Neurofibroma of the urinary bladder is rare. Only isolated case reports have appeared. Information regarding the long term follow-up of patients with neurofibroma is limited.
Neurofibroma of the urinary bladder is rare. Only isolated case reports have appeared. Information regarding the long term follow-up of patients with neurofibroma is limited.
The authors studied 4 cases of neurofibroma of the bladder diagnosed at Mayo Clinic from 1965 through 1990. Immunostains for S-100 protein, neurofilament protein, epithelial membrane antigen (EMA), cytokeratin (CAM 5.2; AE 1/3), Type IV collagen, MIB-1, and p53 protein were performed in all cases, as was Alcian blue at pH 2.5. The mean follow-up was 9.6 years (range, 2–18 years).
The mean age at diagnosis was 17 years (range, 7–28 years); the male-to-female ratio was 1:1. All four patients exhibited physical stigmata of neurofibromatosis type 1. Clinical presentations included hematuria (one patient), irritative symptoms (two patients), and pelvic mass (one patient). Long term urinary complications included bladder atony (two patients), neurogenic bladder (one patient), and recurrent urinary tract infection with hematuria (one patient). Subsequently, two patients underwent partial cystectomy and one a complete cystectomy. Involvement of the bladder was generalized in all four cases. Three tumors were transmural, showing a diffuse and plexiform pattern of growth; in the fourth case, a superficial biopsy showed only diffuse submucosal growth with conspicuous pseudo-Meissnerian corpuscle formation. An Alcian blue positive, variably collagenized matrix was present in all cases. Tumor cells displayed immunoreactivity for S-100 protein and Type IV collagen in all cases. Neurofilament protein positive axons were evident in three cases; all other immunostains were negative. The mean MIB-1 labeling index was 3.2% (range, 0.9–7.3%). No malignant transformation was observed during a mean follow-up of 9.6 years.
Neurofibroma of the bladder presents early in life, is of the plexiform type with a diffuse component, and usually occurs in the setting of generalized neurofibromatosis type 1 rather than as isolated visceral neurofibromatosis. Malignant transformation did not occur in any of these 4 patients during a mean follow-up time of 9.6 years. Cancer 1999;86:505–13. © 1999 American Cancer Society.
Neurofibroma is a benign nerve sheath tumor characterized by the proliferation of Schwann and perineurium-like cells as well as fibroblasts and cells of intermediate type. The issue of whether neurofibroma is hyperplastic or neoplastic in nature was once a matter of controversy, but recent evidence favors a neoplastic process.1 Neurofibromas of the urinary bladder occur infrequently; fewer than 60 cases have been reported. Most have only limited follow-up, and their biologic behavior is uncertain. We evaluated the clinical, pathologic, and immunohistochemical features of four cases of neurofibroma of the urinary bladder, with long term follow-up, and compared our findings with those reported in the literature.
Four cases of neurofibroma of the urinary bladder, all treated at the Mayo Clinic between 1965 and 1998, were retrieved from the Mayo Clinic registry. Clinical findings, operative data, and patient follow-up were obtained from medical records. All histologic slides were reviewed by the authors. Histochemical stains (Alcian blue at pH 2.5) and immunohistochemical preparations were performed on formalin fixed, paraffin embedded tissue in all cases. Antisera applied in immunostainings included ones directed against cytokeratins (AE 1/3, monoclonal, Boeringer Mannheim, Indianapolis, IN; dilution 1:100; and cytokeratin CAM 5.2, monoclonal, Beckton Dickinson, San Jose, CA; 1:50), epithelial membrane antigen (EMA) (monoclonal, Dako, Carpinteria, CA; 1:20), S-100 protein (polyclonal, HSC, Toronto, Canada; 1:2000), neurofilament protein (monoclonal, Dako; 1:75), Type IV collagen (collagen IV; monoclonal, Dako; 1:25), p53 (DO-7, Monoclonal, Dako; 1:100), and Ki-67 antigen (MIB-1, monoclonal, Immunotech, Westbrook, ME; 1:50). Positive and negative controls were run in parallel with each batch and stained appropriately. Quantification of MIB-1(Ki-67) labeling was performed using the CAS 200 digital image analyzer and proliferation index software programs (Beckton Dickinson, Cellular Imaging Systems, San Jose, CA).
Clinical findings are summarized in Table 1. The mean patient age at diagnosis was 17 years (range, 7–28 years); the male-to-female ratio was 1:1. The mean duration of follow-up was 9.6 years (range, 2–18 years). All patients had neurofibromatosis type 1, three with obvious generalized signs of the disease and one only associated with cafe-au-lait spots. Clinical presentations included hematuria (one patient), irritative symptoms (two patients), and pelvic mass (one patient). Subsequently, two patients underwent partial cystectomy and one had a complete cystectomy. No malignant transformation was observed over a mean follow-up period of 9.6 years (range, 2.2–17.5 years). Long term urinary complications included bladder atony (two patients), neurogenic bladder (one patient), and recurrent urinary tract infection with hematuria (one patient).
|Case||Age (yrs)||Gender||Family history of NF type 1a||Generalized signsb||Clinical presentation||Bladder imaging findings||Cystoscopic findings||Extent||Type of neurofibroma||Treatment||Follow-up (mos)||Outcome|
|1||7||M||No||Present||Hematuria||Irregular bladder wall thickening||Neoplasm||Entire bladder||Diffuse and plexiform||Partial cystectomy||26||Neurogenic bladder|
|2||28||M||No||Present||Irritative symptoms||Bilateral ureteral obstruction||Erythematous||Entire bladder||Diffuse and plexiform||Cystectomy||119||Hematuria and recurrent UTI|
|3||16||F||Yes||Present||Pelvic mass||Filling defect||Neoplasm||Entire bladder||Diffuse and plexiform||Partial cystectomy||210||Atonic bladder|
|4||18||F||No||Present||Irritative symptoms||Thickening of bladder wall||Nodular mass||Entire bladder||Diffuse||Transurethral resection||108||Atonic bladder|
Histologically, bladder involvement was generalized in all cases. In three cases (Cases 1, 2, and 3) there was transmural involvement by both diffuse and plexiform neurofibroma components (Figs. 1 and 2); one superficial biopsy showed only diffuse submucosal involvement with bandlike subepithelial pseudo-Meissnerian corpuscle formation and accentuation of small submucosal nerves (Fig. 3). Diffuse components were mucopolysaccharide-rich, hypocellular, and composed of small-to-medium-sized spindle cells with ovoid-to-elongate nuclei. Cytoplasmic processes of these cells were difficult to discern but were highlighted on immunostaining for S-100 protein. An Alcian blue positive, variably collagenized matrix was present in all cases. Mast cells in small numbers were seen in all cases. Histochemical and immunohistochemical findings are summarized in Table 2. Immunostains for S-100 protein and collagen IV were positive in the majority of tumor cells. Neurofilament protein positive axons were noted in three cases. All other immunostains, including epithelial membrane antigen (EMA), cytokeratin (CAM 5.2 and AE 1/3), and p53 protein were negative. The mean MIB-1 labeling index was 3.2% (range, 0.9–7.3%).
|Case||Alcian blue||CK AE1/3||CK CAM 5.2||EMA||S-100 protein||Neurofilament||Collagen IV||p53||MIB-1 labeling index|
Neurofibromatosis type 1 (von Recklinghausen disease) is an autosomal dominant disorder with an estimated occurrence in 1 of 3000 live births.2–4 It is characterized by multiple cafe-au-lait spots; axillary frecking; multiple cutaneous neurofibromas; neurofibromas of cranial or spinal nerves; plexiform neurofibromas; localized hypertrophic neuropathy; pigmented iris hamartomas (Lish nodules); skeletal changes, such as scoliosis and thoracic meningomyelocele; and a variety of intracranial and optic gliomas.1, 5 Genetic mutations responsible for this common disorder are located on the long arm of chromosome 17, a gene spanning 350 kb of genomic DNA.2 Its gene product, neurofibromin, is normally expressed in various tissues and may function as a tumor suppressor gene regulating ras p21.4 Neurofibromas are the hallmark of neurofibromatosis type 1. Visceral neurofibromas are a component of the disease, but they only infrequently come to clinical attention. Urinary tract involvement is rarely reported.
The urinary bladder is the most common site of genitourinary tract involvement in neurofibromatosis. There have been approximately 50 reported cases of neurofibroma of the urinary bladder since 1932 (Table 3). 6–39 The tumors typically occur in young patients with neurofibromatosis type 1. Clinical presentations are similar to those related to posterior urethral valves in male patients. The mean age at diagnosis is reportedly 17 years (range, 1 month to 54 years), and the male-to-female ratio is 2.3:1. Involvement of the bladder is often extensive, necessitating cystectomy in approximately one-third of cases. Only 3 tumors (6%) underwent malignant transformation;14, 32, 33 none of these occurred in children. In this report, we found that neurofibroma of the bladder presents early in life and occurs more often in the setting of generalized disease than as isolated visceral neurofibromatosis. Histologically, the tumors are usually of the plexiform and diffuse type. None of our patients experienced malignant transformation over a mean follow-up of 9.6 years.
|Authors||Age/gender (yrs)||NF type 1b||Extent of urinary tract involvement||Treatment||Follow-up (mos)||Outcome|
|Kass et al., 19326||7/M||Present||Bladder (6–8 cm)||None||1||Died of bronchopneumonia|
|McDonnell, 19367||37/M||Present||Bladder, prostate, seminal vesicles, penis, and urethra||Decompression of bladder||—||—|
|Mintz, 19408||28/M||None||Entire bladder||Excision||—||—|
|Thompson and McDonald, 19409||59/M||None||Bladder||TURB||4||Alive without recurrence|
|Chalkey and Bruce, 194211||9/M||Present||Entire bladder, prostate, and retroperitoneum||None||2||Asymptomatic|
|Kimbrough et al., 194810||29/F||None||Bladder||Excision||—||—|
de Klerk et al., 195413
|39/M||None||Bladder (377 g)||Excision||100||Alive without recurrence|
|20/M||Present||Bladder (13 cm)||Excision||—||—|
|Pitts, 194912||7/M||None||Entire bladder, prostate, penis, and scrotum||Radiation (24.85 Gy to pelvis)||24||Increasing tumor size|
Ross et al., 195714
|54/M||Present||Bladder (the size of a walnut)||None||24||Developed sarcomatous transformation 6 mos later|
|Schoenberg et al., 196115||4.5/M||Present||Bladder, prostate, and pelvic wall||Suprapubic cystostomies||0||Died of cardiac arrest|
|Gonzalez-Angulo and Reyes, 196316||0.4/M (4.5 mos)||Present||Bladder, prostate, ureter||Ureterostomy||—||—|
|19/F||Present||Bladder (6 cm)||Excision||—||—|
|van Buskirk et al., 196417||1.7/F (20 mos)||Present||Entire bladder, retroperitoneum, pelvic wall, and mesentery of sigmoid colon||None||1.0||Recurrence|
|Pessin and Bodian, 196418||0.1/F (1 mo)||Present||Entire bladder and urethra||Nephrostomy and cystostomy||3.5||Died of urinary obstruction|
|0.1/M (1 mo)||Present||Entire bladder, prostate and seminal vesicles, penis, and ureter||Cystoprostatectomy, uretrostomy, and cystostomy||2||Alive without recurrence|
|Torres and Bennett, 196620||27/F||Present||Entire bladder||Cystectomy||48||Alive without recurrence Died of unknown cause|
|Deniz et al, 196619||40/F||None||Entire bladder and uterus||Cystectomy||—||—|
|Carlson and Wilkinson, 197221||12/M||Present||Entire left wall of the bladder||Partial cystectomy||30||Alive without recurrence|
|6/M||Present||Dome of bladder and sigmoid colon||None||—||—|
|7/M||Present||Entire bladder, extending above pelvis||Bladder neck resection||226||Improvement in hydroephrosis Bilateral nephrostomy|
|Ray et al., 197322||13/M||Present||Entire bladder, prostate, and pelvic wall||Radical cystoprostatectomy||156||Alive without recurrence|
|Clark et al., 197723||36/M||Present||Entire bladder, prostate, and seminal vesicle||Radical cystoprostatectomy||90||Alive without recurrence|
|Matych and Bieniak, 197824||50/M||None||Bladder (the size of a man's fist)||Resection||—||—|
|Borden and Shrader 198025||5/M||Present||Entire bladder, prostate, penis, and pelvic wall||Cystoprostatectomy||12||Alive without recurrence|
|Kramer et al., 198126||3.5/M||Present||Bladder, prostate, and ureter||Radical cystoprostatectomy||18||Alive without recurrence|
|16/F||Present||Bladder (neck and dome)||Segmental resection||84||Multiple recurrences|
|Elliott et al., 198127||18/F||Present||Bladder and pelvic wall||Cystectomy||18||Recurrence|
|Rink and Mitchell, 198328||3/M||Present||Entire bladder, ureter, and spermatic cord||Resection of bladder tumor||—||Progressive penile enlargement and orchitectomy|
|5/F||Present||Bladder, ureter, clitoris, and vaginal wall||Resection of tumor Partial clitorectomy Ureteroneocystostomy||—||—|
|Winfield and Catalona, 198529||30/F||None||Trigone and posterior wall of the bladder||Cystectomy||Periodically||Alive without recurrence|
|Brooks and Scally,198530||37/M||Present||Entire bladder||None||—||—|
|Gersell and Fulling, 198931||28/F||None||Bladder, uterus, vagina, and vulva||Cystectomy, hysterectomy, and bilateral salpingo-oophorectomy||—||—|
|52/M||Present||Bladder||None||192||Developed sarcomatous transformation and distant metastasis 16 yrs later Died of cardiovascular disease|
Rober et al., 199133
|29/M||Present||Posterior wall of the bladder (20 cm mass)||Radical cystectomy||0.1||Diagnosed with MPNST at cystectomy Abdominal recurrence at the last follow-up|
|Sane et al., 199134||2/M||Present||Bladder (from posterior wall to trigone)||None||—||—|
|Shonnard et al., 1992||3.5/F||Present||Bladder and pelvic wall||Anterior pelvic exenteration||—||—|
|18/F||Present||Bladder, pelvic wall, and rectum||Cystectomy Transureteroureterostomy||—||—|
|10/F||Present||Entire bladder, uterus, and vagina||Cystectomy, hysterectomy Transureteroureterostomy||—||—|
|Barone et al., 1995||5/F||Present||Bladder||Continent urinary reservoir||12–48||Alive without recurrence|
|7/M||Present||Bladder||Cystoprostatectomy||12–48||Alive without recurrence|
|aDahms et al., 1995||33/M||Present||Bladder||Partial resection||18||Developed sarcomatous transformation 1.5 yrs later, treated with radical cystoprostatectomy|
|Nguyen et al., 1997||0.3/M (4 mos)||None||Entire bladder, prostate, and seminal vesicles||Radical cystoprostatectomy||2||Alive without recurrence|
|0.3/M (4 mos)||None||Entire bladder, prostate, seminal vesicles, rectum, and pelvic wall||Transureteroureterostomy||36||Alive with disease|
|Kaeffer et al., 1997||14/F||Present||Bladder, urethra, and vaginal wall||Anterior pelvic exenteration||36||Alive without recurrence|
|3/M||Present||Bladder, ureter, spermatic cord, and rectum||Transureteroureterostomy||96||Upper tract damage orchitectomy|
|3/M||Present||Bladder, pelvic wall, and left mesocolon||Transureteroureterostomy||18||Ureteral obstruction Scheduled for urinary diversion|
|13/F||Present||Bladder, pelvic wall, and urethra||None||—||Asymptomatic|
|5/F||Present||Bladder, clitoris, vaginal wall, and buttock||Partial clitorectomy||132||No recurrence; ureterectomy|
Significant morbidity may be associated with neurofibroma of the bladder. Extensive vesicular involvement may result in urinary tract obstruction. Early diagnosis and treatment avert upper tract damage and the need for radical surgery of extensive disease, but the inherently progressive nature of vesical involvement in many cases leaves this issue open. The histologic appearance of neurofibroma in the bladder is indistinguishable from that seen in other organs and is characterized by a proliferation of spindle cells with ovoid or elongate nuclei in a mucinous stroma. Differential diagnostic considerations include low grade malignant peripheral nerve sheath tumor (MPNST), leiomyoma, postoperative spindle cell nodule, inflammatory pseudotumor, low grade leiomyosarcoma, and rhabdomyosarcoma. The distinctive clinical, histologic, and immunohistochemical findings usually permit a definitive diagnosis. The presence of nuclear atypia or diffuse hypercellularity in neurofibroma may lead to an erroneous diagnosis of malignancy. Malignant transformation of neurofibroma is a life-threatening condition. It is critical to distinguish neurofibroma of atypical or cellular type from MPNST.1 Unlike MPNST, atypical neurofibromas lack mitotic figures or appreciable MIB-1 labeling. Their large cells with pleomorphic nuclei and smudged chromatin are reminiscent of those seen in ancient schwannoma. Cellular neurofibroma, on the other hand, are distinguished from MPNST by their smaller cell size, infrequent mitotic figures, lack of significant cytologic atypia and nuclear pleomorphism, and lack of necrosis. In the absence of definite cellular crowding, nuclear enlargement (≥3 times the size of ordinary neurofibroma nuclei) and hyperchromia, the finding of rare mitotic figures in a cellular neurofibroma is not sufficient for a diagnosis of malignancy. Adequate sampling is critical when increased cellularity is noted in superficial biopsies. Furthermore, transformation of neurofibroma to MPNS may be limited to small areas in otherwise benign-appearing lesions. This is particularly true in plexiform tumors, in which the process is often multifocal.
The histogenesis of neurofibroma of the bladder is uncertain. Because involvement of bladder by neurofibromatosis is usually extensive, such tumors likely originate from the adjacent pelvic autonomic plexus, which is in anatomic continuity with nerves innervating the ureter, vesical neck, and urethra. This would also explain the high frequency of autonomic ganglia involvement and of coexistent neurofibroma in other portions of the genitourinary and gastrointestinal tracts.
The optimal management of patients with neurofibroma of the bladder is unsettled.3, 40 Surgical intervention appears to be the treatment of choice for symptomatic patients. Radiation therapy was attempted in one patient with vesical neurofibroma, but without significant improvement in outcome.12 Conservative treatment by transurethral resection or partial cystectomy may be appropriate for patients without upper tract obstruction. When the process is extensive and symptomatic, radical cystectomy or pelvic exenteration often becomes necessary. Complete surgical excision is difficult or impossible in many instances. All 3 documented examples of neurofibroma with malignant transformation (6% of all cases) have occurred in adult patients. Despite a low risk of malignant transformation, careful clinical follow-up and continued surveillance is mandatory.
In summary, neurofibroma of the urinary bladder often presents early in life, is usually of the plexiform and diffuse type, and occurs more often in the setting of generalized disease than as isolated visceral neurofibromatosis. Despite long term follow-up, malignant transformation appears to be uncommon. A diagnosis of neurofibroma should be considered for children who present with urinary tract obstruction in the setting of neurofibromatosis type 1.