Blue light transurethral resection and biopsy of bladder cancer with hexaminolevulinate: Histopathological characteristics and recurrence rates in a single UK centre study

Abstract Introduction Blue light cystoscopy with hexaminolevulinate (HAL) during transurethral resection of bladder cancer (TURBT) has been shown to improve detection, thereby reducing bladder cancer recurrence compared with white light cystoscopy. Methods Single‐centred UK (United Kingdom) study on 101 patients who underwent blue light cystoscopy between July 2017 and November 2020, performed by a single surgeon. Our study was divided into two arms; the primary arm had no prior diagnosis of bladder malignancy (N = 41), whereas secondary re‐resection arm had (N = 57). Three patients with non‐urothelial bladder cancer were excluded. Patients were followed up for 24 months. Data were collected on biopsy quality, histopathological characteristics and recurrence. The end points of the study were recurrence rate at 24 months in both arms and detection of CIS in patients who undergo TURBT or biopsy after initial white light study in the secondary, re‐resection arm. This was analysed with Fisher's exact test. Results Of 98 patients, 39 had malignancy in their first blue light TURBT/biopsy: primary arm (10/41, 24.4%) and secondary arm (29/57, 50.9%), with detrusor present in 80.5% and 80.7%, respectively. In the secondary arm, blue light re‐resection TURBT detected significantly more CIS (20.7% vs 51.7%, p = 0.0277) compared with white light with 3.4% upstaged to muscle invasive bladder cancer (G3pT2). Median time to re‐resection was 3.06 months. Recurrence rate was 33.3% in the primary arm and 37.5% in the secondary arm after 24 months of follow‐up. Conclusion Our data confirm that blue light TURBT with HAL provides superior detection and diagnosis of CIS in patients with previous white light cystoscopy.


| INTRODUCTION
According to GLOBOCAN data, more than 570 000 cases of bladder cancers were diagnosed in 2020, making BC the 11th most common cancer worldwide. In the United Kingdom, bladder cancer is the ninth most common cancer, with more than 12 000 cases diagnosed annually.
The majority of BCs are urothelial cancer, making up 90% of all cases. Urothelial bladder cancer consists of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Approximately 75% of newly diagnosed bladder cancer are NMIBC at presentation, 1  invasion. 2 Rate of recurrence and progression after TURBT for NMIBC, however, could be as high as 60%-70% and 20%-30%, respectively, depending on the grade of bladder tumour. 3 Failure to detect satellite lesions, small papillary tumours and CIS in WLC could lead to progression to invasive tumour, whereas incomplete resection and diffuse premalignant field result in recurrence. A study showed residual non-invasive tumour in 75% of patients with superficial bladder tumour in their repeat TURBT within 2-6 weeks after initial resection, with 28% upstaged to invasive tumour. 4 Furthermore, identification of CIS could be difficult in WLC.
Novel therapies such as photodynamic diagnosis (PDD) have therefore been developed to enhance tumour detection and guide resection. PDD involves the instillation of photosensitiser hexaminolevulinate (HAL) into the urinary bladder via a urethral catheter 1 h before cystoscopy. HAL is a haem precursor of photoactive intermediate protoporphyrins IX (PpIX), which preferentially accumulates in neoplastic tissue due to increased mitotic rate. Exposure to blue light (wavelength 380-450 nm) results in activation of PpIX, emitting a pink-red colour. Neoplastic tissue therefore appears pink-red and demarcated, as opposed to normal bladder mucosa, which appears dark blue. This helps in the identification of bladder cancer. One meta-analysis showed that blue light cystoscopy (BLC) detected significantly more CIS lesions than WLC. The same meta-analysis also showed that in 26.7% of patients, CIS was only detected by blue light, which was significant in both patients with recurrent and primary bladder cancer. 5 BLC was introduced in our trust in 2017. We report results from our site since its introduction. We assessed BLC with HAL (BLC-HAL) on tumour recurrence rate at 24 months and evaluated detection of CIS in patients who undergo re-resection BLC-HAL-TURBT/biopsy after initial white light TURBT/biopsy.
Inclusion criteria for referral to BLC-HAL in the primary arm (see Section 2.3) are multiple red patches suggestive of CIS on flexible cystoscopy (FC), atypical urine cytology, high-grade disease suspected upon FC and patients with history of keratinising squamous metaplasia of bladder. In the secondary (re-resection) arm, patients with first diagnosis of high-grade disease or who have incomplete resection (where no muscle has been identified in histology) on initial white light TURBT/biopsy was included. In 2016, the World Health Organisation (WHO) classified bladder cancers based on differentiation as low grade or high grade. 6 The distinction between low-grade and high-grade urothelial disease is important as it has implications related to risk stratification and management of patients.

| HAL treatment and fluorescence detection
HexVix© was supplied as 85 mg of active ingredient HAL in 50 mL of phosphate saline diluent. Patients were asked to completely empty their bladder before HexVix© was instilled into the urinary bladder via a urethral catheter. This was retained in the bladder for 1 h and drained in the operating theatre immediately before cystoscopy. A Dlight system provided by Karl Storz was used for fluorescence detection, together with a PDD-compatible telescope. A push button on the charge-coupled camera head allows active operating modes of white and blue light to be used and switched between.

| Study protocol
The study was divided into two arms. Patients in the primary arm had no prior diagnosis of bladder cancer and were referred for BLC biopsy/TURBT based on inclusion criteria. Patients in the secondary arm had been recently diagnosed with bladder cancer from initial white light TURBT/biopsy and were referred to re-resection BLC TURBT/biopsy based on inclusion criteria. All BLC-HAL biopsy/ TURBT were performed by a single surgeon.
In the primary and secondary arms, patients with papillary or suspicious lesions seen in BLC-HAL were excised and biopsied, respectively. The samples were analysed by local pathologists in our trust, who were not involved in the design of this study. The pathology report incorporated both the 1973 WHO and 2004/2016 WHO histological grading of bladder tumour.
Patients with confirmed malignancy in BLC were followed up with white light FC, with the interval for check cystoscopy dependent on the grade and stage of bladder cancer. Patients with suspected bladder cancer on check cystoscopy were re-referred for white light biopsy +/À TURBT to check for recurrence.

| Analysis
Pathological data were collected for patients with BLC malignancy confirmed by local pathologist in both arms. In the secondary arm, for patients with malignancy confirmed on BLC-HAL biopsy/TURBT, retrospective data were collected on their initial pathology in white light.
Based on the pathological data, patients were allocated to different prognostic risk groups based on 2021 European Association of Urology (EAU) scoring model. 7 In cases of multifocal tumour +/À CIS, the highest grade and stage +/À CIS was recorded, with the presence of CIS primarily noted in such cases. The primary detection end point is the proportion of histologically confirmed malignancy in white light who had additional histologically confirmed CIS detected or upstaging in BLC re-resection. Patients with non-urothelial bladder cancer and patients with metastatic bladder cancer were excluded.
The primary and secondary arms were followed up for recurrence.

| Detection
The primary detection endpoint was the proportion of histologically confirmed malignancy in white light who had additional histologically T A B L E 1 Clinical and pathological characteristics of patients enrolled to blue light cystoscopy in both primary and secondary arms.

| CONCLUSION
We report our experience as a single UK centre introducing BLC in our diagnostics. We report superior detection of CIS in patients who had BLC re-resection with statistical significance. We aim to continue recruiting patients with suspected CIS for BLC to improve detection and thereby guide management.