Tumor stage and grade are associated with the risk of lymph node metastasis in MIBC [10, 11]. However, it is not ideal to use staging and grading alone to predict lymph node metastasis. The addition of other important prediction factors, such as age, may improve the risk stratification of patients, and more active, multi-modal treatment may be selected for high-risk patients, thus improving the prognosis. No study has explored the predictive effect of age on LN+ in patients with MIBC. In the current study, we analyzed data of 15624 patients with MIBC extracted from the SEER database. We found that young patients had a higher tendency for LN+ at any T stage. This finding was validated in multivariate analysis including sex, race, grade, LNE, and year of operation. This is consistent with the results reported by Hellenthal et al. that per 10-year age increase, the odds of LN+ in patients with bladder cancer decreased by approximately 20% .
The effect of age on LN+ may be related to biological differences between young and old patients. Migaldi et al. pointed out that low p27Kip1 expression was not related to the risk of recurrence in young patients, whereas decreased p27Kip1 expression was related to an increased risk of recurrence in older patients . More significantly, high Ki67 expression and low cyclinD1 expression were associated with an increased risk of recurrence in young patients, but not in older patients. Thus, compared with older patients, urothelial carcinoma of the bladder in young patients may involve different molecular pathways. In addition, with increasing age, various changes occur in the body, including in the lymph nodes . Aging leads to a decrease in the cortex and medulla of the lymph nodes and an increase in degeneration into inactive lymph nodes without lymph node tissue, resulting in reduced lymph flow to and retraction of the lymph nodes [15, 16]. This may be one of the important reasons for the effect of age on LN+.
Lymph node dissection is an indispensable part of radical resection of bladder cancer. Reasonable PLND has been proved to be helpful in determining the pathological stage and guiding follow-up treatment . However, it is still controversial whether PLND can improve the prognosis of patients. In a retrospective study, young patients with radical cystectomy and PLND had better all cause and cancer specific survival than those with radical cystectomy alone . Another retrospective study has suggested that the survival prognosis of extended lymphadenectomy group is better than that of standard lymphadenectomy group . However, it is worth noting that extended lymphadenectomy is associated with a great risk of Will Rogers phenomenon and stage migration; therefore, the whole concept is blurred on a scientific level when examining retrospective materials . Choi et al. found that compared with standard lymphadenectomy, super-extended or extended lymphadenectomy may have no significant effect on local recurrence, distant metastasis, disease-specific survival, and overall survival . To date, the only randomized phase III trial showed that PLND provides no improvement in either recurrence-free survival, cancer-specific survival, or overall survival . Therefore, more randomized prospective trials are needed to establish whether patients with radical resection of bladder cancer can benefit from PLND. Moreover, extended lymphadenectomy can increase the time of operation and cause potential bleeding, lymphatic leakage, lymphoceles, autonomic nerve and ureteral injury, and serious nutritional and immune problems after operation, which significantly prolong the risk of postoperative rehabilitation and hospitalization [21-25]. This refutes the hypothesis that the benefits associated with PLND are consistent across ages and comorbidities. Considering the lack of a final conclusion on the scope and benefits of lymph node dissection, based on current research results, in elderly patients, because the probability of LN+ is low and their physical status is generally weaker, lymph node involvement should be actively evaluated before operation. In line with our results, Koppie et al. found that for elderly patients with bladder cancer or with more underlying diseases, LN+ was lower with PLND, and thus, they recommended that PLND or regional lymph node dissection should not be performed in these patients . Another study also pointed out that in older and seriously ill patients, radical cystectomy combined with PLND had no significant clinical benefit compared with radical cystectomy alone . When choosing the specific way of lymph node dissection for the elderly, we should try our best to consider the time of operation and anesthesia, and the possible impact of cardiopulmonary complications on the elderly.
Clinical treatment strategies for patients with MIBC vary according to the status of lymph nodes. Accurate prediction of lymph node metastasis is essential to help doctors make reasonable decisions, especially for patients who need to be evaluated for lymph node status before surgery or do not need PLND. Trimodality therapy (TMT) is an alternative for patients who do not undergo or refuse radical resection of bladder cancer . While preserving bladder function, TMT improves the long-term survival rate and the quality of life similar to those of radical resection of bladder cancer [28-30]. However, TMT is not recommended when patients show high-risk features, such as LN+ [27, 31]. Therefore, for patients who opt for TMT, it is important to carefully evaluate lymph node involvement before operation. Because the survival time of young patients with bladder cancer is longer , and according to our results, young patients are more prone to LN+, a comprehensive and professional evaluation of the lymph node area should be done before deciding on TMT, to avoid missed diagnosis of lymph node involvement and wrong treatment.
Several limitations of our study should be noted. First, this study is limited by its long term and retrospective nature. Surgical treatment was affected by the year of diagnosis and clinical factors. These factors were taken into account in the multivariate analysis. However, the clinical treatment of young patients may be more aggressive than that of older patients, which leads to systematic bias. Second, the SEER database collects data from a large number of patients from the population-based cancer registry, but some data may be miscoded or omitted during the registration process. However, this error coding is random and does not introduce any system bias. Finally, the data are representative only for the population in the SEER area and do not apply to other geographic locations.