INCIDENTAL DIAGNOSIS OF PHEOCHROMOCYTOMA OF THE URINARY BLADDER: WHAT ARE THE CLINICAL PROBLEMS THAT CAN ARISE ?

Laura Toffoli1, Renzo Zucconelli1, Pietro Belmonte2
  • 1 Casa di Cura San Giorgio (Pordenone)
  • 2 Casa di Cura San Giorgio (Porddnone)

Objective

Pheochromocytoma of the urinary bladder is a rare tumor. We report a case of bladder pheochromocytoma in a female patient with no clinical symptoms of paraganglioma, radiological and cystoscopy examinations were suggestive of urothelial carcinoma but the histopathological diagnosis was pheochromocytoma.

Materials and Methods

Pheochromocytoma of the urinary bladder is a rare tumor that originates from chromaffin tissue of the sympathetic nervous system associated with urinary bladder wall [1,2]. They account for less than 0.06% of all bladder cancer [3] and less than 1% of all pheocromocytoma. In the genitourinary tract, the urinary bladder is the most common site of pheochromocytoma (79.2%), followed by urethra (12.7%), pelvis (4.9%) and ureter (3.2%) [4]. The pheochromocytoma of the bladder was first described by Zimmermann in 1953 [5]. Pheochromocytoma usually occured in young caucasians adult (mean age, 43.3 years). The most common symptoms and signs of pheochromocytoma of the urinary bladder are hypertension, headache, hematuria and other generalized symptoms due to raised of the catecholamines (blurred vision, hearth palpitation, flushing) [2]. Patients with pheochromocytoma may develop miocardial infarction, cerebral vascular accidents, acute renal failure and in rare cases acute respiratory distress syndrome [6].
Anesthetic management of any surgical patient with pheochromocytoma is challenging, particularly when the tumor has not been diagnosed [7].
In the event of an anesthetic-induced hypertensive crisis, even potent antihypertensives, such as nitroprusside, may be ineffective. Phentolamine, however, proved effective. Phentolamine should be the treatment of choice for pheochromocytoma-related hypertensive crises. Calcium channel antagonists, like nicardipine, have also been shown to control hemodynamic response during resection of pheochromocytoma [7].
Patients with pheochromocytoma are chronically vasoconstricted as a result of the high levels of circulating catecholamines and have a secondary decrease in their blood volume [8].
If pheochromocytoma is diagnosed pre-operatively it’s necessary to start a preparation for surgery.
Preparation for surgery should begin at least 2 weeks prior to allow full alpha-blockade along with gradual restoration of blood volume [7]. A standard protocol for adrenergic blockade is to administer phenoxybenzamine, starting at a dose of 40 mg per day and gradually increasing to 80 to 120 mg per day.
The most common side effect of phenoxybenzamine is postural hypotension. Beta-blockade can be given after starting alpha-blockade, if tachycardia or other cardiac arrhythmias develop. Beta-blockade must never be started prior to adequate alpha-blockade, since in the absence of beta-2-mediated vasodilatation, profound unopposed alpha-mediated vasoconstriction may lead to hypertensive crisis or pulmonary edema [7].
If it is possible to diagnose pheochromocytoma pre-operatively it is necessary to treat patients with alpha-adrenergic blockade, this is helpful for reducing intraoperative hypertension episodes, thus decreasing morbidity and mortality.

Results

A 35 years old female patient was referred to urology service of our hospital for the management of a single episode of monosymptomatic macrohematuria.
The patient hadn’t hypertension or other conditions and didn’t take drugs, she was an ex-smoker and she had stopped 5 years before.
The urine citology has not documented neoplastic cells, urine culture was negative, the routine abdominal ultrasonography was negative for bladder tumors.
We performed a pre operative cystoscopy which documented suspicious papillary tumors in the posterior bladder wall and in the left side.
Computed tomography revealed an expansive formation of 29 mm in the left bladder wall, this lesion showed enhancement.
Cistoscopy and endoscopic resection was performed and two bladder lesion in the posterior bladder wall and one in the left side were removed, intraoperatively the patient’s blood pressure got elevated to 223/109 mmHg, however the anestesiologist was able to control it easily. The histopatological examination of the lesion in the left side revealed tumor cells with eosinophilic cytoplasm and hypercromatic nuclei of variable size, neoplastic cells show the following immunophenotypical profile: panCK-, CK 20-, p 63-, p 53-, CD 44-/+, GATA 3+/-, S100 +, chromogranin +, synaptofysin +, CD 56+, antigen of proliferation Ki 67 +1%. The framework was compatible with paraganglioma (pheochromocytoma).

Discussions

Neuroendocrine tumors of the urinary bladder are rare and comprise <1% of all urinary malignances [4]. These tumors of the urinary bladder range from well-differentiated neuroendocrine neoplasms (carcinoids) to the more aggressive subtypes such as small cell carcinoma. The neuroendocrine tumors of the urinary bladder are subdivided into four subtypes: small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, well-differentiated neuroendocrine tumors carcinoids and paraganglioma [4,9].
The origin of pheochromocytoma of the urinary bladder is uncertained but believed to be related to migration of small nests of paraganglionic tissue along the aortic axis and in the pelvic regions into the bladder wall during embryogenesis; paraganglioma may be of two types, functional (sympathetic chromaffin paragangliomas/pheochromocytomas) that appeared with typical symptoms such as paroxysmal hypertension, hearth palpitations, headache attacks, sweating or non functional pheochromocytoma without chromaffin cells [10].
Beilan et al. extensively reviewed the english litterature on this subject and analyzed a total of 106 patients; symptoms reported in their series ranged from the typical micturations attacks of headache and palpitations to more abstract signs such as paraesthesias and dyspnea [1].
Our case is unusual in that, the patient presented with no obvious symptoms suggestive of pheochromocytoma, the first sign was noticed only intraoperatively in the form of episodic increase in blood pressure.
Pheochromocytomas can be treated in different ways: catecholamine blockade, surgery, chemotherapy and radiation therapy [1]. The standard treatment for localized or locally advanced pheochromocytomas is surgery while metastatic or recurrent tumors are treated with palliative therapy.
The National Cancer Institute (NCI) identifies four pathologic features associated with malignancy: large tumor size, increased number of mitosis, DNA aneuploidy and extensive tumor necrosis [11].
The Auerbuch chemotherapic protocol (cyclophosphamide, vincrastine and dacarbazine) has been shown to be effective against advanced malignant pheocromocytoma [12].
Radiation therapy with I 131-MIBG has been used for the treatment of metastases [13]. Approximately 70% of patients underwent partial cystectomy as primary treatment, it is important to note that 5.3% of patients had recurrence or mestastases.
The lack of uniformity on how oncologic cases were presented makes difficult to characterize the true disease course of bladder pheochromocytoma.
Patients with localized tumor have an extremely favorable prognosis and may be managed by less aggressive modalities whereas patients with metastatic disease have a significant reduction in survival rates despite aggressive treatment. There is a lack of high quality data on post operative follow-up; in patients with benign, localized disease were not recommended follow-up studies. In patients with functional tumors regardless of stage, VMA, metanephrine and catecholamines levels should be monitored within one month post-surgery, then every six months for two years; if metastases are documented CT of the abdomen/pelvis should be performed every three months for one year, then every six months for one year and yearly for three years [1].

Conclusion

The current case report stresses the importance of knowledge of this rare disease which occures mostly in young Caucasian. Initial presentation is extremely varied in these tumors. Moving forward it would be helpful to collect as many cases as possible in order to understand the natural process and outcomes of this disease to standardize the reporting guidelines of pheochromocytoma.

Reference

[1] Beilan JA, Lawton A, Hajdenberg J, Rosser CJ. Pheochromocytoma of the urinary bladder a systemic review of the contemporary literature. BMC Urology 2013; 13:22.

[2] Rajendra BN, Prasad VM, Amey YP, Shishir D, Hiremath MB. Pheochromocytoma of yhe urinary bladder- A case Report of an Unusual Presentation. Indian J Surg Oncol Sept. 2015; 6(3):303-206.

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[4] Kouba E, Cheng L. Neuroendocrine Tumors of the Urinary Bladder According to the 2016 World Health Organization Classification: Molecular and clinical Characteristics. Endocr Pathol. 2016; 27:188-199.

[5] Zimmerman IJ, Biron RE, MacMahan HE. Pheochromocytoma of the urinary bladder. N Engl J Med 1953; 249:25-26.

[6] Kwon SY, Lee KS, Lee JN et al. Risk factors for hypertensive attack during pheochromocytoma resection. IC Urology 2016;57:184-190.

[7] Myklejord D. Undiagnosed pheochromocytoma: the anesthesiologist nightmare. Clin Med Res 2003;2(1):59-62.

[8] Plouin PF, Duclos JM, Soppelsa F, Boublil G et al. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab 2001;86:1480-6.

[9] Burkhard H. Morphology and Therapeutic Strategies for Neuroendocrine Tumors of the Genitourinary Tract. Cancer Oct. 2002; 95(7):1415-1420.

[10] Alberti C. Urology pertinent neuroendocrine tumors: focusing on renal pelvis, bladder, prostate located sympathetic functional paragangliomas. G Chir. March-April 2016; 37(2):55-60.

[11] Deng JH, Li HZ, Zhang YS, Liu GH. Functional paragangliomas of the urinary bladder: a report of 9 cases. Chin J cancer 2010, 29(8):729-734.

[12] Auerbuch SD, Steakley CS, Young RC et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophospamide, vincrastine and dacarbazine. Ann Intern Med 1998; 109(4):267-273.

[13] Gonias S, Goldsby R, Matthay KK et al. Phase II study of high-dose [131I] metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27(25):4162-4168.

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