REVISIÓN

Pelvic lymph node dissection (extended vs standard) and prostate cancer

Rincón Mayans A, Zudaire Bergera JJ, Rioja Zuazu J*, Zudaire Diaz-Tejeiro B**, Barba Abad J, Brugarolas Rosselló X, Rosell Costa D, Berián Polo JM.

Departament of Urology and**Radiodiagnosis. Clínica Universitaria de Navarra (Pamplona).*Departament of Urology. Academis Medical Centrum (Amsterdam).

Actas Urol Esp 2008;32(9):879-887

ABSTRACT

PELVIC LYMPH NODE DISSECTION (EXTENDED vs STANDARD) AND PROSTATE CANCER

The role and potential benefit, if any, of pelvic lymph node dissection (PLND) in prostate cancer are still controversially discussed. It is generally accepted that PLND at the time of radical prostatectomy is the only reliable diagnostic procedure to achieve as much individual histological staging information as possible to trigger postoperative adjuvant management. However, the extent of pelvic lymph node dissection (limited vs. extended) and the most suitable candidates for this procedure are still a matter of intense debate. The aim of this review is to critically evaluate the current status on lymph node dissection in prostate cancer.

Keywords: Prostate cancer. Lymph node. Lymphadenectomy. Radical prostatectomy.

The incidence of lymph node involvement in patients with the diagnosis of clinically localized prostate cancer varies between 4-25 %. Such a wide range is due to the notable heterogeneity of the series and different type of techniques employed^1,3. Moreover, there is an evident trend to a decrease in the number the number of patients with lymph node involvement due to a significant increase in early diagnosis, improvement on clinical classification and consequently better patient selection. Based on more than 7000 patients from six centers of excellence, we may say that the incidence of lymphatic involvement in patients with clinically localized prostate cancer is 3-4%⁴. Although the percentage seems not significant, the incidence of this disease (first tumor diagnosed in males) makes the percentage of patients with positive lymph nodes still important in terms of population.

The study of lymphatic involvement and the role of lymph node dissection (LND) in localized prostate cancer stand on two suppositions:

1. The diagnostic strictness of clinical staging methods is not enough to set the indication of lymph node dissection. Imaging techniques (CT scan or MRI) are in many instances insufficient to detect lymph node involvement^5,6.

2. Histological evaluation is the only effective method to detect lymphatic involvement in patients with diagnosis of clinically localized prostate adenocarcinoma. From that standpoint LND is the method of choice for lymphatic evaluation in patients with diagnosis of prostatic adenocarcinoma.

Two questions should be answered from those standpoints:

Which patients should undergo LND and what kind of LND must be carried out in each case? For that we will perform a detailed study of prostatic drainage, potential benefit of LND on biochemical progression free survival, the anatomic extension of LND and its relationship with complications. We will thoroughly study the role of extended LND.

EVALUATION OF LYMPHATIC INVOLVEMENT IN PROSTATE CANCER

The first challenge is to predict the risk of lymphatic involvement. We analyze the various factors associated with lymphatic involvement.

Clinical variables

The clinical variables related with the risk of lymph node involvement are: clinical stage, serum PSA, and data from the diagnostic biopsy such as Gleason, number and percentage of cores affected, percentage of involvement per core, etc. We analyze each of them.

Clinical stage

Numerous papers include clinical stage as a significant variable. The risk of lymphatic involvement in stage T1a-T1b is 2-3%. At the beginning of the clinical application of serum PSA determination 11% the patient presented T1c stage and the risk of lymph node involvement was 3%⁷. A more recent study shows that 39% of the patients present in stage T1c and the incidence of lymph node involvement is 1%⁸.

In clinical stage T2 the risk has been traditionally 15%, but currently this percentage is closer to 8%. In patients with cT2b the risk is 10%, and 4% for stage cT2a⁹. There is not much information regarding locally advanced stages (cT3) but in historical series that percentage of lymph node involvement varied from 20-50%¹⁰.

Clinical Gleason

Although it is not always a predictive variable¹¹, the association with lymph node metastasis has been described^12-13. Traditionally, the risk for Gleasons 2-4 is 0-20%; for Gleason 5-7 is 31-38%; and for Gleason 8-10 is 62-93%.

PSA

The higher level the PSA the greater the risk of lymph node involvement. In 2439 patients undergoing radical prostatectomy and lymph node dissection¹³, 2% of the patients with PSA between 0.4-4 ng/ml at diagnosis presented positive lymph nodes, 5% of those with PSA 4-10 ng/ml, 11% of the patients with PSA between 10 and 20 ng/ml, 22% with the PSA between 20 and 50 ng/ml, and 38% of the patient with PSA> 50 ng/ml.

Number of biopsy cores involved

The number of positive biopsy cores has not been analyzed until recently. In a recent study the various variables traditionally associated to the presence of positive lymph nodes (PSA, clinical Gleason, and clinical stage) were analyzed and the number of cores and their involvement was added to the study. Such study showed that the percentage of positive cores was an influential variable, but the number or a combination of number and percentage of affected cores were not. Even the percentage of positive cores resulted to be the most influential independent variable in terms of prediction of lymph node involvement (78.5%), over biopsy's Gleason (78.4%), clinical stage (57.4%) and PSA (62.9%).

Nomograms

Prognostic nomograms have been designed using the clinically influential variables previously described. Table 1 shows various models of risk prediction. Only Briganti et al. showed data based on extended lymphadenectomy¹⁵. The rest of the models are constructed after limited lymphadenectomy.

Table 1

	N(+)	AUC
Partin^16	5%	82%
Cagiannos^17	3,7%	78%
Blute^18	6%	84%
Penson^19	3%	76%
Graefen^20	5%	80%
Augustin^21	2,9%	79%
Steuber^22	4,5%	79%
Karakiewicz^23	6%	76%
Briganti^15	11%	76%

Partin`s is the first and most known<sup>16</sup>. His nomogram, one of the most used ones, qualified as low risk, therefore open for not having lymphadenectomy carried out (incidence of lymph node involvement between 1-5%), patients with PSA<10 ng/ml, biopsy`s Gleason <7, and clinical stage ≤T2a. The most influential factor was clinical Gleason. Crawford²⁴, after the analysis of 4690 patients with radical prostatectomy and pelvic lymphadenectomy, describes that patients with clinical Gleason ≤ 6, pre-biopsy PSA≤ 10 ng/ml, and stage cT1c are at lower risk of lymph node involvement. Two studies^25-26 have validated the results of Partin's nomogram in patients undergoing radical prostatectomy and extended lymphadenectomy. They evidence a good correlation between nomogram and results in low risk patients (cT1c, Gleason 2-4 and PSA<10 ng/ml) with no lymphatic involvement detected in any case. In patients with intermediate risk (PSA<10 ng/ml, biopsy Gleason 5-7 and ≤cT2a) results did not differ significantly. Validation is worse in patients with higher preoperative PSA values and Gleason 8-10. Cagiannos¹⁷, with more than 7000 patients designed in 2003 a nomogram of lymph node involvement risk. Using PSA, Gleason and clinical stage, the prediction reliability is 0.78. Validation with boostrap techniques indicates that reliability is greater in patients with risk below 10%. As indicated before, all models except Briganti's are based in the study of specimens obtained from lymphadenectomies limited to the obturator fossa and external iliac area, with an average of 6-9 lymph nodes retrieved²⁷. In the same way, being in many instances historic series, histological criteria are different than current, so that it is difficult to compare with patients recently diagnosed²⁸.

Briganti et al¹⁵ published in 2006 the first prognostic nomogram after performance of extended lymphadenectomy in 602 patients. More than 10 lymph nodes were retrieved per patient (mean: 17.1). In univariate study, clinical stage, PSA and Gleason were related with the risk of lymph node involvement. In multivariate study, only Gleason and clinical stage were. With the data they designed a nomogram with a predictive power of 76.2%. If we add the number of positive cores in the biopsy the predictive power ascends to 83%¹⁴.

Imaging techniques

As we indicated before, imaging techniques do not offer enough diagnostic security to avoid pelvic lymph node dissection. Wolf⁶ analyzed 25 papers studying various techniques, with subsequent histological confirmation. He concluded that both CT-scan and MRI have low sensitivity (36%) and high specificity (97%) for detection of positive lymph nodes. Ponsky²⁹ analyzed the role of ProstaScint in 22 patients undergoing lymphadenectomy limited to the obturator and common iliac lymph nodes; in the same way he detected low sensitivity (17%) and 90% specificity. The false positive rate was 89%.

The usefulness of PET has been also studied, with colin as the best tracer. Jong³⁰ analyzed 67 patients and found an 80% sensitivity and 96% specificity to detect lymph node involvement. In a study with few patients (25 patients) undergoing lymphadenectomy due to biochemical recurrence after radical prostatectomy, colin-PET had 100% sensitivity and 92% security in patients with lymph node recurrence.

Recently, the role of lymphotrophic super magnetic nanoparticles in combination with MRI³¹ is being analyzed, achieving greater sensitivity (90.5%) and specificity (97.8%) in comparison with MRI; nevertheless, sensitivity descends to 41.1% in lymph nodes < 5 mm, those in which lymphadenectomy could have a more important role. Both PET and MRI with nanoparticles continue being experimental due to the low number of publications.

Lymph node dissection

Pelvic LND is the only procedure for the diagnosis of lymph node involvement. Various types of dissection have been described, since there is no consensus regarding its anatomical extension. Lymph node dissection limited to the obturator fossa, standard LND (obturator fossa and external iliac vessels), and extended LND including obturator fossa, external and internal iliac, and common iliac over the ureteroiliac crossing which includes over 10 lymph nodes in the specimen^25-26,31,15.

The first two techniques have been the most frequently carried out. They are based in the idea that initial lymphatic involvement starts in the iliac-obturator territory, therefore these two variants are diagnostic. Nevertheless, that is not true; at least 34% of the patients with positive lymph nodes have them exclusively out the iliac-obturator territory³². Anatomical studies³³ show the prostatic gland drains to three groups of lymph nodes. The superior portion of the prostate drains to the external iliac lymph nodes, the posterior portion to the sacral lymph nodes (subaortic and lateral), and finally the lateral prostatic lymphatic vessels drain to the internal iliac lymph nodes.

Wawoschek³⁴ performed a study of sentinel node detection in 117 patients (mean number of lymph nodes retrieved per patient 21.8). 23.9% presented lymph node involvement. 13.2% of the lymph nodes retrieved were positive. 14.4% of them were external iliac, 11.2% from the obturator fossa, 14.7% hypogastric, 8.3% presacral, and finally 28.5% pararectal, demonstrating that there is not a clear track of lymphatic tumoral dissemination. If LND limited to the obturator fossa was performed then 60% the lymph node metastasis were lost.

Bader³⁵ in a study with 365 patients undergoing LND showed that 58% of the patients with positive lymph nodes had them located in the internal iliac lymph nodes. Heidenreich³⁶ also indicated in a study that 42% of the positive lymph nodes were found out of the external iliac and obturator areas. It has been described lymph node involvement in all areas of prostatic lymphatic drainage (obturator, external iliac, common iliac, pre-sacral, and lateral sacral lymph nodes)³⁷.

Extended lymph node dissection

Only the extended LND matches the anatomical considerations described, because it is the only one exploring and retrieving lymph nodes from all areas theoretically involved, and in all cases the number of lymph nodes retrieved and the percentage of lymph node involvement is greater even in low-risk patients.

Allaf et al³⁸ demonstrated the diagnostic advantage of extended lymphadenectomy in low risk patients (PSA<10 ng/ml, cT1c and clinical Gleason≤ 6) after performing a wider LND^15,38-42. They compared the incidence of lymph node involvement between a group of 2135 patients with the diagnosis of low-risk prostate adenocarcinoma and 1835 patients of the same risk group undergoing limited obturator fossa LND. In the extended LND group the number of lymph nodes retrieved was higher (11.6 versus 8.9; p<0.0001) and the number of lymph node metastases was also greater (3.2% versus 1.1%; p<0.0001).

Moreover, the mean and median number of lymph nodes retrieved was greater in the extended LND (21-28 lymph nodes retrieved with extended LND in comparison to 10-12 with LND limited to the obturator fossa). Probably the number of lymph nodes retrieved is an indirect measure of efficacy. Weingärtner⁴³ determined after the study of cadaver dissections that the number of lymph nodes necessary to perform a proper lymphatic staging is 20. Various studies have shown that the number of lymph nodes retrieved is likewise related to the number of lymph nodes affected⁴⁴. Stone⁴⁵ compared limited and extended laparoscopic LND finding that the number of lymph nodes retrieved was double (9 vs. 18) and the risk of detection of lymphatic metastasis was threefold (7% versus 23%) in the extended variant.

Nevertheless, there is no unanimity. In a randomized study comparing the incidence of lymphatic involvement⁴⁶, there were no differences between both techniques (extended: 3.2% vs. limited: 2.4%). Nevertheless, this study presented some deficiencies: low-risk patients, insufficient number of patients, and histological evaluation protocol incompletely described.

Table 2 shows various studies comparing the number of lymph nodes retrieved and the percentage of tumor involvement.

Table 2

	Extended LND	Limited LND
Lymph nodes retrieved (n)
• Stone^45	17,8	9,3
• Heidenreich^25,26	28	11
• Allaf^38	11,6	8,9
Percentage of affected lymph nodes
• Stone^45	23,1%	7,3%
• Heidenreich^25,26	27%	12%
• Allaf^38	3,2%	1,1%

Extended LND, as an exponent of a rational approach to the prostatic lymphatic drainage territory, detects a greater number of affected lymph nodes being the most suitable technique for staging. A LND limited to the obturator fossa is associated with a high incidence (30-35%) of false negatives³², and up to 35% of metastatic lymph nodes are lost to diagnosis when performing LND limited to the obturator fossa^34,47,48.

Indication for LND (determining factors)

Lymph node dissection is only indicated if there is a risk of metastasis and that determines or conditions treatment or influences survival, and these facts will determine if LND should be limited or extended.

Which patients require extended lymphadenectomy? Briganti et al³² have designed a nomogram (PSA, Gleason and clinical stage) that enables us to detect the risk of lymph node metastasis out of the obturator fossa with the objective of setting or not the indication of extended LND. In this study, Gleason 8-10 is the only independent influential factor. PSA is influential in high levels (> 50 ng/ml), very rare values in patients undergoing radical prostatectomy. The nomogram is very much adjusted in risk values below 5%; it gives underestimates between 5-10% and overestimates for values higher than 15%. With the nomogram, extended LND is avoided in 62% of the patients, with 86% correct staging in patients with lymphatic involvement out of the obturator fossa. Thus patients with PSA ≤10, T1c, and biopsy`s Gleason ≤ 6 have a 0.6% risk of lymphatic metastasis out of the obturator area. In patients with the same characteristics except biopsy`s Gleason≤7 the risk is 1%. The performance of limited iliac-obturator fossa LND in these patients would properly diagnose 99.4% and 99% respectively.

Heidenreich³⁶ defined as group at risk patients with PSA> 10.5 ng/ml or Gleason > 7. In them, the incidence of lymph node metastases was 29% when extended LND was performed. In patients not complying with these criteria the incidence was 2.8%. Keller⁴⁹ performed LND in patients with PSA > 10 ng/ml or Gleason >5 or more than two biopsy cores involved since he considered these patients high risk.

Complications of LND

The complications of standard LND are well known (obturator nerve and artery injury, bleeding from external iliac vessels, abdominal wall hematoma, and lymphocele) but they generally do not result in great morbidity.

There are few papers analyzing the complications of extended LND^{35,36,45,49,50}. Using an open approach, these papers comment that access is difficult from a midline infraumbilical incision⁴⁹, specially to the common iliac lymph nodes in stout patients (mean and median number of nodes retrieved 19 and 18.7 respectively). Local control of the internal iliac vein and its branches, as well as dissection and ligature of the vessels close to the pre-sacral lymph nodes require great surgical expertise³². Table 3 shows various studies and their complication rates.

Table 3

References	Number of pacientes	% de complications
Paul^51	150	51
McDowell^52	217	22
Schuessler^37	147	31
Stone^45	150/39	35,9/2
Briganti^50	963	17,4
Clark^46	123	10,5

If we analyze the references of these papers by year of publication we will realize the number of complications decreased in most recent series. Briganti et al in a paper in 2006 analyzed the complications of LND in 963 patients with the diagnosis of prostate cancer undergoing radical prostatectomy. In 767 of them (79.6%) ≥10 lymph nodes (extended LND) were retrieved and in 196 (20.4%) between 1-9 lymph nodes. They analyzed the general incidence of complications for both procedures, specific etiology of complications (lymphocele, ureteral injury, pelvic hematoma, reoperation secondary to pelvic hematoma), surgical time and hospital stay. Overall, 17.4% of the patients presented complications secondary to LND. The appearance of at least one complication was more frequent in the extended LND group (19.2% vs. 8.2%; OR:2.7; p<0,001). Analyzing each complication individually, only the risk of lymphocele was significantly greater in patients with ≥ 10 lymph nodes retrieved (10.3% vs. 4.6%; OR 2.4; p=0.02). Operation room time was not longer in patients with extended LND (p=0.6). Hospital stay was 1.5 days longer in the extended LND group (p<0.001). In this paper the authors comment on a 95% greater risk of presenting at least 1 complication after LND in those cases with >30 lymph nodes retrieved. On the contrary, when the number of lymph nodes is less than 5 the risk of complications is < 10%.

They state the risk of complications is associated more with the number of lymph nodes retrieved than the extension of LND. Therefore, the greater the number of lymph nodes retrieved the greater the number of complications.

Other papers have described, in the same way, greater number of complications after extended LND^45,46. Stone⁴⁵ does analyze complications after laparoscopic approach and describes a greater incidence of complications of extended LND (35,9% vs 2%;p<0,001).

Currently, the complication rate accepted in expert hands is near 7% for extended LND, with an incidence of symptomatic lymphocele between 2-4%²⁷.Clark (10.5% complication rate)⁴⁶ and Briganti⁵⁰ refer that 75% of the complications are secondary to extended dissections of the lymphatic tissue lateral to the external iliac artery, responsible of the lymphatic drainage of the lower limbs, which curiously is an infrequent area of metastases^25,26. To reduce the risk of complications the recommendation are: to preserve lymphatic vessels lateral to the external iliac artery, tie or clip with small clips (not big) which exercise a greater pressure on the distal end of the lymphatic vessels, use two drain tubes in each side of the pelvis and maintain them until the volume is <50 ml, and the use of low weight heparins.

But not all published papers show differences in the number of complications by technique performed (extended vs limited). Heinderich³⁶ showed a 9% complication rate in patients undergoing extended LND versus 8.7% after less extensive LND. Bader³⁵ describes a 2.1% complication rate for extended LND in 365 patients being these results similar or better than a series of patients undergoing standard LND. Not only a greater number of lymphoceles have been described^49,50, but also ureteral injuries, deep vein thrombosis, embolism, and other complications, without finding significant differences in comparison with standard LND.

Solberg⁵³ compared the risk of lymphocele between open approach (94 patients) and laparoscopic (38 cases) finding significant differences between both groups, with a lower risk for the laparoscopic approach, maybe due to the meticulous hemostasis and field magnification.

Transperitoneal and retroperitoneal laparoscopic LND have been described. The latter is similar to the open approach, and the transperitoneal approach enables a better access to the internal iliac and presacral lymph nodes and the risk of lymphocele seems to be lower.

Influence of LND on biochemichal progression

The presence of lymph node metastases in a patient with the diagnosis of clinically localized prostate cancer dramatically affects prognosis^44,54 39% of the patients with only one lymph node involved are disease free at 45 months, but only 10% if more than one are involved³.

Globally, the beneficial therapeutic effect of systematic LND is very limited. In a non randomized prospective study in low risk patients undergoing LND⁵⁵ with a median follow up of 60 months, LND did not modify the risk of biochemical progression, and even though these facts are confirmed in other works^56-58, we must say the number of lymph nodes retrieved was generally low (less than 9 lymph nodes) and the percentage of patients with positive nodes less than 10%, which is an evaluation bias.

The extension of lymphatic dissection does not seem to influence prognosis either. Boorjian⁵⁹ in a recent paper in which mean number of lymph nodes retrieved was eleven, showed that the number of lymph nodes did not modify prognosis. Masterson, with more than 5000 patients, fails to demonstrate that extending LND improves the biochemical progression rate⁶⁰.

Only in patients with lymph node involvement >15% was extended LND related with lower biochemical progression rate (10% vs 45% at 5 years)³⁸.

CONCLUSIONS

Not all patients with the diagnosis of prostate cancer require the performance of LND, and not all patients undergoing LND require the extended one.

The 2005 EAU Prostate Cancer Clinical Guidelines indicated that patients with PSA ≤ 20 ng/ml; ≤ T2; Gleason ≤ 6 did not require LND because the risk was less than 10%.The rest of the patients required LND without specifying what variant⁶¹. Nevertheless, in the latest EAU Prostate Cancer Clinical Guidelines⁶² despite stating there is no consensus, they recommend to not perform LND in patients with low risk of lymph nodes involvement (cT1c, PSA<10 ng/ml, biopsy Gleason ≤6) and to perform extended LND in intermediate (cT2a, PSA 10-20ng/ml, biopsy Gleason =7) and high risk patients (>cT2b, PSA>20 ng/ml, biopsy Gleason ≥8). A recent study⁶³ demonstrates that LND in low risk patients does not give any benefit in 10 year biochemical progression.

The AUA is not precise in the indication of LND in its clinical guideline⁶⁴.

The only thing we can argue in favor of extended LND is the better lymph node staging because no benefit in progression has been demonstrated. Nevertheless, the fact that extended LND in some tumors (stomach, lung, and bladder in our field)⁶⁵ provides a survival benefit suggest us that an extrapolation to prostate cancer is not mindless.

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Correspondence author: Dr. A. Rincón Mayans

Departamento de Urología

Clínica Universitaria de Navarra

Avda. Pío XII, 36 -31008 Pamplona (Navarra)

Tel.: 948 255 400

Author e-mail: arincon@unav.es

Paper information: Original – Prostate cancer

Manuscript received: february 2008

Manuscript accepted: april 2008