Non‐Functional Paraganglioma of the Urinary Bladder: A Rare Cause of Bladder Tumor

ABSTRACT

Introduction

Paragangliomas of the urinary bladder (PUBs) are rare neuroendocrine tumors, representing less than 0.06% of all bladder neoplasms. While most are functional and associated with catecholamine excess, approximately 15% are non‐functional, often presenting asymptomatically and discovered incidentally. Due to their rarity, standardized management guidelines are lacking.

Case Presentation

We report a 57‐year‐old female evaluated for ureterolithiasis who was incidentally found to have a 1.5 cm posterior bladder lesion. Biopsy confirmed paraganglioma. Functional studies, including plasma and urinary metanephrines, were negative, establishing a non‐functional tumor. DOTATATE PET/CT and genetic testing excluded metastasis and hereditary syndromes. At planned transurethral resection, no residual lesion was identified, and pathology was benign. The patient remains asymptomatic on follow‐up.

Conclusion

This case illustrates the diagnostic challenges of non‐functional PUBs and emphasizes the importance of multidisciplinary evaluation and vigilant follow‐up in the absence of standardized management strategies.

Keynote Message

• Diagnosis of bladder paragangliomas requires histopathology with functional and imaging studies to exclude catecholamine activity, metastasis, and hereditary syndromes.

• In the absence of standardized guidelines, multidisciplinary management and long‐term follow‐up are essential.

1. Introduction

Paragangliomas (PGLs) are rare neuroendocrine tumors derived from embryonic neural crest cells. Unlike pheochromocytomas, PGLs occur outside of the adrenal glands [1]. While these tumors can occur in any location of the body where there is paraganglia tissue, they most commonly occur in the head, neck, and abdomen [1, 2, 3]. Paragangliomas of the urinary bladder (PUBs) are very rare. Since first described by Zimmerman et al. in 1953, there have only been around 200 reported cases in the literature [4, 5].

Most PUBs are functionally active (catecholamine‐secreting) and present with symptoms related to catecholamine excess, such as hypertension, palpitations, sweating, and headaches [6]. However, about 15% of PUBs are non‐functional [6, 7]. The diagnosis and treatment of nonfunctional PUBs can be difficult, as these tumors are often asymptomatic or present with nonspecific urinary symptoms [6]. Furthermore, there are no established guidelines for management due to their extremely rare presentation.

We present the case of a female patient diagnosed with a non‐functional PUB during routine management of ureterolithiasis. We describe the patient's workup, diagnosis, surgical management, and clinical outcome.

2. Case Presentation

The urology service was consulted for management of a 57‐year‐old Caucasian female with a 5 mm proximal ureteral calculus associated with an ESBL urinary tract infection (UTI). The patient underwent cystoscopy and ureteral stent placement. During the procedure, she was noted to have a 1.5 cm non‐papillary, almost submucosal lesion on the posterior bladder wall (Figure 1). Multiple cold cup biopsies were taken and sent for pathologic analysis. These biopsies included mucosa and lamina propria only, without muscularis propria. The lesion appeared to be completely excised with no clearly measurable remaining mass. The patient underwent routine ureteroscopy with laser lithotripsy and stent replacement 2 weeks later after antibiotic treatment of her UTI.

FIGURE 1.

Cystoscopic image of the tumor prior to biopsy.

The pathology results returned approximately 1 month later, after multiple second opinions, and demonstrated a PUB overlying the lamina propria (Figure 2). Morphologically, the tumor demonstrated a neuroendocrine growth pattern composed of cells with finely granular amphophilic cytoplasm. Immunohistochemistry supported the diagnosis, with strong positivity for synaptophysin and chromogranin, and S‐100 highlighting sustentacular cells. SDHB expression was retained, indicating absence of SDHx deficiency. The tumor was negative for cytokeratins (AE1/AE3, CAM5.2), Pax8, Melan‐A, SOX10, HMB45, and lymphoid markers, excluding urothelial, melanocytic, and hematolymphoid neoplasms. Retrospective review of the CT scan obtained during the patient's initial stone evaluation correlated with the cystoscopic findings (Figure 3). Upon further questioning, the patient denied any history of hypertension, palpitations, headaches, or diaphoresis. Furthermore, she had remained normotensive during her previous surgeries as noted in the anesthesia records. Based on these findings, the patient was referred to endocrinology for further workup.

FIGURE 2.

Hematoxylin and eosin staining of tumor showing a neuroendocrine growth pattern composed of cells with finely granular amphophilic cytoplasm consistent with PUBs (A). Immunohistochemical studies showing positive findings for chromogranin (B) and S100 (C).

FIGURE 3.

Sagittal CT of the abdomen showing a 5.4 mm by 8.0 mm lesion on the posterior bladder wall.

Functional studies revealed normal serum catecholamines, plasma metanephrines, and 24‐h urine metanephrines, confirming the diagnosis of a nonfunctional PUB (Table 1). DOTATATE PET/CT nuclear studies failed to visualize the bladder lesion and showed no evidence of metastatic disease. Furthermore, an 11‐panel genetic testing, including FH, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL, was negative for pathogenic variants. After discussion of the case at the tumor board, the recommendation was to proceed with formal complete transurethral resection of the bladder tumor (TURBT), to which the patient was agreeable. Based on the biochemical profiling, no perioperative adrenergic blockade was indicated. No additional contrast‐enhanced CT or MRI was obtained prior to TURBT. Instead, the plan was to re‐evaluate the lesion cystoscopically at the time of resection.

TABLE 1.

Functional testing including plasma and urine catecholamines and metanephrines consistent with a non‐functional paraganglioma.

Plasma fractionated catecholamines (pg/mL)
Epinephrine	< 20	Normal < 58
Norepinephrine	503	Normal 149–564
Catecholamines total	< 546	Normal < 632
Plasma fractionated metanephrines (pg/mL)
Free metanephrines	65	Normal < 57
Free normetanephrines	124	Normal < 148
Total metanephrines	189	Normal < 205
24‐h Urine fractionated catecholamines (μg/24 h)
Epinephrine	7	Normal 2–24
Norepinephrine	37	Normal 15–100
Total (Norepi + Epi)	44	Normal 26–121
24‐h Urine fractionated metanephrines (μg/24 h)
Metanephrines	181	Normal 90–315
Normetanephrines	201	Normal 122–676
Total metanephrines	382	Normal 224–832

The patient underwent TURBT approximately 5 months after the initial identification of the lesion. However, during the cystoscopy, the urothelium at the previous biopsy site appeared completely normal without evidence of residual tumor, inflammation, or scarring. The previous biopsy site was localized using the anatomic location recorded during the initial cystoscopy in conjunction with cystoscopic photographs and the operative note. The TURBT specimen included mucosa, lamina propria, and muscularis propria, and the pathology demonstrated benign cystitis without residual tumor. A follow‐up CT scan confirmed resolution of the lesion.

At 1‐month post‐op, the patient has remained asymptomatic. She will continue to follow regularly for recurrence.

3. Discussion

PUBs are exceedingly rare tumors accounting for a mere 0.05% to 0.06% of all bladder neoplasms [6, 7, 8]. These tumors originate from the sympathetic innervations of the bladder, most commonly affecting the anterior and posterior walls [8]. PUBs predominantly occur in middle‐aged females, either sporadically or in association with hereditary syndromes such as neurofibromatosis 1, Von Hippel–Lindau, and multiple endocrine neoplasias 2 [8]. Their clinical presentation is variable depending on tumor functional status. Functional PUBs present with symptoms of catecholamine excess, including hypertension, tachycardia, and headache [6, 7, 8]. In contrast, non‐functional PUBs are usually asymptomatic, although they may present with hematuria or obstructive symptoms [6, 7, 8]. As a result, nonfunctional PUBs are often detected incidentally during evaluation for unrelated conditions [8].

Non‐functional PUBs present a unique challenge in diagnosis as they lack the classic clinical signs of paragangliomas. This often leads to misidentification as bladder mucosal tumors during presurgical evaluation. A definitive diagnosis requires adequate sampling and careful histopathologic evaluation, which can be challenging because PUBs typically arise within the submucosa or muscularis, often resulting in limited or superficial sampling on initial biopsy [6, 7, 8]. In TURBT specimens, crush and cautery artifact, as well as tissue fragmentation may further obscure the characteristic neuroendocrine architecture, leading to misinterpretation as urothelial carcinoma or other bladder neoplasms [6, 7, 8]. Histologically, paragangliomas demonstrate a characteristic “Zellballen” pattern, consisting of nests of cells with eosinophilic cytoplasm and a delicate fibrovascular stroma [6, 7, 8]. Immunohistochemistry can help confirm the diagnosis, with PUBs typically staining positive for neuroendocrine markers such as CgA, Syn, CD56, and NSE, while being negative for epithelial and mesenchymal markers [6, 7, 8]. PUBs commonly arise in the deep layers of the bladder wall, often infiltrating the surrounding muscle layers [8]. Due to histologic overlap with bladder mucosal tumors, PUBs can be easily misdiagnosed as urothelial carcinoma, even with careful evaluation [8]. Therefore, a high index of suspicion and careful histopathological assessment for accurate diagnosis.

Contemporary concepts of pheochromocytoma and paraganglioma (PPGL) now recognize that all PPGLs possess inherent metastatic potential, as reflected in the updated 2022 WHO classification [9]. Furthermore, approximately 30%–40% of PPGLs harbor germline pathogenic variants [10]. This recognition underscores the need for comprehensive pathologic and molecular evaluation, even in tumors that appear clinically indolent. Several histologic grading systems have been proposed to aid in risk stratification, including the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP), although their validation in bladder paragangliomas is limited [11, 12, 13]. Additionally, SDHB immunohistochemistry serves as an important surrogate marker of SDHx mutation status, as loss of SDHB expression is strongly associated with higher risk of metastasis and poor prognosis [12, 13, 14]. These principles reinforce the importance of integrating histology, immunoprofiling, and genetic evaluation when managing patients with PUBs.

If a paraganglioma is suspected during the presurgical evaluation, biochemical profiling and imaging evaluation are essential for both diagnosis and perioperative management [6, 7, 8]. Serum and urine measurements of metanephrines and catecholamines should be checked to determine tumor functionality and to assess the need for preoperative adrenergic blockade [7, 15]. While the risk of hypertensive crisis is lower in nonfunctional tumors, intraoperative blood pressure instability has been observed during TURBT [6]. Thus, strict blood pressure monitoring during surgery may be necessary regardless of the tumor's functional status. Imaging studies, including ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI), are important for determining tumor size, shape, and location [6]. Functional imaging studies, such as methyliodobenzylguanidine (MIBG), DOTATE, and positron emission tomography (PET) can be valuable for confirming disease and ruling out metastasis [2, 6, 8]. However, they are less widely available and are often more expensive.

While there are no standard guidelines regarding the management of PUBs, surgical resection remains the mainstay of treatment for localized tumors [6, 7, 8]. The choice of surgical approach, whether transurethral resection, partial cystectomy, or radical cystectomy, depends on factors such as tumor size, location, and involvement of surrounding structures [6]. PUBs are generally resistant to chemotherapy and radiation; however, few cases have reported use of chemotherapy and radiation in the neoadjuvant or adjuvant setting [8, 16]. Local recurrence occurs in approximately 5%–15% of cases, even after resection with negative margins [6]. Furthermore, metastasis can occur 20–40 years post‐surgery [6]. Therefore, we suggest lifelong surveillance even for non‐functional and completely excised tumors, with annual plasma or urinary metanephrines and periodic cross‐sectional imaging (every 1–2 years) to monitor for recurrence or delayed metastasis. Although MRI typically offers superior sensitivity for subtle or submucosal bladder wall lesions, CT was appropriate in our case due to the complete cystoscopic resolution and benign repeat biopsy.

A unique aspect of our case is the apparent spontaneous resolution of the tumor before planned TURBT. We believe the most likely explanation for this finding is near‐complete excision during the initial cold‐cup biopsy, particularly given the small size and submucosal location of the lesion. Another plausible mechanism is biopsy‐induced inflammation or ischemic injury, which may have disrupted the tumor's vascular supply and contributed to regression. Although no documented cases describe complete disappearance of a bladder tumor following biopsy alone, it has been shown in other tumor types that infection‐mediated immune activation, biopsy‐related microtrauma, and alterations of the local tumor microenvironment can play pivotal roles in tumor involution and spontaneous regression [17, 18, 19]. These mechanisms provide a biologically reasonable explanation for the absence of residual disease at re‐evaluation in our patient.

Our case report adds to the growing body of literature on non‐functional PUBs, further underscoring the diagnostic and therapeutic challenges posed by this rare entity. While the specific presentation and spontaneous resolution observed in our patient may be unique, it highlights the importance of maintaining a high index of suspicion, utilizing a multidisciplinary approach, and carefully considering all management options. Moving forward, efforts to improve diagnostic accuracy and develop risk‐stratified management strategies are warranted to optimize patient outcomes.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

Informed consent was obtained and is available upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

Wainstein M., Aslot V., Dennie F., Wainstein M., and Chandrasekar T., “Non‐Functional Paraganglioma of the Urinary Bladder: A Rare Cause of Bladder Tumor,” IJU Case Reports 9, no. 2 (2026): e70145, 10.1002/iju5.70145.

Data Availability Statement

The authors have nothing to report.