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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 31-34

Symptomatic bone metastasis revealing an occult malignant paraganglioma of urinary bladder


Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Submission29-May-2020
Date of Acceptance15-Jun-2020
Date of Web Publication08-Jul-2020

Correspondence Address:
Dr. Meenakshi Kamboj
Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, Delhi,
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_14_20

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  Abstract 

Paragangliomas arising in the urinary bladder are rare, and they pose a diagnostic challenge. They need to be differentiated from the more common urothelial carcinoma and the rare morphological mimics, such as granular cell tumor. Majority of these tumors are benign, and malignant counterpart is extremely rare with a handful of cases described in the world literature. We present a case report of a 23-year-old male presenting with the symptoms related to metastatic bone disease, which was subsequently diagnosed as malignant paraganglioma of urinary bladder.

Keywords: Bone, malignant, metastases, paraganglioma, urinary bladder


How to cite this article:
Kamboj M, Pasricha S, Gupta G, Sharma A. Symptomatic bone metastasis revealing an occult malignant paraganglioma of urinary bladder. J Curr Oncol 2020;3:31-4

How to cite this URL:
Kamboj M, Pasricha S, Gupta G, Sharma A. Symptomatic bone metastasis revealing an occult malignant paraganglioma of urinary bladder. J Curr Oncol [serial online] 2020 [cited 2020 Aug 15];3:31-4. Available from: http://www.journalofcurrentoncology.org/text.asp?2020/3/1/31/289121




  Introduction Top


Paraganglioma (PGL) of the urinary bladder is a rare tumor, which clinically, cystoscopically, and histologically mimics a urothelial carcinoma. The majority of these tumors are benign, and malignant PGL of bladder is exceedingly rare. The absolute criterion for malignancy is the presence of metastases.[1] In the present case of a malignant PGL, the patient presented with symptoms related to metastatic disease. Diagnosing PGLs in urinary bladder in the absence of specific local symptoms is a challenge with careful clinical considerations.


  Case Report Top


A 23-year-old male with no significant past and family history presented with gradually increasing pain in lower back and right hip joint of 6 months. Local examination did not reveal any deformity or swelling. His physical and systemic examination was noncontributory, and laboratory investigations were normal.

Magnetic resonance imaging (MRI) of lower spine revealed multiple areas of altered signal intensity, involving lower dorsal and lumbosacral vertebra, with soft tissue component in paraspinal region at L4 level. Whole-body bone scan showed increased tracer uptake in manubrium sterni, bilateral ribs, thoracic vertebra, right humerus, and bilateral femur.

Ultrasonography (USG) showed a mass in urinary bladder with irregular margins near the neck region, measuring 8.4 × 5.9 cm, and grade 1 hydronephrosis in left kidney. Contrast enhanced computed tomography (CECT) of the region depicted a large bladder mass with focal calcification, involving distal right ureter, right seminal vesicle, and prostate, measuring 7.0 × 6.0 × 5.5 cm, along with a lytic lesion in the anterior pillar of left acetabulum [Figure 1]. Hence, a provisional clinical diagnosis of urothelial carcinoma with multiple bone metastases was established.
Figure 1: Axial post-contrast CT scan at the level of pelvis reveals lobulated enhancing mass arising from right lateral wall of urinary bladder with perivesical infiltration into fat (white arrow). Also, an irregular lytic lesion in the anterior pillar of left acetabulum (white arrowhead) is evident

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A cystoscopic cold cup biopsy was carried out, which showed intact urothelial lining with submucosa involved by a tumor, arranged in nests, and surrounded by a layer of spindled cells (Zellballen pattern) [Figure 2]. The tumor cells showed low-grade nuclear atypia with granular nuclear chromatin, tiny nucleoli, and abundant pale eosinophilic cytoplasm, and occasional mitosis. On morphology, the epithelial tumor considered included the nested variant of invasive urothelial carcinoma. Fine needle aspiration cytology (FNAC) performed from pelvic bone lesion showed clusters of discrete neoplastic cells, having oval nuclei with stippled chromatin and abundant fine granular cytoplasm [Figure 3]. On immunohistochemistry (IHC), the tumor cells were negative for pan-cytokeratin (CK) (AE1/AE3, 1:100; Dako, Agilent, Santa Clara, California) [Figure 4]A, p63 (DAK-p63, 1:100; Dako, Agilent), epithelial membranous antigen (EMA) (E29, 1:50; Dako, Agilent), and GATA-3 (L50823, RTU; Cell Marque, Rocklin, California), which excluded the possibility of urothelial carcinoma. The non-epithelial neoplastic differentials were PGL and granular cell tumor. Further, immunohistochemistry showed positivity for vimentin (V9, 1:100; Dako, Agilent), synaptophysin (SP11, 1:100; Thermo Fisher Scientific, Mumbai, India), and chromogranin A [Figure 4]B (LK2410,1:500; Cell Marque), and the sustentacular cells expressed S-100 (S100, 1:400; Dako, Agilent).
Figure 2: Microphotograph showing (A) attenuated urothelial lining with an underlying tumor in Zellballen pattern separated by thin fibrovascular stroma (hematoxylin and eosin [H&E], ×100), (B) higher power view of tumor (H&E, ×200), with inset depicting cells showing abundant pale eosinophilic cytoplasm and low-grade nuclear features (H&E; ×400)

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,
Figure 3: Cytomorphology of left acetabular lesion showing clusters of neoplastic cells, having round to oval nuclei with fine stippled chromatin and abundant cytoplasm

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,
Figure 4: Immunohistochemical marker microphotograph showing (A) pan-cytokeratin highlighting the attenuated urothelium with negative underlying tumor, (B) strong diffuse expression of chromogranin A in tumor cells

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Morphological and IHC findings confirmed the diagnosis of a PGL. Aforementioned findings led to the final diagnosis of malignant PGL of urinary bladder with multiple bone metastasis. The patient was advised chemotherapy, which he was reluctant to take, and he opted for alternative therapy and was lost to follow-up.


  Discussion with Review of Literature Top


PGLs are rare neuroendocrine tumors that arise in sympathetic and parasympathetic paraganglia.[2],[3] Approximately 80%–85% of PGLs arise from the sympathetic paraganglia of adrenal medulla known as pheochromocytomas, whereas 15%–20% are located in extra-adrenal parasympathetic paraganglionic chromaffin tissue.[2],[4]

PGLs occur over a wide age range of 10–88 years with a mean in the fifth decade, and they are generally more common in females with a ratio of 1.4:1.[5] Rate of malignancy ranges from 3% to 36%, with higher rates in PGL than in pheochromocytoma.[6]

Urinary bladder PGLs account for <0.06%–0.10% of all tumors, rarely being malignant. They arise from the chromaffin tissue of the sympathetic nervous system within the bladder wall. Patients usually present with symptoms related to tumor mass with intermittent hematuria or expression of catecholamines, hypertension being the most common feature.[5],[7] They are partially encapsulated tumors, which can be present in any part of the bladder, at any level of wall, with their size at the most being <4 cm. Histologically they show the characteristic tumor with Zellballen pattern.[1],[4],[5]

Urothelial carcinoma accounts for >90% of bladder tumors, and it forms the most important differential, especially the nested variant. The differentials of Zellballen-forming tumors at this site would include PGL and granular cell tumor.[7] Strong diffuse neuroendocrine marker expression with CK negativity should alert the reporting histopathologist to a diagnosis of PGL. In ambiguous cases, serum/urine catecholamines can also be performed preoperatively to reach a diagnosis in functional extra-adrenal PGLs.[4]

The absolute criterion for malignancy is the presence of metastases to sites where chromaffin tissue is not usually present, most common sites being lymph nodes (80%), bones (71%), liver (50%), and lungs (50%).[3] A recent study has documented malignant PGL in bladder in 2 of 14 cases, both with nodal metastasis (one at presentation and other after 120 months of diagnosis).[7]

Clinical features, indicating potential for malignant behavior, include hypertension, “micturition attacks,” and young age.[5] Some authors suggested secretion of noradrenaline and increased levels of plasma dopamine or metabolites as an indication for malignancy. Histological features suggested to indicate malignant characteristics, which include recurrence, gross local invasion, vascular or capsular invasion, tumor necrosis, high cellularity, Ki67 index >3%, size larger than 5 cm, and extra-adrenal location.[1],[2]

Genetically, most of the malignant PGLs are sporadic tumors (with mutations in RET proto-oncogene, Von Hippel–Lindau (VHL), and neurofibromatosis 1 [NF1] gene) or are associated with germ line or somatic mutations of the succinate dehydrogenase subunit B (SHDB) gene, which have almost 50% malignancy rate.[2],[6]

The treatment of choice for bladder PGLs is surgical resection via transurethral resection or partial cystectomy.[2],[7] Malignant PGLs, especially unresectable tumors, are treated with palliative chemotherapy with cyclophosphamide, dacarbazine, and vincristine; external beam radiotherapy (EBRT) for bony metastases; or 131I-labeled metaiodobenzylguanidine (MIBG). Few studies have also investigated the use of targeted therapies in malignant cases with everolimus, imatinib, thalidomide, oral dacarbazine, and sunitinib. However, no standard treatment guidelines have been established for malignant PGLs.[1],[3]

The overall 5-year survival rate of patients with malignant PGLs varies between 34% and 72%, with a worse prognosis (<5 years) seen in patients with liver or lung metastases.[2],[6]

To conclude, PGL should always be suspected in tumors with immunoprofile of negative CK with strong neuroendocrine marker expression. PGL of urinary bladder is rare; however, accurate diagnosis of this entity, especially in the absence of site-specific symptoms, is imperative due to its distinct therapeutic and prognostic implications.

Declaration of Patient Consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgement

We thank Mrs. Sangeeta Arora, Technical Supervisor, Department of Histopathology, Rajiv Gandhi Cancer Institute and Research Center, for technical assistance in performing immunohistochemical stains.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Feng N, Li X, Gao HD, Liu ZL, Shi LJ, Liu WZ. Urinary bladder malignant paraganglioma with vertebral metastasis: A case report with literature review. Chin J Cancer 2013;32:624-8.  Back to cited text no. 1
    
2.
Parenti G, Zampetti B, Rapizzi E, Ercolino T, Giachè V, Mannelli M. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J Oncol 2012;2012:872713.  Back to cited text no. 2
    
3.
Baudin E, Habra MA, Deschamps F, Cote G, Dumont F, Cabanillas M, et al. Therapy of endocrine disease: Treatment of malignant pheochromocytoma and paraganglioma. Eur J Endocrinol 2014;171:R111-22.  Back to cited text no. 3
    
4.
Weiss SW, Goldblum JR. Paraganglioma. In: Weiss SW, Goldblum JR, editors. Enzinger and Weiss’s soft tissue tumors. 5th ed. Philadelphia, PA: Mosby Elsevier; 2008. pp. 989-1016.  Back to cited text no. 4
    
5.
Davis CJ. Paraganglioma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. World Health Organization classification of tumours: Pathology and genetics of tumors of the urinary system and male genital organs. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2016. pp. 136-7.  Back to cited text no. 5
    
6.
Vogel J, Atanacio AS, Prodanov T, Turkbey BI, Adams K, Martucci V, et al. External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. Front Oncol 2014;4:166.  Back to cited text no. 6
    
7.
Menon S, Goyal P, Suryawanshi P, Tongaonkar H, Joshi A, Bakshi G, et al. Paraganglioma of the urinary bladder: A clinicopathologic spectrum of a series of 14 cases emphasizing diagnostic dilemmas. Indian J Pathol Microbiol 2014;57:19-23.  Back to cited text no. 7
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