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Malignant paraganglioma of the bladder: A case report and review of the literature
Pathology – Research and Practice 211 (2015) 183–188
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching case
Malignant paraganglioma of the bladder: A case report and review of the literature Erin E. Quist a , Barry M. Javadzadeh c , Eric Johannesen b , Sonny L. Johansson a , Subodh M. Lele a , Jessica A. Kozel a,∗ a
University of Nebraska Medical Center, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA University of Missouri, Department of Pathology and Anatomical Sciences, M263 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA c CHI Health, Midwest Pathology Specialists, 6901N, 72nd Street, Omaha, NE 68122, USA b
a r t i c l e
i n f o
Article history: Received 15 July 2014 Received in revised form 5 October 2014 Accepted 23 October 2014 Keywords: Malignant paraganglioma Paraganglioma Paraganglioma of urinary bladder
a b s t r a c t Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare, with a mere 37 previously reported cases. We report the case of a 58-year-old man with a malignant paraganglioma of the bladder who sought care secondary to gross hematuria; however, misdiagnosis of this tumor resulted in hypertensive crisis during cystoprostatectomy. Not only does this case present a unique malignant paraganglioma of the bladder, but also it discusses the clinical ramifications when misdiagnosed. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. Additionally, we discuss the unique clinical and pathologic findings of our patient and comprehensively review the previously published cases comparing clinical and pathologic features. Several interesting findings are identified including average age at diagnosis, gender predilection, presenting symptoms, size at diagnosis, and common sites of metastasis. © 2014 Elsevier GmbH. All rights reserved.
Introduction
Materials and methods
Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare with a mere 37 previously reported cases. Similar to paragangliomas and pheochromocytomas of other sites, the definitive criterion for malignancy is metastatic disease [1]. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation and catecholamine release; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. This case report and review of the literature is presented to increase awareness of this unique malignancy as well as some common features that may facilitate early identification and thus alleviate the complications associated with misdiagnosis.
Herein, we describe a case report of a malignant paraganglioma of the urinary bladder which was originally misdiagnosed at an outside institution and referred to our institution after complications arose during surgery secondary to catecholamine release. In order to investigate our case, as well as all other reported cases of malignant paraganglioma of the urinary bladder, we used a PubMed search of the English literature using the keywords “paraganglioma”, “bladder”, “pheochromocytoma”, “metastasis”, and “malignant” to identify other reported cases. After review of the literature, we cross-referenced articles and their listed references to include all previously published cases. Finally, we compiled information regarding key characteristics of these tumors including age at diagnosis, gender, presenting symptoms, location and size of the tumor, site of metastasis, as well as follow-up and circumstances surrounding death, to investigate common features.
∗ Corresponding author. Tel.: +1 402 559 4593; fax: +1 402 559 6018. E-mail addresses: [email protected] (E.E. Quist), [email protected] (B.M. Javadzadeh), [email protected] (E. Johannesen), [email protected] (S.L. Johansson), [email protected] (J.A. Kozel). http://dx.doi.org/10.1016/j.prp.2014.10.009 0344-0338/© 2014 Elsevier GmbH. All rights reserved.
Results A 58-year-old male presented with gross hematuria and no other symptomatology. The patient underwent diagnostic
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E.E. Quist et al. / Pathology – Research and Practice 211 (2015) 183–188
Fig. 1. H&E stain showing plump tumor cells with eosinophilic to amphophilic cytoplasm with the characteristic zellballen appearance (400× magnification).
Fig. 2. H&E stain demonstrating tumor invasion through the muscularis propria and into the perivesicular adipose tissue (100× magnification).
cystoscopy with biopsy. A diagnosis of a high grade urothelial cell carcinoma with invasion was rendered based upon H&E stained slides prepared from the biopsy. The patient then underwent radical cystoprostatectomy. The intraoperative course was complicated by a hypertensive crisis with systolic blood pressures rising to 300 mmHg. Gross examination revealed a solid 8 cm tumor involving the anterior, left and right lateral bladder walls. Microscopically, the tumor was composed of nests of cells with moderately pleomorphic nuclei and moderate to large amounts of eosinophilic to amphophilic cytoplasm (Fig. 1). Nests were surrounded by a thin, fibrovascular connective tissue in a classic “zellballen” configuration. The tumor invaded through the muscularis propria and into the perivesicular adipose tissue (Fig. 2). No angiolymphatic or perineural invasion was observed within the tumor or peritumoral soft tissue. Additionally, no mitotic activity was noted (0/30 HPFs). Sections from perivesicular and right iliac lymph nodes displayed lymphoid tissue with nests of metastatic tumor (Fig. 3). For further characterization, immunohistochemical stains were performed. The tumor was positive for chromogranin, synaptophysin and CD56, while negative for keratins. S-100 highlighted the surrounding sustentacular cells (Fig. 4), and Ki-67 stain revealed a proliferative index of less than 1% (Fig. 5). The morphology and
Fig. 3. Regional lymph node showing nests of metastatic paraganglioma (100× magnification).
Fig. 4. Immunohistochemical staining for chromogranin, synaptophysin, and CD56 were positive in tumor cells, while S100 (shown above) highlighted sustentactular cells (200× magnification).
Fig. 5. Immunohistochemical staining for Ki-67 showed a proliferation index of <1% (200× magnification).
Table 1 displays the 38 known cases of malignant paragangliomas and characteristic features of each including age at presentation, gender, presenting symptoms, location in the bladder, size of the tumor, site of metastasis, year reported, follow up, and circumstances surrounding the patient’s death. Age at diagnosis (years)
Sex
Presenting Symptoms
Location
Size
Site(s) of Metastasis
Year Reported
Follow-up
Circumstances of Death
Lumb et al. and Yoffa et al. [2,3]
56
Female
Posterior wall
13 cm
Lymph nodes
1958, 1967
Alive, 8 years, recurrent disease
–
Pugh et al. [4]
36
Female
Hypertension, palpitations, headache and diaphoresis with micturation Hypertension, headache
“cricket ball”
Liver, lymph nodes
1960
Dead of disease
Scott et al. and DeKlerk et al. [5,6]
14
Male
3–5 cm
Lymph nodes
1960, 1975
28
Male
3 cm
Lymph nodes
1963
Moloney et al. [8]
37
Male
Right side
7 cm
Lymph node, lungs, bone
1966
Alive, 15 years, recurrent disease Alive, 13 months, no evidence of disease Dead of disease
44 h post-cystoscopy; pathology discovered at autopsy –
Glucksman et al. [7]
Outer wall, paravesical tissues Trigone, left lateral wall Dome
Higgins et al. and Higgins et al. [9,10]
14
Male
3.8 cm
Lymph nodes
1966
Shimbo et al. [11]
20
Female
Anterior wall, Dome Bladder, NOS
–
1974
Javaheri et al. [12]
44
Male
Dome
–
Bone, pelvic, para-aortic and mediastinal tissues External iliac artery
Alive, 11 years, recurrent disease Dead of disease
1975
Dead - cause unknown
Javaheri et al. [12]
24
Female
Left lateral wall
–
Lymph nodes
1975
Raju et al. [13]
18
Female
Bladder, NOS
–
Lungs
1977
Alive, 12 months, no evidence of disease Dead of disease
Meyer et al. [14]
12
Female
Anterior wall
5 cm
Lymph nodes
1979
Alive, 24 months, no evidence of disease
Das et al. and Das et al. [15,16]
36
Female
Anterior dome
4 cm
Lymph nodes
1980, 1983
Alive, 36 months, recurrent disease
–
Flanigan et al. [17]
56
Male
Dome
–
Lymph nodes
1980
Alive, 12 months, no evidence of disease
–
Jurascheck et al. [18]
58
Male
Posterior wall
3.2 cm
Bone, lungs, liver, lymph nodes
1983
Dead, likely disease related
Frennby et al. [19]
39
Female
Ovaries, lymph node
1990
Alive, 24 months, no evidence of disease
52
Male
Right anterior and superior aspect Dome
7 cm
Frydenberg et al. [20]
8 cm
Peritoneum
1991
–
–
Grignon et al. [21]
43
Female
Headache, nausea, palpitations, pallor with micturation Frequency, dysuria, hematuria Hematuria
5 months post-operative, massive pulmonary embolism –
Bladder, NOS
–
1991
Alive, 24 years, recurrent disease
–
Asbury et al. [22]
19
Male
Hematuria, diaphoresis, headache, epistaxis, palpitations with micturation
Base of bladder and prostate
4.5 cm
Perivesical and peritoneal soft tissue, lymph nodes Lymph nodes
1996
Alive, 1 year, residual disease
–
Hematuria, hypertension Hematuria, headache with micturation Weakness and headache with micturation Hematuria, headache with micturation Hypertension, hypercalcemia, hyperparathyroidism Hematuria Headache, dizziness, palpitations Headache, hematuria, suprapubic pain Headache, nausea, vomiting, diaphoresis with micturation Subarachnoid hemorrhage, hypertension Hematuria, headache and dizziness with micturation Hematuria
– 4 years post-operative, metastatic disease – 4 years post-operative, metastatic disease 1 year post-operative, cause unknown – Prior to operative intervention –
E.E. Quist et al. / Pathology – Research and Practice 211 (2015) 183–188
Author(s)
185
186
Table 1 (Continued) Author(s)
Age at diagnosis (years)
Sex
Presenting Symptoms
Location
Size
Site(s) of Metastasis
Year Reported
Follow-up
Circumstances of Death
Piedrola et al. [23]
62
Male
Right lateral wall
3.2 cm
Lymph nodes
1997
Alive, 24 months, no evidence of disease
–
Kato et al. [24]
44
Male
Hypertension, malaise, dyspnea, chest pressure, headache, palpitations, facial congestion with micturation Hematuria
Bladder, NOS
2 cm
Bone
1999
–
Kato et al. [24]
31
Male
Dysuria, hematuria
–
Lymph nodes
1999
Cheng et al. [25]
37
Female
Hypertension, pelvic mass
Left anterolateral wall Dome
Alive, 1 year, recurrent disease Dead of disease
–
Distant metastasis, unspecified
2000
Dead of disease
Cheng et al. [25]
47
Female
Bladder, NOS
–
39 47
Male Male
Bladder, NOS Right posterior wall
– 6 cm
Bone, liver, pelvic soft tissue Lymph nodes Bone, lymph nodes
2000
Cheng et al. [25] Taue et al. [26]
Alive, 1.8 years, recurrent disease – Alive, 24 months, no evidence of disease
Ansari et al. [27]
14
Male
Lymph nodes
2001
Alive, 24 months, no evidence of disease
–
31
Female
Anterior bladder wall near neck Bladder, NOS
3 cm
Naguib et al. [28]
9 cm
Bone
2002
22
Male
Bladder, NOS
–
Lymph nodes
2003
Alive, 8 years, recurrent disease –
–
Hwang et al. [29]
Yoshida et al. [30]
34
Male
Lymph nodes
2004
Alive, 65 months, recurrent disease
–
28
Male
4.5 cm
Lymph nodes
2005
–
–
Zwahlen et al. [32]
28
Male
Hematuria
Left posterolateral wall Dome, anterior wall Dome
–
Kovacs et al. [31]
Hypertension, headache Unknown Hypertension, hypertensive heart failure, right superior paraplegia Hematuria, frequency, obstruction with voiding Headache, palpitations, anxiety, hypertension Chest pain, palpitations, headache with micturation Flank pain, hypertension during cystoscopy Hematuria
30 months post-operative, metastatic disease –
7.4 cm
Lymph nodes
2007
–
Huang et al. [33]
21
Male
Bladder, NOS
7 cm
Lymph nodes
2007
Havakes et al. [34]
42
Female
Hematuria, hypertension, headache Hypertension
Alive, 9 months, stable disease Alive, 4 years, disease status unknown
Bladder, NOS
8 cm
2007
–
–
Darlong et al. [35]
61
Male
Bladder, NOS
–
Lymph nodes, peritoneum Bone
2012
–
–
Manohar et al. [36]
33
Male
–
Bone, lymph nodes
2012
–
–
Feng et al. [37]
53
Female
4.7 cm
Bone
2013
30
Male
–
Lymph node
2013
Current case
58
Male
7 cm
Lymph nodes
2014
Alive, 5 years, no evidence of disease Alive, 10 months, no evidence of disease –
–
Maeda et al. [38]
Left anterolateral wall Right anterior wall Right wall Anterior, right and left lateral walls
– –
–
–
–
E.E. Quist et al. / Pathology – Research and Practice 211 (2015) 183–188
Headache, hypertension Hypertension, headache, palpitations, hematuria Hypertension, dysuria, abdominal pain Hypertension, pain with micturation Hematuria
2000 2001
4 years post-operative, metastatic disease
E.E. Quist et al. / Pathology – Research and Practice 211 (2015) 183–188
immunoprofile was consistent with paraganglioma and the presence of lymph node metastases confirmed malignancy. The biopsy material was reviewed and immunohistochemical staining confirmed the presence of paraganglioma. Upon further review, no evidence of urothelial carcinoma was identified on either the biopsy or resection specimen. Follow up laboratory studies approximately 2 weeks post-operatively showed a mild elevation of serum norepinephrine (613 pg/ml; reference range: 80–520 pg/ml), and a normal serum epinephrine and dopamine. Urine metanephrine, normetanephrine, epinephrine, norepinephrine, and dopamine were all within the reference ranges. Further follow up was not obtained. Our review of the literature yielded 38 cases of malignant paragangliomas of the bladder with metastatic disease (Table 1). We review the given clinical and pathologic features of each case as well as the treatment undertaken in an effort to glean relevant information in order to help educate about common features of this rare malignancy. One of the first features shared between these cases of malignant paragangliomas is a predilection for male gender. In our review, 24 of 38 were male. Further comparison shows that malignant forms tend to arise at a younger age than in benign paragangliomas [39]. In our review, the average age of diagnosis was 36 years, and ranged from 12 years to 62 years, whereas according to a study reviewing 236 benign paragangliomas, the average age of diagnosis was 47 years, ±16 years [39]. Review of the presenting symptoms shows that the most common manifestation was the classic catecholamine-related symptoms including hypertension, headaches, palpitations and/or dizziness, which occurred in 27 out of 38 cases. The second most common presentation was hematuria, which was documented in 18 cases. This is likely due to ulceration of the overlying mucosa due to mass effect and can easily lead to a misdiagnosis of the more commonly occurring urothelial dysplasia or malignancy. In ten cases (including ours), hematuria without catecholamine-related symptoms was the only initial presentation. A single patient presented with hypercalcemia [11]. When reviewing the effect of size and metastatic potential, no distinct correlations could be identified. In the 38 cases of malignant paraganglioma, 23 reported a measurement of the primary tumor. Of these 23 cases, 11 cases were larger than 5 cm, with the largest recorded at approximately 13 cm. Twelve cases were 5 cm or smaller. In 15 cases, the tumor size was not given. In regards to predilection of metastasis, in 28 cases, the sites of metastasis were lymph nodes, which included perivesicular, obturator, internal and external iliac nodes, retroperitoneal, pelvic, mesenteric, hypogastric, and para-aortic. Eight cases reported metastatic disease outside the pelvis to sites including the mediastinum, lungs, mesentery, liver, bone (humerus, vertebrae, ribs, pubic ramus, and mandible), and peritoneum. A single case involved a solitary metastasis to the right proximal humerus with multiple subsequent recurrences [28].
Discussion Paragangliomas are tumors which arise from the sympathetic and parasympathetic ganglia of the peripheral autonomic nervous system. The preferred designation is pheochromocytoma when located within the adrenal medulla. Approximately 10% of paragangliomas arise outside of the adrenal, most typically in locations along the autonomic chain including the jugular bulb, the carotid body and the organ of Zuckerkandl among others. Although visceral paragangliomas are exceptional, the urinary bladder is one of the more frequent sites of occurrence [1]. Paragangliomas of this anatomic site are thought to arise from the sympathetic plexus
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innervating the urinary bladder. Per WHO criteria, paragangliomas are defined as malignant if metastatic disease is identified in anatomic sites without ganglia. However, tumors can also behave aggressively with invasion of adjacent tissues and recur without overt metastatic disease [1]. Clinical and histopathologic features and a scoring system have been proposed to aide in predicting aggressive or malignant behavior in paragangliomas; however, these criteria are controversial and not well accepted [40]. This complicates prognosis and makes predicting outcome difficult for both the clinician and the patient. Review of the literature on malignant paragangliomas of the urinary bladder, as highlighted in this paper, demonstrates shared and common features of these malignancies. In summary, malignant paragangliomas of the bladder are exceedingly rare; however, they do need to be considered in the differential diagnosis of bladder neoplasms secondary to the complications which can arise during manipulation at resection. Furthermore, after reviewing the literature and comparing the common characteristics of these bladder tumors, several attributes may be useful to alert clinicians and pathologists to their presence. In general, malignant paragangliomas of the bladder arise in younger to middle aged adults, have a predilection for males over females and commonly present with the prototypical catecholamine crisis symptoms. While size is not correlated with likelihood of metastasis, most metastatic disease involves regional lymph nodes. Acknowledgements There are no acknowledgements or disclosures. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References [1] R.A. DeLellis, R.V. Lloyd, P.U. Heitz, C. Eng (Eds.), World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs, IARC Press, Lyon, 2004. [2] B.R. Lumb, G.A. Gresham, Phaeochromocytoma of the urinary bladder, Lancet 1 (1958) 81–82. [3] D.E. Yoffa, J.F.R. Withycombe, Bladder-pheochromocytoma metastases, Lancet 2 (1967) 422. [4] R.C. Pugh, G.A. Gresham, J. Mullaney, Phaeochromocytoma of the urinary bladder, J. Pathol. Bacteriol. 79 (1960) 89–107. [5] W.W. Scott, S.L. Eversole, Pheochromocytoma of the urinary bladder, J. Urol. 83 (1960) 656–664. [6] D.P. Deklerk, W.J. Catalona, F.A. Nime, C. Freeman, Malignant pheochromocytoma of the bladder: the late development of renal cell carcinoma, J. Urol. 113 (1975) 864–868. [7] M.A. Glucksman, C.P. Persinger, Malignant non-chromaffin paraganglioma of the bladder, J. Urol. 89 (1963) 822–825. [8] G.E. Moloney, R.H. Cowdell, C.L. Lewis, Malignant phaeochromocytoma of the bladder, Br. J. Urol. 38 (1966) 461–470. [9] P.M. Higgins, G.C. Tresidder, Phaeochromocytoma of the urinary bladder, Br. Med. J. 2 (1966) 274–277. [10] P.M. Higgins, G.C. Tresidder, Malignant phaeochromocytoma of the urinary bladder, Br. J. Urol. 52 (1980) 230. [11] S. Shimbo, Y. Nakano, Proceedings: a case of malignant pheochromocytoma producing parathyroid hormone-like substance, Calcif. Tissue Res. 15 (1974) 155–156. [12] P. Javaheri, J. Raafat, Malignant phaeochromocytoma of the urinary bladderreport of two cases, Br. J. Urol. 47 (1975) 401–404. [13] B.S. Raju, S. Vaidyanathan, C.K. Bannerjee, B.C. Bapna, R.P. Sapru, M.S. Rao, Malignant pheochromocytoma of the urinary bladder associated with dystrophic tumor calcification and a bladder stone (a case report with review of literature), J. Assoc. Physicians India 25 (1977) 929–931. [14] J.J. Meyer, S.M. Sane, R.M. Drake, Malignant paraganglioma (pheochromocytoma) of the urinary bladder: report of a case and review of the literature, Pediatrics 63 (1979) 879–885. [15] S. Das, P. Lowe, Malignant pheochromocytoma of the bladder, J. Urol. 123 (1980) 282–284. [16] S. Das, N.V. Bulusu, P. Lowe, Primary vesical pheochromocytoma, Urology 21 (1983) 20–25. [17] R.C. Flanigan, R.P. Wittmann, R.G. Huhn, C.J. Davis, Malignant pheochromocytoma of urinary bladder, Urology 16 (1980) 386–388.
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Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching case
Malignant paraganglioma of the bladder: A case report and review of the literature Erin E. Quist a , Barry M. Javadzadeh c , Eric Johannesen b , Sonny L. Johansson a , Subodh M. Lele a , Jessica A. Kozel a,∗ a
University of Nebraska Medical Center, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA University of Missouri, Department of Pathology and Anatomical Sciences, M263 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA c CHI Health, Midwest Pathology Specialists, 6901N, 72nd Street, Omaha, NE 68122, USA b
a r t i c l e
i n f o
Article history: Received 15 July 2014 Received in revised form 5 October 2014 Accepted 23 October 2014 Keywords: Malignant paraganglioma Paraganglioma Paraganglioma of urinary bladder
a b s t r a c t Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare, with a mere 37 previously reported cases. We report the case of a 58-year-old man with a malignant paraganglioma of the bladder who sought care secondary to gross hematuria; however, misdiagnosis of this tumor resulted in hypertensive crisis during cystoprostatectomy. Not only does this case present a unique malignant paraganglioma of the bladder, but also it discusses the clinical ramifications when misdiagnosed. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. Additionally, we discuss the unique clinical and pathologic findings of our patient and comprehensively review the previously published cases comparing clinical and pathologic features. Several interesting findings are identified including average age at diagnosis, gender predilection, presenting symptoms, size at diagnosis, and common sites of metastasis. © 2014 Elsevier GmbH. All rights reserved.
Introduction
Materials and methods
Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare with a mere 37 previously reported cases. Similar to paragangliomas and pheochromocytomas of other sites, the definitive criterion for malignancy is metastatic disease [1]. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation and catecholamine release; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. This case report and review of the literature is presented to increase awareness of this unique malignancy as well as some common features that may facilitate early identification and thus alleviate the complications associated with misdiagnosis.
Herein, we describe a case report of a malignant paraganglioma of the urinary bladder which was originally misdiagnosed at an outside institution and referred to our institution after complications arose during surgery secondary to catecholamine release. In order to investigate our case, as well as all other reported cases of malignant paraganglioma of the urinary bladder, we used a PubMed search of the English literature using the keywords “paraganglioma”, “bladder”, “pheochromocytoma”, “metastasis”, and “malignant” to identify other reported cases. After review of the literature, we cross-referenced articles and their listed references to include all previously published cases. Finally, we compiled information regarding key characteristics of these tumors including age at diagnosis, gender, presenting symptoms, location and size of the tumor, site of metastasis, as well as follow-up and circumstances surrounding death, to investigate common features.
∗ Corresponding author. Tel.: +1 402 559 4593; fax: +1 402 559 6018. E-mail addresses: [email protected] (E.E. Quist), [email protected] (B.M. Javadzadeh), [email protected] (E. Johannesen), [email protected] (S.L. Johansson), [email protected] (J.A. Kozel). http://dx.doi.org/10.1016/j.prp.2014.10.009 0344-0338/© 2014 Elsevier GmbH. All rights reserved.
Results A 58-year-old male presented with gross hematuria and no other symptomatology. The patient underwent diagnostic
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Fig. 1. H&E stain showing plump tumor cells with eosinophilic to amphophilic cytoplasm with the characteristic zellballen appearance (400× magnification).
Fig. 2. H&E stain demonstrating tumor invasion through the muscularis propria and into the perivesicular adipose tissue (100× magnification).
cystoscopy with biopsy. A diagnosis of a high grade urothelial cell carcinoma with invasion was rendered based upon H&E stained slides prepared from the biopsy. The patient then underwent radical cystoprostatectomy. The intraoperative course was complicated by a hypertensive crisis with systolic blood pressures rising to 300 mmHg. Gross examination revealed a solid 8 cm tumor involving the anterior, left and right lateral bladder walls. Microscopically, the tumor was composed of nests of cells with moderately pleomorphic nuclei and moderate to large amounts of eosinophilic to amphophilic cytoplasm (Fig. 1). Nests were surrounded by a thin, fibrovascular connective tissue in a classic “zellballen” configuration. The tumor invaded through the muscularis propria and into the perivesicular adipose tissue (Fig. 2). No angiolymphatic or perineural invasion was observed within the tumor or peritumoral soft tissue. Additionally, no mitotic activity was noted (0/30 HPFs). Sections from perivesicular and right iliac lymph nodes displayed lymphoid tissue with nests of metastatic tumor (Fig. 3). For further characterization, immunohistochemical stains were performed. The tumor was positive for chromogranin, synaptophysin and CD56, while negative for keratins. S-100 highlighted the surrounding sustentacular cells (Fig. 4), and Ki-67 stain revealed a proliferative index of less than 1% (Fig. 5). The morphology and
Fig. 3. Regional lymph node showing nests of metastatic paraganglioma (100× magnification).
Fig. 4. Immunohistochemical staining for chromogranin, synaptophysin, and CD56 were positive in tumor cells, while S100 (shown above) highlighted sustentactular cells (200× magnification).
Fig. 5. Immunohistochemical staining for Ki-67 showed a proliferation index of <1% (200× magnification).
Table 1 displays the 38 known cases of malignant paragangliomas and characteristic features of each including age at presentation, gender, presenting symptoms, location in the bladder, size of the tumor, site of metastasis, year reported, follow up, and circumstances surrounding the patient’s death. Age at diagnosis (years)
Sex
Presenting Symptoms
Location
Size
Site(s) of Metastasis
Year Reported
Follow-up
Circumstances of Death
Lumb et al. and Yoffa et al. [2,3]
56
Female
Posterior wall
13 cm
Lymph nodes
1958, 1967
Alive, 8 years, recurrent disease
–
Pugh et al. [4]
36
Female
Hypertension, palpitations, headache and diaphoresis with micturation Hypertension, headache
“cricket ball”
Liver, lymph nodes
1960
Dead of disease
Scott et al. and DeKlerk et al. [5,6]
14
Male
3–5 cm
Lymph nodes
1960, 1975
28
Male
3 cm
Lymph nodes
1963
Moloney et al. [8]
37
Male
Right side
7 cm
Lymph node, lungs, bone
1966
Alive, 15 years, recurrent disease Alive, 13 months, no evidence of disease Dead of disease
44 h post-cystoscopy; pathology discovered at autopsy –
Glucksman et al. [7]
Outer wall, paravesical tissues Trigone, left lateral wall Dome
Higgins et al. and Higgins et al. [9,10]
14
Male
3.8 cm
Lymph nodes
1966
Shimbo et al. [11]
20
Female
Anterior wall, Dome Bladder, NOS
–
1974
Javaheri et al. [12]
44
Male
Dome
–
Bone, pelvic, para-aortic and mediastinal tissues External iliac artery
Alive, 11 years, recurrent disease Dead of disease
1975
Dead - cause unknown
Javaheri et al. [12]
24
Female
Left lateral wall
–
Lymph nodes
1975
Raju et al. [13]
18
Female
Bladder, NOS
–
Lungs
1977
Alive, 12 months, no evidence of disease Dead of disease
Meyer et al. [14]
12
Female
Anterior wall
5 cm
Lymph nodes
1979
Alive, 24 months, no evidence of disease
Das et al. and Das et al. [15,16]
36
Female
Anterior dome
4 cm
Lymph nodes
1980, 1983
Alive, 36 months, recurrent disease
–
Flanigan et al. [17]
56
Male
Dome
–
Lymph nodes
1980
Alive, 12 months, no evidence of disease
–
Jurascheck et al. [18]
58
Male
Posterior wall
3.2 cm
Bone, lungs, liver, lymph nodes
1983
Dead, likely disease related
Frennby et al. [19]
39
Female
Ovaries, lymph node
1990
Alive, 24 months, no evidence of disease
52
Male
Right anterior and superior aspect Dome
7 cm
Frydenberg et al. [20]
8 cm
Peritoneum
1991
–
–
Grignon et al. [21]
43
Female
Headache, nausea, palpitations, pallor with micturation Frequency, dysuria, hematuria Hematuria
5 months post-operative, massive pulmonary embolism –
Bladder, NOS
–
1991
Alive, 24 years, recurrent disease
–
Asbury et al. [22]
19
Male
Hematuria, diaphoresis, headache, epistaxis, palpitations with micturation
Base of bladder and prostate
4.5 cm
Perivesical and peritoneal soft tissue, lymph nodes Lymph nodes
1996
Alive, 1 year, residual disease
–
Hematuria, hypertension Hematuria, headache with micturation Weakness and headache with micturation Hematuria, headache with micturation Hypertension, hypercalcemia, hyperparathyroidism Hematuria Headache, dizziness, palpitations Headache, hematuria, suprapubic pain Headache, nausea, vomiting, diaphoresis with micturation Subarachnoid hemorrhage, hypertension Hematuria, headache and dizziness with micturation Hematuria
– 4 years post-operative, metastatic disease – 4 years post-operative, metastatic disease 1 year post-operative, cause unknown – Prior to operative intervention –
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Author(s)
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Table 1 (Continued) Author(s)
Age at diagnosis (years)
Sex
Presenting Symptoms
Location
Size
Site(s) of Metastasis
Year Reported
Follow-up
Circumstances of Death
Piedrola et al. [23]
62
Male
Right lateral wall
3.2 cm
Lymph nodes
1997
Alive, 24 months, no evidence of disease
–
Kato et al. [24]
44
Male
Hypertension, malaise, dyspnea, chest pressure, headache, palpitations, facial congestion with micturation Hematuria
Bladder, NOS
2 cm
Bone
1999
–
Kato et al. [24]
31
Male
Dysuria, hematuria
–
Lymph nodes
1999
Cheng et al. [25]
37
Female
Hypertension, pelvic mass
Left anterolateral wall Dome
Alive, 1 year, recurrent disease Dead of disease
–
Distant metastasis, unspecified
2000
Dead of disease
Cheng et al. [25]
47
Female
Bladder, NOS
–
39 47
Male Male
Bladder, NOS Right posterior wall
– 6 cm
Bone, liver, pelvic soft tissue Lymph nodes Bone, lymph nodes
2000
Cheng et al. [25] Taue et al. [26]
Alive, 1.8 years, recurrent disease – Alive, 24 months, no evidence of disease
Ansari et al. [27]
14
Male
Lymph nodes
2001
Alive, 24 months, no evidence of disease
–
31
Female
Anterior bladder wall near neck Bladder, NOS
3 cm
Naguib et al. [28]
9 cm
Bone
2002
22
Male
Bladder, NOS
–
Lymph nodes
2003
Alive, 8 years, recurrent disease –
–
Hwang et al. [29]
Yoshida et al. [30]
34
Male
Lymph nodes
2004
Alive, 65 months, recurrent disease
–
28
Male
4.5 cm
Lymph nodes
2005
–
–
Zwahlen et al. [32]
28
Male
Hematuria
Left posterolateral wall Dome, anterior wall Dome
–
Kovacs et al. [31]
Hypertension, headache Unknown Hypertension, hypertensive heart failure, right superior paraplegia Hematuria, frequency, obstruction with voiding Headache, palpitations, anxiety, hypertension Chest pain, palpitations, headache with micturation Flank pain, hypertension during cystoscopy Hematuria
30 months post-operative, metastatic disease –
7.4 cm
Lymph nodes
2007
–
Huang et al. [33]
21
Male
Bladder, NOS
7 cm
Lymph nodes
2007
Havakes et al. [34]
42
Female
Hematuria, hypertension, headache Hypertension
Alive, 9 months, stable disease Alive, 4 years, disease status unknown
Bladder, NOS
8 cm
2007
–
–
Darlong et al. [35]
61
Male
Bladder, NOS
–
Lymph nodes, peritoneum Bone
2012
–
–
Manohar et al. [36]
33
Male
–
Bone, lymph nodes
2012
–
–
Feng et al. [37]
53
Female
4.7 cm
Bone
2013
30
Male
–
Lymph node
2013
Current case
58
Male
7 cm
Lymph nodes
2014
Alive, 5 years, no evidence of disease Alive, 10 months, no evidence of disease –
–
Maeda et al. [38]
Left anterolateral wall Right anterior wall Right wall Anterior, right and left lateral walls
– –
–
–
–
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Headache, hypertension Hypertension, headache, palpitations, hematuria Hypertension, dysuria, abdominal pain Hypertension, pain with micturation Hematuria
2000 2001
4 years post-operative, metastatic disease
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immunoprofile was consistent with paraganglioma and the presence of lymph node metastases confirmed malignancy. The biopsy material was reviewed and immunohistochemical staining confirmed the presence of paraganglioma. Upon further review, no evidence of urothelial carcinoma was identified on either the biopsy or resection specimen. Follow up laboratory studies approximately 2 weeks post-operatively showed a mild elevation of serum norepinephrine (613 pg/ml; reference range: 80–520 pg/ml), and a normal serum epinephrine and dopamine. Urine metanephrine, normetanephrine, epinephrine, norepinephrine, and dopamine were all within the reference ranges. Further follow up was not obtained. Our review of the literature yielded 38 cases of malignant paragangliomas of the bladder with metastatic disease (Table 1). We review the given clinical and pathologic features of each case as well as the treatment undertaken in an effort to glean relevant information in order to help educate about common features of this rare malignancy. One of the first features shared between these cases of malignant paragangliomas is a predilection for male gender. In our review, 24 of 38 were male. Further comparison shows that malignant forms tend to arise at a younger age than in benign paragangliomas [39]. In our review, the average age of diagnosis was 36 years, and ranged from 12 years to 62 years, whereas according to a study reviewing 236 benign paragangliomas, the average age of diagnosis was 47 years, ±16 years [39]. Review of the presenting symptoms shows that the most common manifestation was the classic catecholamine-related symptoms including hypertension, headaches, palpitations and/or dizziness, which occurred in 27 out of 38 cases. The second most common presentation was hematuria, which was documented in 18 cases. This is likely due to ulceration of the overlying mucosa due to mass effect and can easily lead to a misdiagnosis of the more commonly occurring urothelial dysplasia or malignancy. In ten cases (including ours), hematuria without catecholamine-related symptoms was the only initial presentation. A single patient presented with hypercalcemia [11]. When reviewing the effect of size and metastatic potential, no distinct correlations could be identified. In the 38 cases of malignant paraganglioma, 23 reported a measurement of the primary tumor. Of these 23 cases, 11 cases were larger than 5 cm, with the largest recorded at approximately 13 cm. Twelve cases were 5 cm or smaller. In 15 cases, the tumor size was not given. In regards to predilection of metastasis, in 28 cases, the sites of metastasis were lymph nodes, which included perivesicular, obturator, internal and external iliac nodes, retroperitoneal, pelvic, mesenteric, hypogastric, and para-aortic. Eight cases reported metastatic disease outside the pelvis to sites including the mediastinum, lungs, mesentery, liver, bone (humerus, vertebrae, ribs, pubic ramus, and mandible), and peritoneum. A single case involved a solitary metastasis to the right proximal humerus with multiple subsequent recurrences [28].
Discussion Paragangliomas are tumors which arise from the sympathetic and parasympathetic ganglia of the peripheral autonomic nervous system. The preferred designation is pheochromocytoma when located within the adrenal medulla. Approximately 10% of paragangliomas arise outside of the adrenal, most typically in locations along the autonomic chain including the jugular bulb, the carotid body and the organ of Zuckerkandl among others. Although visceral paragangliomas are exceptional, the urinary bladder is one of the more frequent sites of occurrence [1]. Paragangliomas of this anatomic site are thought to arise from the sympathetic plexus
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innervating the urinary bladder. Per WHO criteria, paragangliomas are defined as malignant if metastatic disease is identified in anatomic sites without ganglia. However, tumors can also behave aggressively with invasion of adjacent tissues and recur without overt metastatic disease [1]. Clinical and histopathologic features and a scoring system have been proposed to aide in predicting aggressive or malignant behavior in paragangliomas; however, these criteria are controversial and not well accepted [40]. This complicates prognosis and makes predicting outcome difficult for both the clinician and the patient. Review of the literature on malignant paragangliomas of the urinary bladder, as highlighted in this paper, demonstrates shared and common features of these malignancies. In summary, malignant paragangliomas of the bladder are exceedingly rare; however, they do need to be considered in the differential diagnosis of bladder neoplasms secondary to the complications which can arise during manipulation at resection. Furthermore, after reviewing the literature and comparing the common characteristics of these bladder tumors, several attributes may be useful to alert clinicians and pathologists to their presence. In general, malignant paragangliomas of the bladder arise in younger to middle aged adults, have a predilection for males over females and commonly present with the prototypical catecholamine crisis symptoms. While size is not correlated with likelihood of metastasis, most metastatic disease involves regional lymph nodes. Acknowledgements There are no acknowledgements or disclosures. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References [1] R.A. DeLellis, R.V. Lloyd, P.U. Heitz, C. Eng (Eds.), World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs, IARC Press, Lyon, 2004. [2] B.R. Lumb, G.A. Gresham, Phaeochromocytoma of the urinary bladder, Lancet 1 (1958) 81–82. [3] D.E. Yoffa, J.F.R. Withycombe, Bladder-pheochromocytoma metastases, Lancet 2 (1967) 422. [4] R.C. Pugh, G.A. Gresham, J. Mullaney, Phaeochromocytoma of the urinary bladder, J. Pathol. Bacteriol. 79 (1960) 89–107. [5] W.W. Scott, S.L. Eversole, Pheochromocytoma of the urinary bladder, J. Urol. 83 (1960) 656–664. [6] D.P. Deklerk, W.J. Catalona, F.A. Nime, C. Freeman, Malignant pheochromocytoma of the bladder: the late development of renal cell carcinoma, J. Urol. 113 (1975) 864–868. [7] M.A. Glucksman, C.P. Persinger, Malignant non-chromaffin paraganglioma of the bladder, J. Urol. 89 (1963) 822–825. [8] G.E. Moloney, R.H. Cowdell, C.L. Lewis, Malignant phaeochromocytoma of the bladder, Br. J. Urol. 38 (1966) 461–470. [9] P.M. Higgins, G.C. Tresidder, Phaeochromocytoma of the urinary bladder, Br. Med. J. 2 (1966) 274–277. [10] P.M. Higgins, G.C. Tresidder, Malignant phaeochromocytoma of the urinary bladder, Br. J. Urol. 52 (1980) 230. [11] S. Shimbo, Y. Nakano, Proceedings: a case of malignant pheochromocytoma producing parathyroid hormone-like substance, Calcif. Tissue Res. 15 (1974) 155–156. [12] P. Javaheri, J. Raafat, Malignant phaeochromocytoma of the urinary bladderreport of two cases, Br. J. Urol. 47 (1975) 401–404. [13] B.S. Raju, S. Vaidyanathan, C.K. Bannerjee, B.C. Bapna, R.P. Sapru, M.S. Rao, Malignant pheochromocytoma of the urinary bladder associated with dystrophic tumor calcification and a bladder stone (a case report with review of literature), J. Assoc. Physicians India 25 (1977) 929–931. [14] J.J. Meyer, S.M. Sane, R.M. Drake, Malignant paraganglioma (pheochromocytoma) of the urinary bladder: report of a case and review of the literature, Pediatrics 63 (1979) 879–885. [15] S. Das, P. Lowe, Malignant pheochromocytoma of the bladder, J. Urol. 123 (1980) 282–284. [16] S. Das, N.V. Bulusu, P. Lowe, Primary vesical pheochromocytoma, Urology 21 (1983) 20–25. [17] R.C. Flanigan, R.P. Wittmann, R.G. Huhn, C.J. Davis, Malignant pheochromocytoma of urinary bladder, Urology 16 (1980) 386–388.
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