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 prognostic indicators, 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 from 15624 MIBC patients 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 those 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. Several studies have shown that reasonable PLND is helpful to determine the pathological stage, guide follow-up treatment, and improve patient prognosis [5, 17, 18]. The survival prognosis of extended lymphadenectomy is better than that of standard lymphadenectomy . According to our results, LN+ is higher in young patients than in elderly patients; thus, extended lymphadenectomy should be performed to remove distant metastatic lymph nodes and reduce the risk of relapse. Moreover, micrometastatic lesions can be removed in this procedure, improving the cure rate . However, 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 . A recent randomized phase 3 trial also showed that extended lymphadenectomy did not have definite survival benefits to patients, compared with standard lymphadenectomy . 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 [22-26]. This refutes the hypothesis that the benefits associated with PLND are consistent across ages and comorbidities. 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 . 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 physique is generally weaker, lymph node involvement should be actively evaluated before operation. If there is no evidence of lymph node metastasis before operation, standard lymph node dissection should be performed to minimize the time of operation and anesthesia, thus reducing the possibility of cardiac and pulmonary complications. In young patients, LN+ is high, the general condition is better, and the benefit of expanded lymph node dissection may be greater.
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 radical resection of bladder cancer [29-31]. However, TMT is not recommended when patients show high-risk features, such as LN+ [28, 32]. 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, so as to avoid missed diagnosis of lymph node involvement and wrong treatment.
According to the guidelines of the European Association of Urology, patients with MIBC can be treated with neoadjuvant chemotherapy (NAC), followed by surgery . Large observational studies by Galsky et al. have shown that NAC can significantly improve the overall survival of patients with bladder cancer with LN+ . However, the role of NAC in patients with stage T2 bladder cancer is still controversial. In a study involving 1057 patients with cT2-4N0M0 bladder cancer, patients with stage cT3-T4N0M0 benefited more from NAC, whereas patients with stage T2N0M0 did not benefit as much . According to the results of this study, LN+ is low in elderly patients, and there are more complications in the elderly; hence, they are less likely to tolerate chemotherapy . Therefore, for patients with stage T2 bladder cancer undergoing NAC, it is important to carefully evaluate the lymph node status, so as to prevent inappropriate NAC in patients without lymph node metastasis and avoid chemotherapy toxicity and delay of operation .
Several limitations of our study should be noted. First, this study is limited by its long term and retrospective nature. The way patients receive surgery is 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.
In conclusion, our analysis of data in the SEER database showed that after considering other predictive factors, there is an increased risk of LN+ in young MIBC patients. Considering the different lymph node invasiveness in patients of different ages, our results can guide clinicians to choose the best treatment; more active treatment strategies can be considered in young patients to improve prognosis, and overtreatment should be avoided in elderly patients. Our findings are worthy of further study and may influence the assessment of lymph node invasiveness in patients with MIBC.