Isolated intestinal neurofibromatous proliferations (IINP) are benign neural lesions of the lower gastrointestinal tract which may be the initial manifestation of generalized systemic NF1 or MEN 2b. In these settings, IINP may manifest as single or multiple well-defined stromal neoplasms or as a diffuse neuronal hyperplasia, commonly termed ganglioneuromatosis. The clinical, radiographic, and histologic findings of such lesions are not specific to NF1 or MEN 2b, and identical features have been reported in association with juvenile and adenomatous colonic polyposis[3,4
] and as an isolated finding in patients with no additional clinical evidence of neurocutaneous, intestinal polyposis, or multiple endocrine neoplasia syndromes[5,6
The clinical presentation of neurofibromatous lesions of the lower gastrointestinal tract are myriad and are dependent upon the focal or diffuse nature of the lesions, their location, their effect on gastrointestinal motility, and their possible impingement on adjacent structures. Affected patients may present with altered bowel habits including constipation or diarrhea[7,8
], abdominal pain[9
], intestinal obstruction[10
], or with palpable abdominal masses[6
]. In the setting of NF1, associated clinical findings including the classic dermal neurofibromas, café-au-lait macules, and Lisch nodules may be seen. In the setting of MEN 2b, the characteristic facies including thickened lips from mucosal neuromas, marfanoid habitus, and even features of medullary carcinoma of the thyroid may be present. In IINP, the intestinal symptoms manifest without demonstrable clinical evidence of associated systemic syndromes.
Radiographically, lower gastrointestinal neurofibro-matous lesions may manifest as diffuse, confluent thickening of portions of the intestine or as single or multiple discrete lesions of the intestinal wall or mesentery. The radiographic differential diagnosis of single or multiple nodular neurofibromatous lesions is wide and includes many epithelial and stromal neoplasms as well as nodular lymphomas. The diffuse forms of IINP may mimic the radiographic appearance of Crohn’s
disease on barium studies and computed tomography scans. In a report by Charagundla et al[7
], a patient with signs and symptoms of colitis was found to have segmental thickening of an extended portion of the distal ileum radiographically. Clinically, Crohn’s disease was suspected, but subsequent small bowel resection showed diffuse IINP. At least two other reports have documented similar findings[11,12
The endoscopic appearance of IINP depends on the focal or diffuse nature of the lesions. As the lesions arise deep to the epithelium, they manifest as single or multiple subepithelial masses of variable size and distribution. In some cases, numerous small lesions carpet a portion of the lower gastrointestinal tract, while in others, a larger lesion may predominate and significantly stenose the lumen of the affected area. Endoscopic biopsies are the mainstay of diagnosis, but when used in an attempt to sample deep-seated lesions, the biopsies may yield only unaffected overlying bowel mucosa or minimally diagnostic superficial lesional tissue. Ulceration, due to erosion of the epithelium over the surface of lesions, has been described, particularly in larger solitary lesions, but occasional cases have been described in which ulceration was sufficiently widespread and significant to raise the endoscopic differential diagnosis of idiopathic inflammatory bowel disease. In the current case, the endoscopic appearance was that of multiple small cecal polyps and nodular colonic mucosa, and endoscopic sampling yielded only the most superficial portion of the neurofibromatous proliferation. No associated ulceration was identified.
Grossly, the intestinal neurofibromatous proliferations tend to be firm, solid, and white to tan throughout. Hemorrhage and necrosis are exceptional, but superficial ulceration has been reported in lesions of varying size. The lesions may manifest as confluent neurofibromatous proliferations involving contiguous sections of bowel or as focal polypoid lesions with a sporadic distribution. The varied gross manifestations of IINP generally have a similar histologic appearance, consisting of a proliferation of neural elements including nerve fibers and supporting cells which may be diffusely intermingled or arranged in fascicles of bland spindle-shaped cells. The cells exhibit elongated nuclei with inconspicuous nucleoli and moderate amounts of eosinophilic cytoplasm. Ganglion cells may be present in variable numbers. Despite their sometimes striking cellularity and occasional cellular pleomorphism, mitotic activity in these lesions is minimal. Immunohistochemically, the cells show a variable degree of expression for S100 protein and synaptophysin.
IINP most frequently involve the colon, terminal ileum, and appendix[13
], but similar neurofibromatous proliferations isolated to the upper gastrointestinal tract have been described. Siderits et al[2
] reported a case of sporadic ganglioneuromatosis of the gastroesophageal junction in a patient with gastroesophageal reflux, and solitary neurofibromas of the esophagus have also been documented[14
]. These lesions show endoscopic and biopsy features identical to their counterparts in the lower gastrointestinal tract.
The treatment of IINP is primarily surgical and is dependent on the location and size of the lesions. Solitary, well-circumscribed lesions may be only incidental findings at the time of screening endoscopy and require no further therapy, but larger solitary lesions may come to clinical attention due to intestinal obstruction or impingement on adjacent structures and require resection. For lesions that are more diffusely distributed, treatment strategies are dictated by the symptomatology. Intractable abdominal pain, constipation, and diarrhea may require palliative resection of the involved segment of lower gastrointestinal tract. Accurate histopathologic categorization of biopsy and resection specimens is required to guide appropriate surgical therapy.