REVIEWS Diagnosis and management of intradiverticular bladder tumours Nicholas Faure Walker, Christine Gan, Jonathon Olsburgh and Muhammad Shamim Khan Abstract | Intradiverticular bladder tumours (IDBT) account for approximately 1% of all urinary bladder tumours. The risk of developing a tumour within a bladder diverticulum is considered to be greater than in the main bladder, possibly owing to prolonged contact of potential carcinogens with the mucosal lining from urinary stasis. Patients with these tumours most commonly present with visible haematuria. Diagnostic tests include urine cytology, cystoscopy, ultrasonography, CT, MRI, and biopsy. Lack of muscle in the diverticula increases the risk of bladder perforation during biopsy and makes pathological staging difficult as there is no T2 stage; instead, data suggest that any invasion beyond the lamina propria should be described as T3. IDBT can be managed by transurethral resection and adjuvant intravesical therapy, diverticulectomy, or cystectomy (partial or radical), as outlined by the only guidelines to specifically address the management of IDBT, which were published by the Cancer Committee of the French Association of Urology (CCAFU) in 2012. The prognosis of patients with intradiverticular bladder tumours has always been perceived to be worse than those with intravesical tumours; however, the only study of 5‑year survival rates for patients with IDBT suggests that prognosis might be comparable for these conditions. Faure Walker, N. et al. Nat. Rev. Urol. 11, 383–390 (2014); published online 17 June 2014; doi:10.1038/nrurol.2014.131
Introduction
Department of Urology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK (N.F.W., C.G., J.O., M.S.K.). Correspondence to: M.S.K. shamim.khan@ gstt.nhs.uk
Bladder diverticula are of variable sizes, ranging from 10 cm, with an average size of about 5 cm.1,2 They are usually thin-walled with a narrow neck or ostium communicating with the bladder lumen,3 and can be either congenital or acquired. Congenital diverticula, which are most common in children under 10 years of age and are almost exclusively found in boys, are considered to be ‘true’ diverticula as they contain all layers constituting the main bladder, namely the urothelium, lamina propria, and muscularis propria.3 Congenital diverticula tend to be solitary and are not usually associated with bladder trabeculations.3–6 In adults, bladder diverticula are almost always acqui red rather than congenital, and are termed ‘pseudo diverticula’ as they lack a muscle layer. These lesions are usually found near the ureteric orifices, as these sites represent the embryological junction of the ureteric bud with the urogenital sinus.3 Relatively few longi tudinal smooth-muscle fibres exist in the intramural ureter, 7,8 so a rise in intravesical pressure can cause the mucosa and submuscosa to herniate and form a pseudod iverticulum. When present, the few muscle fibres in the wall of a bladder diverticulum tend to be dysfunctional and disordered leading to poor bladder emptying.3 Pseudodiverticula, which usually occur in groups of multiple lesions, affect patients with bladder outflow obstruction or neurogenic bladder, and are more common in men over age 60 years, owing to the high Competing interests The authors declare no competing interests.
prevalence of prostatic enlargement. As such, they are often associated with substantial trabeculations in the main bladder.2,9–12 In the only published autopsy study to investigate the prevalence of bladder diverticula, 23.4% of cadavers had bladder diverticula, most of which were asymptomatic during life.5 Bladder diverticula are associated with urinary stasis, which can lead to an increased risk of UTI, bladder calculi, and neoplasms, owing to prolonged exposure to carcinogens such as aromatic amines from cigarette smoke.3,6,13–17 Bladder tumours within bladder diverticula account for 0.8–10.8% of all vesical tumours.4,14,18,19 Given the relatively low prevalence of symptomatic diverticula, most of the data relating to diverticula and associated pathologies have been gathered from case reports or case series and very few large-scale prospective studies are available to formulate guidelines for the standardization of management. From the limited existing data, it seems that most patients present in their 60s (although age at presentation has been reported to range from 44–88 years),13 and intradiverticular bladder tumours (IDBTs) are 11–12 times more common in men than in women. In this article, we review the existing literature on IDBTs and highlight the challenges that exist in the management of malignant and premalignant conditions within bladder diverticula. We also outline the only guidelines currently available for the management of IDBT, the Cancer Committee of the French Association of Urology (CCAFU) guidelines,20 and provide our own recommendations as a framework for the diagnosis and treatment of these conditions.
NATURE REVIEWS | UROLOGY
VOLUME 11 | JULY 2014 | 383 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Intradiverticular bladder tumours (IDBT) are rare, accounting for approximately 1% of all bladder tumours; the true prevalence of bladder diverticula is not known as most are asymptomatic ■■ Urine cytology, ultrasonography, and cystoscopy should be used in the initial assessment of a suspected IDBT; cross-sectional imaging can complement these techniques, and is also important in staging ■■ Bladder-conserving treatments including transurethral resection, diverticulectomy, or partial cystectomy with or without intravesical adjuvant therapy can be used in patients with low-grade, low-volume, noninvasive disease ■■ Radical cystectomy, with or without systemic neoadjuvant or adjuvant therapy, is required for patients with large, invasive tumours, or tumours that are associated with poor bladder function (chronic retention) ■■ 5-year survival rates of 72% and 45% have been reported for patients with IDBT and, specifically, T3 IDBTs, respectively; these rates are comparable to those for intravesical bladder cancer
Diagnosis Urine cytology The diagnosis of IDBT is made using a similar array of tests to those used for the diagnosis of tumours in the main bladder, including urine cytology, imaging, cysto scopy, and histopathological examination of a resected specimen.21,22 Urine cytology is the pathological examination of voided urine for exfoliated cancer cells.19 It is a highly specific and noninvasive diagnostic tool; however, although highly sensitive for high-grade tumours and carcinoma in situ (CIS; up to 80–90% sensitivity), lower sensitivity has been reported for low-grade tumours (around 20%) owing to a lower volume of cells shed from these tumours, as well as more subtlety in the type of cellular changes seen.23 In patients with IDBT, sensitivity might be further compromised if the ostium of the bladder diverticulum is very narrow. The presence of UTI, stones, or inflammation as a result of recent bladder instillations or instrumentation can make the interpretation of urine cytology more difficult. Cytological interpretation is user-dependent and has a specificity of >90% if done by an experienced cytopathologist.24 We recommend cytology as a useful adjunct in the detection of IDBT, especially for high-grade tumours, and this test is particularly useful in cases when cystoscopy is not feasible. However, given the low sensitivity of cytology for low-grade tumours, it is important to be careful with regards to false-negative results. Cytology is also valuable in the follow-up assessment of patients who have had bladder‑conserving treatment for IDBTs. Cystoscopy Cystoscopic assessment can be compromised if the neck of the diverticulum is too narrow to allow passage of the cystoscope;25 a flexible ureteroscope might be of value in this situation. Knappenberger et al.26 reported that, if a patient has a bladder diverticulum and bladder cancer, then the bladder tumour is more likely to arise from the diverticulum than from the main bladder. This observation is supported by two studies of patients with blad der tumours and bladder diverticula; in these studies, tumours were found within the diverticula (rather than in the main bladder) in 31 of 48 (64.6%) patients and 384 | JULY 2014 | VOLUME 11
seven of eight (87.5%) patients, respectively.6,14 It is, therefore, imperative to inspect the entire mucosa of the diverticulum during diagnostic cystoscopy if anatomy permits; this might require the use of a 70° lens, as well as standard 12° or 30° cystoscopes.
Imaging If cystoscopic inspection of the diverticulum is not possible, imaging will have a crucial role in diagnosis and staging. An ideal imaging technique would detect all IDBTs with high sensitivity and specificity, and reliably ascertain the level of tumour invasion. Ultrasonography and cross-sectional imaging have different roles in the investigation of bladder diverticula and IDBT. As part of the initial assessment of haematuria or infection, ultrasonography might identify a bladder diverticulum or an IDBT. Ultrasonography can also determine how well a bladder diverticulum empties on voiding. The CCAFU IDBT guideline suggests that ultrasonography is useful for diagnosing larger tumours but its sensitivity is poor if the IDBT is
Introduction
Department of Urology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK (N.F.W., C.G., J.O., M.S.K.). Correspondence to: M.S.K. shamim.khan@ gstt.nhs.uk
Bladder diverticula are of variable sizes, ranging from 10 cm, with an average size of about 5 cm.1,2 They are usually thin-walled with a narrow neck or ostium communicating with the bladder lumen,3 and can be either congenital or acquired. Congenital diverticula, which are most common in children under 10 years of age and are almost exclusively found in boys, are considered to be ‘true’ diverticula as they contain all layers constituting the main bladder, namely the urothelium, lamina propria, and muscularis propria.3 Congenital diverticula tend to be solitary and are not usually associated with bladder trabeculations.3–6 In adults, bladder diverticula are almost always acqui red rather than congenital, and are termed ‘pseudo diverticula’ as they lack a muscle layer. These lesions are usually found near the ureteric orifices, as these sites represent the embryological junction of the ureteric bud with the urogenital sinus.3 Relatively few longi tudinal smooth-muscle fibres exist in the intramural ureter, 7,8 so a rise in intravesical pressure can cause the mucosa and submuscosa to herniate and form a pseudod iverticulum. When present, the few muscle fibres in the wall of a bladder diverticulum tend to be dysfunctional and disordered leading to poor bladder emptying.3 Pseudodiverticula, which usually occur in groups of multiple lesions, affect patients with bladder outflow obstruction or neurogenic bladder, and are more common in men over age 60 years, owing to the high Competing interests The authors declare no competing interests.
prevalence of prostatic enlargement. As such, they are often associated with substantial trabeculations in the main bladder.2,9–12 In the only published autopsy study to investigate the prevalence of bladder diverticula, 23.4% of cadavers had bladder diverticula, most of which were asymptomatic during life.5 Bladder diverticula are associated with urinary stasis, which can lead to an increased risk of UTI, bladder calculi, and neoplasms, owing to prolonged exposure to carcinogens such as aromatic amines from cigarette smoke.3,6,13–17 Bladder tumours within bladder diverticula account for 0.8–10.8% of all vesical tumours.4,14,18,19 Given the relatively low prevalence of symptomatic diverticula, most of the data relating to diverticula and associated pathologies have been gathered from case reports or case series and very few large-scale prospective studies are available to formulate guidelines for the standardization of management. From the limited existing data, it seems that most patients present in their 60s (although age at presentation has been reported to range from 44–88 years),13 and intradiverticular bladder tumours (IDBTs) are 11–12 times more common in men than in women. In this article, we review the existing literature on IDBTs and highlight the challenges that exist in the management of malignant and premalignant conditions within bladder diverticula. We also outline the only guidelines currently available for the management of IDBT, the Cancer Committee of the French Association of Urology (CCAFU) guidelines,20 and provide our own recommendations as a framework for the diagnosis and treatment of these conditions.
NATURE REVIEWS | UROLOGY
VOLUME 11 | JULY 2014 | 383 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Intradiverticular bladder tumours (IDBT) are rare, accounting for approximately 1% of all bladder tumours; the true prevalence of bladder diverticula is not known as most are asymptomatic ■■ Urine cytology, ultrasonography, and cystoscopy should be used in the initial assessment of a suspected IDBT; cross-sectional imaging can complement these techniques, and is also important in staging ■■ Bladder-conserving treatments including transurethral resection, diverticulectomy, or partial cystectomy with or without intravesical adjuvant therapy can be used in patients with low-grade, low-volume, noninvasive disease ■■ Radical cystectomy, with or without systemic neoadjuvant or adjuvant therapy, is required for patients with large, invasive tumours, or tumours that are associated with poor bladder function (chronic retention) ■■ 5-year survival rates of 72% and 45% have been reported for patients with IDBT and, specifically, T3 IDBTs, respectively; these rates are comparable to those for intravesical bladder cancer
Diagnosis Urine cytology The diagnosis of IDBT is made using a similar array of tests to those used for the diagnosis of tumours in the main bladder, including urine cytology, imaging, cysto scopy, and histopathological examination of a resected specimen.21,22 Urine cytology is the pathological examination of voided urine for exfoliated cancer cells.19 It is a highly specific and noninvasive diagnostic tool; however, although highly sensitive for high-grade tumours and carcinoma in situ (CIS; up to 80–90% sensitivity), lower sensitivity has been reported for low-grade tumours (around 20%) owing to a lower volume of cells shed from these tumours, as well as more subtlety in the type of cellular changes seen.23 In patients with IDBT, sensitivity might be further compromised if the ostium of the bladder diverticulum is very narrow. The presence of UTI, stones, or inflammation as a result of recent bladder instillations or instrumentation can make the interpretation of urine cytology more difficult. Cytological interpretation is user-dependent and has a specificity of >90% if done by an experienced cytopathologist.24 We recommend cytology as a useful adjunct in the detection of IDBT, especially for high-grade tumours, and this test is particularly useful in cases when cystoscopy is not feasible. However, given the low sensitivity of cytology for low-grade tumours, it is important to be careful with regards to false-negative results. Cytology is also valuable in the follow-up assessment of patients who have had bladder‑conserving treatment for IDBTs. Cystoscopy Cystoscopic assessment can be compromised if the neck of the diverticulum is too narrow to allow passage of the cystoscope;25 a flexible ureteroscope might be of value in this situation. Knappenberger et al.26 reported that, if a patient has a bladder diverticulum and bladder cancer, then the bladder tumour is more likely to arise from the diverticulum than from the main bladder. This observation is supported by two studies of patients with blad der tumours and bladder diverticula; in these studies, tumours were found within the diverticula (rather than in the main bladder) in 31 of 48 (64.6%) patients and 384 | JULY 2014 | VOLUME 11
seven of eight (87.5%) patients, respectively.6,14 It is, therefore, imperative to inspect the entire mucosa of the diverticulum during diagnostic cystoscopy if anatomy permits; this might require the use of a 70° lens, as well as standard 12° or 30° cystoscopes.
Imaging If cystoscopic inspection of the diverticulum is not possible, imaging will have a crucial role in diagnosis and staging. An ideal imaging technique would detect all IDBTs with high sensitivity and specificity, and reliably ascertain the level of tumour invasion. Ultrasonography and cross-sectional imaging have different roles in the investigation of bladder diverticula and IDBT. As part of the initial assessment of haematuria or infection, ultrasonography might identify a bladder diverticulum or an IDBT. Ultrasonography can also determine how well a bladder diverticulum empties on voiding. The CCAFU IDBT guideline suggests that ultrasonography is useful for diagnosing larger tumours but its sensitivity is poor if the IDBT is
