Clinical Advances in Hematology & Oncology
December 2012, Volume 10, Issue 12
Amruth R. Palla, MD, MPH1
Thomas Hogan, MD2
Sindhu Singh, MD2
1Department of Internal Medicine, Danbury Hospital, Danbury, CT; 2Department of Internal Medicine, Section of Hematology and Oncology, Mary Babb Randolph Cancer Hospital, West Virginia University, West Virginia
Address correspondence to:
Amruth R. Palla, MD, 5212 Avalon Valley Drive, Danbury, CT 06810; Phone: 646-775-1985; Fax: 304-293-2519; E-mail: dr_amruth@yahoo.com.
Introduction
Paragangliomas are neuroendocrine tumors arising from the extra-adrenal sympathetic or parasympathetic nervous system,1 either from the chromaffin-positive paraganglionic tissue or the chromaffin-negative glomus cells2 derived from the embryonic neural crest. They are localized in either the head and neck, thorax, or abdominal area, and they are usually benign but can occasionally show malignant behavior.3 Although all paragangliomas contain neurosecretory granules, a few secrete clinically significant levels of catecholamines (functional paragangliomas)4 and can cause symptoms of sympathetic surge, including hypertension, anxiety, headaches, diaphoresis, and palpitations. Many paragangliomas are sporadic, but a few cases of familial disease—associated with mutations in the succinyl dehydrogenase genes and multiple endocrine neoplasia 2 syndromes—have been reported.5 Paraganglioma of the urinary bladder is rare, accounting for approximately 0.06% of all bladder tumors.6
Case Presentation
A 45-year-old woman with a history of rheumatoid arthritis, secondary hypertension, and anxiety was referred by her urologist for further evaluation and management of paraganglioma of the urinary bladder, which had been recently diagnosed through a recent transurethral resection for bladder tumor (TURBT) performed for severe hematuria. The patient had experienced symptoms of urinary urgency and back/flank pain since the age of 10 and episodes of hypertension and anxiety since her second decade. She recently had experienced suprapubic discomfort and severe hematuria necessitating the TURBT. Initial positron-emission tomography (PET) and computed tomography (CT) scans performed at our hospital showed a bladder tumor and involvement of a single pelvic lymph node (Figure 1).
The patient underwent partial cystectomy with pelvic lymphadenectomy. Follow-up PET/CT scans remained negative 14 months after the surgery (Figure 2). Urine catecholamine levels at 2 and 6 months postoperatively were within the normal range. Chromogranin levels were mildly elevated 2 months after the surgery, but were normal on a repeat check 6 months postoperatively and have remained normal since. The patient’s symptoms of back/flank pain and urinary urgency resolved after the surgery. However, the patient continued to experience hypertension and anxiety, which are therefore considered unrelated to the paraganglioma.
Discussion
Malignant paraganglioma of the urinary bladder constitutes 10–15% of all the bladder paragangliomas.7 Malignant paraganglioma cannot essentially be differentiated from benign bladder paragangliomas based on gross anatomy or histology, and the malignant behavior is determined based on deep local invasion, lymph node involvement, or metastasis either locally or to distant organs.8
Grossly, these tumors are well-circumscribed nodules or nodular aggregates that can be found anywhere on the bladder wall. On microscopy, the tumor cells are arranged in a Zellballen pattern8 and are surrounded by a fibrous network rich in blood vessels (Figure 3). On immunohistochemical analysis, the chief cells of the tumors are positive for neuroendocrine markers, such as chromogranin and synaptophysin (Figure 4). The sustentacular cells are positive for S100 protein but negative for epithelial markers, such as cytokeratin. This characteristic differentiates paraganglioma from urothelial cancers and carcinoid tumors, which are positive for cytokeratin and melanomas on HMB-45 and melanin A stains.9
Functional tumors can lead to symptoms of catecholamine surge (eg, hypertension, anxiety, paroxysmal headaches, diaphoresis, and palpitations),10 especially during micturition. Nonfunctional tumors can be asymptomatic. Painless hematuria is another commonly reported symptom. Rarely, the tumors can also cause urinary obstruction, depending on their location.11
Surgery is the most common mode of treatment, and patients generally undergo partial cystectomy with lymphadenectomy. Radiation12 and chemotherapy, either in the neoadjuvant13 or adjuvant14,15 setting, has been used in a few cases. There are infrequent reports of hypertensive urgency, due to release of excess catecholamines during surgery, and appropriate perioperative preparation for this possibility must be included in the management plan. Because bladder paragangliomas are likely to recur and to metastasize, lifelong follow-up with annual measurement of catecholamine levels is essential.10
A Medline/PubMed search of the term malignant paraganglioma of the urinary bladder yielded a total of 76 articles in many languages; 44 were pertinent to our study. Sixty cases of bladder paragangliomas were described in these 44 articles, with 30 malignant cases being reported thus far in the literature. The ages of the patients ranged from 12–77 years (irrespective of benign or malignant status). Surgery was the most commonly applied treatment modality, with a few cases mentioning the use of radiation or chemotherapy. One report described the use of cisplatin and etoposide,16 and 2 other reports described the use of cyclophosphamide, vincristine, and dacarbazine.13,15 One case described a woman with hypertension that persisted for 30 years before she was diagnosed with malignant bladder paraganglioma.16 Otherwise, diagnosis was usually made within 3–5 years after symptom onset.
Since our patient continued to have hypertension and anxiety despite the surgery, and also given the fact that her catecholamine levels were always within normal limits, it is opined that these comorbidities were unrelated to the paraganglioma, which was most likely non-functional in nature. Her hypertension could be related to vasculitis from the underlying rheumatoid arthritis.
Conclusion
Urinary bladder paraganglioma, although rare, should be included in the differential diagnosis of patients presenting with nonspecific urinary symptoms along with symptoms of catecholamine excess. An early cystoscopy, if considered in such patients, may help diagnose this clinical entity prior to malignant transformation and will enable prompt treatment that can reduce morbidity and offer quicker symptom relief. It should be noted that patients can have hypertension (primary or secondary) from other causes coexisting with a non-functional paraganglioma, as in the case described.
Information regarding the natural history of this disease is available through case reports that followed patients prospectively for recurrence. Our case is one of very few that provide retrospective information on the presence of symptoms for a prolonged period of time prior to the diagnosis of the bladder paraganglioma.
References
1. Renard J, Clerici T, Licker M, Triponez F. Pheochromocytoma and abdominal paraganglioma. Visc Surg. 2011;148:e409-e416.
2. Mariman EC, van Beersum SE, Cremers CW, Struycken PM, Ropers HH. Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity. Hum Genet. 1995;95:56-62.
3. Boedeker CC. Paragangliomas and paraganglioma syndromes. Laryngorhinootologie. 2011;(suppl 1):S56-S82.
4. Plouin PF, Amar L, Lepoutre C. Phaeochromocytomas and functional paragangliomas: clinical management. Best Pract Res Clin Endocrinol Metab. 2010;24:933-941.
5. Iacobone M, Schiavi F, Bottussi M, et al. Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas? Surgery. 2011;150:1194-1201.
6. 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;60:137-140.
7. Ahmet MH, Cengiz M, Veli U, Abdullah M. Malignant paraganglioma of the urinary bladder. Eur J Radiol Extra. 2006;58:53-58.
8. Kairi-Vassilatou E, Argeitis J, Nika H, Grapsa D, Smyrniotis V, Kondi-Pafiti A. Malignant paraganglioma of the urinary bladder in a 44-year-old female: clinicopathological and immunohistochemical study of a rare entity and literature review. Eur J Gynaecol Oncol. 2007;28:149-151.
9. Jiang Z. Bladder paraganglioma pathology. http://emedicine.medscape.com/article/1627819-overview#aw2aab6b5. Updated July 14, 2011. Accessed October 24, 2012.
10. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocytoma. J Urol. 1992;147:1-10.
11. Yadav R, Das AK, Kumar R. Malignant non-functional paraganglioma of the bladder presenting with azotemia. Int Urol Nephrol. 2007;39:449-451.
12. Yoshida S, Nakagomi K, Goto S, Kobayashi S. Malignant pheochromocytoma of the urinary bladder: effectiveness of radiotherapy in conjunction with chemotherapy. Int J Urol. 2004;11:175-177.
13. Ibuki N, Komura K, Koyama K, et al. A pheochromocytoma of urinary bladder treated with neoadjuvant chemotherapy. Hinyokika Kiyo. 2009;55:765-768.
14. Zwahlen D, Fishman PN, Honey J, Milosevic M, Tannock I. Malignant pheochromocytoma of the urinary bladder. Can J Urol. 2007;14:3455-3457.
15. Takeda M, Katagiri A, Kanai T, et al. Treatment of malignant pheochromocytoma by combination of CVD regimen and transarterial embolization. Nihon Hinyokika Gakkai Zasshi. 1991;82:826-829.
16. Nepomniashchaia KV. Multiple primary malignant paragangliomas of the bladder and retroperitoneal space. Arkh Patol. 1985;47:54-57.
Review
Paraganglioma of the Bladder
Robert Jansen, MD, and
Stanley Zaslau, MD, MBA, FACS
West Virginia University, Division of Urology, Morgantown, West Virginia
Palla and colleagues reported a case of a malignant bladder paraganglioma in a 45-year-old woman.1 Paragangliomas are pheochromocytomas that arise outside of the adrenal medulla. According to the “rule of tens,” 10% of pheochromocytomas occur outside of the adrenals; however, the actual incidence of paragangliomas has been reported to be as high as 23%.2 These tumors may arise in the head/neck, thorax, and/or abdominopelvic regions. Bladder paragangliomas, in particular, represent 0.06% of all bladder tumors and less than 1% of all catecholamine-secreting tumors.3 Pheochromocytomas normally arise from chromaffin cells in the adrenal medulla. Chromaffin tissue is also located along the para-aortic sympathetic chain, the sympathetic chain in the neck and mediastinum, and within the wall of the urinary bladder.4 The source of the bladder chromaffin tissue is uncertain. Some researchers suspect that chromaffin tissue migrates to the bladder wall during embryonic development.5 Others have discovered small nests of paraganglionic tissue in the muscularis propria and deep submucosal layers of the trigone, posterior wall, and anterior wall of the bladder.6
Pheochromocytomas and paragangliomas may arise sporadically or as part of a familial pattern. Recent studies have shown a heritability of 27.4–51.7% for pheochromocytomas and paragangliomas, leading some to recommend genetic testing for affected individuals. Certain tumor syndromes, including Von Hippel–Lindau, multiple endocrine neoplasia type I, and neurofibromatosis type I, have associations with both tumor types, and multiple gene mutations, including RET, NF1, VHL, and SDH, have been discovered.7 Bladder paragangliomas show a slight female predominance, with patients usually presenting in the third, fourth, or fifth decades.8,9
As pheochromocytomas and paragangliomas arise from neuroendocrine tissue, 80% of cases have the ability to produce catecholamines and are termed functional tumors.10 Presenting symptoms such as palpitations, pallor, headache, and diaphoresis occur due to a sympathetic surge from catecholamine release. Less common presentations may include hyperglycemia, panic attacks/anxiety, fever, weight loss, myocardial infarctions, and Raynaud’s phenomenon.11 Paragangliomas occurring in the bladder may cause gross hematuria in up to 60% of cases, although patients may also present with microhematuria or unremarkable urinalyses.3 The onset of the aforementioned symptoms, particularly with bladder tumors, is usually induced by micturition, bladder distention, or sexual activity.4,11
Malignancy is present in approximately 10% of pheochromocytomas and 5–20% of paragangliomas.12 Although definitions of malignancy vary, it is usually defined as the presence of distant metastases, as even tumors that locally invade adjacent organs may maintain an indolent course. Malignant tumors do not differ histologically or genetically from benign tumors, however, they tend to be larger and secrete more dopamine than benign lesions.13,14 Five-year survival rates of patients with malignant pheochromocytomas are between 36–60%.10
Diagnosis of bladder paragangliomas is accomplished using imaging, measurement of hormonal metabolites, and direct visualization via cystoscopy. On cystoscopy, the paraganglioma is a nondistinct entity, appearing as a homogenous submucosal mass with abundant vascularity.3,5,9 Immediate biopsy should be avoided due to the risk of precipitating massive catecholamine release and life-threatening complications. Whereas diagnosticians previously looked to serum/urine catecholamines to determine the presence of a functional tumor, researchers are now focusing on metanephrines. As such, recommendations from the 2005 International Symposium on Pheochromocytoma state that along with initial testing, evaluation should include measurements of plasma-free and urinary metanephrines, along with catecholamine levels.15 Sensitivity and specificity of 24-hour urine metanephrine measurement is 87–90% and greater than 99%, respectively, whereas serum metanephrine measurement carries a sensitivity of 85% and a specificity of 96%.11 Compared to pheochromocytomas, bladder paragangliomas typically secrete a higher ratio of norepinephrine:epinephrine due to the lack of the PNMT conversion enzyme.3 Imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI), have previously been used with good sensitivity in detecting the presence of tumors, although they lack specificity in identifying functional tumors. The standard functional imaging studies are 123I-metaiodobenzylguanidine (MIBG) scintigraphy and 131I-MIBG scintigraphy, which are useful in localizing metastatic deposits or multifocal tumors. Newer imaging modalities, such as 18F-fluorodopa positron-emission tomography (FDOPA-PET), have been evaluated in comparative studies; Fottner and colleagues report a sensitivity of 98% and specificity of 100% for FDOPA-PET, compared to 53% and 91% for 131I-MIBG.16
The treatment of choice for malignant pheochromocytomas and paragangliomas is surgical resection. Prior to surgery, blood pressure should be normalized, as preoperative blood pressure has been linked to perioperative complications.17 Patients also require preoperative alpha- and beta-adrenergic blockade to avoid intraoperative sympathetic surge from tumor manipulation.10 Partial cystectomy is mainly performed for resection of bladder paragangliomas, although radical cystectomy may be considered for trigonal tumors or tumors exhibiting local invasion or multifocality. It is interesting to note that in this patient, although partial cystectomy was performed, hypertension and anxiety have continued postoperatively. These conditions are likely not related to the paraganglioma. It is conceivable that the paraganglioma did not produce hypertension and was likely hormonally inactive in that regard.
In select cases, consideration for regional lymphadenectomy should be contemplated. Transurethral resection has been performed and may be useful for noninvasive tumors measuring less than 2–3 cm; however, due to the significant risk of hemorrhage, this modality is not preferred.6,18 Chemotherapy and radiation are generally considered palliative only, although some cases have shown effective treatment of metastatic disease.9,10,13
Long-term follow-up should be pursued, as metastatic disease may present as long as 41 years after tumor resection.19 Some authors recommend clinical and biochemical (metanephrine measurement) assessment at 6 months and then annually thereafter in patients affected by a malignant tumor. Cystoscopy and imaging (CT, MIBG) may be considered as well, although there is no official algorithm or protocol defining the timing or necessity of these studies. Patients with suspected benign tumors (<5 cm, solitary, sporadic) may pursue follow-up with clinical and biochemical testing every 2 years.20
Conclusion
Bladder paragangliomas are rare tumors with certain malignant potential. Functional tumors induce symptoms that are attributed to catecholamine release, although these symptoms may overlap with other clinical entities, presenting an obstacle to prompt diagnosis and determination of true tumor functionality.
References
1. Palla AR, Hogan T, Singh S. Malignant paraganglioma of the urinary bladder in a 45-year-old woman. Clin Adv Hematol Oncol. 2012;11:836-839.
2. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89:479-491.
3. Tsai CC, Wu WJ, Chueh KS, et al. Paraganglioma of the urinary bladder first presented by bladder bloody tamponade: two case reports and review of the literatures. Kaohsiung J Med Sci. 2011;27:108-113.
4. Young WF Jr. Paragangliomas: clinical overview. Ann NY Acad Sci. 2006;1073:21-29.
5. Kappers MH, van den Meiracker AH, Alwani RA, Kats E, Baggen MG. Paraganglioma of the urinary bladder. Neth J Med. 2008;66:163-165.
6. Kairi-Vassilatou E, Argeitis J, Nika H, Grapsa D, Smyrniotis V, Kondi-Pafiti A. Malignant paraganglioma of the urinary bladder in a 44-year-old female: clinicopathological and immunohistochemical study of a rare entity and literature review. Eur J Gynaecol Oncol. 2007;28:149-151.
7. Iacobone M, Schiavi F, Bottussi M, et al. Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas? Surgery. 2011;150:1194-1201.
8. Schaefer IM, Gunawan B, Füzesi L, Blech M, Frasunek J, Loertzer H. Chromosomal imbalances in urinary bladder paraganglioma. Cancer Genet Cytogenet. 2010;203:341-344.
9. Deng JH, Li HZ, Zhang YS, Liu GH. Functional paragangliomas of the urinary bladder: a report of 9 cases. Chin J Cancer. 2010;29:729-734.
10. Zwahlen D, Fishman PN, Honey J, Milosevic M, Tannock I. Malignant pheochromocytoma of the urinary bladder. Can J Urol. 2007;14:3455-3457.
11. Lee JA, Duh QY. Sporadic paraganglioma. World J Surg. 2008;32:683-687.
12. Gimm O, DeMicco C, Perren A, Giammarile F, Walz MK, Brunaud L. Malignant pheochromocytomas and paragangliomas: a diagnostic challenge. Langenbecks Arch Surg. 2012;397:155-177.
13. Plouin PF, Amar L, Lepoutre C. Phaeochromocytomas and functional paragangliomas: clinical management. Best Pract Res Clin Endocrinol Metab. 2010;24:933-941.
14. Korevaar TI, Grossman AB. Pheochromocytomas and paragangliomas: assessment of malignant potential. Endocrine. 2011;40:354-365.
15. Eisenhofer G, Tischler AS, de Krijger RR. Diagnostic tests and biomarkers for pheochromocytoma and extra-adrenal paraganglioma: from routine laboratory methods to disease stratification. Endocr Pathol. 2012;23:4-14.
16. Fottner C, Helisch A, Anlauf M, et al. 6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression. J Clin Endocrinol Metab. 2010;95:2800-2810.
17. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab. 2001;86:1480-1486.
18. Pastor-Guzmán JM, López-García S, Giménez-Bachs JM, et al. Paraganglioma of the bladder: controversy regarding treatment. Urol Int. 2004;73:270-275.
19. Das S, Lowe P. Malignant pheochromocytoma of the urinary bladder. J Urol. 1980;123:282-284.
20. Amar L, Fassnacht M, Gimenez-Roqueplo AP, et al. Long-term postoperative follow-up in patients with apparently benign pheochromocytoma and paraganglioma. Horm Metab Res. 2012;44:385-389.