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 autosomal, dominantly inherited multiple endocrine neoplasia (MEN)syndromes provide some of the best examples of the practical applicationof advancing technology, not only in the detection and treatment of neoplasticdisease but also in the understanding of the mechanisms involved in theinitiation and progression of malignancies.
The term MEN has replaced the earlier term multiple endocrine adenomatosisor MEA because many of the tumors are malignant rather than benign.
Multiple endocrine neoplasia type 1 (MEN 1) involves tumors of the parathyroidand pituitary glands and benign or malignant tumors of the pancreatic isletcells. Multiple endocrine neoplasia type 2 (MEN 2) involves medullary thyroidcancers, adrenal pheochromocytomas, and parathyroid tumors.
MEN 2A, the more common MEN 2 type, includes medullary thyroid cancersand tumors of the adrenal medulla and/or the parathyroids. MEN 2B includesmedullary thyroid cancers, which are generally more aggressive with anearlier age of onset, and pheochromocytomas, as well as mucosal neuromas(bumpy lips and bumpy tongue), a Marfan-likehabitus, and intestinal ganglioneuromas, but no parathyroid tumors.
Excellent references on the MEN syndromes are available from the twomost 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 ifhe doesn't possess suitable and necessary tools to explore them. MEN 2provides a great example of the possibilities created when new researchtools are applied in oncology.
This growth in knowledge began in the 1960s with Sipple's clinical andpathological descriptions of the syndromes. In the 1970s, Tashjian andassociates applied a radioimmunoassay for calcitonin to the detection ofmedullary thyroid cancer in high-risk families (facilitating its earlyremoval and surgical cure). In the 1980s, the MENS 2 gene was localizedto 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 affectedfamily member now permits curative total thyroidectomy at age 5 or 6 yearssolely on the basis of mutation analysis.
The Two-Hit Cancer Theory
MEN 2 has also provided additional information confirming Knudson'smultiple-mutational-event or two-hit theory on the initiation of cancer.C-cell or calcitonin-cell hyperplasia of the thyroid was found in hereditarymedullary thyroid cancer as the premalignant stage and the manifestationof the first or genetic mutation.
The finding of C-cell hyperplasia adjacent to the cancers only in familialmedullary thyroid cancer or MEN 2 cases provided evidence for the two-hittheory, as did the bilaterality seen in hereditary cases and the earlierage of onset in hereditary than in sporadic cases.
MEN 2 was one of the earliest hereditary cancer conditions to be foundto be caused by germ-line mutations in an oncogene rather than in a tumor-suppressorgene.
When confronted with a case of medullary thyroid cancer, it would beworthwhile for the oncologist to attempt to determine if it is one of the20% to 25% of cases that are hereditary. This is important because of thelikelihood of pheochromocytomas and hyperparathy-roidism if it should behereditary and also because of the possibility of detecting curable conditionswithin the patient's family.
The bilaterality of hereditary medullary thyroid cancer and the coexistenceof parathyroid or adrenal medullary tumors in the patient or the patient'sfamily may provide a clue. However, the presence of C-cell hyperplasiadistal to the medullary thyroid cancer can be the best evidence for thehereditary nature of the condition.
If there is evidence to suggest that the cancer is genetic, it wouldbe 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 thecause of medullary thyroid cancer in about 90% to 95% of known high-riskfamilies.
Mutation analysis in medullary thyroid cancer can also be helpful tothe clinician regarding which cases might be expected to have the otherendocrine tumors of MEN 2 (JAMA 276:1575-1579, 1996). So far, none of theexon 13 or 14 families has been found to develop endocrine tumors otherthan medullary thyroid cancer, and exon 16 mutations have been observedonly in MEN 2B.
At present, the absence of a mutation does not assure one that the caseis not hereditary because of the remaining 5% to 10% of affected familiesin which mutations have yet to be identified.
Unfortunately, no effective treatment has been found for individualswith recurrent medullary thyroid cancer detected by persistent calcitoninelevations after surgery. Thus, adequate excision of the entire thyroidgland initially by an experienced surgeon is important.
Some surgeons are suggesting extensive node dissection in patients withrecurrences. However, the advisability of such surgery is not generallyaccepted in these cancers, which have often been found to be relativelynonaggressive when followed by calcitonin studies.
MEN 1 Gene Still Unidentified
The gene for MEN 1 has been localized to a small area on chromosome11, and it is known to be a tumor-suppressor gene. However, the MEN 1 genehas not yet been identified, and no mutations have been found in any proposedcandidate genes.
The diagnosis of MEN 1 depends upon a thorough family history and endocrinestudies, including calcium and PTH for the most common parathyroid manifestations;gastrin and other hormone assays for pancreatic islet cell tumors (about50% of which are malignant); and prolactin assays and MRI studies for pituitarytumors.
Other tumors found in MEN 1 patients include lipomas, benign or malignantadrenal 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 membersearly by genetic linkage studies of marker genes that have been found tobe closely linked to the gene. This allows the physician to focus endocrinestudies on those affected individuals and to perform surgery for the tumorsearly.
The finding of the gene for MEN 1 and the mutations within it will undoubtedlyhave markedly beneficial effects in MEN 1 families, just as the advancesin MEN 2 have had in MEN 2 families.