Systemic cisplatin-based chemotherapy is regarded as the therapy of choice in metastatic UC. However, the role of adjuvant or neoadjuvant chemotherapy remains under debate [10, 11]. Most urological and oncological guidelines recommend neoadjuvant cisplatin-based chemotherapy as the therapy of choice in locally advanced bladder cancer . Because the description of several rare variants of UC of the bladder in the WHO classification of 2004, descriptions of their clinical course and the molecular features have become more prevalent. However, despite improved knowledge regarding the molecular characteristics of the histologic subtypes of bladder cancer, the impact of these differences on systemic therapies is lacking. Most patients with locally advanced UC are treated without regard to the underlying histology, although it has been reported that tumors with variant histology are associated with a higher risk of progression than conventional high grade UC . As for PUC we could show in the largest series described to date, that on the one hand this subtype of UC accumulates prognostic unfavourable molecular features, like such as the loss of CK20, a high proliferation index and p53 accumulation, and as well as on the other hand exhibits characteristic molecular features, like such as a complete loss of membranous E-cadherin expression . Moreover, our results from this study demonstrate that patients suffering from PUC are of younger age than those suffering from UC or MPC. However, therapeutic strategies with radical cystectomy and cisplatin-based chemotherapy does not seem to be as effective for PUC as it is described for locally advanced UC or MPC, even though the number of patients is limited and may serve as a bias. As it was reported recently, a complete response to adjuvant chemotherapy administering M-VEC and neoadjuvant chemotherapy using gemcitabine and cisplatin may occur at least in a subgroup of PUC -patients . Therefore, chemotherapy in a neoadjuvant or adjuvant setting should be part of the therapeutic considerations. In the present study, we could not confirm these results in our analysis of adjuvant cisplatin-based chemotherapy with a median overall survival of 27.4 months, which is approximately half of that observed in the patients suffering from conventional locally advanced UC (Kaplan-Meier analysis). Thus, PUC tumor biology represents a negative prognostic factor for patients suffering from this histologic variant. Loss of E-cadherin as a sign of epithelial-mesenchymal transition (EMT) and upregulation of transcriptional repressors of E-cadherin may contribute to the aggressiveness of these tumors and a possibly reduced sensitivity to chemotherapeutic agents [4, 15, 16].
Micropapillary carcinomas have been described in different tumor entities, such as colorectal, breast, lung and others [17–19]. Thus, immunohistochemical panels for discriminating micropapillary tumors of different origins have been reported previously. Within this broad molecular panel, CK20 and uroplakin are the best molecular markers to determine urothelial origin of MPC . In MPC, the initial molecular data explaining their unfavourable clinical course were recently identified, with HER2/neu gene amplification, amongst others, as a frequent molecular alteration in this variant . Clinical reports suggest these are markers of biologically aggressive carcinoma with frequent lymphatic vessel invasion in TURB specimens and lymph node metastasis [6, 8, 21]. Moreover, clinical upstaging to locally advanced diseases occurs in the vast majority of the cases and represents a problem in planning therapeutic strategies . In response, Compérat et al. highlighted the importance of adequate tumor sampling, including analysis of the detrusor muscle, to avoid possible upstaging. Moreover, they state that due to the associated aggressive behaviour, the proportion of micropapillary differentiation should be reported in all cases, even if it represents less than 10% of the specimen, as it has prognostic relevance . Additionally, inter-observer reproducibility of the diagnosis of MPC is low , which may lead to treatment delays or the use of inappropriate therapeutic strategies adversely affecting patients’ survival. Therefore, pathologists should be aware of the histologic subtypes on diagnosis. Furthermore, urologists or oncologists should take this information into account when planning surgical or chemotherapeutic treatment options. Supporting the recommendations of Compérat and coworkers Kamat et al. postulated that even papillary and non-invasive MPC should be treated by radical cystectomy to prevent progression and systemic disease [22, 24]. In their analysis they demonstrated that neoadjuvant cisplatin-based chemotherapy did not result in an improved 5-year overall survival and that intravesical immunotherapy using BCG was not effective in this histologic variant . Most studies on MPC describe poor disease-specific survival following adjuvant chemotherapy [8, 20, 25]. However, our data are in contrast to the experiences reported previously. We demonstrated that the survival rates were comparable for MPC and UC if treated with radical cystectomy and adjuvant chemotherapy. These contradictory results may be explained by the prospective randomized nature in which the patients were recruited and included only upon the ability to compare UC, MPC and PUC within a single trial. Although the relatively low number of patients suffering from MPC or PUC may limit the value of our study, it provides important information regarding their clinical course and the aggressive biology of the tumor subtypes. A possible limitation of our study might be the interobserver variability in defining histological subtypes as there is still no consensus on the optimal cut off value of variant histology in the specimen to define PUC or MPC. Another limitation of our results is the measurement of overall survival in our series as this could be affected by several variables besides tumor characteristics. However, on the other hand chemotherapy can have effects on comorbidity and therefore finally affect overall survival what is of relevance for the patients. Awareness of these different bladder cancer variants appears to be crucial when analyzing the molecular characteristics of advanced bladder cancers and when tailoring personalized therapeutic procedures in the future.