Clinical Significance of Lymph Node Dissection in Patients with Muscle-Invasive Upper Urinary Tract Transitional Cell Carcinoma Treated with Nephroureterectomy

Radical nephroureterectomy with bladder cuff resection is the standard treatment for patients with transitional cell carcinoma of the upper urinary tract (UUT-TCC). Even after this radical procedure (1, 2), however, UUT-TCC shows high rates of local recurrence and systemic disease, with lymph nodes as the major site of metastases (3-5).

In bladder cancer, extended lymphadenectomy improves both staging and prognosis (6-8). The role of lymphadenectomy in the surgical treatment of UUT-TCC is more difficult to establish, because the disease is relatively rare. Several recent studies have suggested a possibly curative effect of lymph node dissection in the treatment of patients with infiltrative UUT-TCC (9-13).

Nonetheless, lymphadenectomy is not used routinely, for either therapy or staging, especially in clinically N0 UUT-TCC. In this study, we investigated the clinical significance of lymph node dissection (LND) in patients with cN0 muscle-invasive UUT-TCC who underwent nephroureterectomy.

Sixty-three patients (41.4%) underwent LND, with a median number of 6 lymph nodes harvested (range, 1 to 35). Of these 63 patients, 9 patients showed lymph node involvement (14.3%) (Table 1). During follow-up, LR occurred in 29 patients (19.1%), DR in 63 patients (41.4%), and disease-specific death in 55 patients (36.2%). Five-year LR-, DR-free, and disease-specific survival rates were 78.2%, 56.9%, and 66.1%, respectively.

A chi-square test of linear trend showed that when patients were subdivided into three groups, based on median number of lymph nodes harvested (n=0, 0<n<6, n≥6), an increase in the number of lymph nodes harvested was associated with the reduction of LR (χ²_trend=6.755, P=0.009), especially in the T2 subgroup (χ²_trend=4.095, P=0.043). The T3, T4 subgroups showed a linear trend with borderline significance (χ²_trend=3.157, P=0.076). However, the number of lymph nodes harvested and DR (χ²_trend=1.558, P=0.212) were not related (Table 2).

Table 2
Comparisons of locoregional recurrence and disease recurrence according to T stage and number of lymph nodes harvested

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In the survival analysis, T stage had a significant influence on LR-free (P=0.0002), DR-free survival (P=0.0002), and disease-specific survival (P=0.0009), but tumor location, size, multiplicity, grade, and adjuvant chemotherapy did not affect LR-free, DR-free, or disease-specific survival (P>0.05) (Table 3). The N stage (P=0.0251) and LND (P=0.0073) had a significant influence on LR-free survival, but not on DR-free and disease-specific survival (P>0.05) (Table 3). Multivariate Cox proportional hazards models revealed that N stage (P=0.041) and LND (P=0.012) were independently related to LR-free survival (Table 4). Although patients who did not undergo LND had a higher probability of LR than those who did, there was no difference in LR-free, DR-free, and disease-specific survival curves according to the number of lymph nodes harvested (0<n<6 vs. n≥6) (Fig. 1). Patients with pNx tumors showed a poorer LR-free survival curve than those with pN0 tumors (P=0.0074, Fig. 1); however, there was no difference between these two tumor types in the DR-free or disease-specific survival curves (P>0.05).

Fig. 1
Locoregional recurrence-free survival curves according to number of lymph nodes harvested (A) and N stage (B).

NLN, number of lymph nodes harvested.

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Table 3
Survival analysis of locoregional recurrence, disease recurrence, and disease-specific death

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Table 4
Multivariate Cox proportional hazards model for locoregional recurrence

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Regional lymphadenectomy is widely accepted in the management of bladder cancer, because extended lymphadenectomy improves staging and prognosis (6-8). In UUT-TCC, the role of LND is less clear. Although UUT-TCC is histologically similar to bladder cancer, and LND improves staging, data do not yet support a therapeutic benefit from this procedure, and the variability in the lymphatic drainage precludes a standard template for LND. Urologists tend to omit lymphadenectomy at the time of nephroureterectomy if no evidence is found for lymph node involvement by surgical or radiological evaluation. Our study shows, however, that approximately 15% of patients with cN0 muscle-invasive UUT-TCC experience LR.

Komatsu et al. first suggested a therapeutic benefit for lymphadenectomy based on two long-term survivors with lymph node metastases, one of whom received adjuvant chemotherapy and one who did not (10). Park et al. reported a more favorable outcome for patients with UUT-TCC treated with lymphadenectomy, as compared with previous studies, and suggested that this surgical procedure had specifically increased survival (16). However, the therapeutic effect of routine lymphadenectomy for patients with UUT-TCC has not been specifically evaluated.

Although not yet confirmed prospectively, two recent retrospective studies support the therapeutic use of lymphadenectomy, in conjunction with nephroureterectomy, for UUT-TCC. Brausi et al. maintained that retroperitoneal LND (with five or more lymph nodes removed) and T-stage independently influence prognosis. A Japanese study showed that patients who underwent complete lymphadenectomy (with a median of seven lymph nodes removed) had a better prognosis than those who did not, especially among patients with advanced disease (≥pT3) (11). However, our study demonstrated that an increased number of lymph nodes harvested was associated with the reduction of LR, and that LND had a significant influence on LR-free survival, but not on DR-free and disease-specific survival. This is because distant metastasis usually coincides with locoregional spread in UUT-TCC. Miyake et al. showed that lymphadenectomy improves prognosis in patients with no lymph vessel invasion, but not in those with lymph vessel invasion (12). They concluded that patients with lymph vessel invasion have systemic disease, and that these patients should receive aggressive systemic adjuvant therapies rather than regional lymphadenectomy. These observations are consistent, in part, with ours.

Kondo et al. showed that the primary site of lymph node metastasis depends on the primary tumor location and lateral orientation (17). Although this study does not provide a well-defined template for LND that may be generally applied, it does take a significant step toward determining the optimal extent of lymphadenectomy. They recommend that radical lymphadenectomy for right renal pelvic and ureteral tumors should extend to the posterior aspect of the inferior vena cava by transection of the lumbar veins. When the tumors are located at the upper and middle ureter, the dissection should extend further, to the inter-aortocaval nodes. In contrast, lymphadenectomy for tumors of the left renal pelvis and upper two-thirds of the left ureter should extend only to the renal hilum and para-aortic nodes. Clearly, either a hilar or a limited LND will not remove all of the primary lymphatic drainage area of the kidneys or ureters.

It is well known that lymph node involvement is closely associated with T stage and tumor grade (10, 13, 17). Kondo and his colleagues reported that the incidence of lymphatic involvement varied according to stage and grade, with 0%, 5%, 24%, and 84% of Tis-1, T2, T3, and T4 tumors, and 0%, 11%, and 35% of G1, G2, and G3 tumors, respectively, showing such involvement (17). Regional lymphadenectomy might be safely omitted in UUT-TCC patients with low-grade or low-stage tumors at preoperative biopsy or imaging evaluation. However, CT or magnetic resonance imaging prior to surgery may not clearly reveal T1 and T2 disease, and sampling error, particularly with larger tumors, may limit the accuracy in grading. Relevant to this are recent studies showing that laparoscopic procedures for radical nephrouterectomy may facilitate patient recovery, with disease control comparable to that of traditional open surgery. But although oncological outcomes for the two procedures compare favorably, questions remain concerning lymphadenectomy, especially if radical in extent, because laparoscopic retroperitoneal LND in conjunction with nephroureterectomy presents a technical challenge (18-20). Typically, the use, extent, and pattern of LND in UUT-TCC have been left to the surgeon's discretion, and for this reason, a large number of patients with UUT-TCC has rarely, if ever, received lymphadenectomy in the same clinical setting (13). From this point of view, prospective randomized studies are needed to define the indications, most effective techniques, and optimal anatomical range for lymphadenectomy.

In conclusion, we found that approximately 15% of patients with cN0 muscle-invasive UUT-TCC who received LND showed lymph node involvement on pathologic examination. Our results suggest that LND can improve the control of locoregional cancer, as well as staging accuracy, but that LND does not clearly influence survival in patients with this disease.