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Evaluation of lymph node counts in primary retroperitoneal lymph node dissection
Version of Record online: 3 NOV 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 22, pages 5243–5250, 15 November 2010
How to Cite
Thompson, R. H., Carver, B. S., Bosl, G. J., Bajorin, D., Motzer, R., Feldman, D., Reuter, V. E. and Sheinfeld, J. (2010), Evaluation of lymph node counts in primary retroperitoneal lymph node dissection. Cancer, 116: 5243–5250. doi: 10.1002/cncr.25266
- Issue online: 3 NOV 2010
- Version of Record online: 3 NOV 2010
- Manuscript Accepted: 11 NOV 2009
- Manuscript Revised: 6 NOV 2009
- Manuscript Received: 18 SEP 2009
- lymph nodes;
- lymph node excision;
- neoplasm staging
Lymph node counts are a measure of quality assurance and are associated with prognosis for numerous malignancies. To date, investigations of lymph node counts in testis cancer are lacking.
By using the Memorial Sloan-Kettering Testis Cancer database, the authors identified 255 patients who underwent primary retroperitoneal lymph node dissection (RPLND) for nonseminomatous germ cell tumors (NSGCTs) between 1999 and 2008. Features that were associated with lymph node counts, positive lymph nodes, the number of positive lymph nodes, and the risk of positive contralateral lymph nodes were evaluated with regression models.
The median (interquartile range [IQR]) total lymph node count was 38 lymph nodes (IQR, 27-53 total lymph nodes), and it was 48 (IQR, 34-61 total lymph nodes) during the most recent 5 years. Features that were associated with higher lymph node count on multivariate analysis included high-volume surgeon (P = .034), clinical stage (P = .036), and more recent year of surgery (P < .001); whereas pathologist was not associated significantly with lymph node count (P = .3). Clinical stage (P < .001) and total lymph node count (P = .045) were associated significantly with finding positive lymph nodes on multivariate analysis. The probability of finding positive lymph nodes was 23%, 23%, 31%, and 48% if the total lymph node count was <21, 21 to 40, 41 to 60, and >60, respectively. With a median follow-up of 3 years, all patients remained alive, and 16 patients developed recurrent disease, although no patients developed recurrent disease in the paracaval, interaortocaval, para-aortic, or iliac regions.
The current results suggested that >40 lymph nodes removed at RPLND improve the diagnostic efficacy of the operation. The authors believe that these results will be useful for future trials comparing RPLNDs, especially when assessing the adequacy of lymph node dissection. Cancer 2010. © 2010 American Cancer Society.
Cancer-specific death from clinical stage I or IIA nonseminomatous germ cell tumors (NSGCT) should be the rare exception with proper observation, retroperitoneal lymph node dissection (RPLND), and/or chemotherapy. For patients with clinical stage I or IIA NSGCT, the most likely site of metastatic spread is the retroperitoneum, and up to 90% of patients have disease limited to the retroperitoneum. Thus, a properly performed RPLND has both a diagnostic and therapeutic role and is the preferred treatment modality for patients with high-risk clinical stage I NSGCT and all patients with clinical stage IIA NSGCT at Memorial Sloan-Kettering Cancer Center (MSKCC) in the setting of normal serum tumor markers. However, the potential risks of an uncontrolled retroperitoneum are late relapse,1 need for reoperation,2 salvage chemotherapy, and malignant transformation of unresected teratoma.
Historically, RPLND has been associated with ejaculatory morbidity because of interruption of the sympathetic trunks, hypogastric plexus, and/or postganglionic efferent nerve fibers. In effort to thwart these side effects, multiple modified templates were proposed that limited the contralateral dissection to preserve antegrade ejaculation. However, the oncologic efficacy of template-limited dissection recently was reassessed because of concerns regarding extratemplate disease3, 4; in fact, recent observations suggest that 3% to 23% of patients (depending on the template used) with clinical stage I or IIA NSGCT actually harbor extratemplate disease.4 Moreover, with improved surgical technique using a nerve-sparing approach, there is near uniform preservation of antegrade ejaculation without the need to modify a standard bilateral template.5
More recently, laparoscopic RPLND has been reported as technically feasible and has been associated with improved pain control and shorter convalescence.6-9 However, the number of lymph nodes removed with laparoscopic RPLND (mean, 16 total lymph nodes in a recent meta-analysis)6 seems much lower than our anecdotal experience. In addition, there is a substantial volume of literature demonstrating that lymph node counts have important staging and clinical implications in numerous malignancies10-17; however, a thorough investigation of lymph node counts is lacking for testis cancer. Therefore, this study was undertaken to evaluate contemporary lymph node counts with open RPLND to provide a benchmark for comparison with novel surgical approaches. We also investigated features associated with lymph node counts and analyzed which factors predict for identifying patients with positive lymph nodes.
MATERIALS AND METHODS
After obtaining Institutional Review Board approval, we queried the prospective MSKCC Testis Cancer Registry and identified 273 patients who underwent primary RPLND for NSGCT between the years 1999 and 2008. Eighteen patients who did not have a discernable lymph node count (ie, “multiple benign lymph nodes”) were excluded, leaving 255 patients available for the current analysis. The MSKCC Testis Cancer Registry is maintained prospectively with >100 variables collected and recorded for all patients who undergo RPLND at MSKCC. For this project, charts were reviewed for all patients to ensure that the location and number of lymph nodes recorded in the registry were accurate.
Operative Boundaries and Pathologic Sectioning
For nearly all patients, upper limits of dissection included the skeletonized renal vessels and crus of the diaphragm, whereas lower limits included the external iliac vessels on the ipsilateral side and the bifurcation of the great vessel on the contralateral side. Packets consisting of the paracaval, interaortocaval, para-aortic, and ipsilateral iliac lymph nodes were submitted routinely for pathologic examination. On occasion, interiliac or contralateral iliac lymph nodes were removed and submitted separately. The lymph node packets were received in pathology from the operating room in a fresh state. By using visual inspection, palpation, and blunt dissection with a scalpel blade, the adipose tissue was dissected free; then, all firm, rubbery areas suspicious for a lymph node were separated and submitted for microscopic examination. If no lymph nodes are palpated, then the tissue was submitted for microscopic examination in its entirety.
Clinical and Pathologic Features
The clinical and pathologic features studied included lymph node counts from the paracaval, interaortocaval, and para-aortic regions; total lymph node count; pathologist; surgeon; clinical stage; primary tumor histology; year of surgery; pathologic stage; number of positive lymph nodes; location of positive lymph nodes, and timing and location of relapse. For simplicity and when performed, right iliac lymph nodes were included in the paracaval lymph node region, interiliac lymph nodes were included in the interaortocaval region, and left iliac lymph nodes were included in the para-aortic region. A high-volume surgeon was defined as one who performed >10 primary RPLNDs, and a high-volume pathologist was defined as one who evaluated >10 primary RPLNDs over the study period.
The clinical and pathologic features were summarized and are provided as medians and interquartile ranges (IQR) or as frequencies and percentages, as appropriate. Features potentially associated with higher lymph node counts were evaluated using linear regression models in both univariate and multivariate analyses adjusting for year of surgery, surgeon (dichotomized as high volume vs low volume), clinical stage (stage I vs II), and pathologist (high volume vs low volume). To evaluate features associated with the finding of positive lymph nodes, we performed logistic regression analysis based on the total lymph node count with the model adjusted for features associated with the total lymph node count. In these models, the total lymph node count was treated both as a continuous variable and as a binary variable split at a count of 40 lymph nodes, which seemed appropriate because the mean total lymph node count was 38, and the median total lymph node count was 42. Then, we investigated whether the total lymph node count was associated with the number of positive lymph nodes using linear regression models in univariate analysis and, and after adjusting for features that were associated significantly with the total lymph node count, in multivariate analysis. Next, we used logistic regression models to evaluate whether positive ipsilateral/in-template lymph nodes were associated with positive outside-of-template lymph nodes (defined as positive para-aortic lymph nodes with a right-sided primary tumor or positive interaortocaval or paracaval lymph nodes with a left-sided primary tumor) both in univariate analysis and after adjusting for clinical stage, total number of lymph nodes, side of primary tumor, and year of surgery. Statistical analyses were performed with the Stata software package (version 8.2; Stata Corp., College Station, Tex), all tests were 2-sided, and P values <.05 were considered statistically significant.
A summary of baseline features for the 255 patients studied is detailed in Table 1. The median (IQR) age at RPLND was 30 years (IQR, 23-37 years). The most common primary tumor histology was mixed NSGCT with embryonal predominance, which was noted in 112 patients (44%). Only 26 patients (10%) had clinical stage IA disease, and the remaining patients had stage IB disease (n = 147; 58%) or stage IIA disease (n = 82; 32%). Among the 26 patients who had clinical stage IA NSGCT, 21 patients had either embryonal and/or teratoma features in the primary tumor. Overall, positive lymph nodes were identified in 75 patients, including 56 patients (75%) with viable tumor only, 10 patients (13%) with viable tumor and teratoma, and 9 patients (12%) with teratoma only. Positive lymph nodes were identified in 2 patients (8%) with clinical stage IA NSGCT, in 34 patients (23%) with clinical stage IB NSGCT, and in 39 (48%) patients with clinical stage IIA NSGCT.
|Feature||No. of Patients||%|
|Pure malignant transformation||1||0.4|
|Year of RPLND|
|Pathologic lymph node status|
|Viable GCT (only)||56||22|
|Viable GCT and teratoma||10||4|
A summary of lymph node counts by region is detailed in Table 2. The median (IQR) total lymph node count was 38 (IQR, 27-53 total lymph nodes). In the subset of 129 patients who were treated over the last 5 years (from 2004 through 2008), the median (IQR) total lymph node count increased to 48 (IQR, 34-61 total lymph nodes). Features that were predictive of a higher total lymph node count on univariate and multivariate analyses included year of surgery, surgeon, and clinical stage (Table 3). On average, 2.5 additional lymph nodes were counted with each increasing year during the study time frame, 8.3 additional lymph nodes were counted if a high-volume surgeon performed the RPLND, and 5.3 additional lymph nodes were counted if the clinical stage was IIA versus I. Although high-volume pathologists were significantly more likely to have higher lymph node counts on univariate analysis, after adjusting for year of surgery, surgeon, and clinical stage, the pathologist no longer was associated significantly with higher lymph node counts (P = .3).
|Lymph node count|
|Total lymph node count||38||27-53|
|Coefficient (95% CI)||P||Coefficient (95% CI)||P|
|Year of surgery||3.0 (2.2-2.8)||<.001||2.5 (1.6-3.5)||<.001|
|Surgeon: High volume vs low volume||15.0 (7.0-23.0)||<.001||8.3 (0.6-16.0)||.034|
|Clinical stage: I vs II||5.8 (0.3-11.4)||.027||5.4 (0.4-10.4)||.036|
|Pathologist: High volume vs low volume||9.7 (4.6-14.9)||<.001||2.8 (-2.5-8.1)||.3|
Then, we evaluated the features associated with positive lymph nodes (vs pathologically negative lymph nodes [pN0]) at the time of RPLND. Clinical stage and total lymph node count were significantly associated with positive lymph nodes, as demonstrated in Table 4, whereas year of surgery and surgeon were not. The odds of finding positive lymph nodes were >3 for patients who had clinical stage II NSGCT compared with patients who had clinical stage I NSGCT (P < .001). Each additional lymph node removed was associated with a nearly 2% increase in the odds of finding a positive lymph node (P = .029). In a predetermined analysis of dichotomizing lymph node count, patients who had total lymph node counts >40 had a nearly 2 times increased odds of having positive lymph nodes compared patients who had total lymph node counts ≤40 (odds ratio, 1.9; 95% confidence interval [CI], 1.1-3.3; P = .019). In multivariate analysis, total lymph node count >40 retained a significant association with positive lymph nodes even after adjusting for year of surgery, clinical stage, and surgeon (odds ratio, 2.0; 95% CI, 1.1-3.7; P = .026). Figure 1 demonstrates the frequency of positive lymph nodes by total lymph node count. The chances of finding positive lymph nodes were 23%, 23%, 31%, and 48% in patients who had total lymph node counts of <21, 21 to 40, 41 to 60, and >60, respectively.
|OR (95% CI)||P||OR (95% CI)||P|
|Year of surgery||1.0 (0.9-1.1)||.7||0.9 (0.8-1.0)||.145|
|Surgeon: High volume vs low volume||1.4 (0.6-3.3)||.5||1.3 (0.5-3.5)||.6|
|Clinical stage: I vs II||3.5 (2.0-6.1)||<.001||3.3 (1.8-5.9)||<.001|
|Total lymph node count||1.01 (1.00-1.03)||.029||1.02 (1.00-1.03)||.045|
Next, we evaluated whether the total lymph node count was associated with the absolute number of positive lymph nodes. In total, 75 patients had positive lymph nodes, including 27 with 1 positive lymph node, 20 patients with 2 positive lymph nodes, 11 patients with 3 positive lymph nodes, and 17 patients with >3 positive lymph nodes. One notable patient with clinical stage IB NSGCT had 37 positive nodes among 112 that were counted. In a linear regression model, a higher total lymph node count was associated significantly with a higher number of positive lymph nodes (coefficient, 0.03 for each additional lymph node counted; 95% CI, 0.01-0.05; P = .005 (Fig. 2). A higher total lymph node count retained a significant association with a higher number of positive lymph nodes even after adjusting for year of surgery, surgeon, and clinical stage in multivariate analysis (coefficient, 0.03 for each additional lymph node counted; 95% CI, 0.01-0.05; P = .004).
We also evaluated the features that were predictive of positive lymph nodes outside the surgical template (ie, positive para-aortic lymph nodes with a right-sided primary tumor and positive paracaval or interaortocaval lymph nodes with a left-sided primary tumor). Among the 75 patients who had positive lymph nodes, 39 patients had right-sided primary tumors, and 36 patients had left-sided primary tumors. The number of patients with right-sided and left-sided primary tumors who had positive lymph nodes outside the template was 7 (18%) and 8 (22%), respectively. Among all patients, those with positive in-field lymph nodes were >6 times more likely to have positive contralateral lymph nodes compared with patients who had benign in-field lymph nodes (odds ratio, 6.28; 95% CI, 2.06-19.11; P = .001 (Fig. 2). This association remained significant even after adjusting for clinical stage, total number of lymph nodes, side of primary tumor, and year of surgery (odds ratio, 4.7; 95% CI, 1.5-15.0; P = .009) in multivariate analysis. Among the 15 patients who had contralateral positive lymph nodes, the median total positive lymph node count was 4 (IQR, 3-11 total positive lymph nodes), including 7 patients who had ≤3 total positive lymph nodes. It is noteworthy that 5 patients (2%) had positive lymph nodes outside the template without any positive lymph nodes inside the template.
In general, patients with viable germ cell tumors who with pN1 lymph node status were observed after RPLND, while those with pN2 disease received good-risk chemotherapy in the form of 4 cycles of etoposide and cisplatin.18 At last follow-up, all patients remained alive, and 16 patients relapsed after a median of 3.2 months (range, 1-20 months). The median follow-up for patients who did not relapse was 3.0 years. Most relapses were in the lung (n = 11; 69%), and no patient had a relapse in the paracaval, interaortocaval, para-aortic, or iliac regions. Because of the limited number of relapses and 100% survival at last follow-up, outcome analyses were not performed.
There is a substantial volume of literature demonstrating that the number of lymph nodes removed is paramount for many malignancies, including bladder,10 lung,11 esophageal,12 pancreatic,13 breast,14 gastric,15 and colon cancers.16, 17 Although the mechanisms underlying the association between survival and lymph node count remain unknown for many of these malignancies, it seems intuitive for testicular cancer—a cancer that spreads primarily through lymphatic channels. Thus, when the decision to perform a primary RPLND is made, it is important to maximize both the diagnostic and therapeutic benefits of the operation. This not only will identify patients who may benefit from adjuvant chemotherapy, but it also will serve to prevent over treatment for those who do not need chemotherapy. Young men with early stage testis cancer should expect a near 100% cure and a life expectancy ≥50 years; whereas a suboptimal RPLND risks late relapse,1 need for reoperation,2 salvage chemotherapy, and malignant transformation of unresected teratoma. However, a systematic investigation of normal lymph node counts during primary RPLND is lacking. Herein, we present the first evaluation to our knowledge of normal lymph node counts during primary RPLND at a center that routinely performs a full bilateral dissection.
In this report, we detail our experience with lymph node counts during primary RPLND for patients who were treated at MSKCC over the last decade. The median total lymph node count was 38 over the last 10 years and increased to 48 (mean, 50) during the most recent 5 years. In a recent meta-analysis of 34 contemporary laparoscopic RPLND articles, the mean lymph node count was 16 (among the 3 articles that reported lymph node counts).6 It should be noted, however, that modified templates were used in all of the laparoscopic RPLND reports,6 although more recent laparoscopic RPLND data suggest that a nerve-sparing bilateral template RPLND is technically feasible in experienced hands.19 However, a count of 16 lymph nodes falls far below the value of 40 lymph nodes, which we identified as a significant count in terms of finding positive lymph nodes and properly staging patients. Every effort should be made not only to remove the lymph nodes but also to evaluate them morphologically, because this has important ramifications when selecting adjuvant chemotherapy after primary RPLND.
In this report, we observed that surgeon was associated significantly with lymph node counts. Indeed, the median total lymph node count was 40 for high-volume surgeons compared with 28 for low-volume surgeons. Although this difference may be explained in part by the finding that low-volume surgeons were more likely to perform RPLND earlier in during study period (a feature strongly associated with diminished total lymph node counts), surgeon remained significantly associated with higher lymph node counts on multivariate analysis (including adjustment for year of surgery). We believe that this observation, if validated by others, will serve to set benchmarks not only for surgeons at our institution but also for all surgeons who perform primary RPLND. We also evaluated pathologist, including 39 different pathologists who reviewed primary RPLND slides over the last decade. It is noteworthy that we did not observe a significant difference in total lymph node counts among high-volume and low-volume pathologists in multivariate analysis. We believe that this information demonstrates a relative uniformity among pathologists at a specialized cancer center, and we postulate that this uniformity would apply equally to many academic centers of specialized care.
Our data also suggest that a higher total lymph node count is associated significantly with the finding of more positive lymph nodes. This has important clinical implications, because observation generally is recommended for patients who have pathologic stage IIA NSGCT, whereas chemotherapy is given to patients who have pathologic stage IIB or greater NSGCT (which includes >5 positive lymph nodes).18 In addition, positive lymph nodes on the ipsilateral side of the primary tumor were associated significantly with finding positive contralateral lymph nodes, and 2% of patients harbored positive lymph nodes that were restricted to the contralateral side. Thus, a full bilateral RPLND with nerve sparing maximizes both the diagnostic and therapeutic goals of surgery with the benefit of minimizing ejaculatory morbidity and reducing the need for chemotherapy and its associated long-term sequelae.19, 20
In a recent randomized, controlled trial comparing primary RPLND with chemotherapy in the community setting, Albers et al reported that disease recurrence after RPLND was significantly higher compared with disease recurrence after 1 cycle of bleomycin, etoposide, and cisplatin.21 Among 191 patients who underwent with primary RPLND, 13 recurrences were noted, including 9 in the retroperitoneum or scrotal region.21 It is noteworthy that all recurrences after RPLND occurred within 17 months, and modified templates were used. In contrast, we did not observe a single recurrence in the paracaval, interaortocaval, or para-aortic regions; and only 1 of 255 patients developed recurrences in the inguinal/scrotal region after RPLND with a bilateral nerve-sparing dissection. The results from the trial by Albers et al demonstrate the importance of experienced surgeons if RPLND is used as a treatment option.21 It also should be noted that chemotherapy or observation for stage I NSGCT requires surveillance of the retroperitoneum. Recent evidence suggests that radiation exposure from repeated computerized tomography may increase the risk of secondary malignancies.22-24 In fact, Tarin et al suggest that the relative risk of a secondary malignancy in a surveillance protocol for clinical stage I NSGCT patients is approximately 15 compared with primary RPLND.23 In our practice, patients with pN0 lymph node status receive only 1 scheduled computed tomography scan after primary RPLND assuming their chest x-ray and tumor markers remain normal.
This report is not without limitations. Although the data were collected in a prospective fashion, they were analyzed retrospectively and are subject to the many inherent biases associated with this approach. For example, surgical decisions, such as performing a more extensive dissection if suspicious lymph nodes are identified intraoperatively, cannot be accounted for in the current analysis. In addition, pathologic evaluation of more lymph nodes once positive lymph nodes are identified may have an impact on the results presented. Furthermore, there are limitations to using the lymph node count as a surrogate for oncologic efficacy, and further follow-up with additional events is needed to determine whether the lymph node count is associated with improved outcomes. Nevertheless, as a part of quality assurance, the pathology reports for all 273 patients who we initially identified were reviewed to ensure accuracy regarding the number and location of lymph node counts. Furthermore, although the majority of RPLNDs at our institution were performed by a single surgeon who used similar boundaries of dissection over the entire study period, lymph node counts clearly increased over the last decade. We believe this observation probably reflects an increased emphasis on lymph node counts by all pathologists for many malignancies that occurred during the last 10 years.10-17
One additional point deserves mention. Although chemotherapy has revolutionized the field of testis cancer, providing a cure for many of the most advanced stages, it should be emphasized that chemotherapy is not without long-term adverse consequences. Increased risks of endothelial dysfunction, infertility, pulmonary fibrosis, cardiovascular disease, and secondary malignancies have been reported recently as long-term side effects of chemotherapy for NSGCT.25, 26 A properly performed RPLND can obviate the need for chemotherapy in patients with pathologic stage IIA disease, reduce the need for intense radiographic surveillance, and reduce the risk of malignant transformation from unresected teratoma. For these reasons, we advocate a thorough dissection, including the paracaval, interaortocaval, and para-aortic regions, which, currently, should yield 40 to 50 lymph nodes on average in patients who undergo primary RPLND.
CONFLICT OF INTEREST DISCLOSURES
This research was supported by the Sidney Kimmel Foundation for Urologic Cancer. There were no financial disclosures associated with this project.
- 8Laparoscopic retroperitoneal lymph node dissection combined with adjuvant chemotherapy for pathological stage II disease in nonseminomatous germ cell tumours: a 15-year experience. BJU Int. 2008; 102: 844-848., , , et al.
- 9[Retroperitoneal laparoscopic lymphadenectomy for stage I nonseminomatous testicular cancer.] Arch Esp Urol. 2007; 60: 59-66., , , et al.
- 21Randomized phase III trial comparing retroperitoneal lymph node dissection with 1 course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol. 2008; 26: 2966-2972., , , et al.