Introduction

Paragangliomas are neuroendocrine tumors that originate from the neural crest cells of the parasympathetic and sympathetic ganglia of the peripheral nervous system.¹ Paraganglioma of the urinary bladder (PUB) is a tumor comprising chromaffin cells originating from the sympathetic innervations of the bladder wall.² Known to be extremely rare, they account for around 0.05% of all bladder tumors.²

Case Presentation

A 75-year-old Caucasian female was referred to the urology outpatient clinic by the Rapid Diagnostic Center after being evaluated for mild anemia and raised inflammatory markers. Her medical history included hypertension and type 2 diabetes, along with polymyalgia rheumatica, for which she was managed with steroids. She was otherwise fit and well and had no history of smoking. Her initial evaluation in the Rapid Diagnostic Center included a CT scan of the abdomen and pelvis which revealed an abnormal ovoid density seen within the urinary bladder (Figure 1). At presentation, she reported no visible hematuria or bladder storage symptoms. On physical examination, there were no abdominal masses and her blood pressure was well controlled with long-term antihypertensive medication.

Figure 1. CT of abdomen and pelvis showing a dense ovoid opacity at the bladder base, close to the bladder neck. An artifact from the left hip replacement is seen.

Subsequently, a flexible cystoscopy was carried out and an unusual, perfectly rounded, vascular lesion measuring around 2 cm was seen toward the bladder base in close proximity to, almost involving, the bladder neck (Figure 2). The rest of the bladder appeared normal. Urine cytology revealed inflammatory reactive changes, but no malignant cells. To investigate the nature of the lesion, transurethral resection of the bladder tumor (TURBT) was carried out and the specimen was sent for histopathological assessment. On microscopic examination, the bladder wall appeared infiltrated by sheets of bland epithelioid tumor cells arranged in small nests with intervening rich sinusoidal vasculature, fibrotic hyalinized stroma, and unremarkable surface urothelium. Tumor cells were diffusely and strongly positive for synaptophysin, chromogranin, and GATA3, negative for CK7, PAX8, CD10, RCC, AMACR, and CD117, with retained expression of SDH-B immunohistochemical stain. SOX10 highlights the sustentacular cells at the periphery of the nests (Figure 3, A-E). Based on these morphological features and immunoprofile, the final diagnosis of a bladder paraganglioma was made.

Figure 2. Flexible cystoscopy revealed a smooth, well-defined, rounded vascular lesion at the base of the bladder close to the bladder neck.

Figure 3. Histopathological features and immunoprofile of the tumor. A, Bladder wall infiltrated by sheets of epithelioid tumor cells arranged in small nests with intervening delicate sinusoidal vasculature. H&E, reduced from ×400. B, Tumor cells are positive for GATA3, however in a lower intensity in comparison to the represented surface urothelium. GATA3, reduced from ×400. C, Tumor cells are negative for CK7 in comparison the surface urothelium. CK7, reduced from ×400. D, Tumor cells are strongly and diffusely positive for synaptophysin and chromogranin immunohistochemical stains in comparison to the surface urothelium. Synaptophysin and chromogranin, reduced from ×400. E, SOX10 immunohistochemical stain highlights the sustentacular cells at the periphery of the tumour nests. SOX10, reduced from ×400.

Further workup included expert input from the department of endocrinology, followed by a biochemical assessment which revealed an elevated serum chromogranin A of 233 µg/L (normal level: <102 µg/L) but normal plasma metanephrines (metadrenaline: 232 pmol/L [normal level: <450 pmol/L], normetadrenaline: 646 pmol/L [normal level: <730 pmol/L], and 3-methoxytyramine: 100 pmol/L [normal level: <180 pmol/L]), indicating that it was a nonsecretory bladder paraganglioma. Further investigation with meta-iodo-benzyl-guanidine and MRI scans, leveled from skull base to pelvis, ruled out any evidence of metastases or additional paragangliomas elsewhere.

Considering the absence of symptoms and the nonfunctioning nature of the tumor with no evidence of metastases, options of treatment were discussed with her. A radical cystectomy was considered and declined by the patient, and partial cystectomy was not feasible due to the proximity of the tumor to the bladder neck. A transurethral re-resection was discussed, but the patient opted against it due to risk of incontinence. Instead, she preferred the option of active surveillance. A structured surveillance plan was agreed with the patient and included a flexible cystoscopy (Figure 4) and MRI of the bladder every 6 months for a year, followed by annual surveillance in case of satisfactory findings.

Figure 4. Follow-up flexible cystoscopy at 6 months showing a central scar that remains from the previous transurethral resection of bladder tumor. No evidence of progressing lesion is seen.

Discussion

PUB can be classified as functional or nonfunctional, based on whether the tumor cells secrete catecholamines. Presenting symptoms in case of functional tumors include hypertension, headache, micturition syncope, diaphoresis, and palpitations secondary to catecholamine secretion, besides painless visible hematuria, abdominal pain, flank pain, and lower urinary tract symptoms that can be seen among both the groups.² A very small percentage of the cases may be asymptomatic at presentation with diagnosis being an incidental finding.² In accordance with WHO criteria, PUBs are classified as malignant only in the presence of metastatic disease.¹ Considering the infrequent occurrence, little is known of the epidemiology of this condition; however, overall incidence rates have been found to be similar among males and females.² According to Quist et al, average age at presentation for malignant PUBs lies at around the mid 30s,³ which is much earlier compared to their benign counterparts, presenting toward the late fourth and fifth decades of life.⁴

Imaging modalities including CT and MRI, being nonconfirmatory, play a complementing role in arriving at a diagnosis. PUB is most likely to be homogenous, broad based, oval in shape, and well defined in comparison to urothelial bladder cancers.^5,6 Confirmation of diagnosis can only be achieved with histopathology and immunohistochemistry. Being a rare bladder tumor, paraganglioma may be misdiagnosed as urothelial carcinoma, especially in small diagnostic biopsies with diathermy artifact if not considered in the differential diagnosis. This distinction is of paramount significance due to therapeutic and prognostic implications. Hence, a thorough morphological assessment, a high index of suspicion, and confirmatory immunohistochemistry including neuroendocrine markers and CK7 in addition to GATA3 would help with definitive diagnosis.^7,8

Due to the rarity of bladder paragangliomas and their variation in presentation, there are currently no standard guidelines on treatment or follow-up. Most of the patients tend to undergo surgical treatment with TURBT, partial cystectomy or radical cystectomy. Cai et al’s analysis revealed that partial cystectomy is the most frequent and effective treatment, which in this case was a complicated option due to tumor location close to the bladder neck. Radical cystectomy is favored for malignant, functional paragangliomas.⁹ According to Henderson et al, TURBT approach and surveillance is suitable for smaller, nonfunctioning tumors less than 3 cm in size without evidence of muscle invasion.¹⁰

Overall, the treatment plan takes a tailored path and patient choice plays an important part. In this regard, TURBT was performed in this case, and due to the asymptomatic nature of the tumor and the bladder neck involvement, the patient opted to be followed with flexible cystoscopy and MRI surveillance rather than carrying out a more extensive surgical approach straightaway.