Multiple Mucosal Neuromata

Introduction

The multiple endocrine neoplasia (MEN) syndromes are characterized by tumors of neuroendocrine origin. The third of these to be reported, MEN III syndrome, also called MEN IIB syndrome or multiple mucosal neuroma syndrome, was initially described by Wagenmann in 1922.

The disease is associated with adrenal pheochromocytoma, medullary thyroid carcinoma, diffuse alimentary tract ganglioneuromatosis, and multiple small submucosal neuroma nodules of the upper aerodigestive tract. The disease is inherited as an autosomal dominant trait, although many cases appear to be spontaneous mutations.

The affected individual has a tall, lanky, marfanoid body type, with a narrow face and perhaps with muscle wasting. The adrenal and thyroid tumors typically do not present until after puberty while the oral mucosal neuromas usually develop during the first decade of life. Mucosal neuromas are extremely rare, perhaps unheard of, outside of the MEN III syndrome.

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Clinical Features

The oral mucosal neuroma of this disease presents as a 2-7 mm. yellowish-white, sessile, painless nodule of the lips, anterior tongue and buccal commissures. Usually there are 2-8 (or more) neuromas, with deeper lesions having normal coloration. There may be enough neuromas in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the eyelids, sometimes producing eversion of the lid, and on the sclera. Facial skin, especially around the nose, may also be involved..

Abnormal laboratory values are part of this syndrome. When a medullary thyroid carcinoma is present, serum and urinary calcitonin levels are elevated. When a pheochromocytoma is present, there often is an increase in the serum levels of vanillylmandelic acid (VMA) and altered epinephrine/norepinephrine ratios.

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Pathology and Differential Diagnosis

The mucosal neuroma is comprised of a partially encapsulated aggregation or proliferation of nerves, often with thickened perineurium, intertwined with one another in a plexiform pattern (Figure 3). This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma. Individual nerves flow in fascicles of 2-3 fibers and are histologically normal except for occasional hyperplasias and bulbous expansions.

Luxol fast blue staining will identify myelin sheathing of some fibers, and lesional cells react immunohistochemically for S-100 protein, collagen type IV, vimentin, NSE, and neural filaments. More mature lesions will react also for EMA, indicating a certain amount of perineurial differentiation. Early lesions have a stroma rich in acid mucopolysaccharides, hence, will stain positively with alcian blue.

Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues. There may be close microscopic similarity with traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma.

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Treatment and Prognosis

The mucosal neuromas of this syndrome are asymptomatic and self limiting, and present no problem requiring treatment. They may, however, be surgically removed for esthetic purposes or if they are being constantly traumatized. The patient should be followed by an internist, endocrinologist or other appropriate clinician relative to his or her potential adrenal or thyroid cancer. Because of the serious nature of the latter conditions, it is strongly suggested that other family members be evaluated for MEN III.

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References

353. Wagenmann A. Multiple neurome des Auges und der Zunge. Ber Dtsch Opthalmol Ges 1922; 43:282-285.

354. Gorlin RJ, et al. Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid. A syndrome. Cancer 1968; 22:293-299.

355. Miller RL, et al. The ultrastructure of oral neuromas in multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma syndrome. J Oral Pathol 1977; 6:253-263.

356. Dyck PJ, et al. Multiple endocrine neoplasia, type 2b: phenotype recognition; neurological features and their pathological basis. Ann Neurol 1979; 6:302-314.

357. Schenberg ME, et al. Multiple endocrine neoplasia syndrome - type 2b: case report and review. Int J Oral Maxillofac Surg 1992; 21:110-114.

358. Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genetics 1996, 33:779-782.

359. Pujol RM, Matias-Guiu X, Miralles J, et al. Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity? J Am Acad Dermatol 1997; 37:349-352.

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