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Pheochromocytomas of the vesical and paravesical region

August 8, 2012/by admin Z.9

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

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

John Banerjee², Ramani Manoj Kumar³,Simon Rajaratnam¹

1. Department of Endocrinology; 2 Department of Urology; 3 Department of Pathology, Christian Medical College, Vellore, India

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

Abstract

Purpose

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

Material and Methods

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

Results and Conclusion

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

Introduction

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

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

Case Report 1

A 28 year old woman presented in 1996 with a history of recurrent episodes of chest pain with profuse sweating and palpitation for 4 years, 5 these episodes usually occurred during micturition or soon after micturition. One month prior to admission she also had an episode of hematuria. Prior to the onset of her symptoms she went through two uneventful vaginal deliveries. Her family history was unremarkable.

On examination, her pulse rate was 90/min and blood pressure 140/90 mmHg. After micturition her pulse rate increased to120/min and blood pressure increased to 160/110 mmHg. Cardiovascular, respiratory system, abdominal and CNS examination were all normal. No bruits were heard over the abdomen. Fundus examination revealed grade 2 hypertensive changes.

Her full blood count and urea and electrolytes were normal. Urine microscopy was normal; there was no proteinuria or glycosuria. Twenty four hour urinary Vanillyl Mandelic Acid (VMA) levels were elevated at 8 mg and 11mg (normal <7 mg/24 hours). ECG revealed sinus tachycardia with no evidence of LVH. Chest X ray was normal. Ultrasound revealed an intravesical mass extending into the perivesical space. MIBG (Meta-Iodo-Benzyl-Guanidine) scan showed tracer uptake over the tumor.

After adequate control of blood pressure she underwent partial cystectomy. The post operative period was uneventful and all anti-hypertensive agents were successfully withdrawn. She has remained asymptomatic on follow up.

Case Report 2

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

Case Report 3

A 28 year old woman, presented in 2010 with a history of intermittent severe headache for 15 years. Two years following the onset of these symptoms she had an episode of severe headache and loss of consciousness. She was hospitalized and was found to have sustained a right hemiparesis secondary to an intracerebral bleed. She gradually regained motor power on the affected side, but continued to experience frequent headaches.

One year before she started complaining of blurring of vision and was found to have severe hypertension. Her documented blood pressure readings were as high as 210/140 mmHg. She complained of severe headache, palpitations and sweating following micturition.

On examination her blood pressure was 150/110 mmHg. Following micturition her blood pressure rose to 190/130 mmHg. There were no bruits over her abdomen. She had grade 1 hypertensive changes in her fundi. The rest of the systemic examination was normal.

On investigation she had mild anemia. Her serum calcium, phosphorus, electrolytes and creatinine were normal. Urine examination showed no abnormality. Her chest X-ray, ECG and echocardiogram showed left ventricular hypertrophy. Her 24 hour urinary metanephrine level was 88 μg/1450 ml (normal < 350 μg/24 hour) and urinary

nor-metanephrine level was 1848 μg/1450 ml (normal <600 μg/24 hour).

CT angiogram revealed a 4.3 x 4 cm hypervascular mass in the inferolateral wall of the urinary bladder bulging into the lumen. Her MIBG scan however showed no uptake over the lesion.

After adequate control of blood pressure she proceeded to surgery. Cystoscopy revealed a normal external urethral meatus, normal urethra and ureteric orifices. The bladder mucosa appeared normal. At laparotomy, there was a 5 x 5 cm mass involving the anterior and left lateral wall of the bladder. At cystotomy, the mucosa appeared normal but the tumor could be felt extending up to the bladder neck, adjacent to the ureteric orifice. A partial cystectomy was performed and the tumor was excised with a margin beyond its palpable edge. The postoperative period was uneventful and her anti-hypertensive medication was discontinued. Histopathological examination revealed features of pheochromocytoma, with typical ‘zell-ballen’ arrangement of tumour cells, separated by a delicate network of capillary sized blood vessels. There was mild nuclear pleomorphism, but no evidence of malignancy. The tumour cells were positive for Chromogranin A, synaptophysin, and negative for cytokeratin (Fig 1 & 2).

Figure 1.

Figure 2.

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

Case Report 4

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

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

Figure 3.

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

Figure 4.

Figure 5.

Discussion

Pheochromocytoma of the urinary bladder is a rare tumor. Such tumors arise from the chromaffin tissues associated with sympathetic nerves located within the bladder wall. They are hormonally active and cause symptoms including palpitations, sweating, headache and hypertension (paroxysmal/sustained). These symptoms are usually precipitated by micturition.[6] A rise in blood pressure can be demonstrated immediately following micturition. The other precipitating factors include abdominal palpation, defecation and sexual intercourse. However, not all patients demonstrate these signs and symptoms due to receptor down regulation following prolonged catecholamine exposure. Signs and symptoms of urethral obstruction may also occur. [7] Painless hematuria occurs in 50-60% of patients. The diagnosis of this condition warrants a high index of clinical suspicion.

The most useful laboratory test is to determine blood and urinary catecholamine levels and measure their metabolic byproducts. Urinary VMA levels >9.0 mg/24 hours, nor epinephrine > 80 μg/24 hours and epinephrine > 20 μg/24 hours have been found in most patients. While CT/MR aid in the anatomical localization of these tumors, iodine-131– metaiodobenzylguanidine (MIBG) and indium-111 pentoctreotide scintigraphy serve as complementary functional diagnostic tools as they have 85-100% sensitivity in localizing these tumors.[8,9] One of our patients, (case 3) however had a negative MIBG scan. Positron emission tomography (PET) using 6 – [18F] fluorodopamine is a more recently developed tool for imaging these tumors.

As preoperative preparation patient require alpha adrenoreceptor blockers for at least 2 weeks, beta blockers are subsequently added to control heart rate. They also need adequate hydration to increase intravascular volume prior to surgery.

Most vesical pheochromocytomas are intramural as the sympathetic plexus is scattered between all the layers of the bladder wall. At cystoscopy these tumors may appear granulated and lobulated with or without ulceration.[2] Transurethral resection is not recommended as it will not remove the entire tumor. Open surgery is required to completely resect these tumors. [2,7,11] Laparoscopic tumor resection has also been attempted.[10]

As part of the intraoperative strategy, the use of cystoscopic examination may help delineate the exact location of these tumors and identify the depth of invasion and the involvement of the ureters. However, cystoscopic examination in case 3 was non-contributory probably due to the intramural nature of the tumor. In this case excision with a margin was guided by palpation. A thorough examination of surrounding structures and regional lymph nodes should be done as the malignant potential of these tumors is predicted not by histology but by clinical evaluation. In addition, these patients should also be monitored for post-operative complications such as stricture or obstruction at the urethral reimplantation site.

Overall, pheochromocytomas of the urinary bladder have a slightly better prognosis as compared to other extra adrenal pheochromocytomas. As these tumors are known for recurrence and metastases, these patients will require lifelong follow up. Though the diagnosis of pheochromocytoma is confirmed biochemically and the tumor located by using imaging techniques, biochemical evidence of excess catecholamine production usually antedates clinical symptoms, and therefore annual determination of urinary catecholamine / metabolites is recommended.[13,14] Prognosis will depend on the presence of familial endocrinopathy or the presence of metastases .[11]

In summary, due to varied symptomatology and nonspecific physical findings, a high index of suspicion is often required for accurate diagnosis and management of these patients.[15]

References

1. Onishi T, Sakata Y, Yonemura S, et al. Pheochromocytoma of the urinary bladder without typical symptoms. Int J Urol 2003; 10:398-400.

2. Doran F, Varinli S, Bayazit Y, et al. Pheochromocytoma of the urinary bladder. APMIS 2002; 110:733-6.

3. Salanitri J, Smith P, Schlicht S. Multifocal malignant extra-adrenal paragangliomas of the Organ of Zuckerkandl and urinary bladder. Australas Radiol 2001; 45:229-32.

4. Tan TL, Young BW (1962) Pheochromocytoma of the bladder: Case report. J Urol 87:63–67

5. S Rajaratnam, MS Seshadri, G Gopalakrishnan, SM Chandy(1999) Pheochromocytoma of the urinary bladder. J Assoc Physicians India Vol 47: 246-247.

6. Bowne RB, Beltaos E (1967) Pheo of the bladder: Case report and summary of literature. J Urol 98:361

7. Bonacrzu Kazzi G. Asymptomatic bladder pheochromocytoma in a 7-year-old boy. J. Paediatr Child Health 2001; 37:600-2.

8. Berglund AS, Hulthen UL, Manhem P, et al. Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice. Primary and secondary evaluation for localization pheochromocytomas. J Int Med 2001; 249:247-51.

9. Nakatani T, Hayama T, Uchida J, et al. Diagnostic localization of extra-adrenal pheochromocytoma: Comparison of (123)I-MIBG imaging and (131)I-MIBG imaging. Oncol Reports 2002; 9:1225-7.

10. Kozlowski PM, Mihm F, Winfield HN. Laparoscopic management of bladder pheochromocytoma. Urology 2001; 57:365.

11. Hwang JJ, Shoaf G, Uchio EM, et al. Laparoscopic management of extra-adrenal pheochromocytoma. J Urol 2004; 171:72-6.

12. Snavely MD, Mohan LC, O’Conor DT, Insel PA (1983) Selective down regulation of adrenergic receptor subtype in tissues from rats with pheochromocytoma. Endocrinology 113:354–361

13. Whalen RK, Althausen AF, Gilbert HD (1992) Extra-adrenal pheochromocytoma. J Urol 147:1–10

14. Ahmed S. Safwat, Nabil K. Bissada, Raouf M. Seyam, Saif Al Sobhi, Kamal A. Hanash. The clinical spectrum of pheochromocytoma: analysis of 115 patients. BJUI 2008; 101: 1561-1564

15. Safwat S. Ahmed; Bissada K. Nabil. Pheochromocytoma of the urinary bladder. Can J Urol 2007; 14: 3757 – 3760

Date added to bjui.org: 08/08/2012

DOI: 10.1002/BJUIw-2011-144-web

Pheochromocytoma in the urinary bladder

September 20, 2011/by admin Z.9

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

Authors: Song Wu^1,2, 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