Variants of UC tend to be underdiagnosed or misclassified for several reasons .
Tumors are heterogeneous and subsampling can compromise the histological recognition of these entities. This explains the variable agreement rate between the specimen of TURB and radical cystectomy (RC) reported in the literature; while some studies show relatively low agreement [4, 5], others report such high rates 83.6% . In our study was able to show a 36% agreement rate.
However, the histology of these variants is difficult to interpret due to the heterogeneity and the percentage of each variant. In addition, it is not uncommon to have several types of variants in the same tumor.
The therapeutic management of various histological variants remains controversial . It is essentially based on the identification of subtypes responding to non-surgical treatment (systemic therapy, intravesical therapy, radiotherapy, etc.) before radical treatment .
The role of neoadjuvant chemotherapy (NAC) in the therapeutic arsenal of these variants has shown an improvement in overall survival mainly in the neuroendocrine component and a decrease in the tumor stage compared to other differentiations.
Vetterlein et al. reported significant overall survival in patients with neuroendocrine bladder tumors who received NAC. In addition, patients with micropapillary differentiation and sarcomatoid differentiation have shown a decrease in the disease stage pT3 and/or pN1 when they received NAC . Neoadjuvant chemotherapy has not been used in our population.
The micropapillary component of these variants does not confer a worse prognosis than pure UC in terms of overall survival after total cystectomy. However, NAC was not significantly associated with better survival outcomes, and it resulted in a significant rate of decline in the stage of the disease .
Although there is no clear recommendation in the management of these entities, several studies have proven the place of total cystectomy.
Veskimäe et al. reported that in the majority of these variants, such as the micropapillary and plasmocytoid component, the treatment is mainly NAC and radical cystectomy .
A meta-analysis published in 2017 reported that the UC variants did not predict a poor prognosis for patients treated with RC. However, the data have shown patients with these variants who receive RC as soon as possible for better results .
Stroman et al. reported a decrease in overall survival in patients with histological variants at 14% at 2 years and 23% at 5 years after RC compared to pure UC. Patients should be informed about the high risk and unpredictable nature of these entities and the recommendation for the first RC performed for this indication .
The overall survival at 20 months in our study was 70% and 40% for the patients who had RC and the other therapeutic (TURB alone or a TURB with an adjuvant), respectively.
Regarding BCG immunotherapy, Gofrit et al. reported that patients treated with BCG intravesical immunotherapy did not show efficacy even when confirmation of diagnosis with re-evaluation TURB and rigorous follow-up. The progression rate of these patients is high (40% at 5 years compared to 17.5% pure high grade UC). Patients treated with BCG intravesical immunotherapy have a 27% chance of dying from this disease within 5 years, compared with 7.5% chance of high grade UC. As such, these patients should be informed of this adverse clinical course and considerations for cystectomy are strongly recommended .
A recent study of 114 phase 2 patients (PURE-01) administered to patients with impure UC three cycles of 200 mg of pembrolizumab preceding a RC. The preliminary results of this study confirm the activity of pembrolizumab in neoadjuvant the treatment of UC infiltrating the muscle with a histological variant .
The limitations of this study were mainly the reduced number of patients and the selection bias by default of randomization. Finally, the heterogeneity of both histological variants of urothelial carcinoma of the bladder and also the use of curative therapies are important limits to emphasize. These results are well worth investigating in multicentric prospective studies with a larger sample.