Medullar thyroid cancer

Introduction of medullar thyroid cancer (MTC)
This type makes up about 3 percent of all thyroid cancers and is the only neuroendocrine cancer of the thyroid. It begins in the C cells of the thyroid. Cancer that starts in the C cells can make abnormally high levels of calcitonin. Medullary thyroid cancer tends to grow slowly. It can be easier to control if it's found and treated before it spreads to other parts of the body. MTC is distinct as it presents in four different clinical settings:

  1. Sporadic in around 80% of cases. This means that there are no familial features and no associated endocrine tumors.
  2. MEN2A
    MEN 2 is an autosomal dominant hereditary cancer syndrome that implies a 50% risk to offspring of a carrier to inherit the disorder. It is caused by missense mutations in the RET protooncogene, that result in ‘‘gain of function’’. All three clinical subtypes of MEN 2 are characterized by the presence of MTC. In MEN2A a mutation in the RET proto-oncogene causes MTC, pheochromocytoma (PHEO) and hyperparathyroidism (PHPT). Time of onset, severity of disease and penetrance of associated tumors are closely linked to the type of RET mutation. In the known familial setting profylactic surgery is advocated depending on the type of mutation.
  3. MEN2B
    This syndrome also has MTC and PHEO, but only rarely will have PHPT. Instead these patients have an unusual appearance which is characterized by mucosal ganglioneuromas (tumors in the mouth) and a Marfanoid habitus. Mutations in the RET proto-oncogene is responsible also in MEN2B.
  4. Familial MTC (FMTC) is a clinical variant of MEN2A in which MTC is the only manifestation.


Genetics of medullar thyroid cancer
Role of germline RET testing in MTC patients. Germline testing of RET can be used to distinguish cases of sporadic from hereditary MTC, and the precise RET mutations may suggest a predilection toward a particular phenotype and clinical course. This is important because the patient may also require surveillance and management of PHEO and PHPT, and additional family members may be at risk for developing MTC. Knowledge of the RET mutation can guide decisions regarding prophylactic thyroidectomy and intra-operative management of the parathyroid glands. Approximately 95% of patients with MEN 2A and MEN2B, and 88% of those with FMTC will have an identifiable RET mutation.

Nearly 90% of gene carriers will develop MTC, but this is dependent upon the mutation. The risk of developing unilateral or bilateral pheochromocytoma is as high as 57%, and 15–30% of gene carriers will develop hyperparathyroidism. In the vast majority of cases, MEN2A is caused by mutations affecting cysteine residues in codons 634 (87%), 620 (6%), 618 (3%), 611 (2%) and 609 (<1%) in exon 11 of RET. As mentioned, there is a strong genotype-phenotype correlation that is affecting clinical decision making. It has been shown that profylactic surgery in patients with known RET mutations can prevent recurrent or persistent MTC if surgery is performed at young age.

MEN 2B is the most rare and aggressive form of MEN 2 based on its development of MTC earlier in life. The average age of onset of MTC is 10 years earlier than seen inMEN 2A. More than 50% of cases are de novo germline RET mutations. In multivariate analyses that incorporate disease stage and other factors, it has been suggested that the higher mortality rate of MEN 2B reflects its more advanced stage at presentation, rather than the tumor behavior once established. Like MEN 2A, MEN 2B is associated with PHEO. The youngest age at diagnosis of PHEO has been 12 years of age for the most common 918 RET mutation. This mutation is seen in 94% of MEN2B patients followed by 883 (5%) and 804 (<1%).

Familial medullar thyroid cancer (FMTC)
To prove that a particular kindred has FMTC it is necessary to demonstrate the absence of a PHEO or PHPT in two or more generations within a family or to have a RET mutation identified only in kindreds with FMTC. In smaller kindreds or in those with a single affected generation, caution should be exercised in the classification of FMTC as there is the possibility of failure to recognize MEN 2A and the risk of PHEO. The most common RET codon mutations in FMTC are: 618 (30%), 634 (26%), 620 (21%), 768 (8%) and, 609 (4%).

Risk of developing aggressive MTC and recommended age of profylactic surgery for patients with known germ-line mutation according to the American Thyroid Association guidelines (D is highest risk).

RET mutation MTC risk Age of profylactic surgery
918 D As soon as possible and within 1st year of life
883 D  
634 C Surgery before age 5 years
620 B Consider surgery before age 5.
618 B May delay surgery beyond age 5 years
611 B if stringent criteria are met (a)
609 B  
768 A May delay surgery beyond age 5 years
if stringent criteria are met.

(a) A normal annual basal ± stimulated serum Calcitonin, normal annual neck US, less aggressive MTC family history, and family preference.


Surveillance for PHEO and PHPT
Screening abdominal imaging for PHEO is not recommended in the absence of symptoms or biochemical data suggesting the tumor, except for the rare urgent need to exclude PHEO. Symptoms or signs consistent with catecholamine excess, or an adrenal mass, should prompt biochemical testing for a PHEO.

In the absence of symptoms or an adrenal mass to suggest the possibility of PHEO, surveillance (including preoperative testing) should include annual plasma free metanephrines and normetanephrines, or 24-hour urine collection for metanephrines and normetanephrines beginning by age 8 years in carriers of RET mutations associated with MEN 2B and in codons 630 and 634, and by age 20 years in carriers of other MEN 2A RET mutations. Patients with RET mutations associated only with FMTC should be screened at least periodically from the age of 20 years.

Surveillance for PHPT should include annual albumincorrected calcium or ionized serum calcium measurements (with or without serum intact-parathyroid hormone [PTH]) beginning by age 8 years in carriers of RET mutations in codons 630 and 634, and by age 20 years in carriers of other MEN 2A RET mutations, and periodically with RET mutations associated only with FMTC starting from age 20 years.

Surgery for clinically apparent medullar thyroid cancer
If a nodule preoperatively is proven to be MTC and/or patient has elevated calcitonin levels the preoperative workup includes a mandatory skilled preoperative US of the neck and upper mediastinum to check for lymph node involvment. Preoperative RET testing is recommended. Measure calcium (and PTH) to be able to treat PHPT when treating MTC. Exclude PHEO before surgery of the neck, and if PHEO is found treat this before surgery of the neck. Surgery is performed with total thyroidectomy and clearance of central lymph nodes, typically combined with lateral lymph node clearance on the same side as the tumor of the thyroid. If PHPT is present we advocate removal of enlarged parathyroids only.

Follow-up consists of regular measurements of calcitonin and different imaging modalities such as US, CT and FDG- and 5HTP-PET. Recurrent disease and metastatic disease is handled by combinations of chemotherapy, external beam radiation therapy, surgery and newer therapies such as tyrosine kinase inhibitors.