Microscopic Description:

Zellballen Pattern: The tumor cells are arranged in characteristic nests or clusters called "zellballen," which are surrounded by a network of sustentacular cells and capillaries.

Chief Cells: The nests are composed of polygonal chief cells with eosinophilic (pink) to amphophilic (purple) cytoplasm. The nuclei are round to oval, often with a "salt-and-pepper" chromatin pattern.

Sustentacular Cells: These are spindle-shaped cells that form a delicate framework around the zellballen clusters. They can be highlighted using immunohistochemical stains for S-100 protein.

Vascular Stroma: A rich vascular network often surrounds the tumor cell nests, contributing to the highly vascular nature of the tumor.

Immunohistochemistry: The tumor cells typically stain positive for neuroendocrine markers such as chromogranin, synaptophysin, and neuron-specific enolase (NSE). Sustentacular cells are S-100 positive. In summary, paragangliomas of the bladder typically show positive staining for SDH-B (when deficient), synaptophysin, and GATA-3, and negative staining for AE1/AE3. SALL4 and OCT3/4 are typically not relevant markers for this tumor type, and would appear negative.

Macroscopic Description:

Paragangliomas of the bladder typically presents as a well-circumscribed, submucosal or intramural mass. These tumors are often spherical or oval-shaped and have been found to range in size from 1.0 to 9.1 cm, with an average size of approximately 3.9 cm at presentation.

On gross examination, the cut surface of the tumor is usually a brownish color and homogeneous; however, larger tumors may exhibit more complex features such as central necrosis and hemorrhage. The tumor margins are generally well-defined, and the mass may show increased vascularity, which can be observed on imaging studies like ultrasound and MRI.

Discussion:

Rarity and Epidemiology:

  • Paraganglioma of the bladder is a rare neuroendocrine tumor, accounting for less than 0.05% of all bladder tumors.
  • Most commonly occurs in the fourth to fifth decade of life, with a slight female predominance.
  • Paragangliomas of the bladder usually occur in the lateral and posterior wall of the bladder. They are most commonly diagnosed in younger adults, with a median age of around 50 years. There is a slight female predominance, with a male-to-female ratio of approximately 1:3.

Clinical Presentation:

  • Common symptoms include hematuria, hypertension, and catecholamine-related symptoms (e.g., palpitations, headaches, sweating).
  • Hypertension may be episodic, particularly triggered by micturition, due to catecholamine release.

Diagnostic Challenges:

  • Differential diagnosis includes more common bladder pathologies (e.g., urothelial carcinoma, cystitis).
  • Elevated catecholamines in blood and urine are key diagnostic clues.
  • Imaging studies (CT, MRI, MIBG scan) are crucial for tumor localization and assessment.

Management Strategies:

  • Preoperative blood pressure control is essential to manage catecholamine-induced hypertensive crises.
  • Surgical resection (partial cystectomy) is the treatment of choice, with attention to perioperative blood pressure management.
  • Consideration of long-term follow-up due to the risk of recurrence or metastasis.

Prognosis:

  • Generally favorable with complete surgical resection, but regular follow-up is necessary to monitor for recurrence.
  • Malignant potential exists, though rare, necessitating vigilant post-treatment surveillance.

Implications for Practice:

  • Importance of considering paraganglioma in patients with unexplained hematuria and hypertension.
  • Multidisciplinary approach involving urology, endocrinology, and oncology is key to optimal management.
References:

Akbulut, D., & Al-Ahmadie, H. (2024). Updates on Urinary Bladder Tumors With Neuroendocrine Features. Advances in Anatomic Pathology, 31(3), 169–177. https://doi.org/10.1097/pap.0000000000000433

Cai, T., Lu, J., Lin, Z., Luo, M., Liang, H., Qin, Z., & Ye, Y. (2022). Bladder paraganglioma: basic characteristics and new perspectives on perioperative management. World Journal of Urology, 40(11), 2807–2816. https://doi.org/10.1007/s00345-022-04166-1

Male, M., Ye, T., Tao, J., Chen, Z., & Peng, E. (2019). Differentiating Nonfunctional Paraganglioma of the Bladder from Urothelial Carcinoma of the Bladder: Pitfalls and Breakthroughs. BioMed Research International, 2019, 1–7. https://doi.org/10.1155/2019/1097149

Marletta, S., Martignoni, G., Ghimenton, C., Stefanizzi, L., Marcolini, L., & Caliò, A. (2022). Well-differentiated neuroendocrine tumor of the urinary bladder expressing GATA 3. Virchows Archiv, 482(4), 783–788. https://doi.org/10.1007/s00428-022-03478-2

Mason, E. F., Sadow, P. M., Wagner, A. J., Remillard, S. P., Flood, T. A., Belanger, E. C., Hornick, J. L., & Barletta, J. A. (2013). Identification of Succinate Dehydrogenase–deficient Bladder Paragangliomas. American Journal of Surgical Pathology, 37(10), 1612–1618. https://doi.org/10.1097/pas.0b013e318293d83c

Purnell, S., Abhinav Sidana, Mahir Maruf, Grant, C., & Agarwal, P. K. (2017). Genitourinary paraganglioma: Demographic, pathologic, and clinical characteristics in the surveillance, epidemiology, and end results database (2000–2012). Urologic Oncology: Seminars and Original Investigations, 35(7), 457.e9–457.e14. https://doi.org/10.1016/j.urolonc.2017.02.006

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