Recurrent bladder paraganglioma with peritoneal dissemination: An unusual pattern of metastatic progression. Case report and literature review

Abstract

We report the case of a 26-year-old man diagnosed with multifocal bladder paraganglioma, an exceptionally rare neuroendocrine tumor. The patient presented with hypertension and adrenergic symptoms triggered by micturition, associated with elevated metanephrines and multiple pelvic lesions. He underwent complete laparoscopic resection, including partial cystectomy, achieving initial biochemical remission. Early local recurrence and subsequent peritoneal carcinomatosis, an uncommon metastatic pattern, were observed, requiring systemic therapy. This case highlights the diagnostic challenges, potential for aggressive behavior, and limited therapeutic options in metastatic bladder paraganglioma, underscoring the need for high clinical suspicion, adequate preoperative management, and long-term follow-up.

1. Introduction

Paragangliomas are neuroendocrine tumors, histologically similar to pheochromocytomas, but originating from extra-adrenal chromaffin tissue.¹ They may secrete catecholamines in up to 40 % of cases,² which leads to typical symptoms such as headache, sweating, or palpitations.¹ Bladder localization accounts for less than 6 % of all paragangliomas and less than 0.1 % of all bladder tumors.³ Most cases correspond to solitary masses (approximately 85 %)^4,5 and usually exhibit benign behavior; however, 24–30 % of patients develop metastases.^4,5

2. Case report

The patient was a 26-year-old male with no relevant past medical history. Since adolescence, he had presented with headaches, hypertension, presyncopal episodes, sweating, and palpitations related to micturition. At the time of the initial evaluation, he required up to three antihypertensive medications to achieve adequate blood pressure control.

In the context of the evaluation for secondary hypertension, plasma catecholamines were requested, revealing a marked elevation of normetanephrine (values > 2400), along with an abdominal ultrasound, which identified a “tumor measuring 4.74 × 5.63 cm arising from the right lateral wall.” Subsequently, given the high suspicion of bladder paraganglioma, a computed tomography (CT) scan and a single-photon emission computed tomography (SPECT)/CT with ¹²³I-MIBG were requested to assess the presence of functional chromaffin tissue. The CT scan demonstrated a right paravesical lesion (Fig. 1) and a 2-cm external iliac lymph node. On SPECT/CT, the paravesical lesion showed no uptake; however, three other foci of increased uptake were identified (Fig. 2), one of which corresponded to the lymph node visualized on CT. A SPECT/CT with 99mTc-HYNIC-TOC (technetium-99m–hydrazinonicotinyl–Tyr3-octreotide) was subsequently performed, in which the paravesical mass did show uptake.

Fig. 1.

Abdominal CT scan. Solid, mildly lobulated, contrast-enhancing mass measuring 5.8 × 6.2 cm on the axial plane and 3.3 cm on the craniocaudal plane, surrounding the right anterosuperior aspect of the urinary bladder. A) Coronal CT. B) Axial CT.

Fig. 2.

¹²³I-MIBG SPECT/CT. The main image shows a foci of increased uptake lesion at the level of the left psoas muscle. In the secondary SPECT image (∗), an additional second lesion lateral to the right ureter (corresponding to that described on CT) and a third lesion in the anterolateral periphery of the left psoas muscle are also observed.

After completion of the staging work-up, the case was discussed at the Uro-Oncology Tumor Board, and surgical intervention was decided. Surgery was performed using a laparoscopic approach. Resection of the three described lesions was carried out, with the largest lesion at the bladder level requiring a partial cystectomy.

The patient's postoperative course was uneventful, and he was discharged with a urinary catheter on postoperative day 6. Normalization of catecholamine levels was confirmed 18 days after surgery, and the catheter was removed at 3 weeks. Final histopathological examination revealed the presence of multiple paragangliomas (Fig. 3); the left para-aortic and right iliac lesions were not considered tumor implants, as it was not possible to determine whether they corresponded to infiltrated lymph nodes. Subsequently, the patient underwent genetic testing, which revealed a mutation in the B subunit of succinate dehydrogenase (SDHB).

Fig. 3.

A) Hematoxylin–eosin staining (10 × ). Zellballen pattern consisting of nests of tumor cells delimited by capillaries and thin fibrovascular septa. B) Chromogranin staining (20 × ). Intense diffuse membranous and cytoplasmic positivity is observed in the neoplastic cells.

Three months after surgery, the patient presented with recurrence of symptoms despite normal catecholamine levels. PET/CT revealed a possible 0.7-cm paravesical lesion compatible with recurrence, which did not show uptake on SPECT/CT with 99mTc-HYNIC-TOC. Based on these findings, exploratory laparoscopy was performed, revealing multiple millimetric, rounded, erythematous, and hyperemic lesions, highly suspicious for carcinomatosis, from which intraoperative samples were taken and confirmed to be positive for paraganglioma. Therefore, the patient was diagnosed with recurrent paraganglioma in the form of miliary carcinomatosis (Stage IV). After discussion at a multidisciplinary tumor board, treatment with lanreotide was initiated (July 20, 2023). At the fourth month of treatment, the patient showed elevated normetanephrine levels, although no radiological progression was observed on ¹⁸F-FDG PET/CT. The patient continued to have elevated normetanephrine levels on subsequent follow-up, and 19 months after starting treatment, radiological progression was detected on ¹⁸F-FDG PET/CT and SPECT/CT with 99mTc-HYNIC-TOC at hepatic, bone, and peritoneal levels. At the Endocrine-Oncology Tumor Board, the possibility of ablative treatment with ¹³¹I-MIBG was considered; however, SPECT/CT with ¹²³I-MIBG was negative. Finally, initiation of continuous sunitinib at a dose of 37.5 mg/day was decided in May 2025. The clinical course of the patient is summarized in Table 1.

Table 1.

Clinical timeline of the case.

Date	Clinical event
February 2022	Laparoscopic surgical resection including partial cystectomy.
December 2022–January 2023	Radiological suspicion of local recurrence (18F-FDG PET/CT and CT scan); SPECT/CT with99ᵐTc-HYNIC-TOC negative.
March–May 2023	Restaging imaging confirming persistent local disease; suspected hepatic lesion on18F-FDG PET/CT ruled out by MRI.
June 2023	Exploratory laparoscopy revealing miliary peritoneal carcinomatosis.
July 2023	Initiation of lanreotide therapy.
March 2024	Elevation of plasma metanephrines with stable findings on follow-up imaging studies.
February 2025	Persistent elevation of metanephrines with radiological progression involving bone, liver, and peritoneum (18F-FDG PET/CT and99ᵐTc-HYNIC-TOC SPECT/CT).
May 2025	Initiation of sunitinib therapy.

3. Discussion

Bladder paraganglioma is a neuroendocrine neoplasm of low prevalence, accounting for less than 1 % of all bladder neoplasms and approximately 80 % of genitourinary paragangliomas.³ It typically presents in young adults around the fourth decade of life, with no clear predominance between men and women.^3,5 Bladder paragangliomas may produce catecholamines in approximately 70–81 % of cases,^5,6 which has implications for their clinical presentation and management.

In addition, bladder paragangliomas show a higher frequency of germline mutations, particularly in genes of the succinate dehydrogenase (SDH) complex or in the von Hippel–Lindau (VHL) gene, compared with paragangliomas at other sites (56–63 % vs. 40 %, respectively).^5,7,8 Among these alterations, mutation in the SDH subunit B (SDHB)—present in our patient—is independently associated, across paragangliomas overall, with a higher risk of developing metastases.^8,9 Nevertheless, although SDHB mutation confers a more aggressive phenotype, it has not been independently correlated with worse overall survival once adjusted for the presence of metastases and age.⁹

The suspected diagnosis is based on the patient's clinical presentation, laboratory tests, imaging studies, and histology.

Clinical presentation varies depending on the ability to produce catecholamines. In the case of catecholamine-producing bladder paragangliomas, nearly 90 % present with typical symptoms triggered by micturition, such as paroxysmal hypertension, headache, or palpitations.^1,5 In contrast, non-functioning tumors are usually clinically silent, with incidental diagnosis in up to one third of patients.⁵ However, they may occasionally give rise to nonspecific symptoms such as hematuria, dysuria, urinary frequency, or abdominal pain 5.

Laboratory tests used in the diagnosis of bladder paragangliomas are the same as those for pheochromocytomas and other paragangliomas and focus on the determination of free metanephrines and normetanephrines in urine and/or plasma. These metabolites have higher diagnostic sensitivity than direct measurement of plasma catecholamines (norepinephrine and epinephrine, respectively).¹⁰

Imaging studies constitute an essential tool in the diagnostic and therapeutic approach to these patients. In early stages, when there is high clinical suspicion, the modalities of choice are CT and MRI.¹¹ MRI shows higher sensitivity than CT and provides more detailed anatomical resolution. In addition, it is useful in the differential diagnosis with other intramural lesions, such as leiomyoma, whose appearance on CT may mimic that of a paraganglioma.¹²

Nuclear medicine techniques, such as SPECT/CT and PET/CT, play a fundamental role in diagnostic confirmation and functional staging of paragangliomas. SPECT/CT with ¹²³I-MIBG was, for many years, the reference test for the evaluation of thoracoabdominal paragangliomas due to its high specificity, close to 100 %.^7,12 However, its sensitivity is limited, which has led to it no longer being considered the first-line functional modality at present.¹¹ On the other hand, because these tumors variably express somatostatin receptors, SPECT/CT with indium-111–labeled octreotide (¹¹¹In-pentetreotide) represents a useful alternative, especially in non-functioning tumors that are not detectable with ¹²³I-MIBG.

However, in recent years, PET/CT with gallium-68–labeled DOTA-(Tyr3)-octreotate (⁶⁸Ga-DOTATATE) or with 6-18Ffluoro-L-3,4-dihydroxyphenylalanine (¹⁸F-DOPA) has emerged as the modality of choice for the detection of paragangliomas, due to its higher overall detection rate.¹² Finally, it should be noted that ¹⁸F-FDG PET/CT, although it has been displaced by ⁶⁸Ga-DOTATATE and ¹⁸F-DOPA, remains useful for evaluating aggressive or rapidly progressive forms, especially in tumors with SDH mutations that show high uptake.¹¹

Before considering any type of intervention on these tumors, adequate preoperative preparation is required to avoid hypertensive crises. The use of an adrenergic receptor antagonist (doxazosin or phenoxybenzamine) is recommended, initiated 7–14 days before the procedure.^1,2 A beta-blocker may also be added in cases of persistent tachycardia despite adequate alpha blockade.

The treatment of localized disease is complete tumor resection, with transurethral resection of the bladder (TURB) or partial cystectomy being the most commonly used approaches, reserving radical cystectomy for advanced cases.² Yu et al. reported that first-line treatment does not influence the need for a second surgery, residual disease, or the development of metastases.⁵ However, Li et al. noted that patients initially treated with TURB had a higher rate of residual tumor and intraoperative complications (54 % vs. 3 % for cystectomy).⁶

Despite the generally benign behavior of these tumors, Yu et al. reported that up to 30 % of patients develop metastatic disease, with a 5-year overall survival of 60 %.⁵ Other large series have reported a similar proportion of such patients (24 %).⁴ Patients with distant disease were younger (HR 0.97, 95 % CI 0.94–0.99; p = 0.024), had larger tumors (HR 1.69, 95 % CI 1.31–2.17; p < 0.001), and exhibited higher catecholamine secretion (HR 5.48, 95 % CI 1.40–21.39; p = 0.014) compared with those without distant disease.⁵ Most patients had metachronous metastases, and the most frequent metastatic sites were bone, lymph nodes, and lung (Table 2) ^4,5.

Table 2.

Main published cohorts of metastatic bladder paraganglioma.

Study (year)	Total N	N with metastases (Synchronous/Metachronous/Not specified)	Metastatic sites	Treatment for advanced disease	Survival
Pang et al., 20234	106	25 (12 synchronous/13 asynchronous)	Lymph nodes 19 (18 %) Bone 15 (14 %) Lung 8 (7.5 %)	Not specified	Not reported
Yu et al., 20225	110	33 (9 synchronous/24 metachronous)	Bone 22 (67 %) Lymph nodes 19 (58 %) Lung 8 (24 %) Liver 3 (9 %)	Surgery alone Chemotherapy PRRT 131I-MIBG TKI Radiotherapy Ablation	5-year OS 60 %

PRRT = Peptide receptor radionuclide therapy; TKI = Tyrosine kinase inhibitor.

OS = Overall survival.

Due to this low prevalence, evidence regarding therapeutic management at this stage of the disease is quite limited. However, data obtained from studies on pheochromocytomas and metastatic paragangliomas in general can be extrapolated to guide clinical decision-making. It should be acknowledged that this reliance on heterogeneous, non–bladder-specific cohorts represents an inherent limitation when interpreting treatment outcomes in bladder paraganglioma.

¹³¹I-MIBG and PRRT with ¹⁷⁷Lu-DOTATATE are first-line therapies in these patients, with the choice between them depending on functional imaging. ¹³¹I-MIBG is indicated in patients with adrenergic receptor expression. This therapy can be classified as conventional/low specific activity (LSA) ¹³¹I-MIBG and high specific activity (HSA) ¹³¹I-MIBG.¹³ In the case of the former, studies have reported disease control (at least stable disease) rates of up to 65 % in the first year, albeit with high toxicity.¹⁴ For HSA ¹³¹I-MIBG, disease control outcomes are superior (92 %) and are associated with an acceptable toxicity profile¹⁵; however, it is currently not available in Europe.^{13 177}Lu-DOTATATE represents a promising option, especially in patients with non-functioning tumors, achieving disease control rates of up to 84 %.¹⁶

Other therapeutic options include chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD), which achieves disease control rates of up to 81 % and biochemical response rates of 91 %¹⁷; temozolomide, a prodrug of dacarbazine that can be administered orally, appears to have greater activity in patients with SDHB mutations¹⁸; tyrosine kinase inhibitors, which can achieve disease control rates of up to 85 % in the case of sunitinib and 94 % in the case of cabozantinib¹⁹; “cold” somatostatin analogues, such as lanreotide or octreotide, which were used in the present case and have shown conflicting results in the literature¹³; and belzutifan, a hypoxia-inducible factor inhibitor, which achieves objective response (at least partial response) rates of 26 % and disease control rates of 85 %.²⁰

In the cases reported by Yu et al. (Table 2), 26 patients (25 %) received multiple therapies (including surgery, systemic therapies, and radiotherapy); however, it is not specified whether this exclusively involved a metastatic population.⁵

4. Conclusions

Bladder paraganglioma is an extremely rare entity with a low potential to develop metastases. However, the clinical course observed in this case demonstrates that early metastatic recurrence can occur despite macroscopically complete surgical resection. The development of peritoneal carcinomatosis, an uncommon metastatic pattern in this setting, further underscores the aggressive potential of the disease. Accordingly, long-term follow-up based on combined biochemical and imaging assessments is warranted, especially in patients with SDHB-associated disease.

CRediT authorship contribution statement

Paolo Guedes Oliva: Writing – review & editing, Writing – original draft, Visualization, Data curation, Conceptualization. Pablo Jiménez Marrero: Writing – review & editing, Writing – original draft, Conceptualization. Rubén Espino Espino: Writing – review & editing. Reinaldo Marrero Domínguez: Writing – review & editing. Irene Expósito Remedios: Visualization. Rafael Camacho Galán: Visualization.

Funding

This research was funded by the Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC). No specific grant number is applicable.