Journal of Pediatric Urology (2015) 11, 26.e1e26.e5
Bladder urothelial neoplasms in pediatric age: Experience at three tertiary centers A. Berrettini a, M. Castagnetti b, A. Salerno c, S.G. Nappo c, G. Manzoni a, W. Rigamonti b, P. Caione c a
Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 10, 20122 Milano, Italy
b Section of Paediatric Urology, Urology Unit, Department of Oncological and Surgical Sciences, University Hospital of Padova, Via Giustiniani, 2, 35128 Padua, Italy c Department NephrologyUrology, Division of Pediatric Urology, ‘Bambino Gesu `’ Children’s Hospital Rome, IRCCS, Piazza S. Onofrio, 4, 00165 Roma, Italy
Correspondence to: M. Castagnetti, Section of Paediatric Urology, Urology Unit, Department of Oncological Sciences, University Hospital of Padova, Monoblocco Ospedaliero, Via Giustiniani, 2, 35100 Padua, Italy, Tel.: þ39 049 8212737; fax: þ39 049 8212721 [email protected] (A. Berrettini) [email protected], [email protected] (M. Castagnetti) [email protected] (A. Salerno) [email protected] (S.G. Nappo) [email protected] (G. Manzoni) [email protected] (W. Rigamonti) [email protected] (P. Caione) Keywords Urothelial tumors; Bladder tumors; Children; Painless hematuria; Transurethral resection Received 21 February 2014 Accepted 11 August 2014 Available online 28 September 2014
Summary Introduction Urothelial bladder neoplasms (UBN) typically occur in patients in their sixth or seventh decade of life while they are infrequent in children and young adults. They occur in 0.1e0.4% of the population in the first two decades of life. Their management is controversial and paediatric guidelines are currently unavailable. Objective To further expound the available data on the outcome of patients younger than 18 year old diagnosed with UBN. Study design We retrospectively reviewed the files of all the consecutive paediatric patients with UBN treated in three tertiary paediatric urology units from January 1999 to July 2013. Lesions were classified according to the 2004 WHO/ISUP criteria as urothelial papillomas (UP), papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma (LGUC), and high-grade urothelial carcinoma (HGUC). Results The table shows the results. No. of pt Sex Age at diagnosis Mean (range) yr Presenting symptom Workup imaging
18 Males
Gross haematuria Ultrasound (US) US + CT scan
Lesion size Mean (range) mm Intravescical location
Surgical treatment
Additional treatments Histology
Lateral wall Posterior wall Para-ureteral Meatus Trans-urethral resection of bladder (TURB) Intravesical instillation Mitomycin-C UP PUNLMP LGUC HGUC
9 11 (3e17) 16 14 3 16.7 (5e50) 4 6 8 18
1
8 8 1 1
Management after TURB varied among centres. One centre recommended only follow-up US at increasing intervals whereas another follow-up US plus urine cytologies and endoscopies, every three months in the first year, and at increasing intervals thereafter. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed disease recurrence or progression. Discussion UBN is an uncommon condition in children and adolescents and, unlike in adults, its incidence, follow-up and outcome still controversial. Paediatric guidelines are currently lacking and management varies among centres. Gross painless haematuria is the most common presenting symptom. Therefore, this symptom should never be underestimated. US is generally the first investigation and additional imaging seems unnecessary. TURB often allows for complete resection. Lesions are generally solitary, non-muscle invasive, and low-grade (mainly UP and PUNLMP). Ideal follow-up protocol is the most controversial point. Reportedly, recurrence or progression during follow-up is uncommon in patients under 20 years, recurrence rate 7% and a single case of progression reported so far. Accordingly, a follow-up mainly based on serial US might be considered in this age group compared to adults where also serial endoscopies and urine cytologies are recommended. In the selection of the follow-up investigations, it should also be taken into consideration that urine cytology has a low sensibility in the detection of low-grade lesions while cystoscopy in young patients requires a general anaesthesia and hospitalization, and carries an increased risk of urethral manipulation. Conclusion UBN is a rare condition in children. Ultrasound is generally accurate in order to visualize the lesion, and TURB can treat the condition. Lesions are generally low-grade and non-muscle invasive, but high-grade lesions can also be detected. In present series, after TURB, follow-up US monitoring at increasing intervals was used at all centres, followup cystoscopies were added in two centres, but with different schedules. Urine cytologies were considered only at one centre. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed recurrence or progression of the disease.
http://dx.doi.org/10.1016/j.jpurol.2014.08.008 1477-5131/ª 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Bladder urothelial neoplasms in pediatric age
Introduction Urothelial bladder neoplasms (UBN) typically occur in patients in their sixth or seventh decade of life, often in relation to a history of smoking or occupational exposure to carcinogenic agents; they are infrequent in children and young adults. Reportedly, they occur in 1e2.4% of the population younger than 40 years, and in 0.1e0.4% of the population in the first two decades of life [1,2]. Given the small number of cases, prognosis of UBN in children is poorly known, and their management is controversial as pediatric guidelines are currently unavailable. One option is to manage these patients by periodical imaging and endoscopic controls, according to common practice in adults [3]. Nevertheless, some authors advocate that UBN in the first two decades of life is a peculiar clinical entity, with a clinical behavior different from the condition seen in adults. They are often solitary, low-grade and nonmuscle invasive, and seem to have minimal potential for local recurrence or progression [4]. Accordingly, a less aggressive approach has been advocated [4]. The present study reports the experience with UBN at three tertiary pediatric urology centers, in order to expound the available data on the outcome of these tumors.
Materials and methods The files of all the consecutive pediatric patients with UBN, treated in three tertiary Italian pediatric urology units from January 1999 to July 2013, were retrospectively reviewed. In all the cases, the diagnosis was confirmed histologically according to the 2004 World Health Organization/International Society of Urological Pathology (2004 WHO/ISUP) criteria [5]. Cases without endoscopic and histological confirmation of the lesion, and those with bladder tumors other than urothelial neoplasm, were excluded. Lesions were classified according to the 2004 WHO/ISUP criteria as: urothelial papillomas (UP), papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma (LGUC), and high-grade urothelial carcinoma (HGUC) [5]. Data gathered for each study case included gender, age at diagnosis, symptom of presentation, size, location and histology of the lesion, imaging performed for work-up, stage, treatment, follow-up and final outcome in terms of disease progression or recurrence. Given the small sample size, only descriptive statistics were used. Categorical variables were expressed as ratios, and continuous ones as medians (ranges).
26.e2 where a 15 mm lesion was discovered during a routine ultrasound (US) in the absence of urinary symptoms. Urinary tract US was the initial investigation in the 17 patients with a preoperative diagnosis. It showed a solitary bladder lesion with a larger median diameter of 17 mm (range 5e50 mm). In the patient with the incidental diagnosis during endoscopy, the last US had been performed five months before the endoscopy and did not show any evidence of the lesion after retrospective review. This patient was also the only case in the present study with evidence of upper urinary tract dilatation; they had a hydroureteronephrosis with an antero-posterior pelvic diameter of 12 mm and a retro-vesical ureter of 7 mm. All the patients underwent cystoscopy and transurethral resection of the bladder (TURB). Cystoscopy confirmed the presence of a solitary lesion in all of the patients. The tumor was located on the lateral wall of the bladder in four cases, on the posterior wall above the trigone in six, and near the ureteral orifices in the eight remaining patients. The endoscopic resections always appeared to be macroscopically complete. No postoperative complications were observed. On histological examination, the removed specimen turned up to be a UP in eight cases, a PUNLMP in eight cases, a LGUC in one case and a HGUC in one case. Distribution of the lesions by age is reported in Table 1. None of the lesions had histological evidence of invasion of the underlying tissues, namely: all were non-muscle invasive. In one center, three patients underwent a Computer Tomography (CT) scan for staging after TURB. The scan showed no evidence of additional lesions. No radiological work-up was performed in the other two centers. One patient with histological diagnosis of PUNLMP received a single intravesical instillation of Mitomycin C after TURB. No intravesical therapy was otherwise used. Table 2 summarizes the follow-up investigations performed at the three centers. At all centers, US monitoring at increasing intervals was used. Follow-up cystoscopies were used in two centers, but with different schedules. Urine cytologies were considered in one center. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed recurrence or progression of the disease.
Discussion In this retrospective study of patients with UBN younger than 18 years, all the lesions were solitary and non-muscle invasive, and all but one were low-grade. Transurethral Table 1
Results A total of 18 patients (nine males), who were followed-up during the study period, were identified. Median age at diagnosis was 11 years (range 3e17), with the age distribution reported in Table 1. The presenting symptom was painless gross hematuria in 16 cases, while in two cases the diagnosis was incidental. The latter included a three-yearold boy, in whom a 12 mm lesion was discovered during a cystoscopy for endoscopic treatment of VUR in a duplex system, and a 12-year-old girl with acanthosis nigricans,
Distribution of tumors by age.
Age range
Number of patients
Histology
15-years old
2
1 1 1 4 1 2
UP UP; 4 PUNLMP; LGUC UP; 4 PUNLMP; HGUC UP
UP: urothelial papilloma; PUNLMP: papillary urothelial neoplasm of low malignant potential; LGUC: low-grade urothelial carcinoma; HGUC: high-grade urothelial carcinoma.
26.e3
A. Berrettini et al.
resection was complete in all, follow-up protocols varied among centers, but no recurrence was observed during follow-up. Urothelial bladder neoplasms are an uncommon condition in children and adolescents. In the present collaborative study, 18 cases were diagnosed over a 14-year period in three pediatric urology units in Italy. The actual incidence of the condition is difficult to determine, due to a possible publication bias of series reporting higher incidences, and the use of different cut offs to define ‘young patients’, i.e. 20, 30, or even 40 years of age [6,7]. Concerning patients younger than 18 years, as in present series, the Surveillance Epidemiology and End Results database, which is estimated to cover about one fourth of the USA population, included 84 cases diagnosed with UBN between 1973 and 2003 [2]. Urothelial bladder neoplasms were the predominant bladder tumor occurring in patients younger than 18 years, in fact, 80% were diagnosed between 13 and 18 years of age [2]. According to a recent systematic review, 103 cases younger than 20 years were reported between 1960 and 2010; two third were in patients older than 15 years, whereas only 14 were in patients younger than 10 years [8]. As in previous reports [8e10], gross painless hematuria was the most common presenting symptom, and urinary tract US was almost invariably the first investigation that was performed. Ultrasound generally proved to be specific, i.e. had no false positives, and was capable of detecting lesions as small as 5 mm. The only case without preoperative US detection of the mass was a patient with VUR, where the US had been performed 5 months before the endoscopy; it is possible that the lesion grew in the time elapsed between the last US and the endoscopy. Paner et al. reported that delayed diagnosis occurs in up to one fourth of pediatric patients with UBN [8]. Diagnosis can also be delayed in symptomatic patients because painless hematuria is often considered to be a benign condition in children, and additional investigations are only performed if the symptom persists [11]. This emphasizes the importance of performing bladder US in any patients with any degree of hematuria that is not associated with UTI or trauma [12]. In two centers, no workup investigations were performed after US, whereas in the remainder, a CT scan was performed, as it is standard practice in adults [13]. The scan showed no evidence of additional lesions in any patients. Hence, the costs of the procedure and the risks of exposure to radiation should be balanced against the disease likelihood in the young patient cohort [8,12].
Table 2
In all the cases, a cystoscopy was performed in order to confirm the presence of the tumor and to obtain a specimen for histological diagnosis. Consistently with previous reports [4,8,10], all the lesions were solitary and non-muscle invasive. The more prevalent histological variants were UP and PUNLMP, with eight cases each. Papillary urothelial neoplasm of low malignant potential is a histological variant that was introduced in the 2004 WHO/ISUP classification [5] to describe a UBN with low biological risk of progression [9]. The introduction of PUNLMP histological variant has essentially caused a downgrading of a few lesions that were previously labeled as bladder cancers grade 1 or 2 [10]. Two patients had other histological variants including LGUC and HGUC. It is believed that only seven cases of HGUC in patients younger than 18 years old have previously been reported [8,14,15]. In all cases in the present study, TURB allowed for complete resection of the lesion. Management after TURB of young patients diagnosed with UBN is controversial, as guidelines for pediatric patients are currently lacking. All the guidelines in adults recommend the management to be individualized, based on a risk stratification of patients, but all recommend at least a single postoperative instillation of intravesical chemotherapy, and serial endoscopies for follow-up [13,16e18]. In the present study, only one patient received an intravesical instillation of Mitomycin C right after TURB; this was quite an early patient in the study. Such a treatment has occasionally been used in children [10], but it is not recommended in most of the recent studies [3,4,8,10]. Attitudes for long-term disease surveillance varied widely among the three centers. One center performed follow-up US, urine cytologies and endoscopies every three months in the first year, and at increasing intervals thereafter. Another only recommended follow-up ultrasound at increasing intervals. Such variability is common in the literature [3,4,8,10,19]. The issue lies in the fact that the intensity of follow-up should be proportional to the risk of disease recurrence or progression, and information on the natural history of UBN in children is inconsistent. Some studies have suggested that these tumors might have a biological and clinical behavior similar to the same condition in adults, thereby requiring aggressive follow-up [20,21]; others, that they might have a substantially benign clinical course, making aggressive follow-up unnecessary [7,8,10]. As mentioned before, the two major factors confounding the dispute are the variable cut offs used to define young patients [6e8], and the evolving classification with the introduction of the PUNLMP variant [10]. Paner et al. stratified all the cases
Surveillance investigations performed at the three centers.
Investigation
Center 1
Center 2
Center 3
Ultrasound
Three, six and twelve months, then annually
Three, six and twelve months, then annually
Cystoscopies
Every three months in the first year Every six months in the second year Yearly thereafter for five years Same schedule as for ultrasound
No
Urine cytology
Same schedule as for ultrasound
At thee months. If negative, no additional endoscopies No
No
Bladder urothelial neoplasms in pediatric age reported so far by the decade of life, and noted a striking difference in the prevalence of low-grade lesions and outcome between patients diagnosed in the first two decades of life compared to those diagnosed in the following two [8]. Cumulative data of patients aged 20 years or younger (Table 3) suggest that urothelial bladder tumors in this age group have a low recurrence rate (around 7%), and progression almost never occurs (a single case of progression reported). From a biological point of view, these neoplasms might be an indolent variant of the tumors seen in adults, or an entirely different condition. Cytogenitic studies are underway [8,10]. Of note, the anecdotic cases of high-grade and invasive urothelial tumors, as well as those experiencing disease progression, almost invariably ended up with patient demise, which suggests that the low-grade and low-stage of the disease in the majority of pediatric patients plays an important role in determining the good outcome of these neoplasms in children [8,14,22e24]. Overall, the studies have clearly shown that despite the benign course, low-grade non-muscle invasive bladder urothelial tumors, including UP and PUNLMP, can recur [10]. Moreover, recurrences can be multiple and can occur many years after the initial diagnosis [3,10]. Fine et al. described a case detected after seven-and-a-half years of follow-up [10]. Therefore, the issue is to find the least invasive and most cost-effective tool that allows for long-term surveillance of patients with a condition carrying a low, but sizable risk of recurrence. Accordingly, cystoscopy, which is considered to be the standard in adults, seems too invasive in children as it may require hospitalization and a general anesthesia, and exposes to the risk of urethral manipulation. Urine cytology is non-invasive, but its sensitivity in detecting low-grade lesions is reportedly low [4,17]. Ultrasound seems intuitively to be the best tool, and it has been suggested to be extremely effective for surveillance
26.e4 [12]. In the present study, it proved specific for diagnosis and no discrepancies were observed between US and cystoscopy in the single center where both investigations were performed during follow-up. Nevertheless, Paduano and Chiella reported that recurrences were overlooked by US and detected only on endoscopy in two of their three cases [3]. Although US imaging has much improved since the late eighties, when this observation was done, accurate data about the sensitivity of the test is still lacking, i.e. the risk of false negatives. Limitations of present study include its retrospective nature, the small sample size, and the long study period. This impaired assessment of some variables, such as the smoking habit of patients and their parents, or the exposure to carcinogens. On the other hand, it is one of the largest series reported in this age group and length of follow-up was up to 14 years.
Conclusions Urothelial bladder neoplasms are a rare condition in children, and they almost invariably present with gross painless hematuria. Ultrasound is generally accurate in order to visualize the lesion, and endoscopy with transurethral resection should follow. Lesions are generally non-muscle invasive and low-grade, but high-grade lesions can also be detected. In the present series, transurethral resection was always complete and no recurrence was observed during follow-up. Nevertheless, recurrences have been reported; therefore, long-term follow-up is recommended. Pediatric guidelines for management and follow-up are currently unavailable, but disease surveillance after endoscopic resection might possibly be less aggressive than is generally recommended in adults, particularly for low-grade neoplasms.
Table 3 Reported risk of disease recurrence or progression in patients diagnosed with urothelial bladder neoplasms in the first two decades of life. Series Javadpour et al. J Urol 1969 [22] Benson et al. J Urol 1983 [23] Magdar et al. J Urol 1988 [6] Paduano et al. J Urol 1988 [3] Hoenig et al. J Urol 1996 [12] Fine et al. J Urol 2005 [10] Patel et al. Pediatr Surg Int 2008 [19] Lerena et al. J Pediatr Urol 2010 [4] Present study Total
Number of patients with follow-up
Length of follow-up mean/median (range)
Recurrences (%)
Progression
36
NA (3e20) years
1 (2.5)
1
12
6 (1e18) years
1 (8)
0
7
NA (2e16) years
0
0
3
3 (1.0e4.5) years
2 (66)
0
5
3.5 (0.7e6.0) years
1 (20)
0
23
4.5 (0.5e13.0) years
3 (13)
0
2
both 4 years old
0
0
6
3.2 (1.5e5.0) years
0
0
4.5 (0.5e13.0) years
0 8 (7)
0 1
18 112
26.e5
Conflict of interest statement None declared.
Ethical approval None sought.
Acknowledgment None declared.
References [1] Kutarski PW, Padwell A. Transitional cell carcinoma of the bladder in young adults. Br J Urol 1993;72:749e55. [2] Alanee S, Shukla AR. Bladder malignancies in children aged
Bladder urothelial neoplasms in pediatric age: Experience at three tertiary centers A. Berrettini a, M. Castagnetti b, A. Salerno c, S.G. Nappo c, G. Manzoni a, W. Rigamonti b, P. Caione c a
Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 10, 20122 Milano, Italy
b Section of Paediatric Urology, Urology Unit, Department of Oncological and Surgical Sciences, University Hospital of Padova, Via Giustiniani, 2, 35128 Padua, Italy c Department NephrologyUrology, Division of Pediatric Urology, ‘Bambino Gesu `’ Children’s Hospital Rome, IRCCS, Piazza S. Onofrio, 4, 00165 Roma, Italy
Correspondence to: M. Castagnetti, Section of Paediatric Urology, Urology Unit, Department of Oncological Sciences, University Hospital of Padova, Monoblocco Ospedaliero, Via Giustiniani, 2, 35100 Padua, Italy, Tel.: þ39 049 8212737; fax: þ39 049 8212721 [email protected] (A. Berrettini) [email protected], [email protected] (M. Castagnetti) [email protected] (A. Salerno) [email protected] (S.G. Nappo) [email protected] (G. Manzoni) [email protected] (W. Rigamonti) [email protected] (P. Caione) Keywords Urothelial tumors; Bladder tumors; Children; Painless hematuria; Transurethral resection Received 21 February 2014 Accepted 11 August 2014 Available online 28 September 2014
Summary Introduction Urothelial bladder neoplasms (UBN) typically occur in patients in their sixth or seventh decade of life while they are infrequent in children and young adults. They occur in 0.1e0.4% of the population in the first two decades of life. Their management is controversial and paediatric guidelines are currently unavailable. Objective To further expound the available data on the outcome of patients younger than 18 year old diagnosed with UBN. Study design We retrospectively reviewed the files of all the consecutive paediatric patients with UBN treated in three tertiary paediatric urology units from January 1999 to July 2013. Lesions were classified according to the 2004 WHO/ISUP criteria as urothelial papillomas (UP), papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma (LGUC), and high-grade urothelial carcinoma (HGUC). Results The table shows the results. No. of pt Sex Age at diagnosis Mean (range) yr Presenting symptom Workup imaging
18 Males
Gross haematuria Ultrasound (US) US + CT scan
Lesion size Mean (range) mm Intravescical location
Surgical treatment
Additional treatments Histology
Lateral wall Posterior wall Para-ureteral Meatus Trans-urethral resection of bladder (TURB) Intravesical instillation Mitomycin-C UP PUNLMP LGUC HGUC
9 11 (3e17) 16 14 3 16.7 (5e50) 4 6 8 18
1
8 8 1 1
Management after TURB varied among centres. One centre recommended only follow-up US at increasing intervals whereas another follow-up US plus urine cytologies and endoscopies, every three months in the first year, and at increasing intervals thereafter. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed disease recurrence or progression. Discussion UBN is an uncommon condition in children and adolescents and, unlike in adults, its incidence, follow-up and outcome still controversial. Paediatric guidelines are currently lacking and management varies among centres. Gross painless haematuria is the most common presenting symptom. Therefore, this symptom should never be underestimated. US is generally the first investigation and additional imaging seems unnecessary. TURB often allows for complete resection. Lesions are generally solitary, non-muscle invasive, and low-grade (mainly UP and PUNLMP). Ideal follow-up protocol is the most controversial point. Reportedly, recurrence or progression during follow-up is uncommon in patients under 20 years, recurrence rate 7% and a single case of progression reported so far. Accordingly, a follow-up mainly based on serial US might be considered in this age group compared to adults where also serial endoscopies and urine cytologies are recommended. In the selection of the follow-up investigations, it should also be taken into consideration that urine cytology has a low sensibility in the detection of low-grade lesions while cystoscopy in young patients requires a general anaesthesia and hospitalization, and carries an increased risk of urethral manipulation. Conclusion UBN is a rare condition in children. Ultrasound is generally accurate in order to visualize the lesion, and TURB can treat the condition. Lesions are generally low-grade and non-muscle invasive, but high-grade lesions can also be detected. In present series, after TURB, follow-up US monitoring at increasing intervals was used at all centres, followup cystoscopies were added in two centres, but with different schedules. Urine cytologies were considered only at one centre. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed recurrence or progression of the disease.
http://dx.doi.org/10.1016/j.jpurol.2014.08.008 1477-5131/ª 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Bladder urothelial neoplasms in pediatric age
Introduction Urothelial bladder neoplasms (UBN) typically occur in patients in their sixth or seventh decade of life, often in relation to a history of smoking or occupational exposure to carcinogenic agents; they are infrequent in children and young adults. Reportedly, they occur in 1e2.4% of the population younger than 40 years, and in 0.1e0.4% of the population in the first two decades of life [1,2]. Given the small number of cases, prognosis of UBN in children is poorly known, and their management is controversial as pediatric guidelines are currently unavailable. One option is to manage these patients by periodical imaging and endoscopic controls, according to common practice in adults [3]. Nevertheless, some authors advocate that UBN in the first two decades of life is a peculiar clinical entity, with a clinical behavior different from the condition seen in adults. They are often solitary, low-grade and nonmuscle invasive, and seem to have minimal potential for local recurrence or progression [4]. Accordingly, a less aggressive approach has been advocated [4]. The present study reports the experience with UBN at three tertiary pediatric urology centers, in order to expound the available data on the outcome of these tumors.
Materials and methods The files of all the consecutive pediatric patients with UBN, treated in three tertiary Italian pediatric urology units from January 1999 to July 2013, were retrospectively reviewed. In all the cases, the diagnosis was confirmed histologically according to the 2004 World Health Organization/International Society of Urological Pathology (2004 WHO/ISUP) criteria [5]. Cases without endoscopic and histological confirmation of the lesion, and those with bladder tumors other than urothelial neoplasm, were excluded. Lesions were classified according to the 2004 WHO/ISUP criteria as: urothelial papillomas (UP), papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade urothelial carcinoma (LGUC), and high-grade urothelial carcinoma (HGUC) [5]. Data gathered for each study case included gender, age at diagnosis, symptom of presentation, size, location and histology of the lesion, imaging performed for work-up, stage, treatment, follow-up and final outcome in terms of disease progression or recurrence. Given the small sample size, only descriptive statistics were used. Categorical variables were expressed as ratios, and continuous ones as medians (ranges).
26.e2 where a 15 mm lesion was discovered during a routine ultrasound (US) in the absence of urinary symptoms. Urinary tract US was the initial investigation in the 17 patients with a preoperative diagnosis. It showed a solitary bladder lesion with a larger median diameter of 17 mm (range 5e50 mm). In the patient with the incidental diagnosis during endoscopy, the last US had been performed five months before the endoscopy and did not show any evidence of the lesion after retrospective review. This patient was also the only case in the present study with evidence of upper urinary tract dilatation; they had a hydroureteronephrosis with an antero-posterior pelvic diameter of 12 mm and a retro-vesical ureter of 7 mm. All the patients underwent cystoscopy and transurethral resection of the bladder (TURB). Cystoscopy confirmed the presence of a solitary lesion in all of the patients. The tumor was located on the lateral wall of the bladder in four cases, on the posterior wall above the trigone in six, and near the ureteral orifices in the eight remaining patients. The endoscopic resections always appeared to be macroscopically complete. No postoperative complications were observed. On histological examination, the removed specimen turned up to be a UP in eight cases, a PUNLMP in eight cases, a LGUC in one case and a HGUC in one case. Distribution of the lesions by age is reported in Table 1. None of the lesions had histological evidence of invasion of the underlying tissues, namely: all were non-muscle invasive. In one center, three patients underwent a Computer Tomography (CT) scan for staging after TURB. The scan showed no evidence of additional lesions. No radiological work-up was performed in the other two centers. One patient with histological diagnosis of PUNLMP received a single intravesical instillation of Mitomycin C after TURB. No intravesical therapy was otherwise used. Table 2 summarizes the follow-up investigations performed at the three centers. At all centers, US monitoring at increasing intervals was used. Follow-up cystoscopies were used in two centers, but with different schedules. Urine cytologies were considered in one center. After a median follow-up of 5 years (range 9 monthse14.5 years), none of the patients showed recurrence or progression of the disease.
Discussion In this retrospective study of patients with UBN younger than 18 years, all the lesions were solitary and non-muscle invasive, and all but one were low-grade. Transurethral Table 1
Results A total of 18 patients (nine males), who were followed-up during the study period, were identified. Median age at diagnosis was 11 years (range 3e17), with the age distribution reported in Table 1. The presenting symptom was painless gross hematuria in 16 cases, while in two cases the diagnosis was incidental. The latter included a three-yearold boy, in whom a 12 mm lesion was discovered during a cystoscopy for endoscopic treatment of VUR in a duplex system, and a 12-year-old girl with acanthosis nigricans,
Distribution of tumors by age.
Age range
Number of patients
Histology
15-years old
2
1 1 1 4 1 2
UP UP; 4 PUNLMP; LGUC UP; 4 PUNLMP; HGUC UP
UP: urothelial papilloma; PUNLMP: papillary urothelial neoplasm of low malignant potential; LGUC: low-grade urothelial carcinoma; HGUC: high-grade urothelial carcinoma.
26.e3
A. Berrettini et al.
resection was complete in all, follow-up protocols varied among centers, but no recurrence was observed during follow-up. Urothelial bladder neoplasms are an uncommon condition in children and adolescents. In the present collaborative study, 18 cases were diagnosed over a 14-year period in three pediatric urology units in Italy. The actual incidence of the condition is difficult to determine, due to a possible publication bias of series reporting higher incidences, and the use of different cut offs to define ‘young patients’, i.e. 20, 30, or even 40 years of age [6,7]. Concerning patients younger than 18 years, as in present series, the Surveillance Epidemiology and End Results database, which is estimated to cover about one fourth of the USA population, included 84 cases diagnosed with UBN between 1973 and 2003 [2]. Urothelial bladder neoplasms were the predominant bladder tumor occurring in patients younger than 18 years, in fact, 80% were diagnosed between 13 and 18 years of age [2]. According to a recent systematic review, 103 cases younger than 20 years were reported between 1960 and 2010; two third were in patients older than 15 years, whereas only 14 were in patients younger than 10 years [8]. As in previous reports [8e10], gross painless hematuria was the most common presenting symptom, and urinary tract US was almost invariably the first investigation that was performed. Ultrasound generally proved to be specific, i.e. had no false positives, and was capable of detecting lesions as small as 5 mm. The only case without preoperative US detection of the mass was a patient with VUR, where the US had been performed 5 months before the endoscopy; it is possible that the lesion grew in the time elapsed between the last US and the endoscopy. Paner et al. reported that delayed diagnosis occurs in up to one fourth of pediatric patients with UBN [8]. Diagnosis can also be delayed in symptomatic patients because painless hematuria is often considered to be a benign condition in children, and additional investigations are only performed if the symptom persists [11]. This emphasizes the importance of performing bladder US in any patients with any degree of hematuria that is not associated with UTI or trauma [12]. In two centers, no workup investigations were performed after US, whereas in the remainder, a CT scan was performed, as it is standard practice in adults [13]. The scan showed no evidence of additional lesions in any patients. Hence, the costs of the procedure and the risks of exposure to radiation should be balanced against the disease likelihood in the young patient cohort [8,12].
Table 2
In all the cases, a cystoscopy was performed in order to confirm the presence of the tumor and to obtain a specimen for histological diagnosis. Consistently with previous reports [4,8,10], all the lesions were solitary and non-muscle invasive. The more prevalent histological variants were UP and PUNLMP, with eight cases each. Papillary urothelial neoplasm of low malignant potential is a histological variant that was introduced in the 2004 WHO/ISUP classification [5] to describe a UBN with low biological risk of progression [9]. The introduction of PUNLMP histological variant has essentially caused a downgrading of a few lesions that were previously labeled as bladder cancers grade 1 or 2 [10]. Two patients had other histological variants including LGUC and HGUC. It is believed that only seven cases of HGUC in patients younger than 18 years old have previously been reported [8,14,15]. In all cases in the present study, TURB allowed for complete resection of the lesion. Management after TURB of young patients diagnosed with UBN is controversial, as guidelines for pediatric patients are currently lacking. All the guidelines in adults recommend the management to be individualized, based on a risk stratification of patients, but all recommend at least a single postoperative instillation of intravesical chemotherapy, and serial endoscopies for follow-up [13,16e18]. In the present study, only one patient received an intravesical instillation of Mitomycin C right after TURB; this was quite an early patient in the study. Such a treatment has occasionally been used in children [10], but it is not recommended in most of the recent studies [3,4,8,10]. Attitudes for long-term disease surveillance varied widely among the three centers. One center performed follow-up US, urine cytologies and endoscopies every three months in the first year, and at increasing intervals thereafter. Another only recommended follow-up ultrasound at increasing intervals. Such variability is common in the literature [3,4,8,10,19]. The issue lies in the fact that the intensity of follow-up should be proportional to the risk of disease recurrence or progression, and information on the natural history of UBN in children is inconsistent. Some studies have suggested that these tumors might have a biological and clinical behavior similar to the same condition in adults, thereby requiring aggressive follow-up [20,21]; others, that they might have a substantially benign clinical course, making aggressive follow-up unnecessary [7,8,10]. As mentioned before, the two major factors confounding the dispute are the variable cut offs used to define young patients [6e8], and the evolving classification with the introduction of the PUNLMP variant [10]. Paner et al. stratified all the cases
Surveillance investigations performed at the three centers.
Investigation
Center 1
Center 2
Center 3
Ultrasound
Three, six and twelve months, then annually
Three, six and twelve months, then annually
Cystoscopies
Every three months in the first year Every six months in the second year Yearly thereafter for five years Same schedule as for ultrasound
No
Urine cytology
Same schedule as for ultrasound
At thee months. If negative, no additional endoscopies No
No
Bladder urothelial neoplasms in pediatric age reported so far by the decade of life, and noted a striking difference in the prevalence of low-grade lesions and outcome between patients diagnosed in the first two decades of life compared to those diagnosed in the following two [8]. Cumulative data of patients aged 20 years or younger (Table 3) suggest that urothelial bladder tumors in this age group have a low recurrence rate (around 7%), and progression almost never occurs (a single case of progression reported). From a biological point of view, these neoplasms might be an indolent variant of the tumors seen in adults, or an entirely different condition. Cytogenitic studies are underway [8,10]. Of note, the anecdotic cases of high-grade and invasive urothelial tumors, as well as those experiencing disease progression, almost invariably ended up with patient demise, which suggests that the low-grade and low-stage of the disease in the majority of pediatric patients plays an important role in determining the good outcome of these neoplasms in children [8,14,22e24]. Overall, the studies have clearly shown that despite the benign course, low-grade non-muscle invasive bladder urothelial tumors, including UP and PUNLMP, can recur [10]. Moreover, recurrences can be multiple and can occur many years after the initial diagnosis [3,10]. Fine et al. described a case detected after seven-and-a-half years of follow-up [10]. Therefore, the issue is to find the least invasive and most cost-effective tool that allows for long-term surveillance of patients with a condition carrying a low, but sizable risk of recurrence. Accordingly, cystoscopy, which is considered to be the standard in adults, seems too invasive in children as it may require hospitalization and a general anesthesia, and exposes to the risk of urethral manipulation. Urine cytology is non-invasive, but its sensitivity in detecting low-grade lesions is reportedly low [4,17]. Ultrasound seems intuitively to be the best tool, and it has been suggested to be extremely effective for surveillance
26.e4 [12]. In the present study, it proved specific for diagnosis and no discrepancies were observed between US and cystoscopy in the single center where both investigations were performed during follow-up. Nevertheless, Paduano and Chiella reported that recurrences were overlooked by US and detected only on endoscopy in two of their three cases [3]. Although US imaging has much improved since the late eighties, when this observation was done, accurate data about the sensitivity of the test is still lacking, i.e. the risk of false negatives. Limitations of present study include its retrospective nature, the small sample size, and the long study period. This impaired assessment of some variables, such as the smoking habit of patients and their parents, or the exposure to carcinogens. On the other hand, it is one of the largest series reported in this age group and length of follow-up was up to 14 years.
Conclusions Urothelial bladder neoplasms are a rare condition in children, and they almost invariably present with gross painless hematuria. Ultrasound is generally accurate in order to visualize the lesion, and endoscopy with transurethral resection should follow. Lesions are generally non-muscle invasive and low-grade, but high-grade lesions can also be detected. In the present series, transurethral resection was always complete and no recurrence was observed during follow-up. Nevertheless, recurrences have been reported; therefore, long-term follow-up is recommended. Pediatric guidelines for management and follow-up are currently unavailable, but disease surveillance after endoscopic resection might possibly be less aggressive than is generally recommended in adults, particularly for low-grade neoplasms.
Table 3 Reported risk of disease recurrence or progression in patients diagnosed with urothelial bladder neoplasms in the first two decades of life. Series Javadpour et al. J Urol 1969 [22] Benson et al. J Urol 1983 [23] Magdar et al. J Urol 1988 [6] Paduano et al. J Urol 1988 [3] Hoenig et al. J Urol 1996 [12] Fine et al. J Urol 2005 [10] Patel et al. Pediatr Surg Int 2008 [19] Lerena et al. J Pediatr Urol 2010 [4] Present study Total
Number of patients with follow-up
Length of follow-up mean/median (range)
Recurrences (%)
Progression
36
NA (3e20) years
1 (2.5)
1
12
6 (1e18) years
1 (8)
0
7
NA (2e16) years
0
0
3
3 (1.0e4.5) years
2 (66)
0
5
3.5 (0.7e6.0) years
1 (20)
0
23
4.5 (0.5e13.0) years
3 (13)
0
2
both 4 years old
0
0
6
3.2 (1.5e5.0) years
0
0
4.5 (0.5e13.0) years
0 8 (7)
0 1
18 112
26.e5
Conflict of interest statement None declared.
Ethical approval None sought.
Acknowledgment None declared.
References [1] Kutarski PW, Padwell A. Transitional cell carcinoma of the bladder in young adults. Br J Urol 1993;72:749e55. [2] Alanee S, Shukla AR. Bladder malignancies in children aged
