Outcome of Regional Lymph Node Dissection in Conjunction with Laparoscopic Nephroureterectomy for Urothelial Carcinoma of the Upper Urinary Tract

Abstract

Objective:

To obtain accurate disease staging, we routinely perform regional lymph node dissection (LND) in conjunction with laparoscopic nephroureterectomy (NU) to treat urothelial carcinoma of the upper urinary tract. The present study evaluated the feasibility and usefulness of LND in laparoscopic NU.

Patients and Methods:

Thirty-nine patients undergoing laparoscopic NU with regional LND were included in the present study. We evaluated the number of lymph nodes (LNs) resected, pathological node status, adverse events, and survival data. Node count was compared with that of 41 patients who underwent open NU between 1990 and 2008.

Results:

The median number of LNs removed was 10 (range, 2–59) in the laparoscopic NU group and 10 (range, 1–65) in the open NU group (Mann–Whitney U-test, p = 0.82). Pathological examination demonstrated positive LNs in four patients (10.3%) and three of the four patients received adjuvant chemotherapy. Although chylous drain discharge was detected just after resuming dietary intake in eight patients, it resolved without significant problem. Five-year overall survival by stage was 100% for pT2≥ disease, 55% for pT3 disease, and 0% for pT4 disease.

Conclusions:

LND can be performed safely and effectively during laparoscopic nephroureterectmy. We consider that accurate node staging and subsequent stratification are mandatory for disease management.

Introduction

S ince the initial description in 1991 by Clayman et al,¹ laparoscopic nephroureterectomy (NU) has become an accepted alternative to open NU for urothelial carcinoma (UC) of the upper urinary tract (UUT) with decreased perioperative morbidity and shortened convalescence. In addition, data on midterm oncologic outcomes have been accumulating and are comparable to those of open NU.^2

–5 In the treatment of UC of the UUT, the role of lymph node dissection (LND) remains debatable. To date, there have not been sufficient results to conclude whether regional LND should be simultaneously performed with NU. In this situation, surgeons might be more reluctant to perform LND in laparoscopic NU because of its technical difficulty. At present, there are sparse data on regional LND in laparoscopic NU.^6
–8

Since 2000, we have been performing laparoscopic NU in our hospital. Focusing on accurate disease staging as well as potential therapeutic benefit, we have been actively performing LND in conjunction with laparoscopic NU as well as open NU. The present study investigated the feasibility and usefulness of LND in laparoscopic NU.

Patients and Methods

After obtaining Institutional Review Board approval, the medical records of 89 patients who underwent NU for UC of the UUT at Hokkaido University Hospital between 1990 and 2009 were reviewed. Of these patients, 45 patients underwent laparoscopic NU. Excluding 5 patients who did not undergo LND and the one who was converted to an open procedure because of severe adhesion, 39 patients underwent laparoscopic NU with regional LND. Regarding the indication for laparoscopic NU, we currently select the laparoscopic approach in patients without apparent lymph node (LN) swelling, severe hydronephrosis, or perirenal/periureteral invasion. We do not consider the location of the tumor when selecting the approach. Open approach is currently selected for advanced cases such as patients requiring neoadjuvant chemotherapy for node swelling.

Laparoscopic NU was performed by a retroperitoneal approach combined with a Pfannenstiel or Gibson incision for specimen removal and open bladder cuff excision. After performing NU, LND was performed laparoscopically in patients with renal pelvic tumor, or endopelvic LND was performed through Gibson incision in those with lower ureteral tumor. Regarding the extent of LND, we established general guidelines for LND according to tumor location early in the study period. According to these guidelines, patients with renal pelvis or upper ureter tumor (above the crossing of the common iliac artery) underwent renal hilar, paracaval, retrocaval plus interaortocaval LND (right-sided), or renal hilar plus para-aortic LND (left-sided) laparoscopically, whereas patients with lower ureteral tumor underwent ipsilateral obturator, common iliac, external iliac plus internal iliac LND through Gibson incision. Regarding the upper and lower limits of laparoscopoic LND in the renal pelvis or upper ureter tumor, the LNs between the region 1–2 cm above the renal hilus and the level of aortic bifurcation were removed, taking care to prevent injury to the adrenal gland or inferior mesenteric artery. In case of right renal pelvic tumor, we transected several lumbar veins after the placement of Hemolock clips and retrocaval/interaortocaval LND was performed by lifting the vena cava. Regarding the management of lymphatic vessels, Endoclips or Hemolock clips were used for large vessels, and bipolar coagulation was performed for small vessels. All tumors were graded according to the WHO grading for UC and staged by different pathologists according to the TNM classification (TNM 1997).^9,10

In the current study, we reviewed the data on LND, pathology, postoperative events, and patient survival. As for the number of LNDs removed, we compared this number with that of 41 patients who underwent open NU plus LND between 1990 and 2008. χ ²-test or Mann–Whitney U-test were used to compare groups. Overall survival rate was evaluated by the Kaplan–Meier method. All statistical calculations were performed using JMP^® version 6.03. p-values <0.05 were considered significant.

Results

The left column of Table 1 shows the characteristics of patients undergoing laparoscopic NU. The median patient age was 72 years (range, 41–93). A large proportion of patients had disease in the renal pelvis. The median follow-up time was 30 months (range, 5–111). One patient with apparent node swelling was treated by the laparoscopic approach. The median surgical duration was 353 minutes (range, 135–470). The median blood loss was 350 mL (range, 20–1000), and one patient required blood transfusion. There were no intraoperative complications in this series. Figure 1 shows intraoperative photographs during laparoscopic LND. The right column of Table 1 shows the characteristics of 41 patients undergoing open NU. There were significant differences in follow-up time, tumor location, clinical node stage, and blood loss between the two groups.

FIG. 1.

Intraoperative photographs during lymph node dissection. (a–c) A case of right renal pelvic tumor. Retrocaval and interaortocaval lymph node dissection was performed by lifting the vena cava after transecting several lumbar veins. (d) Para aortic lymph node dissection in a case of left pelvic tumor. VC = vena cava; LV = lumbar vein; RRA = right renal artery; RRV = right renal vein; LNs = lymph nodes; Ao = aorta; LRA = left renal artery; LND = lymph node dissection.

Table 1.

Patients' Characteristics

	Laparoscopic nephroureterectomy, n = 39	Open nephroureterectomy, n = 41	p-Value
Age, years	Median 72 (range, 41–93)	Median 69 (range, 52–82)	0.2783
Sex
Male	28 (72%)	26 (63%)	0.4238
Female	11 (28%)	15 (37%)
Side
Right	16 (41%)	21 (51%)	0.3607
Left	23 (59%)	20 (49%)
Follow-up time, months	Median 30 (range, 5–111)	Median 48 (range, 1–232)	0.0389
Location of tumor
Renal pelvis	33 (85%)	19 (46%)	0.0016
Ureter	5 (13%)	18 (44%)
Renal pelvis+ureter	1 (2%)	4 (10%)
Clinical node stage
cN0	38 (97%)	31 (76%)	0.0024
cN+	1 (3%)	10 (24%)
Surgical duration, minutes	Median 353 (range, 135–470)	Median 334 (range, 155–490)	0.7727
Blood loss, mL	Median 350 (range, 20–1000)	Median 450 (range, 0–2300)	0.0097
Pathology
Low grade (G1, G2)	23 (59%)	22 (54%)	0.6319
High grade (G3)	16 (41%)	19 (46%)
pTa + pTis	11 (28%)	5 (12%)	0.0717
pTI	4 (10%)	12 (29%)
pT2	6 (15%)	5 (12%)
pT3	16 (41%)	13 (32%)
pT4	2 (5%)	6 (15%)
pN0	35 (90%)	30 (73%)	0.0577
pN+	4 (10%)	11 (27%)

Table 2 shows a summary of LND in conjunction with laparoscopic NU. The median number of LNs removed was 10 (range, 2–59). When comparing this number with that of open surgery, the result was almost the same (open group; median 10, range 1–65. Mann–Whitney U-test, p = 0.82). Pathological examination demonstrated positive LNs in four patients as shown in Table 1 (4/39, 10.3%). All four patients had pT3≤ disease and three of them received adjuvant chemotherapy. After surgery, chylous drain discharge was detected just after the start of dietary intake in eight patients (right renal pelvic tumor; n = 3, left renal pelvic tumor; n = 5). However, it resolved spontaneously.

Table 2.

Summary of Lymph Node Dissection

Extent of LND	n	No. of LNs resected
Right side
Hilar+paracaval+retrocaval+interaortocaval	7	Median 12 (range, 3–17)
Hilar+paracaval	3	Median 7 (range, 3–18)
Hilar	2	9
Others	4	Median 9.5 (range, 4–11)
Leftside
Hilar+para aorta	19	Median 11 (range, 2–59)
Hilar	2	Median 4 (range, 3–5)
Others	2	Median 16.5 (range, 16–17)
	Total = 39	Median 10 (range, 2–59)

LN = lymph node; LND = lymph node dissection.

Figure 2a shows the overall survival curve in patients undergoing laparoscopic NU. Overall survival was 84% and 74% at 2 and 5 years, respectively. In the open group, overall survival was 77% and 60% at 2 and 5 years, and there was not a significant difference in survival between the two groups (log-rank test, p = 0.1816). In the laparoscopic group, the 5-year overall survival by stage was 100% for pT2≥ disease, 55% for pT3 disease, and 0% for pT4 disease (Fig. 2b).

FIG. 2.

(a) Kaplan–Meier overall survival curve for patients undergoing laparoscopic nephroureterectomy. (b) Kaplan–Meier overall survival curves divided by pT stage.

Discussion

There are some retrospective studies supporting the survival benefit of LND during resection of UC of the UUT.^11

–16 Brausi et al¹¹ demonstrated that disease-free survival and cancer-specific survival were significantly higher in patients who underwent retroperitoneal LND in conjunction with NU than in patients who did not undergo LND. Roscigno et al¹² reported that the actuarial 5-year cancer-specific survival in pN0 patients was significantly better than that in pNx patients (73% vs. 48%, p = 0.001). Our group also reported a significant difference in cancer-specific survival as well as recurrence-free survival between pN0 and pNx patients, indicating a possibility that eliminating micrometastasis by LND promotes better survival in the pN0 group.^13,14 In consideration of these findings and to obtain accurate disease staging, we have been actively performing LND in conjunction with laparoscopic NU as well as open NU.

Regarding LND in laparoscopic NU, we found three previous studies. Klingler et al⁶ reported that they performed lymphadenectomy in 74% (14/19) of the laparoscopic group, removing a mean of 8.7 LNs (range, 5–11). Busby et al⁷ reported a median of six LNs resected in the laparoscopic NU group and three in the open NU group, and laparoscopic LND had been performed well. Hattori et al⁸ also reported an average of 11.6 LNs for laparoscopic NU group. In the present study, a median of 10 LNs was removed (range, 2–59). Based mainly on open NU cohorts, Kondo et al¹⁶ previously reported that a median of seven LNs was in the complete LND group. Roscigno et al¹⁷ recently reported a study regarding the minimal number of LNs needed to detect LN metastasis and demonstrated that eight LNs need to be removed at radical NU to achieve a 75% probability of finding ≥1 positive nodes. Taking these findings together, we consider that a median of 10 LNs in our series is acceptable and further supports the feasibility of laparoscopic LND.

In the present study, we did not observe any severe adverse events associated with LND. Although chylous drain discharge was detected just after dietary intake was resumed, in eight patients, it resolved spontaneously without significant problem. Completing the LND usually required an additional 0.5–1 hour, although the exact time was not recorded in every case. Actually, the overall surgical duration in our series was longer than that of other series,^2

–5 and we must make a continuing effort to shorten the surgical duration. However, at present, we consider that the benefit of LND overcomes these minor disadvantages. Imaging studies, cytology, and/or biopsy findings cannot reliably identify patients with node metastasis preoperatively. In the present study, node disease was confirmed in 10.3% of patients. As shown in Figure 2, survival outcome in this series was relatively favorable compared with that of previous studies.^2
–4 We consider that accurate node staging and subsequent stratification might produce a positive impact on the final outcome.

To date, information about the appropriate extent of LND for UC of the UUT has been very limited. Historically, in a study of renal lymphatic-drainage of stillborn fetuses, Parker and coworkers¹⁸ reported that the right kidney drained to the precaval, retrocaval, and interaortocaval LNs, whereas the left drained to the paraaortic, preaortic, and retroaortic LNs. Kondo et al¹⁹ recently reported very important findings that the retrocaval LNs were an important primary site of metastasis for tumor in the right renal pelvis and upper two-thirds of the right ureter, and the interaortocaval LNs were primary sites for tumors in the upper two-thirds of the right ureter. Based on these observations, we established a rule regarding the extent of LND. As described in the Patients and Methods section, interaortocaval LND can be performed by lifting the vena cava after transecting several lumbar veins. We suppose that laparoscopic LND can be performed safely and effectively using Hemolock clips, Endoclips, bipolar coagulation device, or vessel sealing device. Recently, we have started a multi-institutional prospective clinical trial to determine appropriate areas of LND according to the location of primary tumors.

Very recently, we reported node disease prevalence (the incidence of node disease at surgery plus node relapse after surgery in pN0/pNx patients) in UC of the UUT based on follow-up data from 293 patients. Our findings were 1.9% for pTa+pTis disease, 4.5% for pT1 disease, 8.9% for pT2 disease, 28.7% for pT3 disease, and 70.1% for pT4 disease.¹⁴ Miyao et al²⁰ reported that the distribution of LN metastasis in UC of the UUT was 0% (0/9) for pTa disease, 13.3% (2/15) for pT1 disease, 14.3% (2/14) for pT2 disease, 20% (5/25) for pT3 disease, and 60% (3/5) for pT4 disease. Taking these findings together, we suppose that it would be safe to perform LND in patients with pT1 or greater UC of the UUT to diagnose the node stage accurately. However, a major problem is that it is not easy to determine the tumor depth preoperatively in patients with UC of the UUT. It is sometimes difficult to distinguish Ta disease from T1 disease before surgery. Therefore, at present, we routinely perform LND without risk stratification.

A limitation of our study is its retrospective nature. Further, the number of patients is small and standardized LND was not performed in some cases. However, our study demonstrates that LND during laparoscopic NU can be performed effectively and safely.

Conclusion

LND during laparoscopic NU can be performed effectively and safely. We consider accurate node staging mandatory for determining the optimal postoperative management.

Footnotes

Disclosure Statement

No competing financial interests exist related to this article.

Abbreviations Used

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