necessity to definitely locate macrophages in the prostate specimen at the final pathological evaluation, as it is statistically found in patients with higher stages and GS.
This is a preliminary study in which we laid down groundwork for further studies, and we found correlation between high macrophage infiltration and unfavorable prognoses after RP. Moreover M2 macrophage phenotype was significantly associated with ECE, even if this phenotype prevalence was not initially capable of predicting BCR. Macrophage phenotype has proven to be fascinating and valuable in rationalizing a more aggressive adjuvant approach, even if further studies are needed for verification.
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M. Lanciotti,a L. Masieri,a M. R. Raspollini,b A. Minervini,a A. Mari,a G. Comito,c E. Giannoni,c M. Carini,a P. Chiarugi,c and S. Serni,a as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aDepartment of Urology, University of Florence, Careggi Hospital, Viale San Luca, 50134 Florence, Italy
bDepartment of Pathology, University of Florence, Careggi Hospital, Florence, Italy
cDepartment of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy