Paragangliomas are neuroendocrine neoplasms and they are derived neural crest arising from adrenal medulla (pheochromocytoma) and extra-adrenal paraganglia. They can be seen in many different localizations such as lower abdomen, retroperitoneum, pelvis. It is rarely observed in the bladder. It constitutes 0.06% of all bladder tumors [1]. They can be functional or non-functional. Functional ones may cause clinical symptoms related to catecholamine secretion [2]. Presentation at a young age, the presence of many tumor foci, and its extraadrenal location are mostly associated with the presence of germline mutations [3].

Von Hippel-Lindau Syndrome (VHL) syndrome is an autosomal dominant disease caused by pathogenic germline variants in the VHL tumor suppressor gene. Many different tumors can be seen in the urinary tract or central nervous system associated with VHL syndrome [4]. In this case report, a case of paraganglioma located in the bladder in a patient followed up with VHL syndrome is presented.

Paragangliomas are non-epithelial tumors derived from paraganglion cells. The paraganglion system can be divided into as adrenal medulla and extra-adrenal paraganglion system. Extra-adrenal paraganglion system can be subdivided parasympathetic and sympathetic.

Parasympathetic paraganglia is primarily located in the head and neck region, sympathetic paraganglia is located along sympathetic nerve chains [5].

Most paragangliomas are sympathetic and functional. They can cause symptoms related to catecholamine release or mass effect. Symptoms such as palpitation, sweating, anxiety, paroxysmal hypertension may be seen due to adrenaline/noradrenaline release [6]. Our patient was nonsymptomatic.

Approximately 30-40% of paragangliomas in adults develop on the basis of hereditary disease [7]. They may be associated with various syndromes and familial conditions such as SDHx-related syndromes, VHL, neurofibromatosis type 1, multiple endocrine neoplasia type 2, hereditary leiomyomatosis and renal cell carcinoma, TMEM mutations, MAX mutations, EPAS1 mutations (Pazak-Zhuang syndrome), EGLN1/2 mutations, MDH2 mutations, KIF1B mutations, multiple endocrine neoplasia type 1, Carney triad. Susceptibility genes are grouped as pseudohypoxia-associated cluster (SDH, VHL, EGLN1, EGLN2, HIF2A), Krebs cycle genes (FH, IDH1, IDH2, MDH2), a kinase signaling clusters (RET, TMEM127, HRAS, NF1), WNT altered clusters (CSDE1 and MAML3) [8].

VHL is an autosomal dominant disease with a frequency of 2.8 per 100,000 [9]. VHL syndrome is caused by a pathogenic germline variant of the VHL tumor suppressor gene located on chromosome 3p25.3. Type 1 VHL syndrome has deletion and truncation mutation; type 2 VHL syndrome has missense mutation [10]. Central nervous system hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, pancreatic endolymphatic sac tumor and pancreatic neuroendocrine tumor are associated with this syndrome. Our patient had a history of partial nephrectomy for clear cell renal cell carcinoma.

Paraganglioma exhibits a nested pattern causing the appearance of zellballen. They are surrounded by sustantacular cells within the fibrovascular stroma. The nucleus is oval-round in shape and the cytoplasm is eosinophilic. Tumour cells show diffuse positive staining with neuroendocrine markers such as synaptophysin and chromogranin A. Sustantacular cells show positive immune reaction with S100 and SOX10.

Some paragangliomas may have clear cytoplasm and may be mistaken for prostate or kidney cancer. They require differential diagnosis with invasive urothelial carcinoma due to their localization in the lamina propria. The hemangioblastoma seen in VHL syndrome is composed of neoplastic stromal cells arranged among numerous small vessels. Stromal cells have clear, foamy cytoplasm with lipid-containing vacuoles. These cells are differentiated from paragangliomas by positive staining with inhibin, S100, carbonic anhydrase IX.

Pecoma may be considered in the differential diagnosis as it consists of non-cohesive epithelioid cells with clear to eosinophilic granular cytoplasm. Tumor cells show positive staining for melanocytic markers (MART-1, HMB45, MiTF) and myogenic markers (SMA, desmin, kaldesmon).

Neuroendocrine tumors are composed of monotonously regular cells with round or oval nuclei with salt and pepper chromatin and moderately eosinophilic granular cytoplasm, arranged in nests, trabecular or insular patterns. These tumors show positive immune reaction for neuroendocrine markers as well as keratins and transcription factors of specific site origin.

Scoring systems such as Pheochromocytoma of the Adrenal gland Scaled Score and Grading of Adrenal Pheochromocytoma and Paraganglioma exist to predict the likelihood of tumor metastasis. Malignant behavior is known to be defined on the basis of metastatic spread. Large tumor size, extra adrenal tumor location, catecholamine profile and SDHB mutation status are considered risk factors for metastatic behavior [11].

Paragangliomas are neuroendocrine neoplasms. They may accompany various hereditary syndromes. Differential diagnosis with many different tumor types is necessary to reach the correct diagnosis. Regular follow- up of patients with inherited syndromes allows early diagnosis and treatment of possible tumors.