Role of lymph node dissection in the management of upper tract urothelial carcinomas: a meta-analysis

Urothelial carcinomas are the fourth most common tumors [1]. However, upper tract urothelial carcinomas (UTUC) are comparatively uncommon compared to bladder cancer and occupy only 5–10% of urothelial carcinomas [2, 3]. Approximately 30% of patients suffered from muscle-invasive UTUC at presentation and the incidence of lymph node metastasis ranges from 30% to 40% at surgery [4, 5].

Radical nephroureterectomy (RNU) with bladder cuff resection and regional lymph node dissection (LND) is the backbone of management [3, 6, 7]. Generalizing results from previous bladder cancer researches [8‐13], it seems reasonable to believe that LND in conjunction with RNU may provide not only utile staging and prognostic information but also a therapeutic benefit in selected patients with UTUC. Nevertheless, the therapeutic benefit of LND in improving survival remains controversial [14‐16].

For these reasons, we systematically reviewed the published studies and performed a meta-analysis of studies in which data were reported for the treatment of LND to assess whether patients who achieved LND had improved cancer-specific survival (CSS) or recurrence-free survival (RFS) compared with patients who did not achieve LND, as a means for providing data for standardizing the indication of LND and assisting in creating a better management strategy for UTUC.

Radical cystectomy with pelvic LND for muscle-invasive bladder cancer is relatively standardized because it improves tumor staging and survival of patients [32, 33]. However, potential benefit of LND during RNU on survival for UTUC is still controversial [15, 30]. On the basis of the latest European guidelines on UTUC, LND should be performed in conjunction with RNU not only for better tumor staging but also for prognosis improvement [3]. Nevertheless, this recommendation is only Level III evidence. Thus, we reviewed the published studies and conducted a meta-analysis to clarify the prognostic value of LND in patients with UTUC.

In the present research, 11 studies were eligible and the HRs of cumulative survival rates were summarized quantitatively. Our analysis revealed that pN+ patients had significantly worse prognosis when compared to pN0 patients. The same results were observed when restricting the analyses to patients with muscle-invasive carcinomas, who should, anyway, be systematically considered for staging LND in light of this growing body of data.

However, no difference was found in survival or disease recurrence when comparing pN0/pNx individuals and the LND/NLND groups. The sample size of the included studies could explain these results. Most of the early years studies include small numbers of patients (less than 200), while larger series (more than 1000) with more events only emerged recently. Besides, the decision to perform LND was left to the discretion of the surgeon, it is possible that those NLND patients had less aggressive disease than LND patients, and that a true benefit to LND does exist. An increased risk of cancer-related death is usually related to higher tumor stage and grade. In this comparison, there was no significant difference in CSS and RFS between the LND group and the NLND group, which may reversely suggest the possible therapeutic value of LND for patients with more aggressive tumors. Nevertheless, the results remained no significant difference when controlling for tumor stage. Conversely, in a review by Kondo and Tanabe [34], it was highlighted that when the regional nodes were completely dissected, the patients with the advanced stage had significantly higher survival compared with those without LND.

Interestingly, pNx was not associated with poor CSS and RFS in patients with muscle-invasive carcinomas and in overall population. Several explanations may account for our results. First, pNx individuals were most likely identified by their surgeons as low risk for nodal metastases. It is also possible that pNx individuals may harbor micrometastatic lymph node deposits, which could be either destroyed or removed during the surgery, without being identified as pN1 by the pathologist. Furthermore, the lack of standardized anatomical limits and indication for the LND could account for our results: some patients certainly had very limited dissection and unsuitable for tumor location, leading to a wrong histological report of pN0 stage even though they had nodal metastasis not including in the LND.

It is noteworthy that 49.0% RNU patients were staged as pNx in our studies. In 2009, Roscigno et al. pointed out that patients with pN0 disease had a better prognosis than pNx disease in patients with muscle-invasive carcinomas [28]. It is conceivable that, despite a higher pNx rate at tertiary care centers, the extent of LND in those in whom it was performed was substantially greater than the LND extent in the community. Under this premise, a more important stage migration towards true pN0 status may have occurred at tertiary care centers than in the current population-based series [14]. Taken together, our findings suggest that pNx individuals have no better prognosis than pN0 individuals.

Without standardized criteria for who should receive LND and how extensive LND should be, comparisons between series proved to be challenging. It was reported that the patients with incomplete LND in showed lower survival than those with complete LND, which reached statistical significance. Five-year CSS in the patients with pT2 or higher and pT3 or higher was 77.9% and 73.2% in the patients with complete LND, but just 54.0% and 43.7% in those with incomplete LND and 59.0% and 47.3% in those with NLND [34].

The most important finding of our study is that LND patients had no worse prognosis than NLND patients, especially in those with muscle-invasive carcinomas. According to a recent review, carrying out LND for UTUC is unlikely to be time-consuming and to increase the risk of major complications [34]. Although the current quality of evidence is generally not high, which may lead to biased and uncertain results, it might still suggest that the role of LND in UTUC is of importance, as UTUC is likely to simulate the biological behavior of bladder cancer because of the same histology among the two diseases.

Limitation should also be considered. First, the sources of the publications were limited, thus potentially introducing inevitable publication bias. Second, although 11 eligible studies involving 7516 patients were included in this meta-analysis, most of them were retrospective studies and the sample sizes of some selected studies are small, which might render the results less reliable. Third, marked heterogeneity of studies was seen in pooled-analysis of CSS and RFS. Furthermore, 7 of the 11 included studies provided the extent of LND, but the indication and extent of LND were not standardized. Last but not the least, as the included studies spanned a 10-year interval, the year in which the surgery occurred could be associated with different survival rates due to better imaging, earlier diagnosis and improved peri-operative strategies of care. In the future, the role of LND should be further examined by validating templates of regional lymph nodes, and by prospective studies with larger numbers of patients. Then, we will discuss whether LND can be a standard treatment for UTUC.

LND during RNU allows more accurate staging and prediction of survival, but it remains uncertain whether LND independently improves survival in patients with UTUC. However, standard use of LND should be further investigated in a multi-center, prospective evaluation to obtain a definitive statement regarding this matter.