Diffuse ganglioneuromatosis and plexiform neurofibroma of the urinary bladder: report of a pediatric example and literature review

Diffuse ganglioneuromatosis and plexiform neurofibroma of the urinary bladder: report of a pediatric example and literature review

Human Pathology (2008) 39, 1708–1712 www.elsevier.com/locate/humpath Case study Diffuse ganglioneuromatosis and plexiform neurofibroma of the urina...

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Human Pathology (2008) 39, 1708–1712


Case study

Diffuse ganglioneuromatosis and plexiform neurofibroma of the urinary bladder: report of a pediatric example and literature review Bernd W. Scheithauer MD a,⁎, Mariarita Santi MD b , Eric R. Richter MD d , Barry Belman MD c , Elisabeth J. Rushing MD e a

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55905, USA Division of Pathology, Children's National Medical Center, Washington DC 20010, USA c Division of Urology, Children's National Medical Center, Washington DC 20010, USA d Urology Department, Walter Reed Army Medical Center, Washington DC 20307, USA e Department of Neuropathology and Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington DC 20306, USA b

Received 19 December 2007; revised 5 February 2008; accepted 12 February 2008

Keywords: Urinary bladder; Ganglioneuromatosis; Plexiform neurofibroma; Neurofibromatosis type 1; Immunohistochemistry

Summary As an initial manifestation of neurofibromatosis type 1, isolated neurofibroma of the urinary bladder occurs only rarely in the first 2 decades of life. We report a case of a 6-year-old AfricanAmerican girl who presented in this manner and was found to have a plexiform neurofibroma as well as diffuse ganglioneuromatosis of the urinary bladder. We describe the clinical presentation, diagnostic procedures, and pathologic features encountered. In addition, we review the literature with respect to etiology, current treatment strategies, and the issue of surveillance for this complex lesion occurring in the pediatric population. Neurofibroma of the bladder should be considered in the differential diagnosis of painless hematuria in childhood. Its presentation in such patients warrants a complete evaluation to establish the diagnosis of neurofibromatosis type 1 and begin long-term surveillance for its associated manifestations. At present, there are no established criteria for the treatment of this rare lesion. © 2008 Published by Elsevier Inc.

1. Introduction Pediatric tumors of the urinary bladder are rare, rhabdomyosarcoma being the most frequently occurring lesion. Most are low grade and present at an early stage; reported cure rates approach 70% to 80% [1]. Painless hematuria is the usual presentation. The diagnosis is often ⁎ Corresponding author. E-mail address: [email protected] (B. W. Scheithauer). 0046-8177/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.humpath.2008.02.019

suggested by sonography, but its confirmation requires cystoscopy or open biopsy [2,3]. Controversy persists regarding long-term preservation of bladder function, efficacy of radiotherapy, timing of reconstructive surgery, and the utility of molecular markers in monitoring disease progression [2]. Other bladder tumors are exceedingly uncommon in the pediatric age group. These include transitional cell papillomas, papillary carcinoma, inflammatory myofibroblastic tumors, and very rarely neurofibromas [1-11]. Of these, some are associated with genetic risk factors [2,4].

Diffuse ganglioneuromatosis and plexiform neurofibroma of the urinary bladder


reported example of this rare lesion complex and the first to affect the urinary bladder of a child.

2. Case history

Fig. 1 A urinary bladder ultrasound demonstrates an area of marked (2.5 cm) mural thickening of the posterior bladder wall (A). Cystoscopy revealed a well-circumscribed, midline submucosal mass posterior and distal to the trigone (B).

Neurofibromatosis (NF1), an autosomal dominant disorder affecting approximately 1 in 3000 individuals, is characterized by a wide variety of lesions, most notably café-au-lait spots, skin fold freckling, Lisch nodules, cutaneous, and plexiform, as well as massive soft tissue neurofibromas, learning disabilities, and a propensity to develop malignant tumors of the peripheral and central nervous systems [12]. Approximately half of all cases are sporadic and represent new mutations. Neurofibromin, the product of the affected tumor suppressor gene, acts as a GTPase-activating protein and, in part, functions as a negative regulator of Ras. The NF1 locus is situated at 17q11.2 within a domain near the centromere [13]. Neurofibromas rarely manifest in the genitourinary tract; fewer than 70 cases with bladder involvement have been reported to date [4,5]. Of these, only about 25 cases have occurred in the pediatric population [5]. We describe an unusual case of plexiform neurofibroma and diffuse ganglioneuromatosis of the bladder presenting with painless hematuria in a child with NF1. Ours is but the second

The patient, a previously healthy 6-year-old AfricanAmerican girl, presented with a 6-day course of painless, gross hematuria. She had no prior history of trauma, and culture of the grossly bloody urine was negative for bacterial, fungal, and mycobacterial infection. Both parents were in good health and had neither a family history nor stigmata of NF1. On physical examination, multiple café-au-lait spots were noted on the skin of the abdomen as was axillary and inguinal freckling. These findings in conjunction with the nature of bladder lesion described herein confirmed the diagnosis of NF1. A renal and urinary bladder ultrasound was obtained. It demonstrated a 4.5-cm (transverse) by 1.7-cm (anteroposterior) area of marked (2.5 cm) mural thickening of the posterior bladder wall extending laterally from the midline (Fig. 1A). Cystoscopy revealed a wellcircumscribed, midline submucosal mass posterior and distal to the trigone (Fig. 1B). Under direct cystoscopic observation, three 18-guage needle biopsies were obtained. One was subject to frozen section. A diagnosis of “benign neoplasm; favor neurofibroma” was made. Given the benign gross and histologic appearance of the lesion, a partial cystectomy was performed. The dissection was carried through the rectus fascia to enter the space of Retzius. The bladder was opened vertically revealing an obvious tumor more extensive than suggested on cystoscopy. It encompassed much of the bladder wall but showed no extravesical extension. With the use of cautery, the thickened bladder wall was only partly resected. A total resection was not compatible with sparing of bladder function. Thus, after

Fig. 2 Whole mount section of the bladder wall showing massive thickening, expansion of superficial portions by diffuse neurofibroma and the submucosa and muscularis by plexiform neurofibroma.


B. W. Scheithauer et al.

Fig. 3 The diffuse neurofibroma component consists of individual small spindle-shaped cells in a delicate collagenous matrix (A) (original magnification ×64), whereas the plexiform neurofibroma component consists of numerous sinuous expansions of nerve fascicles (B) (original magnification ×250). Strong immunoreactivity for S-100 protein was noted in both the diffuse (C) and plexiform (D) components of the neurofibroma (original magnification: C and D, ×100).

debulking the majority of the tumor, the bladder was closed in 2 layers followed by the rectus fascia, deep dermis, and skin. Postoperatively, the patient experienced an uncomplicated recovery without hematuria or irritative voiding. Biannual ultrasound surveillance of the patient's bladder will be undertaken, but no additional treatment is planned.

3. Pathology Grossly, the bladder wall was thick (Fig. 2) and showed sinuous nodularity. Histopathologic examination revealed a neurofibroma in association with ganglioneuromatosis. Thus, the process involved both sensorimotor nerves and the submucosal and myenteric autonomic plexuses. The neurofibromatous component showed 2 histologic patterns, one diffuse and involving both lamina propria and submucosa (Fig. 3A), the other a more deeply situated plexiform element (Fig. 3B). These consisted of crowded, spindle-shaped cells with scant, pale cytoplasm, and elongate, wavy nuclei set in a delicate, collagenous stroma.

No cytologic atypia was seen. As expected, the cells comprising both neurofibromatous components expressed S-100 protein (Fig. 3C,D). Axons within the plexiform, epithelial membranous antigen–immunopositive, perineurium-bounded fascicles were labeled for neurofilament proteins (Fig. 4A,B). Small, immature neurons exceed intermediate and fully mature neurons within the ganglioneuromatous component (Fig. 5A). Immunostaining of these cells revealed strong nuclear reactivity for NeuN (Chemicon, Temecula, CA; dilution 1:10000, no clone; Fig. 5B), chromogranin (Chemicon; dilution 1:500, clone LK2H10) (Fig. 5C), and, to some extent, neurofilament protein (Dako, Carpinteria, CA; dilution 1:800, clone 2F11). Low-level MIB-1 labeling was noted in small neurons (Fig. 5D).

4. Discussion Gross hematuria, unless associated with urinary tract infection, calculus disease, or trauma, is an unusual

Diffuse ganglioneuromatosis and plexiform neurofibroma of the urinary bladder

Fig. 4 Affected fascicles of the plexiform neurofibroma contained neurofilament protein–positive axons (A) and were bounded by epithelial membranous antigen–immunopositive perineurium (B). (Hematoxylin and eosin, original magnification: A, × 100; B, × 250.)

occurrence in the pediatric population and warrants further evaluation. In a study of 342 children examined over a 10year-year period, Greenfield et al [3] found gross hematuria to be more common in boys and to generally relate to benign processes. In their series, only 5% of patients had neoplasms [3]. Sonography and voiding cystourethrography have been found to be sensitive techniques for identifying primary bladder tumors in children [2]. Cystoscopy should be reserved for cases in which imaging findings are ambiguous [3]. Magnetic resonance imaging is recommended as the best method for staging disease and treatment planning [10]. In the present case, painless hematuria was the initial manifestation of a plexiform neurofibroma and ganglioneuromatosis, a rare lesion complex at any age, but particularly in children. Although very uncommon, neurofibroma has been reported to involve nearly every level of the genitourinary system, the bladder being most often affected [9]. It affects both spinal (pudendal) and auto-


nomic nerves of the bladder wall, the latter including involvement of visceral ganglia. Neurofibromas, be they diffuse or intraneural, are immunoreactive for both S-100 protein and type IV collagen [5]. Most examples are benign, although approximately 5% of plexiform examples are known to undergo malignant transformation [14]. Only 2 published reports describe neurofibromas of the urinary bladder having undergone malignant transformation [8,11]. In the report by Hulse [8], a 52-year-old man with a history of multiple cutaneous neurofibromas presented with a flaccid, neurogenic bladder thought to be related to a neurofibroma in the lumbosacral region. Subsequent autopsy examination revealed extensive malignant peripheral nerve sheath tumor of the bladder [8]. In the other report, a 29-year-old man with known NF1 was found to have a large malignant peripheral nerve sheath tumor replacing the entire posterior wall of the bladder. The treatment of plexiform neurofibroma is problematic given its tendency to involve innumerable branches or an entire plexus of nerves, thereby making it difficult or impossible to achieve a total resection [9]. In a 4-case Mayo Clinic series of neurofibroma of the urinary bladder reported by Cheng et al [5], mean patient age at diagnosis was 17 years (range, 7-28 years). The male-tofemale ratio was 1:1, and all exhibited diagnostic stigmata of NF1. The clinical presentations were hematuria (n = 1), irritative symptoms (n = 2), and pelvic mass (n = 1) [5]. In 3 instances, histopathologic examination revealed transmural involvement by both diffuse and plexiform neurofibroma. In the fourth, the biopsy was superficial and showed only diffuse submucosal involvement with abundance of pseudoMeissnerian corpuscles. It is of note that no evidence of malignant transformation was noted over a mean follow-up period of 9.6 years. The only previous case of plexiform neurofibroma in association with diffuse ganglioneuromatosis was confined to the gastrointestinal tract of a 20-year-old man [7]. In that example, the ileal wall, including submucosa and muscularis propria, was replaced by tumor. In addition, a plexiform neurofibroma was found in the mesentery. Although this patient was said to exhibit no stigmata of NF1, the disease may be subtle and, in some instances, its manifestations are localized in distribution.

5. Conclusion This report emphasizes that neurofibroma and variations in its morphology including ganglioneuromatosis should be considered in the differential diagnosis of painless hematuria in childhood. Once the diagnosis is confirmed, longterm surveillance is essential to monitor continued tumor growth, the unlikely occurrence of malignant transformation, and the development of other neoplastic manifestations of NF1.


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Fig. 5 The ganglioneuromatosis element showed relative abundance of small neurons as compared to large ganglion cells (A) (hematoxylin and eosin, original magnification × 250). The ganglion cells, large and small, showed strong nuclear staining for NeuN (B) and chromogranin (C). MIB-1 Labeling was localized to small neurons (D). (Immunostains, original magnification: B, ×160; C, 400; D, 250.)

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[8] Hulse CA. Neurofibromatosis: bladder involvement with malignant degeneration. J Urol 1990;144:742-3. [9] Kaefer M, Adams MC, Rink RC, Keating MA. Principles in management of complex pediatric genitourinary plexiform neurofibroma. Urology 1997;49:936-40. [10] 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. [11] Rober PE, Smith JB, Sakr W, Pierce Jr JM. Malignant peripheral nerve sheath tumor (malignant schwannoma) of urinary bladder in von Recklinghausen neurofibromatosis. Urology 1991;38:473-6. [12] Scheithauer BW, Woodruff J, Erlandson RA. Neurofibromatosis (Chapter 13). In: Rosai J, Sobin LH, editors. Atlas of tumor pathology— tumors of the peripheral nervous system, Third series, Fascicle 24. Washington (DC): Armed Forces Institute of Pathology; 1999. p. 385-415. [13] Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop DT, Carey J, Baty B, Kivlin J, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science (New York, NY) 1987;236:1100-2. [14] Scheithauer BW, Woodruff J, Erlandson RA. Neurofibroma (Chapter 8). In: Rosai J, Sobin LH, editors. Atlas of tumor pathology—tumors of the peripheral nervous system, Third series, Fascicle 24. Washington (DC): Armed Forces Institute of Pathology; 1999. p. 177-218.