Diagnostic roles of proliferative markers in pathological Grade of T1 Urothelial Bladder Cancer

Abstract

The stage T1 urothelial bladder cancer (T1 UBC) tumor grade classification is important for prognosis and clinical management. However, the reproducibility of this two-grade classification system is limited in regards to pathological diagnosis, and there is lack of ideal, objective and easily detected markers for pathological diagnosis. In our study, bladder urothelial lesions from a total of 124 patients diagnosed pathologically after transurethral resection of the bladder tumor (TURBT) were collected, including non-cancerous lesions from 33 patients and lesions from 91 T1 UBC patients. A series of previous studies have suggested some common and valuable factors in the diagnosis and prognosis of UBC, but there are still some controversial factors, such as the mitotic figure (MF) of tumor cell, cell proliferation index Ki-67, graded differentiation marker CK20, P53, P504S and carcinogenesis associated telomerase reverse transcriptase (TERT) promoter mutations. The purpose of this study was to evaluate the value of these factors in the pathological grading diagnosis of T1 UBC. The results showed that gender, lesion size, mitotic index (MI), CK20, P53, Ki-67, P504S and TERT promoter hot spot mutations (C228T and C250T) were correlated with T1 UBC diagnosis (P<0.05). The MI, Ki-67 and P504S were correlated with the pathological grade of T1 UBC (P<0.05). Logistic regression analysis showed that the MI and Ki-67 were independent risk factors for high-grade (HG) of T1 UBC (P<0.05). The combined detection of the MI, Ki-67 and P504S in a multivariate diagnostic model improved the diagnostic accuracy of assigning the T1 UBC pathological grade (AUC=0.904, 95%CI: 0.824~0.956, P<0.05). In conclusion, MI and Ki-67, as important markers of histopathology and cell proliferation, can be easily measured and have good reproducibility. These markers may be meaningful parameters for assigning the pathological grade of UBC.

Keywords: Ki-67; mitotic index; telomerase reverse transcriptase promoter mutations; urothelial bladder cancer.

Figure 1

The parameters were correlated with the pathological diagnosis of T1 UBC. The mitotic index (MI) in T1 UBC A. MI ≤ 2 (200×), B. MI > 2 (200×). Expression of Ki-67and P504S in immunohistochemistry (IHC) C. Ki-67, D. P504S. Hot spot mutations of the TERT promoter in UBC (C250T and C228T) E.

Figure 2

Multiparametric ROC curve related to the pathological grade of the T1 UBCs (MedCalc ROC analysis).