Currently, an estimated 429,000 new cases of UC were diagnosed, with 165,000 deaths per year in the world[17]. Moreover, there are 80,000 new cases of UC with 33,000 deaths in China per year [18]. Despite the improvement in diagnostic techniques and the progress in surgical therapies, UC has a high recurrence rate risk and the prognosis remains poor in UC patients with high grade or MIBC [19]. UC is considered a life-threatening disease, and routine cystoscopic check is usually performed to screen the recurrence of UC following TUR [20].
Although some noninvasive examinations have been applied to UC detection and screening the recurrence of UC, such as urine cytology and biomarkers, many studies still show low sensitivity of UC diagnosis [21, 22]. Therefore, novel examination and diagnosis innovations are needed for patients with UC. At present, various studies have suggested that FISH, an examination which uses four-colored fluorescence in situ hybridizations, is superior to conventional urine cytology and can improve the diagnosis of UC[23, 24]. Thus, FISH can assist in improving UC detection compared to those using urine cytology. However, FISH also has many disadvantages, which limit its application in UC diagnosis: it requires special supporting equipment; the experimental procedures are relatively complicated and costly; final decision of UC requires pathologists with rich experience in diagnosis.
CellDetect staining is a unique platform for cancer diagnosis,the proprietary plant extract and dyes enable color distinction between benign and malignant cells based on staining color and morphology. CellDetect was able to spot CIS cases even when cystoscopy missed, and for some cases of high grade UC, the nucleus of tumor cells shrinked while inflammatory cells enlarged, it's easy to confuse pathologist. However we found that the nuclei of high grade UC tend to be smaller, they also lose their round shape and smooth nuclear membrane, which can be easily observed with CellDetect. A previous study indicated that 94% sensitivity and 89% specificity to detect UC using CellDetect, which had overall superior sensitivity compared to urine cytology[25]. Another study also suggested that the sensitivity of CellDetect was 84%, which is more efficient than that of BTA stat in detecting UC[16].
In this study, we compared diagnostic value among CellDetect, FISH, and urine cytology in UC. Our results indicated that CellDetect and FISH have equal-level sensitivity in the diagnosis of UC, and both are significantly superior to conventional urine cytology. However, there was no significant difference in specificity between the three staining techniques. In addition, the sensitivity of CellDetect has no correlation with tumor location and clinical stage. However, the sensitivity of CellDetect in low grade and high grade UC was 51.6% and 92.8%, which suggests that the screening ability of CellDetect in high grade UC is significantly superior to that in low grade UC. In a previous study on the diagnostic value of FISH and cytology in UC, the sensitivity of FISH in low grade and high grade UC was 25% and 73%, and the sensitivity of cytology was 36% and 75%[25]. Studies have found that the expression of E-cadherin was down-regulated in high-grade, invasive and distant metastatic UC, suggests that reduced expression of adhesion-related protein weakens cell-cell adhesion, and causes tumor cells to detaches from the primary site and develop invasion and metastasis [26, 27]. These also explains why the detection rate of high grade UC is generally higher than that of low grade UC by different staining methods based on urine exfoliation cytology.
Due to the high recurrence of bladder cancer after TUR, bladder infusion chemotherapy combined with regular cystoscopy is the conventional strategy in the management of lower urinary tract UC, however, cystoscopy has some recognized limitations, such as, small or occult tumor lesions are not easy to visualize and diagnose[28]. In addition, the morphological characteristics of CIS under cystoscopy usually appear as erythematous areas, make it difficult to distinguish CIS from inflammatory lesions[29]. Finally, some patients cannot tolerate cystoscopy, thus, noninvasive monitoring and diagnostics are extremely important for the screening of patients with lower urinary tract UC. We predicted that novel urine stain for exfoliated cells will have an expectable clinical application prospect, CellDetect combined imaging examination may play an important role in monitoring recurrence of lower urinary tract UC, it is worth of further study in the future. Moreover, upper urinary tract UC is defined as a tumor involving the urinary tract between pelvis and ureter. The muscle layers of upper urinary tract are thinner than the bladder, so the UC cells can easily penetrates the muscle layer to form invasive disease, and the prognosis of upper tract UC is poor. Unlike lower urinary tract UC, imaging diagnosis of upper urinary tract UC is usually difficult to determine the diagnosis, patients generally have poor tolerance to ureteroscopy, which also could cause local and distant spread of UC cells. Therefore, early noninvasive screening and diagnosis are extremely important for the prognosis. In our study, the diagnostic value of CellDetect in upper urinary tract UC was equal to that in lower urinary tract UC, which suggests that CellDetect also plays an important role in screening of upper urinary tract UC.