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Year : 2014  |  Volume : 57  |  Issue : 1  |  Page : 19-23
Paraganglioma of the urinary bladder: A clinicopathologic spectrum of a series of 14 cases emphasizing diagnostic dilemmas

1 Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Urologic Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

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Date of Web Publication17-Apr-2014


Background: Paraganglioma (PG) of the urinary bladder is a rare neuroendocrine neoplasm, accounting for < 0.1% of all bladder tumours. Distinction from urothelial carcinoma is imperative as management and prognosis vary markedly. In this report, we describe our experience with the histopathology of paragangliomas of the urinary bladder with emphasis on the histologic features that have led to their being misdiagnosed as conventional urothelial cancer and, most importantly, those that will help pathologists recognize this rare tumor of the bladder. Materials and Methods: All cases of PG of urinary bladder diagnosed at our institute from 2002-2012 were retrieved and diagnosis confirmed in accordance with WHO classification. Clinical and treatment details were obtained from hospital medical records. Results: Fourteen cases of PG of urinary bladder including 5 consult cases were analysed. These included 11 transurethral resections ± partial cystectomies, 2 partial cystectomies and 1 radical cystectomy. Two out of the 5 consult cases had been submitted with a diagnosis of urothelial carcinoma and 1 with that of a rhabdomyosarcoma. Age ranged from 15-84 years (median, 43 years) with a male to female ratio of 1:2.5. Presenting symptoms were haematuria, dysuria and flank pain; only 1 case had antecedent hypertension. Histologically, typical 'zellballen' (72%), diffuse (21%) and ribbon-like (7%) growth patterns amidst a richly vascularised stroma were seen. Muscularis propria invasion and necrosis was present in 72% and 21%, respectively. Substantial cautery artifacts led to misdiagnosis in the 3 erroneous cases. Tumour cells were positive for chromogranin, synaptophysin; sustentacular cells were S-100 positive. Follow up was available in 6 patients; median follow-up was 29 months (8-120 months). One patient developed distant metastasis in cervical lymph node 10 years after diagnosis; remaining were alive without evidence of disease. Conclusions: Paraganglioma of the urinary bladder is a rare tumor and may be misdiagnosed as urothelial cancer especially on TURBT, but a high index of suspicion, careful search for the characteristic histological features and supportive immunohistochemical studies should lead to a correct diagnosis

Keywords: Hematuria, immunohistochemistry, paraganglioma, urinary bladder

How to cite this article:
Menon S, Goyal P, Suryawanshi P, Tongaonkar H, Joshi A, Bakshi G, Desai S. 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

How to cite this URL:
Menon S, Goyal P, Suryawanshi P, Tongaonkar H, Joshi A, Bakshi G, Desai S. Paraganglioma of the urinary bladder: A clinicopathologic spectrum of a series of 14 cases emphasizing diagnostic dilemmas. Indian J Pathol Microbiol [serial online] 2014 [cited 2021 Jul 30];57:19-23. Available from: https://www.ijpmonline.org/text.asp?2014/57/1/19/130873

   Introduction Top

Paraganglioma is a rare neoplasm that account for <0.06% of all urinary bladder tumors and 6% of all extra-adrenal pheochromocytomas. It arises from chromaffin tissue of the sympathetic nervous system within the layers of the bladder wall. [1] The common presenting symptoms include hematuria, paroxysmal hypertension, post-micturition syncope, headache, sweating, and palpitation with raised catecholamine levels. But only minority of the cases are associated with the symptoms that might prompt consideration of the diagnosis. [2] As many as 50% of the paraganglioma are hereditary and may be associated with familial paraganglioma, neurofibromatosis type 1, von Hippel Lindau disease, and Carneys triad. [3] Since histomorphological overlap occurs with urothelial carcinoma and its variants, especially the nested variant, a careful assessment on microscopy coupled with ancillary immunohistochemical methods prevent misdiagnosis and help in proper diagnosis of this tumor. Treatment modalities include trans-urethral resection and cystectomy (partial or complete) combined with pelvic nodal dissection, especially in presence of proven metastasis. Prognosis is similar to that of adrenal pheochromocytomas. [4]

   Material and Methods Top

All cases of urinary bladder paraganglioma were retrieved from the archives of our department (from 2002-2012). The histology including immunohistochemistry of all cases were reviewed with clinicoradiological details and cystoscopic findings in available cases.

Histological features of paraganglioma were evaluated on hematoxylin and eosin-stained slides including growth pattern ("Zellballen," diffuse and others), presence of delicate fibrovascular septa, tumor necrosis, invasion of lamina propria and detrusor muscle, lymphovascular invasion, perineural invasion, presence of significant cautery artifacts (involving >50% of the specimen), change in overlying epithelium, nuclear pleomorphism (3 times the size of adjacent one), and mitosis. Immunohistochemistry profile was evaluated by reviewing the available immunostained slides.

Clinical treatment details and follow-up details were obtained from hospital medical records.

   Results Top

Fourteen cases of paraganglioma of bladder were studied, of which five cases referral/consult cases diagnosed on the paraffin blocks were submitted for histological evaluation in our department. Amongst the 14 cases studied, 4 were males and 10 were females. The age ranged between 15 and 84 years and median age was 43 years. Duration of the symptoms ranged from 2 to 36 months (Mean duration is 19 months). In five patients, referral pathology blocks/ slides were available and minimal details of clinical presentation /history were provided (all 5 cases had hematuria in history as per referral notes). The optimal biochemical evaluation was not provided by referring clinician/pathologist. Three of these five consult cases were misdiagnosed outside (two as urothelial carcinoma and one as rhabdomyosarcoma). Of the remaining nine patients (all of these had presented with hematuria), six patients were referred to our institute after TURBT and/or partial cystectomy or radical cystectomy (referred as suspected urothelial carcinoma) and three were in-house patients. None of the six referred patients had preoperative urinary VMA levels or proper preoperative details. The patient records from outside did not reveal hypertension in these patients. Of the three patients worked up at our institute, the urinary VMA level was raised to 10.97mg/gm creatinine in one patient only (Normal range: 1.5-7 mg/g creatinine) and documented hypertension was seen in only one patient. The location and size of the tumor varied in all cases. Cystoscopically, as per recorded clinical notes and referral requisitions (in available cases), seven of these tumors were seen as an exophytic / Polypoidal / nodular submucosal growth with hyperemic appearance and normal mucosal covering. There was no site predilection in the bladder wall. Urine cytology was negative in all the cases. Diagnosis was made either on trans-urethral resection of the bladder tumor (TURBT) followed by partial cystectomy or on partial cystectomy specimens. Interestingly, uncontrolled hypertension with blood pressure reading of 240/160mm Hg was seen during surgical manipulation in one of the cases.

Characteristic histological features included typical "zellballen" pattern with rich stromal vascularity, large tumor cells with low nuclear to cytoplasmic ratio, and cytoplasmic granularity was seen in 10 cases (72%). Variable histological features that could lead to misdiagnosis included muscularis propria invasion seen in 10 cases (72%), focal sheet-like pattern in 3 cases (21%), ribbon-like growth pattern in 1 case (7%), focal necrosis in 3 cases (21%), intracytoplasmic brownish melanin pigment noted in 1 case (7%), and associated significant cautery artifacts in 3 cases (21%).([Figure 1]a-d)Nuclei were mostly uniform with occasional nuclear atypia seen in 2 cases. Mitosis was seen rarely overall.
Figure 1: Paraganglioma is seen at low power in the TURBT specimen (1a, original magnification ×40) with cells having amphophilic cytoplasm. Paraganglioma of bladder showing the characteristic "Zellballen" or nesting pattern with delicate blood vessels interspersed between tumor cells (1b, original mag ×100). Paraganglioma of bladder with intracytoplasmic pigment and inset showing strong chromogranin positivity (1c, original mag ×100). Paraganglioma of urinary bladder invading muscularis propria with, which may lead to misdiagnosis of urothelial carcinoma (1d, original magnification ×100)

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This dilemma of the histological differential diagnosis was addressed by application of immunohistochemistry. One referred case of malignant paraganglioma with regional nodal metastasis was observed but had no blocks for evaluation. All other cases were positive for synaptophysin and chromogranin except one case which was negative for synaptophysin. S 100 protein was positive in the sustentacular cells in all the cases. Markers for epithelial and muscle differentiation were negative. Follow-up was available in only 6 of 14 cases. The median follow up was 29 months (8-120 months). One patient developed cervical lymph nodal metastasis at 120 months. All other 5 patients were alive and well with no evidence of disease recurrence at last follow up. The clinicopathologial details, IHC markers, management, and follow up is summarized in [Table 1].
Table 1: Demographic details, cystoscopic/radiologic fi ndings, histologic features, and treatment/follow-up of urinary bladder paraganglioma

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   Discussion Top

Paraganglioma of the urinary bladder is a rare tumor with characteristic histologic and immunohistochemical features. However, it may be misdiagnosed as urothelial cancer because of

  1. Its frequent involvement of the detrusor muscle layer;
  2. Morphology that may suggest urothelial cancer in transurethral resection specimens, particularly if there are artifactual changes induced by surgical cautery;
  3. Failure of pathologists to include it in their differential diagnosis when evaluating a bladder tumor; and
  4. Occurrence of catecholamine-associated symptoms that might prompt consideration of the diagnosis, is seen in only few cases. It is very important to distinguish paraganglioma from urothelial carcinoma as they differ in treatment and prognosis. [5]

Patients of paraganglioma are generally 1 to 2 decade younger than those of urothelial carcinoma. Median age for paraganglioma is 43 years in our study and 43 to 45 years in other series, compared with 60 to 70 years for the patients with urothelial carcinoma. [4] Some paragangliomas are functional which are manifested by catecholamine-induced symptoms like episodic and sustained hypertension or headache associated with voiding in 60 to 70% cases. [4] In our study, only one case presented with hypertension that raised the suspicion of this diagnosis and majority had complaints of hematuria only. Intraoperatively, uncontrolled hypertension may be disastrous in such cases, as was seen in one patient in this study. Hence, the awareness of this entity in the urinary bladder is of utmost importance to the treating urologist and pathologist. A smooth polypoidal mass which causes interventional rise in blood pressure should alert the urologist of this tumor.

There is no site predilection found in our study. However, various studies found lateral wall, posterior wall, and trigone as the most frequent site of the tumor. [6]

Zhou M et al. [5] studied 15 cases of paraganglioma of urinary bladder, 2 of which had symptoms suggestive of diagnosis including hypertension during cystoscopy and episodic headache. Histologically, "zellballen" and diffuse patterns were present in 12 (80%) and 3 (20%) of their cases. A delicate fibrovascular stroma was obvious in 14 (93%) cases. Tumor necrosis, significant cautery artifact, and muscularis propria invasion were present in 1 (7%), 3 (20%), and 10 (67%) cases, respectively. Our study is also comparable with the above study.

There are many tumors which need to be considered in the differential diagnosis of paraganglioma. The most common and important is urothelial carcinoma, especially its nested variant. Nested variant of urothelial carcinoma is characterized by confluent small nests and abortive tubules of mildly atypical neoplastic cells infiltrating the lamina propria and/or muscularis propria. This lesion is reported to have an aggressive behavior. Immunohistochemistry is very useful in distinguishing nested variant of urothelial carcinoma which express cytokeratin and other epithelial markers while paraganglioma express neuroendocrine markers. [7],[8],[9] The pathologist need to be aware that significant cautery artifacts can lead to morphological appearances similar to urothelial carcinomas, especially at the edges of the TURBT specimens.

Other rare differential diagnosis which may morphologically resemble a bladder paraganglioma include malignant melanoma, metastatic renal cell carcinoma (RCC), prostate carcinoma, carcinoid tumors, and granular cell tumor. [5],[10],[11],[12] RCC may have a nested growth pattern and delicate fibro vascular septa and granular cytoplasm. However, overall clinical and histological appearance is usually different and immunohistochemistry (RCC being positive for CK, EMA, and CD10 and negative for neuroendocrine markers) provides additional support to distinguish it from paraganglioma.

Carcinoma of prostate can grow in bladder wall by direct extension and may have nesting pattern, uniform nuclei, and monomorphic appearance, resembling a paraganglioma. However, it usually has prominent nucleoli and cells are positive for CK, PSA, and AMACR and are negative for neuroendocrine markers. [6]

Melanoma is another masquerader of many tumors including paraganglioma. Presence of melanin pigment is not necessary for the diagnosis of melanoma. Pigmented variant of paragangliomas have been reported, with presence of melanin pigment in the cytoplasm of the cells. [10] One of the 14 cases in our study had abundant intracellular melanin pigment. However, morphologically the tumor had characteristic pattern of paraganglioma and cells had amphophilic cytoplasm. On immunohistochemistry, melanomas are positive for S-100P, HMB- 45, and melan A, while negative for neuroendocrine markers. Carcinoid and other neuroendocrine tumors may very rarely present in the urinary bladder and may have insular growth pattern that can mimic paraganglioma. However, most of the carcinoid are immunoreactive with cytokeratin, which helps to differentiate this tumor from paraganglioma. [5],[6]

Finally, granular cell tumor may also mimic paraganglioma, which is characterized by cohesive groups of cells arranged in lobules by dividing fibrous septae and granular cytoplasm. Granular cell tumor is differentiated by positivity for S 100 in the tumor cells while paraganglioma shows S 100 positivity only in sustentacular cells. [12]

The accurate diagnosis of paraganglioma is essential as its management and biologic behavior are vastly different from the aforementioned diagnostic entities, especially urothelial carcinoma which are managed by intravesical BCG, surveillance and re-TURBT or by radical cystoprostatectomy in muscle invasive setting. In a majority of cases of bladder paraganglioma, the treatment of choice is surgical resection either TURBT after control of concomitant hypertension or a partial cystectomy. The biologic behavior is difficult to predict; however, superficial tumors have better prognosis compared to invasive tumors. For metastatic tumors, chemotherapy and radiotherapy appear to be effective. [13],[14] Also, it is estimated that up to 30% of paragangliomas/pheochromocytomas are familial and harbor germline mutations associated with von-Hippel Lindau(VHL) syndrome, MEN2 syndrome, NF1, RET oncogene, and recently elucidated succinate dehydrogenase (SDH) mutations of familial paraganglioma-phaeochromocytoma syndromes, some of which may be detected using immunohistochemistry. These patients would be ideal candidates for genetic counseling and further genetic testing of family members. [15] The importance of SDH mutations in these extra-adrenal paragangliomas has gained importance owing to the fact that they are more likely to have malignant behavior. [16] It would have been interesting to perform these mutational studies on our material, especially the two malignant cases. However, these genetic studies were not done in the present study due to financial constraints.

In conclusion, paraganglioma of the urinary bladder is a rare tumor and may cystoscopically and histologically mimic a urothelial neoplasm. Presence of muscle invasion coupled with significant cautery artifacts in a transurethral resection specimen may mislead a pathologist to a wrong diagnosis. Hence, awareness of this entity amongst urologist and pathologist is of utmost importance, to avoid surgical misadventures and mislabeling of this entity as a urothelial neoplasm. A high index of suspicion, careful search for the characteristic histologic features, and application of immunohistochemistry is important to differentiate this tumor from other bladder tumors.

   References Top

1.Leestma JE, Price EB. Paraganglioma of the urinary bladder. Cancer 1971;28:1063-73.  Back to cited text no. 1
2.Heinrich E, Gattenloehner S, Mueller-Hermelink HK, Michel MS, Schoen G. Paraganglioma of urinary bladder. Urol J 2008;5:57-9.  Back to cited text no. 2
3.Young WF Jr. Paraganglioma: Clinical overview. Ann N Y Acad Sci 2006;1073:21-9.  Back to cited text no. 3
4.Thrasher JB, Rajan RR, Perez LM, Humphrey PA, Anderson EE. Pheochromocytoma of urinary bladder: Contemporary method of diagnosis and treatment options. Urology 1993;41:435-9.   Back to cited text no. 4
5.Zhou M, Epstein JI, Young RH. Paraganglioma of the urinary bladder: A lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol 2004;28:94-100.  Back to cited text no. 5
6.Crismond K, Davis CJ Jr, Mostofi FK. Paraganglioma of bladder: Clinico-pathological study of 77 cases. Mod Pathol 2000;13:97A.   Back to cited text no. 6
7.Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, Reuter VE. Nested variant of urothelial carcinoma: A clinicopathological and immunohistochemical study of 12 cases. Mod Pathol 2003;16:1289-98.  Back to cited text no. 7
8.Cintorino M, Del Vecchio MT, Bugnoli M, Petracca R, Leoncini P. Cytokeratin pattern in normal and pathological bladder urothelium: Immunohistochemical investigation using monoclonal antibodies. J Urol 1988;139:428-32   Back to cited text no. 8
9.Grignon DJ, Ro JY, Mackay B, Ordóñez NG, el-Naggar A, Molina TJ, et al. Paraganglioma of urinary bladder: Immunohistochemical, ultrastructural and DNA flowcytometric studies. Hum Pathol 1991;22:1162-9.   Back to cited text no. 9
10.Moran CA, Albores-Saavedra J, Wenig BM, Mena H. Pigmented extraadrenal paragangliomas. A clinicopathologic and immunohistochemical study of five cases. Cancer 1997;79:398-402.  Back to cited text no. 10
11.Sim SJ, Ro JY, Ordonez NG, Park YW, Kee KH, Ayala AG. Metastatic renal cell carcinoma to urinary bladder: A clinico-pathologic and immunohistochemical study. Mod Pathol 1999;12:351-5.  Back to cited text no. 11
12.Fletcher MS, Aker M, Hill JT, Pryor JP, Whimster WF. Granular cell myoblastoma of urinary bladder. Br J Urol 1985;57:109-10.  Back to cited text no. 12
13.Siatelis A, Konstantinidis C, Volanis D, Leontara V, Thoma-Tsagli E, Delakas D. Pheochromocytoma of the urinary bladder: Report of 2 cases and review of literature. Minerva Urol Nefrol 2008;60:137-40.  Back to cited text no. 13
14.Cheng L, Leibovich BC, Cheville JC, Ramnani DM, Sebo TJ, Neumann RM, et al. Paraganglioma of urinary bladder: Can biologic potential be predicted? Cancer 2000;88:844-52.   Back to cited text no. 14
15.van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: A retrospective and prospective analysis. Lancet Oncol 2009;10:764-71.   Back to cited text no. 15
16.van Hulsteijn LT, Dekkers OM, Hes FJ, Smit JW, Corssmit EP. Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: A systematic review and meta-analysis. J Med Genet 2012;49:768-76.  Back to cited text no. 16

Correspondence Address:
Santosh Menon
Associate Professor, Department of Pathology, 8th Floor, Annexe Building, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: The present study was conducted with close cooperation of Molecular and Cellular Research department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,, Conflict of Interest: None

DOI: 10.4103/0377-4929.130873

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