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Malignant Non-Urothelial Neoplasms of the Urinary Bladder: A Review
European Urology
European Urology 44 (2003) 672–681
Review
Malignant Non-Urothelial Neoplasms of the Urinary Bladder: A Review Philipp Dahma, Ju¨rgen E. Gschwendb,* a
Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA Department of Urology, Ulm University Medical Center, Prittwitz-Strasse 43, 89075 Ulm, Germany
b
First published online 27 August 2003
Abstract Objectives: Non-urothelial bladder tumors frequently present a diagnostic and therapeutic challenge. We review the peer-reviewed literature to summarize the available evidence on the etiology, diagnosis and optimal management of malignant non-urothelial bladder tumors. Methods: A comprehensive MEDLINE database search was performed. In addition, the proceedings of recent national and international urological and cancer society meetings were reviewed. Results: Primary non-urothelial bladder tumors are rare in Europe and North America representing less than 5% of all bladder lesions combined. A large number of risk factors have been implicated in the etiology of nonschistosomiasis-related squamous cell carcinoma, yet their exact pathomechanism remains poorly defined. Squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma and carcinosarcoma/sarcomatoid tumors share an unfavorable prognosis despite aggressive surgical management that relates both to an aggressive biological behaviour as well as to an often times advanced stage at the time of diagnosis. Inflammatory pseudotumors are benign tumors of uncertain histogenesis that may mimic sarcomas. Paraganglioma, primary melanoma and lymphoma represent additional, exceedingly rare bladder tumors. Conclusions: The systematic investigation of most non-urothelial bladder tumors is limited by the rarity of these lesions. A concerted effort of multiple institutions linked together in a national or international tumor registry will be necessary to advance our understanding of these tumors, evaluate treatment strategies and optimize patient outcome in the future. # 2003 Elsevier B.V. All rights reserved. Keywords: Non-urothelial; Bladder tumors
1. Introduction Non-urothelial neoplasms of the bladder are rare entities in Europe and North America. They are vastly outnumbered by urothelial tumors and account for less than 5% of all vesical tumors combined. In fact, most types of non-urothelial bladder tumors may not be encountered within a lifetime of practicing urology. Despite the low incidence of non-urothelial neoplasms, urologists should be familiar with these tumors and *
Corresponding author. Tel. þ49-731-500-27808; Fax: þ49-731-500-33166. E-mail address: [email protected] (J.E. Gschwend).
consider them in the differential diagnosis of all bladder masses, in particular those of unusual clinical presentation. The following attempts to provide a comprehensive review of the peer-reviewed literature on primary, malignant, non-urothelial bladder tumors according to the histological classification by the World Health Organization (WHO) (Table 1) [1]. It summarizes the available evidence on the etiology, diagnosis and therapeutic management of these rare malignant masses that, with exception of schistosomiasis-related squamous cell carcinoma, is mainly derived from small retrospective case series and case reports. While pseudo-inflammatory tumors are histologically benign, they may closely mimic sarcomatous neoplasms and should therefore be considered in the differential diagnosis.
0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0302-2838(03)00416-0
P. Dahm, J.E. Gschwend / European Urology 44 (2003) 672–681 Table 1 World Health Organization (WHO) histological classification of bladder tumors I. Epithelial Tumors A. Transitional cell papilloma B. Transitional cell papilloma, inverted type C. Squamous cell papilloma D. Transitional cell carcinoma E. Variants of transitional cell carcinoma 1. With squamous metaplasia 2. With glandular metaplasia 3. With squamous and glandular metaplasia F. Squamous cell carcinoma G. Adenocarcinoma H. Undifferentiated carcinoma II. Nonepithelial Tumors A. Benign B. Malignant 1. Rhabdomyosarcoma 2. Others III. Miscellaneous Tumors A. Pheochromocytoma/Paraganglioma B. Lymphoma C. Carcinosarcoma D. Malignant melanoma E. Others IV. Metastatic Tumors and Secondary Extensions V. Unclassified Tumors VI. Epithelial Abnormalities A. Papillary (polypoid) ‘‘cystitis’’ B. Von Brunn’s nests C. ‘‘Cystitis’’ cystica D. Glandular metaplasia E. ‘‘Nephrogenic’’ adenoma F. Squamous metaplasia VII. Tumorlike Lesions A. Follicular cystitis B. Malakoplakia C. Amyloidosis D. Fibrous (fibroepithelial) polyp E. Endometriosis F. Hamartoma G. Cysts
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2. Squamous cell carcinoma Second to urothelial carcinoma, squamous cell carcinoma (SCC) is the most prevalent epithelial neoplasm of the bladder, accounting for an approximate 3– 5% of bladder tumors in Western countries [2]. Microscopically the tumor may be well differentiated, consisting of well defined islands of squamous cells with keratinization, prominent intercellular bridges, and minimal nuclear pleomorphism, or poorly differentiated, with marked nuclear pleomorphism and only focal squamous differentiation (Table 2) [3]. A diagnosis of SCC is restricted to pure tumors only without identifiable urothelial carcinoma. While the histogenesis of SCC of the bladder has only been partially elucidated, it is thought to involve factors that result in chronic bladder infection and irritation. In contrast, SCC of the bladder in countries of the Middle East and Egypt has a distinct pathogenesis that is linked to chronic infections with schistosoma haematobium. In regions where this waterborne parasitic pathogen is endemic, SCC not only represents the most common histological type of bladder tumor, but also the most prevalent form of cancer in men overall, accounting for 30% of cancers. There it is also the second most common type of malignant neoplasm in women after breast cancer [4]. Due to characteristic differences in the etiology and epidemiology of schistosoma-unrelated and -related SCC, they will be reviewed separately.
3. Non-schistosoma-related SCC Pure SCC of the bladder is a rare finding in Western countries and is to be distinguished from urothelial bladder cancer with partial squamous differentiation, a
Table 2 Summary of characteristic features of malignant, primary non-urothelial bladder tumors in Western countries Histological type
Percentage of bladder tumors
Squamous cell carcinoma
3–5
Adenocarcinoma
0.5–2.0
Small cell carcinoma Sarcoma Carcinosarcoma/ sarcomatoid tumors Paraganglioma
<0.5 <0.1 <0.1
Melanoma Lymphoma
<0.1 <0.1
<0.1
Histological features Epithelial neoplasm that exclusively displays squamous features such as squamous pearls, intercellular bridges, and keratohyaline granules Epithelial neoplasm characterized by neoplastic glandular structures lined by mucin-secreting cells similar to colonic carcinoma Undifferentiated tumor of neuroendocrine derivation that resembles oat cell carcinoma of the lung. Malignant connective tissue tumor composed of bundles of malignant spindle cells Biphasic tumor with malignant epithelial (carcinoma) and soft tissue elements (sarcoma) Extraadrenal tumor of neural crest derivation that classically demonstrates groups of fairly uniform, polygonal cells (‘‘Zellballen’’) Malignant neoplasm composed of malignant cells arranged in nests with variable amount of pigment Hematological malignancy demonstrating dense lymphoid aggregates that may involve all layers of the bladder
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Table 3 Risk factors of non-schistosoma associated squamous cell carcinoma Risk factor
Reference
Black race Bladder diverticulum Chronic urinary tract infection Chronic indwelling catheter Cyclophosphamide-treatment Intravesical Bacillus Calmette-Guerin (BCG) Male gender Smoking Vesical calculi/foreign bodies
Porter et al. (2002) [55] Montaque et al. (1976) [56] Kantor et al. (1988) [57] Stonehill et al. (1997) [12] Wall et al. (1975) [58] Brenner et al. (1989) [59] Lynch and Cohen (1995) [60] Kantor et al. (1988) [57] Stonehill et al. (1997) [12]
relatively common finding in radical cystectomy specimens. In a large recent cystectomy series from the Memorial Sloan Kettering Cancer Center (MSKCC), only 2.8% of patients demonstrated pure SCC [5]. While a number of etiological factors have been implicated in the pathogenesis of SCC (Table 3), the most relevant common factor appears to be some form of chronic bladder irritation. In the United States, spinal cord injured (SCI) patients that rely on catherization for bladder drainage have the highest prevalence of SCC [6]. Meanwhile, it remains uncertain how high this risk for developing SCC is: Earlier studies reported incidence rates in the range of 2–10% [6–9], while more recent studies suggest a much lower risk. In a retrospective study of over 30,000 veterans with SCI the 5-year risk for developing bladder cancer was only 0.4% [10]. Of note, only one-third of these tumors were SCC, while 55% were urothelial bladder cancers. A recent survey of European centers caring for SCI patients found an even lower incidence of lower urinary tract cancer of 0.11% [11]. These authors suggested that the lower incidence rates in contemporary studies might be a reflection of the trend away from chronic indwelling catheters to clean intermittent catherization. In light of an estimated 15,000 patients that develop SCI annually in the US [10] the relative risk of SCI patents for developing SCC is an important aspect in the controversy as to whether to screen those patients for bladder cancer [9,12]. Proponents of screening programs for SCI patients emphasize that asymptomatic patients diagnosed with SCC by cystoscopy, cytology, or a combination of both may be diagnosed at an earlier disease stage and have a more favorable prognosis. Well-designed prospective studies addressing the clinical and economical aspects of screening remain pending and general recommendations for the screening of SCI patients have not been broadly endorsed. Meanwhile, urologists should be aware of the association of SCI and SCC and have a low threshold for additional diagnostic measures in patients of
this population presenting with symptoms such as hematuria or chronic bladder infections. Patients with non-schistosomiasis-related SCC of the bladder have an unfavorable prognosis, in large due to locally advanced disease at the time of presentation [9]. A study of 25 patients treated with bilateral pelvic node dissection and radical cystectomy reported by Richie et al. [13] found a 5-year survival rate of 48% and identified tumor stage as the most important predictor of outcome. In a large contemporary series, Serrata et al. reviewed 19 cases of pure SCC of the bladder over an 8-year period [2]. The majority of patients were men and the mean age of presentation in the late sixties not different from that of urothelial tumors. All cases presented as solitary, yet locally advanced tumors and were treated by radical cystectomy. Extravesical extension beyond the bladder wall was identified in 74% of patients, upper tract involvement in 26% and involvement of the prostatic urethra in 35% of men. During a mean follow-up period of 52 months, 63% of patients died of locally recurrent bladder cancer, with distant metastases present only in one patient. Based on these results, the authors emphasized that early diagnosis and local control were paramount in patients with SCC of the bladder. Preoperative radiation has been proposed to improve local control, but remains of uncertain benefit [14]. Standard chemotherapy regimens appear to have limited impact on the disease due to the relative chemo-resistance of SCC. The transfer of novel chemotherapy regimens, such as the combination of paclitaxel, carboplatin and gemcitabine that have demonstrated efficacy in patients with SCC of other locations such as the head and neck may offer promise for the future [15].
4. Schistosoma-related SCC In areas where schistosoma is endemic, bladder cancer is a common disease, and SCC constitutes the most common histological type [16]. Compared to urothelial bladder cancer, the age of presentation is lower, affecting mainly men in their fifth decade of life. Schistosoma-related SCC may be regarded a potentially preventable disease, affecting mainly patients who are repeatedly exposed and re-infected by the schistosoma parasite, that completes it life cycle by depositing its eggs into the bladder wall. The ova constitute a chronic source of inflammation and irritation. Together with less well-defined environmental carcinogens such as nitrosamines, they appear to increase the rate of malignant transformation towards SCC of the bladder, as well as urothelial carcinoma and
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adenocarcinoma [4]. While the association of schistosomiasis and bladder cancer of a predominantly squamous type is well established, the exact pathogenic pathway remains unclear and comparative analyses of chromosomal aberrations in bilharzial and non-bilharzial bladder cancer have been inconclusive [17,18]. In a series of 1026 cystectomy patients from a geographic region of endemic schistosomiasis, Ghoneim et al. [16], reported that 59% of bladder tumors were SCC, 22% urothelial carcinoma and 11% adenocarcinoma. Bilharzia ova were identifiable in 88% of SCC and 78% of urothelial carcinoma specimens. The stage distributions of SCC and TCC within this series were not significantly different with 13.5% and 14.9% of cancers, respectively, demonstrating extravesical extension. The overall 5-year survival rate of SCC patients was 50.3%. While a number of variables were of prognostic significance when applying univariate analysis, a multivariate analysis identified only T- and N-stage as independent predictors of survival. Standard treatment of bilharzia-related SCC is radical cystectomy and urinary diversion. A potential role for neoadjuvant or adjuvant radiation and chemotherapy remains poorly defined.
5. Adenocarcinoma Pure adenocarcinoma of the bladder represents the third most common type of epithelial tumor comprising 0.5–2.0% of all bladder tumors [19]. It occurs more frequently in geographic regions where schistosomiasis is endemic [20] and is the most common tumor arising in the bladder of exstrophy patients, who have a reported 4% life-time risk for developing this type of malignancy [21]. While there is some variability in the defining adenocarcinoma in the literature, the pathological hallmark of this tumor are neoplastic cells that form glandular structures that may more or less resemble colonic adenocarcinoma (enteric type) and/or may produce large amounts of intra- (signet cell type) or extracellular mucin (mucinous type) [22]. To establish the diagnosis of primary adenocarcinoma of the bladder, other potential primary tumors such as adenocarcinoma of the prostate or rectum should be ruled out. Urachal adenocarcinoma account for approximately one-third of primary adenocarcinomas [19] and arise from an urachal remnant. Nonurachal adenocarcinomas make up for the remainder and are associated with chronic bladder irritation and exposure to certain ill-defined carcinogens. These are believed to increase the rate of neoplastic transformation from either normal urothelium cells or pluripotent
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bladder stem cells into adenocarcinoma [23]. Meanwhile, the previously assumed association of cystitis glandularis, a form of intestinal metaplasia of the bladder most often seen in patients with pelvic lipomatosis or exstrophy has been questioned: In a series of 53 exstrophy patients with documented cystitis glandularis and a minimum follow-up of 10 years, none developed adenocarcinoma [24]. Clinically, the distinction of urachal and non-urachal adenocarcinoma may be difficult, in particular if the tumor is locally extensive. Criteria that have been proposed to distinguish urachal from non-urachal adenocarcinoma of the dome of the bladder include the presence of an urachal remnant, an intact or ulcerated urothelium without metaplastic changes, a predominant invasion of the muscularis or deeper structures of the bladder or extension to the space of Retzius, anterior abdominal wall or umbilicus [22,25]. For practical purposes all adenocarcinomas of the dome should be considered as urachal in origin until proven otherwise, and treated as such [26,27]. While standard treatment of all vesical adenocarcinomas consists in radical cystectomy and pelvic node dissection, locally invasive urachal adenocarcinoma may further mandate en bloc surgical removal of the urachal ligament, umbilicus and part of the anterior abdominal wall (Fig. 1) [25,28]. The prognosis of urachal adenocarcinoma is generally unfavorable with 5-year survival rates ranging between 11% and 55% (Table 4). Survival correlates with local extent, which may be categorized according the staging system proposed by Sheldon [25] and adapted by Nakanishi [29] (Table 5). In addition, margin status has been identified as an important predictor of outcome, emphasizing the importance of complete surgical resection [28]. Currently there is no established chemotherapy regimen for patients with metastatic urachal carcinoma: In a recent series of 9 patients with metastatic urachal adenocarcinoma treated with multimodality chemotherapy at M.D. Anderson Cancer Center the median survival was only 20 months. Although objective responses were documented in 3/9 patients to 5-FU and cisplatin based regimens, chemotherapy was not shown to improve outcome significantly [28]. Similarly, the 5-year survival rates of patients with non-urachal adenocarcinomas are poor, ranging between 27% and 61% (Table 5). Among these, the largest series of non-urachal adenocarcinomas was reported by El Mekresh et al. from a region of endemic schistosomiasis [20]. Of note, in contrast to studies of non-bilharzial adenocarcinoma [19,23], over half the tumors (52%) in this series were low grade. This
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Fig. 1. Urachal adenocarcinoma of the urinary bladder in a 30 year old female. CT scan depicting the location of the mass at the dome of the bladder (A). Intraoperative view of the bladder dome and tumor with adjacent urachal remnant (B). Haematoxylin and eosin section depicting small nests of cells appearing to float in pools of extracellular mucin (C).
Table 4 Review of reported outcomes of patients with non-urachal and urachal adenocarcinomas Author
Patients
Survival
Non-urachal adenocarcinoma Anderstro¨ m et al. (1982) [23] El Mekresh et al. (1998) [20] Grignon et al. (1991) [22]
64 185 48
5-year: 11% 5-year: 55% 5-year: 31%; 10-year: 28% 5-year: 17% 3-year: 48%
Kramer et al. (1979) [61] Wilson et al. (1991) [19] Urachal adenocarcinoma Anderstro¨ m et al. (1982) [23] Grignon et al. (1991) [22] Henly et al. (1993) [27] Nakanishi et al. (1996) [29] Siefker-Radtke et al. (2003) [28] Wilson et al. (1991) [19]
15 10 29 24 34 41 42 6
5-year: 27% 5-year: 61%; 10-year: 46% 5-year: 43% 5-year: 50% 5-year: 40% 3-year: 31%
difference likely reflects a different tumor biology of bilharzial adenocarcinomas that may account for a more favorable prognosis observed in this series.
Signet cell carcinoma is a rare variant of adenocarcinoma of the bladder. Approximately 70 cases have been reported in the literature, of which twothirds originated in the bladder proper and one-third in the urachus [30,31]. The pathological hallmark of this tumor is cells containing vacuoles of PAS positive staining mucin. In approximately 30% of cases cystoscopic findings are unspecific and no exophytic tumor is identified due to a subepithelial, infiltrative growth, which is comparable to linitis plastica of the stomach. The natural history of these tumors can be one of silent, asymptomatic local progression, leading to a late diagnosis. Radiographically, the bladder may appear partially or diffusely thickened [32]. Radical surgery is considered the best available treatment, both in regards to potential cure as well as for disease palliation. However, up to half the patients present with locally advanced, unresectable disease. Radiation and chemotherapy have limited effect and average patient survival is less than one year [33].
Table 5 Proposed staging systems and outcome of patients with urachal adenocarcinoma Sheldon et al. (1994) [25]
Nakanishi et al. (1996) [29]
5-year survival [29]
A invading into the bladder, but not abdominal wall, peritoneum, or other viscera
58% (n ¼ 30)
B invading abdominal wall, peritoneum or other viscera than bladder
42% (n ¼ 6)
C metastasis to regional lymph nodes or distant sites
0% (n ¼ 5)
I no invasion beyond urethral mucosa II invasion confined to urachus III A local extension into the bladder III B local invasion into abdominal wall III C local invasion into peritoneum III D local invasion into other viscera than the bladder IV A metastasis to regional lymph nodes IV B metastasis to distant sites
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Fig. 2. CT scan of a small cell carcinoma of the urinary bladder with tumor extension into the anterior abdominal wall in a 72 year old male prior to neoadjuvant chemotherapy (A). Haematoxylin and eosin section demonstrating high-grade features (B). Immunohistochemical staining of the same tumor demonstrating a high MIB-1 index (Ki 67 antigen) consistent with a high-grade neuroendocrine carcinoma of the small cell type (C).
6. Small cell carcinoma Primary small cell or neuroendocrine carcinoma of the bladder is an extremely uncommon entity and accounts for less than 0.5% of bladder tumors or approximately 130 reported cases [34,35]. Microscopically, it resembles small cell carcinoma of the lung, composed of a population of relatively uniform cells with scant cytoplasm and hyperchromatic nuclei. Extensive necrosis and frequent mitotic figures are common [3]. The histogenesis of small cell carcinoma of the bladder is uncertain; both derivation from rare neuroendocrine cells of bladder and multipotent stem cells of the bladder has been proposed [36]. While the diagnosis is usually made by haematoxylin and eosin staining (Fig. 2), special immunohistochemical stains including neurospecific enolase (NSE) are valuable for distinguishing small cell carcinoma from similarly appearing tumors such as lymphoreticular neoplasms [35]. Additional immunohistochemical staining for chromogranin A and synaptophysin is mandatory to confirm the neuroendocrine origin [37]. Poorly differentiated neuroendocrine carcinomas typically display a MIB-1 proliferation index (KI-67) greater than 80%. Standard treatment for patients with localized small cell carcinoma consists of radical cystectomy and extended pelvic lymphadenectomy. The outcome of most patients, however is poor: In a series reported by Trias et al. [35] median patient survival was less than one year and extended survival of 5 years or greater was extremely uncommon. More than half the patients had metastatic spread to the loco-regional lymph nodes, liver or bone at the time of presentation. Meanwhile, in an earlier series of 22 patients, Holma¨ ng et al.
reported that 5/18 patients (23%) with localized disease (pT2-4N0M0) who underwent complete tumor resection experienced long-term recurrence-free survival of 6 years and beyond. Of these patients, 3 underwent transurethral resection, 1 patient partial cystectomy, 1 patient radical cystectomy and 4/5 patients received either neoadjuvant or adjuvant radiation therapy in addition. While cautioning that only a minority of small cell tumors (less than 10%) was not metastasized at the time of diagnosis the authors concluded that patients with localized disease benefited from aggressive local resection that should possibly be combined with radiotherapy. In light of the dismal prognosis of most patients treated by radical surgery alone though, neo-adjuvant and adjuvant chemotherapy regimens employing modern agents have recently been increasingly explored. Walther has recently reported favorable response rates when treating 7 patients with non-metastatic small cell carcinoma with systemic etoposide and cisplatin in a neo-adjuvant and adjuvant setting [34]. In addition, monitoring of serum levels of NSE is evolving as a valuable adjunct in measuring the response of patients with small cell carcinoma to systemic chemotherapy.
7. Bladder sarcoma While all types of non-epithelial bladder tumors are extremely rare, malignant soft tissue tumors represent the most common histological type. A recent review of the literature identified a total of 192 reported cases of adult bladder sarcoma, of which 50% were leiomyosarcomas, 20% rhabdomyosarcomas, and the remainder
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angio-, osteo- and carcinosarcoma [38]. Leiomyosarcomas, the most common type of sarcoma in adults, are histologically characterized by interwoven bundles of spindle shaped cells. Their incidence may be increased in patients who have previously undergone local radiation treatment or systemic chemotherapy for an unrelated neoplasm [39]. Sub-classification of sarcomas employs special immunohistochemical stains and grade carries important prognostic implications. In contrast to other tumors, tumor grade is established on the basis of mitotic rate and proliferation indices (i.e. KI 67 immunohistochemistry), rather than nuclear atypia [39]. A series of 10 patients with bladder sarcoma from the Memorial Sloan-Kettering Cancer represents one of the largest single-institution experiences reported to date [40]. Most tumors presented with symptoms of hematuria leading to a relatively early diagnosis compared to sarcomas of other locations. Although 8/10 bladder sarcomas were high grade, the 5-year survival rate was 80%. Due to the propensity of the tumor to recur locally, the preferred treatment for localized disease is radical cystectomy and complete margin negative resection. Metastatic sarcomas are treated employing multimodality protocols, and doxorubicin and ifosfamide appear to be the most active singleagents available to date. Furthermore, preoperative chemotherapy and radiation as advocated for pediatric soft tissue sarcoma patients have been adapted for adult patients with locally extensive tumors to allow a complete tumor resection or to avoid disfiguring procedures.
8. Carcinosarcoma and sarcomatoid tumors The term carcinosarcoma describes a rare biphasic type of primary bladder tumor composed of an intimate admixture of both malignant epithelial (carcinoma) and malignant soft tissue elements (sarcoma). Meanwhile, the term sarcomatoid tumor has been used to describe a malignant primarily spindle cell type tumor with epithelial differentiation [41]. In light of the controversy over these definitions, the Mayo Clinic reviewed their experience of 15 patients with carcinosarcoma and 26 patients with sarcomatoid tumors treated over more than fifty years [41]. Both tumor entities shared a similar presentation in predominantly elderly, male patients. The most common epithelial component in both was urothelial. Local extent correlated with outcome, yet most patients had locally advanced tumors at the time of diagnosis.
Outcome was poor in both patients with carcinosarcoma and sarcomatoid tumors, with patients succumbing to their disease within 1–2 years despite aggressive surgical management. Recently, a favorable response of metastatic sarcomatoid tumor to cisplatin and gemcitabine has been reported [42], however further studies are indicated to define the role of systemic chemotherapy in an adjuvant or neo-adjuvant setting.
9. Paraganglioma Paragangliomas are extraadrenal neoplasms of neural crest derivation that are termed pheochromocytoma if hormonally active. Bladder pheochromocytomas are exceedingly rare, accounting for less than 0.05% of bladder tumors. Histologically they are characterized by cells arranged in discrete nests (‘‘Zellballen’’) separated by a prominent sinusoidal network. They are believed to arise from embryonic rests of chromaffin cells in the sympathetic plexus of the detrusor muscle and represent approximately 10% of extraadrenal pheochromocytomas [43]. Although an association of vesical pheochromocytomas with neurofibromatosis von Recklinghausen exists, most reported vesical pheochromocytomas appear as sporadic tumors. Approximately 10% of bladder pheochromocytomas are malignant, demonstrating local invasion, regional lymph node metastasis or distant spread. Symptoms at presentation are mostly nonspecific, but may include micturional attacks (paroxysmal hypertension, headaches, palpitations, blurred vision, diaphoresis) resulting from catecholamine excess triggered by voiding [44]. If a bladder pheochromocytoma is suspected, cystoscopy should only be performed following adrenergic blockade in a controlled environment such as the operating room. The macroscopic appearance is often that of a solitary submucosal or intramural nodule. Biopsy should be avoided. Computed tomography and/or magnetic resonance imaging are used to determine the size, location and local extent of the lesion. Nuclear medicine scanning using the radioisotope 131iodine metaiodinebenzylguinidine (MIBG) is the imaging study of choice for localizing small pheochromocytomas and has a sensitivity and specificity of 77–90% and 95–100%, respectively [45]. Recently, positron emission tomography (PET) imaging has been described as a highly sensitive adjunctive study for detecting vesical pheochromocytomas [44]. Standard treatment of localized pheochromocytoma consists in complete local excision of the tumor that
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can often be accomplished by partial cystectomy combined with pelvic lymph node dissection. Surgery is planned in a similar fashion as in adrenal pheochromocytomas and involves volume expansion and adrenergic blockade [45]. No defined histological features have been identified to safely distinguish benign and malignant pheochromocytomas. In light of the propensity of malignant pheochromocytomas to recur locally and develop metachronous metastasis, lifelong followup is warranted.
10. Inflammatory pseudotumors These represent rare, spindle-cell type neoplasms, which are also referred to as pseudosarcomatous tumors or myofibroblastic tumors [46]. Although these tumors are benign, they combine pathological features of both inflammatory and neoplastic processes that can make the differential diagnosis to sarcoma extremely difficult. The histogenesis of inflammatory pseudotumors remains largely unclear. A subset of these tumors present within 3 months of a surgical procedure [47] and are referred to as ‘‘postoperative spindle-cell tumors’’. In a review of 38 spindle-cell tumors from several institutions, Iczkowski et al. identified 17 inflammatory pseudotumors and described criteria to distinguish them from other entities such as leiomyosarcomas [47]. These include: The absence of significant nuclear atypia, less than 3 mitotic figures per high power field and spindle-cell like cells with myxoid degeneration and eosinophilic cytoplasm. Some tumors may display a fascicular growth pattern with interstitial collagen [48] and assume a very large size, with the largest reported pseudotumor reaching 38 cm in diameter [47]. Following complete tumor resection either by transurethral resection or partial/radical cystectomy, none of the patients reported by Iczkowski et al. developed local recurrence or distant metastasis, confirming the benign nature of these lesions [47]. The differential diagnosis to sarcomas though can be very difficult and require processing of the complete tumor specimen.
11. Melanoma Melanoma of the bladder is most commonly a secondary presentation of patients with widespread metastatic melanoma originating from the skin. However, rare cases of primary melanoma of the bladder and female urethra, reportedly the most frequent location of primary melanoma of the urinary tract, have
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been described [39,49]. In such cases, a detailed patient history, careful examination of the patient’s skin and evaluation for other viszeral primary sites are necessary to confirm the primary nature of the tumor [50]. Histologically, melanoma of the bladder resemble other melanoma and consist of large malignant cells arranged in nests with variable amounts of pigment [3]. The histogenesis of primary bladder melanoma is uncertain, and an origin from cells of the neural crest has been proposed [39]. Meanwhile, there is no association between malignant melanoma and melanosis of the bladder, a benign condition characterized by hyperpigmentation of the urothelium due to an enrichment of cytoplasmatic melanin granula. Treatment of the rare localized primary melanoma of the bladder is radical surgery. The prognosis is guarded [51,52].
12. Lymphoma Most frequently, bladder lymphoma reflects widespread metastatic disease of systemic hematological disease. However, rare primary lymphomas of the bladder occur. Histologically, these tumors consist of a diffuse, infiltrative proliferation of lymphoid cells surrounding and permeating normal structures rather than replacing them [3]. A recent review identified 84 cases of primary lymphoma [53] that were more common in women than men (3:1) and in large proportion represented so-called Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT). These tumors have the distinction of being mostly localized and of low grade and carry an excellent prognosis. In contrast to most other primary bladder tumors, primary treatment consists in local radiation, which achieves remissions in a high percentage of patients and can result in extended recurrence-free survival [53,54].
13. Conclusions Primary non-urothelial bladder tumors often present a diagnostic and therapeutic challenge. While this review provides a framework to direct patient management, it appears important to account for the fact that available evidence on many of these rare malignancies stems from small, retrospective case series. As in other rare tumors it will likely take the concerted effort of many institutions linked together by a national or international tumor registry to develop and evaluate effective treatment strategies in an attempt to optimize patient outcome in the future.
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Review
Malignant Non-Urothelial Neoplasms of the Urinary Bladder: A Review Philipp Dahma, Ju¨rgen E. Gschwendb,* a
Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA Department of Urology, Ulm University Medical Center, Prittwitz-Strasse 43, 89075 Ulm, Germany
b
First published online 27 August 2003
Abstract Objectives: Non-urothelial bladder tumors frequently present a diagnostic and therapeutic challenge. We review the peer-reviewed literature to summarize the available evidence on the etiology, diagnosis and optimal management of malignant non-urothelial bladder tumors. Methods: A comprehensive MEDLINE database search was performed. In addition, the proceedings of recent national and international urological and cancer society meetings were reviewed. Results: Primary non-urothelial bladder tumors are rare in Europe and North America representing less than 5% of all bladder lesions combined. A large number of risk factors have been implicated in the etiology of nonschistosomiasis-related squamous cell carcinoma, yet their exact pathomechanism remains poorly defined. Squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma and carcinosarcoma/sarcomatoid tumors share an unfavorable prognosis despite aggressive surgical management that relates both to an aggressive biological behaviour as well as to an often times advanced stage at the time of diagnosis. Inflammatory pseudotumors are benign tumors of uncertain histogenesis that may mimic sarcomas. Paraganglioma, primary melanoma and lymphoma represent additional, exceedingly rare bladder tumors. Conclusions: The systematic investigation of most non-urothelial bladder tumors is limited by the rarity of these lesions. A concerted effort of multiple institutions linked together in a national or international tumor registry will be necessary to advance our understanding of these tumors, evaluate treatment strategies and optimize patient outcome in the future. # 2003 Elsevier B.V. All rights reserved. Keywords: Non-urothelial; Bladder tumors
1. Introduction Non-urothelial neoplasms of the bladder are rare entities in Europe and North America. They are vastly outnumbered by urothelial tumors and account for less than 5% of all vesical tumors combined. In fact, most types of non-urothelial bladder tumors may not be encountered within a lifetime of practicing urology. Despite the low incidence of non-urothelial neoplasms, urologists should be familiar with these tumors and *
Corresponding author. Tel. þ49-731-500-27808; Fax: þ49-731-500-33166. E-mail address: [email protected] (J.E. Gschwend).
consider them in the differential diagnosis of all bladder masses, in particular those of unusual clinical presentation. The following attempts to provide a comprehensive review of the peer-reviewed literature on primary, malignant, non-urothelial bladder tumors according to the histological classification by the World Health Organization (WHO) (Table 1) [1]. It summarizes the available evidence on the etiology, diagnosis and therapeutic management of these rare malignant masses that, with exception of schistosomiasis-related squamous cell carcinoma, is mainly derived from small retrospective case series and case reports. While pseudo-inflammatory tumors are histologically benign, they may closely mimic sarcomatous neoplasms and should therefore be considered in the differential diagnosis.
0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0302-2838(03)00416-0
P. Dahm, J.E. Gschwend / European Urology 44 (2003) 672–681 Table 1 World Health Organization (WHO) histological classification of bladder tumors I. Epithelial Tumors A. Transitional cell papilloma B. Transitional cell papilloma, inverted type C. Squamous cell papilloma D. Transitional cell carcinoma E. Variants of transitional cell carcinoma 1. With squamous metaplasia 2. With glandular metaplasia 3. With squamous and glandular metaplasia F. Squamous cell carcinoma G. Adenocarcinoma H. Undifferentiated carcinoma II. Nonepithelial Tumors A. Benign B. Malignant 1. Rhabdomyosarcoma 2. Others III. Miscellaneous Tumors A. Pheochromocytoma/Paraganglioma B. Lymphoma C. Carcinosarcoma D. Malignant melanoma E. Others IV. Metastatic Tumors and Secondary Extensions V. Unclassified Tumors VI. Epithelial Abnormalities A. Papillary (polypoid) ‘‘cystitis’’ B. Von Brunn’s nests C. ‘‘Cystitis’’ cystica D. Glandular metaplasia E. ‘‘Nephrogenic’’ adenoma F. Squamous metaplasia VII. Tumorlike Lesions A. Follicular cystitis B. Malakoplakia C. Amyloidosis D. Fibrous (fibroepithelial) polyp E. Endometriosis F. Hamartoma G. Cysts
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2. Squamous cell carcinoma Second to urothelial carcinoma, squamous cell carcinoma (SCC) is the most prevalent epithelial neoplasm of the bladder, accounting for an approximate 3– 5% of bladder tumors in Western countries [2]. Microscopically the tumor may be well differentiated, consisting of well defined islands of squamous cells with keratinization, prominent intercellular bridges, and minimal nuclear pleomorphism, or poorly differentiated, with marked nuclear pleomorphism and only focal squamous differentiation (Table 2) [3]. A diagnosis of SCC is restricted to pure tumors only without identifiable urothelial carcinoma. While the histogenesis of SCC of the bladder has only been partially elucidated, it is thought to involve factors that result in chronic bladder infection and irritation. In contrast, SCC of the bladder in countries of the Middle East and Egypt has a distinct pathogenesis that is linked to chronic infections with schistosoma haematobium. In regions where this waterborne parasitic pathogen is endemic, SCC not only represents the most common histological type of bladder tumor, but also the most prevalent form of cancer in men overall, accounting for 30% of cancers. There it is also the second most common type of malignant neoplasm in women after breast cancer [4]. Due to characteristic differences in the etiology and epidemiology of schistosoma-unrelated and -related SCC, they will be reviewed separately.
3. Non-schistosoma-related SCC Pure SCC of the bladder is a rare finding in Western countries and is to be distinguished from urothelial bladder cancer with partial squamous differentiation, a
Table 2 Summary of characteristic features of malignant, primary non-urothelial bladder tumors in Western countries Histological type
Percentage of bladder tumors
Squamous cell carcinoma
3–5
Adenocarcinoma
0.5–2.0
Small cell carcinoma Sarcoma Carcinosarcoma/ sarcomatoid tumors Paraganglioma
<0.5 <0.1 <0.1
Melanoma Lymphoma
<0.1 <0.1
<0.1
Histological features Epithelial neoplasm that exclusively displays squamous features such as squamous pearls, intercellular bridges, and keratohyaline granules Epithelial neoplasm characterized by neoplastic glandular structures lined by mucin-secreting cells similar to colonic carcinoma Undifferentiated tumor of neuroendocrine derivation that resembles oat cell carcinoma of the lung. Malignant connective tissue tumor composed of bundles of malignant spindle cells Biphasic tumor with malignant epithelial (carcinoma) and soft tissue elements (sarcoma) Extraadrenal tumor of neural crest derivation that classically demonstrates groups of fairly uniform, polygonal cells (‘‘Zellballen’’) Malignant neoplasm composed of malignant cells arranged in nests with variable amount of pigment Hematological malignancy demonstrating dense lymphoid aggregates that may involve all layers of the bladder
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Table 3 Risk factors of non-schistosoma associated squamous cell carcinoma Risk factor
Reference
Black race Bladder diverticulum Chronic urinary tract infection Chronic indwelling catheter Cyclophosphamide-treatment Intravesical Bacillus Calmette-Guerin (BCG) Male gender Smoking Vesical calculi/foreign bodies
Porter et al. (2002) [55] Montaque et al. (1976) [56] Kantor et al. (1988) [57] Stonehill et al. (1997) [12] Wall et al. (1975) [58] Brenner et al. (1989) [59] Lynch and Cohen (1995) [60] Kantor et al. (1988) [57] Stonehill et al. (1997) [12]
relatively common finding in radical cystectomy specimens. In a large recent cystectomy series from the Memorial Sloan Kettering Cancer Center (MSKCC), only 2.8% of patients demonstrated pure SCC [5]. While a number of etiological factors have been implicated in the pathogenesis of SCC (Table 3), the most relevant common factor appears to be some form of chronic bladder irritation. In the United States, spinal cord injured (SCI) patients that rely on catherization for bladder drainage have the highest prevalence of SCC [6]. Meanwhile, it remains uncertain how high this risk for developing SCC is: Earlier studies reported incidence rates in the range of 2–10% [6–9], while more recent studies suggest a much lower risk. In a retrospective study of over 30,000 veterans with SCI the 5-year risk for developing bladder cancer was only 0.4% [10]. Of note, only one-third of these tumors were SCC, while 55% were urothelial bladder cancers. A recent survey of European centers caring for SCI patients found an even lower incidence of lower urinary tract cancer of 0.11% [11]. These authors suggested that the lower incidence rates in contemporary studies might be a reflection of the trend away from chronic indwelling catheters to clean intermittent catherization. In light of an estimated 15,000 patients that develop SCI annually in the US [10] the relative risk of SCI patents for developing SCC is an important aspect in the controversy as to whether to screen those patients for bladder cancer [9,12]. Proponents of screening programs for SCI patients emphasize that asymptomatic patients diagnosed with SCC by cystoscopy, cytology, or a combination of both may be diagnosed at an earlier disease stage and have a more favorable prognosis. Well-designed prospective studies addressing the clinical and economical aspects of screening remain pending and general recommendations for the screening of SCI patients have not been broadly endorsed. Meanwhile, urologists should be aware of the association of SCI and SCC and have a low threshold for additional diagnostic measures in patients of
this population presenting with symptoms such as hematuria or chronic bladder infections. Patients with non-schistosomiasis-related SCC of the bladder have an unfavorable prognosis, in large due to locally advanced disease at the time of presentation [9]. A study of 25 patients treated with bilateral pelvic node dissection and radical cystectomy reported by Richie et al. [13] found a 5-year survival rate of 48% and identified tumor stage as the most important predictor of outcome. In a large contemporary series, Serrata et al. reviewed 19 cases of pure SCC of the bladder over an 8-year period [2]. The majority of patients were men and the mean age of presentation in the late sixties not different from that of urothelial tumors. All cases presented as solitary, yet locally advanced tumors and were treated by radical cystectomy. Extravesical extension beyond the bladder wall was identified in 74% of patients, upper tract involvement in 26% and involvement of the prostatic urethra in 35% of men. During a mean follow-up period of 52 months, 63% of patients died of locally recurrent bladder cancer, with distant metastases present only in one patient. Based on these results, the authors emphasized that early diagnosis and local control were paramount in patients with SCC of the bladder. Preoperative radiation has been proposed to improve local control, but remains of uncertain benefit [14]. Standard chemotherapy regimens appear to have limited impact on the disease due to the relative chemo-resistance of SCC. The transfer of novel chemotherapy regimens, such as the combination of paclitaxel, carboplatin and gemcitabine that have demonstrated efficacy in patients with SCC of other locations such as the head and neck may offer promise for the future [15].
4. Schistosoma-related SCC In areas where schistosoma is endemic, bladder cancer is a common disease, and SCC constitutes the most common histological type [16]. Compared to urothelial bladder cancer, the age of presentation is lower, affecting mainly men in their fifth decade of life. Schistosoma-related SCC may be regarded a potentially preventable disease, affecting mainly patients who are repeatedly exposed and re-infected by the schistosoma parasite, that completes it life cycle by depositing its eggs into the bladder wall. The ova constitute a chronic source of inflammation and irritation. Together with less well-defined environmental carcinogens such as nitrosamines, they appear to increase the rate of malignant transformation towards SCC of the bladder, as well as urothelial carcinoma and
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adenocarcinoma [4]. While the association of schistosomiasis and bladder cancer of a predominantly squamous type is well established, the exact pathogenic pathway remains unclear and comparative analyses of chromosomal aberrations in bilharzial and non-bilharzial bladder cancer have been inconclusive [17,18]. In a series of 1026 cystectomy patients from a geographic region of endemic schistosomiasis, Ghoneim et al. [16], reported that 59% of bladder tumors were SCC, 22% urothelial carcinoma and 11% adenocarcinoma. Bilharzia ova were identifiable in 88% of SCC and 78% of urothelial carcinoma specimens. The stage distributions of SCC and TCC within this series were not significantly different with 13.5% and 14.9% of cancers, respectively, demonstrating extravesical extension. The overall 5-year survival rate of SCC patients was 50.3%. While a number of variables were of prognostic significance when applying univariate analysis, a multivariate analysis identified only T- and N-stage as independent predictors of survival. Standard treatment of bilharzia-related SCC is radical cystectomy and urinary diversion. A potential role for neoadjuvant or adjuvant radiation and chemotherapy remains poorly defined.
5. Adenocarcinoma Pure adenocarcinoma of the bladder represents the third most common type of epithelial tumor comprising 0.5–2.0% of all bladder tumors [19]. It occurs more frequently in geographic regions where schistosomiasis is endemic [20] and is the most common tumor arising in the bladder of exstrophy patients, who have a reported 4% life-time risk for developing this type of malignancy [21]. While there is some variability in the defining adenocarcinoma in the literature, the pathological hallmark of this tumor are neoplastic cells that form glandular structures that may more or less resemble colonic adenocarcinoma (enteric type) and/or may produce large amounts of intra- (signet cell type) or extracellular mucin (mucinous type) [22]. To establish the diagnosis of primary adenocarcinoma of the bladder, other potential primary tumors such as adenocarcinoma of the prostate or rectum should be ruled out. Urachal adenocarcinoma account for approximately one-third of primary adenocarcinomas [19] and arise from an urachal remnant. Nonurachal adenocarcinomas make up for the remainder and are associated with chronic bladder irritation and exposure to certain ill-defined carcinogens. These are believed to increase the rate of neoplastic transformation from either normal urothelium cells or pluripotent
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bladder stem cells into adenocarcinoma [23]. Meanwhile, the previously assumed association of cystitis glandularis, a form of intestinal metaplasia of the bladder most often seen in patients with pelvic lipomatosis or exstrophy has been questioned: In a series of 53 exstrophy patients with documented cystitis glandularis and a minimum follow-up of 10 years, none developed adenocarcinoma [24]. Clinically, the distinction of urachal and non-urachal adenocarcinoma may be difficult, in particular if the tumor is locally extensive. Criteria that have been proposed to distinguish urachal from non-urachal adenocarcinoma of the dome of the bladder include the presence of an urachal remnant, an intact or ulcerated urothelium without metaplastic changes, a predominant invasion of the muscularis or deeper structures of the bladder or extension to the space of Retzius, anterior abdominal wall or umbilicus [22,25]. For practical purposes all adenocarcinomas of the dome should be considered as urachal in origin until proven otherwise, and treated as such [26,27]. While standard treatment of all vesical adenocarcinomas consists in radical cystectomy and pelvic node dissection, locally invasive urachal adenocarcinoma may further mandate en bloc surgical removal of the urachal ligament, umbilicus and part of the anterior abdominal wall (Fig. 1) [25,28]. The prognosis of urachal adenocarcinoma is generally unfavorable with 5-year survival rates ranging between 11% and 55% (Table 4). Survival correlates with local extent, which may be categorized according the staging system proposed by Sheldon [25] and adapted by Nakanishi [29] (Table 5). In addition, margin status has been identified as an important predictor of outcome, emphasizing the importance of complete surgical resection [28]. Currently there is no established chemotherapy regimen for patients with metastatic urachal carcinoma: In a recent series of 9 patients with metastatic urachal adenocarcinoma treated with multimodality chemotherapy at M.D. Anderson Cancer Center the median survival was only 20 months. Although objective responses were documented in 3/9 patients to 5-FU and cisplatin based regimens, chemotherapy was not shown to improve outcome significantly [28]. Similarly, the 5-year survival rates of patients with non-urachal adenocarcinomas are poor, ranging between 27% and 61% (Table 5). Among these, the largest series of non-urachal adenocarcinomas was reported by El Mekresh et al. from a region of endemic schistosomiasis [20]. Of note, in contrast to studies of non-bilharzial adenocarcinoma [19,23], over half the tumors (52%) in this series were low grade. This
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Fig. 1. Urachal adenocarcinoma of the urinary bladder in a 30 year old female. CT scan depicting the location of the mass at the dome of the bladder (A). Intraoperative view of the bladder dome and tumor with adjacent urachal remnant (B). Haematoxylin and eosin section depicting small nests of cells appearing to float in pools of extracellular mucin (C).
Table 4 Review of reported outcomes of patients with non-urachal and urachal adenocarcinomas Author
Patients
Survival
Non-urachal adenocarcinoma Anderstro¨ m et al. (1982) [23] El Mekresh et al. (1998) [20] Grignon et al. (1991) [22]
64 185 48
5-year: 11% 5-year: 55% 5-year: 31%; 10-year: 28% 5-year: 17% 3-year: 48%
Kramer et al. (1979) [61] Wilson et al. (1991) [19] Urachal adenocarcinoma Anderstro¨ m et al. (1982) [23] Grignon et al. (1991) [22] Henly et al. (1993) [27] Nakanishi et al. (1996) [29] Siefker-Radtke et al. (2003) [28] Wilson et al. (1991) [19]
15 10 29 24 34 41 42 6
5-year: 27% 5-year: 61%; 10-year: 46% 5-year: 43% 5-year: 50% 5-year: 40% 3-year: 31%
difference likely reflects a different tumor biology of bilharzial adenocarcinomas that may account for a more favorable prognosis observed in this series.
Signet cell carcinoma is a rare variant of adenocarcinoma of the bladder. Approximately 70 cases have been reported in the literature, of which twothirds originated in the bladder proper and one-third in the urachus [30,31]. The pathological hallmark of this tumor is cells containing vacuoles of PAS positive staining mucin. In approximately 30% of cases cystoscopic findings are unspecific and no exophytic tumor is identified due to a subepithelial, infiltrative growth, which is comparable to linitis plastica of the stomach. The natural history of these tumors can be one of silent, asymptomatic local progression, leading to a late diagnosis. Radiographically, the bladder may appear partially or diffusely thickened [32]. Radical surgery is considered the best available treatment, both in regards to potential cure as well as for disease palliation. However, up to half the patients present with locally advanced, unresectable disease. Radiation and chemotherapy have limited effect and average patient survival is less than one year [33].
Table 5 Proposed staging systems and outcome of patients with urachal adenocarcinoma Sheldon et al. (1994) [25]
Nakanishi et al. (1996) [29]
5-year survival [29]
A invading into the bladder, but not abdominal wall, peritoneum, or other viscera
58% (n ¼ 30)
B invading abdominal wall, peritoneum or other viscera than bladder
42% (n ¼ 6)
C metastasis to regional lymph nodes or distant sites
0% (n ¼ 5)
I no invasion beyond urethral mucosa II invasion confined to urachus III A local extension into the bladder III B local invasion into abdominal wall III C local invasion into peritoneum III D local invasion into other viscera than the bladder IV A metastasis to regional lymph nodes IV B metastasis to distant sites
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Fig. 2. CT scan of a small cell carcinoma of the urinary bladder with tumor extension into the anterior abdominal wall in a 72 year old male prior to neoadjuvant chemotherapy (A). Haematoxylin and eosin section demonstrating high-grade features (B). Immunohistochemical staining of the same tumor demonstrating a high MIB-1 index (Ki 67 antigen) consistent with a high-grade neuroendocrine carcinoma of the small cell type (C).
6. Small cell carcinoma Primary small cell or neuroendocrine carcinoma of the bladder is an extremely uncommon entity and accounts for less than 0.5% of bladder tumors or approximately 130 reported cases [34,35]. Microscopically, it resembles small cell carcinoma of the lung, composed of a population of relatively uniform cells with scant cytoplasm and hyperchromatic nuclei. Extensive necrosis and frequent mitotic figures are common [3]. The histogenesis of small cell carcinoma of the bladder is uncertain; both derivation from rare neuroendocrine cells of bladder and multipotent stem cells of the bladder has been proposed [36]. While the diagnosis is usually made by haematoxylin and eosin staining (Fig. 2), special immunohistochemical stains including neurospecific enolase (NSE) are valuable for distinguishing small cell carcinoma from similarly appearing tumors such as lymphoreticular neoplasms [35]. Additional immunohistochemical staining for chromogranin A and synaptophysin is mandatory to confirm the neuroendocrine origin [37]. Poorly differentiated neuroendocrine carcinomas typically display a MIB-1 proliferation index (KI-67) greater than 80%. Standard treatment for patients with localized small cell carcinoma consists of radical cystectomy and extended pelvic lymphadenectomy. The outcome of most patients, however is poor: In a series reported by Trias et al. [35] median patient survival was less than one year and extended survival of 5 years or greater was extremely uncommon. More than half the patients had metastatic spread to the loco-regional lymph nodes, liver or bone at the time of presentation. Meanwhile, in an earlier series of 22 patients, Holma¨ ng et al.
reported that 5/18 patients (23%) with localized disease (pT2-4N0M0) who underwent complete tumor resection experienced long-term recurrence-free survival of 6 years and beyond. Of these patients, 3 underwent transurethral resection, 1 patient partial cystectomy, 1 patient radical cystectomy and 4/5 patients received either neoadjuvant or adjuvant radiation therapy in addition. While cautioning that only a minority of small cell tumors (less than 10%) was not metastasized at the time of diagnosis the authors concluded that patients with localized disease benefited from aggressive local resection that should possibly be combined with radiotherapy. In light of the dismal prognosis of most patients treated by radical surgery alone though, neo-adjuvant and adjuvant chemotherapy regimens employing modern agents have recently been increasingly explored. Walther has recently reported favorable response rates when treating 7 patients with non-metastatic small cell carcinoma with systemic etoposide and cisplatin in a neo-adjuvant and adjuvant setting [34]. In addition, monitoring of serum levels of NSE is evolving as a valuable adjunct in measuring the response of patients with small cell carcinoma to systemic chemotherapy.
7. Bladder sarcoma While all types of non-epithelial bladder tumors are extremely rare, malignant soft tissue tumors represent the most common histological type. A recent review of the literature identified a total of 192 reported cases of adult bladder sarcoma, of which 50% were leiomyosarcomas, 20% rhabdomyosarcomas, and the remainder
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angio-, osteo- and carcinosarcoma [38]. Leiomyosarcomas, the most common type of sarcoma in adults, are histologically characterized by interwoven bundles of spindle shaped cells. Their incidence may be increased in patients who have previously undergone local radiation treatment or systemic chemotherapy for an unrelated neoplasm [39]. Sub-classification of sarcomas employs special immunohistochemical stains and grade carries important prognostic implications. In contrast to other tumors, tumor grade is established on the basis of mitotic rate and proliferation indices (i.e. KI 67 immunohistochemistry), rather than nuclear atypia [39]. A series of 10 patients with bladder sarcoma from the Memorial Sloan-Kettering Cancer represents one of the largest single-institution experiences reported to date [40]. Most tumors presented with symptoms of hematuria leading to a relatively early diagnosis compared to sarcomas of other locations. Although 8/10 bladder sarcomas were high grade, the 5-year survival rate was 80%. Due to the propensity of the tumor to recur locally, the preferred treatment for localized disease is radical cystectomy and complete margin negative resection. Metastatic sarcomas are treated employing multimodality protocols, and doxorubicin and ifosfamide appear to be the most active singleagents available to date. Furthermore, preoperative chemotherapy and radiation as advocated for pediatric soft tissue sarcoma patients have been adapted for adult patients with locally extensive tumors to allow a complete tumor resection or to avoid disfiguring procedures.
8. Carcinosarcoma and sarcomatoid tumors The term carcinosarcoma describes a rare biphasic type of primary bladder tumor composed of an intimate admixture of both malignant epithelial (carcinoma) and malignant soft tissue elements (sarcoma). Meanwhile, the term sarcomatoid tumor has been used to describe a malignant primarily spindle cell type tumor with epithelial differentiation [41]. In light of the controversy over these definitions, the Mayo Clinic reviewed their experience of 15 patients with carcinosarcoma and 26 patients with sarcomatoid tumors treated over more than fifty years [41]. Both tumor entities shared a similar presentation in predominantly elderly, male patients. The most common epithelial component in both was urothelial. Local extent correlated with outcome, yet most patients had locally advanced tumors at the time of diagnosis.
Outcome was poor in both patients with carcinosarcoma and sarcomatoid tumors, with patients succumbing to their disease within 1–2 years despite aggressive surgical management. Recently, a favorable response of metastatic sarcomatoid tumor to cisplatin and gemcitabine has been reported [42], however further studies are indicated to define the role of systemic chemotherapy in an adjuvant or neo-adjuvant setting.
9. Paraganglioma Paragangliomas are extraadrenal neoplasms of neural crest derivation that are termed pheochromocytoma if hormonally active. Bladder pheochromocytomas are exceedingly rare, accounting for less than 0.05% of bladder tumors. Histologically they are characterized by cells arranged in discrete nests (‘‘Zellballen’’) separated by a prominent sinusoidal network. They are believed to arise from embryonic rests of chromaffin cells in the sympathetic plexus of the detrusor muscle and represent approximately 10% of extraadrenal pheochromocytomas [43]. Although an association of vesical pheochromocytomas with neurofibromatosis von Recklinghausen exists, most reported vesical pheochromocytomas appear as sporadic tumors. Approximately 10% of bladder pheochromocytomas are malignant, demonstrating local invasion, regional lymph node metastasis or distant spread. Symptoms at presentation are mostly nonspecific, but may include micturional attacks (paroxysmal hypertension, headaches, palpitations, blurred vision, diaphoresis) resulting from catecholamine excess triggered by voiding [44]. If a bladder pheochromocytoma is suspected, cystoscopy should only be performed following adrenergic blockade in a controlled environment such as the operating room. The macroscopic appearance is often that of a solitary submucosal or intramural nodule. Biopsy should be avoided. Computed tomography and/or magnetic resonance imaging are used to determine the size, location and local extent of the lesion. Nuclear medicine scanning using the radioisotope 131iodine metaiodinebenzylguinidine (MIBG) is the imaging study of choice for localizing small pheochromocytomas and has a sensitivity and specificity of 77–90% and 95–100%, respectively [45]. Recently, positron emission tomography (PET) imaging has been described as a highly sensitive adjunctive study for detecting vesical pheochromocytomas [44]. Standard treatment of localized pheochromocytoma consists in complete local excision of the tumor that
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can often be accomplished by partial cystectomy combined with pelvic lymph node dissection. Surgery is planned in a similar fashion as in adrenal pheochromocytomas and involves volume expansion and adrenergic blockade [45]. No defined histological features have been identified to safely distinguish benign and malignant pheochromocytomas. In light of the propensity of malignant pheochromocytomas to recur locally and develop metachronous metastasis, lifelong followup is warranted.
10. Inflammatory pseudotumors These represent rare, spindle-cell type neoplasms, which are also referred to as pseudosarcomatous tumors or myofibroblastic tumors [46]. Although these tumors are benign, they combine pathological features of both inflammatory and neoplastic processes that can make the differential diagnosis to sarcoma extremely difficult. The histogenesis of inflammatory pseudotumors remains largely unclear. A subset of these tumors present within 3 months of a surgical procedure [47] and are referred to as ‘‘postoperative spindle-cell tumors’’. In a review of 38 spindle-cell tumors from several institutions, Iczkowski et al. identified 17 inflammatory pseudotumors and described criteria to distinguish them from other entities such as leiomyosarcomas [47]. These include: The absence of significant nuclear atypia, less than 3 mitotic figures per high power field and spindle-cell like cells with myxoid degeneration and eosinophilic cytoplasm. Some tumors may display a fascicular growth pattern with interstitial collagen [48] and assume a very large size, with the largest reported pseudotumor reaching 38 cm in diameter [47]. Following complete tumor resection either by transurethral resection or partial/radical cystectomy, none of the patients reported by Iczkowski et al. developed local recurrence or distant metastasis, confirming the benign nature of these lesions [47]. The differential diagnosis to sarcomas though can be very difficult and require processing of the complete tumor specimen.
11. Melanoma Melanoma of the bladder is most commonly a secondary presentation of patients with widespread metastatic melanoma originating from the skin. However, rare cases of primary melanoma of the bladder and female urethra, reportedly the most frequent location of primary melanoma of the urinary tract, have
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been described [39,49]. In such cases, a detailed patient history, careful examination of the patient’s skin and evaluation for other viszeral primary sites are necessary to confirm the primary nature of the tumor [50]. Histologically, melanoma of the bladder resemble other melanoma and consist of large malignant cells arranged in nests with variable amounts of pigment [3]. The histogenesis of primary bladder melanoma is uncertain, and an origin from cells of the neural crest has been proposed [39]. Meanwhile, there is no association between malignant melanoma and melanosis of the bladder, a benign condition characterized by hyperpigmentation of the urothelium due to an enrichment of cytoplasmatic melanin granula. Treatment of the rare localized primary melanoma of the bladder is radical surgery. The prognosis is guarded [51,52].
12. Lymphoma Most frequently, bladder lymphoma reflects widespread metastatic disease of systemic hematological disease. However, rare primary lymphomas of the bladder occur. Histologically, these tumors consist of a diffuse, infiltrative proliferation of lymphoid cells surrounding and permeating normal structures rather than replacing them [3]. A recent review identified 84 cases of primary lymphoma [53] that were more common in women than men (3:1) and in large proportion represented so-called Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT). These tumors have the distinction of being mostly localized and of low grade and carry an excellent prognosis. In contrast to most other primary bladder tumors, primary treatment consists in local radiation, which achieves remissions in a high percentage of patients and can result in extended recurrence-free survival [53,54].
13. Conclusions Primary non-urothelial bladder tumors often present a diagnostic and therapeutic challenge. While this review provides a framework to direct patient management, it appears important to account for the fact that available evidence on many of these rare malignancies stems from small, retrospective case series. As in other rare tumors it will likely take the concerted effort of many institutions linked together by a national or international tumor registry to develop and evaluate effective treatment strategies in an attempt to optimize patient outcome in the future.
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