The autosomal, dominantly inherited multiple endocrine neoplasia (MEN) syndromes provide some of the best examples of the practical application of advancing technology, not only in the detection and treatment of neoplastic disease but also in the understanding of the mechanisms involved in the initiation and progression of malignancies.
The term MEN has replaced the earlier term multiple endocrine adenomatosis or MEA because many of the tumors are malignant rather than benign.
Multiple endocrine neoplasia type 1 (MEN 1) involves tumors of the parathyroid and pituitary glands and benign or malignant tumors of the pancreatic islet cells. Multiple endocrine neoplasia type 2 (MEN 2) involves medullary thyroid cancers, adrenal pheochromocytomas, and parathyroid tumors.
MEN 2A, the more common MEN 2 type, includes medullary thyroid cancers and tumors of the adrenal medulla and/or the parathyroids. MEN 2B includes medullary thyroid cancers, which are generally more aggressive with an earlier age of onset, and pheochromocytomas, as well as mucosal neuromas (bumpy lips and bumpy tongue), a Marfan-like habitus, and intestinal ganglioneuromas, but no parathyroid tumors.
Excellent references on the MEN syndromes are available from the two most recent international workshops on MEN (Henry Ford Hosp Med J 40:157-318, 1992; J Intern Med 238:231-288, 319-373, 1995).
MEN 2 and Mutation Analysis
Claude Bernard in 1865 stated that man is a prisoner of his ideas if he doesn't possess suitable and necessary tools to explore them. MEN 2 provides a great example of the possibilities created when new research tools are applied in oncology.
This growth in knowledge began in the 1960s with Sipple's clinical and pathological descriptions of the syndromes. In the 1970s, Tashjian and associates applied a radioimmunoassay for calcitonin to the detection of medullary thyroid cancer in high-risk families (facilitating its early removal and surgical cure). In the 1980s, the MENS 2 gene was localized to chromosome 10 by linkage studies of large families, and in the 1990s, the RET oncogene and the causative mutations within that gene were identified.
The identification of the particular mutation within a definitely affected family member now permits curative total thyroidectomy at age 5 or 6 years solely on the basis of mutation analysis.
The Two-Hit Cancer Theory
MEN 2 has also provided additional information confirming Knudson's multiple-mutational-event or two-hit theory on the initiation of cancer. C-cell or calcitonin-cell hyperplasia of the thyroid was found in hereditary medullary thyroid cancer as the premalignant stage and the manifestation of the first or genetic mutation.
The finding of C-cell hyperplasia adjacent to the cancers only in familial medullary thyroid cancer or MEN 2 cases provided evidence for the two-hit theory, as did the bilaterality seen in hereditary cases and the earlier age of onset in hereditary than in sporadic cases.
MEN 2 was one of the earliest hereditary cancer conditions to be found to be caused by germ-line mutations in an oncogene rather than in a tumor-suppressor gene.
When confronted with a case of medullary thyroid cancer, it would be worthwhile for the oncologist to attempt to determine if it is one of the 20% to 25% of cases that are hereditary. This is important because of the likelihood of pheochromocytomas and hyperparathy-roidism if it should be hereditary and also because of the possibility of detecting curable conditions within the patient's family.
The bilaterality of hereditary medullary thyroid cancer and the coexistence of parathyroid or adrenal medullary tumors in the patient or the patient's family may provide a clue. However, the presence of C-cell hyperplasia distal to the medullary thyroid cancer can be the best evidence for the hereditary nature of the condition.
If there is evidence to suggest that the cancer is genetic, it would be worthwhile to have DNA studies done on the five RET exons (10, 11, 13, 14 in MEN 2A and 16 in MEN 2B) where mutations have been found to be the cause of medullary thyroid cancer in about 90% to 95% of known high-risk families.
Mutation analysis in medullary thyroid cancer can also be helpful to the clinician regarding which cases might be expected to have the other endocrine tumors of MEN 2 (JAMA 276:1575-1579, 1996). So far, none of the exon 13 or 14 families has been found to develop endocrine tumors other than medullary thyroid cancer, and exon 16 mutations have been observed only in MEN 2B.
At present, the absence of a mutation does not assure one that the case is not hereditary because of the remaining 5% to 10% of affected families in which mutations have yet to be identified.
Unfortunately, no effective treatment has been found for individuals with recurrent medullary thyroid cancer detected by persistent calcitonin elevations after surgery. Thus, adequate excision of the entire thyroid gland initially by an experienced surgeon is important.
Some surgeons are suggesting extensive node dissection in patients with recurrences. However, the advisability of such surgery is not generally accepted in these cancers, which have often been found to be relatively nonaggressive when followed by calcitonin studies.
MEN 1 Gene Still Unidentified
The gene for MEN 1 has been localized to a small area on chromosome 11, and it is known to be a tumor-suppressor gene. However, the MEN 1 gene has not yet been identified, and no mutations have been found in any proposed candidate genes.
The diagnosis of MEN 1 depends upon a thorough family history and endocrine studies, including calcium and PTH for the most common parathyroid manifestations; gastrin and other hormone assays for pancreatic islet cell tumors (about 50% of which are malignant); and prolactin assays and MRI studies for pituitary tumors.
Other tumors found in MEN 1 patients include lipomas, benign or malignant adrenal cortical tumors, and benign or malignant carcinoid tumors. (Peculiarly, these tumors are primarily thymic in males and pulmonary in females.)
In large MEN 1 families, it has been possible to identify affected members early by genetic linkage studies of marker genes that have been found to be closely linked to the gene. This allows the physician to focus endocrine studies on those affected individuals and to perform surgery for the tumors early.
The finding of the gene for MEN 1 and the mutations within it will undoubtedly have markedly beneficial effects in MEN 1 families, just as the advances in MEN 2 have had in MEN 2 families.