Case 2 -

Paraganglioma with Diffuse Growth Pattern Andrew J. Evans, Toronto General Hospital, Toronto, ON, Canada

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Introduction: A 47 year-old man presented to his family physician with sudden-onset painless, gross hematuria. There were no other urinary symptoms. The patient's past medical history included mild essential hypertension of 5 years duration. He also had a history of cigarette smoking (1 pack per day x 25 years), although he had quit smoking roughly one year prior to presentation. He had no known occupational exposures to urinary tract carcinogens. At cystoscopy, a single 2 cm dome-shaped nodule was noted on the right lateral bladder wall. There was no ulceration or active bleeding. Urine cytology was negative for malignant cells. He underwent a transurethral resection. A post-transurethral resection MRI scan of the abdomen and pelvis showed mucosal enhancement on the right lateral wall of the bladder consistent with the effects of the recent procedure. There was no evidence of locally advanced disease, lymphadenopathy or visceral metastases. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: H&E sections from the transurethral resection specimen showed a neoplasm comprising diffuse sheets of polygonal epithelioid cells with abundant basophilic granular cytoplasm. The nuclei were round and uniform with finely granular chromatin and inconspicuous nucleoli (Figure 1). There was no necrosis and mitotic figures were not identified. While there was a prominent microvasculature within the tumor, discrete nests of tumor cells were not apparent (Figure 2). The tumor was sub-mucosal in nature and had a minimally infiltrative border with the adjacent bladder tissue (Figure 3). It was, however, present within the thick muscle bundles of the muscularis propria (Figure 4). Lymphovascular invasion was not identified. The urothelium in the specimen showed no features of dysplasia or carcinoma in situ (Figure 5). Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 High magnification (400x) H&E features – polygonal cells with abundant basophilic granular cytoplasm and uniform nuclei with even, finely granular chromatin and inconspicuous nucleoli. Case 2 - Figure 2 Medium magnification (100x) H&E features – diffuse growth pattern (no nesting or zellballen) with prominent microvasculature. Case 2 - Figure 3 Low magnification (50x) H&E features – sub- mucosal location with a relatively well-defined border with the adjacent bladder stroma. Case 2 - Figure 4 Presence of tumor within muscularis propria Case 2 - Figure 5 Surface urothelium showing no dysplasia or carcinoma in situ. Case 2 - Figure 6 Negative staining of the tumor cells for pancytokeratin AE1/AE3 (right) in contrast to the expected positive staining of the surface urothelium (left). Case 2 - Figure 7 Immunhistochemical staining of the tumor for neuroendocrine markers. Case 2 - Figure 8 Negative immunohistochemical staining of the tumor cells for S100. Note that no sustentacular cells were identified. Case 2 - Figure 9 Immunohistochemical staining with SDHB – speckled, granular cytoplasmic staining in liver (positive control); negative staining of tumor cells in a pheochromocytoma from a patient with a known SDHB mutation; positive staining of the bladder pararganglioma in the present case. Differential Diagnoses: While the differential diagnosis for this tumor included invasive urothelial carcinoma with involvement of muscularis propria (pT2), the tinctorial appearance of the tumor cells along with the granular nature of the cytoplasm strongly suggested the possibility of a neuroendocrine tumor such as low grade-neuroendocrine carcinoma/carcinoid and paraganglioma. An additional possibility was granular cell tumor, which can also occur in the bladder. With this differential in mind, the following immunohistochemical stains were ordered: pancytokeratin (AE1/AE3), low molecular weight cytokeratin (Cam 5.2), cytokeratin 7, cytokeratin 20, high molecular weight keratin (34βE12), vimentin, S100, neuron-specific enolase, chromogranin A, synaptophysin and tyrosine hydroxylase. The tumor cells were completely negative for all epithelial markers (Figure 6). As a positive on-slide control, the overlying urothelium showed the predicted positive immunoreactivity with pancytokeratin (AE1/AE3), low molecular weight cytokeratin (Cam 5.2) and cytokeratin 7. S100 staining was also completely negative (Figure 7). In particular, no sustentacular cells were identified. The tumor cells were diffusely positive for the neuroendocrine markers neuron-specific enolase, chromogranin A, synaptophysin and tyrosine hydrolase (Figure 8). Final Diagnosis: Paraganglioma with diffuse growth pattern. The H&E morphology and complete absence of keratin staining with strong immunoreactivity for the neuroendocrine markers, tyrosine hydroxylase in particular, lead to a diagnosis of bladder paraganglioma. This tumor showed a diffuse growth pattern without the classical "zellballen". Additional Clinical Information: The transurethral resection specimen was originally reported at another institution as an invasive urothelial carcinoma with invasion of muscularis propria (pT2). Radical cystoprostatectomy with a pelvic lymph node dissection was recommended. The patient sought a referral to University Health Network (UHN) for a second opinion on this treatment plan. A pathology review was requested by the UHN uro-oncologist, primarily to confirm the pathologic stage so the patient could be re-assured that cystoprostatectomy would be appropriate. When the revised diagnosis of paraganglioma was issued, the patient underwent a repeat cystoscopy at UHN which showed no gross evidence of residual disease. He then underwent a partial cystectomy which contained no residual tumor. Clinical, biochemical and radiologic follow-up over the last 8 years has been negative for recurrence or progression of paraganglioma. The patient's mild hypertension persisted following surgery and was therefore not felt to be related to the bladder tumor. Case Discussion: Paraganglioma of the urinary bladder is a rare neoplasm, accounting for 0.5% of bladder tumors. There is a female predominance (M:F ratio of 1:3) with a mean age of presentation of 45 years [1]. The clinical presentation includes hematuria, hypertension and so-called micturition attacks related to catecholamine production by some, but not all of these tumors [2]. Micturition attacks occur in roughly 50% of patients and are characterized by episodic hypertension, syncope, headaches, anxiety, palpitations and/or sweating at the time of urination. The histogenesis is uncertain, but is thought to be related to the presence of embryonic rests of neural crest-derived chromaffin cells in the sympathetic plexus of the detrusor muscle. Autopsy studies have shown paraganglia to be present in over 50% of bladders, with over 60% them being found in the detrusor muscle [3]. Cystoscopically, these tumors typically appear as smooth-domed nodules with normal overlying urothelium. On imaging, they may or may not be distinguishable from other bladder neoplasms [4]. Methyliodobenzylguanidine (MIBG) scintigraphy can be useful to visualize the extent of the tumor for surgical planning [5]. Complete surgical resection of tumors confined to the bladder wall is usually curative [6], however up to 20% will show malignant behavior [7]. Paraganglioma is defined as being malignant only after it has spread to body sites where paraganglion tissue is not normally found. Predicting malignant behavior for these tumors is problematic. In the largest series published to date, Cheng et al reviewed 16 cases of bladder paraganglioma and identified no reliable criteria to distinguish benign from malignant paraganglioma, including nuclear pleomorphism, mitotic figure, necrosis, DNA ploidy, p53 alterations and MIB-1 labeling index. They did, however, find an association between the presence of tumor beyond the muscularis propria (pT3) and an increased risk of metastasis and disease [7]. While these tumors can occur sporadically, it is important to be aware of their association with inherited tumor syndromes such multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, neurofibromatosis type 1 (NF1) and paraganglioma/pheochromocytoma syndrome (HPGL/PCC) [8]. In particular, the HPGL/PCC syndrome is an autosomal dominant disorder with variable penetrance. It is associated with young age at presentation (mean age 30 years) and frequent malignant behavior [8]. Germline mutations in the succinate dehydrogenase B (SDHB) catalytic subunit of the SDH complex, at the interface of the Kreb's cycle and the electron transport chain, have been found with high frequency in HPGL/PCC patients [8]. Immunohistochemical staining for SDHB has been shown to be a highly reliable method of screening these tumors to identify patients with germline mutations in SDH who would be at risk for malignant paraganglioma. Negative SDHB staining of the tumor cells is highly sensitive (100%) and specific (84%) for the presence of germline mutations in SDHB (as well as SDHC and SDHD) [9]. Positive SDHB immunoreactivity, defined as strong speckled cytoplasmic staining (Figure 9), will be found in the vast majority of sporadic tumors. At UHN, we currently screen sections from newly diagnosed extra-adrenal paraganglioma and pheochromytoma tumors with SDHB immunohistochemistry. Patients with tumors showing negative staining are referred for genetic testing to confirm the presence of SDHB, SDHC or SDHD mutations. This process also identifies patients whose family members require similar screening. SDHB immunohistochemistry was not available when the present case was diagnosed in 2004. Retrospective SDHB staining in this tumor was positive (Figure 9), correlating with the benign behavior observed over the last 8 years. The main take-home point from this case is the potential to misdiagnose bladder paraganglioma as invasive urothelial carcinoma in transurethral resection specimens. As pointed out by Zhou et al [11], this can happen for several reasons including: the frequent presence of paraganglioma in the muscularis propria, the frequent lack of symptoms such as micturition attacks, distortion of tissue by electrocautery during the resection process and the failure of pathologists to include it in their differential diagnosis. These authors reviewed a series of 11 consult cases of bladder paraganglioma, 3 of which were originally called urothelial carcinoma and 4 of which were called "bladder tumor". Diagnostic confusion was most commonly associated with a diffuse growth pattern, as shown by the tumor in our case. As illustrated by Zhou et al, recognition of granular cytoplasm and uniform nuclei with even chromatin should prompt a pathologist to consider the possibility of paraganglioma and order the appropriate immunohistochemical stains to arrive at the correct diagnosis. This case also illustrates the importance of making the correct diagnosis in terms of management and potential morbidity for this patient. He ultimately received bladder conserving surgery for paraganglioma as opposed to radical cystoprostatectomy with extensive lymph node dissection that was originally planned based on a diagnosis of pT2 urothelial carcinoma. Conclusion(s): 1) Paraganglioma of the urinary bladder is a rare and can potentially be misdiagnosed as invasive urothelial carcinoma. This has significant implications for patient treatment and morbidity. 2) Careful attention to the cytoplasmic and nuclear features of this tumor will prompt pathologists to order the appropriate panel of immunohistochemical stains. Negative staining with cytokeratins and positive staining with neuroendocrine markers (especially tyrosine hydroxylase) will allow the correct diagnosis to be made. 3) Predicting malignant behavior in paraganglioma cannot be done based on standard morphology. 4) Urinary bladder paraganglioma can be associated with a variety of tumor syndromes. HPGL/PCC syndrome, in particular, is strongly associated with malignant behavior. Immunohistochemical staining of tumor tissue with SDHB is a reliable method for identifying extra- adrenal paraganglioma/pheochromytoma patients who should have genetic testing for germline SDHB, SDHC or SDHD mutations. References: Grignon DJ. Neoplasms of the urinary bladder. In: Bostwick DG, Eble JN, editors Urologic surgical pathology. St. Louis: Mosby-Year Book Inc., 1997:214-305. Leestma JE Price EB Jr. Paraganglioma of the urinary bladder. Cancer 1971;28:1063-73. Honma K. Paraganglia of the urinary bladder: an autopsy study. Zentralbl Pathol 1994;139:465-9. Sahdev A, et al. CT and MR imaging of unusual locations of extra-adrenal paragangliomas (pheochromocytomas). Eur Radiol 2005;15:85-92. Sakashita S, et al. Paraganglioma of urinary bladder, visualization with 131I-MIBG scintigraphy. Urol Int 1987;42:237-40. Thrasher JB, et al. Pheochromocytoma of the urinary bladder: contemporary methods of diagnosis and treatment options. Urology 1993;41:435-39. Cheng L, et al. Paraganglioma of the urinary bladder: can biologic potential be predicted. Cancer 2000;88:844-52. Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta 2011;1807:1432-1443. Van Nederveen F, et al. An immunohistochemical procedure to detect patients with paraganglioma and pheochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009;10:764-71. Zhou M, Epstein JI, Young RH. Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol 2004;28:94-100.