Diagnosis and Discussion -- Hypercalcemia

Case Discussion

This patient has a strong family history of Multiple Endocrine Neoplasia Syndrome. Now, she has proven parathyroid and pituitary tumors, with new serologic evidence of a pancreatic tumor. She had multiple parathyroid resections, but still suffered from hypercalcemia. The anterior mediastinal mass most recently resected has the histologic appearance of a neuroendocrine (carcinoid) tumor. The enlarged ectopic parathyroid gland is most likely responsible for the elevated PTH level pre-operatively. With the findings of parathyroid, pituitary and pancreatic neoplasms, this patient has MEN type I.

The multiple endocrine neoplasia, or MEN syndromes, first described early in this century, belong to several categories, but they share some common characteristics. The usual tumor is composed of one or more specific polypeptide- and biogenic amine- producing cell types which has been given the acronym APUD (amine precursor uptake and decarboxylation). Major exceptions to this are lipomas, which can be associated with Type I MEN, and mucosal neuromas and colonic polyps, which can be associated with Type IIB MEN. Another feature is a histological progression of the associated neoplasias from hyperplasia to adenoma, and in some cases, to carcinoma. The development of hyperplasia is thought to be a multicentric process, with each focus of tumor derived from a single clone. These syndromes have an autosomal dominant pattern of inheritance. (1)

MEN Type I, which was first described as a clinical and genetic syndrome by Wermer in 1954 (hence the designation Wermer's syndrome), is characterized by parathyroid, pancreatic, and pituitary neoplasms. A few patients may have adrenal cortical hyperplasia and C-cell hyperplasia of the thyroid. Genetic studies have implicated the loss of a tumor suppressor gene in chromosome 11 in these group of patients. (1,2)

Hyperparathyroidism is the most common manifestation of MEN I. This may appear as early as the second decade of life, and by age 40 almost all family members carrying the gene for MEN Type I are likely to be hypercalcemic.(1-4) In the early stages of the disease the associated histologic lesion is hyperplasia of multiple parathyroid glands, but later adenomatous changes may be found on a background of multiglandular parathyroid hyperplasia. Surgery is the treatment of choice of this condition, but recurrence of hypercalcemia due to hyperplasia of other foci of the parathyroids is quite common, necessitating repeated surgical procedures. (1, 4)

Pancreatic islet cell tumors is the second most common manifestation of MEN Type I, occurring in about 80 % of patients. The Zollinger-Ellison syndrome due to a gastrinoma is more frequently found than an insulinoma, and it is not unusual to see patients with a glucagonoma, the watery diarrhea syndrome, and elevations of pancreatic polypeptide. One may expect to see pituitary adenomas in more than half of these patients. In order of frequency, these are likely to be a prolactinoma, a growth hormone producing tumor, and lastly, an ACTH producing tumor. Carcinoid tumors are found with less frequency. These are usually found in the foregut, and are most likely to involve the thymus in men and the lung in women. (1)


1. Gagel RF, Multiple Endocrine Neoplasia, in William's Textbook of Endocrinology, Wilson JD and Foster DW (eds.), W.B. Saunders Co., Philadelphia, 1992 ; p. 1537-1553.

2. Cotran RS, Kumar V, and Robbins, SL, in Robbins Pathologic Basis of Disease, W.B. Saunders Co., Philadelphia, 1994 ; p. 1169-1170.

3. Skogseid B, Eriksson B, Lundqvist G, et al., Multiple Endocrine Neoplasia Type I: A 10-Year Prospective Screening Study in Four Kindreds. J Clin Endocrinol Metab 1991;73:281-7.

4. Hellman P, Skogseid B, Juhlin C, et al., Findings and Long-Term Results of Parathyroid Surgery in Multiple Endocrine Neoplasia Type I. World J Surg. 1992;16:718-23.

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