For recurrence and progression, their most important prognostic factors are the number, size, the prior recurrence rate, T category, grade, and CIS’ presence of tumors, these factors represent the biological aggressiveness of Bca (2). Furthermore, NMIBC shows quite diverse natural histories and prognoses(12). Previous studies have identified tumor grade to be one of the most important prognostic factors for recurrence or progression of NMIBC(3).
In pathology, the grade of the tumor is determined by the highest pattern even it is a small focus(13). Even though the 1973/2016 version of the WHO and ISUP system classification provide the clear histological diagnostic criteria for each diagnostic classification, Knowles et al(14)found that the condition of MG also existing in patients with urothelial carcinoma. Cheng et al(11)also found that about one-third of the 164 patients with Ta urothelial carcinoma had more than one histological grade. The reason for this phenomenon may be related to the activation of the two pathways in the same bladder, generating a mixed tumor or tumors with LG plus HG histology, including FGFR3 mutation in Ta tumors and p53 and Rb pathway alterations in muscle-invasive tumors(14). Therefore, it is difficult for pathologists to determine MG heterogeneity(14). However, the heterogeneity in the pathology and clinical behavior of bladder tumors presents significant problems in evaluation at diagnosis and in longer term clinical management.
To date, researchers have reported several studies on systematic evaluation of the incidence and clinical significance of MG tumors., and they had different opinions on this issue(6–9). They defined the biological aggressiveness of MG by comparing the recurrence and progression rates with LG and HG in NMIBC. Gofrit et al(6)first reported that the clinical course of patients with MG tumors parallels to that of patients with LG tumors (about 5% of patients with non-muscle invasive tumors). They explained that the major LG component dictated the postoperative clinical course and not the minor early HG component, but these patients all received the aggressive treatment of induction and maintenance instillations of BCG. Therefore, such results are controversial. Schubert et al(9)reported that MG exhibits a significantly better response profile to intravesical BCG therapy compared to HG. Such researchers thought that it may be better to allow for a safe reduction in the use of toxic BCG regimens for MG patients, and it may be useful to consider grade heterogeneity in the development of new risk stratification systems for NMIBC. However, in the above studies of MG, a tumor was designated as MG when LG as well as HG elements were present in the same lesion but less than 10% or 50% of it was HG. Mai et al(7)thought that these sections diagnostically challenging and are wrongly assigned a high grade since this determines prognosis. As a result, the clinician's judgment on the prognosis and the subsequent treatment may be improper.
At the molecular level, while several molecular markers for the development, recurrence and progression of bladder cancer, such as p53 and Rb, have been studied(15–17), the limited value of these established prognostic markers called for prediction tools of Bca outcomes. In order to test the molecular markers, it is a expensive and complicated process and takes a long time; and the accuracy and reliability are to be confirmed in clinical research.
The American Joint Committee on Cancer (AJCC) TNM staging system(10) has been used widely to predict the risk of disease recurrence in patients treated with radical cystectomy (RC). However, this system has been shown to be less accurate at prediction when incorporating several clinical variables. Apart from standard oncologic features, BCa patients are generally elderly and have significant comorbidities, so it’s needed to do competing-risk analyses to choose individualized therapies (18). EORTC scoring system was based on the follow six most relevant clinical and pathologic predictors of outcomes: tumor stage and grade, number of tumors, tumor size, concomitant CIS, and history of prior disease recurrence (2). EORTC risk scores were used to externally evaluate the risk of recurrence and progression for patients who undergo TURB and recommended by international guidelines(1). However, external validation of this risk score in MG patients is still required. The purpose of the present study was to evaluate the prognosis of patients with MG NMIBC and to validate the feasibility of EORTC risk scores.
In our study, the mean follow-up period was slightly shorter than the original data of Reis et al (33 vs. 39.7 months). Reis et al(8)also estimated the risk of recurrence-free survival and progression-free survival on the basis of a single institution of 31 patients with a history of LG, MG, HG NMIBC. The recurrence-free survival was (22.1 vs 45.2%) and progression-free survival was (5.9% vs 0). However, the rates of grade progression of our cohort were (3.0% vs 12.9%) and stage progression (3.0% vs 0). Our study revealed that MG patients had lower rate of recurrence and grade progression while the rate of stage progression was higher as compared with the previous studies. The main reason for the slightly higher stage progression rate might be the intravesical treatment consisting of bacillus Calmette-Guérin (BCG) in their study. Howver, as seen from the data, MG patients had a better prognosis even if they did not receive overly aggressive treatment. Reis et al also found that the recurrence rate and progression rate of LG and HG were 53.8%, 6.7% and 36.1%, 36.1%, respectively. Compared with LG and HG, the recurrence and progression rates of MG in our cohort were lower. The reason might be that the main component of the tumor was LG and the invasive part of the tumor was HG. The results further illustrated that the pathology and clinical behavior of MG is benign.
In our study, the tumor size, number of tumors, tumor grade, T category, and prior recurrence rate were associated with a higher recurrence risk after TURBT. Meanwhile, the variables proven to be predictive to progression risk were tumor size, prior recurrence rate, CIS, T category, and tumor grade. It has been reported that 54% patients with CIS and without any treatment would progress to muscle-invasive disease(19). According to our study, CIS was not an independent factor for predicting tumor recurrence, possibly due to the relatively small sample size in our cohort. Therefore, further study is required in the future.
In this study, we found that EORTC risk scores are suitable for MG patients for recurrence and progression prediction. Kaplan–Meier curves showed significant differences among the 2 RFS (P = 0.0362 < 0.05, log-rank test) and 3 PFS (P = 0.0077 < 0.01, log-rank test) levels separately, demonstrating that EORTC risk scores is predictive to tumor recurrence and prognosis of MG patients. These results are consistent with previous research by Wang et al(20), who reported that EORTC risk scores were better for predicting recurrence and progression in Chinese patients with NMIBC. The results of our study showed that the short-term recurrence rate of bladder cancer is basically consistent with the EORTC system. However, the recurrence rate in each group of short-term recurrence is lower than the average value of the expected recurrence rate, because the effect of intravesical treatment in preventing tumor recurrence is fully reflected, which further reduces the recurrence rate. We can conclude that EORTC risk scores are predictive to the short-term prognosis of MG is of significance to some extent. As for the patient number with progression, the number of patients in the MG group is higher than that for EORTC risk scores. Therefore, high-risk patients in EORTC risk scores may need more aggressive treatment with regard to the adjuvant intravesical instillations of bacillus Calmette-Guérin, and even determining RC in a timely manner to maximize the chances of bladder preservation and cancer control. EORTC risk scores have some limitations in predicting the prognosis of MG, because postoperative intravesical instillations is difficult to be uniform, thus affecting the accuracy of the prognostic judgment of the system.
There were several limitations in our study:(i)This study is a retrospective study with a single center and limited sample size, so further prospective studies are needed to validate the reliability of the predictions; (ii) We classified the tumor grade of MG patients into G2 stage in the statistics. As a result, there were no patients in Group 0 and Group 10–17 in the recurrence cohort and Group 14–23 in the progression cohort, affecting the accuracy of the risk scores for the prediction to some certain extent, and causing certain bias; (iii) Due to the shorter follow-up period, only one-year recurrence rate and progression rate were compared; (iv) Study cases were limited in a subgroup of MG with no cases of LG and HG, lacking of single-center LG and (or) HG cases for the controlled study.