- Email: [email protected]
Evaluation of Sonographic Features for Patients with Urinary Bladder Paraganglioma: A Comparison with Patients with Urothelial Carcinoma
Ultrasound in Med. & Biol., Vol. 40, No. 3, pp. 478–484, 2014 Copyright Ó 2014 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2013.10.014
d
Original Contribution EVALUATION OF SONOGRAPHIC FEATURES FOR PATIENTS WITH URINARY BLADDER PARAGANGLIOMA: A COMPARISON WITH PATIENTS WITH UROTHELIAL CARCINOMA YANMI LI,* AITAO GUO,y JIE TANG,* QIUYANG LI,* XIANG FEI,* YAN ZHANG,* and JIANGPING GAOz y
* Department of Ultrasound, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; and z Department of Urology, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China (Received 8 March 2013; revised 13 October 2013; in final form 15 October 2013)
Abstract—The goals of the work described here were to analyze the ultrasonographic characteristics of urinary bladder paraganglioma and to evaluate the use of ultrasonography (US) in diagnosis. Ten patients with bladder paraganglioma (3 males, 7 females) and 51 patients with urothelial carcinoma (37 males, 14 females) were enrolled. Ultrasonographic characteristics as well as clinical features were analyzed. Patients with urothelial carcinoma were significantly older than those with paraganglioma (62.9 y vs. 48.1 y, p 5 0.001). The patients with paraganglioma had higher average systolic blood pressure than those with urothelial carcinoma (146.7 mm Hg vs. 130.7 mm Hg, p 5 0.012). All bladder paragangliomas were solitary, and 40% were located on the dome. There was a statistically significant difference in location of lesions between the bladder paraganglioma and urothelial carcinoma groups (p 5 0.014). The longest diameters in 80% of the bladder paragangliomas were in the range 1.1–3.0 cm; 60% were hypoechoic, and 40% were located in the submucosa of the bladder. Color Doppler revealed that 40% of the bladder paragangliomas were highly vascular. One patient with paraganglioma and four patients with urothelial carcinoma underwent contrast-enhanced ultrasound, which revealed rapid contrast enhancement and slow wash-out, with a non-enhanced area. Contrast-enhanced ultrasound of urothelial carcinomas revealed rapid homogeneous enhancement and variable wash-out patterns. Pre-operative ultrasonography detected all neoplasms of the urinary bladder in the 10 patients with pathologically confirmed paraganglioma, but made the correct diagnosis in only 2 cases (20%). Although there is overlap in US findings among different diseases, solitary, submucosal masses arising on the dome may be the key US imaging characteristic for bladder paraganglioma. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Ultrasonography, Urinary bladder paraganglioma, Contrast-enhanced ultrasound, Urothelial carcinoma.
The typical symptom of urinary bladder paraganglioma is paroxysmal hypertension during micturition. Laboratory tests include plasma and urinary levels of catecholamines and their metabolites. However, the hypertension is intermittent and varies (Baguet et al. 2004), and the laboratory tests may be normal in some cases (Doran et al. 2002). The clinical ‘‘silence’’ may delay the correct diagnosis from the onset of the abnormal blood pressure. Moreover, urinary bladder paraganglioma can be easily misdiagnosed as bladder urothelial carcinoma (Deng et al. 2010). Trans-urethral resection, cystoscopy and biopsy are common procedures in bladder neoplasms. Unfortunately, during these manipulations, patients with paraganglioma may experience lethal complications such as hypertensive crisis (Tazi et al. 2009). The suspicion of paraganglioma determines surgical
INTRODUCTION Pheochromocytoma is a tumor derived from chromaffin cells, which secrete catecholamines. At present, heterotopic or extraadrenal pheochromocytoma is called paraganglioma on the basis of its anatomic location and function. Paragangliomas of the urinary bladder arise from the chromaffin tissue of the bladder wall (Onishi et al. 2003; Salanitri et al. 2001) and constitute approximately 6% of all paragangliomas and less than 1% of all bladder tumors (Pastor et al. 2004).
Address correspondence to: Jie Tang, Department of Ultrasound, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing, People’s Republic of China 100853. E-mail: [email protected]. com 478
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
and anesthetic management, which plays a key role in the prognosis. Therefore, an imaging examination is vital to establish the correct diagnosis. Ultrasonography (US) is frequently used because of its high sensitivity for detecting neoplasms of the urinary bladder. It serves as an excellent non-invasive first-line investigative diagnostic modality to pick up silent as well as functioning paragangliomas (Halefoglu et al. 2006). However, there is little information regarding US findings in bladder paraganglioma. And the accuracy of US in the diagnosis of bladder paraganglioma remains unclear. Therefore, we compared US findings for paraganglioma of the urinary bladder with those for urothelial carcinoma of the urinary bladder. The aims of this study were to identify which US features can facilitate diagnosis and to assess the clinical role for pre-operative US in the diagnosis of bladder paraganglioma. METHODS Study population This study was approved by our local ethics committee and informed consent was obtained from all patients. We reviewed the data on surgical excisions of bladder neoplasms performed at our hospital from September 2008 to December 2012, and enrolled 10 patients (3 men, 7 women) diagnosed with urinary bladder paraganglioma; their ages ranged from 26 to 69 y. Next, we randomly selected 51 of 483 patients with urothelial carcinoma for the control group. This control group consisted of 14 women and 37 men ranging in age from 26 to 88 y. Clinical features and pre-operative plasma levels of epinephrine, as well as pre-operative 24-h urinary excretion of vanillylmandelic acid, were recorded (J.G.). Ultrasonography techniques Ultrasonographic examinations were performed by three radiologists with more than 6 y of experience in bladder imaging (X.F., Y.Z., Q.L.). The bladder was evaluated when it is moderately filled and was scanned in the transverse and sagittal planes. Different equipment was used for the US examinations. The bladder was scanned with the Logiq 9 equipped with a 4C probe (GE Healthcare, Milwaukee, WI, USA); the Voluson E8 equipped with a 4C-D probe (GE Healthcare); the Acuson Sequoia 512 equipped with a 4 V1 probe (Siemens Medical Solutions, Mountain View, CA, USA); and the Philips IU22 equipped with a C5-2 probe (Philips Medical Systems, Bothell, WA, USA). Female patients underwent trans-vaginal examination with an IC5-9-D probe (4.0–9.0 MHz) (GE Healthcare). Contrast-enhanced ultrasound (CEUS) was performed with the Voluson E8, a 2-5 MHz probe and a mechanical index of 0.10. The contrast agent used was SonoVue
479
(Bracco, Milan, Italy). A bolus of 1.2 mL contrast agent was injected and followed by a 5-mL normal saline flush using a three-way stopcock to ensure that no residual contrast agent remained in the intravenous catheter. System calipers were used for measurements. Images were sent to a picture archiving and communication system workstation. Image interpretation Ultrasonographic images of bladder lesions were assessed independently by two radiologists (Y.L., J.T.), both of whom have more than 10 y of experience in ultrasound imaging. In cases of disagreement, the opinion of a third author (X.F.) was solicited, and the disagreement was resolved by majority opinion after discussion. Each neoplasm was evaluated for the following US features: location (dome/trigone/fundus/lateral wall/multiple positions), size (longest diameter) and echogenicity (hypoechoic/isoechoic/hyperechoic/markedly hyperechoic). The dome is the roof of the bladder, the trigone is a triangle-shaped region near the junction of the urethra and the bladder, the fundus is directed downward and backward toward the rectum and the lateral walls are the walls on the right and left sides of the trigone. On the basis of the blood signals within the lesion on color Doppler, blood flow was graded as absent, mild or high. Lesions in which color Doppler indicated one or two vessels were labeled ‘‘mildly vascular,’’ whereas lesions for which Doppler signals indicated more than two vessels were labeled ‘‘highly vascular.’’ The perfusion patterns observed on CEUS were divided into the arterial phase and venous phase. The arterial phase was defined as the time of maximal hyperechogenicity within the aorta, starting about 15–20 s after injection of the contrast agent. The venous phase was defined as the time at which the vascular tree becomes hypoechoic and starts approximately 30 s after injection. We classified the enhancement and wash-out patterns of bladder lesions. Enhancement of the lesion was compared with that of adjacent normal bladder wall. For patients with multiple tumors, only the largest tumor with US images was selected for evaluation. Pathologic analysis Specimens were classified by one uropathologist with 17 y experience in pathology who was blind to the US findings (A.G.). Briefly, cells of bladder paragangliomas were arranged in discrete nests, in the ‘‘Zellballen’’ pattern, and comprised eosinophilic or grandular cytoplasm. On immunohistochemistry, these cells reacted positive for the neuroendocrine markers, such as chromogranin, synaptophysin and CD56, and negative for epithelial markers, such as CK7, CK20 and pan-CK AE1/AE3. Conversely, lesions with marked cytologic
480
Ultrasound in Medicine and Biology
atypia and positive for epithelial markers were diagnosed as urothelial carcinoma. Statistical analysis Patients in the control group were recruited using the random sampling function. Student’s t-test was used to evaluate continuous variables, and the c2 test was used to compare quantitative variables. A two-tailed p-value , 0.05 was considered to indicate a significant statistical difference. Statistical analyses were performed using SPSS software, Version 16.0 (SPSS, Chicago, IL, USA). RESULTS Clinical features Among the patients with urinary bladder paraganglioma, there was a slight female predominance (seven women, three men). Conversely, there were more male patients in the urothelial carcinoma group (37 men, 14 women). The patients with urothelial carcinoma were significantly older than those with paraganglioma (62.9 6 12.6 y vs. 48.1 6 13.2 y, p 5 0.001). Two patients with urinary bladder paraganglioma complained of gross hematuria, and one complained of headache; gross hematuria was the most common symptom in the urothelial carcinoma group (80%, 41/51). Average blood pressure was higher in patients with paraganglioma than in those with urothelial carcinoma group (systolic: 146.7 vs. 130.7 mm Hg, p 5 0.012; diastolic: 85.5 vs. 79.2 mm Hg, p 5 0.153). Though most patients with paraganglioma had a history of hypertension, only two complained of paroxysmal hypertension during micturition. Plasma epinephrine level and 24-h urinary excretion of vanillylmandelic acid were measured for only two patients with paraganglioma. Other patients did not undergo these measurements because bladder paraganglioma was not considered pre-operatively. The average plasma level of epinephrine was 1.3 mg/L/h, and 24-h urinary excretion vanillylmandelic acid was 58.0 mmol/d. Clinical features of these patients are summarized in Table 1.
Volume 40, Number 3, 2014
Ultrasonography findings All bladder paragangliomas were solitary oval neoplasms, with 40% (4/10) arising on the dome, 20% on the trigone, 20% on the fundus and the remainder on the lateral walls. About 33.3% of patients with urothelial carcinoma had multiple lesions. Among the solitary urothelial carcinomas, the trigone of the bladder was the most common location, and the dome was the least common. Location of lesions differed statistically significantly between the bladder paraganglioma and urothelial carcinoma groups (p 5 0.014). The longest diameters in 80% of bladder paragangliomas ranged from 1.1 to 3.0 cm. More than half of the bladder paragangliomas appeared as hypoechoic, vascular lesions. Differences between the two groups in longest diameter, echogenicity
Table 1. Clinical features of the bladder paraganglioma and urothelial carcinoma groups Clinical feature
Bladder paraganglioma
Number of patients 10 (3/7) (male/female) Age (y): mean (range) 48.1 (26–69) Gross hematuria (n) 2 Mean blood pressure (mm Hg) Systolic 146.7 Diastolic 85.5
Urothelial carcinoma
p-value
51 (37/14)
0.024
62.9 (26–88) 41
0.001 0.000
130.7 79.2
0.012 0.153
Fig. 1. Ultrasonography (US) and immunochemistry results for a 46-y-old woman complaining of abdominal pain. (a) Transvaginal US revealed a paraganglioma (arrow) within the submucosa of the urinary bladder (UB), and the color Doppler study revealed blood flow within the lesion. This lesion was classified as ‘‘highly vascular,’’ as the Doppler signals indicated more than two vessels. As seen in the image, there were more flow signals peripherally than centrally, possibly indicating the vascular blood supply of the lesion. (b) The immunostain for chromogranin A was positive (3200).
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
and color Doppler pattern were not statistically significant. Forty percent of bladder paraganglioma appeared as submucosal masses (Fig. 1); the remainder appeared as polypoid masses projecting into the lumen of the bladder (Fig. 2). The US features of these cases are summarized in Table 2. One patient with bladder paraganglioma and four patients with urothelial carcinoma underwent CEUS examination. CEUS of the bladder paraganglioma revealed rapid contrast enhancement and slow wash-out compared with the adjacent normal bladder wall. There was a nonenhanced area within the lesion, which is a feature of hemorrhage or necrosis (Fig. 3). CEUS of four urothelial carcinomas revealed rapid homogeneous enhancement (Fig. 4), but the wash-out patterns varied (rapid: n 5 3, slow: n 5 1).
481
Table 2. Ultrasound features of the bladder paraganglioma and urothelial carcinoma groups
Ultrasound feature Location Dome Trigone Fundus Lateral wall Multiple Longest diameter #1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm $4.1 cm Echogenicity Hypoechoic Isoechoic Hyperechoic Markedly hyperechoic Color Doppler Highly vascular Mild vascular Absent
Bladder paraganglioma (n 5 10)
Urothelial carcinoma (n 5 51)
p-value
4 (40)* 2 (20) 2 (20) 2 (20) 0 (0)
3 (5.9) 15 (29.4) 6 (11.8) 10 (19.6) 17 (33.3)
0.011 0.711 0.607 1.000 0.049
1 (10) 3 (30) 5 (50) 0 (0) 1 (10)
6 (11.8) 13 (25.5) 16 (31.3) 10 (19.6) 6 (11.8)
1.000 0.713 0.291 0.191 1.000
6 (60) 4 (40) 0 (0) 0 (0)
21 (41.2) 9 (17.6) 10 (19.6) 11 (21.6)
0.315 0.198 0.191 0.184
4 (40) 5 (50) 1 (10)
12 (23.5) 32 (62.8) 7 (13.7)
0.431 0.495 1.000
* Number (%) of nodules.
Pre-operative ultrasonographic diagnosis of paraganglioma All neoplasms of the urinary bladder in patients who had pathologically confirmed paraganglioma were detected by US. The smallest lesion revealed by US was less than 1.0 cm (Fig. 5). In only two cases (20%), however, was a pre-operative diagnosis of paraganglioma made by US. In these two cases, US revealed oval lesions on the submucosa of the bladder. Pre-operative US misdiagnosed 30% (3/10) of the patients with urothelial carcinoma, 20% (2/10) with papilloma and 30% (3/10) as undetermined. DISCUSSION
Fig. 2. Ultrasonography (US) results for a 49-y-old woman complaining of intermittent palpitation of 3-y duration. (a) US revealed a tumor (arrow) protruding into the wall of the urinary bladder (UB), which was pathologically confirmed as a paraganglioma. (b) The bladder parganglioma was composed of round or polygonal epithelioid cells with abundant eosinophilic cytoplasm. The cells were arranged in discrete nests (‘‘Zellballen’’ pattern) separated by a prominent vascular network (3200).
Pheochromocytomas and paragangliomas secrete excess catecholamines, resulting in a series of clinical manifestations including hypertension, tachycardia and hypertensive crisis (Bravo et al. 2003). There is no consistent correlation between circulating levels of catecholamines and the presence of symptoms. In general, tumors that secrete both epinephrine and norepinephrine are usually associated with episodic or paroxysmal hypertension, whereas norepinephrine-secreting tumors are associated with sustained hypertension (Roderick 2013). About 67% to 80% of paragangliomas are functional and secrete norepinephrine (Erickson et al. 2001). Accurate early diagnosis leads to specific care and may result in cure of both the tumor and high blood pressure
482
Ultrasound in Medicine and Biology
Fig. 3. Ultrasonography results for a 69-y-old woman with no complaints of discomfort. (a) Gray-scale US revealed a lesion on the dome of the submucosa of the urinary bladder (UB). (b) Contrast-enhanced US revealed strong contrast enhancement of the bladder paraganglioma (arrow) in the arterial phase, as well as a non-enhanced area (*), which is a feature of hemorrhage or necrosis.
(Vesin et al. 2009). However, only a few cases are associated with symptoms at the time of diagnosis despite, at times, elevated catecholamine levels (Kopetschke et al. 2009; Shen et al. 2010). Indeed, our study indicated that some cases were discovered in routine checkups; the proportion of bladder paragangliomas detected as an incidental imaging finding was 40%. Their ‘‘silence’’ was presumably due to individual sensitivity to catecholamines or receptors in target tissues. Moreover, with small tumors, catecholamine secretion might increase for only brief periods during contraction of a distended urinary bladder. Our study found that some patients did not undergo laboratory measurements because bladder paraganglioma was not considered preoperatively. Therefore, negative symptoms and relevant
Volume 40, Number 3, 2014
laboratory tests could not exclude the possibility of bladder paraganglioma. Pre-operative imaging diagnosis of bladder paraganglioma is important. Because it is readily available and easily tolerated, US is the initial investigation most patients undergo (Dahm et al. 2003). It is critical that radiologists distinguish bladder paragangliomas from other bladder diseases, because different therapies required. There are few reports comparing US findings for paraganglioma and non-paraganglioma lesions of the urinary bladder. Our study is noteworthy for analyzing US findings for paraganglioma and urothelial carcinoma. In our study, paraganglioma and urothelial carcinoma arose on different sites of the bladder. The common location for paraganglioma was the dome (40%), whereas urothelial carcinomas were located at multiple sites (33%), with the difference being statistically significant. Ultrasonographically, most paragangliomas appeared as well-demarcated soft tissue masses ranging from 1.0 to 3.0 cm in diameter. In no paraganglioma was there diffuse thickening of the bladder wall, a possible feature of diffuse carcinoma or infectious inflammation of the bladder. The key imaging feature in the diagnosis of paraganglioma is a lesion arising from the submucosa, which occurred in 40% of cases and is less common in urothelial carcinoma. Differences in vascular patterns between paraganglioma and urothelial carcinoma were not statistically significant. Color Doppler revealed that 40% of bladder paragangliomas were highly vascular, and CEUS of one case revealed an abundance of blood vessels. As heterogeneous and discrete cystic areas are often seen in adrenal pheochromocytoma, our study revealed the phenomenon of a non-enhanced area within the paraganglioma. CEUS imaging of four patients with urothelial carcinoma revealed rapid contrast enhancement, which was variable in the venous phase. In three of the four patients, washout was rapid, and in one, it was slow. A recent article by Nicolau et al. (2010) confirmed these results. The variable wash-out patterns on CEUS can be explained by the different size and histologic degree of cellular differentiation, with more rapid wash-out in high-grade infiltrating bladder cancers. Unfortunately, our study indicated that bladder paragangliomas and urothelial carcinomas did not differ greatly in enhancement pattern; however, only one patient with paraganglioma underwent CEUS, a limitation of our study. Future studies should include CEUS examinations of more patients to determine the enhancement pattern of paraganglioma. Some studies have found that extra-adrenal paragangliomas are associated with higher rates of distant metastasis and local recurrence than adrenal pheochromocytomas (Amar et al. 2005). But it is almost
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
483
Fig. 4. Ultrasonography (US) results for a 68-y-old man with urothelial carcinoma. (a) Gray-scale US revealed a lesion on the trigone of the urinary bladder that projected into the lumen of the bladder. (b) Contrast-enhanced ultrasound revealed strong and homogeneous enhancement of the lesion.
impossible to differentiate benign and malignant bladder paragangliomas on the basis of US imaging. Moreover, it is difficult to do so histologically, and it has been proposed that the only proof of malignancy is the presence of metastases at sites that do not normally exhibit paraganglia (Solcia et al. 2000). In our study, pre-operative US revealed all lesions, but its ability to make the correct diagnosis was limited. There are several reasons for this. First, US characteristics were non-specific for some masses, for example, small masses or polypoid masses projecting into the lumen of the bladder. Second, the limited understanding of this disease may result in misdiagnosis.
CONCLUSIONS The present study confirms that although there is overlap in US findings for paraganglioma and urothelial carcinoma, there are some features that can be used to differentiate them. Solitary, submucosal masses arising on the dome may be the key US imaging characteristic of bladder paraganglioma. We believe that high-quality US examination, careful evaluation and an understanding of the existence and imaging features of paraganglioma can help in diagnosis. Acknowledgments—This work was supported by a grant from the National Natural Science Foundation of China (No. 81000619).
REFERENCES
Fig. 5. Ultrasonography (US) results for a 56-y-old woman complaining of discomfort. Trans-abdominal US revealed a tumor (arrow) less than 1 cm on the urinary bladder (UB) wall, which was pathologically confirmed as a paraganglioma.
Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90: 2110–2116. Baguet JP, Hammer L, Mazzuco TL, Chabre O, Mallion JM, Sturm N, Chaffanjon P. Circumstances of discovery of pheochromocytoma: A retrospective study of 41 consecutive patients. Eur J Endocrinol 2004;150:681–686. Bravo EL, Tagle R. Pheochromocytoma: State-of-the-art and future prospects. Endocr Rev 2003;24:539–553. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: A review. Eur Urol 2003;44:672–681. 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. Doran F, Varinli S, Bayazit Y, Bal N, Ozdemir S. Pheochromocytoma of the urinary bladder. APMIS 2002;110:733–736. Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA, Young WF Jr. Benign paragangliomas: Clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001;86:5210–5216.
484
Ultrasound in Medicine and Biology
Halefoglu AM, Miroglu C, Uysal V, Mahmutoglu A. Malignant paraganglioma of the urinary bladder. Eur J Radiol Extra 2006;58: 53–58. Kopetschke R, Slisko M, Kilisli A, Tuschy U, Wallaschofski H, Fassnacht M, Ventz M, Beuschlein F, Reincke M, Reisch N, Quinkler M. Frequent incidental discovery of phaeochromocytoma: Data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 2009;161:355–361. Nicolau C, Bunesch L, Sebastia C, Salvador R. Diagnosis of bladder cancer: Contrast-enhanced ultrasound. Abdom Imaging 2010;35: 494–503. Onishi T, Sakata Y, Yonemura S, Suqimura Y. Pheochromocytoma of the urinary bladder without typical symptoms. Int J Urol 2003;10: 398–400. Pastor GJM, L opez GS, Gimenez BJM, Ruız MR, Ca~namares PL, Atienzar TM, Casado ML, Virseda RJA. Paraganglioma of the bladder: Controversy regarding treatment. Urol Int 2004;73: 270–275.
Volume 40, Number 3, 2014 Roderick CB. Diagnosis of silent pheochromocytoma and paraganglioma. Endocrinol Metab 2013;8:47–57. Salanitri J, Smith P, Schlicht S. Multifocal malignant extra-adrenal paragangliomas of the organ of Zuckerkandl and urinary bladder. Australas Radiol 2001;45:229–232. Shen WT, Grogan R, Vriens M, Clark OH, Duh QY. One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. Arch Surg 2010; 145:893–897. Solcia E, Kl€oppel G, Sobin LH. Histological typing of endocrine tumours. In: World Health Organization International Histological Classification of Tumours. 2nd ed. London: Springer; 2000. Tazi MF, Ahallal Y, Tazi E, Benlemlih A, Chbani L, Amarti A, El Fassi MJ, Farih MH. Pheochromocytoma of the urinary bladder: A case report. Cases J 2009;2:8585. Vesin C, Cadi P, Thony F, Picard JC, Descotes JL, Calizzano A, Baguet JP. A rare cause of complicated hypertension: Urinary bladder paraganglioma. South Med J 2009;102:1173–1175.
http://dx.doi.org/10.1016/j.ultrasmedbio.2013.10.014
d
Original Contribution EVALUATION OF SONOGRAPHIC FEATURES FOR PATIENTS WITH URINARY BLADDER PARAGANGLIOMA: A COMPARISON WITH PATIENTS WITH UROTHELIAL CARCINOMA YANMI LI,* AITAO GUO,y JIE TANG,* QIUYANG LI,* XIANG FEI,* YAN ZHANG,* and JIANGPING GAOz y
* Department of Ultrasound, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; and z Department of Urology, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China (Received 8 March 2013; revised 13 October 2013; in final form 15 October 2013)
Abstract—The goals of the work described here were to analyze the ultrasonographic characteristics of urinary bladder paraganglioma and to evaluate the use of ultrasonography (US) in diagnosis. Ten patients with bladder paraganglioma (3 males, 7 females) and 51 patients with urothelial carcinoma (37 males, 14 females) were enrolled. Ultrasonographic characteristics as well as clinical features were analyzed. Patients with urothelial carcinoma were significantly older than those with paraganglioma (62.9 y vs. 48.1 y, p 5 0.001). The patients with paraganglioma had higher average systolic blood pressure than those with urothelial carcinoma (146.7 mm Hg vs. 130.7 mm Hg, p 5 0.012). All bladder paragangliomas were solitary, and 40% were located on the dome. There was a statistically significant difference in location of lesions between the bladder paraganglioma and urothelial carcinoma groups (p 5 0.014). The longest diameters in 80% of the bladder paragangliomas were in the range 1.1–3.0 cm; 60% were hypoechoic, and 40% were located in the submucosa of the bladder. Color Doppler revealed that 40% of the bladder paragangliomas were highly vascular. One patient with paraganglioma and four patients with urothelial carcinoma underwent contrast-enhanced ultrasound, which revealed rapid contrast enhancement and slow wash-out, with a non-enhanced area. Contrast-enhanced ultrasound of urothelial carcinomas revealed rapid homogeneous enhancement and variable wash-out patterns. Pre-operative ultrasonography detected all neoplasms of the urinary bladder in the 10 patients with pathologically confirmed paraganglioma, but made the correct diagnosis in only 2 cases (20%). Although there is overlap in US findings among different diseases, solitary, submucosal masses arising on the dome may be the key US imaging characteristic for bladder paraganglioma. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Ultrasonography, Urinary bladder paraganglioma, Contrast-enhanced ultrasound, Urothelial carcinoma.
The typical symptom of urinary bladder paraganglioma is paroxysmal hypertension during micturition. Laboratory tests include plasma and urinary levels of catecholamines and their metabolites. However, the hypertension is intermittent and varies (Baguet et al. 2004), and the laboratory tests may be normal in some cases (Doran et al. 2002). The clinical ‘‘silence’’ may delay the correct diagnosis from the onset of the abnormal blood pressure. Moreover, urinary bladder paraganglioma can be easily misdiagnosed as bladder urothelial carcinoma (Deng et al. 2010). Trans-urethral resection, cystoscopy and biopsy are common procedures in bladder neoplasms. Unfortunately, during these manipulations, patients with paraganglioma may experience lethal complications such as hypertensive crisis (Tazi et al. 2009). The suspicion of paraganglioma determines surgical
INTRODUCTION Pheochromocytoma is a tumor derived from chromaffin cells, which secrete catecholamines. At present, heterotopic or extraadrenal pheochromocytoma is called paraganglioma on the basis of its anatomic location and function. Paragangliomas of the urinary bladder arise from the chromaffin tissue of the bladder wall (Onishi et al. 2003; Salanitri et al. 2001) and constitute approximately 6% of all paragangliomas and less than 1% of all bladder tumors (Pastor et al. 2004).
Address correspondence to: Jie Tang, Department of Ultrasound, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing, People’s Republic of China 100853. E-mail: [email protected]. com 478
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
and anesthetic management, which plays a key role in the prognosis. Therefore, an imaging examination is vital to establish the correct diagnosis. Ultrasonography (US) is frequently used because of its high sensitivity for detecting neoplasms of the urinary bladder. It serves as an excellent non-invasive first-line investigative diagnostic modality to pick up silent as well as functioning paragangliomas (Halefoglu et al. 2006). However, there is little information regarding US findings in bladder paraganglioma. And the accuracy of US in the diagnosis of bladder paraganglioma remains unclear. Therefore, we compared US findings for paraganglioma of the urinary bladder with those for urothelial carcinoma of the urinary bladder. The aims of this study were to identify which US features can facilitate diagnosis and to assess the clinical role for pre-operative US in the diagnosis of bladder paraganglioma. METHODS Study population This study was approved by our local ethics committee and informed consent was obtained from all patients. We reviewed the data on surgical excisions of bladder neoplasms performed at our hospital from September 2008 to December 2012, and enrolled 10 patients (3 men, 7 women) diagnosed with urinary bladder paraganglioma; their ages ranged from 26 to 69 y. Next, we randomly selected 51 of 483 patients with urothelial carcinoma for the control group. This control group consisted of 14 women and 37 men ranging in age from 26 to 88 y. Clinical features and pre-operative plasma levels of epinephrine, as well as pre-operative 24-h urinary excretion of vanillylmandelic acid, were recorded (J.G.). Ultrasonography techniques Ultrasonographic examinations were performed by three radiologists with more than 6 y of experience in bladder imaging (X.F., Y.Z., Q.L.). The bladder was evaluated when it is moderately filled and was scanned in the transverse and sagittal planes. Different equipment was used for the US examinations. The bladder was scanned with the Logiq 9 equipped with a 4C probe (GE Healthcare, Milwaukee, WI, USA); the Voluson E8 equipped with a 4C-D probe (GE Healthcare); the Acuson Sequoia 512 equipped with a 4 V1 probe (Siemens Medical Solutions, Mountain View, CA, USA); and the Philips IU22 equipped with a C5-2 probe (Philips Medical Systems, Bothell, WA, USA). Female patients underwent trans-vaginal examination with an IC5-9-D probe (4.0–9.0 MHz) (GE Healthcare). Contrast-enhanced ultrasound (CEUS) was performed with the Voluson E8, a 2-5 MHz probe and a mechanical index of 0.10. The contrast agent used was SonoVue
479
(Bracco, Milan, Italy). A bolus of 1.2 mL contrast agent was injected and followed by a 5-mL normal saline flush using a three-way stopcock to ensure that no residual contrast agent remained in the intravenous catheter. System calipers were used for measurements. Images were sent to a picture archiving and communication system workstation. Image interpretation Ultrasonographic images of bladder lesions were assessed independently by two radiologists (Y.L., J.T.), both of whom have more than 10 y of experience in ultrasound imaging. In cases of disagreement, the opinion of a third author (X.F.) was solicited, and the disagreement was resolved by majority opinion after discussion. Each neoplasm was evaluated for the following US features: location (dome/trigone/fundus/lateral wall/multiple positions), size (longest diameter) and echogenicity (hypoechoic/isoechoic/hyperechoic/markedly hyperechoic). The dome is the roof of the bladder, the trigone is a triangle-shaped region near the junction of the urethra and the bladder, the fundus is directed downward and backward toward the rectum and the lateral walls are the walls on the right and left sides of the trigone. On the basis of the blood signals within the lesion on color Doppler, blood flow was graded as absent, mild or high. Lesions in which color Doppler indicated one or two vessels were labeled ‘‘mildly vascular,’’ whereas lesions for which Doppler signals indicated more than two vessels were labeled ‘‘highly vascular.’’ The perfusion patterns observed on CEUS were divided into the arterial phase and venous phase. The arterial phase was defined as the time of maximal hyperechogenicity within the aorta, starting about 15–20 s after injection of the contrast agent. The venous phase was defined as the time at which the vascular tree becomes hypoechoic and starts approximately 30 s after injection. We classified the enhancement and wash-out patterns of bladder lesions. Enhancement of the lesion was compared with that of adjacent normal bladder wall. For patients with multiple tumors, only the largest tumor with US images was selected for evaluation. Pathologic analysis Specimens were classified by one uropathologist with 17 y experience in pathology who was blind to the US findings (A.G.). Briefly, cells of bladder paragangliomas were arranged in discrete nests, in the ‘‘Zellballen’’ pattern, and comprised eosinophilic or grandular cytoplasm. On immunohistochemistry, these cells reacted positive for the neuroendocrine markers, such as chromogranin, synaptophysin and CD56, and negative for epithelial markers, such as CK7, CK20 and pan-CK AE1/AE3. Conversely, lesions with marked cytologic
480
Ultrasound in Medicine and Biology
atypia and positive for epithelial markers were diagnosed as urothelial carcinoma. Statistical analysis Patients in the control group were recruited using the random sampling function. Student’s t-test was used to evaluate continuous variables, and the c2 test was used to compare quantitative variables. A two-tailed p-value , 0.05 was considered to indicate a significant statistical difference. Statistical analyses were performed using SPSS software, Version 16.0 (SPSS, Chicago, IL, USA). RESULTS Clinical features Among the patients with urinary bladder paraganglioma, there was a slight female predominance (seven women, three men). Conversely, there were more male patients in the urothelial carcinoma group (37 men, 14 women). The patients with urothelial carcinoma were significantly older than those with paraganglioma (62.9 6 12.6 y vs. 48.1 6 13.2 y, p 5 0.001). Two patients with urinary bladder paraganglioma complained of gross hematuria, and one complained of headache; gross hematuria was the most common symptom in the urothelial carcinoma group (80%, 41/51). Average blood pressure was higher in patients with paraganglioma than in those with urothelial carcinoma group (systolic: 146.7 vs. 130.7 mm Hg, p 5 0.012; diastolic: 85.5 vs. 79.2 mm Hg, p 5 0.153). Though most patients with paraganglioma had a history of hypertension, only two complained of paroxysmal hypertension during micturition. Plasma epinephrine level and 24-h urinary excretion of vanillylmandelic acid were measured for only two patients with paraganglioma. Other patients did not undergo these measurements because bladder paraganglioma was not considered pre-operatively. The average plasma level of epinephrine was 1.3 mg/L/h, and 24-h urinary excretion vanillylmandelic acid was 58.0 mmol/d. Clinical features of these patients are summarized in Table 1.
Volume 40, Number 3, 2014
Ultrasonography findings All bladder paragangliomas were solitary oval neoplasms, with 40% (4/10) arising on the dome, 20% on the trigone, 20% on the fundus and the remainder on the lateral walls. About 33.3% of patients with urothelial carcinoma had multiple lesions. Among the solitary urothelial carcinomas, the trigone of the bladder was the most common location, and the dome was the least common. Location of lesions differed statistically significantly between the bladder paraganglioma and urothelial carcinoma groups (p 5 0.014). The longest diameters in 80% of bladder paragangliomas ranged from 1.1 to 3.0 cm. More than half of the bladder paragangliomas appeared as hypoechoic, vascular lesions. Differences between the two groups in longest diameter, echogenicity
Table 1. Clinical features of the bladder paraganglioma and urothelial carcinoma groups Clinical feature
Bladder paraganglioma
Number of patients 10 (3/7) (male/female) Age (y): mean (range) 48.1 (26–69) Gross hematuria (n) 2 Mean blood pressure (mm Hg) Systolic 146.7 Diastolic 85.5
Urothelial carcinoma
p-value
51 (37/14)
0.024
62.9 (26–88) 41
0.001 0.000
130.7 79.2
0.012 0.153
Fig. 1. Ultrasonography (US) and immunochemistry results for a 46-y-old woman complaining of abdominal pain. (a) Transvaginal US revealed a paraganglioma (arrow) within the submucosa of the urinary bladder (UB), and the color Doppler study revealed blood flow within the lesion. This lesion was classified as ‘‘highly vascular,’’ as the Doppler signals indicated more than two vessels. As seen in the image, there were more flow signals peripherally than centrally, possibly indicating the vascular blood supply of the lesion. (b) The immunostain for chromogranin A was positive (3200).
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
and color Doppler pattern were not statistically significant. Forty percent of bladder paraganglioma appeared as submucosal masses (Fig. 1); the remainder appeared as polypoid masses projecting into the lumen of the bladder (Fig. 2). The US features of these cases are summarized in Table 2. One patient with bladder paraganglioma and four patients with urothelial carcinoma underwent CEUS examination. CEUS of the bladder paraganglioma revealed rapid contrast enhancement and slow wash-out compared with the adjacent normal bladder wall. There was a nonenhanced area within the lesion, which is a feature of hemorrhage or necrosis (Fig. 3). CEUS of four urothelial carcinomas revealed rapid homogeneous enhancement (Fig. 4), but the wash-out patterns varied (rapid: n 5 3, slow: n 5 1).
481
Table 2. Ultrasound features of the bladder paraganglioma and urothelial carcinoma groups
Ultrasound feature Location Dome Trigone Fundus Lateral wall Multiple Longest diameter #1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm $4.1 cm Echogenicity Hypoechoic Isoechoic Hyperechoic Markedly hyperechoic Color Doppler Highly vascular Mild vascular Absent
Bladder paraganglioma (n 5 10)
Urothelial carcinoma (n 5 51)
p-value
4 (40)* 2 (20) 2 (20) 2 (20) 0 (0)
3 (5.9) 15 (29.4) 6 (11.8) 10 (19.6) 17 (33.3)
0.011 0.711 0.607 1.000 0.049
1 (10) 3 (30) 5 (50) 0 (0) 1 (10)
6 (11.8) 13 (25.5) 16 (31.3) 10 (19.6) 6 (11.8)
1.000 0.713 0.291 0.191 1.000
6 (60) 4 (40) 0 (0) 0 (0)
21 (41.2) 9 (17.6) 10 (19.6) 11 (21.6)
0.315 0.198 0.191 0.184
4 (40) 5 (50) 1 (10)
12 (23.5) 32 (62.8) 7 (13.7)
0.431 0.495 1.000
* Number (%) of nodules.
Pre-operative ultrasonographic diagnosis of paraganglioma All neoplasms of the urinary bladder in patients who had pathologically confirmed paraganglioma were detected by US. The smallest lesion revealed by US was less than 1.0 cm (Fig. 5). In only two cases (20%), however, was a pre-operative diagnosis of paraganglioma made by US. In these two cases, US revealed oval lesions on the submucosa of the bladder. Pre-operative US misdiagnosed 30% (3/10) of the patients with urothelial carcinoma, 20% (2/10) with papilloma and 30% (3/10) as undetermined. DISCUSSION
Fig. 2. Ultrasonography (US) results for a 49-y-old woman complaining of intermittent palpitation of 3-y duration. (a) US revealed a tumor (arrow) protruding into the wall of the urinary bladder (UB), which was pathologically confirmed as a paraganglioma. (b) The bladder parganglioma was composed of round or polygonal epithelioid cells with abundant eosinophilic cytoplasm. The cells were arranged in discrete nests (‘‘Zellballen’’ pattern) separated by a prominent vascular network (3200).
Pheochromocytomas and paragangliomas secrete excess catecholamines, resulting in a series of clinical manifestations including hypertension, tachycardia and hypertensive crisis (Bravo et al. 2003). There is no consistent correlation between circulating levels of catecholamines and the presence of symptoms. In general, tumors that secrete both epinephrine and norepinephrine are usually associated with episodic or paroxysmal hypertension, whereas norepinephrine-secreting tumors are associated with sustained hypertension (Roderick 2013). About 67% to 80% of paragangliomas are functional and secrete norepinephrine (Erickson et al. 2001). Accurate early diagnosis leads to specific care and may result in cure of both the tumor and high blood pressure
482
Ultrasound in Medicine and Biology
Fig. 3. Ultrasonography results for a 69-y-old woman with no complaints of discomfort. (a) Gray-scale US revealed a lesion on the dome of the submucosa of the urinary bladder (UB). (b) Contrast-enhanced US revealed strong contrast enhancement of the bladder paraganglioma (arrow) in the arterial phase, as well as a non-enhanced area (*), which is a feature of hemorrhage or necrosis.
(Vesin et al. 2009). However, only a few cases are associated with symptoms at the time of diagnosis despite, at times, elevated catecholamine levels (Kopetschke et al. 2009; Shen et al. 2010). Indeed, our study indicated that some cases were discovered in routine checkups; the proportion of bladder paragangliomas detected as an incidental imaging finding was 40%. Their ‘‘silence’’ was presumably due to individual sensitivity to catecholamines or receptors in target tissues. Moreover, with small tumors, catecholamine secretion might increase for only brief periods during contraction of a distended urinary bladder. Our study found that some patients did not undergo laboratory measurements because bladder paraganglioma was not considered preoperatively. Therefore, negative symptoms and relevant
Volume 40, Number 3, 2014
laboratory tests could not exclude the possibility of bladder paraganglioma. Pre-operative imaging diagnosis of bladder paraganglioma is important. Because it is readily available and easily tolerated, US is the initial investigation most patients undergo (Dahm et al. 2003). It is critical that radiologists distinguish bladder paragangliomas from other bladder diseases, because different therapies required. There are few reports comparing US findings for paraganglioma and non-paraganglioma lesions of the urinary bladder. Our study is noteworthy for analyzing US findings for paraganglioma and urothelial carcinoma. In our study, paraganglioma and urothelial carcinoma arose on different sites of the bladder. The common location for paraganglioma was the dome (40%), whereas urothelial carcinomas were located at multiple sites (33%), with the difference being statistically significant. Ultrasonographically, most paragangliomas appeared as well-demarcated soft tissue masses ranging from 1.0 to 3.0 cm in diameter. In no paraganglioma was there diffuse thickening of the bladder wall, a possible feature of diffuse carcinoma or infectious inflammation of the bladder. The key imaging feature in the diagnosis of paraganglioma is a lesion arising from the submucosa, which occurred in 40% of cases and is less common in urothelial carcinoma. Differences in vascular patterns between paraganglioma and urothelial carcinoma were not statistically significant. Color Doppler revealed that 40% of bladder paragangliomas were highly vascular, and CEUS of one case revealed an abundance of blood vessels. As heterogeneous and discrete cystic areas are often seen in adrenal pheochromocytoma, our study revealed the phenomenon of a non-enhanced area within the paraganglioma. CEUS imaging of four patients with urothelial carcinoma revealed rapid contrast enhancement, which was variable in the venous phase. In three of the four patients, washout was rapid, and in one, it was slow. A recent article by Nicolau et al. (2010) confirmed these results. The variable wash-out patterns on CEUS can be explained by the different size and histologic degree of cellular differentiation, with more rapid wash-out in high-grade infiltrating bladder cancers. Unfortunately, our study indicated that bladder paragangliomas and urothelial carcinomas did not differ greatly in enhancement pattern; however, only one patient with paraganglioma underwent CEUS, a limitation of our study. Future studies should include CEUS examinations of more patients to determine the enhancement pattern of paraganglioma. Some studies have found that extra-adrenal paragangliomas are associated with higher rates of distant metastasis and local recurrence than adrenal pheochromocytomas (Amar et al. 2005). But it is almost
Sonographic features of urinary bladder paraganglioma d Y. LI et al.
483
Fig. 4. Ultrasonography (US) results for a 68-y-old man with urothelial carcinoma. (a) Gray-scale US revealed a lesion on the trigone of the urinary bladder that projected into the lumen of the bladder. (b) Contrast-enhanced ultrasound revealed strong and homogeneous enhancement of the lesion.
impossible to differentiate benign and malignant bladder paragangliomas on the basis of US imaging. Moreover, it is difficult to do so histologically, and it has been proposed that the only proof of malignancy is the presence of metastases at sites that do not normally exhibit paraganglia (Solcia et al. 2000). In our study, pre-operative US revealed all lesions, but its ability to make the correct diagnosis was limited. There are several reasons for this. First, US characteristics were non-specific for some masses, for example, small masses or polypoid masses projecting into the lumen of the bladder. Second, the limited understanding of this disease may result in misdiagnosis.
CONCLUSIONS The present study confirms that although there is overlap in US findings for paraganglioma and urothelial carcinoma, there are some features that can be used to differentiate them. Solitary, submucosal masses arising on the dome may be the key US imaging characteristic of bladder paraganglioma. We believe that high-quality US examination, careful evaluation and an understanding of the existence and imaging features of paraganglioma can help in diagnosis. Acknowledgments—This work was supported by a grant from the National Natural Science Foundation of China (No. 81000619).
REFERENCES
Fig. 5. Ultrasonography (US) results for a 56-y-old woman complaining of discomfort. Trans-abdominal US revealed a tumor (arrow) less than 1 cm on the urinary bladder (UB) wall, which was pathologically confirmed as a paraganglioma.
Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90: 2110–2116. Baguet JP, Hammer L, Mazzuco TL, Chabre O, Mallion JM, Sturm N, Chaffanjon P. Circumstances of discovery of pheochromocytoma: A retrospective study of 41 consecutive patients. Eur J Endocrinol 2004;150:681–686. Bravo EL, Tagle R. Pheochromocytoma: State-of-the-art and future prospects. Endocr Rev 2003;24:539–553. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: A review. Eur Urol 2003;44:672–681. 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. Doran F, Varinli S, Bayazit Y, Bal N, Ozdemir S. Pheochromocytoma of the urinary bladder. APMIS 2002;110:733–736. Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA, Young WF Jr. Benign paragangliomas: Clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001;86:5210–5216.
484
Ultrasound in Medicine and Biology
Halefoglu AM, Miroglu C, Uysal V, Mahmutoglu A. Malignant paraganglioma of the urinary bladder. Eur J Radiol Extra 2006;58: 53–58. Kopetschke R, Slisko M, Kilisli A, Tuschy U, Wallaschofski H, Fassnacht M, Ventz M, Beuschlein F, Reincke M, Reisch N, Quinkler M. Frequent incidental discovery of phaeochromocytoma: Data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 2009;161:355–361. Nicolau C, Bunesch L, Sebastia C, Salvador R. Diagnosis of bladder cancer: Contrast-enhanced ultrasound. Abdom Imaging 2010;35: 494–503. Onishi T, Sakata Y, Yonemura S, Suqimura Y. Pheochromocytoma of the urinary bladder without typical symptoms. Int J Urol 2003;10: 398–400. Pastor GJM, L opez GS, Gimenez BJM, Ruız MR, Ca~namares PL, Atienzar TM, Casado ML, Virseda RJA. Paraganglioma of the bladder: Controversy regarding treatment. Urol Int 2004;73: 270–275.
Volume 40, Number 3, 2014 Roderick CB. Diagnosis of silent pheochromocytoma and paraganglioma. Endocrinol Metab 2013;8:47–57. Salanitri J, Smith P, Schlicht S. Multifocal malignant extra-adrenal paragangliomas of the organ of Zuckerkandl and urinary bladder. Australas Radiol 2001;45:229–232. Shen WT, Grogan R, Vriens M, Clark OH, Duh QY. One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. Arch Surg 2010; 145:893–897. Solcia E, Kl€oppel G, Sobin LH. Histological typing of endocrine tumours. In: World Health Organization International Histological Classification of Tumours. 2nd ed. London: Springer; 2000. Tazi MF, Ahallal Y, Tazi E, Benlemlih A, Chbani L, Amarti A, El Fassi MJ, Farih MH. Pheochromocytoma of the urinary bladder: A case report. Cases J 2009;2:8585. Vesin C, Cadi P, Thony F, Picard JC, Descotes JL, Calizzano A, Baguet JP. A rare cause of complicated hypertension: Urinary bladder paraganglioma. South Med J 2009;102:1173–1175.