Introduction

Up to 10% of pheochromocytomas are located outside the adrenal glands, mainly originating from chromaffin cells in sympathetic ganglia.¹ These tumors, commonly known as paraganglioma, arise from the urinary bladder in 1% of the cases and correspond to less than 1% of bladder tumors, with 6%–11% being malignant.² Aside from symptoms related to paroxysmal release of catecholamines, bladder paragangliomas can present with hematuria and urinary symptoms;¹ however, up to 10%–15% are nonfunctional and 10% could have a subclinical release of hormones related to changes in bladder volume.³ We present the case of a young female with bladder paraganglioma diagnosed after 4 years of unusual paroxysmal symptoms and a diagnosis of hypertension at an early age.

Clinical Case

A 25-year-old female with recent diagnosis of hypertension presented to the emergency department with palpitations, exertion and nausea. After further questioning, she complained of episodes of tachycardia, nausea, dizziness and headache after urinating, associated to progressive weakening and intermittence of the urinary stream, straining and feeling of incomplete voiding for the past 2 years. She was being followed by her family physician for a vesical mass found incidentally during a transvaginal ultrasound done a month earlier for vaginal bleeding.

Physical examination was unremarkable. Initial workup included a normal complete blood count, normal renal function, and an electrocardiogram that showed a supraventricular tachyarrhythmia and an abdominal ultrasound that reveled the vesical mass mentioned by the patient. A computerized tomography (CT) urogram was ordered to assess the mass and rule out the presence of adrenal masses; plasma and urine metanephrines were ordered with the suspicion of a catecholamine-producing tumor. No adrenal masses were found on the CT, but a 63×44×41 mm exophytic mass in the inferior lateral wall of the bladder with cystic necrotic foci appeared to obstruct the bladder outlet (Fig. 1). Although cystoscopy revealed a 5 cm diameter mass in close proximity to the left ureteral meatus that lateralized it, the tumor appeared to be confined to the submucosa and no lesions of the urothelium were documented, which suggested that a transurethral approach would not remove the mass completely. Anesthesia and endocrinology were consulted with plans of open surgery, and adrenergic blockade was recommended for 2 weeks before surgery, especially due to poor blood pressure control since admission despite combination of ≥3 antihypertensive agents.

Figure 1. Abdominal CT urogram.

Figure 2. Endoscopic view of mass after ureteral stent placement.

Figure 3. Surgical specimen.

Figure 4. Paraganglioma of the urinary bladder. Zellballen growth pattern (hematoxylin–eosin, original magnification: ×400).

Figure 5. Paraganglioma of the urinary bladder. Diffuse and strong cytoplasmatic positive synaptophysin immunostaining in tumor cells (original magnification: ×400).

During surgery, endoscopic passage of a left ureteral stent was done in a first step (Fig. 2), then through an open partial cystectomy a heavily vascularized ovoid mass adhered to the left lateral wall of the bladder was completely resected (Fig. 3). Right after removal of the tumor, the patient’s blood pressured dropped, requiring intraoperative vasopressor therapy with noradrenaline and vasopressin. After a 2-day stay in the intensive care unit vasopressor therapy was discontinued and on postoperative day 8 the patient was discharged. The JJ stent and urinary catheter were removed within the following 2 weeks.

Tumor histology consisted of round epithelioid cells arranged in discrete nests with intervening vascular septa (Fig. 4), abundant eosinophilic cytoplasm and finely granular chromatin in their nuclei. Immunohistochemistry showed positivity for neuroendocrine markers chromogranin A and synaptophysin (Fig. 5), but no immunoreactivity for pancytokeratin AE1/AE3, ruling out nested variant of urothelial carcinoma and confirming the diagnosis of paraganglioma. After 4 months of followup, the patient has no urinary symptoms, hypertension has resolved and life has gone back to normal.

Discussion

Bladder paraganglioma is an extremely rare neuroendocrine tumor with symptoms related to paroxysmal release of catecholamines and unusual urinary symptoms.¹ Within the 144 cases that had been published in the literature until 2015, 51% presented with hematuria, 45% with hypertension and 40% with micturition attacks.¹ These attacks occur as a result of catecholamine release during micturition, resulting in diaphoresis, palpitations, headache, flushing, increase in blood pressure or even syncope after voiding.¹

Due to its rarity and symptomatic variability, diagnosis might be challenging.² Imaging studies such as contrasted CT are useful to guide the diagnosis, having a sensitivity of 94% for pheochromocytoma and 82% for paraganglioma outside the adrenal glands.⁴ Common findings include a mass under 4 cm with marked attenuation to contrast, a finding rarely present in urothelial carcinoma, its main differential diagnosis.^4,5 Magnetic resonance imaging should be used whenever available due to its high sensitivity and the advantage of assessing the tumor’s relationship to the surrounding tissues without ionizing radiation.¹ T2 sequences display bladder wall infiltration, whereas T1 sequences detect lymphadenopathies or extension to adjacent organs.³ Having a high sensitivity and specificity of 96% and 98% for hormone-producing tumors, catecholamine levels in urine and plasma can aid the diagnosis.⁶ Cystoscopy, on the other hand, can be useful to rule out urothelial malignancy as most paraganglioma arise from the submucosa and present as a mass covered by healthy, hypervascularized urothelium.⁷ Definitive diagnosis is done pathologically with findings of polygon-shaped cells in bed of fibromuscular stroma.¹ Immunohistochemistry can confirm the presence of neuroendocrine markers such as chromogranin, synaptophysin and neurofilament protein with absence of cytokeratins, characteristic of epithelial tumors.^1,8

Despite the lack of guidelines, and the controversies of surgical approach, surgery is a mainstay of treatment.⁹ Tumors that involve the muscle layer of the bladder should be treated by partial cystectomy, whereas superficial tumors confined to the mucosa might be successfully treated endoscopically.⁹ Regardless of type of surgical approach, all patients should undergo adrenergic blockade before surgery as tumor manipulation could result in uncontrolled intraoperative release of catecholamines and cardiovascular events.⁹ Local and metastatic recurrence has been reported in the literature in 10% of cases, and imaging and biochemical followup are recommended.¹⁰

Conclusion

Bladder paraganglioma should be considered in patients with paroxysmal increase in blood pressure, palpitations and tachycardia associated with voiding, especially if hematuria is present. An abdominal image, such as a contrasted abdominopelvic CT scan, can aid in the diagnosis with metanephrins in blood and urine being highly specific tests that can confirm the diagnosis in hormone-producing tumors. Surgical resection with negative margins is key for definitive cure.