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Article of the Week: URB937 reduces PGE2-induced bladder overactivity

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats

Naoki Aizawa*, Giorgio Gandaglia†‡, Petter Hedlund§, Tetsuya Fujimura, Hiroshi Fukuhara, Francesco Montorsi, Yukio Homma¶ and Yasuhiko Igawa*

 

Departments of *Continence Medicine, Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan, Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy, Department of Clinical and Experimental Pharmacology, Lund University, Lund, and §Division of Drug Research, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden

 

Objective

To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E2 (PGE2) instillation in rats.

Materials and methods

In female Sprague–Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE2-induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Aδ- and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE2 (50 or 100 μm) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2, in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence.

May AOTW 2 resutls

Results

During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE2-induced changes in urodynamic variables. PGE2 increased the SAAs of C-fibres, but not Aδ-fibres. URB937 (1 mg/kg) depressed Aδ-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE2. The DRG nerve cells showed strong staining for FAAH, CB1 and CB2, with a mean (sem) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively.

Conclusion

The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE2, suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.

Editorial: Unmasking roles of the peripheral endocannabinoid system associated with bladder overactivity

Identifying regulatory roles of peripheral endocannabinoid systems for bladder function is a highly intricate task; nonetheless, in this issue of BJUI, a research report by Aizawa et al. [1] shows functional evidence for a role of fatty acid amide hydrolase (FAAH) in improving bladder overactivity induced by prostaglandin E2 (PGE2) in rats. By systemically blocking FAAH with URB937, an inhibitor of FAAH that does not penetrate the CNS, the authors found that afferent nerve activity and bladder cystometric parameters decreased in a rat overactive bladder model induced by intravesical perfusion of PGE2. Confirmation that ≈80% of dorsal root neurones at the Lumbar-6 dorsal root ganglia co-express FAAH and cannabinoid receptors 1 and 2 (CB1, CB2), emphasises the role of the peripheral endocannabinoid system during bladder overactivity induced by increased activity of C-fibres during PGE2 application.

Because FAAH catabolises CB ligands rapidly, a key regulatory role for pain perception was initially proposed [2]. Now, we recognise that the peripheral endocannabinoid system participates in both normal physiology and pathological conditions of the heart, liver, immune system, bone, skin, skeletal muscle, reproduction, and gastrointestinal tract [3]. The participation of the endocannabinoid system in regulating lower urinary tract function has been less studied; however, research evidence suggest an important regulatory role at different levels of the micturition reflex [4]. The study of Aizawa et al. [1] is important because it shows that the rat urinary bladder can be affected by the catabolism of endogenous ligands for CB1 and CB2 during systemic FAAH inhibition in conditions of bladder overactivity induced by PGE2. However, the experiments were performed in conditions where the urothelial cell layer was disturbed with the intravesical application of protamine sulphate. Although this seems to be the best approach to induce bladder overactivity with PGE2, it disturbs the sensory role of the urothelium for monitoring the urinary bladder filling status [5]. Thus, an alternative model for bladder overactivity requires an evaluation of an FAAH inhibitor. Supporting this suggestion, a recent report by Wang et al. [6] shows that intravesical application of a CB1agonist decreases bladder overactivity induced by intravesical nerve growth factor (NGF) in mice with an intact urothelial layer. Additionally, NGF did not induce bladder overactivity in knockout mice for the FAAH enzyme, reinforcing the suggestion for Aizawa et al. [1] about testing the peripherally-restricted inhibition of FAAH with URB937 in urothelium-intact rats.

The above comments and references recommend the performance of a pre-clinical evaluation of the endocannabinoid system using FAAH inhibitors to treat, for instance, neurogenic bladder overactivity in rats with spinal cord injury. Naturally, this overactive bladder model will prove to be more complicated and challenging to evaluate, but the results may provide overwhelming support for a rigorous assessment of the use of cannabinoids to treat urinary bladder dysfunction in humans [3]. At the mechanistic level it would be interesting to know at what part(s) of the micturition reflex is FAAH regulating bladder function. How significant is the catabolism of endogenous CB1/CB2 receptors during the storage and contraction phases of either normal or altered micturition? While the current study of Aizawa et al. [1] contributes to a deeper knowledge of the cannabinoid system in bladder dysfunction, additional studies are required to determine whether systemic inhibition of FAAH improves C-fibre mediated bladder sensory pathways in other animal models of detrusor and bladder overactivity.

Alvaro Munoz, Assistant Research Professor of Urology
Departments of Regenerative Medicine and Urology, Houston Methodist Research Institut e and Houston Methodist Hospital, Houston, TX, USA

 

References

 

 

2 Cravatt BF, Demarest K, Patricelli MP et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001; 98: 93716

 

3 Maccarrone M, Bab I, Bıro T et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015; 36: 27796

 

 

5 Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013; 93: 65380

 

 

Article of the week: Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by prominent members of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Angela Smith and David Johnson discussing their paper.

If you only have time to read one article this week, it should be this one.

Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity

David C. Johnson*, Matthew E. Nielsen*†‡, Jonathan Matthews*, Michael E. Woods*, Eric M. Wallen*, Raj S. Pruthi*, Matthew I. Milowsky*†§ and Angela B. Smith*

*Department of Urology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Cancer Outcomes Research Group, Multidisciplinary Genitourinary Oncology, Department of Epidemiology, Gillings School of Global Public Health, and §Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Read the full article
OBJECTIVE

To determine whether neoadjuvant chemotherapy (NAC) is a predictor of postoperative complications, length of stay (LOS), or operating time after radical cystectomy (RC) for bladder cancer.

PATIENTS AND METHODS

A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC before RC from 2005 to 2011. Bivariable and multivariable analyses were used to determine whether NAC was associated with 30-day perioperative outcomes, e.g. complications, LOS, and operating time.

RESULTS

Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. In all, 457 of the 878 patients (52.1%) undergoing RC had at least one complication ≤30 days of RC, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (P = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (P = 0.87), re-operation (P = 0.16), wound infection (P = 0.32), or wound dehiscence (P = 0.32). Using multiple linear regression, NAC was not a predictor of increased operating time (P = 0.24), and patients undergoing NAC had a decreased LOS (P = 0.02).

CONCLUSIONS

Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. Considering these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.

Editorial: Unveiling the surgical risk associated with neoadjuvant chemotherapy in bladder cancer

In this issue of BJU International, Johnson et al. [1] examine the association between neoadjuvant chemotherapy (NAC) for bladder cancer and 30-day morbidity related to radical cystectomy (RC). Level 1 evidence supports use of cisplatin-based NAC for bladder cancer; a meta-analysis of 11 randomised trials including 3005 patients who received NAC found a 5% absolute increase in 5-year overall survival and a 9% absolute increase in 5-year disease-free survival compared with RC alone [2]. Despite this, recent studies have reported underutilisation of NAC at ≈20% [3], with several reasons proposed for this ‘non-compliance’ to guidelines. A 2013 National Cancer Data Base (NCDB) analysis found that increasing age, lower patient income, and treatment at a non-academic institution (P < 0.01) negatively influenced the receipt of NAC, while higher clinical stage and fewer comorbid conditions were associated with higher likelihood of receiving NAC (P < 0.01) [3].

Another relevant concern is that NAC may increase perioperative complications for RC given the toxicities associated with chemotherapy, advanced age and often high rates of renal and cardiac comorbidities among potential candidates [4]. Credit should be given to Millikan et al. [5] for first negating this fear in 2001 with a randomised trial comparing NAC vs adjuvant chemotherapy in patients with bladder cancer; this study did not find any increase in perioperative morbidity.

The present analysis by Johnson et al. [1] further debunks this misconception in contemporary practice (2005–2011), drawing on the American College of Surgeons National Surgical Quality Improvement Program (NSQIP), which prospectively collects a sample of risk-adjusted validated surgical patient data from >450 participating USA hospitals. The authors show that NAC was not an independent predictor of complications, reoperation, wound infection or dehiscence. The robustness of these findings is reinforced by the shorter adjusted length of stay among patients receiving NAC. Given that scant data exists on this topic, the authors contribute a valuable paper that substantially adds to the literature.

Despite its strengths, the study should be interpreted in light of notable limitations that the authors acknowledge. Many crucial variables are not tracked by the NSQIP and therefore cannot be accounted for, including type of chemotherapy regimen, delay between chemotherapy and surgery, surgical technique (open, laparoscopic, robotic), surgical quality (margins, extent of lymphadenectomy), clinical/pathological stage of bladder cancer, and hospital/surgeon volume. Besides, because RC is a morbid procedure with a mean length of stay of 11 days, 30-day complication rates do not capture its true morbidity as well as 90-day rates. In particular, several common complications, such as postoperative ileus or small bowel obstruction, tend to occur later during the postoperative recovery period. As such, chances are that the event rate is biased downward by the short-term duration of data capture by the NSQIP. This study also cannot fully examine the association of NAC with certain subtypes of complications, including gastrointestinal or bleeding complications, especially when other investigators examining robotic RC have reported a conflicting increase in perioperative complications associated with NAC [6] driven by a 27% rate of gastrointestinal complications, which are not tracked by the NSQIP. Of note, unadjusted rates of transfusion and bleeding events were both higher in the NAC group in the present study.

One of the relevant and heartening observations of the report is the gradual increase in the use of NAC over the study period from 4% of eligible patients to 11%, close to the NCDB estimates of 7.6% in 2006 to 20.9% in 2010 (P < 0.01) [3]. Interestingly, there was an increased probability of any complication in the most recent time period (odds ratio 0.47 for 2005–2009 relative to 2010–2011 in the primary multivariate model, P < 0.001). A plausible explanation is that as physicians have heeded the message to increase usage of NAC, treatment has expanded into a wider population with more comorbidities and therefore a greater propensity for complications. It would have been of interest to address this point by restricting the analyses to the most recent data to see if NAC does indeed predict perioperative complications in the most recent period from 2010 to 2011.

Finally, given the lack of detail available in the NSQIP, other relevant questions could not be addressed. Among them it would be relevant to know if complication rates vary between standard MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and newer chemotherapy regimens such as dose dense MVAC (DD-MVAC) or gemcitabine plus cisplatin (GC). Similarly, the role of the delay or the elapsed time between chemotherapy and surgery on complications might be helpful in future trial planning.

Additional work still needs to be done to identify prognostic factors for both perioperative complications and long-term outcomes after NAC, so that this valuable therapy can be appropriately provided to the correct patients. Indeed, given the lack of randomised controlled trial data investigating less toxic regimens than MVAC, perhaps NAC is underused because clinicians and patients are underserved by the available data. The authors should be commended for their efforts in deconstructing possible barriers to increased uptake of NAC, a therapy known to confer survival benefits for our patients with bladder cancer.

Joaquim Bellmunt,* Jeffrey J.Leow and William Martin-Doyle§
*Bladder Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA; University Hospital Del Mar-IMIM, Barcelona, Spain; Brigham and Women’s Hospital, Division of Urology and Center for Surgery and Public Health, Boston, MA, USA; §University of Massachusetts Medical School, Worcester, MA, USA

Read the full article

References

  1. Johnson DC, Nielsen ME, Matthews J et al. Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. BJU Int 2014; 114: 221–228
  2. Bellmunt J, Orsola A, Wiegel T et al. Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Working Group. Ann Oncol 2011; 22 (Suppl. 6): 45–49
  3. Zaid HB, Patel SG, Stimson CJ et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 2014; 83: 75–80
  4. Meeks JJ, Bellmunt J, Bochner BH et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2012; 62: 523–533
  5. Millikan R, Dinney C, Swanson D et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001; 19: 4005–4013
  6. Johar RS, Hayn MH, Stegemann AP et al. Complications after robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium. Eur Urol 2013; 64: 52–57

Video: Time to increase use of multimodal therapy in bladder cancer

Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity

David C. Johnson*, Matthew E. Nielsen*†‡, Jonathan Matthews*, Michael E. Woods*, Eric M. Wallen*, Raj S. Pruthi*, Matthew I. Milowsky*†§ and Angela B. Smith*

*Department of Urology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Cancer Outcomes Research Group, Multidisciplinary Genitourinary Oncology, Department of Epidemiology, Gillings School of Global Public Health, and §Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Read the full article
OBJECTIVE

To determine whether neoadjuvant chemotherapy (NAC) is a predictor of postoperative complications, length of stay (LOS), or operating time after radical cystectomy (RC) for bladder cancer.

PATIENTS AND METHODS

A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC before RC from 2005 to 2011. Bivariable and multivariable analyses were used to determine whether NAC was associated with 30-day perioperative outcomes, e.g. complications, LOS, and operating time.

RESULTS

Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. In all, 457 of the 878 patients (52.1%) undergoing RC had at least one complication ≤30 days of RC, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (P = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (P = 0.87), re-operation (P = 0.16), wound infection (P = 0.32), or wound dehiscence (P = 0.32). Using multiple linear regression, NAC was not a predictor of increased operating time (P = 0.24), and patients undergoing NAC had a decreased LOS (P = 0.02).

CONCLUSIONS

Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. Considering these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.

Pheochromocytomas of the vesical and paravesical region

We report our experience with four cases of vesical and paravesical pheochromocytomas treated in our hospital over the past 15 years.

Authors: Nitin Kapoor1,M.S Seshadri 1,Nihal Thomas1, Antony Devasia2

John Banerjee2, Ramani Manoj Kumar3,Simon Rajaratnam1
1. Department of Endocrinology; 2 Department of Urology;   3 Department of Pathology,  Christian Medical College, Vellore, India

Corresponding Author: Dr Simon Rajaratnam, Department of Endocrinology, Diabetes & Metabolism,  Christian Medical College, Vellore, India. 632004.   Email: [email protected] ; Phone: +91-416-2282528

 

Abstract

 

Purpose
Pheochromocytomas of the urinary bladder are extremely rare. They account for less than 0.06% of all the tumors arising from the urinary bladder. Even though 10% of pheochromocytomas occur at extra adrenal sites, barely 1% arise from the urinary bladder. Embryonic rests of chromaffin tissue within the sympathetic plexus in the bladder wall are the source of these tumors. Due to varied symptomatology and nonspecific physical findings, a high index of suspicion is required for accurate diagnosis. Therapeutic strategies are not well-defined owing to the rarity of these tumors.

 

Material and Methods
We report a series of four cases of vesical and para vesical pheochromocytoma treated in our hospital over the past 15 years. Here, the authors have described the clinical presentation, physical findings, laboratory investigations and treatment provided in all the 4 cases. We have also included radiological images and histopathology slides with input from both radiologists and pathologists. Surgical management and post-operative follow up are discussed, as are details of previous published data.

 

Results and Conclusion
Bladder pheochromocytomas are rare but unique tumors. We share our experience with four cases treated in our hospital.

 

Introduction
Pheochromocytomas of the urinary bladder are extremely rare. They account for less than 0.06% of all tumors arising from the urinary bladder. [1, 2] Even though 10% of pheochromocytomas occur in extra adrenal sites, barely 1% arise from the urinary bladder.[3] Embryonic rests of chromaffin tissue arising from the sympathetic plexus within the bladder wall are the source of these tumors .[4] Due to varied symptomatology and nonspecific physical findings, a high index of suspicion is required for accurate diagnosis. Therapeutic strategies are not well-defined owing to the rare occurrence of these tumors.
We report our experience with four cases of vesical and paravesical pheochromocytomas treated in our hospital over the past 15 years.

 

Case Report 1
A 28 year old woman presented in 1996 with a history of recurrent episodes of chest pain with profuse sweating and palpitation for 4 years, 5 these episodes usually occurred during micturition or soon after micturition. One month prior to admission she also had an episode of hematuria. Prior to the onset of her symptoms she went through two uneventful vaginal deliveries. Her family history was unremarkable.
On examination, her pulse rate was 90/min and blood pressure 140/90 mmHg. After micturition her pulse rate increased to120/min and blood pressure increased to 160/110 mmHg. Cardiovascular, respiratory system, abdominal and CNS examination were all normal. No bruits were heard over the abdomen.  Fundus examination revealed grade 2 hypertensive changes.
Her full blood count and urea and electrolytes were normal. Urine microscopy was normal; there was no proteinuria or glycosuria. Twenty four hour urinary Vanillyl Mandelic Acid (VMA) levels were elevated  at 8 mg and 11mg (normal <7 mg/24 hours). ECG revealed sinus tachycardia with no evidence of LVH. Chest X ray was normal. Ultrasound revealed an intravesical mass extending into the perivesical space. MIBG (Meta-Iodo-Benzyl-Guanidine) scan showed tracer uptake over the tumor.
After adequate control of blood pressure she underwent partial cystectomy. The post operative period was uneventful and all anti-hypertensive agents were successfully withdrawn. She has remained asymptomatic on follow up.

 

Case Report 2
A 50 year old man who was being treated for diabetes and hypertension presented in 1999,  with a one year history of fatigue, weight loss, palpitations and breathlessness. Routine ultrasound examination revealed a paravesical mass. CT scan revealed a large 10 x 10 cm heterogeneous mass at the superior aspect of the prostate and base of the bladder, extending up to the symphysis pubis. He had no bowel or micturition related symptoms. He underwent laparotomy at his local hospital.  Since the tumor could not be excised he was referred to us for further management. A biopsy was reported as showing a paraganglioma. MIBG scan showed uptake over the tumor. He underwent cysto-prostatectomy with Mainz II pouch diversion. The immediate post-operative period was uneventful, however  he later developed sepsis and succumbed on the 10th postoperative day.

 

Case Report 3
A 28 year old woman, presented in 2010 with a history of intermittent severe headache for 15 years. Two years following the onset of these symptoms she had an episode of severe headache and loss of consciousness. She was hospitalized and was found to have sustained a right hemiparesis secondary to an intracerebral bleed. She gradually regained motor power on the affected side, but continued to experience frequent headaches.
One year before she started complaining of blurring of vision and was found to have severe hypertension. Her documented blood pressure readings were as high as 210/140 mmHg. She complained of severe headache, palpitations and sweating following micturition.
On examination her blood pressure was 150/110 mmHg. Following micturition her blood pressure rose to 190/130 mmHg. There were no bruits over her abdomen. She had grade 1 hypertensive changes in her fundi. The rest of the systemic examination was normal.
On investigation she had mild anemia. Her serum calcium, phosphorus, electrolytes and creatinine were normal. Urine examination showed no abnormality. Her chest X-ray, ECG and echocardiogram showed left ventricular hypertrophy. Her 24 hour urinary metanephrine level was 88 μg/1450 ml (normal < 350 μg/24 hour) and urinary
nor-metanephrine level was 1848 μg/1450 ml (normal <600 μg/24 hour).
 CT angiogram revealed a 4.3 x 4 cm hypervascular mass in the inferolateral wall of the urinary bladder bulging into the lumen. Her MIBG scan however showed no uptake over the lesion.
After adequate control of blood pressure she proceeded to surgery. Cystoscopy revealed a normal external urethral meatus, normal urethra and ureteric orifices. The bladder mucosa appeared normal. At laparotomy, there was a 5 x 5 cm mass involving the anterior and left lateral wall of the bladder. At cystotomy, the mucosa appeared normal but the tumor could be felt extending up to the bladder neck, adjacent to the ureteric orifice.  A partial cystectomy was performed and the tumor was excised with a margin beyond its palpable edge. The postoperative period was uneventful and her anti-hypertensive medication was discontinued. Histopathological examination revealed features of pheochromocytoma, with typical ‘zell-ballen’ arrangement of tumour cells, separated by a delicate network of capillary sized blood vessels. There was mild nuclear pleomorphism, but no evidence of malignancy. The tumour cells were positive for Chromogranin A, synaptophysin, and negative for cytokeratin (Fig 1 & 2).

 

Figure 1.

 

Figure 2.

 

At subsequent follow up her urinary nor- metanephrine level had normalized (180 µg/24 hours), she however needed to be restarted on antihypertensive medication. Follow up cystogram was normal.

 

Case Report 4
A 24 year old man presented in 2011 with intermittent painless hematuria for 12 years. There was no history of headache, blurred vision, palpitations or syncope. He was not on any medication. He had been evaluated elsewhere and found to have a bladder tumor for which he underwent 4 transurethral resections over a period of 9 years. An open resection was also attempted but surgery was abandoned as the patient developed extremely high intraoperative blood pressure.

 

The patient was evaluated at our centre and found to have elevated urinary nor-metanephrine levels (3019 µg/24 hours) and normal urinary metanephrine levels (141 µg/24 hours). His MIBG scan showed a functioning neuroendocrine tumor in the superolateral aspect of the bladder. CT scan revealed a well defined enhancing mass lesion arising from the right lateral wall of the urinary bladder.

 

Figure 3.

 

Cystoscopy under general anesthesia revealed a 3 x 3 cm extra mucosal mass arising from the right lateral bladder wall, above the right ureteric orifice. There was a 1X1cm ulcerated area at the center of the lesion. The left ureteric orifice and the rest of the bladder mucosa were found to be normal. We proceeded with excision of the mass with partial cystectomy. The mass was found to be adherent to the lateral pelvic wall probably due to previous attempts at excision. There was no fluctuation of blood pressure during surgery. Histopathology of the tumour came back as showing malignant pheochromocytoma arising from the bladder wall. On follow up his urinary metanephrine levels have normalized and he has remained asymptomatic.

 

Figure 4.

 

Figure 5. 

 

Discussion
Pheochromocytoma of the urinary bladder is a rare tumor. Such tumors arise from the chromaffin tissues associated with sympathetic nerves located within the bladder wall. They are hormonally active and cause symptoms including palpitations, sweating, headache and hypertension (paroxysmal/sustained). These symptoms are usually precipitated by micturition.[6] A rise in blood pressure can be demonstrated immediately following micturition. The other precipitating factors include abdominal palpation, defecation and sexual intercourse. However, not all patients demonstrate these signs and symptoms due to receptor down regulation following prolonged catecholamine exposure. Signs and symptoms of urethral obstruction may also occur. [7] Painless hematuria occurs in 50-60% of patients. The diagnosis of this condition warrants a high index of clinical suspicion.
The most useful laboratory test is to determine blood and urinary catecholamine levels and measure their metabolic byproducts. Urinary VMA levels >9.0 mg/24 hours, nor epinephrine > 80 μg/24 hours and epinephrine > 20 μg/24 hours have been found in most patients. While CT/MR aid in the anatomical localization of these tumors, iodine-131– metaiodobenzylguanidine (MIBG) and indium-111 pentoctreotide  scintigraphy serve as complementary functional diagnostic tools as they have 85-100% sensitivity in localizing these tumors.[8,9] One of our patients, (case 3) however had a negative MIBG scan. Positron emission tomography (PET) using 6 – [18F] fluorodopamine is a more recently developed tool for imaging these tumors.
As preoperative preparation patient require alpha adrenoreceptor blockers for at least 2 weeks, beta blockers are subsequently added to  control heart rate. They also need adequate hydration to increase intravascular volume prior to surgery.
Most vesical pheochromocytomas are intramural as the sympathetic plexus is scattered between all the layers of the bladder wall. At cystoscopy these tumors may appear granulated and lobulated with or without ulceration.[2] Transurethral resection is not recommended as it will not remove the entire tumor. Open surgery is required to completely resect these tumors. [2,7,11] Laparoscopic tumor resection has also been attempted.[10]
As part of the intraoperative strategy, the use of cystoscopic examination may help delineate the exact location of these tumors and identify the depth of invasion and the involvement of the ureters. However, cystoscopic examination in case 3 was non-contributory probably due to the intramural nature of the tumor. In this case excision with a margin was guided by palpation. A thorough examination of surrounding structures and regional lymph nodes should be done as the malignant potential of these tumors is predicted not by histology but by clinical evaluation. In addition, these patients should also be monitored for post-operative complications such as  stricture or obstruction at the urethral reimplantation site.
Overall, pheochromocytomas of the urinary bladder have a slightly better prognosis as compared to other extra adrenal pheochromocytomas. As these tumors are known for recurrence and metastases, these patients will require lifelong follow up. Though the diagnosis of pheochromocytoma is confirmed biochemically and the tumor located by using imaging techniques, biochemical evidence of excess catecholamine production usually antedates clinical symptoms, and therefore annual determination of urinary catecholamine / metabolites is recommended.[13,14] Prognosis will depend on the presence of familial endocrinopathy or the presence of metastases .[11]
In summary, due to varied symptomatology and nonspecific physical findings, a high index of suspicion is often required for accurate diagnosis and management of these patients.[15]

 

References
1. Onishi T, Sakata Y, Yonemura S, et al. Pheochromocytoma of the urinary bladder without typical symptoms. Int J Urol 2003; 10:398-400.
2. Doran F, Varinli S, Bayazit Y, et al. Pheochromocytoma of the urinary bladder. APMIS 2002; 110:733-6.
3. Salanitri J, Smith P, Schlicht S. Multifocal malignant extra-adrenal paragangliomas of the Organ of Zuckerkandl and urinary bladder. Australas Radiol 2001; 45:229-32.
4. Tan TL, Young BW (1962) Pheochromocytoma of the bladder: Case report. J Urol 87:63–67
5. S Rajaratnam, MS Seshadri, G Gopalakrishnan, SM Chandy(1999) Pheochromocytoma of the urinary bladder. J Assoc Physicians India Vol 47: 246-247.
6. Bowne RB, Beltaos E (1967) Pheo of the bladder: Case report and summary of literature. J Urol 98:361
7. Bonacrzu Kazzi G. Asymptomatic bladder pheochromocytoma in a 7-year-old boy. J. Paediatr Child Health 2001; 37:600-2.
8. Berglund AS, Hulthen UL, Manhem P, et al. Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice. Primary and secondary evaluation for localization  pheochromocytomas. J Int Med 2001; 249:247-51.
9. Nakatani T, Hayama T, Uchida J, et al. Diagnostic localization of extra-adrenal pheochromocytoma: Comparison of (123)I-MIBG imaging and (131)I-MIBG imaging. Oncol Reports 2002; 9:1225-7.
10. Kozlowski PM, Mihm F, Winfield HN. Laparoscopic management of bladder  pheochromocytoma. Urology 2001; 57:365.
11. Hwang JJ, Shoaf G, Uchio EM, et al. Laparoscopic management of extra-adrenal pheochromocytoma.  J Urol 2004; 171:72-6.
12. Snavely MD, Mohan LC, O’Conor DT, Insel PA (1983) Selective down regulation of adrenergic receptor subtype in tissues from rats with pheochromocytoma. Endocrinology 113:354–361
13. Whalen RK, Althausen AF, Gilbert HD (1992) Extra-adrenal pheochromocytoma. J Urol 147:1–10
14. Ahmed S. Safwat, Nabil K. Bissada, Raouf M. Seyam, Saif Al Sobhi, Kamal A. Hanash. The clinical spectrum of pheochromocytoma: analysis of 115 patients. BJUI 2008; 101: 1561-1564
15. Safwat S. Ahmed; Bissada K. Nabil. Pheochromocytoma of the urinary bladder. Can J Urol 2007; 14: 3757 – 3760

 

Date added to bjui.org: 08/08/2012
DOI: 10.1002/BJUIw-2011-144-web

 

Pheochromocytoma in the urinary bladder

We describe here the symptoms, diagnosis, and treatment of a pheochromocytoma in the urinary bladder. 

 

Authors: Song Wu1,2, Yingying He1, Kai Yao4, Yongqin Lai2, Zhiming Cai3, Fangjian Zhou4

1 Anhui Medical University, Hefei 230022, An Hui, China
2 Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, Guangdong, China
3 The First Hospital of Shenzhen University, Shenzhen 518036, Guangdong, China
4 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China

 
Corresponding Author: Fangjian Zhou, Email: [email protected] and Zhiming Cai, E-mail: [email protected]

 

Abstract
Pheochromocytoma of the urinary bladder is a rare neoplasm of the chromaffin tissue of the sympathetic nervous system that occurs within the layers of the bladder wall. The diagnosis is based largely on the presence of clinical symptoms related to catecholamine hypersecretion, although the differential diagnosis of carcinoma of bladder must be excluded. The pathological features of benign and malignant tumors overlap so there are no reliable features of malignancy. In the majority of cases, the treatment of choice is surgical resection.

 

Introduction 
Pheochromocytoma is a neoplasm that develops from cells of the chromaffin tissuescells, which are derived from the ectodermic neural systemneuroendocrine system. Most pheochromocytomas are situated within the adrenal medulla[1] and pheochromocytoma of the urinary bladder is rare [2]. At our centers, 432 cases of pheochromocytoma have been managed between December 1999 and December 2010., of whichOf this number, extra-adrenal pheochromocytomas accounted for 16 cases, which and this included three cases of urinary bladder pheochromocytoma. We report and analyze the clinical manifestations, diagnosis, and treatment in a specific case of bladder pheochromocytoma.

 

Case report
A 62-year-old man presented at midnight with a history of severe hypertension. Further detailed questioning revealed that he had been experiencing occasional attacks of a throbbing headaches and palpitations associated with micturition at midnight as his only other symptoms. The headaches and palpitations started approximately 2 minutes after urination, and continued for approximately 3 minutes. He was asymptomatic in between these episodes.
His medical, surgical, and family histories were significant only for a positive history of diabetes. On examination he was thin, with a pulse of 86 beats per minute and a blood pressure of 115/80 mmHg. Ultrasonography showed a mass in his urinary bladder wall that measured 2 × 2 cm (Figure 1), which was confirmed on computed tomography (CT) scan (Figure 2).
 

Figure 1. Ultrasonography showing a heterogeneous mass located in the bladder dome, and Ultrasound of the urinary bladder revealed a vascular, nearly homogenous mass in the anterior wall of the urinary bladder (arrow).

 

 

Figure 2. CT showing tumour located in the anterior front of the bladder with well

 

This scan also showed that his adrenal glands were completely normal. The results of routine laboratory examinations (full blood count, blood chemistry, coagulation studies, and urinalysis) were within normal limits. His plasma metanephrine was 0.25 nmol/L (normal range at our hospital laboratory, 0.00–0.49 nmol/L) and plasma normetanephrine 4.50 nmol/L (normal range, 0.00–0.89 nmol/L). Vanillylmandelic acid (VMA) in a 24-hour urine collection was normal (20 μmol/24 hours, with a control of 10–35 μmol/24 hours). His chest radiograph and electrocardiogram were normal.
He was diagnosed with a urinary bladder pheochromocytoma and underwent partial cystectomy. During the surgery, his arterial blood pressure was stable and within normal limits. An extended partial cystectomy was performed because the tumor was involving the whole thickness of the bladder wall and the peritoneum covering the bladder wall at the site where the tumor was located. In view of this, to completely remove the tumor, a part of the peritoneum covering the bladder was also removed (Figure 3).
 

Figure 3. Postoperative specimen: the mass showed pink and inhomogeneity

 

To our knowledge, this is the first case of a bladder pheochromocytoma managed with extended partial cystectomy.
Pathological evaluation revealed that the tumor was a paraganglioma. On histopathological examination, the tumor cells were arranged in a nested pattern (Figure 4).
 

Figure 4. Tumors proliferation composed of small cells associated to endocrine visualization. (4 a,b: HES x 200; 4 c,d: HES x 400)

 

The tumor cells showed strong positive enhancement with S-100 (Figure 5a), synaptophysin (Figure 5b), CD56 (Figure 5c), and k-167 (Figure 5d), while immunostaining for CK7, P53, PSA, and P63 was negative. The patient recovered uneventfully and his symptoms related to micturition at midnight disappeared.
 

Figure 5. (a) Immunostaining for S-100 is strongly positive (DAB ×400). (b) Immunostaining for synaptophysin is positive (DAB ×400). (c) Immunostaining for CD56 is positive (DAB ×400). (d) Immunostaining for k-167 is strongly positive (DAB ×400).

 

 

The procedures of this study were in accordance with the ethical standards of the World Medical Association. Our Institutional Review Board approved this retrospective study, and informed consent was waived.

 

Discussion
Pheochromocytoma of the urinary bladder was first reported in 1953 by Zimermana Zimmerman [3]  and to date about 300 cases have been reported in the literature. Pheochromocytoma of the urinary bladder accounts for less than 1% of pheochromocytomas in humans and less than 0.06% of bladder tumors [4,5].
The symptoms of bladder pheochromocytoma, such as headaches, palpitations, dizziness, and sweating, are similar to those of adrenal pheochromocytoma. However, the symptoms are usually associated with micturition or defecation. Gross or microscopic hematuria was noted in 60% of patients with bladder pheochromocytoma. The hypertensive crises result from excessive catecholamine secretion, which usually accompanies voiding [6,7] . Other symptoms such as dysuria or suprapubic pain are rare. It has been reported that 17% of bladder pheochromocytomas are hormonally nonfunctional and asymptomatic [8,9] .
Our patient presented with paroxysmal hypertension and symptoms related to excessive catecholamine secretion only when he got up to urinate at midnight. This might be explained by the following: (i) the low probability that this was a functional tumor or the small size of the tumor; (ii) his sympathetic nervous system being more excitable when he woke up at midnight; or (iii) the peritoneum being closely attached to the bladder tumor, so that the tumor was easily stimulated by stretching when he got up to urinate at midnight.
The diagnosis of pheochromocytoma is generally established by measurement of catecholamines in plasma, and catecholamine metabolites (metanephrine and normetanephrine) in a 24-hour urine collection.
On ultrasonography, pheochromocytomas appear as solid masses or contain foci of hemorrhage and necrosis. CT can detect larger bladder tumors, but its sensitivity is just 82%. Magnetic resonance imaging (MRI) is superior to CT in locating tumors and differentiating them from surrounding structures. In 2010, Wang reported the use of MRI in the diagnosis of a bladder paraganglioma [10] . He found that homogeneous T1 hyperintensity was a diagnostic characteristic of bladder paraganglioma on MR imaging, and that necrosis, oval shape, and lower apparent diffusion coefficient (ADC) values provided further support for the diagnosis of bladder paraganglioma.
Surgical removal of the tumor was the most effective treatment for bladder pheochromocytoma. In the report of Das et al. with 100 cases of bladder pheochromocytoma, partial cystectomy accounted for 84% and total cystectomy 7% of the treatments performed [11] . Transurethral resection was performed in about 7% of cases as an alternative for small and well-defined lesions. It was unclear if there was any advantage for total cystectomy over partial cystectomy in terms of disease control. As the majority of tumors (94%) involve the muscularis propria of the bladder wall, it has been proposed that transurethral resection is insufficient and that partial cystectomy remains the first-choice treatment for bladder pheochromocytomas[12-15]. We believe that extended partial cystectomy is sufficient to control the disease in patients with lesions that involve the whole thickness of the bladder wall, and that total cystectomy, which impairs patient quality of life is not necessary.

 

Conclusion
A case of bladder pheochromocytoma with symptoms related to increased catecholamine release after urination at midnight only was successfully treated with extended partial cystectomy.

 

References
1. Zhou M, Epstein JI, Young RH: Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol 2004;28:94-100.
2. Kovacs K, Bell D, Gardiner GW, et al:Malignant paraganglioma of the urinary bladder: Immunohistochemical study of prognostic indicators. Endocr Pathol 2005; 16:363-369.
3. Zimmerman IJ, Biron RE, MacMmahon HE: Pheochromocytoma of the urinary bladder. N Engl J Med 1953; 249:25-26.
4. Whalen RK, Althausen AF, Daniels GH: Extraadrenal pheochromocytoma. J.Urol. 1992;147:1-10.
5. Sweetser PM, Ohl DA, Thompson NW: Pheochromocytoma of the urinary bladder. Surgery 1991;109:677-681.
6. Whalen RK, Althausen AF, Daniels GH: Extraadrenal pheochromocytoma. J.Urol 1992;147:1-10.
7. Gyftopoulos K, Perimenis P, Ravazoula P: Pheochromocytoma of the urinary bladder presenting only with macroscopic hematuria. Urol Int 2000;65:173-5.
8. Piedrola G, Lopez E, Rueda MD, et al:Malignant pheochromocytoma of the bladder: current controversies. Eur Urol 1997;31: 122-5.
9. Xu DF, Chen M, Liu YS:Non-functional paraganglioma of the urinary bladder: a case report.J Med Case Reports 2010,4:216.
10. Haiyi W , Huiyi Y , Zhiwei F,et al:Bladder paraganglioma in adults: MR appearance in four patients.Eur J Radiol 2010;10:4972-4976.
11. Das S, Bulusa NV, Lowe P:Primary vesicle vesical pheochromocytoma. Urology 1983;21:20-5.
12. Piedrola G, Lopez E, Rueda MD, et al: Malignant pheochromocytoma of the bladder: current controversies. Eur Urol 1997;31: 122-5.
13. Naqiyah, Dohaizak M, Meah F:Pheochromocytoma of the urinary bladder. Singapore Med.2005;46:344-346.
14. Dilbaz B, Bayoglu Y, Oral S,et al: Laparoscopic resection of urinary bladder paraganglioma: a case report. Surg Laparosc Endosc Percutan Tech 2006; 16:58-61.
15. Ikeda M, Endo F, Shiga Y, et al:Cystoscopy-assisted partial cystectomy for paraganglioma of the urinary bladder. Hinyokika Kiyo 2008, 54:611-614.

 
Date added to bjui.org: 20/09/2011


DOI: 10.1002/BJUIw-2011-032-web

 

Ileal Conduit stoma site metastasis in squamous cell carcinoma of urinary bladder

Authors: Gupta, Chaitali; Kumar, Rajeev
 
Corresponding Author: Shailesh Sahay, All India Institute of Medical Sciences, Urology, New Delhi, India.  Email: [email protected]

Abstract
 
Tumour recurrence at the site of an ileal conduit stoma is rare. A 65 years old male chronic smoker was diagnosed as having squamous cell carcinoma of the urinary bladder. He underwent radical cystourethrectomy and ileal conduit urinary diversion. Three months after the surgery, he developed a subcutaneous swelling at the stoma site. Wedge biopsy of the swelling revealed a metastatic squamous cell carcinoma.

 

Introduction
 
Bladder cancer most commonly spreads by haematogenous and lymphatic routes. It also spreads by implantation in abdominal wounds, denuded urothelium, resected prostatic fossa, or traumatised urethra [1]. Implantation of tumour cells occurs most commonly with high-grade tumours. Tumour implantation into the resected prostatic fossa is uncommon but can occur primarily with high-grade and multiple tumours [2]. Rarely, inadvertent bladder perforation during endoscopic resection can result in tumour seeding or metastases [3]. Cancer recurrence after radical cystectomy has-been reported in ureteroileal anastomosis. Metastasis at an ileal conduit stoma site after radical cystectomy has not been reported in literature as far as we aware. We report squamous cell carcinoma (SCC) at the conduit stoma site after radical cystectomy for SCC of urinary bladder.

 

Case Report
A 65 year old male was diagnosed with squamous cell carcinoma of the urinary bladder on the basis of a transurethral resection biopsy of a bladder tumour. He underwent radical cystoprostatectomy and urethrectomy with ileal conduit urinary diversion. The specimen was removed en bloc. The histopathological examination revealed squamous cell carcinoma with muscle invasion (Figure 1A). All the margins (urethra, bilateral ureters, seminal vesicles and vas deferens) were free of tumour. Pelvic lymph nodes were not involved. Tumour was staged as pT2bNOMO. Three months after surgery, induration was noted near the ileal conduit stoma and wound infection was noted in the perineum and the penile shaft. Contrast-enhanced CT scan showed 3 X 2.5 cm soft tissue mass lesion in subcutaneous plain and infiltrating the right anterior abdominal wall at the site of the ileal conduit (Figure 1B). Wedge biopsy was taken from the perineal wound and peristomal mass lesion. The biopsy from perineum showed only chronic inflammatory infiltrates with granulation tissue. The biopsy from the conduit stoma edge was squamous cell carcinoma (Figure 1D).
 

Figure 1. A )Pre operative contrast-enhanced CT Scan abdomen showing urinary bladder tumour. B) Ileal conduit stoma site showing metastasis. C) Post operative abdominal CT scan showing conduit site metastasis. D) Microscopic photograph of conduit site showing squamous cell carcinoma. 

 

 

Cytology from the conduit urine did not show any malignant cells. The perineal wound infection was managed and the patient was scheduled for chemoradiotherapy for metastasis at the stoma site.

 

Discussion
 
Ileal conduit has been widely in use for urinary diversion after a radical cystectomy, and primary malignant tumours arising in these conduits are uncommon. Although several cases have been reported, most are either transitional cell carcinoma (TCC) or adenocarcinoma. A case of squamous cell carcinoma (SCC) arising in a right ureteroileal anastomosis extending to an ileal conduit, which developed 11 years after a radical cystectomy for TCC of the bladder, has been reported [4]. Involvement of an ileal conduit with recurrent carcinoma following a radical cystectomy for TCC of the bladder is relatively rare. Rosvanis et al reviewed the reported cases of recurrent TCC in an Ileal conduit and found that most of the patients with upper urinary tract tumours recurred at the ureteroileal anastomosis. The authors suggested that surgical implantation or auto implantation from the upper tract might have influenced recurrence at the ureteroileal junction [5]. Most recurrent tumours in the ileal conduit reported to date have been either TCC or adenocarcinoma [6]. Filmer and Spencer reviewed primary malignancies in bladder augmentations and urinary conduits, most of which were adenocarcinoma, and suggested that the inflammatory response associated with bacteriuria at the anastomotic site between transitional and enteric epithelia render the area more susceptible to malignant transformation [7].
Our case had all the resection margins negative for malignancy including both ureters. All the lymph nodes were negative for tumour. The possible explanation in this patient can be by tumour implantation theory. As the same set of instruments was used in radical cystectomy and constructing the ileal conduit, there might have been some tumour cell implantation in stoma site.  This in our knowledge is the first case of squamous cell carcinoma urinary bladder developing metastasis at conduit stoma site without involving the ureteroileal anastomosis.

 

References
 
1. Weldon TE, Soloway MS: Susceptibility of urothelium to neoplastic cellular implantation.  Urology 1975; 5:824
2. Green LF, Yalowitz PA: The advisability of concomitant transurethral excision of vesical neoplasm and prostatic hyperplasia.  J Urol  1972; 107:445
3.  Mydlo JH, Weinstein R, Shah S, et al: Long-term consequences from bladder perforation and/or violation in the presence of transitional cell carcinoma: Results of a small series and review of the literature.  J Urol  1999; 161:1128.
4. Yamada Y, Fujisawa M, Nakagawa H etal: Squamous Cell Carcinoma in an Ileal Conduit. Int J Urol 1998;5:613-614.
5. Rosvanis TK, Rohner TJ, Abt AB :Transitiona1 cell carcinoma in an ileal conduit. Cancer 1989;63:1233-1236.
6.Sakano S,Yoshihiro S, Jolto I, Icawano H, Naito I : Adenocarcinoma developing in an ileal conduit. J Urol 1995; 153:146-8.
7.Filmer RB, Spencer JR: Malignancies in bladder augmentations and intestinal conduits. J Urol 1990;143:671-678.

 
Date added to bjui.org: 24/06/2011 


DOI: 10.1002/BJUIw-2011-029-web

 

A rare case of isolated ganglioneuroma of urinary bladder

Authors: Gupta, Narmada; Chatterjee, Priti; Sahay, Shailesh Chandra

Corresponding Author: Dr Shailesh Chandra Sahay, MBBS, MS ( General Surgery), MCh (Urology) Corresponding address: Room No 5030, Department of Urology, All India Institute of Medical Sciences, Ansari Nagar, Post: New Delhi, Pin: 110029, India Email: [email protected]

 

Case report
A 30 year old woman with a history of polycystic ovarian disease was incidentally found to have a urinary bladder mass of 2X2 cm on Ultrasound. She did not have any urinary symptoms or haematuria. Contrast enhanced computed tomography (CECT) scan showed a focal minimally enhancing soft tissue mass lesion of 17X13X16 mm size on the right side of the bladder dome, with perivesical fat stranding. There was no significant locoregional adenopathy. (Fig 1A,B,C)

 

Figure 1
1A, 1B: Contrast enhanced CT scan of pelvis. The arrow shows the mass in the urinary bladder near the dome
Figure 1C: follow up CT scan at 6 months showing no tumour
Figure 1D: Cystoscopy showing the laminated appearance of the tumour on resection
Pic1webSS

 

Urine routine examination showed 1-2 red blood cells / high power field (hpf) and 2-3 white blood cells / hpf. Her renal function tests were within normal limits. Urine cytology did not reveal any malignant cells.
The patient was taken up for cystoscopy with a provisional diagnosis of Carcinoma of the  urinary bladder. There was no perivesical streaking or infiltration as noted on contrast enhanced CT scan. Clinical staging was T2 N0 M0. Cystoscopy was done under general anaesthesia. There was a bulge noted at the dome and right posterolateral wall with intact mucosa over it. Bipolar resectoscope was used for resection. On resecting the mucosa the tumor seemed to be situated in the bladder wall, with a laminated appearance suggestive of its mesenchymal origin (Figure 1D). Intraperitoneal bladder perforation occurred accidentally while trying to achieve complete tumor resection, as tumor was extending up to the serosa. An abdominal drain was placed for 4 days. A cystogram done on the seventh post operative day showed no leak and a regular bladder wall outline. The Foley catheter was removed on the 7th postoperative day and the patient was discharged.The pathological report came as ganglioneuroma of urinary bladder invading the bladder wall (Figure 2).

 

Figure 2 Histologic appearance of the tumour showing Ganglioneuroma of urinary bladder:
Figure (2A)- Hemotoxyline and eosin stain, 40X, Arrow showing muscularis propria infiltration by the tumour
Figure (2B)- Hemotoxyline and eosin stain, 40X, Arrow showing  numerous ganglion cells in a fibrillary background
Figure (2C)- 200X, S 100, Immunohistochemistry, Arrow showing S100 positivity in nucleus of tumour tissue, indicating neuronal origin
Figure (2D)- 200X, SMA, Immunohistochemistry, SMA negative in tumour tissue, indicating no smooth muscle differentiation. SMA positive only in blood vessel walls (arrow)
Picture2webSS

 

Immunohistochemistry with S100 was positive, while SMA (smooth muscle antigen) was negative. The patient recovered well. Follow up CECT scans at 3, 6 and 12 months showed no recurrence of tumour in the urinary bladder.

 

Discussion
Ganglioneuroma is a benign neurogenic tumor arising from sympathetic ganglia. They are rare tumors that most frequently start in the autonomic nerve cells, which may be in any part of the body. Ganglioneuromas are thought to be the fully differentiated counterpart of neuroblastomas. They are highly differentiated benign tumors and are compatible with long-term disease free survival, even though surgical treatments are unsatisfactory (1). About 60% of all patients with these tumors are younger than 20 years, most being less than 10 years of age. There is a slight female preponderance. Since ganglioneuromas may release catecholaminergic peptides, surgeons should be aware of the possibility of hypertensive crisis during the surgery (2). Ganglioneuromas most frequently occur in the posterior mediastinum 43%, followed by the retroperitoneum 32% and the neck 8% (3). Ganglioneuromas involving the genitourinary tract are extremely rare but are potentially serious tumors. It consists of spindle cells, fascicles composed of neuritic processes, Schwann cells, perineural cells and numerous ganglion cells. Immunohistochemically they are characterized by reactivity with S100 and neuronal markers such as NSE (neuron specific enolase) and synaptophysin4. According to many authors, surgical excision is sufficient for the treatment. Partial cystectomy or radical cystectomy is the recommended treatment modality. Preoperative or postoperative chemotherapy or radiotherapy have no value in the treatment except when it is associated with ganglioneuroblastoma changes when there might be some role for chemotherapy. Even with residual disease, cessation of all other treatments and a close follow-up may be adequate (4).
Five cases of composite paraganglioma-ganglioneuroma of the urinary bladder (CPGUB) have been reported in the English-language literature. These cases showed no malignant features, such as extra-bladder infiltration and metastasis, and no recurrence in the short period of follow up. A case of malignant peripheral nerve sheath tumor of the bladder in a 57-year-old man with multiple neurofibromatosis type 1 has been reported. The patient had a recent history of a transurethrally resected bladder ganglioneuroma. A probable histogenetic association between these two extremely rare neoplasms is proposed (5). Isolated Ganglioneuroma of urinary bladder without any other systemic disease has not been reported in literature so far.

 

Conclusion
Ganglioneuroma is a rare tumor of urinary bladder. TURBT with resection of full thickness of bladder wall provided a complete resection of tumor in this case. TURBT can be a treatment option in such tumours as an alternative to partial cystectomy.

 

References
 
1. Hayes FA, Green AA, Rao BN. Clinical manifestations of ganglioneuroma. Cancer 1989;63:1211-4.
2. Moriwaki Y, Miyaka M, Yamamoto T, Tsuchida T, Takahashi. S, Hada T et al.  Retroperitoneal ganglioneuroma: a case report and review of the Japanese literature. Intern Med 1992;31:82-5.
3. Jasinki RW, Samuels BI, Silver TM. Sonographic features of retroperitoneal ganglioneuroma. J. Ultrasound Med 1984;3:413-5.
4. Kleihues P, Cavenee WK. World Health Organization Classification of tumors, pathology and genetics of tumors of the nervous system. Lyon 2000;153-61.
5. Kalafatis P, Kavantzas N, Pavlopoulos PM, Agapitos E, Politou M, Kranides A. Malignant Peripheral Nerve Sheath Tumor of the Urinary Bladder in von Recklinghausen Disease. Urol Int 2002;69:156-9.

 

Date added to bjui.org: 04/10/2010

 

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