Neurofibroma of the urinary bladder

Authors


Abstract

BACKGROUND

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.

METHODS

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).

RESULTS

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.

CONCLUSIONS

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.

MATERIALS AND METHODS

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).

RESULTS

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).

Table 1. Clinical and Pathologic Findings in Neurofibroma of the Urinary Bladder
CaseAge (yrs)GenderFamily history of NF type 1aGeneralized signsbClinical presentationBladder imaging findingsCystoscopic findingsExtentType of neurofibromaTreatmentFollow-up (mos)Outcome
  • NF: neurofibroma; UTI: urinary tract infection.

  • a

    NF type 1: neurofibromatosis type I.

  • b

    Patient 1 had optic glioma, scoliosis, and systemic neurofibromas involving the gastrointestinal tract, spinal cords, arms, and legs. Patient 2 had mental retardation and multiple neurofibromas involving the spinal cord and the obturator nerve. Patient 3 had neurofibroma of the right arm and radial nerves. Patient 4 had diffuse cafe-au-lait spots (≥6) only.

17MNoPresentHematuriaIrregular bladder wall thickeningNeoplasmEntire bladderDiffuse and plexiformPartial cystectomy26Neurogenic bladder
228MNoPresentIrritative symptomsBilateral ureteral obstructionErythematousEntire bladderDiffuse and plexiformCystectomy119Hematuria and recurrent UTI
316FYesPresentPelvic massFilling defectNeoplasmEntire bladderDiffuse and plexiformPartial cystectomy210Atonic bladder
418FNoPresentIrritative symptomsThickening of bladder wallNodular massEntire bladderDiffuseTransurethral resection108Atonic 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%).

Figure 1.

Neurofibroma of the urinary bladder (Case 1) is shown. (A) The tumor displays diffuse and plexiform growth. (B) Neurofilament staining is shown. (C) Ganglion cells show involvement with neurofibroma. (D) S-100 protein immunostaining is diffusely positive. (E) Immunoreactivity for neurofilament protein is strong. (F) Submucosal tissue shows involvement with neurofibroma.

Figure 2.

In Case 3, the tumor shows a proliferation of uniform neurofibroma cells. The cellularity of the tumor is increased.

Figure 3.

In Case 4, superficial, bandlike, subepithelial, pseudo-Meissnerian corpuscles are prominent (A). These pseudo-Meissnerian corpuscles are immunoreactive for S-100 protein (B).

Table 2. Immunohistochemical Findings in Cases of Neurofibroma of the Urinary Bladder
CaseAlcian blueCK AE1/3CK CAM 5.2EMAS-100 proteinNeurofilamentCollagen IVp53MIB-1 labeling index
  1. CK: cytokeratin; EMA: epithelial membrane antigen; −: negative; +: positive.

1++++01.0
2++++07.3
3++++03.7
4+++00.9

DISCUSSION

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.

Table 3. Neurofiboma of the Urinary Bladder: Literature Review
AuthorsAge/gender (yrs)NF type 1bExtent of urinary tract involvementTreatmentFollow-up (mos)Outcome
  • a

    These cases were considered to have malignant degeneration in the original studies, but do not fulfill current criteria for the diagnosis of malignant peripheral nerve sheath tumor (MPNST).

  • b

    Malignant transformation was reported.

Kass et al., 193267/MPresentBladder (6–8 cm)None1Died of bronchopneumonia
McDonnell, 1936737/MPresentBladder, prostate, seminal vesicles, penis, and urethraDecompression of bladder
Mintz, 1940828/MNoneEntire bladderExcision
Thompson and McDonald, 1940959/MNoneBladderTURB4Alive without recurrence
Chalkey and Bruce, 1942119/MPresentEntire bladder, prostate, and retroperitoneumNone2Asymptomatic
Kimbrough et al., 19481029/FNoneBladderExcision
a

de Klerk et al., 195413

39/MNoneBladder (377 g)Excision100Alive without recurrence
 20/MPresentBladder (13 cm)Excision
Pitts, 1949127/MNoneEntire bladder, prostate, penis, and scrotumRadiation (24.85 Gy to pelvis)24Increasing tumor size
b

Ross et al., 195714

54/MPresentBladder (the size of a walnut)None24Developed sarcomatous transformation 6 mos later
Schoenberg et al., 1961154.5/MPresentBladder, prostate, and pelvic wallSuprapubic cystostomies0Died of cardiac arrest
Gonzalez-Angulo and Reyes, 1963160.4/M (4.5 mos)PresentBladder, prostate, ureterUreterostomy
 19/FPresentBladder (6 cm)Excision
van Buskirk et al., 1964171.7/F (20 mos)PresentEntire bladder, retroperitoneum, pelvic wall, and mesentery of sigmoid colonNone1.0Recurrence
Pessin and Bodian, 1964180.1/F (1 mo)PresentEntire bladder and urethraNephrostomy and cystostomy3.5Died of urinary obstruction
 0.1/M (1 mo)PresentEntire bladder, prostate and seminal vesicles, penis, and ureterCystoprostatectomy, uretrostomy, and cystostomy2Alive without recurrence
Torres and Bennett, 19662027/FPresentEntire bladderCystectomy48Alive without recurrence Died of unknown cause
Deniz et al, 19661940/FNoneEntire bladder and uterusCystectomy
Carlson and Wilkinson, 19722112/MPresentEntire left wall of the bladderPartial cystectomy30Alive without recurrence
 6/MPresentDome of bladder and sigmoid colonNone
 7/MPresentEntire bladder, extending above pelvisBladder neck resection226Improvement in hydroephrosis Bilateral nephrostomy
Ray et al., 19732213/MPresentEntire bladder, prostate, and pelvic wallRadical cystoprostatectomy156Alive without recurrence
Clark et al., 19772336/MPresentEntire bladder, prostate, and seminal vesicleRadical cystoprostatectomy90Alive without recurrence
Matych and Bieniak, 19782450/MNoneBladder (the size of a man's fist)Resection
Borden and Shrader 1980255/MPresentEntire bladder, prostate, penis, and pelvic wallCystoprostatectomy12Alive without recurrence
Kramer et al., 1981263.5/MPresentBladder, prostate, and ureterRadical cystoprostatectomy18Alive without recurrence
 16/FPresentBladder (neck and dome)Segmental resection84Multiple recurrences
Elliott et al., 19812718/FPresentBladder and pelvic wallCystectomy18Recurrence
Rink and Mitchell, 1983283/MPresentEntire bladder, ureter, and spermatic cordResection of bladder tumorProgressive penile enlargement and orchitectomy
 5/FPresentBladder, ureter, clitoris, and vaginal wallResection of tumor Partial clitorectomy Ureteroneocystostomy
Winfield and Catalona, 19852930/FNoneTrigone and posterior wall of the bladderCystectomyPeriodicallyAlive without recurrence
Brooks and Scally,19853037/MPresentEntire bladderNone
Gersell and Fulling, 19893128/FNoneBladder, uterus, vagina, and vulvaCystectomy, hysterectomy, and bilateral salpingo-oophorectomy
b

Hulse, 199032

52/MPresentBladderNone192Developed sarcomatous transformation and distant metastasis 16 yrs later Died of cardiovascular disease
b

Rober et al., 199133

29/MPresentPosterior wall of the bladder (20 cm mass)Radical cystectomy0.1Diagnosed with MPNST at cystectomy Abdominal recurrence at the last follow-up
Sane et al., 1991342/MPresentBladder (from posterior wall to trigone)None
Shonnard et al., 19923.5/FPresentBladder and pelvic wallAnterior pelvic exenteration
 18/FPresentBladder, pelvic wall, and rectumCystectomy Transureteroureterostomy
 10/FPresentEntire bladder, uterus, and vaginaCystectomy, hysterectomy Transureteroureterostomy
Barone et al., 19955/FPresentBladderContinent urinary reservoir12–48Alive without recurrence
 7/MPresentBladderCystoprostatectomy12–48Alive without recurrence
aDahms et al., 199533/MPresentBladderPartial resection18Developed sarcomatous transformation 1.5 yrs later, treated with radical cystoprostatectomy
Nguyen et al., 19970.3/M (4 mos)NoneEntire bladder, prostate, and seminal vesiclesRadical cystoprostatectomy2Alive without recurrence
 0.3/M (4 mos)NoneEntire bladder, prostate, seminal vesicles, rectum, and pelvic wallTransureteroureterostomy36Alive with disease
Kaeffer et al., 199714/FPresentBladder, urethra, and vaginal wallAnterior pelvic exenteration36Alive without recurrence
 3/MPresentBladder, ureter, spermatic cord, and rectumTransureteroureterostomy96Upper tract damage orchitectomy
 3/MPresentBladder, pelvic wall, and left mesocolonTransureteroureterostomy18Ureteral obstruction Scheduled for urinary diversion
 13/FPresentBladder, pelvic wall, and urethraNoneAsymptomatic
 5/FPresentBladder, clitoris, vaginal wall, and buttockPartial clitorectomy132No 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.

Ancillary