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An unusual presentation of teenage testicular cancer

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We present an unusual case of testicular cancer in a 13-year-old boy, referred by his GP with an acute onset of right testicular pain and a provisional diagnosis of testicular torsion. 

Authors: Harwood R, Short M, Hosie G

Royal Victoria Infirmary, Newcastle Upon Tyne, UK

Corresponding Author: Harwood Rachel, Royal Victoria Infirmary, Newcastle Upon Tyne, UK. E-mail: [email protected]

Abstract
A 13-year-old Afro-Caribbean boy presented with acute testicular pain. His examination was not typical of testicular torsion and an ultrasound scan suggested malignancy. In view of his resulting pathology, his case is unusual both in presentation and epidemiology. This case highlights the need to remain vigilant for alternative differential diagnoses when assessing a child with testicular pain. It has been proven that obesity can increase cancer risk, learn how to prevent it by reading this article from DiscoverMagazine.
Case history
We present what, in our experience, is an unusual case of testicular cancer.  The patient is an Afro-Caribbean 13-year-old boy, referred by his General Practitioner with an acute onset of right testicular pain and a provisional diagnosis of testicular torsion. On further questioning he was found to have had right testicular pain for four hours but an increase in the size of his right testicle over the previous 2 months. Prior to this, he had no history of cryptorchidism, testicular trauma or previous surgery. He was otherwise fit and well and not on any regular medication. There was no significant history of cancer in first degree relatives, but three uncles had died between 60 and 70 years of age from lung, liver and prostate cancer. On examination he was found to have a mildly tender, firm, smooth right testicle with normal position and lie. There was no associated erythema, skin discoloration or swelling. The left testicle was normal and abdominal examination was unremarkable.  He was graded as Tanner Stage 4.
Investigations
In view of his history, an ultrasound scan was requested and showed a 2.5 x 1.5cm avascular mass within the right testicle.
Figure 1. 

Tumour markers at presentation were within normal ranges for his sex and age (beta-HCG (bHCG) <1, alpha-feto-protein (AFP) 3).
Treatment and Follow-Up
At surgery, the patient was found to have a macroscopically normal testicle and a radical orchidectomy was performed via a groin incision. Histology revealed a mixed seminoma and germ-cell tumour.
Figure 2. 
Figure 3. 
Postoperatively, he underwent a staging CT scan.  No evidence of metastases was found and he is being followed up with biochemical marker monitoring.
Discussion
Although testicular tumours are the most common malignancy in men aged 15-35 yrs [1], they are rare in children under 15yrs of age, accounting for <2% of solid tumours [2].  The most common type of gonadal tumour in children are germ cell tumours, which are divided into subgroups based on cellular components and degree of differentiation [3] [4].
There are many causes for testicular pain in children.  The incidence of testicular torsion is 26% with a peak in adolescence, torted Hydatid of Morgagni 45%, epididymitis 10%, incarcerated inguinal hernia 8% and other conditions including malignancy 11% [5].  Testicular tumours most commonly present as a testicular mass, a symptom which RW had had for two months.  A much less common presentation is testicular pain or a dragging sensation. This boy’s acute symptoms were consistent with testicular torsion.  Had attention not been paid to his extended history and scrotal exploration been performed through a scrotal excision, an inappropriate surgical approach would have been undertaken, risking seeding of the tumour to the inguinal lymph nodes.
It is well documented within observational studies of adults that there is a significantly smaller incidence of testicular cancer within the Afro-Caribbean population (0.3-1.4 per 100,000) than in the Caucasian population (3.2-6.2 per 100,000) [6] [4].  There is little information about the incidence in boys of RW’s age with regards to ethnicity, however in the UK in 2008 there were only three new cases of testicular neoplasm in boys aged 10-14 (rate 0.2 per 100,000) [7].
In our patient, tumour markers were all within normal range and in combination with the factors mentioned above made us wary of performing an orchidectomy without a histological diagnosis. However, in view of his history and radiological findings, this was decided as being the most appropriate surgical management.  We were undeterred by his tumour markers as AFP is increased in 50-70% of non-seminomatous germ cell tumours (NSGCTs) and bHCG is elevated in 40-60% of patients with NSGCTs [8].
Conclusion
This case highlights the importance of remaining vigilent to uncommon causes of unilateral testicular pain in children. A careful history and examination is important as is imaging when there is doubt over the diagnosis. This case is of particular interest in the UK given the rarity of testicular cancer both in this age-range and in this ethnic group.
With thanks to Dr A. Husain (Dept. Cellular Pathology)
References
 
1. Fernandes ET, Etcubanas E, Rao BN, Kumar AP, Thompson EI, Jenkins JJ. Two decades of experience with testicular tumors in children at St Jude Children’s Research Hospital. J Pediatr Surg. 1989 Jul;24(7):677-81; discussion 682
2. Ross JH, Kay R. Prepubertal Testis Tumours; J Pediatr Surg. 1989 Jul;24(7):677-81
3. Stringer M, Oldham K, Mouriquand P. Pediatric Surgery and Urology – long term outcomes;  2nd Edition 2006
4. Alanee S, Shukla A. Paediatric testicular cancer: an updated review of incidence and conditional survival from the Surveillance, Epidemiology and End Results database; BJU International. 2009 Nov;104(9):1280-3
5. Makela E, Lahedes-Vasama T et al.  A 19-year review of paediatric patients with acute scrotum;  Scand J Surg. 2007;96(1):62-6.
6. Holmes L Jr, Escalante C, Garrison O, Foldi BX, Ogungbade GO, Essien EJ, Ward D. Testicular cancer incidence trends in the USA (1975-2004): plateau or shifting racial paradigm? Public Health. 2008 Sep;122(9):862-72
7. National Office for Statistics, 2010
8. European Society of Urology, Guidelines on testicular cancer, 2010

Date added to bjui.org: 21/10/2011


DOI: 10.1002/BJUIw-2011-063-web

Potentially Fatal Lingual Angioedema in Everolimus Treated Metastatic Renal Cell Carcinoma

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We describe a case of an acute onset of severe everolimus-induced lingual angioedema in a 70 year-old man, who received everolimus 10 mg in the treatment of mRCC.

Authors: Martijn van Dorp1, Sevilay Altintas1, Johan Feyen2, Luc Vanuytrecht3

1Department of Medical Oncology, University Hospital Antwerp, Antwerp, Belgium.
2Department of Orthopaedic Surgery, AZ St Dimpna, Geel, Belgium.
3Department of Head and Neck Surgery, AZ St Dimpna, Geel, Belgium.

 
Corresponding Author: Martijn van Dorp, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Antwerp, Belgium. Tel: +3238214973. Fax: +3238214102. E-mail: [email protected]

 

Abstract
Everolimus is commonly used as a second line therapeutic option in the treatment of metastatic renal cell carcinoma (mRCC). Angioedema is a well described adverse event of everolimus treatment in the transplant area, where it is used as an immunosuppressant. However this is an extremely rare adverse event when everolimus is used in the treatment of mRCC.
We describe a case of an acute onset of severe everolimus-induced lingual angioedema in a 70 year-old man, who received everolimus 10 mg in the treatment of mRCC. Complete resolution occurred when everolimus was withdrawn. After re-administration of a reduced dose no recurrence was observed during a follow-up period of 11 months. During and after the onset of lingual angioedema, we opted not to terminate the administration of an angiotensin-converting enzyme (ACE) inhibitor, showing that everolimus was synergistic for the occurrence of this event.
We concluded that the occurrence of lingual angioedema in this particular case was an adverse event associated with everolimus treatment. In the literature, as in our case, a strong association between the co-administration of an ACE inhibitor and an inhibitor of the mammalian target of rapamycin (mTOR) is described.

 

Introduction 
Targeted therapy is now the standard treatment for metastatic renal cell carcinoma (mRCC). In recent years, there have been a series of phase III randomized trials showing benefit of targeted therapy, i.e. the small molecule multitargeted tyrosine kinase inhibitors sunitinib [1], sorafenib [2] and pazopanib [3], the vascular endothelial growth factor inhibitor bevacizumab [4] and the mammalian target of rapamycin (mTOR) inhibitors everolimus [5] and temsirolimus [6].
Everolimus demonstrated a significant improvement in progression free survival of 4.9 months versus 1.9 months for placebo in the phase III RECORD-1 study [5]. Upcoming are a phase II RECORD-2 study [7], everolimus and bevacizumab versus interferon alfa and bevacizumab in first-line, and a phase II RECORD-3 study [8], everolimus as first-line therapy followed by second-line sunitinib versus sunitinib as first-line followed by second-line everolimus. Usage of everolimus is an important contributor in the treatment of mRCC. Other tumor types in which mTOR inhibitors are explored include breast cancer, GIST, gastric carcinoma, hepatocellular carcinoma and B-cell lymphoma. [9]
The most common grade 3 or 4 adverse events for mTOR inhibitors are hyperlipidaemia, hyperglycaemia, stomatitis, non-infectious pneumonitis and myelosuppression. [5, 6] In this case we report a potentially fatal [10] but rare toxicity: lingual angioedema.

 

Case
 
We present a 70-year old white male who underwent a nephrectomy for a pT1bN0M0 renal cell carcinoma of the clear cell type, who developed diffuse skin, bone, lung and lymph node metastases 14 years later. After radiotherapy to a single bone metastasis in the tibia, he initially started on sorafenib 400 mg bid. One and a half years later the patient progressed and at that time he opted to participate into the RAD001 expanded access trail. He received oral everolimus 10 mg qd.
114 days after initiation of this therapy, he experienced a progressive swelling and a burning sensation of the tongue at 3:00 am. Within an hour he presented to the emergency department with a vast, swollen and oedematous tongue, as a result of which he wasn’t able to close his mouth (Figure 1).

 

Figure 1. Lingual angioedema five hours after presentation

 

 

He was unable to speak and had  stridorous breathing. Physical examination revealed diffuse bilateral swelling and redness of the base of the mouth, the soft palate and the tongue. He did not have hives, pruritus, nor were there signs of peripheral edema. The patient did not have a history of allergic reactions and these symptoms occurred for the first time in his life. His concurrent medications included quinapril 5 mg qd, indapamide 2.5 mg qd and atorvastatine 20 mg qd.
At the time of presentation, total and differential leukocyte counts, thrombocyte counts, liver enzymes and coagulation factors were within the normal range. However, there was a marked rise in the fibrin degradation products and iron deficiency anaemia.
Indirect laryngoscopy revealed diffuse nasopharyngeal, oropharyngeal and laryngeal swelling without critical airway obstruction. Chest X-ray showed no significant abnormalities. He was diagnosed with lingual angioedema.
 
Everolimus was discontinued and intravenous treatment with methylprednisolone 125 mg, ranitidine 50 mg, promethazine 25 mg and cetirizine 10 mg was started and improved the patients’ symptoms. The dosages of his other medications, including quinapril, were not altered. Although the progression of the swelling was clearly brought to a halt five hours after administration of medication, there was no decrease noted in the volume of the tongue. Therefore intravenous hydrocortisone 250 mg in combination with ranitidine 50 mg was administrated and a CT scan was performed. The CT scan (Figure 2) revealed narrowing of the naso- and oropharynx, a dilated soft palate and an unmistakable voluminous tongue.

 

Figure 2. Computed tomography showing nearly complete obstruction of the oropharynx and obvious swelling of the tongue
 
 
He remained hospitalised for four more days in which time he received a declining dose of methylprednisolone, starting at 40 mg qd. His tongue returned to normal 18 hours after commencement. He was discharged with methylprednisolone 16mg qd for three more days.
Everolimus was re-administered nine days after the initial event at a reduced dose of 5 mg per day. More than 11 months after reinitiation, there has been no recurrence.

 

Discussion
 
To our knowledge this is the second reported case of lingual angioedema as a result of using a mTOR inhibitor in the treatment of mRCC. Mackenzie and Wood [11] described a 61-year old man treated with everolimus 10 mg qd in second line and who developed lingual angioedema after 21 days of treatment. Interestingly this patients’ concurrent medication also contained an angiotensin-converting enzyme (ACE) inhibitor, ramipril 10mg qd.  Everolimus was initially stopped, but resumed one week later with no recurrence of the noticed side-effect.
In transplant medicine, there is longstanding clinical experience with mTOR inhibitors, where sirolimus and everolimus have been used as immunosuppressants. Everolimus is administrated at a dosage of 3 mg qd, as part of triple therapy, together with a calcineurin inhibitor and prednisone. Calcineurin inhibitors (like cyclosporine and tacrolimus) and everolimus are both metabolized by the CYP3A4 isoenzyme system, and their concomitant administration increases everolimus exposure by 2- to 3-fold. [12]
The largest series reports on 309 german kidney transplant recipients who had received mTOR inhibitors as immunosuppressants. Nine patients developed angioedema after a mean period of 123 days under combined therapy of an mTOR- and an ACE inhibitor. Six of these nine patients ceased the administration of the ACE inhibitor, no recurrence took place. In the three patients who continued to take the ACE inhibitor, angioedema recurred. All patients continued their mTOR inhibitor after the onset of the angioedema. In seven patients the everolimus or sirolimus levels were measured at the time of the event and six of them had increased plasma concentration levels. After replacement of the ACE inhibitor by an angiotensin receptor blocker (ARB) no recurrence was noticed. [13]
Stallone et al [14] were in 2004 the first to report the development of lingual angioedema in five kidney transplant recipients, one month after initiating the combination everolimus and an ACE inhibitor. Interestingly, in these five patients both drugs were administered at high dosages. The sirolimus dosage was decreased and the ACE inhibitor was stopped, but later reintroduced without recurrence of the assumed side effect. The authors hypothesized a dosage dependent synergistic effect when combining both drugs.
No reports of temsirolimus associated with lingual angioedema were found. Of note, temsirolimus is not used in the transplant population and is a newer agent.
Angioedema is a well-known side effect of ACE inhibitors. The OCTAVE trial reported the occurrence of ACE inhibitor induced angioedema in 0,68% out of >12,000 patients. [15] 99% of all cases present within the first year of therapy, of which a clear majority present within the first 8 weeks. [15, 16] Our patient had taken quinapril, in a low dose, for 2 years and 9 months without any adverse clinical events.
The concomitant administration of everolimus and inhibitors or inducers of the CYP3A4 enzyme system may affect everolimus blood levels. Concomitant administration of typical CYP3A4 inhibitors (ketoconazole [17] and erythromycin [18]) has been shown to significantly increase everolimus maximum concentration and everolimus area under the curve.
ACE inhibitors are also metabolized by the CYP3A4 enzyme system. CYP3A4 interaction could be an important part in linking the occurrence of angioedema to the concomitant administration of everolimus and an ACE inhibitor.
Furthermore, the incidence of angioedema is greater in the transplant setting. This might be because of the additional CYP3A4 interactions induced by the administration of calcineurin inhibitors.

 

Conclusion
 
In recent years different types of cancer are being treated by targeted therapy, given the relatively favorable side effects in comparison to chemotherapy. An impressive advance, especially in renal cell cancer, is made in increasing overall survival and disease free survival due to the specialized form of inhibiting tumor proliferation and differentiation.
In an area where targeted therapy is being examined and experimented on all types of cancer, one must never forget to think about possible drug interactions and side effects.
We describe the occurrence of lingual angioedema due to everolimus treatment. As in our patient, literature revealed a strong association with concomitant administration of ACE inhibitors. We demonstrated that interrupting everolimus therapy, while continuing the ACE inhibitor, led to a resolution of lingual angioedema. Furthermore we showed that a rechallenge with a reduced dose of everolimus within two weeks after the initial event was safe and the patient could be treated for a further 11 months.
Dosage of everolimus and drug interaction most probably play an important role in the pathogenesis of lingual angioedema.

 

References
 
1. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med 2007; 356:115-124.
2. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125-134.
3. Sternberg Co, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trail. J Clin Oncol 2010; 8:1061-1068.
4. Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-2111.
5. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2010; 372:449-456.
6. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271-2281.
7. NCT00719264: A randomized, open-label, multi-center phase II study to compare bevacizumab plus RAD001 versus interferon alfa-2a plus bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney. Available at: https://www.clinicaltrials.gov. Last accessed Dec 22, 2009.
8. NCT00903175: Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma. Available at: https://www.clinicaltrials.gov. Last accessed Jun 23, 2009.
9. Chan H, Grossman AB, Bukowski RM. Everolimus in the treatment of renal cell carcinoma and neuroendocirne tumors. Adv Ther 2010; 278:495-511.
10. Ulmer JL, Garvey MJ. Fatal angioedema associated with lisinopril. Ann Pharmacother 1992; 26:1245-6.
11. M. Mackenzie, L. A. Wood. Lingual angioedema associated with everolimus. Acta Oncologica 2010; 49:107-109.
12. Schaffer SA, Ross HJ. Everolimus: efficacy and safety in cardiac transplantation. Expert Opin Drug Saf 2010; 9:843-854.
13. Duerr M, Glander P, Iekmann F et al. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 2010; 5:703-708.
14. Stallone G, Infante B, Di Paolo S et al. Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients. Nephrol Dial Transplant 2004; 19:2906-2908.
15. Kostis JB, Kim HJ, Rusnak J et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 2005; 165:1637-1642.
16. Schuster C, Reinhart WH, Hartmann K et al. Angioedema induced by ACE inhibitors and angiotensin II-receptor antagonists: analysis of 98 cases. Schweiz Med Wochenschr 1999; 129:362.
17. Kovarik JM, Beyer D, Bizot MN et al. Blood concentrations of everolimus are markedly increased by ketoconazole. J Clin Pharmacol 2005; 45:514-158.
18. Kovarik JM, Beyer D, Bizot MN et al. Effect of multiple-dose erythromycin on everolimus pharmacokinetics. Eur J Clin Pharmacol 2005; 61:35-38.

The authors have declared no conflicts of interest.

 

Date added to bjui.org: 20/10/2011


DOI: 10.1002/BJUIw-2011-069-web

 

Scrotal leiomyosarcoma

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A case of a 30 year old male presented with a slowly-enlarging, painless lump on the skin of his left hemiscrotum. 

 

Authors: Quinlan, Mark1; D’Arcy, Frank1; Corcoran, Shane1; Casey, Mary1; Harding, Brian2; Hussey, Alan1; Durkan, Garrett1

1. University College Hospital Galway, Ireland
2. Portiuncula Hospital, Ballinasloe, Galway, Ireland

 
Corresponding Author: Mark Quinlan, University College Hospital Galway, Ireland.  Email: [email protected], [email protected]

 

Case history 
A 30 year old male presented with a slowly-enlarging, painless lump on the skin of his left hemiscrotum. It had been present for approximately six months. He had no significant medical history. He had a 10-pack year smoking history. Two maternal aunts had been treated for breast cancer and a grandfather had died of lung cancer. Following examination, the clinical impression was of a 3cm benign sebaceous cyst. There was no inguinal lymphadenopathy. At the presenting hospital, the lesion was excised under local anaesthetic (see Figure 1).
 

Figure1. Site of initial excision 

 

Surprisingly, the histopathologist reported a well to moderately differentiated  leiomyosarcoma with a high mitotic rate (see Figures 2 and 3).

 

Figure 2. Histology shows parallel arrays of eosinophilic fascicles of malignant spindle cells. Individual cells are slender or slightly plump.
 

 

Figure 3.  High power photomicrograph of cytologic features showing eosinophilic cytoplasm and blunt-ended nuclei. Occasional cells have perinuclear vacuoles. Two mitotic figures are present (arrow)
 A staging CT scan of thorax, abdomen and pelvis was negative for metastases. He was referred to our institution for further management.
Following review at the Uro-Oncology MDT meeting, wide local excision (WLE) was recommended. Prior to surgery, he underwent a scrotal ultrasound which was unremarkable. WLE with 3cm circumferential margins was carried out (see Figure 4).

 

Figure 4. WLE specimen

 

 

Frozen section confirmed the margins were negative and there was no residual tumour apparent. The wound was closed primarily without the need for grafting or reconstruction. A further, small cystic lesion was excised from the posterior scrotum (see Figure 5). There were no post-operative complications.

 

Figure 5. Primary closure of WLE defect with posterior cyst excision below (arrow)

 

 

Final histology revealed patchy chronic inflammation and giant cell reaction to suture material. There was no residual leiomyosarcoma. The smaller, posterior scrotal lesion was an epidermal cyst with an acute and chronic granulomatous inflammatory reaction. There was no evidence of malignancy. A medical oncology opinion was sought, and no adjuvant treatment was advised. However, regular, lifelong clinical follow-up with appropriate imaging is indicated.

 

Discussion
Primary cutaneous leiomyosarcoma is an uncommon malignancy with a predilection for the lower extremities [1]. Pure scrotal leiomyosarcomas are particularly rare. To the best of our knowledge, it has never previously been described in Ireland. Only 30 cases have been reported in the world literature. It typically occurs in middle-aged/elderly men. It presents as a painless, slow-growing, cutaneous lesion and often resembles a cyst [2]. It is easily mistaken for a benign condition.  The lymphatic drainage is to the inguinal and iliac nodes.
An aggressive initial resection with wide margins is required. Debate exists as to the optimal extent of an oncologically safe margin, chiefly because of the rarity of the tumour and the lack of randomised studies. McKee et al. showed that the local recurrence-free interval at 5 years for soft tissue sarcomas was higher with a margin of >10 mm (84%) than margins of 1–9 mm (58%) [3]. Inguinal lymph node dissection is not routinely advocated, unless there is a high degree of suspicion for lymph node metastases. Some argue that compared to leiomyosarcomas arising from other locations, aggressive evolution is not habitual in the scrotum [4]. Nonetheless, long-term follow-up of patients with cutaneous leiomyosarcoma is mandatory to detect local recurrence and distant metastases that can occur years after the initial excision [2]. Recurrence most commonly tends to be local but distant metastases in the bones and lungs have been reported [4, 5].

 

Conflict of interest statement
The authors declare that there are no conflicts of interest

 

References
 
[1] Limaiem F, Chelly I, Bellil S, Mekni A, Nidhameddine K, Haouet S, Bellil K, Zitouna M. Primary cutaneous leiomyosarcoma: a histological and immunohistochemical study of 4 cases. Pathologica. 2007 Dec;99(6):415-9.
 [2] John T, Portenier D, Auster B, Mehregan D, Drelichman A, Telmos A. Leiomyosarcoma of scrotum – case report and review of literature. Urology. 2006 Feb;67(2):424.e13-424.e15. Review.
[3] McKeeMD, Dong Feng Liu, Brooks J, et al. The prognostic significance of margin width for extremity and trunk sarcoma. Journal of Surgical Oncology. 2004;85:68– PubMed ;76.
[4] Diz Rodríguez MR, Vírseda Chamorro M, Ramírez García JR, Merino Royo E, Moreno Reyes A, Paños Lozano P. Scrotal leiomyosarcoma with bone metastasis]. Actas Urol Esp. 2006 Jun;30(6):638-40. Review.
[5] Johnson H Jr. Leiomyosarcoma of scrotum. Urology 29:436-438, 1987.

 
Date added to bjui.org: 18/10/2011


DOI: 10.1002/BJUIw-2011-056-web

 

Calcified ureterocoele causing renal tract obstruction in an adult

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We believe this is the first report of a calcified ureterocoele, containing no calculi, and causing significant renal tract obstruction in an adult.

 

Corresponding Author: Ashley Ridout, Croydon University Hospital, Department of Urology, Croydon, UK. Email: [email protected]

Abstract
 
The ureterocele is an intravesical cystic dilatation of the terminal ureter, often due to a congenital weakness in the lower ureteric wall.  Adult orthotopic ureterocoeles, although more common in women, remain a rare clinical entity. We believe this is the first report of a calcified ureterocoele, containing no calculi, and causing significant renal tract obstruction in an adult. We report the case of an elderly Caucasian female patient, presenting with a calcified, right sided, simple orthotopic ureterocoele, mimicking a right vesicoureteric junction (VUJ) calculus.

 

Case Report
 
An 84-year old female presented to the emergency department with a short history of worsening right-sided abdominal pain. Cognitive function was well preserved despite significant medical comorbidities, including a previous cerebrovascular accident with residual right hemiplegia, atrial fibrillation (for which she was taking warfarin), giant cell arteritis, ischaemic heart disease and congestive cardiac failure. On general examination, the patient appeared cushingoid and was drowsy, confused, tachycardic and hypotensive. Abdominal examination revealed tenderness in the right loin and right iliac fossa, with no evidence of peritonism. Blood tests revealed acute renal failure (Ur 14.2, Cr 145), raised inflammatory markers (CRP >250) and a raised serum lactate (6.7). The patient was also in fast atrial fibrillation, with rate-related ischaemia evident on ECG.
The patient responded well to appropriate fluid resuscitation and intravenous antibiotics. Ultrasound of the renal tract reported right hydronephrosis, with a calculus at the right vesicoureteric junction. Subsequent CT scan of the abdomen & pelvis reported a calculus at the right VUJ and moderate right hydronephrosis and hydroureter (Figure 1a/1b).

 

Figure 1a. CT scan 

 

Figure 1b. CT scan 

 

Although no calculus was identifiable on limited IVU, hydronephrosis and hydroureter in a single collecting system with obstruction at the level of the right VUJ was reported. The ‘cobra head’ sign pathognomic of a ureterocele was not evident.
Once clinically stable and fit for general anaesthetic, retrograde ureteric stenting was arranged. During the procedure, a ureterocoele was noted at the right ureteric orifice. The site and appearance of the left ureteric orifice was cystoscopically normal. Transurethral de-roofing of the right ureterocoele was performed. No calculus was present in the ureterocele, or at the vesicoureteric junction. A ureteric stent was inserted without complication, and the patient recovered well from the procedure. Renal function normalised (Creatinine 79, Urea 7) and the patient was discharged three days after the procedure. The stent was removed without incident 4 weeks post-procedure, and the patient remains well.

 

Discussion
 
The ureterocoele is a congenital abnormality, commonly now identified with antenatal screening. Ureterocoeles may be either intravesical or ectopic in location, and there is a great clinical spectrum of symptoms and functional consequences. The precise aetiology of ureteroceles is uncertain – it is most widely accepted that obstruction of the ureteral orifice during embryogenesis, with incomplete dissolution of the Chwalla membrane, predisposes to ureterocoele formation. Occasionally, ureterocoeles are discovered in adulthood – these are typically intravesical, and associated with a single collecting system[1]. Presentation may include flank/back pain, recurrent urinary tract infections, urosepsis, voiding difficulty or loin to groin pain. In addition, they may be detected incidentally at endoscopy, or radiologically[1-5].  Stones are known to form in ureterocoeles, thought to be secondary to ureteral atony and urinary stasis – it is reported that stone formation in ureterocoeles in more common in males than females [1,5].
In our patient, the decision for retrograde stenting instead of nephrostomy and antegrade stenting was based on availability of resources at the time for urgent intervention.  If antegrade stenting were performed, the ureterocoele may not have been identified and treated, as was the outcome in our patient. Endoscopic management is the gold standard therapy for management for symptomatic adult ureterocoele [2,6].  Timely diagnosis and endoscopic de-roofing of obstructing ureterocoeles may avert recurrent presentations with infection and obstruction, and thereby significantly reduce subsequent morbidity. This is especially important in patients such as ours, with multiple other co-morbidities, which may be exacerbated by episodes of sepsis.
Adult ureterocoele, although an uncommon clinical entity, should be considered in the differential diagnoses of patients presenting with urinary symptoms. Cystoscopic examination in those presenting with refractory and/or severe urinary symptoms may allow correct and timely recognition and management of previously unidentified ureterocoeles.

 

Conclusion
 
We believe this is the first reported case of a ureterocoele mimicking a ureteric calculs. Our patient was admitted acutely unwell, with urinary sepsis and radiological findings suggestive of obstructing ureteric stone. The cystoscopic finding of a calcified ureterocoele, with no obstructing calculus, was unexpected. After definitive management of the ureterocoele, the patient recovered rapidly, and remains well.

 

References

 

1. Vasu TS, Elliot WC, Lai RS. Bilateral ureteroceles progressing to reversible acute renal failure in an adult.
Can J Urol. 2006 Feb;13(1):2993-6
2. Halachmi S, Pillar G. Congenital urological anomalies diagnosed in adulthood – management considerations.
J Pediatr Urol. 2008 Feb;4(1):2-7
3. Tomaszewski JJ, Turner RM 2nd, Ost MC. Stone Cobras: Adult bilateral single system ureteroceles presenting with multiple calculi.
Urology 2011 Feb 17 (Epub ahead of print)
4. Berger MB, Larson KA, DeLancey JO. An incidental finding: routing cystoscopy after pelvic floor reconstruction surgery revealed a bladder mass.
Am J Obstet Gynecol. 2010 Nov;203(5):518e1
5. Shamsa A, Asadpour AA, Abolbashari M, Hariri MK. Bilateral simple orthotopic ureteroceles with bilateral stones in an adult: a case report and review of literature.
Urol J. 2010 Summer;7(3):209-11
6. Singh I. Adult bilateral non-obstructing orthotopic ureteroceles with multiple calculi: endoscopic management with a review of literature.
Int Urol Nephrol. 2007;39(1):71-4

 

Date added to bjui.org: 17/10/2011 


DOI: 10.1002/BJUIw-2011-076-web

 

Acute renal failure in a case of unilateral contracted kidney after extracorporeal shock-wave lithotripsy

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We report a patient who experienced acute renal failure following ESWL therapy undertaken three times in consecutive two months. 

 

Authors: Hugo You-Hsien Lin1,2,3, Szu-Chia Chen 1,4, Mei-Yu Jang 5, Hung-Chun Chen1,6

1.Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University
2.Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3.Department of Internal Medicine , Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University
4.Department of Internal Medicine and 5. Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University
6.Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

 
Corresponding Author: Hung-Chun Chen, MD, PhD, Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Telephone: 886-7-3121101 ext 7351-11E-mail: [email protected]: 100 Tzyou First Road, Kaohsiung 807, TAIWAN

 

Abstract
 
  Acute renal failure is a relatively less common complication of extracorporeal shock-wave lithotripsy (ESWL), as compared to renal colic and perinephric haematoma. We report a patient who experienced acute renal failure following ESWL therapy undertaken three times in consecutive two months. Computed tomography showed a perinephric hematoma compressing the right kidney, calculi in the mid right middle ureter with hydronephrosis, and an atrophic left kidney. He received temporary hemodialysis twice, and then was treated with ureteroscopy and intracorporeal lithotripsy for the ureteric calculi. His serum creatinine recovered to his baseline value after one month. Follow-up imaging 6 months later showed resolution of the hematoma. The risk of acute renal failure, although rare, should be considered in patients with an atrophic kidney who have undergone ESWL.

 

Introduction
 
Extracorporeal shock-wave lithotripsy (ESWL) is currently the non-invasive treatment of choice for people with renal stones. However, this non-invasive procedure can result in complications such as loss of corticomedullary differentiation, perinephric fluid, subcapsular hematoma, and hemorrhage into a renal cyst.[1-4] Acute renal failure (ARF) related to ESWL has rarely been reported.[5-7] Here, we report ARF following ESWL in a patient in whom one kidney show atrophic changes. The cause of ARF may be related to perinephric hematoma with hydronephrosis and a contralateral atrophic kidney.

 

Case Presentation
 
A 60-year-old man with history of chronic kidney disease and hypertension presented to the emergency room with right flank pain. The patient’s pain was intermittent and he had taken diclofenac (25mg) twice daily for 3 days. He had undergone ESWL three times, with a total of 10,200 shock waves (15kv), for right renal stones in the preceding two months. Blood tests revealed a hemoglobin level of 4.9 g/dL (compared with a baseline of 10.0 g/dL recorded previously), and raised serum blood urea nitrogen and creatinine levels of 127.5 mg/dL and 15.26 mg/dl respectively (with a baseline creatinine of 4.2 mg/dL recorded previously) and a high anion gap metabolic acidosis. Urinalysis revealed hematuria (occult blood, 3+; red blood cells, 10-25/high-powered field). The patient’s coagulation test results, including platelet count, prothrombin time, partial thromboplastin time, and bleeding time, showed were normal. Non-contrast abdominal computed tomography revealed a large perinephric hematoma compressing right kidney, with an atrophic left kidney, and several right mid ureteric calculi with  hydronephrosis (Figure 1).
 

Figure 1. Coronal non-contrast computed tomography revealed a large perirenal hematoma (black arrow) compressing right kidney, with left atrophic kidney, several right middle third ureteral calculi (arrowhead), and right hydronephrosis (white arrow).

 

 

The patient’s daily urine output was 1480ml/day. He received temporary hemodialysis twice due to severe azotemia and anemia, and then underwent ureteroscopy and intracorporeal lithotripsy for the ureteric calculi. His postrenal obstruction was then relieved. After six months, follow-up computed tomography showed resolution of the hematoma. His serum creatinine decreased to 4.0 mg/dL.

 

Discussion
 
We report an unusual case of a patient who developed ARF after ESWL, with the contralateral kidney showing atrophic changes. ESWL is effective and relatively noninvasive with low morbidity, and is the first choice of treatment for calculi in the kidney. Major complications of ESWL include pain, ureteric obstruction, and sepsis induced by the destruction of infected calculi.[8] Moreover, hemorrhagic complications such as hematuria and hematoma had also been reported.[9-10] ARF after ESWL has rarely been described. Lifuori et al.[5] reported a 68-year-old male who experienced an elevation of his creatinine from 1.2mg/dl to 9.1mg/dl after ESWL. His renal function recovered within 4 weeks with conservative treatment. The postulated the mechanism of his ARF was a reduction in renal blood flow due to elevation of the intrarenal resistance index. Lipski et al. [11] reported ARF in a 43 year-old man with a solitary kidney. As a consequence of a perinephric hematoma developing after ESWL, anuria and renal failure occurred. After 4 units of packed red blood cells were transfused to maintain a hematocrit of 30%, a, ureteral stent was placed to ensure renal drainage and the patient’s serum creatinine decreased from 7.6mg/dl to 2.8 mg/dl. Tuteja et al.[12] reported a 72-year-old white man who received a total of  2,200 shocks (19kv) bilaterally with 1,200 to the right kidney and 1,000 to the left. Anuric ARF caused by bilateral perinephric hematoma occurred with elevation of creatinine up to 4.3 mg/dl from a baseline value of 1.5 mg/dl. Over the ensuing 48 hours, 8U of packed red blood cells were administered to maintain his hematocrit. Renal function improved after supportive care, with hemodialysis undertaken two weeks later. An overview of these reports shows that the risk factors for ARF after ESWL include solitary functioning kidney, hypertension, perinephric hematoma after ESWL, and old age. Whether chronic kidney disease is also a risk factor for ARF post ESWL is still uncertain. Our patient was 60 years of age, with hypertension, chronic kidney disease and one atrophic kidney. Perinephric hematoma post ESWL affecting his conbtralateral normal sized kidney, may be one of causes of the deterioration in his renal function. The partial obstruction of his right ureter, due to the presence of stones, also affected his renal function.
 Reports of perinephric hematoma complicating ESWL are rare.[5, 8, 13] Treatment with ESWL induces changes in the kidney similar to that of renal trauma, consisting primarily of intraparenchymal and perinephric hemorrhage and edema[5]. The acute effects of ESWL are well tolerated by most patients, but the long-term sequelae of this therapy are not well established. In cases with post ESWL-related hematoma, underlying coagulopathy[14-15], hypertension[11] and hydrocalyx[16] are statistically associated with their incidence. Pastor Navarro H. et al.[17-18] reviewed 4,815 patients undergoing ESWL and concluded that renal and perinephric bleeding are related to the power of energy used and patient’s age. Our patient, who had chronic kidney disease, received serial ESWL (a total of 10,200 shocks) three times in two months. That he had poor platelet dysfunction related to the impaired renal function, may also be the cause of his bleeding. He was not prescribed any anticoagulant or hemostatic medications. Several previous  reports suggest that hemorrhage post ESWL could be detected in 15% to 30% of patients by computed tomography or magnetic resonance imaging, and that the incidence of clinically significant hemorrhage is less than 1%[19-20]. Chronic kidney disease may give clinicians a warning sign of high risk of post ESWL-bleeding.
The management of this patient is challenging. Should we arrange operation first to relieve the perinephric hematoma? Most patients recover from intrarenal or perinephric hematoma without blood transfusion or surgical intervention [5, 12-13]. In most cases of death due to haemarrhage following a medical procedure, the measurement of blood pressure and hemoglobin concentration are usually not well performed [13]. Although deaths from  hemorrhage post ESWL are rare, it has been reported recently[13]. The guidelines of surgical management of post ESWL need further evaluation. For this patient, we arranged hemodialysis first instead of operation due to severe uremic symptoms and signs, metabolic acidosis and severe anemia. Ureteroscopy one week-later relieved the ureteric obstruction. The patient’s renal function recovered back to its initial level after one month and he was withdrawn from dialysis.
In summary, we report a patient with a unilateral atrophic kidney who developed ARF with hematoma formation after ESWL. After emergency hemodialysis and ureteroscopy, his renal function recovered. Patients with chronic kidney disease, especially if only one of the kidneys is functioning, may be at high risk of ARF post ESWL. To prevent ARF and hematoma formation post ESWL, pre treatment work up including assessment of kidney size and coagulation profile particularly in patients with chronic renal failure case is advised.

 

Reference
 
1. Gordetsky, J., et al., Subcapsular hepatic hematoma with right hepatic vein thrombosis: a complication of shock wave lithotripsy. Can Urol Assoc J., 2008. 2(1): p. 61-3.
2. Uemura, K., et al., A death due to perirenal hematoma complicating extracorporeal shockwave lithotripsy. J Forensic Sci., 2008. 53(2): p. 469-71.
3. Beatrice, J., et al., Life-threatening complication after right renal extracorporeal shock wave lithotripsy: large hepatic haematoma requiring embolisation of the right hepatic artery. Eur Urol, 2007. 52(3): p. 909-11.
4. Kaude, J., et al., Renal morphology and function immediately after extracorporeal shock-wave lithotripsy. AJR Am J Roentgenol. , 1985. 145(2): p. 305-13.
5. Liguori, G., et al., Reversible acute renal failure after unilateral extracorporeal shock-wave lithotripsy. Urol Res. , 2004. 32(1): p. 25-7.
6. Catalano, C., et al., Reflex anuria from unilateral ureteral obstruction. Nephron, 2002. 90(3): p. 349-51.
7. Treglia, A. and M. Moscoloni, Irreversible acute renal failure after bilateral extracorporeal shock wave lithotripsy. J Nephrol., 1999. 12(3): p. 190-2.
8. Inoue, H., et al., Massive retroperitoneal haemorrhage after extracorporeal shock wave lithotripsy (ESWL). Int J Legal Med, 2010. Epub ahead of print.
9. Skolarikos, A., G. Alivizatos, and J.d.l. Rosette, Extracorporeal shock wave lithotripsy 25 years later: complications and their prevention. Eur Urol, 2006. 50: p. 981-990.
10. Labanaris, A., R. Kühn, and G. Schott, Peritoneal hematomas induced by extracorporeal shock wave lithotripsy (ESWL): therapeutic management. Scientific World Journal, 2007. 7: p. 1563-1566.
11. Lipski, B., et al., Acute renal failure from a subcapsular hematoma in a solitary kidney: an unusual complication of extracorporeal shock wave lithotripsy. J Urol. , 1997. 157(6): p. 2245.
12. Tuteja, A., et al., Anuric renal failure from massive bilateral renal hematoma following extracorporeal shock wave lithotripsy. Urology, 1997. 50(4): p. 606-8.
13. Uemura, K., et al., A death due to perirenal hematoma complicating extracorporeal shockwave lithotripsy. J Forensic Sci. , 2008. 53(2): p. 469-71.
14. GM Sare, FR Lloyd, and M. Stower, Life-threatening haemorrhage after  extracorporeal shockwave lithotripsy in a patient taking clopidogrel. BJU Int, 2002. 90: p. 469.
15. H Van der Eecken, et al., Major intra-abdominal complications following extracorporeal shockwave lithotripsy (ESWL) in a patient with Ehlers-Danlos syndrome. Urology, 2002. 42: p. 635- 6.
16. Orozco Fariñas R, I.P.J., Massarrah Halabi J, Mancebo Gómez JM, Perez-Castro Ellendt E., Renal hematoma after extracorporeal shockwave lithotripsy in a series of 324 consecutive sessions with the DOLI-S lithotripter: incidents, characteristrics, multifactorial analysis and review. Arch Esp Urol, 2008. 61(8): p. 889-914.
17. Noji, E., Prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med, 1990. 323: p. 550.
18. Navarro, H.P., et al., Renal hematomas after extracorporeal shock-wave lithotripsy (ESWL). Actas Urol Esp, 2009. 33(3): p. 296-303.
19. LH Newman and B. Saltzman, Identifying risk factors in development of clinically significant post-shock-wave lithotripsy subcapsular hematomas. J Uro, 1991. 38: p. 35-38.
20. PA Knorr and J. Woodside, Large perirenal hematoma after extracorporeal shock-wave lithotripsy. Urology, 1990. 35: p. 151-153.

 
Date added to bjui.org: 03/10/2011


DOI: 10.1002/BJUIw-2011-046-web

 

An Unusual Case of Duplex kidney: Giant Hydroureter of Upper Moiety presenting as abdominal lump

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We report a case of giant hydroureter of an upper moiety presenting as abdominal lump.

 

Authors: Javali, Tarun; Gupta, Narmada 

Corresponding Author: Tarun Javali, A.I.I.M.S., Urology department, New Delhi, India.  Email: [email protected]

Introduction
 
Most patients with duplex kidneys are asymptomatic, with genitourinary abnormalities being detected incidentally on imaging performed for some other reasons. In complete duplication, the upper pole ureter usually drains caudal and medial to the lower pole ureter (Weigert Meyer rule). Ectopic insertion of the upper pole ureter may cause hydronephrosis as a consequence of stenosis of the ureteric orifice. However massive dilatation of just the upper pole ureter (with a small and atrophic upper pole renal moiety) is rare. Here we report a case of giant hydroureter of an upper moiety presenting as abdominal lump.

 

Case report
A 31 year old male presented with dull ache in his right flank and progressively increasing abdominal swelling for the previous 8 months. There was no history of fever or lower urinary tract symptoms. The patient also gave a history of constipation for the past  month. Examination revealed an ill-defined abdominal mass, soft in consistency, and occupying the right flank and right hypochondrium,  extending into the right iliac fossa and umbilical regions.
On rectal examination, a soft cystic mass was palpable anterior to the rectum and causing extrinsic rectal compression.
Routine blood and urine tests were within normal limits. A contrast enhanced CT scan of the kidneys, ureters and bladder [Fig. 1] and an MR urogram [Fig. 2] were performed.

 

Figure 1. CT scan of the kidneys, ureters and bladder

 


 
Figure 2. MR urogram

 

A voiding cystogram showed no evidence of vesicoureteric reflux. On cystoscopic examination, the ectopic orifice of the right upper moiety ureter could not be identified. The right lower moiety ureter was stented. Transperitoneal laparoscopic upper pole nephroureterectomy was performed [Fig.3].

 

Figure 3.  Transperitoneal laparoscopic upper pole nephroureterectomy 

 

After ligating the upper pole renal vessel, the abnormal ureter was dissected close to its wall. The giant hydroureter contained 8 litres of turbid urine. The ectopic ureter was found opening into the posterior urethra. A 3cm Gibson incision was performed for specimen removal [Fig.4].

 

Figure 4.  A 3cm Gibson incision was performed for specimen removal

 


 
Figure 5. 

 


 
Discussion
 
This case has been reported to highlight the extent to which a ureter can dilate. There are only a few cases of duplex kidney/ectopic ureter reported in the literature in which the ureter has assumed such massive proportions, completely overshadowing the renal pelvis and parenchyma. Uson et al reported a case of a giant ectopic ureter presenting as an abdominal mass in a newborn infant [1]. Mahajan et al reported a case of an adult woman who had unilateral upper-pole giant hydroureter in a duplex kidney which was incidentally detected during cesarean section [2]. Heminephrectomy was performed, and the hydroureter was found to contain 2 litres of fluid. Whitmore et al reported a case of giant hydronephrosis of a duplex system associated with ureteral ectopia [3].
In the present case, the ectopic ureter of upper moiety of the right kidney was dilated to such an extent, that it presented as an abdominal mass and also caused constipation due to extrinsic rectal compression. Laparoscopic upper pole nephroureterectomy was successfully carried out and the patient’s symptoms were relieved after surgery.

 

References
 
1. Uson AC, Womack CE, Berdon WE. Giant ectopic ureter presenting as an abdominal mass in a newborn infant. The Journal of Pediatrics. 1972; 80:473-76.
2. Mahajan NN, Sahay S, Kale A, Nasre M. Unilateral upper-pole giant hydroureter in a duplex renal system: an incidental finding in cesarean section. Arch Gynecol Obstet. 2008; 278:149-51.
3. Whitmore RB, Schellhammer PF. Giant hydronephrosis of a duplex system associated with ureteral ectopia. J Urol. 1989; 141:1186-8.

 

Date added to bjui.org: 29/09/2011 


DOI: 10.1002/BJUIw-2011-073-web

 

Fournier’s Gangrene Complicating Diverticular Colovesical Fistula

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We present an 82 year old gentleman who developed Fournier’s gangrene as a result of a colovesical fistula secondary to diverticular disease of sigmoid colon. 

 

Authors: Mr. Yao Pey YONG, SHO General Surgery, Doncaster Royal Infirmary.

Mr. Vivek Kumar, Consultant Urology, Doncaster Royal Infirmary

 
Corresponding Author: Mr. Yao Pey YONG, E:mail: [email protected]

 

Abstract
Colovesical fistula has been described as a cause of Fournier’s gangrene but it is a rare occurence. We present an 82 year old gentleman who developed Fournier’s gangrene as a result of a colovesical fistula secondary to diverticular disease of sigmoid colon. The unusual findings during debridement were gangrene of the urethra and testicles. The patient subsequently had a Hartmann’s procedure and closure of the bladder defect. Fournier’s gangrene is a urological emergency that requires a multidisciplinary team approach to optimise patient outcome.

 

Introduction
 
Fournier’s gangrene is necrotising fasciitis of the male genitalia. It was first described by Avicenna in 1025 but was named after a French professor in syphilology in 1883 after he described a series of five previously healthy young men suffering from a rapidly progressive gangrene of the penis and scrotum without apparent cause. We present an unusual case of Fournier’s gangrene complicating colovesical fistula secondary to sigmoid diverticulosis, with urethra and bilateral testicular involvement. Although diverticular disease is known to be one of the causes of Fournier’s gangrene, the authors have yet to come across any similar cases in the literature during the writing of this manuscript.

 

Case Report
 
An 82 year old gentleman was admitted through the Accident and Emergency Department with a one day history of lower abdominal pain and rigors. His past medical history included osteoarthritis, benign prostatic hypertrophy and colovesical fistula secondary to sigmoid diverticulosis, which was diagnosed one month previously on computerised tomography (CT) scan.

 

Figure 1. CT scan

 

 

He was awaiting elective surgery due a week from the date of admission. His vital signs were as follows: temperature 38°C, blood pressure 120/65mm Hg, heart rate 108/minute, respiratory rate 24/minute and oxygen saturation 98% on room air. Physical examination revealed tenderness across the lower abdomen with minimal voluntary guarding. Initial laboratory studies revealed the following values: haemoglobin 11.1 g/dl, white cell count 7.4 x109/L, C-reactive protein 65.5 mg/L, amylase 54 U/l, creatinine 143 umol/L, urea 12.8 mmol/L, sodium 133 mmol/L and potassium 4.6 mmol/L. Urinalysis revealed protein, leucocytes and nitrites. A diagnosis of acute renal failure and urinary sepsis secondary to colovesical fistula was made. He was fluid resuscitated and commenced on intravenous antibiotics.
On day five of admission, he complained of pain in the perineal region. Physical examination revealed swelling of his penis, scrotum and perineum.

 

Figure 2. Physical examination 

 

 

Blood cultures taken on admission revealed an Enterococcus and antibiotics were changed after discussion with the Department of Microbiology. Repeated physical examination the following day revealed patchy necrotic penile skin. A diagnosis of Fournier’s gangrene was made and an immediate urological referral made. Repeated laboratory studies at this point revealed the following values: haemoglobin 8.7 g/dl, white cell count 27.8 x109/L, creatinine 140 umol/L, urea 11.0 mmol/L, sodium 134 mmol/L and potassium 4.1 mmol/L.
The patient had a  metabolic acidosis and was fully resuscitated prior to the operation. He underwent four separate operations. The initial procedure was an extensive debridement of perineal, scrotal and penile skin. Surprisingly, deeper structures were involved as well, including the full length of the urethra, and perineal fat. The proximal urethra was ligated. Bowel diversion was deferred due to poor general condition of the patient.

 

Figure 3. The initial procedure was an extensive debridement of perineal, scrotal and penile skin.

 

 

He was brought back to the operating room the next day for further debridement, Hartmann’s procedure, closure of bladder defect and suprapubic cystostomy. He had two further debridements subsequently. Negative pressure wound therapy was applied to the perineal wound (VAC therapy).

 

Discussion
 
Fournier’s gangrene is an acute and potentially fatal, deep-seated bacterial infection with secondary necrosis of the skin and soft tissue of the scrotum, perineum and abdominal wall. The infection spreads very rapidly and progressively along the deep fascia.[1] The risk factors include old age, diabetes, alcoholism, malignancy, immunosuppression and any conditions that involve the genitourinary tract or gastrointestinal tract that present potential portals of entry for opportunistic bacteria. A primary source can be identified in 95% of cases.[2] However, Efem[3] argues that Fournier’s gangrene is never idiopathic, and when the cause is not found, it implies that the clinician is unable to determine the cause because the portal of entry may have been so trivial that it was overlooked. In our case, the patient’s risk factors were old age and colovesical fistula secondary to sigmoid diverticulosis.
The symptoms of rigor and discomfort in the external genitalia were initially overshadowed by lower abdominal pain and a positive urinalysis. As the patient had a prior diagnosis of colovesical fistula secondary to diverticulosis, a preliminary diagnosis of lower urinary infection was made on admission. Garcea [4] in his study, showed the most common presenting symptoms of colovesical fistula were pneumaturia (90.1%), faecaluria (76.2%), abdominal pain (70.1%) and recurrent urinary tract infection (66.7%). Diverticulosis is known to be the most common cause of colovesical fistula and occurs mainly in the sixth and seventh decade of life. It is reported that male to female ratio is between 5 to 1 and 1.5 to 1.[5] This is thought to be due to the protective effect of the female reproductive organs as a physical barrier to fistulisation from diseased bowel.[5,6,7] Studies have shown that 50% of women have had a hysterectomy before the development of colovesical fistula. Other causes include Crohn’s disease, malignancy, radiation therapy, trauma and rarely, appendicitis.
The identification and diagnosis of Fournier’s gangrene is challenging in the early stages. Hefny[1] reported only 4 out of 11 patients in his study had a correct preliminary diagnosis. Patients usually present with an insidious onset of pruritis and discomfort in the external genitalia. This is followed by pain, swelling and systemic symptoms including rigors. When gangrene develops, pain may actually subside due to destruction of nerve tissue. The bacteria involved are usually both aerobes and anerobes, with E. coli the predominant aerobe and Bacteroides the predominant anaerobe.[8] They act synergistically with enzymes to invade and destroy fascial planes. As obliterative endarteritis develops, cutaneous and subcutaneous vascular necrosis leads to localised ischemia and further bacterial proliferation.[8] The infection in Colles fascia may spread to the penis and scrotum via Buck’s and Dartos fascia or to the anterior abdominal wall via Scarpa’s fascia. Colles fascia is attached to the perineal body and urogenital diaphragm posteriorly and to the pubic rami laterally, thus limiting progression in these directions.[8] As the infection spreads, induration worsens and bullae are formed. The overlying skin becomes anaesthetised and necrotic at a very late stage.
Fournier’s gangrene is primarily a clinical diagnosis. However, radiological evaluation may aid to reach the diagnosis if in doubt. Plain films are commonly performed and may reveal air in the soft tissue. This is not pathognomonic but nevertheless should alert the clinician to the possibility of necrotising fasciitis.[9] Ultrasonography may be a more useful diagnostic tool as it may show a thickened scrotal wall and peritesticular fluid.[10] Echogenic shadows with ring down artifact represent air, which is the ultrasonographic hallmark of Fournier’s gangrene.[10,11] An infected hydrocoele may mimic Fournier’s gangrene as the testes may be surrounded by fluid. However, no air should be seen in the subcutaneous tissues.[10] CT findings of Fournier’s gangrene include asymmetric fascial thickening, subcutaneous emphysema, fluid collections and abscess formation.[10] Although CT provides higher specificity, ultrasonography is inexpensive and may provide similar findings to those of CT. Magnetic resonance imaging may be used to aid the diagnosis of Fournier’s gangrene, however the evidence is limited.
Textbooks often describe sparing of the testes as their blood supply is directly from the aorta. However, some authors[9,12,13,14] have argued that the incidence of patients requiring orchidectomy for non-viable testes is up to 21%, but in most cases the indications for orchidectomy were pre-existing epididymo-orchitis, scrotal abscess and extensive tissue damage in the surrounding scrotum, groin, and perineal area. Interestingly, Gupta et al[15] did report a case of bilateral testicular gangrene in Fournier’s gangrene. Erke16 stated that the testicular involvement was rare and that when it occurs it indicates a retroperitoneal or intra abdominal source of infection. In our case, the patient had bilateral orchidectomy as the gangrenous tissue was extensive and the testes appeared non-viable. In addition it is unusual to find gangrene of the urethra. In this particular case, the whole of the urethra was gangrenous.
A review done by Elliott et al[17] stated that colostomy was not routinely performed even when the infection involved the perianal area as Fournier’s gangrene can ascend the anterior abdominal wall. Withholding colostomy until the infection has been halted, rather than performing it at initial presentation, may be prudent.[17] Hartmann’s procedure and bladder repair was performed to disconnect the fistula as it was the source of infection in our patient. Although there is limited randomised trials to clarify the role and efficacy of VAC therapy, it appears to be an effective tool for post-operative wound management in Fournier’s gangrene.[18]

 

Conclusion
 
Fournier’s gangrene is a potentially fatal, rapidly spreading necrotising soft tissue infection. Clinicians should have a high index of suspicion in patients who carry risk factor(s). Early diagnosis, resuscitation and aggressive debridement are paramount to a favourable outcome.

 

Conflict of Interest
The authors have no competing interests.

 

References
 
1. Hefny AF, Eid HO, Al-Hussona M, et al. Necrotising fasciitis: A challenging diagnosis. European Journal of Emergency Medicine 2007;14:50–52.
2. Champion SE. A case of Fournier’s gangrene. Urol Nurse 2007;27:296-299.
3. Efem SE. The features and aetiology of Fournier’s gangrene. Postgrad Med J 1994;70:568-571.
4. Garcea G, Majid I, Sutton CD, et al. Diagnosis and management of colovesical fistulae: Six-year experience of 90 consecutive cases. Colorectal Disease 2006;8:347-352.
5. Hsieh JH, Chen WS, Jiang JK, et al. Enterovesical fistula: 10 year experience. Chin Med J (Taipei) 1997;59:283-8.
6. Abeshouse BS, Robbins MA, Gann M, et al. Intestinovesical fistulas: Report of seven cases and review of the literature. JAMA 1957;164:251-7.
7. Carpenter WS, Allaben RD, Kambouris AA. One-stage resections for colovesical fistulas. J Urol 1972;108:265-7.
8. Marynowski MT, Aronson AA. Fournier Gangrene in Emergency Medicine. https://emedicine.medscape.com/article/778866-overview#a0104 (access 27 May 2011)
9. Smith GL, Bunker CB, Dinneen MD. Review: Fournier’s gangrene. British Journal of Urology 1998;81:347-355.
10. Safriel Y, Cohen HL, Torrisi J. Ultrasound Imaging of Scrotal Wall Thickening and Its Significance in the Diagnosis of Fournier’s Gangrene in Older Men. Journal of Diagnostic Medical Sonography 2000;16:29-33.
11. Tsai MJ, Lien CT, Chang WA, et al. Transperineal ultrasonography in the diagnosis of Fournier’s gangrene. Ultrasound Obstet Gynecol 2010;36:387-391.
12. Hejase MJ, Simonin JE, Bihrle R, et al. Genital Fournier’s gangrene: Experience with 38 patients. Urology 1996;47:734-9.
13. Hohenfellner M, Santucci RA. Fournier’s gangrene. In: Heyns CF, Theron PD (Eds.) Emergencies in Urology. Germany: Springer; 2007. p50 – 59.
14. Ayan F, Sunamak O, Paksoy SM, et al. Fournier’s gangrene: A retrospective clinical study of forty one patients. ANZ J Surg 75:1055-1058.
15. Gupta A, Dalela D, Sankhwar SN, et al. Bilateral testicular gangrene: Does it occur in Fournier’s gangrene? Int Urol Nephrol 2007;39:913-915.
16. Eke N. Fournier’s gangrene: A review of 1726 cases. Br J Surg 2000;87(6):718-728.
17. Elliott DC, Kufera JA, Myers RAM. Necrotizing soft tissue infections: Risk factors for mortality and strategies for management. Annals of Surgery 1996;224(5):672-683.
18. Tucci G, Amabile D, Cadeddu F, el al. Fournier’s gangrene wound therapy: Our experience using VAC device. Langenbecks Arch Surg 2009;394:759-760.

 
Date added to bjui.org: 27/09/2011


DOI: 10.1002/BJUIw-2011-071-web
 

Avascular necrosis of hip secondary to sunitinib

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We report a case of a 73 year old patient who developed AVN of her left hip while on sunitinib for mRCC.

 

Authors: Dr Muhammad A Khattak, MBBS1, Dr Hilary L Martin, MBBS2, Dr Chris Karapetis,MBBS, FRACP1

1. Oncology Registrar, Flinders Medical Centre

2. Oncology Registrar, Calvary Hospital

 
Corresponding Author: Dr Muhammad A Khattak, Oncology Registrar, Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, South Australia – 5042.   Tel: +61 8 8204 5511, Fax: +61 8 8404 2152 , Email: [email protected]

 

Introduction
 
Avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC).  Avascular necrosis secondary to anti-angiogenic agents is possibly a rare complication of these drugs and the likely pathogenesis is microvascular compromise. We report a case of a 73 year old patient who developed AVN of her left hip while on sunitinib for mRCC.

 

Case report
A 73 year old woman was investigated for chest pain and found to have multiple pulmonary lesions and a mass in her right kidney.  Biopsy of the renal mass (FNA) was performed.  Histology was consistent with renal cell carcinoma (ovoid to irregular, pleomorphic nuclei, dispersed chromatin, obvious, single nucleoli and abundant vacuolated lightly staining cytoplasm).  She was commenced on sunitinib 50mg daily on 9 March 2007.  After a couple of weeks she developed an upper torso rash, mucositis and thrombocytopaenia, and sunitinib was ceased temporarily and recommenced at a dosage of 25mg daily on 20 April 2007 with a planned cycle of four weeks on and two weeks off.  This dosage was tolerated well, with no clear treatment related side effects. A computed tomography (CT) scan performed on 10 July 2007 showed a radiologic response to treatment. Besides sunitinib, the patient was taking the following medications on a daily basis; enalapril 10mg, simvastatin 40mg, diltiazem 360mg, pantoprazole 40mg, furosemide 40mg, hydroxychloroquine 200mg, and thyroxine 100mcg. She had also taken warfarin, which was ceased recently.
She developed left hip pain for the first time in November 2007. A whole body bone scan at that time revealed diffuse uptake involving the left femoral head and neck, which was thought to be atypical for both degenerative change and bony metastatic disease (figure 1).

 

Figure 1. A whole body bone scan revealed diffuse uptake involving the left femoral head and neck.

 

 

She subsequently developed erythema and swelling of the lower limb which was thought to be due to sunitinib.  This was ceased on 19 December 2007 along with her diltiazem and thyroxine.  The patient’s pain deteriorated with time, with reduction in her mobility and restriction of movement at the left hip . She had an antalgic gait. X-ray of the hip revealed degenerative changes, with reduction of the joint space, and altered contour of the left femoral head in addition to collapse. There was no fracture or dislocation. An MRI performed in February 2008 showed a large left hip joint effusion with synovial thickening and a crescentic low signal focus consistent with a fragment of cortical bone. The femoral head demonstrated marked deformity with collapse of the superior contour and crescentic fluid cleft, associated with cortical defect superoanteriorly. The femoral head showed a low T1 and intermediate T2 signal consistent with diffuse edema. The overall appearances were thought to reflect avascular necrosis with collapse of the left femoral head, diffuse edema and advanced secondary degenerative changes (figure 2 and 3).

 

Figure 2. 

 

 

Figure 3. 

 


 
No convincing evidence of metastatic deposits was found. She was referred to an orthopaedic surgeon and a total hip replacement was performed.
The patient did not have any predisposing medical conditions for avascular necrosis of the hip and had never used steroids. She was a non-smoker with minimal alcohol consumption. There was no history of trauma to the left hip and she had never received any radiotherapy. This led to the hypothesis that sunitinib could have led to this through compromise of the microvasculature of the left femoral head (due to its antiangiogenic activity), which is thought to be the main pathologic process underlying this condition eventually leading to mechanical compromise of the hip.

 

Discussion
Osteonecrosis (ON), also known as avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. According to Kerachain et al , decreased local blood flow to the femoral head and microvascular thrombosis is the most accepted mechanism in the pathogenesis of ON. It is associated with traumatic and various non-traumatic causes including corticosteroid use, smoking, alcohol consumption, radiotherapy (osteoradionecrosis), hyperuricaemia and hyperlipidaemia. Corticosteroid and alcohol use are thought to be associated with >90% of cases .
Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC) and as second line treatment in metastatic gastrointestinal stromal tumours (mGIST). Sunitinib was evaluated in a phase III trial of 750 patients with metastatic clear cell RCC who had not received prior systemic treatment . Patients were randomly assigned to sunitinib or interferon alfa. The updated results published by Motzer et al  showed that the median overall survival was greater in the sunitinib group than in the IFN-alpha group but not statistically significant (26.4 v 21.8 months, respectively; hazard ratio [HR]= 0.821; 95% CI, 0.673 to 1.001; P = 0.051). Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P<.001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P<0.001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
There have been two of reports of ON related to targeted therapy like bevacizumab and single case reports with sorafenib and sunitinib , . To our knowledge, this is the second case of ON related to suntinib treatment. According to the Naranjo scale  for determining the likelihood of an adverse drug reaction as a side effect of a particular drug compared to other factors, the imputability of sunitinib in this case is ‘probable’ (score 5). Our patient was on diltiazem regularly for management of hypertension before sunitinib was started and its concurrent administration could have lead to toxicity with sunitinib through a pharmacokinetic interaction by inhibiting cytochrome P-450 (CYP3A4) ,  resulting in an increased sunitinib concentration.
Although the targeted agents have revolutionalised the field of medical oncology, we have to be cautious about under recognized and rare side effects of these agents impacting on the quality of life of cancer patients. Osteonecrosis secondary to anti-angiogenic agents is possibly a rare class effect of these drugs and the likely pathogenesis is microvascular compromise eventually ending up in mechanical failure. The treating physician needs to be aware that new onset musculoskeletal hip pain in patients on anti-angiogenic agents could be related to therapy related complication, besides disease progression and secondary skeletal events. Early recognition and prompt treatment of these complications can be beneficial in minimizing the patient symptoms and disability. Therefore, new onset hip pain in a patient on these agents should be investigated sooner rather later with imaging including plain X-rays and MRI.
 

References
1. Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head: Vascular hypotheses. Endothelium. 2006 Jul: 13:237-244
2. Mont MA, Hungerford DS. Non-traumatic avascular necrosis of the femoral head. J Bone Joint Surg Am.  1995 Mar: 77:459-74
3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan: 356:115-24
4. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug: 27:3584-90
5. Guillet M, Walter T, Scoazec JY, et al. Sorafenib-induced bilateral osteonecrosis of femoral heads. J Clin Oncol. 2010 Jan: 28: e14. Epub 2009 Nov
6. Mir O, Coriat R, Gregory T, Ropert S, et al. Avascular necrosis of the femoral head: a rare class-effect of anti-VEGF agents. Invest New Drugs. 2011 Aug. 29: 716-8 Epub 2010 Feb
7. Naranjo C, Busto U, Sellers E, et al. A method for estimating the probability of adverse drug reactions.. Clin Pharmacol Ther. 1981 Aug: 30: 239-45
8. Haouala A., Widmer N., Montemurro M, et al. Cardiovascular drug interactions with tyrosine kinase inhibitors. Cardiovascular Medicine. 2010 May: 13: 147-54
9. Izzedine H, Massard C, Spano J, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer. 2010 Jan: 46:  439-48

 
Date added to bjui.org: 21/09/2011


DOI: 10.1002/BJUIw-2011-058-web

 

Pheochromocytoma in the urinary bladder

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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

 

Ewing’s Sarcoma with Isolated Bladder Metastasis

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We describe a case of an isolated bladder metastasis in EWS, which, to our knowledge, has not been previously reported.

 

Authors: Alexander Yeates MBBS, Peter Campbell FRACS, Queen Elizabeth II Jubilee Hospital, Brisbane, Australia
 
Corresponding Author: Alexander Yeates MBBS, Queen Elizabeth II Jubilee Hospital, Brisbane, Australia. Email: [email protected], [email protected]

 

Abstract
Ewing’s sarcoma (EWS) can occur in almost any bone or soft tissue, however cases involving the bladder are exceedingly rare. We describe a case of an isolated bladder metastasis in EWS, which, to our knowledge, has not been previously reported.
A twelve year old boy was initially diagnosed with primary EWS of the skull.  He was treated with local surgical resection, radiotherapy and chemotherapy.  He had no recurrence until four years later when he presented with painless haematuria.  Urinary cytology revealed small, round atypical cells, and he was referred for a urological opinion.  An intravenous pyelogram was normal.  Rigid cystoscopy revealed a 20 x 15mm lesion that was resected and histology confirmed recurrence of EWS.  After careful consideration, a partial cystectomy was performed with good post-operative recovery and subsequently he completed a course of adjuvant chemotherapy.  40 months of follow-up including blood tests, rigid cystoscopy, CXR, CT and USS have not revealed further recurrence.
The prognosis following recurrence of Ewing’s sarcoma is usually guarded, however features specific to this case, such as the prolonged interval to recurrence and presence of a distant, isolated recurrence are relatively reassuring.

 

Introduction
Ewing’s sarcoma (EWS) was initially described by James Ewing in 1921 as an undifferentiated, small, round cell tumour involving the diaphysis of long bones [1].  More recently, EWS, primitive neuroectodermal tumour and Askin’s tumour have all been classified under the common term of the Ewing’s sarcoma family of tumours following identification of the common translocation t(11;22)(q24;q12) resulting in the formation of the EWS-ETS fusion gene [2,3].  These tumours can occur in almost any bone or soft tissue, however cases of EWS involving the bladder are exceedingly rare [4,5] and a case of an isolated recurrence in the bladder has not previously been reported.

 

Case Report
An otherwise healthy twelve year old boy was diagnosed with EWS of the skull in 2003.  He was initially treated with local excision, radiotherapy (50.4Gy) and chemotherapy (vincristine 15mg/m2, cyclophosphamide 17,400mg/m2, doxorubicin 480mg/m2, ifosfamide 39,000mg/m2, carboplatin 3,000mg/m2 and etoposide 1,950mg/m2) followed by stem cell rescue.  Four years later he presented to an Accident and Emergency Department following a single episode of frank haematuria.  Abdominal and pelvic ultrasound scan demonstrated normal upper urinary tracts with a large amount of echogenic material consistent with clot within the bladder.  Urine microscopy showed clusters of small round atypical cells, lymphocytes and erythrocytes. An intravenous pyelogram was normal.
Following referral to a Urologist, rigid cystoscopy identified a 20x15mm solid necrotic lesion on the left lateral wall of the bladder (Figure 1).

 

Figure 1.Rigid cystoscopy showing bladder lesion.

 

 

The lesion was excised with a 26 Fr resectoscope.  Microscopic examination of the lesion revealed sheets of small, undifferentiated malignant cells invading into muscle (Figure 2).

 

Figure 2. Undifferentiated malignant tumour of bladder. (H&E stained section, original magnification x400)

 

Immunohistochemical testing showed the cells were strongly positive for CD99 in a membranous pattern with scattered cells positive for NFP and synaptophysin.  They were negative for S100, Desmin, Myo D1 and SMA.  Fluorescence in-situ hybridisation (FISH) using the Vysis [6] EWSR1 (22q12) dual colour break apart rearrangement probe showed rearrangement of the EWSR1 gene region confirming the diagnosis of metastatic EWS (Figure 3).

 

Figure 3. Fluorescence in-situ hybridisation of the bladder lesion using the Vysis EWRS1 (22q12) dual break apart probe shows rearrangement of the EWSR1 gene region, confirming the diagnosis of metastatic EWS.

 

 

Staging investigations (whole body bone scan and CT abdomen and pelvis) showed no evidence of disease elsewhere in the body.
Given that this appeared to represent an isolated tumour recurrence, the decision was made to perform a partial cystectomy in October 2007.  The lesion was identified and excised with a four centimetre margin (Figure 4).

 

Figure 4. Partial cystectomy specimen showing central area of ulceration.

 

 

Histology of the excised specimen showed an area of ulceration that was clear of the margins.  There was no evidence of residual tumour.  Post-operative recovery was uneventful.
Following partial cystectomy, the patient received adjuvant chemotherapy of topotecan (36mg/m2) and cyclophosphamide (18,000mg/m2).  This was adequately tolerated.  The patient was considered for sperm storage but was found to be azoospermic.
Follow-up has involved surveillance rigid cystoscopy and examination under anaesthesia at three-monthly intervals with interim outpatient reviews with surveillance full blood count, electrolytes and liver function blood tests, chest x-ray, abdominal and pelvic CT and ultrasound scans to exclude further metastatic disease.  Surveillance for over 40 months has so far revealed no evidence of local recurrence or further metastases.

 

Discussion
Rare cases of primary EWS of the bladder have been reported [4,5] and EWS has also been described as arising in the bladder as a second tumour in paediatric patients with a previous haematological malignancy [7].   To our knowledge this case represents the first report of primary skeletal EWS with an isolated bladder metastasis.    Given that the five-year survival rate for patients with recurrent EWS has been reported to be as low as 13% [8], the initial prognosis for this patient was guarded.  Significant risk factors for death following recurrence in Leavey’s study [9] included recurrence at combined local and distant sites, elevated LDH at initial diagnosis and initial recurrence less than two years following diagnosis.  In contrast, this patient had recurrence at a single distant site four years after the primary diagnosis of EWS and is now disease free four years after excision of the recurrent lesion.  This is relatively reassuring when considering the long-term prognosis.
It is also worth noting that this adolescent patient presented clinically with an episode of macroscopic haematuria.  This symptom cannot be ignored and should lead to consideration of cystoscopic examination of the bladder particularly in patients with a significant previous medical history [10].

 

References
1.  Ewing J.  Diffuse endothelioma of bone.  Proc NY Pathol Soc 1921;21:17-24.
2.  Aurias A, Rimbaut C, Buffe D, Zucker JM, Mazabraud A.  Translocation involving chromosome 22 in Ewing’s sarcoma: a cytogenic study of four fresh tumors.  Cancer Genet Cytogenet 1984;12:21-25.
3.  Whang-Peng J, Triche TJ, Knutsen T, Miser J, Douglass EC, Israel MA.  Chromosomal translocation in peripheral neuroepithelioma. N Engl J Med 1984;311:584-585.
4.  Gousse AE, Roth DR, Popek EJ, Cooley LD, Horowitz ME.  Primary Ewing’s sarcoma of the bladder associated with an elevated antinuclear antibody titer.  J. Urol.  1997;158:2265-2266.
5.  Okada Y, Kamata S, Akashi T, Kurata M, Nakamura T, Kihara K.  Primitive neuroectodermal tumor/Ewing’s sarcoma of the urinary bladder: a case report and its molecular diagnosis.  Int J Clin Oncol.  2010 Nov 10. [Epub ahead of print].
6.  Vysis package insert.  Invitrogen Spot-Light tissue Pre-treatment Kit package insert. KOJI,T, Molecular Histochemical Techniques, Springer- Verlag, Tokyo, 2000.
7.  Osone S, Hosoi H, Tanaka K, Tsuchiya K, Iehara T, Morimoto A, Hashida T, Yamashita M, Kawabata K, Nishijo K, Toguchida J, Hata J, Sugimoto T.  A case of a Ewing sarcoma family tumor in the urinary bladder after treatment for acute lymphoblastic leukemia.  J Pediatr Hematol Oncol. 2007 Dec;29(12):841-4.
8.  Bacci G, Ferrari S, Longhi A, Donati D, De Paolis M, Forni C, Versari M, Setola E, Briccoli A, Barbieri E.  Therapy and survival after recurrence of Ewing’s tumours: the Rizzoli experience in 195 patients treated with adjuvant and neo-adjuvant chemotherapy from 1979 to 1997.  Ann. Oncol 2003;14:1654-1659.
9.  Leavey PJ, Mascarenhas L, Marina N, Chen Z, Krailo M, Miser J, Brown K, Tarbell N, Bernstein ML, Granowetter L, Gebhardt M, Grier HE.  Prognostic Factors for Patients with Ewing sarcoma (EWS) at First Recurrence Following Multimodality Therapy – A Report from the Children’s Oncology Group.    Pediatr Blood Cancer. 2008 September ; 51(3): 334–338.
10.  Gordon C, Stapleton FB. Hematuria in adolescents.  Adolesc Med Clin. 2005;16:229-39.

 

Date added to bjui.org: 06/09/2011 


DOI: 10.1002/BJUIw-2011-028-web

 

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