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Clinical Cancer Research Vol. 12, 5741-5745, October 1, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Nuclear Localization of Nuclear Factor-{kappa}B p65 in Primary Prostate Tumors Is Highly Predictive of Pelvic Lymph Node Metastases

Laurent Lessard, Pierre I. Karakiewicz, Pascale Bellon-Gagnon, Mona Alam-Fahmy, Hazem A. Ismail, Anne-Marie Mes-Masson and Fred Saad

Authors' Affiliations: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Institut du Cancer de Montréal, and the Department of Surgery/Urology, CHUM, University of Montréal, Montréal, Québec, Canada

Requests for reprints: Fred Saad, Centre Hospitalier de l'Université de Montréal, 1560 rue Sherbrooke est, Montréal, Québec, Canada H2L 4M1. Phone: 514-890-8000-27466; Fax: 514-412-7620; E-mail: fred.saad.chum{at}ssss.gouv.qc.ca.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Lymph node invasion (LNI) is associated with increased risk of prostate cancer progression. Unfortunately, pelvic lymph node dissections are fraught with a high rate of false-negative findings, emphasizing the need for highly accurate markers of LNI. Because nuclear factor-{kappa}B (NF-{kappa}B) is a candidate marker of prostate cancer progression, we tested the association between nuclear localization of NF-{kappa}B in radical prostatectomy specimens and the presence of LNI.

Experimental Design: NF-{kappa}B expression in radical prostatectomy specimens was assessed with a monoclonal NF-{kappa}B p65 antibody, in 20 patients with LNI and in 31 controls with no LNI and no biochemical relapse 5 years after radical prostatectomy. Univariate and multivariate logistic regression models were used. The accuracy of multivariate predictions with and without NF-{kappa}B was quantified with the area under the receiver operating characteristics curve and 200 bootstrap resamples were used to reduce overfit bias.

Results: Univariate regression models showed a 7% increase in the odds of observing LNI for each 1% increase in NF-{kappa}B nuclear staining (odds ratio, 1.07; P = 0.003). In multivariate models, each 1% increase in NF-{kappa}B was associated with an 8% increase in the odds of LNI (odds ratio, 1.08; P = 0.03) and its statistical significance was only surpassed by the presence of seminal vesicle invasion (P = 0.003). Addition of NF-{kappa}B to all other predictors increased the accuracy of LNI prediction by 2.3% (from 84.8% to 87.1%; P < 0.001).

Conclusion: This is the first study that shows that the extent of nuclear localization of NF-{kappa}B in primary prostate tumors is highly accurately capable of predicting the probability of locoregional spread of prostate cancer.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related mortality in North American men. Most tumors are now detected at an early stage due to prostate-specific antigen (PSA) screening. Definitive treatment of localized prostate cancer predominantly consists of radical prostatectomy or radiation therapy. Unfortunately, pelvic lymph node metastases may be present in a significant number of patients at the time of surgery and are associated with an increased risk of disease recurrence and progression to distant metastases and death (1–3). Lymph node status is frequently unknown because pelvic lymph node dissections are often omitted. When pelvic lymph node dissection is done, many surgeons limit the dissections to the obturator lymph nodes. Recent data suggest that more extensive pelvic lymph node dissection might be necessary to detect occult lymph nodes metastases, as the prevalence of lymph node invasion (LNI) might be directly related to pelvic lymph node dissection extent (4–6). Indeed, a more extensive pelvic lymph node dissection identifies metastases that would not be detected by limited dissections, as prostate cancer nodal metastases do not follow a predefined pathway of metastatic spread (7). This observation was confirmed by several studies, where a limited pelvic lymph node dissection was associated with a high prevalence of false-negative findings (4, 5, 7–15). For example, Bader et al. (4) reported that up to 19% of patients with LNI may have metastases in the internal iliac distribution, which is not subjected to routine pelvic lymph node dissection.

In individuals at risk of LNI, accurate markers are needed to predict the probability of occult locoregional spread. Moreover, informative preoperative markers are also needed to more accurately predict in whom a pelvic lymph node dissection should be done and what should be its extent. Given that the ability of clinical markers is limited, the focus has shifted to molecular markers. Among several novel markers, nuclear factor-{kappa}B (NF-{kappa}B) represents a promising predictor of stage and prognosis.

The NF-{kappa}B family of transcription factors comprises five subunits that interact to form homodimers or heterodimers (16). These include c-Rel, RelB, NF-{kappa}B2/p52, and the classic p65 and NF-{kappa}B1/p50 subunits. The p65-p50 dimer is normally retained in the cytoplasm by the I{kappa}B ({alpha}, ß, or {varepsilon}) family of inhibitory proteins. Activation and nuclear import of p65-p50 requires the induction of signaling pathways that converge to the I{kappa}B kinase complex composed of I{kappa}B kinase-{alpha}, I{kappa}B kinase-ß, and NEMO/I{kappa}B kinase-{gamma}. The activated I{kappa}B kinase complex phosphorylates I{kappa}B proteins that are subsequently degraded by the proteasome. Once released from its inhibitor, the p65-p50 dimer translocates into the nucleus and binds consensus promoter sequences to activate transcription. NF-{kappa}B target genes are involved in multiple cellular processes, such as inflammation, proliferation, survival, angiogenesis, and invasion, which have been shown to function aberrantly in several cancers. As such, elevated NF-{kappa}B activity has been observed in many tumors (17, 18), including prostate cancer (19). In metastatic prostate cancer, inhibition of NF-{kappa}B activity in PC-3 cells is associated with reduced expression of vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 and a concomitant decrease in angiogenesis, invasion, and metastasis in nude mice (20).

We and others have shown that assessment of the expression (21) or the nuclear localization (22–24) of NF-{kappa}B (p65) can improve the predictions of biochemical recurrence in patients with prostate cancer. Additionally, we recently detected high levels of NF-{kappa}B p65 nuclear localization in >80% of prostate cancer lymph node metastases (25). However, to date, the ability of NF-{kappa}B to predict LNI has not been explored. Based on this consideration, we hypothesized that NF-{kappa}B represents a statistically significant, independent and informative predictor of LNI after accounting for powerful and established variables, such as pathologic stage, grade, and PSA. To test this hypothesis, we assessed the association between the extent of nuclear expression of NF-{kappa}B and the rate of LNI after accounting for radical prostatectomy stage, grade, and preoperative PSA.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Selection of patients. Following informed consent, patients who underwent a radical prostatectomy at our institution between years 1990 and 2000 were selected from the laboratory database according to their LNI status and radical prostatectomy specimen availability. A total of 51 patients were included. Of these, 20 had LNI and 31 without LNI were used as controls. The selection of controls was done from a subset of patients who remained free of biochemical recurrence for at least 5 years after radical prostatectomy. No patient received neoadjuvant radiotherapy or hormonal therapy.

Immunohistochemistry. NF-{kappa}B expression in prostate tumor sections was assessed with the monoclonal p65 NF-{kappa}B F6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) that recognizes an NH2-terminal sequence of the p65 subunit. Immunostaining was done with the biotin-streptavidin-peroxidase method. Briefly, formalin-fixed paraffin-embedded sections were deparaffinized in toluene and rehydrated through graded ethanol followed by distilled water. Endogenous peroxidase was quenched in 3% hydrogen peroxide and antigen retrieval was done by boiling the slides in a microwave for 15 minutes in citrate buffer (pH 6.0). Nonspecific sites were blocked with serum-free protein block for 5 minutes (Dako Diagnostics Canada, Inc., Mississauga, Ontario) and slides were then incubated with the primary antibody at 1:50 dilution for 1 hour at room temperature. A biotinylated secondary antibody followed by streptavidin-horseradish peroxidase (Dako Diagnostics Canada) was applied for 20 minutes each. All rinsing steps between antibodies were done in PBS for 5 minutes. Chromogen reaction with a 3,3'-diaminobenzidine tetrahydrochloride solution kit (Dako Diagnostics Canada) was carried out for 5 minutes. Slides were counterstained with Harris hematoxylin for 10 seconds, dehydrated in ethanol and toluene, and then mounted. Negative controls were included where the primary antibody was replaced by PBS.

Evaluations and quantification. Between two and three slides per patient were analyzed for the extent of nuclear localization of NF-{kappa}B by two evaluators. The average proportion of cancer cells with nuclear NF-{kappa}B staining was estimated for each slide. For each patient, the tumor specimen with the highest proportion of nuclear NF-{kappa}B staining was selected for data analysis. Interpretations diverging >10% were independently reanalyzed, resulting in concordance scores.

Statistics. Statistical tests were done with S-PLUS Professional version 1. Univariate and multivariate logistic regression was used to test the association between NF-{kappa}B and LNI. Multivariate models were adjusted for the contribution of preoperative PSA, radical prostatectomy Gleason sum, extracapsular extension, and seminal vesicle invasion. NF-{kappa}B, like PSA, was coded as a continuous variable and each unit corresponded to the recorded proportion (%) of cancer cells that showed nuclear NF-{kappa}B staining. The predictive accuracy of multivariate models with and without NF-{kappa}B was quantified using receiver operating characteristics–derived area under the curve. To reduce overfit bias, we used 200 bootstrap resamples. The distributions of predictive accuracy estimates, of models with and without NF-{kappa}B, were compared with the independent sample t test.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Table 1 shows the clinical and pathologic features of our patient cohorts. Age at surgery ranged from 52 to 72 years for metastatic patients (mean, 63.3 years) and from 51 to 72 years for the control group (mean, 62.1 years). Mean preoperative PSA was 13.9 (range, 4.0-36.3) for LNI patients compared with 9.7 (range, 0.67-32.0) for controls. Median Gleason sum was 7 for metastatic patients and 6 for controls. In patients with LNI, extracapsular extension was present in 50%, versus 25.8% for controls. The mean number of resected lymph nodes was 12.7 for LNI patients and 12.1 for the control group. The average number of positive lymph nodes was 1.4.


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  		Table 1. Clinical and pathologic characteristics of 51 patients treated with radical prostatectomy

 
Cytoplasmic staining was observed in cancer glands, prostate intraepithelial neoplasia (PIN), and, to a lesser extent, in normal glands. Nuclear staining was found mostly in cancer cells (Fig. 1 ). A significant difference in nuclear staining of cancer glands was observed between the two groups. Primary tumors of patients with LNI had an average of 21.25% of tumor cells with nuclear NF-{kappa}B expression as opposed to 9.42% of tumor cells of control patients (P = 0.001; Table 1). Most benign and high-grade PIN glands in both cohorts had <5% of cells positive for nuclear NF-{kappa}B. The nuclear staining of benign glands was not specific to areas immediately surrounding cancer or to presence of inflammation. These observations indicate that nuclear NF-{kappa}B expression is elevated in invasive cancer epithelium. Moreover, our findings show that within that epithelium, it is differentially expressed according to the rate of LNI.


Figure 1
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  		Fig. 1. Immunohistochemical detection of NF-{kappa}B p65 in prostate cancer tissues. A, predominant cytoplasmic staining. B, mixed cytoplasmic and nuclear staining. C, predominant nuclear staining. Magnification, x200.

 
We tested the strength and the statistical significance of the association between the extent of NF-{kappa}B staining and LNI in univariate and multivariate logistic regression models (Table 2 ). In univariate analyses, all predictors, including NF-{kappa}B (odds ratio, 1.07; P = 0.003), were statistically significant (all P values ≤0.006), except for preoperative serum PSA (P = 0.1) and extracapsular extension (P = 0.08). The univariate NF-{kappa}B odds ratio of 1.07 showed that the odds of lymph node metastases increases by 7% for each unit increase in observed extent of nuclear NF-{kappa}B staining.


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  		Table 2. Univariate and multivariate models predicting lymph node metastasis at surgery

 
In multivariate analyses, the association between NF-{kappa}B and LNI was adjusted for the effect of preoperative PSA, radical prostatectomy Gleason sum, extracapsular extension, and seminal vesicle invasion. In the multivariate model, NF-{kappa}B showed a statistically significant (P = 0.03) odds ratio of 1.08. It indicates that after accounting for all covariates, the odds of lymph node metastases increases by 8% for each unit increase in the extent of nuclear NF-{kappa}B staining. It is noteworthy that, along with seminal vesicle invasion (P = 0.003), NF-{kappa}B represented the only statistically significant predictor of LNI. The significance of NF-{kappa}B exceeded that of PSA, extracapsular extension, and of radical prostatectomy Gleason sum, which represent highly established predictors of LNI.

Assessment of overall model accuracy, with and without NF-{kappa}B, showed that the addition of NF-{kappa}B (multivariate P = 0.03) to all covariates (i.e., PSA, radical prostatectomy Gleason sum, seminal vesicle invasion, and extracapsular extension) increased accuracy from 84.8% to 87.1%. This 2.3% (95% confidence interval, 1.29-3.43%) increase was highly statistically significant when the means of 200 bootstrap-corrected accuracy estimates were compared (P < 0.001).


   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
In this study, we tested the hypothesis that NF-{kappa}B can improve the prediction of LNI. The average proportion of cancer cells positive for nuclear NF-{kappa}B was quantified for LNI-positive and LNI-negative patients. The LNI-positive group distinguished itself from the controls by an elevated nuclear NF-{kappa}B staining (P = 0.001). In univariate logistic regression models, NF-{kappa}B emerged as a highly significant predictor variable (P = 0.003). In multivariate analyses, NF-{kappa}B represented the second most significant predictor of LNI (P = 0.03). Its significance was only exceeded by seminal vesicle invasion (P = 0.003), which represented the only other statistically significant predictor of LNI. This suggests that the association between NF-{kappa}B and LNI is stronger than that of PSA, radical prostatectomy Gleason sum, and extracapsular extension, as these variables failed to reach statistical significance. Although the significance of covariates was potentially undermined by sample size, it can be postulated that NF-{kappa}B represents a strong marker of LNI.

Kattan recommends that a novel marker should not only be judged according to its multivariate statistical significance. Instead, he suggests that the addition of a truly informative novel marker to established predictors of the outcome of interest should increase the combined predictive accuracy of base predictors, in addition to confirming the independent, multivariate predictor status of this marker (26). We followed this recommendation and tested the accuracy of the model without including NF-{kappa}B. After 200 bootstrap resamples, which were used to reduce potential overfit bias, we found the model to be 84.8% accurate in predicting the probability of LNI. Inclusion of NF-{kappa}B increased the accuracy by 2.3% (95% confidence interval, 1.3-3.4%; P < 0.001). This result indicates that NF-{kappa}B satisfies the Kattan criterion, as it improves the predictive ability of the model in a highly statistically significant manner.

Our findings indicate that if predictions were applied to a cohort of 1,000 patients, use of NF-{kappa}B, relative to a model without NF-{kappa}B, would result in correct classification of LNI in 24 additional patients. Although such gain may seem trivial, it might be important to the affected individuals, who deserve the most accurate prediction of their disease stage. Moreover, such differences in predictions may be important when risk stratification is used within protocol settings. Finally, increments in predictive accuracy related to the inclusion of a novel predictor should not be interpreted in isolation. Instead, they should be assessed in the light of their combined effect with established predictors, as well as with other novel predictors. Thus, the increments related to the addition of NF-{kappa}B to pathologic stage, grade, and PSA may be further amplified with additional biomarkers. For example, continuously coded serum PSA was shown to improve the accuracy of staging in prostate cancer (9, 27). Recently, transforming growth factor-ß and interleukin-6 were shown to further improve the accuracy of models, which included continuously coded serum PSA (28). Taken together, these findings indicate that small accuracy gains resulting from the addition of one informative predictor may be enhanced with those of other predictors.

Besides showing that NF-{kappa}B represents an informative marker of LNI when radical prostatectomy specimens are used, our findings also justify further studies to validate NF-{kappa}B as a preoperative molecular LNI marker. It can be postulated that NF-{kappa}B might exert an even stronger effect on the accuracy of LNI predictions when preoperative variables are included instead of radical prostatectomy–derived stage and grade. Clinical stage, PSA, and biopsy Gleason sum are routinely used to predict LNI (8, 9, 29). However, their prognostic ability is lower than that of pathologic variables, as evidenced by substantially lower predictive accuracy of the preoperative biochemical recurrence nomogram (73%) relative to the postoperative biochemical recurrence nomogram (89%; refs. 29, 30). Thus, it can be argued that the multivariate association between NF-{kappa}B and LNI would be stronger if the covariates consisted of less informative preoperative variables, rather than highly informative postoperative variables. To formally test this hypothesis, we are presently optimizing immunohistochemical protocols to quantify NF-{kappa}B in biopsy cores, with the intent of determining whether it can be used to predict LNI before definitive treatment.

Sample size represents one of the limitations of our study. Although it clearly did not affect the ability of NF-{kappa}B to predict LNI, it could have undermined the ability of other predictors to reach statistical significance in the multivariate models. Despite power limitations, NF-{kappa}B did achieve a highly statistically significant predictor status, which underscores the strength of the association between NF-{kappa}B and LNI. Sample size and power are less instrumental to predictive accuracy than to statistical significance. However, a different sample size may change the strength of the association between NF-{kappa}B and LNI, which may also be reflected in predictive accuracy estimates. Moreover, our results should be confirmed in prospective series.

Our findings are biologically plausible. The extent of staining noted in radical prostatectomy specimens correlates well with high levels of nuclear NF-{kappa}B observed in lymph node metastases (25) and with the increased invasive metastatic potential of prostate cancer cells that display elevated NF-{kappa}B activity (20, 31). Interestingly, a recent study has shown that the presence of nuclear NF-{kappa}B in prostate cancer cells located in the perineural space is associated with the expression of antiapoptotic genes and with a decrease in recurrence-free survival (22). Perineural invasion is believed to be an important mechanism by which prostate cancer cells can spread to extraprostatic tissues. Overall, the activation of NF-{kappa}B may confer a selective advantage to prostate cancer cells by inducing the expression of genes involved in survival, angiogenesis, motility, and invasion. Taken together, these observations support our findings, which identify radical prostatectomy specimen NF-{kappa}B as an indicator of locoregional cancer spread.

In summary, this is the first study that shows that the extent of nuclear localization of NF-{kappa}B in primary prostate tumors is highly accurately capable of predicting the probability of locoregional spread of prostate cancer.


   Acknowledgments
 
We thank the Division of Urology, Centre Hospitalier de l'Université de Montréal and the Pathology Department of Notre-Dame Hospital for their contribution to this research.


   Footnotes
 
Grant support: Canadian Prostate Cancer Research Foundation; Chercheur National fellowship from the Fonds de la Recherche en Santé du Québec (A-M.M. Mason); Fonds de la Recherche en Santé du Québec, the Centre Hospitalier de l'Université de Montréal Foundation, the Department of Surgery, and Les Urologues Associés du Centre Hospitalier de l'Université de Montréal (P.I. Karakiewicz); and Canadian Institute of Health Research/Canadian Prostate Cancer Research Initiative studentship (L. Lessard).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/13/06; revised 6/ 6/06; accepted 7/17/06.


   References
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 Patients and Methods
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 References
 

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