Emanuele Rubilotta

Prognostic Value of Renal Cell Carcinoma Nuclear Grading: Multivariate Analysis of 333 Cases

Objective: To evaluate the independent predictive value of the nuclear grading system according to Fuhrman in relation to the disease-specific survival of patients with renal clear cell carcinoma. Material and Methods: 333 patients who underwent radical nephrectomy for renal clear cell carcinoma between 1983 and 1999 were evaluated. In all patients we retrospectively studied nuclear grading, average tumor size, multifocality, pathologic stage of primary tumor, vein invasion, lymph node involvement and distant metastases. The Kaplan-Meier method was applied to evaluate disease-specific survival rates. The log rank test was used to compare survival curves and for univariate analysis. The Cox proportional hazards model was used for the multivariate analysis. Results: Histologic grade was G1 in 83 cases (25%), G2 in 117 cases (35%), G3 in 110 cases (33%) and G4 in 23 cases (7%). Our data showed that nuclear grading according to Fuhrman is related to medium tumor size (p < 0.0001), pathologic stage of cancer (p < 0.001), venous system invasion (p < 0.001), lymph node involvement (p < 0.001) and distant metastases (p < 0.001). The disease-specific survival after 5 and 10 years was 94 and 88%, respectively, in patients with G1, 86 and 75% in patients with G2, 59 and 40% in patients with G3 and 31% in patients with G4 (log rank p value < 0.0001). Multivariate analysis showed that nuclear grading by Fuhrman has a prognostic independent predictive value (hazard ratio = 1.8461, p = 0.002). Conclusions: Nuclear grading is an important independent predictive factor of disease-specific survival in patients with renal cell carcinoma.

Investigative clinical study on prostate cancer part II: on the role of the pretreatment total PSA to free testosterone ratio as a marker assessing prostate cancer prognostic groups after radical retropubic prostatectomy.

Objectives: To explore the significance of the pretreatment total prostate-specific antigen (PSA) to free testosterone (FT) ratio (PSA/FT) as a marker for assessing the pathologic Gleason sum (pGS) and levels of tumor extension (pT) in prostatectomy specimens. Patients and Methods: 128 of 135 consecutive patients diagnosed with prostate cancer underwent radical prostatectomy. Simultaneous pretreatment serum samples were obtained to measure serum total testosterone, FT and total PSA levels. The statistical design of the study included 2 sections: the first part trying to explore the role of the PSA/FT ratio in clustering patients with different pathologic prognostic factors, and the second to investigate the PSA/FT ratio distribution in different groups of patients according to the pathologic stage and pGS of the specimen after radical prostatectomy. Results: The average age was 65.80 (range 51.21–77.26) years, mean PSA was 8.88 (range 1.22–44.27) µg/l, mean FT was 35.32 (range 13.70–69.30) pmol/l, and the mean PSA/FT ratio was 0.27 (range 0.04–1.48). The PSA/FT ratio significantly clustered both the pT and pGS groups. Analysis of variance for the distribution of the PSA/FT ratio was significant for the pT model groups. The mean PSA/FT ratio increased as the tumor extended and grew through the prostate gland (high-stage disease). Analysis of variance for the different distributions of the PSA/FT ratio was significant for all model pGS groups. In our investigation we also found (data not shown) that a PSA/FT ratio of ≧0.40 was strongly correlated with large extensive (pT3b+pT4) and high-grade cancers (pGS8+pGS9). Conclusions: Prostate cancer patients may be classified into 3 different pathologic prognostic groups according to the PSA/FT ratio: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40), and high risk (PSA/FT >0.40 and ≤1.5). The PSA/FT ratio may be considered as the marker expressing different biology groups of prostate cancer patients, and it is strongly associated with pT and pGS.

Investigative Clinical Study on Prostate Cancer Part III: Exploring Total PSA and Free Testosterone Distributions and Linear Correlations in Groups and Subgroups of Operated Prostate Cancer Patients according to the Total PSA/FT Ratio

Objectives: Prostate cancer is an interesting tumor for endocrine investigation. The prostate-specific antigen/free testosterone (PSA/FT) ratio has been shown to be effective in clustering patients in prognostic groups as follows: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40) and high risk (PSA/FT >0.40 and ≤1.5). In the present study we explored the total PSA and FT distributions, and linear regression of FT predicting PSA in the different groups (PSA/FT, pT and pG) and subgroups (pT and pG) of patients according to the prognostic PSA/FT ratio. Patients and Methods: The study included 128 operated prostate cancer patients. Pretreatment simultaneous serum samples were obtained for measuring free testosterone (FT) and total PSA levels. Patients were grouped according to the total PSA/FT ratio prognostic clusters (≤0.20, >0.20 and ≤0.40, >0.40), pT (2, 3a and 3b+4) and pathological Gleason score (pG) (≤6, = 7 >3 + 4, ≧7 >4 + 3). The pT and pG sets were subgrouped according to the prognostic PSA/FT ratio. Linear regression analysis of FT predicting total PSA was computed according to the different PSA/FT prognostic clusters for the: (1) total sample population, (2) pT and pG groups, (3) intraprostatic (pT2) and extraprostatic disease (pT3a/3b/4), and (4) low-intermediate grade (pG ≤6) and high-grade (pG ≧7) prostate cancer. Results: Analysis of variance always showed highly significant different PSA distributions for (1) the different PSA/FT, pT and pG groups; and (2) the pT and pG prognostic subgroups. Significant FT distributions were detected for the (1) PSA/FT and pT groups; and (2) the pT2, pT3a and pG ≤6 prognostic PSA/FT subgroups. Correlation, variance and linear regression analysis of FT predicting total PSA was significant for (1) the PSA/FT prognostic clusters, (2) all the pT2 and pT3a subgroups, and (3) the pT3b/4 subgroup with PSA/FT >0.20 and ≤0.40, and (4) all the pG subsets. Linear regression analysis showed that the slopes of the predicting variable (FT) were always highly significant for patients with (1) intraprostate and extraprostate disease, and (2) low-grade and high-grade prostate cancer. Conclusions: According to the prognostic PSA/FT ratio, significantly lower levels of FT are detected in prostate cancer patients with extensive and high-grade disease. Also, significant linear correlations of FT predicting PSA are assessed in the different groups and subgroups of patients clustered according to the prognostic PSA/FT ratio. Confirmatory studies are needed.

Investigative Clinical Study on Prostate Cancer Part VI: Follicle-Stimulating Hormone and the Pituitary-Testicular-Prostate Axis at the Time of Initial Diagnosis and Subsequent Cluster Selection of the Patient Population

Aim: To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. Patients and Methods: The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13≤FSH/PSA≤0.57), B (0.57<FSH/PSA≤1.61) and C (1.61<FSH/PSA≤19.4). The model was assessed by simple linear and multiple linear regression analysis and differences between the groups were assessed by analysis of variance. Results: In the patient population, FSH correlated to LH (p < 0.0001), FT (p = 0.007) and age (p = 0.004). FSH was independently predicted by both LH (p < 0.0001) and PSA (p = 0.04). PSA predicted FSH/PSA A (p < 0.0001), B (p < 0.0001) and C (p = 0.04). On multiple regression analysis, FSH/PSA A was predicted by PSA (p < 0.0001), P+ (p = 0.03) and bGS (p = 0.04); FSH/PSA B by LH (p = 0.002) and PSA (p < 0.0001); FSH/PSA C by LH (p < 0.0001) and PSA (p < 0.0001). Moreover, FSH/PSA A, B and C differed for mean values of FSH (p < 0.0001), LH (p < 0.0001), PSA (p < 0.0001) and PSA/FT ratio (p < 0.0001). FSH/PSA clusters showed features of decreasing aggressive disease as the FSH/PSA ratio progressed from A to C. Conclusion:At the diagnosis of prostate cancer and along the pituitary-testis-prostate axis in a patient population FSH significantly correlated to LH, FT and age, and FSH was independently and significantly predicted by both LH and PSA. Because of the independent prediction of PSA by FSH, the prostate cancer population at diagnosis was clustered and ranked according to the FSH/PSA ratio in groups A, B and C. Also, the predictive model of PSA on FSH for the different groups proved to be effective at selecting potential prognostic clusters in which the risk of progression might be assessed as low (group C), intermediate (group B) and high (group A). The FSH/PSA model might be considered as a tool for prostate cancer study and for use in individualized, risk-adapted approaches. However, confirmatory studies are needed.

Follicle-Stimulating Hormone and the Pituitary-Testicular-Prostate Axis at the Time of Initial Diagnosis of Prostate Cancer and Subsequent Cluster Selection of the Patient Population Undergoing Standard Radical Prostatectomy

Aim: A preceding exploratory analysis has shown that follicle-stimulating hormone (FSH) was significantly correlated to and predicted by prostate-specific antigen (PSA) in a prostate cancer population. The aim of the study was to evaluate FSH physiopathology along the pituitary-testicular-prostate (PTP) axis at the time of initial diagnosis of prostate cancer in an operated population clustered according to the FSH/PSA ratio. Patients and Methods: The study included 93 patients who underwent standard radical prostatectomy. Age, percentages of positive cores at transrectal ultrasound scan biopsy (TRUSB) (P+), biopsy Gleason score (bGS), pathology Gleason score (pGS), luteinizing hormone (LH), FSH, prolactin hormone (PRL), total testosterone (TT), free testosterone (FT), estradiol (ESR) and PSA were the continuous variables. Category variables were pT and biopsy/pathology Gleason pattern I/II (b/pGPI/II). The population was clustered according to the FSH/PSA ratio which was computed from empirical data and then ranked for clustering the population as groups A (range 0.13 ≤ FSH/PSA ≤ 0.20), B (range 0.20 < FSH/PSA ≤ 0.50), C (range 0.50 < FSH/PSA ≤ 0.75), D (range 0.75 < FSH/PSA ≤ 1.00), E (range 1.00 < FSH/PSA ≤ 1.25), F (range 1.25 < FSH/PSA ≤ 2.00), G (range 2.00 < FSH/PSA ≤ 2.25), H (range 2.25 < FSH/PSA ≤ 6.40) and I (range 6.40 < FSH/ PSA ≤ 19.40). The model was assessed by simple linear regression analysis and differences between the groups were investigated by analysis of variance (ANOVA) for continuous variables and by contingency tables for category variables. Results: FSH was significantly correlated to and predicted by PSA in groups A (p = 0.04), B (p < 0.0001), C (p < 0.0001), D (p < 0.0001), E (p < 0.0001), F (p < 0.0001), G (p < 0.0001), H (p = 0.0001) and I (p = 0.001). Also, clusters (A–I) differed significantly for mean values of FSH (p < 0.0001), LH (p < 0.0001), TT (p = 0.04), PSA (p < 0.0001), bGS (p = 0.005), pGS (p = 0.01) and PSA/FT ratio (p < 0.0001); moreover, the nine groups showed significant different frequency distributions of pGPI (p = 0.02), pGPII (p = 0.0002) and bGPI (p = 0.04). Conclusion: The ranking FSH/PSA ratio significantly clustered, along the PTP axis, an operated population diagnosed with prostate cancer. Also, the ranking FSH/PSA ratio selected prostate cancer clusters expressing different levels of hormonal disorder along the PTP axis and prognostic potential with different risks of progression. As a theory, in the current advancing world, the ranking FSH/PSA model might be considered as an interesting and effective tool for prostate cancer study as well as individualized, risk-adapted approaches of the disease. However, confirmatory studies are needed.

Investigative clinical study on prostate cancer part IV: exploring functional relationships of total testosterone predicting free testosterone and total prostate-specific antigen in operated prostate cancer patients.

Objectives: To explore, in operated prostate cancer patients, functional relationships of total testosterone (tt) predicting free testosterone (ft) and total PSA. Patients and Methods: 128 operated prostate cancer patients were simultaneously investigated for tt, ft and PSA before surgery. Patients were not receiving 5α-reductase inihibitors, LH-releasing hormone analogues and testosterone replacement treatment. Scatter plots including ft and PSA versus tt were computed in order to assess the functional relationship of the variables. Linear regression analysis of tt predicting ft and PSA was computed. Results: tt was a significant predictor of the response variable (ft) and different subsets of the patient population were assessed according to the ft to tt ratio. PSA was related to tt according to a nonlinear law. tt was a significant predictor of PSA according to an inversely nonlinear law and different significant clusters of the patient population were assessed according to the different constant of proportionality computed from experimental data. Conclusions: In our prostate cancer population, ft was significantly predicted by tt according to a linear law, and the ft/tt ratio was a significant parameter for assessing the different clusters. Also, tt was a significant variable predicting PSA by a nonlinear law and different clusters of the patient population were assessed by the different constants of proportionality. As a theory, we explain the nonlinear relation of tt in predicting PSA as follows: (a) the number of androgen-independent prostate cancer cells increases as tumor volume and PSA serum levels rise, (b) the prevalence of androgen-independent cells producing a substance which inhibits serum LH, and (c) as a result lower levels of serum tt are detected.