The Contemporary Incidence of Lymph Node Metastases in Prostate Cancer: Implications for Laparoscopic Lymph Node Dissection

0022-534 7/93/1496-1488$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 149, 1488-1491, June 1993 Printed in U.S.A.

THE CONTEMPORARY INCIDENCE OF LYMPH NODE METASTASES IN PROSTATE CANCER: IMPLICATIONS FOR LAPAROSCOPIC LYMPH NODE DISSECTION JOHN F. DANELLA, JEAN B. DEKERNION, ROBERT B. SMITH AND JOPH STECKEL From the Division of Urology, Department of Surgery, UCLA Medical Center, Los Angeles, California

ABSTRACT

The incidence of lymphatic metastases in 229 consecutive patients with clinically localized prostatic cancer was assessed. Only 13 patients had nodal metastases, for an incidence of 5.7%. A monoclonal prostatic specific antigen value of more than 40 ng./ml. correlated with a positive predictive value of 53 % for nodal metastases. Routine laparoscopic node dissection is unnecessary considering the low incidence of nodal metastases. KEY WORDS:

prostatic neoplasms, lymph nodes, neoplasm metastasis

Pelvic lymphadenectomy before radical prostatectomy has been the subject of additional focus recently as a result of the evolution of laparoscopic node dissection. The benefits of this procedure are improved pathological staging and the identification of patients who are unlikely to be cured by radical prostatectomy alone. Gervasi et al demonstrated that patients who had only small volume nodal metastases failed locoregional therapy at a rate similar to patients with more extensive disease. 1 Kramer et al could not demonstrate any increase in disease control for radical prostatectomy and pelvic lymphadenectomy when nodal metastases were identified. 2 Therefore, proponents of laparoscopic lymphadenectomy have argued that this technique should be used to assess nodal status to avoid the morbidity of radical prostatectomy in patients with stage Dl disease. An unresolved issue is how patients who harbor nodal metastases might best be identified. Therefore, we reviewed our experience with open pelvic lymph node dissection during the last 3 years, since we contend that this period would accurately reflect the contemporary incidence of pelvic lymph node metastases. MATERIALS AND METHODS

The hospital and office records of 232 consecutive patients whose disease was surgically staged at our institution under the supervision of the 2 senior authors (J. B. D. and R. B. S.) between January 1, 1989 and December 31, 1991 were reviewed. This series includes 10 patients who underwent salvage prostatectomy for radiation failure and 19 who were treated on a neoadjuvant androgen ablation protocol for downstaging of clinical stage C lesions. The remaining 203 patients were judged to have clinically localized disease on the basis of digital rectal examination, serum enzymatic acid phosphatase (thymolphthalein monophosphate substrate method) and nuclear medicine bone scan. Magnetic resonance imaging and pelvic computerized tomography scans were not routinely performed, although many of the patients referred for surgery from elsewhere had undergone these studies. Preoperative Hybritech monoclonal prostate specific antigen (PSA) values were recorded in 207 patients. Clinical stage was assigned according to the WhitmoreJewett system: stage A-cancer detected by microscopic examination of a transurethral prostatectomy specimen or needle biopsy of a gland that is normal to palpation, stage Bl-a nodule or area of induration confined to less than half of 1 lobe of the prostate, stage B2-lesions involving greater than half of a lobe or bilateral involvement but confined within the

prostatic capsule and stage C-extracapsular extension of tumor. All patients were scheduled for radical retropubic prostatectomy and underwent a modified pelvic lymph node dissection. The limits of the dissection were the lateral margin of the external iliac vein from Cooper's ligament to the bifurcation of the common iliac artery, posteriorly to the obturator nerve and vessels. If grossly diseased lymph nodes were identified they were examined by frozen section and the procedure was terminated if metastatic disease was confirmed. Lymphatic tissue that was not palpably suspicious was submitted for permanent sections and radical prostatectomy was completed as planned. Lymph node dissections were not performed on 3 of the salvage prostatectomy patients and they were excluded from the analysis. All specimens were reviewed by our pathologists and pri1. The incidence of pelvic lymph node metastases in surgically staged prostate cancer patients from 1989 to 1991 inclusive

TABLE

Pt. Category

No. Pts.

Stage Dl Ca No.(%)

Standard radical retropubic prostatectomy Salvage radical retropubic prostatectomy Downstaging radical retropubic prostatectomy Totals

203

7 (3.4)

7

1 (14.2)

19

5 (26.3)

229

13 (5.7)

Accepted for publication December 11, 1992.

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TABLE

2. Distribution of tumors by clinical stage and incidence of

lymphatic metastases within each stage Clinical Stage A Bl B2 C

Totals

TABLE

Stage Dl Ca No.(%)

No. Pts. 15 105 90 19 229

1 1 6 5 13

(6.7) (less than 1) (6.7) (26.3) (5. 7)

3. Comparison of node negative to node positive cancer

patients Nodal Status Pos. Mean Gleason score (range) Mean ng./ml. PSA (range) Mean nodes dissected Capsule confined primary tumor(%)

7.1 (5-9)

Neg. 5.8 (2-10)

47.7 (6.5-137)

13.5 (1.2-88.6)

8.9 20

8.1 56

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LYMPH NODE METASTASES IN PROSTATE CANCER TABLE 4.

Node Neg. No./Total

% Sensitivity

% Specificity

% Pas. Predictive Value

9/13

78/219

69

64

10

10/13 8/13 7/13

45/193 7/193 20/193

77 62 54

77 96 90

18 53 26

6/13

4/193

46

98

60

Gleason score 7 or more PSA (ng./ml.): More than 15 More than 40 Gleason score 7 or more and PSA more than 15 Gleason score 7 or more and PSA more than 40

TABLE 5.

Evaluation of parameters to predict for lymphatic metastases

Node Pos. No./Total

Distribution of PSA values and Gleason scores for clinical stage B2 lesions with nodal metastases Pt.

CF AK

MM RW RH DJ*

PSA (ng./ml.) 16.4 9.0 75 137 53 6.5

Gleason Score 6

5 6

9 7

8

* Salvage prostatectomy. TABLE

6. Extended UCLA experience with surgical staging of prostate cancer Yrs.

No. Pts.

Stage Dl Ca No.(%)

1972-1988 1988-1991

265 229

53 (20.0) 13 (5.7)

mary tumors were assessed for capsule invasion, and margin and seminal vesicle involvement. RESULTS

Of the 229 patients analyzed 3 had grossly malignant lymph nodes and prostatectomy was not performed. The remaining 226 patients underwent radical retropubic prostatectomy. The incidence of pelvic lymph node metastases for the patients in each treatment category is listed in table 1. For patients in the standard prostatectomy group (clinically localized disease and no prior radiotherapy) the incidence of pelvic lymph node metastases was 3.4%. Of the 7 patients undergoing salvage prostatectomy who also underwent lymphadenectomy 1 had nodal metastases. Stage Dl disease was identified in 5 of the 19 patients in the neoadjuvant downstaging protocol. A total of 229 patients underwent lymph node dissections and 5. 7% had nodal metastases. Table 2 summarizes the distribution of tumors by clinical stage and the relative incidence of lymphatic metastases within each stage. Of the 15 patients with stage A tumors only 1 had occult nodal metastases for an incidence of 6. 7%. Only 1 of 105 patients with stage Bl lesions (less than 1%) harbored lymphatic metastases, compared to 6 of 90 (6.7%) with stage B2 lesions. Finally, 5 of 19 patients (26.3%) with clinical stage C lesions had occult metastases after pelvic lymph node dissection. Table 3 summarizes the comparison of node negative to node positive patients with regards to Gleason score, preoperative PSA value, number of nodes dissected and extent of primary tumor. Patients with nodal metastases tended to have higher mean Gleason scores and monoclonal PSA values but considerable overlap occurs for the ranges of scores and value for the 2 groups. The mean number of lymph nodes dissected in each group is virtually identical, 8.9 versus 8.1 for node positive and negative cancer patients, respectively. The primary tumor was confined to the capsule in 56% of the patients without evidence of lymph node metastases but only 2 of 10 with nodal metastases who underwent prostatectomy.

We then examined our data in an attempt to define objective parameters that might better predict for malignant nodes. Table 4 summarizes the sensitivity, specificity and positive predictive value for Gleason scores of 7 or more, PSA levels of more than 15 ng./ml. and more than 40 ng./ml., and combinations thereof. A Gleason score of 7 or more correlated with a sensitivity of 69%, specificity 64 % and positive predictive value 10%. A monoclonal PSA value of more than 15 ng./ml. correlated with a sensitivity and specificity of 77% and a positive predictive value of 18%, whereas a value of more than 40 ng./ ml. correlated with a sensitivity of 62%, specificity 96% and positive predictive value 53%. The combination of a Gleason score of 7 or more and a PSA level of more than 15 ng./ml. reduced sensitivity to 54%, and correlated with a specificity of 90% and positive predictive value of 26%. Finally, the combination of a Gleason score of 7 or more and a PSA level of more than 40 ng./ml. increased positive predictive value to 60% and specificity to 98% but decreased sensitivity to 46%. The prognostic significance of clinical stage alone and in conjunction with other parameters with regard to occult lymphatic metastases was also reviewed. The 19 patients treated by neoadjuvant androgen deprivation were judged to have clinical stage C lesions and the incidence of nodal metastases in this population was 26.3%. Table 5 demonstrates the distribution of PSA values and Gleason scores for the 6 patients with clinical stage B2 lesions who had lymph node metastases. Pertaining to histological grade, 3 of 6 men had a Gleason score of 7 or more. Only 2 of the 6 patients had a PSA value of less than 15 ng./ml. by the monoclonal assay and 1 of these patients was from the salvage prostatectomy group. Overall, there were 26 patients with clinical stage B2 tumors and a PSA value of more than 15 ng./ml. Therefore, the positive predictive value for lymphatic metastases for this combination of parameters was 15%. DISCUSSION

Previous large series have cited an incidence of pelvic lymph node metastases of 20 to 24 %.1• 3- 5 Our own experience with radical prostatectomy from 1972 to 1988 demonstrated an incidence of pelvic lymph node metastases of 20% (table 6). This figure represents the minimum rate of metastases for that period, since it excludes patients whose prostatectomy was not completed because grossly positive nodes were identified. Our present experience reflects a sharp reduction in the incidence of nodal metastases, since only 3.4% of the patients with clinically localized disease and no prior therapy had positive nodes. It is unlikely that this is explainable on the basis of patient selection in the last 3 years, since almost as many patients were surgically treated during this period as during the previous 17 years and criteria for radical prostatectomy have not changed. Moreover, Petros and Catalona recently reported remarkably similar data from the Washington University radical prostatectomy experience. 6 They detected an overall incidence of nodal metastases of 6.7% for patients with clinically localized disease. In a striking parallel to our data, their incidence of nodal metastases decreased from 20 to 4.3% for patients treated earlier in their experience versus later. A more extensive pelvic lymph node dissection will increase

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DANELLA AND ASSOCIATES

the detection rate of nodal metastases slightly, as demonstrated by Golimbu et al.7 However, most urological surgeons accept the modified technique as capable of identifying most patients with nodal metastases while minimizing complications, such as lymphedema. 8 This dissection also appears to be the standard as described by laparoscopic surgeons. 9 The ubiquitous clinical practice of screening patients for prostate cancer by measuring serum PSA along with transrectal ultrasound to guide needle biopsies has undoubtedly increased the detection rate for prostatic cancer over digital rectal examination alone. Chodak et al reported a detection rate of 1.5% for patients screened with digital rectal examination and digitally guided needle biopsy .1° Cooner detected prostate cancer in 14.5% of 2,648 patients examined with digital rectal examination, PSA and transrectal ultrasound.11 Results from additional iarge screening studies will determine whether the percentage of radical prostatectomy specimens with capsule confined tumors has increased due to better detection methods. If we are intervening ear lier in the natural history of these tumors, as we suspect, then the incidence of nodal metastases in contemporary radical prostatectomy series will remain low. Since less than 4% of the patients who are believed to have clinically localized disease are found to have unsuspected nodal metastases, the vast majority would not benefit from laparoscopic lymphadenectomy. We attempted to define a subset of patients who might benefit from this procedure by virtue of having nodal metastases. McNeal et al identified 3.2 cc of Gleason histological pattern 4 or 5 as a volume of tumor that was highly predictive for lymph node metastases. 12 We examined the subset of patients with a Gleason score of 7 or more to evaluate this marker as a predictor for nodal metastases, since this score by definition requires at least some Gleason pattern 4. Unfortunately, the positive predictive value of this parameter was only 10%, which we believe is too low to recommend routine laparoscopic lymphadenectomy. The impact of clinical stage upon the advisability of performing laparoscopic dissection to detect unsuspected nodal metastases was also examined. The 19 patients treated with neoadjuvant androgen deprivation presented with clinical stage C lesions. The incidence of nodal metastases in this select group was 26.3%, confirming the previously reported significant risk of lymphatic metastases in patients with advanced local lesions.1· 3Whether routine laparoscopic pelvic lymphadenectomy should be advocated for these patients is predicated upon one's treatment philosophy regarding stage C lesions. Long-term followup of radical prostatectomy patients at our institution has demonstrated that capsule and seminal vesicle involvement by tumor significantly affects clinical progression and PSAfree survival despite the absence of nodal involvement. 13 We are cautious not to overemphasize the prognostic significance of other clinical stages. Since many of the patients had undergone biopsy before referral to our institution for definitive therapy, the digital rectal examination may have been influenced by biopsy artifact. In addition, distinguishing stage Bl from stage B2 lesions is subject to examiner bias. Nonetheless, of the 6 patients with stage B2 lesions who eventually had nodal metastases only 2 had a serum PSA level of less than 15 ng./ml. and 1 of these was from the salvage prostatectomy group. For the entire series 26 patients had clinical stage B2 lesions and a PSA level of more than 15 ng./ml. and 4 had pathological stage Dl disease for an incidence of 15.4%. Because the corresponding positive predictive value of the combination of stage B2 and PSA level of more than 15 ng./ml. (15%) does not exceed the positive predictive value of a PSA level of more than 15 ng./ml. (18%) as an isolated parameter, clinical staging would not appear to influence the decision to perform laparoscopic pelvic lymphadenectomy in patients with clinically organ confined tumors. Many investigators have examined the relationship between levels of PSA and the incidence of nodal metastases. Greskovich

et al noted that no monoclonal assay level of PSA consistently predicted the absence of nodal disease. 14 Indeed, in our series 2 of the 13 patients with lymphatic metastases had preoperative PSA levels of less than 10 ng./ml. Oesterling et al determined that a monoclonal PSA level of 16 ng./ml. or more correlated with a sensitivity of 47% and specificity of 90% for predicting lymphatic metastases. 15 In our present experience a PSA level of more than 15 ng./ml. correlated with a sensitivity and specificity of 77%, and a positive predictive value of 18%. However, a PSA level of more than 40 ng./ml. predicted for malignant nodes in more than 50% of the patients, and had a high specificity (96%) and reasonable sensitivity (62%). If a PSA level of more than 15 ng./ml. rather than 40 ng./ml. had been used as an indication for laparoscopic lymphadenectomy in our patients, an additional 40 procedures would have been required to identify 2 additional patients with nodal metastases. Furthermore, a level of 40 ng./ml. would have identified all 3 patients with grossly involved lymph nodes in whom prostatectomy was not performed. Combinations of a Gleason score of 7 or more and a PSA level of more than 15 or more than 40 ng./ ml. did not improve positive predictive value significantly over the PSA levels alone in our patients. In conclusion, the incidence of pelvic lymph node metastases in prostate cancer has decreased significantly, probably as a result of improved cancer detection techniques allowing for intervention earlier in the natural history of the disease. Only additional experience with surgical staging will allow us to define better parameters that facilitate identification of patients likely to benefit from laparoscopic lymphadenectomy. However, routine laparoscopic node dissection appears unnecessary except in patients with PSA values of more than 40 ng./ ml. and perhaps in those with a Gleason score of 7 or more in conjunction with a PSA level of more than 15 ng./ml. The same rationale can be applied to the indications for lymph node dissection (open or laparoscopic) before radical perinea! prostatectomy. REFERENCES 1. Gervasi, L. A., Mata, J., Easley, J. D., Wilbanks, J. H., Seale-

Hawkins, C., Carlton, C. E., Jr. and Scardino, P. T.: Prognostic significance of lymph nodal metastases in prostate cancer. J. Urol., 142: 332, 1989. 2. Kramer, S. A., Cline, W. A., Jr., Farnham, R., Carson, C. C., Cox, E. B., Hinshaw, W. and Paulson, D. F.: Prognosis of patients with stage Dl prostatic adenocarcinoma. J. Urol., 125: 817, 1981.

3. Donohue, R. E., Mani, J. H., Whitesel, J. A., Mohr, S., Scanavino, D., Augspurger, R.R., Biber, R. J., Fauver, H. E., Wettlaufer, J. N. and Pfister, R. R.: Pelvic lymph node dissection. Guide to patient management in clinically locally confined adenocarcinoma of prostate. Urology, 20: 559, 1982. 4. Smith, J. A., Jr., Seamen, J.P., Gleidman, J.B. and Middleton, R. G.: Pelvic lymph node metastasis from prostatic cancer: influence of tumor grade and stage in 452 consecutive patients. J. Urol., 130: 290, 1983. 5. Fowler, J. E., Jr. and Whitmore, W. F., Jr.: The incidence and extent of pelvic lymph node metastases in apparently localized prostatic cancer. Cancer, 47: 2941, 1981. 6. Petros, J. A. and Catalona, W. J.: Lower incidence of unsuspected lymph node metastases in 521 consecutive patients with clinically localized prostate cancer. J. Urol., 147: 1574, 1992. 7. Golimbu, M., Morales, P., Al-Askari, S. and Brown, J.: Extended pelvic lymphadenectomy for prostate cancer. J. Urol., 121: 617, 1979.

8. Paulson, D. F.: Management of prostatic malignancy. In: Genitourinary Cancer Management. Edited by J. B. deKernion and D. F. Paulson. Philadelphia: Lea & Febiger, pp. 107-160, 1987. 9. Winfield, H. N., Donovan, J. F., See, W. A., Loening, S. A. and Williams, R. D.: Urological laparoscopic surgery. J. Urol., 146: 941, 1991. 10. Chodak, G. W., Keller, P. and Schoenberg, H. W.: Assessment of

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Stephenson, R. A.: Prostate specific antigen in patients with clinical stage C prostate cancer: relation to lymph node status and grade. J. Urol., 145: 798, 1991. 15. Oesterling, J. E., Chan, D. W., Epstein, J. I., Kimball, A. W., Jr., Bruzek, D. J., Rock, R. C., Brendler, C. B. and Walsh, P. C.: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J. Urol., 139: 766, 1988.