Advanced pelvic paraganglioma presenting as hematuria and urinary retention with a large intravesical mass: A case report

Abstract

Paragangliomas are neuroendocrine tumors arising from extra-adrenal chromaffin cells within the autonomic nervous system. Primary urogenital disease is rare (6.7% of paragangliomas), with prostatic involvement reported in only a few case studies. Management follows National Comprehensive Cancer Network (NCCN) guidelines for neuroendocrine and adrenal tumors; however, there is limited data to guide systemic therapy in cases that present with metastasis. We describe a report of a 60-year-old man with metastatic pelvic paraganglioma detected after 4 months of gross hematuria and urinary retention. Despite the large tumor burden, the patient has been successfully treated with systemic therapy after an appropriate workup.

Highlights

• •Prostatic paraganglioma is a rare urogenital neuroendocrine tumor.
• •Treatment is excision for localized disease and systemic therapy for metastatic disease.
• •Germline testing is essential to identify underlying inheritable pathogenic variants.
• •In this case, we highlight the initial workup and preliminary response to systemic treatment.

1. Introduction

Urogenital paragangliomas are rare tumors originating from chromaffin cells within autonomic paraganglia. They comprise approximately 6.7% of all extra-adrenal paragangliomas and typically arise from the autonomic tissue of the detrusor plexus in the bladder.¹ Prostatic paragangliomas are exceedingly rare examples of this type of tumor, and have been described in only 13 case reports to date.¹ These tumors typically present with symptoms of mass effect and hematuria, in addition to increased catecholamine activity-associated symptoms such as hypertension or diaphoresis.² Definitive management of localized disease is surgical resection, with management of metastatic disease paralleling systemic treatment for adrenal and other neuroendocrine tumors as described by the NCCN.³ Specific guidance for the management of pelvic paragangliomas, however, has not been well-defined. Furthermore, while many extra-adrenal paragangliomas are sporadic, up to 30% are associated with inherited cancer syndromes caused by germline pathogenic variants.² Here, we describe a case of a 60-year-old Caucasian male with minimal prior healthcare exposure and no personal or family oncological history who presented after a 4-month history of gross hematuria, clot retention, and lower abdominal pain and swelling. Clinical, radiologic, and pathologic workup revealed an infiltrative paraganglioma involving the bladder and prostate, and appropriate evaluation and treatment were initiated.

2. Case presentation

A 60-year-old man with no personal or family oncological history presented for initial evaluation at the oncology clinic. His medical history included gout, hypertension, hyperlipidemia, and right orchiopexy as a child with a remote personal history of smoking. Over a four-month period, he developed progressive hematuria, accompanied by lower urinary tract symptoms and urinary retention, initially diagnosed as benign prostatic hyperplasia by his primary care physician. Initial office cystoscopy at that time was inconclusive, and the patient was placed on tamsulosin. Over this time, he had two emergency department visits for urinary retention requiring catheter placement; attempts at self-catheterization were unsuccessful. Several urinalyses were negative, antibiotics for presumed urinary tract infections did not improve his symptoms, and he denied any neurologic symptoms.

On presentation, the patient exhibited significant discomfort in his lower abdominopelvic region. Abdominal exam revealed a firm mass extending to the level of the umbilicus. Computed tomography (CT) and magnetic resonance (MR) images showed a large left pelvic mass suspicious for locally advanced bladder or prostate carcinoma and mild to moderate bilateral hydroureteronephrosis. The mass appeared to replace the entire prostate and invade the bladder base, seminal vesicles, and left obturator internus muscle. The mass abutted but did not appear to invade the rectum. Other relevant findings included a 3 cm left pelvic lymph node and 2.6 cm right femur lesion in the greater trochanter, suspicious for metastasis (Fig. 1). Laboratory results were notable for a normal creatinine of 0.83 mg/dL and prostate specific antigen (PSA) of 1.52 ng/mL. Given the normal PSA and diffusely infiltrative radiologic impression, a prostatic sarcoma was suspected, and the patient was scheduled for an urgent transurethral biopsy with examination under anesthesia (EUA).

Fig. 1.

T1 Axial Pelvic MRI (a, b) and CT Abdomen-Pelvis (c-coronal, d-sagittal) characterizing the pelvic mass.

During the procedure, the patient was persistently tachycardic and hypertensive, even after emergence from anesthesia. In hindsight, this should have prompted a potential evaluation for pheochromocytoma. However, because his blood pressure was well controlled, the procedure proceeded. Cystoscopy revealed a significant tissue mass occluding the urethra and infiltrating most of the bladder, with friable, necrotic tissue. Ureteral orifices were grossly uninvolved. Bimanual exam revealed a fixed pelvic mass without evidence of rectal involvement. Tissue samples were obtained and sent for pathologic examination.

Pathologic evaluation revealed a diffusely infiltrative neoplasm composed of solid nests of epithelioid cells with abundant granular cytoplasm, low nuclear to cytoplasmic ratio, and increased mitotic activity (up to 4 per 10 high-power fields (HPF)). The tumor cells displayed positive staining by immunohistochemistry for GATA3, synaptophysin, chromogranin, and S100 (sustentacular cells) and were negative for cytokeratin AE1/AE3, cytokeratin CAM5.2, KRT7, KRT20, p63, Uroplakin II, and NKX3.1. Succinate dehydrogenase B (SDHB) immunohistochemistry showed notable loss of staining in tumor cells. The morphologic and immunophenotypic profile was consistent with paraganglioma of suspected prostatic origin with unfavorable factors including infiltrative growth, large tumor size, increased mitotic activity, and SDHB loss.⁴

An urgent workup was initiated, including plasma metanephrines, PET-DOTATATE scan, and endocrinology referral to initiate alpha blockade. Normetanephrine levels were elevated at >50 nmol/L (normal: 0-8.9 nmol/L), and metanephrine levels were normal (0.22 nmol/L; (normal: 0-0.49 nmol/L). Copper (Cu)-64 DOTATATE scan revealed extensive metastatic disease burden (Fig. 2), including pelvic nodal, hepatic, and bone metastases with metabolic activity near the carotid bifurcation. Cranial osseous spread was also noted, with a 3.2 cm right parietal calvarial metastasis with intracranial extension and mass effect on the brain, along with additional smaller bony skull metastases.

Fig. 2.

Cu-64 DOTATATE PET CT Skull Base to Mid-Thigh highlighting (a) overall burden of disease, (b) pelvic, and (a) liver.

The patient was referred to genetic counseling and underwent genetic testing (Tempus xF+, comprehensive genomic profiling (CGP) assay covering 523 genes utilizing cell-free DNA, i.e., “liquid biopsy”), revealing a SDHB c.136C > G (p.Arg46Gly) loss-of-function variant at high variant allele fraction (VAF 56.9%), compatible with a germline pathogenic variant. CGP also identified a missense gain-of-function variant in FGFR1 (c.1638C > G, p.Asn546Lys, VAF 5.0%), ATRX (c.5738C > G, p.Ser1913*, VAF 12.1%) loss-of-function variant, and a TERT promoter pathogenic variant (c.-124C > T, VAF 3.5%). Circulating tumor DNA (ctDNA) fraction was detected at 4.3%, and blood tumor mutational burden (bTMB) was estimated to be 4.4 mutations/MB, with no microsatellite instability detected.

The patient was initiated with systemic therapy with Cyclophosphamide, Vincristine, Dacarbazine (CVD) chemotherapy, with initial post-treatment imaging at ∼3 months showing a significant reduction in tumor burden (Fig. 3). His urinary system is being managed with an indwelling catheter exchanged every 4-6 weeks with a nephrostomy tube in place, and blood pressure is well controlled with losartan-hydrochlorothiazide and amlodipine. Pending the patient's response to systemic therapy, he may eventually become a candidate for surgery (e.g., radical cystectomy).

Fig. 3.

Predicted impact of SDHB mutation on protein function.

3. Discussion

Pelvic paragangliomas are extremely rare tumors described in only 13 case reports, with management based on standard-of-care workup for better characterized neuroendocrine tumors. Little information exists on patient characteristics and response to treatment in these tumors, especially in patients presenting with metastatic disease. Previous case reports have described localized disease that responds well to local excision.¹ In general, paragangliomas tend to present earlier in life than other prostatic malignancies, including one instance in an 8-year-old boy.⁵ While most tumors are typically functional, causing systemic symptoms, a few have been reported as non-functional. Generally, these reports have highlighted the importance of optimal imaging strategies (including conventional imaging and novel scintigraphy techniques for meta-iodobenzylguanidine MIBG avid disease), differential diagnosis, and intraoperative and postoperative symptomatic management.⁶ Metastatic disease, however, is very rare, only occurring in one case report, and a patient with the extent of metastases described here has not been previously described.

The majority of extra-adrenal paragangliomas (86% outside of the head and neck) are biochemically active, presenting with symptoms of hypertension, hematuria, headaches, palpitations, sweating, and blurred vision.⁷ These symptoms can be triggered by micturition with bladder involvement when detrusor muscle contraction releases catecholamines from the tumor. Prostatic paragangliomas seldom present with micturition-related symptoms, but even in patients with minimal baseline biochemical symptoms, manipulation of the tumor during bladder instrumentation or biopsy, placement of a Foley catheter, vigorous exercise, or even ejaculation⁸ can trigger release of catecholamines and subsequent hemodynamic instability, as was observed during the biopsy and EUA for this patient. To emphasize an important teaching point, if this patient had presented with hypertension and tachycardia preoperatively, he would have been evaluated for paraganglioma, including plasma metanephrines and started on appropriate alpha-blockade in preparation for surgery. His tachycardia and hypertension were well controlled intraoperatively, and therefore the case continued. In a setting where hypertension could not be controlled, the case would be canceled until appropriate alpha-blockade could be performed.

The majority of extra-adrenal paragangliomas in the abdominal and pelvic regions are solitary tumors with metastasis only occurring in 10-30% of patients.⁹ Furthermore, most paragangliomas tend to be indolent and slow-growing. In contrast, this patient's tumor was discovered after 4 months of progressively worsening symptoms, indicating a more rapidly growing tumor. The aggressive behavior of the tumor was confirmed by pathologic evaluation, which displayed infiltrative growth, high mitotic activity, and loss of SDHB by immunohistochemistry (Fig. 4). SDH-deficient paragangliomas, regardless of tumor location, are known to be more aggressive, fast-growing tumors with increased risk of metastasis.

Fig. 4.

Histopathologic and immunophenotypic characteristics of the patient's paraganglioma. (A) The tumor is composed of infiltrative tumor nests of cells with indistinct cell borders (H&E, 400x magnification). (B) GATA3 immunostaining displays nuclear positivity in tumor cells (400x magnification). (C) Synaptophysin immunostain is strongly positive (400x magnification). (D) SDHB immunostaining demonstrates loss of expression in tumor cells with retained cytoplasmic expression in background vessels (400x magnification).

Recent studies have shown that up to 40% of all paragangliomas and pheochromocytomas harbor germline mutations, with even higher rates in extra-adrenal and urogenital locations. Specifically, in a series of patients with urinary bladder paragangliomas (UBPGLs), 63% had underlying germline pathogenic variants, with SDHB variants accounting for the majority, and VHL pathogenic variants also represented.¹⁰ These findings have led to the consensus that all patients with paragangliomas, regardless of location or family history, should be offered germline testing.¹¹ This approach enables risk stratification, guides surveillance for metastatic disease, and informs family counseling, a recommendation that has informed the NCCN guidelines for the evaluation and management of neuroendocrine adrenal and extra-adrenal malignancies.³ Given the increased risk for developing an associated tumor, patients with pathogenic germline variants are recommended to undergo annual history and physical, blood pressure monitoring, fractionated metanephrines testing, and full body MRI every two to three years to screen for tumors.³ Furthermore, the 50% risk of carrier status for first-degree relatives introduces the additional component of testing family members. A skilled genetic counsellor therefore should be involved in helping navigate the complex clinical and ethical challenges of this testing.¹²

In our patient, genetic testing revealed a c.136C > G (p.Arg46Gly) loss-of-function variant in SDHB at high VAF, compatible with a germline pathogenic variant. It is well established that patients with pathogenic variants in the SDHB have upwards of a 25-40% lifetime risk for developing paragangliomas or pheochromocytomas during their lifetime.¹³ This mutation alters iron cluster binding leading to significant decrease in SDH activity and succinate accumulation (Fig. 4A–D).¹⁴ Notably, SDHB pathogenic variants also increases the risk of kidney cancer (lifetime risk of 2-5%, more than double that of the general population), and gastrointestinal stromal tumor (GIST).¹⁵ Genetic testing also detected pathogenic variants in FGFR1 and ATRX (at somatic-level VAFs), which would respectively allow the patient to be eligible for erdafitinib or Olaparib (by clinical trial NCT03375307¹⁶), if clinically indicated.

Current NCCN guidelines recommend individualized management with cytoreductive surgery; it should be considered for symptomatic control in secreting tumors, while observation or systemic therapy may be appropriate for asymptomatic or unresectable cases.¹⁷ In this patient, given the multiple metastatic sites, systemic therapy was pursued with Cyclophosphamide/Vincristine/Dexamethasone. This is the optimal regimen recommended by the NCCN, although its specific utility in the case of primary prostatic paraganglioma with extensive metastases has not been confirmed. In patients with Iodine-131 ((131)I) metaiodobenzylguanidine (MIBG) avidity, Iodine-131 MIBG radiotherapy can also be offered; however, it currently has limited availability. CVD is generally considered a superior option in patients without MIBG avidity, for those without access to MIBG imaging, or in patients with rapidly progressing or aggressive tumors.^3,17

4. Conclusions

While the mainstay of treatment for prostatic paraganglioma is surgical resection, metastatic disease necessitates systemic therapy. Most patients with paragangliomas present with symptoms of catecholamine excess, but a significant proportion are discovered by mass effect or incidentally. As a rare tumor, the treatment algorithms for metastatic disease are poorly understood, however, this patient has shown a significant response to systemic therapy, therefore this approach may inform future management strategies for similar patients. Importantly, all patients with newly diagnosed paragangliomas, regardless of location or family history, should be offered germline genetic testing to screen for an underlying, disease-causing pathogenic variant.

CRediT authorship contribution statement

Thomas Syphan: Writing – review & editing, Writing – original draft, Visualization, Project administration, Data curation, Conceptualization. Heloisa Soares: Writing – review & editing, Conceptualization. Jessica F. Williams: Writing – review & editing, Supervision, Data curation, Conceptualization. Alejandro Sanchez: Validation, Supervision, Data curation, Conceptualization. Christopher Dechet: Writing – review & editing, Supervision, Conceptualization.

Informed consent

Written informed consent was obtained from all individual participants included in the study. They were fully informed about the nature and purpose of the research, and their participation was voluntary.

Disclosure

The authors declare that this work is their own original creation and has not been submitted previously for any other degree or qualification.

Funding

No funding was received for this manuscript.

Conflicts of interest

The authors declare no conflicts of interest.