Multiple endocrine neoplasia type 2 syndrome presenting with bowel obstruction caused by intestinal neuroma: case report.

Abstract: We present the case of a 23-year-old male with a history since early childhood of lip and tongue mucosal neuromas. At the age of 19, he was diagnosed with both medullary thyroid carcinoma and pheochromocytoma within 1 year. These findings, with his marfanoid habitus, led to the diagnosis of multiple endocrine neoplasia type 2 (MEN 2B) syndrome. This was confirmed by a positive RET proto-oncogene. On this admission, he presented with an intestinal obstruction. Abdominal exploration revealed an obstructing tumor mass requiring colectomy, which proved by biopsy to be an intestinal neuroma. This report presents a unique case of a colonic mucosal neuroma causing obstruction in MEN 2B syndrome after the diagnosis of medullary thyroid carcinoma.

Key Words: bowel obstruction, intestinal neuroma, multiple endocrine neoplasia type 2.

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This is the case of a 23-year-old man with multiple endocrine neoplasia type 2B (MEN 2B) syndrome who presented with an intestinal obstruction secondary to intestinal neuroma.

Sipple first described an association between thyroid cancer and pheochromocytoma in 1961. The thyroid cancer associated with pheochromocytoma was discovered to be medullary carcinoma characterized by stromal amyloid in 1965. This familial association of pathology, along with parathyroid hyperplasia, was defined as MEN type 2 (MEN 2) in 1968. Inherited as an autosomal dominant disorder, MEN 2 has three distinct subtypes, including MEN 2A, MEN 2B, and familial medullary thyroid carcinoma-only (FMTC-only). The overall frequency of MEN syndrome in the United States is one case per 30,000 to 50,000 persons (ie, 0.00003 to 0.00002%). In decreasing frequency, MEN syndromes occur as follows: MEN 2A, FMTC-only, and MEN 2B. MEN 2B represents about 5% of all MEN 2 cases. (1) A primary criteria for differentiation of MEN 2B from MEN 2A is the absence of mucosal neuromas in the latter.

Case Report

The patient was a 23-year-old male who had a history of mucosal neuromas in the lips and tongue since early childhood, the significance of which remained unrecognized for years (Fig. 1). At age 19, he presented with extensive cervical lymphadenopathy. Biopsy revealed findings suggestive of thyroid carcinoma. Calcitonin level was elevated, and a subsequent modified total thyroidectomy was performed, revealing medullary carcinoma of thyroid with nodal metastases.

The following year, a screening computed tomographic (CT) scan of the abdomen revealed a left adrenal mass. High urinary metanephrine levels confirmed the diagnosis of a pheochromocytoma, which had remained asymptomatic and untreated. The combination of medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas established the phenotype of MEN 2B syndrome. A positive RET proto-oncogene in codon 918 was confirmatory.

At the time of admission, the patient had been having crampy abdominal pain with diarrhea, followed by the development of obstipation. A CT scan of the abdomen showed colonic distention, with gas and circumferential mucosal thickening, and an apparent obstruction at the level of the mid-descending colon. Colonoscopy showed a diffuse submucosal nodular abnormality of the descending colon (Fig. 2). An exploratory laparotomy revealed an obstructive tumor that was fixed to the retroperitoneum, resulting in mechanical obstruction. A colectomy was performed.

A biopsy of the specimen showed diffuse neural hypertrophy within the muscularis propria, smooth muscle hypertrophy, and a stricture at this level, consistent with mucosal neuroma.

At 8 months' follow-up, the patient was asymptomatic, with no evidence of recurrent bowel obstruction.

Discussion

The hallmark of MEN 2B syndrome is the presence of characteristic mucosal neuromas on the distal portion of the tongue, lips, subconjunctival areas, and throughout the gastrointestinal tract. Thickened medullated corneal nerves may be identified by slit-lamp examination. Ganglioneuromatosis of the gastrointestinal tract can cause obstruction, dilation of the colon, or a colic-like syndrome associated with diarrhea. Other features may include a marfanoid habitus, pectus excavatum, slipped femoral epiphysis, and long, thin extremities. (2-4)

Mucosal neuromas and medullary thyroid carcinoma occur in all affected patients. A marfanoid habitus is present in 75% of patients, and pheochromocytoma in 50%, whereas enteric ganglioneuromatosis is found in more than 40% of those affected. (5) A primary criteria for differentiation of MEN 2B from MEN 2A is the absence of mucosal neuromas in the latter.

Gastrointestinal ganglioneuromatosis is the predominant cause of most alimentary tract symptoms in patients with MEN 2B, resulting from thickening of the myenteric plexuses and hypertrophy of the ganglion cells. (6, 7) These ganglioneuromas may occur anywhere along the gastrointestinal tract and lead to loss of normal bowel tone, distention, segmental dilation, and megacolon. Symptoms in MEN 2B may vary. The most frequently reported symptoms are constipation and intermittent diarrhea. (8) Constipation may be attributed to hypomotility as a result of ganglionic dysfunction and abnormal sphincter function at various levels. These symptoms usually manifest in infancy and childhood, before symptoms of extraintestinal endocrine abnormalities. (9)

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The neuroma is composed of a partially encapsulated aggregation or proliferation of nerves, often with thickened perineurium, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma. Individual nerves flow in fascicles of two to three fibers and are histologically normal except for occasional hyperplasias and bulbous expansions. (10)

Conclusion

In a study group, 93% of patients had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2B. (9) In the literature, three infants are described who presented with intestinal obstruction caused by diffuse transmural intestinal ganglioneuromatosis, followed by the other endocrine manifestations. (11) Although intestinal neuromas causing obstruction usually precede the diagnosis of extra-intestinal endocrine manifestations, our report presents a unique case of a colonic mucosal neuroma causing obstruction in a patient with MEN 2B syndrome 4 years after the diagnosis of medullary thyroid carcinoma.

It has become appallingly obvious that our technology has exceeded our
humanity.
--Albert Einstein

Accepted June 4, 2004

References

1. Multiple Endocrine Neoplasia, Type 2. eMedicine web site article available at http://www.emedicine.com/med/topic 1520.htm.

2. Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumors: a syndrome allied to Von Recklinghausen's disease. J Pathol Bacteriol 1966;91:71-80.

3. Rashid M, Khairi MR, Dexter RN, et al. Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine (Baltimore) 1975;54:89-112.

4. Carney JA, Sizemore GW, Hayles AB. C-cell disease of the thyroid gland in multiple endocrine neoplasia, type 2b. Cancer 1979; 44:2173-2183.

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

6. Mahaffey SM, Martin LW, McAdams J, et al. MEN 2 B with symptoms suggesting Hirschsprung's disease: case report. J Paediatr Surg 1990; 25:101-103.

7. Carney JA, Go VL, Sizemore GW, et al. Alimentary tract ganglion neuromatosis: a major component of the syndrome of MEN type 2B. N Engl J Med 1976;295:1287-1291.

8. Demos TC, Blonder J, Schey WL, et al. Multiple endocrine neoplasia (MEN) syndrome type 2B: gastrointestinal manifestations. Am J Roentgenol 1983;140:73-78.

9. Cohen MS, Phay JE, Albinson C. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg 2002; 235:648-55.

10. Miller RL, Burzynski NJ, Giammara BL. The ultrastructure of oral neuromas in multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma syndrome. J Oral Pathol 1977;6:253-263.

11. Smith VV, Eng C, Milla PJ. Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment. Gut 1999;45:143-146.

RELATED ARTICLE: Key Points

* Multiple endocrine neoplasia type 2B syndrome is distinguished from type 2A by the presence of mucosal neuromas.

* Intestinal neuromas causing obstruction are rare, and usually precede the diagnosis of extra-intestinal endocrine manifestations.

Maitreyi Prabhu, MD, Rami N. Khouzam, MD, and Jonathan Insel, MD

From Tucson Hospitals Medical Education Program, University of Arizona, Tucson, AZ.

Reprint requests to Rami N. Khouzam, MD, 699 Hotchkiss Lane, Memphis, TN 38104. Email: [e-mail]