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Detection of Occult Lymph Node Metastases in Locally Advanced Node-Negative Prostate Cancer

Vincenzo Pagliarulo, Debra Hawes, Frank H. Brands, Susan Groshen, Jie Cai, John P. Stein, Gary Lieskovsky, Donald G. Skinner, Richard J. Cote

From the Departments of Pathology, Urology, and Preventive Medicine, University of Southern California, Keck School of Medicine; and the University of Southern California/Kenneth Norris Comprehensive Cancer Center, Los Angeles, CA

Address reprint requests to Richard J. Cote, MD, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033; e-mail: cote_r{at}ccnt.hsc.usc.edu

	ABSTRACT

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PURPOSE: The purpose of this study was to determine the incidence and clinical significance of occult metastases in the lymph nodes of patients with prostate cancer originally considered node negative by routine histologic evaluation.

METHODS: Two hundred seventy four patients with pT3 prostate carcinoma treated by radical prostatectomy and bilateral lymph node dissection were included in this study. One hundred eighty patients were staged node negative (N0), while 94 patients were lymph node positive (N+), based on routine histologic evaluation. All lymph nodes from the 180 N0 patients were evaluated for occult metastases by immunohistochemistry using antibodies to cytokeratins and, if positive, prostate-specific antigen. Recurrence and overall survival were compared among patients with occult tumor cells (OLN+), with patients whose lymph nodes remained negative (OLN–), and with the 94 N+ patients.

RESULTS: A total of 3,914 lymph nodes were evaluated from 180 N0 patients (average, 21.7 lymph nodes per patient). Occult tumor cells were found in 24 of 180 patients (13.3%). The presence of OLN+ was significantly associated with increased recurrence and decreased survival compared with OLN– patients (P < .001 and P = .019, respectively; relative risk of recurrence, 2.27; relative risk of death 2.07, respectively). The presence of occult lymph node metastases was an independent predictor of recurrence and death in a multivariable analysis. The outcome for patients with OLN+ disease was similar to that for patients with N+ disease.

CONCLUSION: The detection of occult lymph node metastases in patients with pT3N0 prostate cancer identifies those with significantly increased risk of prostate cancer recurrence and death.

	INTRODUCTION

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Staging lymphadenectomy is routinely performed at the time of radical prostatectomy for locally treatable prostate cancer, as the status of the lymph nodes at the time of surgery is the most important determinant of disease progression in patients with no evidence of systemic metastases. While a substantial minority of patients with histologic positive disease can experience long-term recurrence-free survival after definitive local therapy,¹ patients with evidence of pelvic lymph node metastases are at increased risk for disease progression, regardless of the type of local therapy.² There is evidence from a few prospective randomized trials that suggests that immediate adjuvant therapy after definitive local procedure (radical prostatectomy with pelvic lymphadenectomy or radiation) may reduce progression rates and improve survival in patients with locally advanced and node-positive prostate cancer.^3-5 Thus, detection of nodal involvement may identify patients who could benefit from adjuvant therapy. It is known that patients with tumors with extraprostatic tumor extension, in the form of periprostatic fat or seminal vesicle involvement (stage T3a or b), are at increased risk for progression and have a worse prognosis, even in the absence of histopathologic evidence of lymph node metastases.^6,7 It seems likely that at least a portion of these cases have prostate cancer cells metastatic to the lymph nodes that have not been detected by conventional histopathologic means.

In this study, we report the incidence of occult metastasis in the lymph nodes in patients with stage pT3 node negative (N0) prostate cancer. We report that the outcome for patients with occult lymph node metastases is significantly worse than for those without evidence of lymph node involvement, and similar to patients with histopathologic evidence of lymph node metastases.

	METHODS

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Patient Population
Between 1983 and 1991, 556 patients underwent extended bilateral lymph node dissection followed by radical retropubic prostatectomy at the University of Southern California Keck School of Medicine/Norris Comprehensive Cancer Center (Los Angeles, CA); 95% of the operations were performed by two surgeons (G.L., D.G.S.). Lymph node dissection boundries extended proximally from the common iliac bifurcation, laterally to the medial aspect of the external iliac artery, distally to the lymph node of Cloquet, and included the hypogastric and obturator fossae. In the study period, 285 patients had a final diagnosis of pT3 disease (1997 TMA⁸) and of these patients, two patients declined to participate and were excluded from analysis. One hundred eighty six of 283 patients (66%) were N0 by routine histology, 94 of 283 patients (33%) were node positive (N+), and lymph node status was not available for three patients. Of 186 N0 patients, six patients had insufficient tissue for analysis, the remaining 180 patients were analyzed for occult lymph node metastasis. In 1995, we reported on the incidence of lymph node occult metastases in 95 patients.⁹ Clinical outcomes were not evaluated at that time. Seventy nine of these patients were pT3N0 and were included in this study. The 180 N0 patients and the 94 N+ patients represent consecutive cases with pT3 stage disease in whom lymph node analysis was possible. Clinical and pathologic data^8,10 on the 274 patients is given in Table 1. All patients were evaluated at 6-month intervals until year 5, and yearly thereafter. Prostate-specific antigen (PSA; biochemical) recurrence was defined as detectable serum PSA level on consecutive tests spanning at least 30 days. The Hybritech assay (Beckman-Colter, Brea, CA; PSA level, 0.4 ng/mL) was used before July 1994 and the Tosoh assay (Tosoh Corp, Grove City, OH) was used after that (PSA level, 0.05 ng/mL). Clinical recurrence was defined as biopsy-proven local recurrence or metastatic disease confirmed by bone scan or biopsy.¹¹ Median follow-up in this series for the 180 N0 patients was 12.7 years (range, 1.5 years to 19.1 years), and for the 94 N+ patients median follow-up was 13.6 years (range, 0.9 years to 19.7 years); for the entire cohort of 274 patients, median follow-up was 12.9 years (Table 2). This study was approved by the University of Southern California institutional review board (proposal No. 94050).

Two anticytokeratin monoclonal antibodies were used in combination (also referred to as a cocktail); AE-1 (Sigma, Dedham, MA) and CAM5.2 (Becton-Dickinson, San Jose, CA).¹³ If a case was found to be cytokeratin positive by immunohistochemistry, separate slides were incubated with a polyclonal anti-PSA antibody (Dako, Carpinteria, CA) using our previously published protocol¹² to confirm prostatic origin. Antigen-positive (epithelial) cells were stained a red color (precipitation of chromogen), while the nonepithelial cells were negative (blue; Fig 1). Positive controls for each staining series consisted of prostate cancer tissue.

View larger version (68K): [in this window] [in a new window]   Fig 1. Adjacent sections of a lymph node with an occult metastasis, detail at 10x magnification. (A) Hematoxylin and eosin histochemistry. (B) A small focus of positive cells is evident after cytokeratin histochemistry. (C) Prostatic origin of the same cells is confirmed using an antibody against prostate-specific antigen.

N0 patients whose lymph nodes showed no evidence of occult metastases after cytokeratin immunohistochemistry were classified as OLN–, whereas N0 patients with cytokeratin and PSA positive cells were classified as OLN+. Patients with histologic N+ disease were classified as N+.

Statistical Analysis
Outcome was measured by any recurrence and by overall survival. Clinical recurrence was defined as either a local recurrence (positive digital rectal examination with transurethral resection biopsy of the urethrovesical anastomosis) or the development of distant metastases (documented by computed tomography, bone scan, or magnetic resonance imaging). Time to clinical recurrence was calculated as the time from prostatectomy to clinical recurrence or until last follow-up (if the patient had not experienced a clinical recurrence); time to PSA recurrence was calculated as the time from prostatectomy to the first detectable PSA (confirmed by a repeat assay at least 30 days later) or until last follow-up (if the patient had not experienced a PSA recurrence). For purposes of analysis, any recurrence was defined as either a clinical recurrence or a PSA recurrence—whichever was observed first. Patients who died before clinical recurrence or PSA recurrence were censored at the time of death. Survival was calculated as the time from prostatectomy to death due to any cause; patients who were still alive, were censored at the date of last contact.

Pearson's ² test for association, or the Cochran-Mantel-Haenszel test for trend,¹⁴ were used to evaluate the association between lymph node status (OLN– v OLN+ v N+) and tumor grade (Gleason's score 2 to 6 v 7 to 10), tumor stage (pT3a v pT3b), margin status (positive or negative), as well as demographic variables such as age ( 67 years v > 67 years). If the overall test comparing the three groups (OLN–, OLN+, N+) was significant at the .05 level, then the pairwise comparison of groups was undertaken. Kaplan-Meier plots¹⁵ and the log-rank test,¹⁶ or the Tarone test for trend based on the log-rank test statistic calculations,¹⁷ were used to assess the association of lymph node status with survival and time to any recurrence; SEs were based on Greenwoods formula.¹⁶ The stratified log-rank test was used to determine whether lymph node occult metastasis provided prognostic information for Gleason score and tumor stage.¹⁸ Hazard ratios, based on the Pike estimate using the observed and expected number of events as calculated in the logrank test statistic,¹⁹ were used to calculate the relative risks of death or any recurrence. All reported P values are two sided.

The Cox proportional hazards model, with a forward selection algorithm, was used to select a subset of variables that were jointly associated with outcome. Hazard ratios based on the Cox model were used to calculate the relative risks of death or clinical or any recurrence; 95% CIs used variances derived from the information matrix.¹⁶ The statistical analysis was performed (by S.G. and J.C.).

	RESULTS

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Demographics
Table 1 summarizes the distribution of the baseline patient characteristics. The majority of patients (65%) had high-grade (Gleason score, 7 to 10) disease; approximately half of the patients had positive margins and seminal vesicle involvement and the majority (82%) received adjuvant radiation therapy.

Incidence of Occult Lymph Node Metastasis
Immunohistochemical examination of the pelvic lymph nodes revealed the presence of tumor cells in 24 of 180 histologic N0 patients (13.3%; Fig 1, Table 1). Tumor cells were found in multiple lymph nodes in five of the 24 OLN+ patients (21%). A total of 30 of 3,914 lymph nodes (0.77%) were found to contain tumor cells. The average number of prostate cancer cells identified per positive lymph node was 143 (4 to > 500). The microanatomic location of occult metastases included capsular lymphatics in eight lymph nodes, subcapsular sinus in 14 lymph nodes, medullary sinus in five lymph nodes, and lymph node parenchyma in three lymph nodes. In most cases the occult metastases were present at more than one location. Typically, the pattern of metastases was glandular (24 lymph nodes), but individual cells were also identified. The prostatic origin of epithelial cells was confirmed in all cases by PSA immunohistochemistry (Fig 1).

Association of Lymph Node Status With Standard Clinical and Pathologic Parameters and Adjuvant Treatment
Table 1 summarizes the association of lymph node status with standard clinical and pathologic variables. Age was not significantly associated with lymph node status. Compared to OLN– patients, those patients who were OLN+ were more likely to have stage pT3b disease (P < .002). OLN+ patients were more likely to have high Gleason scores^7-10 than OLN– patients, but these results did not reach the level of statistical significance (P = .07). Pathologic stage, Gleason score, and positive surgical margins, were all higher in N+ patients compared with N0 patients. Furthermore, 26% of N+ patients received adjuvant hormonal therapy compared with 3% OLN– patients and 4% OLN+ patients (P < .001). There was no significant difference in the proportion of patients who received adjuvant radiation therapy.

One limitation of our analysis is that a proportion of patients underwent surgery before routine PSA testing was performed in our institution (1988), thus a preoperative and postoperative PSA evaluation was not available before that time. As a consequence, the ability to correlate lymph node status and preoperative PSA is limited, and no association was seen in this study.

Outcome: Time to Recurrence
A total of 141 patients in this series have experienced a recurrence (PSA or clinical): 58 patients in the OLN– group, 15 patients in the OLN+ group, and 68 patients in the N+ group. Of these 141 patients, 71 patients have developed clinical recurrences. The association between lymph node status and time to any recurrence is summarized in Table 2 and in Figure 2A. At 10 years, the estimated probability of developing any recurrence was 0.36 ± 0.04, 0.61 ± 0.10, and 0.69 ± 0.05, for patients with OLN–,OLN+, and N+ disease, respectively. Relative risks (RR) are also provided in Table 2. On average, patients with OLN+ disease were 2.27 times as likely to experience any type of recurrence compared with patients with OLN– disease (P = .004). In comparison, patients with N+ disease were 2.78 times as likely to experience any recurrence compared with OLN– patients (P = .001). The decision to treat with adjuvant radiation or hormone therapy either before or after prostatectomy was made on a per patient basis; importantly for this study, the relative risks and strength of the association between occult lymph node metastasis were not different when stratifying by radiation or hormone therapy (data not shown).

View larger version (20K): [in this window] [in a new window]   Fig 2. Time to any recurrence (A) and overall survival (B) after radical prostatectomy in the 274 patients. The 24 patients with OLN+ disease were at higher risk to develop any type of recurrence (P = .004) and experienced more deaths (P = .019) compared with the 156 OLN– patients. The OLN+ patients had similar recurrence rates and higher death rates than N+ patients.

Examining the standard clinical baseline variables, in univariate analyses, involving all 180 patients with N0 disease, only Gleason score, stage, and presence of occult metastases in the lymph nodes were significantly associated with overall survival (Table 3). In a Cox proportional hazards analysis, only Gleason score and occult metastasis remained significantly associated with overall survival: OLN– versus OLN+: RR, 2.24; 95% CI, 1.26 to 3.97; P = .011; Gleason score 2 to 6 to versus 7 to 10: RR, 3.50, 95% CI, 2.05 to 5.99; P < .001.

	DISCUSSION

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T3N0 prostate cancer continues to be an important disease and these are patients who, while potentially curable using local methods (surgery and radiation), are at substantial risk for recurrence, metastasis, and eventual death due to prostate cancer. Our hypothesis was that a proportion of patients originally identified as pT3N0 may have had lymph node metastasis unidentified by routine methods, and that those were the patients most at risk for disease recurrence and death, who thus might benefit from adjuvant treatment strategies. This study showed that in patients with pT3N0 prostate cancer, treated by radical prostatectomy and pelvic lymph node dissection, those with occult lymph node metastases detected by immunohistochemistry had significantly worse recurrence and survival rates, as compared with patients similarly treated with no evidence of tumor in their lymph nodes, and had similar outcomes as pT3 patients with histologic N+ disease. We found that occult lymph node metastases were independently associated with prostate cancer recurrence and overall survival after multivariable analysis. Thus, when occult metastases are detected in the lymph nodes of patients with pT3N0 prostate cancer, our results suggest they should be treated as high-risk patients, similar to those patients with histologic N+ disease.

In an earlier study, we showed that occult metastases could be detected by immunohistochemistry in the lymph nodes of patients with pT3N0 prostate cancer,⁹ and demonstrated a correlation with substage and histologic (Gleason) grade. We have now extended our cohort to study the impact of occult lymph node metastases on the clinical outcomes of patients with pT3N0 prostate cancer. When immunohistochemistry is used, a significant correlation between occult lymph node metastases and clinical outcome has been shown in many types of cancers, including breast,¹³ colon,²⁰ gastric,²¹ non–small-cell lung,^22,23 and esophageal cancers²⁴ and melanoma.²⁵ In the case of prostate cancer, Shariat et al²⁶ demonstrated that the detection of occult lymph node metastases in pT3N0 patients is significantly associated with clinical outcome, a result that is consistent with this study.

Recent studies have demonstrated that the total number of lymph nodes removed may be important for improving nodal staging of prostate cancer.^27,28 In our series, all patients underwent extended lymph node dissection, with an average of 21.7 lymph nodes removed per patient, which we believe is a strength of this study.

At the time surgery was performed, from 1983 to 1991, there was no consensus on the management of locally advanced prostate cancer. In our cohort, almost all patients with pT3 prostate cancer underwent postoperative adjuvant radiation therapy. Early postoperative adjuvant androgen deprivation was generally not administered if the lymph nodes were negative, but was provided for a substantial number of patients with N+ disease, by means of orchiectomy or pharmacologic castration. It has been demonstrated in a few prospective randomized published trials that patients with N+ prostate cancer, who undergo definitive local therapy (either surgery or radiation therapy), may benefit from early adjuvant androgen blockade.^3,5 In our series, immunohistochemistry stratified two cohorts of lymph node-positive patients: occult (OLN+) and overt (N+). In terms of clinical outcome, comparison of OLN+ versus N+ patients shows no difference in recurrence free survival. Overall survival for OLN+ and N+ patients are similar, but unexpectedly there was a slight survival advantage for the N+ patients, although this did not reach the level of statistical significance. A possible explanation is that early adjuvant treatment may have benefited the survival of patients with N+ disease, an effect that would not have been seen in the OLN+ group, as these patients were not treated with adjuvant systemic therapy. The study by Cheng et al²⁹ suggested that the combination of radical prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy offered an extended progression-free survival rate among patients with lymph node metastasis, supporting this hypothesis.

Although no trial has compared the use of early and deferred treatment in patients with occult lymph node metastases, the results reported by Messing and Bolla^3-5 suggest that patients with occult lymph node metastases from prostate cancer may benefit from immediate adjuvant systemic treatment.

This study examined occult metastasis in the lymph nodes from patients with prostate cancer. Occult systemic dissemination of tumor cells to the bone marrow and blood have been shown to be prognostically important in a variety of epithelial tumor types.^22,30-32 However, the detection of occult metastases in the bone marrow and blood of patients with prostate cancer has failed to demonstrate their prognostic significance.^33-43 Nevertheless, it is likely that detection of occult dissemination of prostate cancer in regional (lymph node) and systemic site (bone marrow, blood) will be important to consider together in evaluating outcomes and thus management discussions in patients with prostate cancer.

We have demonstrated that immunohistochemical assessment of the lymph nodes can detect tumors not recognized at initial histologic examination, and that the presence of occult lymph node metastases identifies patients with pT3N0 prostate cancer at significantly increased risk for recurrence and death. The finding of occult lymph node metastases may have profound implications in terms of the early administration of adjuvant systemic treatment in patients with pT3 prostate cancer whose lymph nodes are negative by routine histologic analysis, an idea that should be examined in future clinical trials.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Susan Groshen, Richard J. Cote Administrative support: Susan Groshen Provision of study materials or patients: John P. Stein, Gary Lieskovsky, Donald G. Skinner Collection and assembly of data: Vincenzo Pagliarulo, Debra Hawes, Frank H. Brands, Susan Groshen, Richard J. Cote Data analysis and interpretation: Susan Groshen, Jie Cai Manuscript writing: Vincenzo Pagliarulo, Debra Hawes, Richard J. Cote Final approval of manuscript: Vincenzo Pagliarulo, Debra Hawes, Frank H. Brands, Susan Groshen, Jie Cai, John P. Stein, Gary Lieskovsky, Donald G. Skinner, Richard J. Cote

 

	ACKNOWLEDGMENTS

 
We are indebted to the patients of the Norris Cancer Center for contributing to this study; to Shan Rong Shi, MD, and Mohammad Alavi-Tafreshi, MD; Lillian Young and William Win for their technical support; and Clive Taylor, MD, PhD, Ram Datar, PhD, John Freeman, MD, and David Esrig, MD, for their support and efforts throughout the course of the study.

	NOTES

 
Supported by Grants No. P30 CA14089 and CA59705 from the National Institute of Health and National Cancer Institute, PC 970406 from the Department of Defense, and 1-II-0181 from the California Cancer Research Program.

There are no directly related manuscripts or abstracts, published or unpublished, by any authors of this paper.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted December 29, 2005; accepted April 10, 2006.

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