Technologic Developments in the Field of Photonics for the Detection of Urinary Bladder Cancer

Abstract

Bladder cancer is a common cause of morbidity and mortality worldwide in an aging population. Each year, thousands of people, mostly men, are diagnosed with this disease, but many of them present too late to receive optimal treatment. As with all cancers, early diagnosis of bladder cancer significantly improves the efficacy of therapy and increases survival and recurrence-free survival rates. Ongoing research has identified many limitations about the sensitivity of standard diagnostic procedures in detecting early-stage tumors and precancerous changes. The consequences of this are often tumor progression and increased tumor burden, leading to a decrease in patient quality of life and a vast increase in treatment costs. The necessity for improved early detection of bladder cancer has spurred on research into novel methods that use a wide range of biological and photonic phenomena. This review will broadly discuss standard detection methodologies and their major limitations before covering novel photonic techniques for early tumor detection and staging, assessing their diagnostic accuracy for flat and precancerous changes. We will do so in the context of both cystoscopic examination and the screening of voided urine and will also touch on the concept of using photonic technology as a surgical tool for tumor ablation.

Introduction

Bladder cancer is the fourth most common cancer in men and the ninth most common cancer in women. Although it has not been confirmed, this gender disparity is thought to be caused by the presence of the androgen receptor in men.¹ The obvious risk association with tobacco smoke² may be the reason that bladder cancer is increasing in developing countries.

Approximately 70% of diagnosed bladder tumors are nonmuscle invasive bladder cancer (NMIBC) presenting as Ta and T1 stages. Ta is an entirely noninvasive papillary tumor of the urothelium, whereas T1, a stage above, invades the subepithelial connective tissue of the lamina propria. Within NMIBC, however, 20% of cases will progress to muscle invasive disease (Figure 1). Some T1 tumors can present with carcinoma in situ (CIS), which is an important prognostic factor of aggressive disease.³ CIS, a precancerous change synonymous with high-grade dysplasia, appears as a flat lesion without membrane or muscle penetration along the bladder wall. It carries high potential to progress to muscle invasive carcinoma if left untreated.

The current gold standard for evaluating patients with hematuria and suspected bladder cancer is white light cystoscopy (WLC) of the bladder together with or without random biopsies. WLC illuminates the area within the bladder, allowing detection of gross morphologic changes and the extent of tumor mass. After this, biopsy analysis by histopathologists can grade and stage tumors according to location, tissue stratification, nucleation, and assays for tumor-specific antigens. Biopsy analysis allows clinicians to determine the protocol for postsurgical monitoring.

The superficial nature of many early, nonmuscle invasive tumors means they can be removed during WLC in a procedure called “transurethral resection” (TURBT). Likewise, the tumorigenic potential of CIS dictates it should be removed in this way as early as possible. In contrast, progressive, muscle-invasive tumors usually can only be adequately treated with radical surgery, removing the bladder (cystectomy) to halt the spread and prevent metastasis (Figure 2). The early detection and response to NMIBC (including CIS) are clinical targets because they will allow effective treatment without the need for radical surgery, increasing patient survival and reducing morbidity.

Complete TURBT, in conjunction with intravesical therapy, generally using mitomycin or other immunostimulants,⁴ has shown reliable results over the years in bladder cancer therapy.⁵ However, several “re-TUR studies” (secondary and second-look TURBT after a period of time) show concerning levels of disease recurrence and progression in patients with NMIBC.⁶ This underscores the limitation to WLC: It has low sensitivity in detecting early precancerous changes (particularly flat lesions, e.g., CIS) and in demarcating tumor boundaries during resection. Random biopsy, already limited by sample size and poor CIS detection by pathologists⁷, is therefore also hampered by an inability to flag all areas of tumors.

These limitations of current diagnostic technologies using WLC can lead to a number of early tumors going unnoticed, being incorrectly staged, or being incompletely removed during resection. Undetected precancerous changes can recur as superficial carcinoma and may develop into devastating muscle invasive disease, requiring radical surgery and displaying poor prognosis. The high risk of disease recurrence in NMIBC means it requires close monitoring and often lifelong follow-up after initial therapy. Monitoring in most cases includes urinary cytology and in all cases cystoscopy. This gives rise to significant associated costs (calculated to be ∼£50 million/year in the United Kingdom), which puts a considerable burden on the National Health Service.⁸

Strengthening the sensitivity of detection systems would therefore have a profound effect in increasing therapeutic efficacy and reducing the recurrence rates. This, of course, would reduce costs associated with procedures and, most important, improve the quality of life of many patients. Some of the most promising technologic developments in the area of high-sensitivity bladder cancer detection are summarized.