MTC make up about 5 percent of thyroid cancers. Most cases, about 85 percent, are sporadic and occur in the absence of a family history. Familial cases make up the other 15 percent and represent an inherited syndrome called multiple endocrine neoplasia type 2 (MEN 2).
MEN 2 is a genetic disorder associated with a high lifetime risk of developing medullary thyroid cancer. MEN 2 is caused by inherited mutations in the RET proto-oncogene located on chromosome 10. Proto-oncogenes are responsible for promoting cell growth. When altered, or mutated, they become oncogenes that can promote uncontrolled cell growth and ultimately tumor formation. Having a mutation in just one of the two copies of a particular proto-oncogene is enough to cause a change in cell growth. For this reason, oncogenes are said to be dominant at the cellular level (although the change in cell growth may or may not be detectable at a clinical level). However, the process of developing a cancer actually requires mutations in multiple growth control genes. Therefore, inheriting a mutation in one copy of the RET gene is just the first step in the process. The remainder of the mutations necessary for tumor development are acquired (not inherited). What causes additional mutations to develop is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in DNA replication. Nearly 100 percent of patients with MEN2 will develop medullary thyroid cancer during their lifetime.
All MEN 2 cases are inherited in an autosomal dominant manner, which means that offspring of an affected person are at a 50 percent risk for inheriting the gene mutation. There are three subtypes of MEN 2, depending on what other clinical characteristics are present (in addition to medullary thyroid cancer):
Multiple endocrine neoplasia (MEN) 2A (60 to 90 percent of MEN cases). Characteristics include:
A high lifetime risk of MTC, up to between 98 and 100 percent
Average age of medullary thyroid cancer diagnosis between 15 and 20 years
Increased risk of pheochromocytoma (a tumor of the chromaffin cells, which are present in the adrenal gland; usually benign, or noncancerous) and parathyroid adenoma or hyperplasia
95 percent of cases have an affected parent*, while 5 percent are de novo (new occurrences in a family)
95 percent of cases have a mutation in the RET gene
* In some cases, a child may be diagnosed with MTC before the parent is diagnosed.
Familial MTC (5 to 35 percent of MEN cases). Characteristics include:
Average age of onset of MTC may be later than with MEN 2A
100 percent of cases have an affected parent*
No pheochromocytoma or parathyroid disease
85 percent of cases have a mutation in the RET gene
FMTC is commonly viewed as a variant of MEN 2A with decreased penetrance of pheochromocytoma and hyperparathyroidism
Multiple endocrine neoplasia (MEN) 2B (5 percent of MEN cases). Characteristics include:
Onset of MTC in infancy or very early childhood
Increased risk of pheochromocytoma
Parathyroid disease is uncommon
Ganglioneuromatosis (inflammation of the nerve cells) in the gastrointestinal tract (40 percent)
Distinctive facial appearance with neuromas (tumors) of the tongue, lips, eyes; lips may look "blubbery"
Tall, thin, Marfanoid body type (75 percent)
Problems of the joints, muscles, and spine
50 percent of cases have an affected parent, while 50 percent are de novo (new occurrences in a family)
The American Society of Clinical Oncologists classifies MEN 2 as a group 1 disorder, which means that genetic testing (in this case for mutations in the RET gene) is considered part of the standard management for first-degree relatives (parent, siblings, children) of affected individuals. People who are mutation-positive may have their thyroid removed as a preventive measure, followed by biochemical screening for the other endocrine tumors. Genetic testing of unaffected relatives is most useful when a germline mutation has already been identified in an affected family member.