Pathology of Urinary Bladder Paraganglioma

Urinary bladder paraganglioma is a rare neoplasm that originates from the paraganglion cells of the urinary bladder and is the same as paraganglioma at other anatomic sites. The tumor arises from the ganglion cell in the bladder wall. Paragangliomas account for less than 0.06% of all bladder tumors ^{[1, 2, 3]}  and occur in all age groups. ^{[4, 5, 6]}

Rarely, paraganglioma of the urinary bladder is associated with neurofibromatosis and urothelial carcinoma. Genetic testing is recommended for patients because up to 25% of apparently sporadic cases are associated with a hereditary syndrome. ^{[7, 8]}

As with other bladder tumors, hematuria is the most common symptom of bladder paraganglioma. ^[3]  A more tumor-specific feature is persistent hypertension. Because the paraganglioma secretes catecholamines, patients may have symptoms of headache, sweating, tremulousness, anxiety, and micturition syncope (the temporary loss of consciousness upon urinating). ^{[1, 2, 9]}  Laboratory tests for catecholamine and its metabolites in serum and urine, as well as immunohistochemical studies (particularly in those with succinate dehydrogenase [SDH] B germline and somatic mutations ^[10] ), can often help in establishing the diagnosis. ^[11]

Localized tumors are generally treated by transurethral resection, wedge resection, or partial cystectomy. Malignant bladder paragangliomas are usually treated with radical cystectomy and tumor removal.

Differential diagnosis

Paraganglioma of the urinary bladder may mimic high-grade urothelial carcinoma with a nest pattern. The differential diagnosis may also include melanoma and carcinoid tumor. Immunohistochemical stains are useful in helping to establish these diagnoses. Urothelial carcinoma and carcinoid tumor are positive for cytokeratin, whereas melanoma cells show positivity of S100, HMB45, and Melan A stains.

Paraganglia are distributed throughout the bladder wall; thus, paraganglioma can be found in any part of the urinary bladder. These tumors are mostly well circumscribed, and they form single small nodules, ranging from a few millimeters to a couple of centimeters. (Intramural and subserosal tumors are generally large and functional. ^[12] ) Multiple tumor nodules or tumoral aggregates are also seen. Placing the tumor in a Zenker fixative turns the tumor color to black; a positive chromaffin reaction helps in the gross diagnosis of the tumor.

There is no standard staging system for paraganglioma. ^{[7, 13]}  Paragangliomas of the urinary bladder may be benign or malignant; however, large tumor size, an increased number of mitoses, and the presence of lymphovascular tumor invasion and succinate dehydrogenase (SDH) B mutations make malignant paraganglioma more likely. ^[14]  DNA aneuploidy and extensive tumor necrosis are also associated with malignancy. ^{[7, 13]}

Histologic features of the tumor are the same as in paraganglioma of other organs, including adrenal pheochromocytoma. The tumor cells grow in a zellballen pattern and are embedded in a fibrous network that is rich with blood vessels (see the following images).

Paraganglioma of the urinary bladder. Microscopic appearance of bladder paraganglioma, low magnification. Tumor cells grow in a zellballen pattern and are embedded in a fibrous network that is rich with blood vessels.

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Paraganglioma of the urinary bladder. Microscopic appearance of bladder paraganglioma, high magnification. Tumor cells grow in a zellballen pattern and are embedded in a fibrous network that is rich with blood vessels.

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Round tumor cells have amphophilic or acidophilic cytoplasm, containing dense granules as identified by ultrastructure study, and round or ovoid nuclei. Bizarre nuclei can be seen but have no significance. Mitosis is rare, but vascular invasion and invasive growth pattern can be present. Desmoplastic reaction is absent.

Paraganglioma of the urinary bladder, as in other organs, usually does not react to epithelium-specific antibodies. The tumor cells are positive for neuroendocrine markers, such as chromogranin and synaptophysin, but are negative for epithelial markers, including cytokeratin and epithelial membrane antigen (EMA). Sustentacular cells of the tumor are positive for S100 protein, and they form a characteristic pattern of staining around the tumor nest. ^{[4, 15, 16, 17]} ​

The prognosis of paraganglioma of the urinary bladder is typically favorable for localized tumors. ^[13] However, patients require life-long follow-up to detect late recurrences. ^[1] Risk factors for recurrence and metastasis of functional tumors include advanced classification (≥T3), multifocal tumors, and CgA (glycoprotein hormones, alpha polypeptide) expression. ^[9]

About 15%-20% of paraganglioma of the urinary bladder cases can develop metastasis, ^[1] and metastasis is the only reliable indicator of malignancy for this tumor. ^[15]  Vascular invasion, a deeply invasive growth pattern, and recurrence are associated with a poor prognosis. Additional risk factors for malignancy include young age, larger tumor size, higher Ki67 proliferation rate, and catecholamine type. ^[18]