Younger Female with Urethral Pain

Specimen Type:

Bladder

History:

An otherwise healthy 18-year-old girl presented with urethral pain and a history of recurrent urinary tract infections. Pelvic ultrasound and cystoscopy revealed diffuse thickening of the posterior bladder wall with erythema of the overlying mucosa. Bladder biopsy was performed.

Pathologic Features:

The lesion is ill-defined and spares the overlying urothelium (Fig. 6.1) It is composed of short intersecting bundles of spindle cells with characteristic wavy hyperchromatic nuclei, fibroblasts, and scattered inflammatory cells dispersed in a uniform matrix of fine fibrillary collagen (Fig. 6.2). There is no cytologic atypia, mitotic activity, or necrosis. Numerous Wagner-Meissner bodies are present (Fig. 6.3). The tumor cells show intense cytoplasmic immunoreactivity for S-100 protein (Fig. 6.4). Neurofilament protein-positive axons are also present (Fig. 6.5); cytokeratin and epithelial membrane antigen are negative (Fig. 6.6).

Differential Diagnosis:

The differential diagnosis includes leiomyoma (Fig. 6.7), neurofibroma (Fig. 6.8), inflammatory pseudotumor (Fig. 6.9), post-operative spindle cell nodule (Fig. 6.10), leiomyosarcoma (Fig. 6.11), and embryonal rhabdomyosarcoma (Fig. 6.12).

Diagnosis:

NEUROFIBROMA OF URINARY BLADDER (in the setting of neurofibromatosis type 1)

Follow-up: This patient had neurofibromatosis type 1 and was found to have cafe-au-lait spots on careful physical examination. No other lesions were noted. The bladder tumor was removed by transurethral resection. Nine years after the diagnosis, the patient was alive, but continued to have urinary symptoms due to atonic bladder.

Key Features:

  • Bladder is the most common site of involvement in the genitourinary tract; others sites include ureter, urethra, prostate, spermatic cord, penis, scrotum, cervix, vulva, labia, and clitoris.
  • Neurofibroma of the bladder presents early in life and is more common in boys
  • Most are plexiform and diffuse, arising in the setting of neurofibromatosis 1 (von Recklinghausen's disease)
  • Presents with recurrent urinary tract infection at young age, urinary obstruction with bilateral hydronephrosis, and a thickened bladder on abdominal ultrasound
  • Partial cystectomy is often unsuccessful due to the diffuse nature of the lesion. Extensive uncontrollable disease may require radical cystectomy with urinary diversion or even pelvic exenteration
  • Urinary obstruction and renal failure may result in death

Discussion: Neurofibromatosis type I (von Recklinghausen's disease) is a common autosomal dominant disorder with a high rate of penetrance, affecting 1 in 3000 live births. It is associated with mutations, deletions, or insertions of the NF1 gene, a tumor suppressor gene spanning 350 kb of genomic DNA on chromosome 17p. The gene product, neurofibromin, is believed to play a role in cell proliferation and differentiation by down regulation of ras p21 gene product. The lesions characterizing NF1 include cafe-au-lait spots, axillary freckling, multiple cutaneous neurofibromas, plexiform neurofibromas, pigmented iris hamartomas, skeletal changes, and intracranial and intraorbital gliomas.

Visceral neurofibromatosis is rare and most affected patients exhibit few external manifestations of NF1. The gastrointestinal tract is most commonly affected, including the esophagus, stomach, and small bowel. Involvement of genitourinary tract is extremely uncommon, with the bladder being the usually affected organ. There are fewer than 75 reported cases of neurofibroma of the bladder in the setting of NF1; rare cases of neurofibroma involving bladder have been reported in the absence of neurofibromatosis. Other genitourinary sites that may be involved include the ureter, urethra, prostate, spermatic cord, penis, scrotum, cervix, clitoris, and vagina.

Neurofibroma of the urinary bladder presents early in life with a mean age at diagnoses of 17 years. There is a slight male predominance (M:F ratio of 2.3:1). Presenting features include irritative voiding symptoms and hematuria due to recurrent urinary tract infections, enuresis, and urinary obstruction. In children, the symptoms of bladder outlet obstruction and radiographic findings of dilated prostatic urethra may occasionally mimic posterior urethral valves (1). Neurofibroma of the urinary bladder is believed to arise from vesicoprostatic plexus in boys and urethrovaginal plexus in girls. The histologic appearance of neurofibroma in bladder is indistinguishable from that seen in other organs, and is usually of plexiform and diffuse type with transmural involvement (2). The distinctive clinical, histologic, and immunohistochemical findings permit its distinction from other spindle cell proliferations including, low-grade malignant peripheral nerve sheath tumor, leiomyoma, post-operative spindle cell nodule, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. Once the diagnosis is made on a biopsy, the extent of the lesion is defined by MRI and CT scan.

Most patients eventually require surgical intervention due to urinary obstruction (3). Partial cystectomy often fails to completely eradicate the tumor due to its diffuse nature, thus accounting for a high recurrence rate. However, the majority of patients with recurrent neurofibroma can be managed expectantly and the role of aggressive surgery such as radical cystectomy with urinary diversion, especially in children, has been questioned (4). Although a benign tumor, it may cause death by urinary obstruction and renal failure. Malignant transformation has been rarely reported, usually in adult patients (5,6,7). Adequate sampling is critical to rule out malignancy when increased cellularity is noted in superficial biopsies.

References:

  1. Brown JA, Levy JB, Kramer SA. Genitourinary neurofibromatosis mimicking posterior urethral valves. Urology 1997; 49(6):960-2.
  2. Cheng L, Scheithauer BW, Leibovich B, Ramnani DM, Cheville JC, Bostwick DG. Neurofibroma of the urinary bladder. Cancer 1999; 86:505-13.
  3. Kaefer M, Adams MC, Rink RC, Keating MA. Principles in management of complex pediatric genitourinary plexiform neurofibroma. Urology 1997; 49:936-40.
  4. Nguyen HT, Kogan BA, Hricak H, Turzan C. Plexiform neurofibroma involving the genitourinary tract in children: Case reports and review of the literature. Urology 1997; 49:257-60.
  5. Rober PE, Smith JB, Sakr W, Pierce JM. Malignant peripheral nerve sheath tumor (malignant schwannoma) of urinary bladder in von Recklinghausen neurofibromatosis. Urology 1991; 38:473-6.
  6. Hulse CA. Neurofibromatosis: Bladder involvement with malignant degeneration. J Urol 1990; 144:742-3.
  7. Dahm P, Manseck A, Flossel C, et al. Malignant neurofibroma of the urinary bladder. Eur Urol 1995; 27(3):261-3.