Richard T. Bryan

Detection of Intestinal Metaplasia in Barrett's Esophagus: An Observational Comparator Study Suggests the Need for a Minimum of Eight Biopsies

OBJECTIVES:Intestinal metaplasia (IM) and dysplasia in Barretts esophagus are recognized surrogates for esophageal adenocarcinoma risk. While few would argue with the “hunt for dysplasia,” there is a divide regarding the usefulness of the histological confirmation of intestinal metaplasia in endoscopically apparent long segment Barretts esophagus. We aimed to assess the frequency of intestinal metaplasia in 125 consecutive patients with columnar-lined esophagus and to determine the optimal biopsy protocol to detect intestinal metaplasia.METHODS:Two-hundred ninety-six endoscopies were performed over a 4-yr period in Barretts esophagus segments of mean length 4 cm (range 1–11 cm) at a single center and the resulting biopsies were analyzed retrospectively. Biopsies were all processed with routine hematoxylin and eosin (H&E) staining, and a subset (N = 92) was subject to alcian blue/periodic-acid Schiff staining.RESULTS:Using H&E staining, we found that the optimum number of biopsies to diagnose intestinal metaplasia was 8 per endoscopy, mean 67.9% endoscopies having intestinal metaplasia. In contrast, if only four were taken the yield was 34.7% with intestinal metaplasia. Unless more than 16 biopsies were taken (100% yield of intestinal metaplasia), no additional significant detection was achieved. Using additional alcian blue/periodic-acid Schiff staining only had a marginal benefit, with 5.4% of new cases of intestinal metaplasia being identified. There is a proximal cephalo-caudal gradient of intestinal metaplasia, especially with increased chronological age, but doing repeat endoscopies on patients did not increase the detection of intestinal metaplasia.CONCLUSIONS:The data suggest that at least 8 random biopsies is the minimum to be taken and analyzed with conventional H&E staining to diagnose benign intestinal metaplasia. Taking more biopsies did not statistically increase the diagnosis of intestinal metaplasia except when greater than 16 were taken when 100% yield was obtained.

Narrow‐band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder

To investigate whether narrow‐band imaging (NBI) flexible cystoscopy improves the detection rate of urothelial carcinomas (UCs) of the bladder. NBI is an optical image enhancement technology in which the narrow bandwidth of light is strongly absorbed by haemoglobin and penetrates only the surface of tissue, increasing the visibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two.

Delay and survival in bladder cancer

Objective To assess in detail and evaluate the effect on survival of delays in the diagnosis and treatment of cancer (which might lead to a worse prognosis), dividing the delay from onset of symptoms to first treatment into several components, comprising patient delay, general practitioner (GP) delay, and two or more periods of hospital delay.

Cadherin Switching and Bladder Cancer

PURPOSE Progression to or presentation with muscle invasive disease represents the critical clinical step in bladder cancer, necessitating more aggressive therapy and carrying a significantly worse survival rate. Bladder tumors typically show decreased expression of the cell-cell adhesion molecule E-cadherin as grade and stage progress, accompanied by increased expression of N-cadherin or P-cadherin in muscle invasive tumors. This phenomenon has been described as cadherin switching and may represent the key step in invasion. We introduce some of the concepts of cadherin mediated cell adhesion and biology, and describe cadherin switching in detail for bladder cancer. MATERIALS AND METHODS We performed a PubMed search for articles summarizing important concepts in cadherin biology and presenting primary evidence of cadherin expression in bladder cancer. RESULTS Cadherin switching promotes a more malignant and invasive phenotype of bladder cancer in patients and laboratory based experimental systems. Bladder cancer is novel in that a switch to N-cadherin and P-cadherin expression occurs, although the precise timing and nature of this process remain unknown. Similarly the associated signaling pathways remain to be fully elucidated. CONCLUSIONS Cadherin switching is an important process late in the molecular pathogenesis of bladder cancer, and it may hold some of the answers to the development of muscle invasive and metastatic disease. Thus, the cadherin cell adhesion molecules represent strong candidate biological and molecular targets for preventing disease progression, and further investigation is warranted.

Cadherin switching dictates the biology of transitional cell carcinoma of the bladder: ex vivo and in vitro studies†

Bladder cancer is the fifth most common malignancy in the UK. Clinically, the most important process in determining prognosis is the development of invasion, initially of the lamina propria and then beyond as these transitional cell carcinomas (TCCs) progress from stage pT1 to stages T2+. Cadherins and catenins are the main mediators of cell–cell interactions in epithelial tissues, and loss of membranous E‐cadherin immunoreactivity is strongly correlated with high grade, advanced stage and poor prognosis in bladder cancer and other malignancies. However, the role of P‐cadherin is yet to be fully elucidated in bladder TCC. The objectives of this study were to establish how the expression of cadherins and catenins determines clinical and in vitro behaviour in bladder TCC. Utilizing immunohistochemistry, immunofluorescence and western blotting, we demonstrated a significant reduction in the expression of E‐cadherin and β‐catenin as grade and stage of bladder TCC progress, accompanied by a significant increase in P‐cadherin expression (all p < 0.05, Pearsons χ2 test). Increased P‐cadherin expression was also associated with a significantly worse bladder cancer‐specific survival (log rank p = 0.008), with Cox regression showing P‐cadherin to be an independent prognostic factor. Utilizing a variety of tissue culture models in a range of functional studies, we demonstrated that P‐cadherin mediates defective cell–cell adhesion and enhances anchorage‐independent growth. The results provide evidence that increased P‐cadherin expression promotes a more malignant and invasive phenotype of bladder cancer, and appears to have a novel role late in the disease. Copyright

Biomarkers in bladder cancer

Detailed molecular insights into bladder cancer biology might allow more detailed prognostication and optimization of treatment with the objective of improving patient outcome and quality of life. However, in bladder cancer research the search for biomarkers has been called into question and has even obtained notoriety. It is unlikely that any single marker will be able to improve prognostication for patients with bladder cancer above and beyond grade and stage, but a combination of multiple independent markers might more precisely predict the outcome. From a previous review, we identified seven biomarkers to study within the setting of the Bladder Cancer Prognosis Programme (BCPP), a 5‐year multicentre programme of research based at the University of Birmingham and funded by Cancer Research UK, investigating their effectiveness in predicting recurrence and progression. As part of the ongoing quality‐assurance process for BCPP we present an updated review of our selected biomarkers, as well as highlighting other recent important developments in bladder cancer research.

‘Superficial’ bladder cancer – time to uncouple pT1 tumours from pTa tumours

The term ‘superficial bladder cancer’ has now become entrenched in urological practice and is generally used to describe pTa and pT1 bladder tumours, as well as primary and concomitant carcinoma in situ (CIS). pTa tumours are those neoplasms that are confined to the epithelial layer of the bladder (‘noninvasive papillary carcinoma’), whereas pT1 tumours are those that invade into the subepithelial connective tissue or lamina propria [1]. CIS is a ‘flat tumour’ of the epithelial layer comprised of highly anaplastic cells [1]. One of the principles of the UICC TNM classification is to classify tumours into pathological and anatomical groups with comparable prognoses, and it thus seems contradictory to consider pTa, pT1 tumours and CIS together as a single entity. One of the possible explanations why these tumours are still grouped together may be the general belief that they are adequately treated with bladder preserving strategies comprising TURBT and intravesical therapy. Courses of intravesical chemotherapy (e.g. mitomycin C) or immunotherapy (e.g. BCG) are reserved for patients with ‘high risk’ disease such as grade 3 histology, CIS, or multiple frequent recurrences, although intravesical therapy is generally underused in the UK [2]. Apart from these ‘high risk’ groups, the outcome from TURBT alone for both pTa and pT1 disease has generally been considered to be comparable and good. However, ourselves and others have published data showing that patients with pT1 disease have a significantly poorer outcome and a significantly greater risk of death from bladder cancer than those with pTa disease (Fig. 1, Table 1) [3,4]. In addition, some workers are currently advocating bladder-preserving treatment strategies for early T2 tumours [5]. If we consider bladder preservation as the defining factor of the term ‘superficial bladder cancer’ then do these early T2 tumours also come into this category? The aim of this review is to show that the term ‘superficial bladder cancer’ is still being frequently used and to argue the case for ceasing to use this term in urological publications. We have reviewed clinical trials and studies from the last 20 years, and although the studies are disparate, involving different groups of patients (newly presenting patients and patients with recurrent tumours), different treatment regimens (TURBT with or without intravesical chemotherapy or immunotherapy, cystectomy, and radiotherapy), different outcome measures (recurrence, progression, survival), and different statistical analyses, their findings are similar. In addition, we briefly review the molecular and genetic background to pTa and pT1 tumours.

The West Midlands Bladder Cancer Prognosis Programme: rationale and design

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

Molecular pathways in bladder cancer: Part 1

This month, three of the mini‐reviews are descriptive of bladder cancer. The first two of these relate to various aspects of molecular pathways in bladder cancer. In this ever‐changing field, it is important to keep abreast of new information, and the authors from Birmingham do this for us in a way that is easy to understand and complete.

The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging–Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging–Assisted TURBT in Primary Non–Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results

BACKGROUND White light (WL) is the established imaging modality for transurethral resection of bladder tumour (TURBT). Narrow band imaging (NBI) is a promising addition. OBJECTIVES To compare 12-mo recurrence rates following TURBT using NBI versus WL guidance. DESIGN, SETTING, AND PARTICIPANTS The Clinical Research Office of the Endourological Society (CROES) conducted a prospective randomised single-blind multicentre study. Patients with primary non-muscle-invasive bladder cancer (NMIBC) were randomly assigned 1:1 to TURBT guided by NBI or WL. INTERVENTION TURBT for NMIBC using NBI or WL. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Twelve-month recurrence rates were compared by chi-square tests and survival analyses. RESULTS AND LIMITATIONS Of the 965 patients enrolled in the study, 481 patients underwent WL-assisted TURBT and 484 patients received NBI-assisted TURBT. Of these, 294 and 303 patients, respectively, completed 12-mo follow-up, with recurrence rates of 27.1% and 25.4%, respectively (p=0.585, intention-to-treat [ITT] analysis). In patients at low risk for disease recurrence, recurrence rates at 12 mo were significantly higher in the WL group compared with the NBI group (27.3% vs 5.6%; p=0.002, ITT analysis). Although TURBT took longer on average with NBI plus WL compared with WL alone (38.1 vs 35.0min, p=0.039, ITT; 39.1 vs 35.7min, p=0.047, per protocol [PP] analysis), lesions were significantly more often visible with NBI than with WL (p=0.033). Frequency and severity of adverse events were similar in both treatment groups. Possible limitations were lack of uniformity of surgical resection, data on smoking status, central pathology review, and specific data regarding adjuvant intravesical instillation therapy. CONCLUSIONS NBI and WL guidance achieved similar overall recurrence rates 12 mo after TURBT in patients with NMIBC. NBI-assisted TURBT significantly reduced the likelihood of disease recurrence in low-risk patients. PATIENT SUMMARY Use of a narrow band imaging technique might provide greater detection of bladder tumours and subsequent treatment leading to reduced recurrence in low-risk patients.