Current status of lymph node-positive prostate cancer

Incidence and predictors of outcome

Authors

  • Gregory P. Swanson MD,

    Corresponding author
    1. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
    2. Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
    • Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive MC 7889, San Antonio TX 78229
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    • Fax: (210) 949-5085

  • Ian M. Thompson MD,

    1. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
    Search for more papers by this author
  • Joseph Basler MD

    1. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Abstract

In early surgical series, the incidence of positive lymph nodes in patients with prostate cancer was approximately 40%. In the modern era of screening and improved patient selection, the incidence is now <10%, although most series excluded patients with higher risk disease. The risk of having positive lymph nodes is influenced by disease stage, prostate-specific antigen level, and tumor grade and by the aggressiveness of lymph node dissection. Many of the same factors predict the outcome of these patients. Although the percentage of patients with positive lymph nodes has declined, there remain significant numbers of patients with lymph node-positive prostate cancer, and it remains a therapeutic dilemma. Cancer 2006. © 2006 American Cancer Society.

In the years prior to the identification of prostate-specific antigen (PSA) as a cancer marker, the incidence of lymph node metastasis in patients who were diagnosed with prostate cancer was high. Early autopsy studies showed that 60% of men with prostate cancer had metastatic involvement of the lymph nodes.1 Early surgical series in men who initially were diagnosed with clinically localized disease showed that the incidence was approximately 40% (Table 1).2

Table 1. Early Studies in Patients with Prostate Cancer (Pre-Circa 1965)
StudyYearsNo. of patientsNo. Positive (%)
Flocks, 195921951–1957384146 (38)
Whitmore and Mackenzie, 195931944–1956209 (45)
Mintz and Smith, 19341193410060 (60)
Arduino and Glucksman, 196241955–19604414 (32)

With the discovery of hormone deprivation as effective therapy in the 1940s, the mainstay of treatment into the 1960s relied on orchiectomy and/or exogenous estrogen. For patients receiving hormone therapy, lymph node status was unimportant and, thus, was not investigated further. Subsequently, more aggressive surgery, such as cystoprostatectomy or exenteration, was attempted for locally advanced disease, but these treatments were associated with significant morbidity and mortality.3–5 Perineal prostatectomy became the initial primary surgical approach for cure as surgical techniques improved. With the recognition that lymph node metastases were the reason for failure in some patients, retropubic prostatectomy with lymphadenectomy was adopted in the 1960s, because it facilitated staging lymphadenectomy.

With lymph node staging, the subsequent literature indicated that patients who had lymph node-positive disease were not curable, and the recommendation was that, if lymph node metastases were encountered, then prostatectomy should be aborted and systemic treatment offered (generally with hormone manipulation).6, 7 There also was evolving interest in exploration of other treatments. One of the first of these techniques was retropubic implantation of radioactive gold (198Au).8, 9 Overall, as surgical procedures became more refined, radical prostatectomy became the most common surgical approach by the 1970s.10

The incidence of surgically proven lymph node metastasis has changed in parallel with improvements in the staging of disease that have accompanied early-detection strategies. Historically, clinical stage was determined by physical examination, acid phosphatase, and bone survey. In early surgical series, as noted above, the incidence of positive lymph nodes was as high as 40% (Table 1). In the era of increasing prostate cancer awareness, better patient selection, and improving or more aggressive treatment (circa 1965–1985), the observed incidence of lymph node metastasis dropped below 30% (Table 2). With the addition of PSA and increased evaluation of asymptomatic men for prostate cancer, the incidence is now <10% (Table 3). Although they may be somewhat comforting, these numbers probably do not reflect the true incidence of men who harbor positive lymph nodes. For example, patients who receive neoadjuvant androgen ablation (or radiation), who ostensibly have more advanced disease, are excluded from most series.11 In addition, almost all of the surgical series include only patients who have undergone completion of prostatectomy, excluding patients who have macroscopically positive lymph nodes or microscopic disease proven on frozen section analysis. There also are variations in patient selection, because some institutions12 regularly operate on and include patients with more advanced stage disease (e.g., Stage T3) in their series, whereas others limit surgery to patients who have more favorable disease.13 It also is interesting to postulate that, with the use of sentinel lymph node detection methodology, the current rate of lymph node involvement actually may be much higher, up to 25%.14

Table 2. Early Studies in Patients with Prostate Cancer: Modern Era (Circa 1965 to 1985)
StudyYearsNo. of patientsPositive (%)Disease stage: No. of patients (%)
A1 (T1a)A2 (T1b)B (T2)B1 (T2a)B2 (T2b)C (T3)C1 (T3a)D1
  • *

    Eighteen patients with elevated prostatic acid phosphatase levels.

  • Excluded some patients with positive lymphangiogram proven by fine-needle aspiration.

Paulson, 198035?14453 (37)        
Paulson and Uro-Oncology Research Group, 197981?13447 (35)        
Fowler and Whitmore, 198134; Leibel et al., 1993571970–1977300119 (40)   5/75 (7)56/129 (43)58/96 (60)  
1970–19851078345 (32)        
Petros and Catalona, 199282; Carter et al., 1989831983–19868517 (20)        
1976–198410816 (15)        
Gervasi et al., 1989581966–1979511152 (30)        
Golimbu et al., 19794019783015 (50)        
Prout et al., 1980841969–19769232 (35)        
McLaughlin et al., 1976431971–197560(35)    /19 (21)/17 (30)12/24 (50) 
Zincke et al., 199216; Cheng et al., 1993851966–19882216382 (18)1/29 (3)8/119 (7) 53/603 (9)152/1038 (15)154/412 (37) 14/15 (93)
1966–19892838653 (23)1/38 (3)17/149 (11) 62/684 (9)251/1353 (19)297/587 (51) 25/27 (93)
Nicholson and Richie, 1977861971–1975476 (13)        
Donohue et al., 1984871971–198440193 (23)0/614/72 (19) 31/205 (15)48/121 (40)   
Babayan et al., 198088198011237 (33) 9/32 (28)10/45 (22)  18/35 (51)  
McDowell et al., 1990441984–1988217*127 (59) 4/8 (50)21/44 (48)  82/147 (56)  
Sadlowski, 1978891973–19764713 (28)   5/213/85/18  
Grossman et al., 19809019809137 (41)0/324/47 (53) 3/18 (174/14 (29)5/9 (56)  
Lieskovsky et al., 1980911971–19778227 (35) 1/8 (13) 3/16 (19)12/39 (31)11/17 (65)  
Smith et al., 1983921971–1981452105 (23)0/418/33 (24) 18/156 (12)43/154 (28)36/38 (53)  
Stamey et al., 198993?10213 (13)0/11/13 0/3111/561/1  
Average 67611801 (27)2/89 (2)68/362 (19)31/89 (35)127/1206 (11)432/1893 (23)518/965 (54)12/24 (50)25/27 (93)
Table 3. Incidence of Positive Lymph Nodes in the Prostate-Specific Antigen Era (Circa 1985 to Present)
StudyYearsNo. of patientsNo. Positive (%)Stage: No. of patients (%)
A1 (T1a)A2 (T1b)B1 (T2a)B2 (T2b)C (T3)
  • *

    Of 367 T1c tumors, 9 lymph node-positive tumors (2.5%) were included in the T2a category (similar lymph node incidence).

  • † Of 638 T1c tumors, 5 lymph node-positive tumors (0.8%) were included in the T2a category (similar lymph node incidence).

  • Excluded patients who received neoadjuvant therapy.

  • §

    Sentinel lymph node biopsy.

  • Pooled data (including Paulson, 198035); 21% of patients were omitted (see text).

  • Included all but Partin 200111 (duplicate data).

Petros and Catalona, 1992821983–199151835 (7)0/322/61 (3)10/189 (5)23/236 (10) 
1986–199038917 (4)     
Puthawala et al., 2001941980–1995556100 (18)     
Daneshmand et al., 2004641972–19991936235 (12)     
Pisansky et al., 1996121988–19923329238 (10)1/25 (4)2/65 (3)15/456 (3)*130/1206 (11)81/320 (25)
Hull et al., 2002951983–1998 71 (7)     
Stone et al., 1977961990–1995189(12)     
Han et al., 2001971982–19992449149 (6)     
Partin, 2001111994–20005079(2)     
Bundrick et al., 1993981987–199117319 (11)     
Bader et al., 2003451989–199936792 (25)     
Swanson et al.991985–199580485 (11)0/192/39 (5)48/456 (11)22/89 (25) 
Heidenreich et al., 200237 (standard)*1999–200020339 (19)     
Clark et al., 20034620021238 (7)     
Steuber et al., 20051001994–2002199080 (4)     
Wawroschek et al., 2003141998–2001348§86 (25)     
Ramos et al., 1999131988–1998107917 (2)  6/696 (1)11/383 (3) 
Cagiannos et al., 2003311985–20005510206 (4)     
Danella et al., 1993291989–199122515 (7)    5/19 (26)
Average 21,2021515 (7)1/76 (1)6/165 (4)79/1797 (4)186/1914 (10)86/339 (25)

Even at an incidence of 5% to 10%, a significant number of patients will have lymph node-positive prostate cancer. Absolute numbers are not available; however, because up to 50% of newly diagnosed patients each year are surgical candidates (n = 100,000 patients), and 8% have lymph node disease, this group represents 8000 patients, which is approximately the same number of men who are diagnosed with esophageal, gastric, or testicular cancer and is more common than Hodgkin lymphoma and laryngeal or thyroid cancer.15 More disconcerting is the finding that, although we have learned much about the incidence of lymph node-positive prostate cancer over the last 40 years, the problem of how to treat these patients best remains an enigma.

The first challenge is to predict who has lymph node metastasis. There are multiple factors that influence the risk of lymph node-positive disease, including stage (bulk or local extent of tumor), grade, and, more recently, PSA.

Stage

Tables 2 and 3 show that the risk of lymph node metastases in incidentally detected cancer (Stage A1-A2, T1a-T1b) is only 2% to 3%, a rate that has changed little over time. PSA-detected disease stage (T1c) was used first 20 years ago but accounts for the majority of currently diagnosed patients. Early in the PSA era, 11% of patients had Stage T1c disease and had a 3% risk of lymph node metastases.12 More recently, 39% of patients have Stage T1c disease, and the incidence of involved lymph nodes is only 1%.13 For patients with palpable disease (Stage B or cT2), the risk of lymph node disease historically was as high as 15%, but it now approaches 8%. Within the cT2 stage, patients who have bulkier tumors (cT2b) have an approximately 10% risk compared with patients who have smaller tumors (cT2a), who that have a risk of about 4%. There is not as much information on locally advanced disease (clinically extraprostatic or cT3), because it was not thought not to be amenable to surgical cure. For the small number of men with cT3 disease who underwent lymphadenectomy, the incidence of lymph node disease was 50% (Table 2). In more contemporary series, the risk is approximately 50% of these historical rates but remains much greater than in men who have disease that is confined clinically to the prostate (Table 3).

The impact of the primary tumor size on survival in lymph node-positive patients is not as clear. Some authors cite a correlation,6, 16, 17 whereas others show no difference between patients with Stage B disease (cT2) and patients with Stage C disease (cT3).18, 19 It should be noted that the studies showing a correlation were among patients who underwent radical prostatectomy, whereas those that showed no correlation involved patients who received radiation.

Grade and Gleason Score

Although they are not always predictive,20 grade and Gleason scores consistently are correlated with the risk of lymph node disease.11, 12 Historically, for Gleason scores 2 through 4, the risk is from 0% to 20%; for Gleason scores 5 through 7, the risk is from 31% to 38%; and, for Gleason scores 8 through 10, the risk is from 62% to 93%. This differs from the lower rates in more contemporary reports,12 with a risk from 3% to 9% in lower grade tumors and 20% to 29% in higher grade tumors.

Grade clearly had an impact on survival in multiple studies.12, 17, 21–26 In several of those studies, grade was the most significant factor in predicting disease outcome.17, 23, 25 For patients with lymph node-positive disease who had well differentiated tumors, the 5 year survival rate was from 83% to 85%; for patients with moderately differentiated disease, the 5-year survival rate was from 72% to 85%; and, for patients with poorly differentiated disease, the survival rate was 36% to 51%. In line with expectations, there also was a correlation with disease recurrence. At 5 years, from 25% to 39% of moderately and well differentiated tumors recurred compared with from 45% to 76% of poorly differentiated tumors.21, 26

PSA

The higher the PSA level, the higher the risk of lymph node metastases. In the largest published series,12 the risk of positive lymph nodes was 2% for men who had PSA levels from 0.1 ng/mL to 4.0 ng/mL, 5% for men who had PSA levels from 4 ng/mL to 10 ng/mL, 11% for men who had PSA levels from 10 ng/mL to 20 ng/mL, 22% for men who had PSA levels from 20 ng/mL to 50 ng/mL, and 38% for men who had PSA levels >50 ng/mL.

It is clear that there are multiple variables that can predict for lymph node involvement and, thus, prognosis.27–29 How these variables are interrelated has led to the development of nomograms or tables to predict lymph node risk. The best known are the tables developed by Partin et al.11 By using data from a series of patients who underwent radical prostatectomy, probability tables were developed based on 3 parameters: stage, Gleason score, and PSA. From those tables, an individual patient's values can be used to determine his risk group and, then, to predict his risk for lymph node metastasis. (Table 4). By analyzing these data, it can be seen that there are large numbers of patients for whom the risk of lymph node metastases can be predicted as <5%. This group generally includes men with Gleason scores ≤6, and their risk is correlated less with PSA and clinical stage. For these men, lymph node dissection may not be necessary, because the potential risk (e.g., lymphocele, deep venous thrombosis, injury to obturator nerve) may be greater than the likelihood of lymph node disease.30 Patients who have bulkier tumors, especially with Gleason scores ≥7 have a risk of lymph node metastasis >20%; and, for these men, lymph node dissection may provide important prognostic information and guide therapy. Although they are important advances, risk nomograms can be misleading because of a variety of biases. In the development of a large, multiinstitutional nomogram,31 6 institutions contributed 7014 patients. In total, 1504 patients (21%) were excluded for various reasons. Seven hundred eighty-three of 7014 patients (11%) were excluded because they received neoadjuvant treatment. However, because neoadjuvant therapy may have been offered only to those patients who had “high-risk disease,” this exclusion may have skewed the results toward a population with a lower risk of lymph node disease. Of the remaining 5510 patients, 206 patients (3.7%) had lymph node-positive disease. If only 25% of the excluded patients had positive lymph nodes, then the absolute overall number would more than double (582 patients; 8.3%). Thus, selection factors likely cause an underestimation of the true incidence of lymph node-positive disease. These flaws seriously call into question the utility and validity of the findings of most studies and the resulting nomograms constructed from them. Although selection biases remain, the early nomograms will have been influenced less by patients who were referred for neoadjuvant therapy and, thus, may be the most accurate.

Table 4. Risk of Lymph Nodes*
 Gleason score (%)
Stage2–678–10
  • PSA indicates prostate-specific antigen.

  • *

    Approximations were based on Partin et al., 2002.11

T1 (nonpalpable)
 PSA 0–4 ng/mL <5
 PSA 4–10 ng/mL   
 PSA >10 ng/mL 911
T2a (nodule <1/2 one lobe)
 PSA 0–4 ng/mL <5
 PSA 4–10 ng/mL<55
 PSA >10 ng/mL 1617
T2b (nodule >1/2 one lobe)
 PSA 0–4 ng/mL <513
 PSA 4–10 ng/mL 711
 PSA >10 ng/mL52427
T2c (both lobes)
 PSA 0–4 ng/mL<579
 PSA 4–10 ng/mL 1317
 PSA >10 ng/mL103538

There are other factors that influence the detection of lymph node metastases. Because lymphadenectomy is considered nontherapeutic, there has been a trend toward reducing morbidity by performing a more limited dissection. Initial techniques removed tissues medial to the genitofemoral nerve and around both the external iliac artery and vein, whereas current dissections often involve only the obturator fossa.32, 33 No standard approach routinely evaluates the posterior drainage to the presacral lymph nodes, and some authors acknowledge that this may underestimate the true incidence of lymph node disease.34

It is believed that lymphatic spread is primarily from vessels that leave the posterior aspect of the gland with extension to hypogastric (primary), obturator (secondary), external iliac (tertiary), and presacral (quaternary) lymphatics.35 Initial studies with blue dye showed that the most common paths are to the obturator/hypogastric and presacral lymph nodes.36 Historically, the most commonly involved lymph nodes reportedly were the obturator-hypogastric (30–60%), the external iliac (20–50%), or both (37%).14, 34, 37, 38, 39 Some studies showed that the external iliac lymph nodes were involved more commonly (60%) than the hypogastric (14%) or the obturator (53%) lymph nodes.40 Some of those differences may be related more to differing definitions of regions of dissection than to actual patterns of lymphatic spread.

If they are sampled, 20% to 80% of presacral and perirectal lymph nodes are involved with prostate cancer.14, 40, 41 This high incidence has been confirmed in modern imaging studies. In a limited study of 6 patients who were injected with contrast agent and then scanned, all showed drainage to the presacral lymph nodes.42 Some surgical series were unable to confirm this risk and reported that only about 1% of these lymph nodes were positive.37 Like the presacral lymph nodes, a more extensive dissection commonly yields positive lymph nodes in other areas. In older series, the common iliac lymph nodes were involved in 20% of patients, and the incidence of paraaortic lymph node involvement was almost as high.38, 39, 43 In a more contemporary study among patients who underwent standard dissection, on average, 11 lymph nodes were removed with a 12% positive rate. If a more extensive dissection was performed (28 lymph nodes removed), then the rate of positive lymph nodes was 26%.36 The finding that the extent of dissection determines the likelihood of positive lymph nodes has not been consistent.44–46 Unfortunately, the small number of patients with lymph node-positive disease in contemporary studies precludes meaningful conclusions. One important observation, however, is that patients who undergo more extended dissections have higher morbidity rates, including higher rates of lymphocele, lower extremity edema, and thrombophlebitis.46

How the removed lymph nodes are evaluated also determines the detection rate. This starts with how aggressively the pathologist evaluates the submitted tissue. For example, the adipose can be defatted to examine more meticulously for small lymph nodes. In addition, the number of sections taken through individual lymph nodes may influence the detection rate of metastasis. Recommendations recently were made regarding a uniform approach.47 Whereas the standard pathologic evaluation of lymph nodes is with hematoxylin and eosin (H&E) staining, it is recognized now that there are more sensitive ways to evaluate for very small areas of metastasis. The first of these was with immunohistochemical staining for markers more specific to prostate cancer. Whether this technique improves detection significantly is controversial. Freeman et al. evaluated 95 patients with pathologic T3 prostate cancer who had negative lymph nodes on H&E staining. By using an anticytokeratin antibody, those authors identified occult lymph node metastases in 15 patients (16%).48 In another study that employed the same antibody, only 1 of 32 patients (3%) had unsuspected metastases.49

An even more sensitive technique utilizes reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. In circulating blood, this technique reportedly is capable of identifying a single prostate cell in 10,000,000 circulating cells. When implementing RT-PCR in otherwise negative lymph nodes (including staining lymph node tissue for PSA), the incidence of positive lymph nodes varied from 18% to 69%.50–53 Others have reported that the risk was <10%, which is more consistent with the relatively low frequency of lymph node metastases in contemporary series54, 55 In 1 study, the RT-PCR finding of positive lymph nodes correlated with the risk of treatment failure.51 Currently, the exact significance of molecularly detected metastasis remains to be determined. The assumption of these techniques is that mere detection of cells producing PSA, prostate-specific membrane antigen, or other “prostate-specific products” in the blood or lymph nodes implies a viable metastasis. However, the immunologic contribution to removal of these cells and whether small numbers of circulating prostate cancer cells have the ability to set up viable metastases is uncertain. A finding of nests or clusters of cells in the lymph nodes with less sensitive analysis, such as H&E staining, may be more likely to represent “functional” metastases.

Number of Positive Lymph Nodes and Prognosis

The extent of lymph node involvement appears to have prognostic significance, although the data supporting this observation have several limitations. The first limitation is the extent of lymphadenectomy performed: The more lymph nodes removed, the greater likelihood of finding positive lymph nodes. In most practices, once a single positive lymph node is identified, surgeons will abandon further lymphadenectomy (and often the prostatectomy as well). Hence, the true incidence of multiple lymph node involvement is unknown, potentially resulting in an artificially poorer reported outcome for patients who have a “single” lymph node metastasis.

A noteworthy confounding factor also affects the interpretation of prognosis associated with lymph node metastases. Some institutions with a long history of reporting their results have a continuously increasing number of patients in their data base. If stage and bulk of cancer remained constant over time, then the varying lengths of patient follow-up would not impact conclusions. However, with the large stage migration that has occurred, the same institution may report different conclusions, depending on the era of publication. An early publication may include patients from the 1980s with a 25% to 30% incidence of lymph node metastases, but relatively short follow-up may be reported for outcomes. Subsequent publications may add a number of more recent patients with lower volume, microscopic lymph node metastases. Those more recent patients will have a very short follow-up, whereas the previous patients (who historically had bulkier disease) now will have a long-term follow-up. Because they have had less time to fail, it will appear that the more recent patients with microscopic disease have a better outcome. By constantly adding patients to a series, interpretations are likely to change over time. For example, in 1 series, it was concluded originally that the prognosis for patients with minimal lymph node disease was the same as that for patients who had no lymph node involvement.56 In a later version of the same study, it was reported that patients who had a single involved lymph node actually fared no better than patients who had multiple involved lymph nodes.19 In a still later update, it was reported that the difference between multiple and single lymph node involvement was indeed a significant predictor of further metastatic disease.57

Another challenge in interpreting studies that describe differences in outcomes based on the number of lymph nodes involved is that the actual numbers of lymph nodes are not always reported.17, 24 Because of these reporting differences, it is not surprising that there are widely different conclusions reached by the various authors.57 Some conclude that, as a rule, lymph node involvement indicates metastatic spread of cancer and that local-regional treatment, at most, is palliative20, 35, 58, 59; while others conclude that, in patients with minimal lymph node disease, local-regional treatment may affect survival favorably.20, 21, 60–63

Because large randomized studies addressing this issue are unlikely to occur, conclusions must be reached based on incomplete and potentially biased data. Table 5 shows that the most commonly reported parameters are 5-year survival and recurrence-free or disease-free survival. Most of those studies took place in the pre-PSA era, and most had small numbers of patients. For patients who had a single positive lymph node, the 5-year survival rate was as high as 85%21 and as low as 45%,60 and 50% was a reasonable middle estimate. In general, the more lymph nodes involved, the worse the survival. For patients who had 2 or 3 involved lymph nodes, the 5-year survival rate appeared to be better than for patients who had >3 involved lymph nodes. Patients who had >1 involved lymph node had a >60% 5-year survival rate. Disease-free survival was much lower, especially when it was determined by PSA. Still, the favorable 5-year survival rates speak to the efficacy of adjuvant hormone therapy. Again, although there is usually a trend, some have not observed a significant change in survival based on the number of involved lymph nodes.58, 59, 64 Some authors reported that the percentage of positive lymph nodes is more predictive than the absolute number.20, 62 The tumor bulk in patients with adenopathy also has been recognized as a prognostic factor,65 and this measure also correlates with tumor Gleason score. For a lymph node tumor volume <0.04 cc, no patient had systemic progression (compared with 13% progression for a tumor volume of 0.05–0.19 cc and 22% progression for a tumor volume ≥0.20 cc; P < 0.0001).65

Table 5. Influence of the Number of Lymph Nodes on Outcome
Study (Initial treatment)YearsNo. of patientsNo. of lymph nodesSurvival rate (%)DFS rate (%)5-Year bNED (%)Died of disease (%)
5 Years10 Years5 Years10 Years
  • DFS indicates disease-free survival; bNED, no biochemical evidence of disease; RP, radical prostatectomy; XRT, radiation; ±, with or without; AA, androgen ablation.

  • *

    Median, 45 months.

  • Mean, 65 months.

  • Median, 80 months.

  • §

    Prostate-specific antigenbased.

  • Single lymph node. Single lymph node.

  • Distant progression free.

  • **

    Cause-specific survival.

Golimbu et al., 198721 (RP ± XRT ± AA)1972–198415185508520  
122–3800700  
14>36410270  
deKernion et al., 198522 (RP, XRT, ± AA)1972–198214157     
222–488     
22>569     
Prout et al., 198084 (RP and/or XRT)1969–1976121  84   
21Multiple  24   
Bader et al., 200345 (RP)1989–1999391    39*8*
202    10*25*
29>2    14*36*
Anscher and Prosnitz, 199260 (XRT)1970–198311145 18   
13>115 0   
Smith and Middleton, 198563 (XRT, none)?18172 44   
 Multiple63 27   
 Macroscopic48 15   
Brawn et al., 1990101 (none, AA)?1417952    
1226628    
33>28528    
Leibel et al., 199357 (implant [21  patients], pelvic XRT)1970–1985117N187 51   
217N262 25   
Kramolowsky, 198826 (RP, cryoablation,  XRT, none, ± AA)1966–198135≤2  60  31
33>2  22  48
Schmid et al., 1997102 (RP)1976–1990 <5 mm   37§  
 >5 mm   25§  
 >1   10§  
Daneshmand et al., 200464  (some XRT, some AA, all RP)1972–19991081947589 70 
522967481 73 
42>5764962 49 
Cheng et al., 199385 (all RP, most AA)1966–19891421  96   
1052–4  86   
24>4  79   
Gervasi et al., 198958 (implant, XRT)1966–1979 1684982**60**  
 Multiple632272**34**  
 Macroscopic693575**42**  

Thus, the bulk of the literature suggests that patients with fewer involved lymph nodes have a better prognosis. Whether this represents a “lead-time” survival bias (with fewer involved lymph nodes considered earlier detection of the same disease) or the beneficial effects of the usually prescribed early adjuvant hormone therapy is uncertain.

Special Issues

DNA content

Perhaps because of the poor prognosis for patients who have lymph node-positive prostate cancer, there has been interest in investigating the issue of DNA content as a predictor for outcome. In a Mayo Clinic series,16 among men who underwent radical prostatectomy and androgen ablation (in most), patients were divided into diploid (138 patients), tetraploid (168 patients), and aneuploid (64 pts) subgroups. Diploid patients had a 28% failure rate and a 13% cancer death rate, tetraploid patients had a 50% failure rate and a 30% cancer death rate, and aneuploid patients had a 55% failure rate and a 44% cancer death rate. A subset of patients did not receive androgen ablation, and it was found that androgen ablation delayed disease progression in all groups but only improved survival in the diploid group. The small number of patients who did not receive androgen ablation makes firm conclusions difficult. In a much smaller study from The University of Texas M. D. Anderson Cancer Center, 33 patients with positive lymph nodes who received androgen ablation were evaluated.66 With the small numbers, only casual observation can be made, and the results depended on how the groups (diploid, “near diploid,” tetraploid, and aneuploid) were divided for analysis. Overall, the 4-year clinical progression rate for the nonaneuploid group was 14% compared with 48% for the aneuploid group (although both groups had a biochemical progression rate of 70%). From both series, it appears that diploid patients had better outcomes, but it is not evident that either institution has altered their treatment approach as a result.

Imaging

Although it is clear that more extended lymph node dissections result in an increase in the finding of positive lymph nodes, it also increases morbidity. Therefore, there is great interest in being able to do directed lymph node dissections. Historically, imaging has not been very reliable for detecting lymph nodes, even those involved with cancer. Standard computed tomography and magnetic resonance imaging (MRI) have not been very sensitive.67, 68 Results with newer techniques are somewhat more promising. In recent study, among 63 metastatic lymph nodes (33 patients) that were documented pathologically, only 29% had been identified as abnormal by size criteria on MRI, but 90.5% were detected as abnormal by using superparmagnetic nanoparticles. The false-positive rate was 4%.69 If they are confirmed by further studies, these results are dramatic.

Positron emission tomography (PET) scanning with 18-fluoro-2-dexyglucose has not been very successful in imaging prostate cancer.70 This has been attributed to the low proliferative rate (and, hence, the low metabolic rate) of prostate cancer. Better results in imaging lymph nodes have been obtained with the 11C-acetate tracer,71, 72 but the sensitivity and specificity of this newer agent have not been defined. The improving results indicate that, with further research, PET still may turn out to be a valuable modality in staging prostate cancer.

Another novel approach is immunoscintigraphy with radiolabeled monoclonal antibodies. In a study of 198 men with a high risk for lymph node metastasis, 39% of men had pelvic lymph node involvement, and monoclonal antibody detected 67% of them.73 Another large study confirmed similar findings, with a positive predictive value of 62% and a negative predictive value of 72%.74 Although they may be better than results from computed tomography or MRI (but not always75), these results alone are not reliable enough for most clinicians to be willing to forgo their standard approach. Most studies have been done with labeled antibodies to the intracellular domain of the prostate-specific membrane antigen. An antibody now has been developed to the extracellular domain. Preliminary results76 have shown a greater sensitivity than that of the previous antibody, and additional research well may prove the utility of this new antibody in detecting positive lymph nodes.

To date, the most promising approach, which has shown some success in other malignancies, is that of sentinel lymph node biopsy. A technetium-labeled substrate is injected into the prostate; and, after allowing for distribution into the lymphatics, imaging is obtained that reveals which lymph nodes have accumulated the tracer (indicating the primary route of lymphatic drainage). In addition, at the time of surgery and lymph node processing, a γ detector is used to find more subtle areas of uptake. With these techniques, the potentially involved “sentinel” lymph nodes can be identified in 90% to 100% of patients.14, 77–79 In 1 study, although the number of patients with positive lymph node status was small (n = 4 men), 100% of positive findings were in sentinel lymph nodes. More important, 2 positive findings were in lymph nodes that would have not been removed in the standard dissection.78 The frequent (>50%) finding of positive sentinel lymph nodes outside the obturator fossa has been observed by others.79, 80 In the largest series (350 patients),14 the false-negative rate (patients with positive lymph nodes without a positive sentinel lymph node) was <1%. With this technique, as discussed above, the overall incidence of positive lymph nodes is much higher than with standard approaches. Although further studies are needed, it appears that sentinel lymph node detection may result in the same information as an extended lymph node dissection but without the morbidity. The downside is that it increases surgical time, a situation that likely will improve with more experience.

In conclusion, with improved awareness and early detection efforts, the incidence of lymph node-positive prostate cancer has declined dramatically over the last 50 years. It is noteworthy that most series on incidence have potential biases; thus, the actual incidence may be higher than what is believed commonly. Disease stage, PSA level, and tumor grade are risk factors for positive lymph nodes in patients with prostate cancer; and those factors, along with the number of involved lymph nodes, are prognostic factors for outcome. The extent of the lymph node dissection influences the likelihood of finding involved lymph nodes, although techniques are under development that likely will make selective lymph node removal a reality in the future. Although the numbers have declined, the number of men with lymph node-positive prostate cancer still is significant, and the challenge of how best to treat these patients remains.

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