Key Points

• Medullary Thyroid Carcinoma (MTC) represents a unique thyroid cancer that occurs either sporadically or in a hereditary form as a component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A, MEN2B, and the related syndrome, familial MTC (FMTC).
• Medullary thyroid carcinoma accounts for 1-2% of thyroid cancers in the United States, a much lower range than frequently cited (3-5%) primarily due to the marked increase in the relative incidence of papillary thyroid carcinoma (PTC) over the last three decades.
• Virtually all patients with MEN2A, MEN2B, and FMTC have RET germline mutations, and approximately 50% of sporadic MTCs have somatic RET mutations.
  • The RET protooncogene (REarranged during Transfection), located on chromosome 10q11.2, encodes a single-pass transmembrane receptor of the tyrosine kinase family. Of sporadic MTCs lacking somatic RET mutations, 18-80% have somatic mutations of HRAS, KRAS, or rarely NRAS.
• RET is a remarkable oncogene that is central not only to the development of sporadic and hereditary MTC but also to other malignant and non-malignant diseases.
• Over 100 mutations, duplications, insertions, or deletions involving RET have been identified in patients with MTC. The aggressiveness of MTC varies with the RET mutation. Therefore, treatment should be guided by genetic testing. (Table 2 summarizes the relative risk of developing an aggressive MTC and the other endocrine tumors and diseases associated with MEN2A and MEN2B.)

Diagnosis

• The current ATA risk categories for hereditary MTC should be changed.
  • The current level D category should be changed to a new category, “highest risk” (HST), that includes patients with MEN2B and the RETcodon M918T mutation.
  • The current level C category should be changed to a new category, “high risk” (H), that includes patients with MEN 2A and RETcodon C634 mutations.
  • The current level A and B categories should be combined into a new category “moderate risk” (MOD) that includes patients with hereditary MTC and RETcodon mutations other than M918T and C634. (C)
• There should be two MEN2 syndromes: MEN2A and MEN2B. Within MEN2A, which accounts for 95% of MEN2 cases, there should be four variants:
  1. Classical MEN2A (represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma (PHEO), or hyperparathyroidism HPTH, or both)
  2. MEN2A with cutaneous lichen amyloidosis (CLA).
  3. MEN2A with Hirschsprung's Disease (HD).
  4. FMTC (families or individuals with RETgermline mutations who have MTC but neither PHEOs or HPTH). (C)
• The recommended method of initial genetic testing for MEN2A is either a single or multi-tiered analysis to detectRETmutations in exon 10 (codons 609, 611, 618, and 620), exon 11 (codons 630 and 634), and exons 8, 13, 14, 15, and 16. (B) The most commonRET mutations associated with MEN2A and MEN2B are shown in Table 2.
• Sequencing of the entire coding region should be reserved for situations where noRETmutation is identified, or there is a discrepancy between the MEN2 phenotype and the expected genotype. (B)
• Patients with the MEN2B phenotype should be tested for theRETcodon M918T mutation (exon 16), and if negative, theRETcodon A883F mutation (exon 15). If there are no mutations identified in these two exons the entireRETcoding region should be sequenced. ( B)
• Patients with presumed sporadic MTC should have genetic counseling and genetic testing to detect aRETgermline mutation. ( B)
• Genetic counseling and genetic testing forRETgermline mutations should be offered to:
  1. first degree relatives of patients with proven hereditary MTC
  2. parents whose infants or young children have the classic phenotype of MEN2B
  3. patients with CLA
  4. infants or young children with HD and exon 10 RETgermline mutations
  5. adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD. (B)

• Other than for academic reasons or physician preference, it is not standard practice to analyze tumors of patients with sporadic MTC for somaticHRAS, KRASorNRASmutations orRETM918Tmutations. (C)
• In very rare families who meet the clinical criteria for MEN2A or 2B, despite negative sequencing of the entire RETcoding region, the relatives at-risk should be periodically screened by conventional methods for MTC, PHEO, and HPTH. After the initial evaluation, screening should continue at 1-3 year intervals. (C)
• Regarding hereditary MTC, the duty to warn a competent and capacitated patient or surrogate decision maker of the risk that an inheritedRETmutation may pose to family members is standard of care.
  • This warning is ideally fulfilled in the setting of genetic counseling and should include a request for the patient to participate in identifying “at-risk” relatives. The “duty to warn” discussion should be a part of the informed consent process, where there is full disclosure of the seriousness of the disease and available forms of prevention and treatment. When a patient refuses to notify relatives or legal dependents of their risks, the physician should consider whether he has an ethical duty or obligation to warn family members at risk. He should consult a certified clinical ethicist either at his medical center, or another medical facility, or contact the American Thyroid Association Ethics Committee for guidance. (A)
• In pediatric patients who have not reached the age of consent it may be necessary for physicians to seek state intervention to prevent harm when there is parental refusal to inform their children of the risk for developing a malignant tumor. Practitioners with pediatric populations should consult published documents for guidance. (A)
• The duty to warn of genetic risk extends to both preconception and prenatal contexts.
  • Genetic counseling about the options of pre-implantation or prenatal diagnostic testing should be considered for all RET mutation carriers of childbearing age, particularly those with MEN2B. Parents who wish not to have prenatal RETmutation testing should be offered genetic counseling and informed of the availability of genetic testing of their child to detect a mutated RETallele. This is particularly important for mutations associated with the onset of MTC before 5 years of age. (A)
• Clinicians should be aware that falsely high or low serum calcitonin (Ctn) levels might occur with a variety of clinical diseases other than MTC and consider this possibility when serum Ctn levels are disproportionate to the expected clinical findings. (C)
• In interpreting serum Ctn data clinicians should be aware that Ctn levels are markedly elevated in children <3 years of age, especially <6 months of age. Also, Ctn levels are higher in males compared to females. (B)
• Basal levels of serum Ctn and carcinoembryonic antigen (CEA) should be measured concurrently. In patients with advanced MTC a marked elevation in the serum CEA level out of proportion to a lower serum Ctn level, or normal or low levels of both serum Ctn and CEA, indicate poorly differentiated MTC. (B).
• The assessment of a thyroid tumor with any feature suggestive of MTC should include immunohistochemical (IHC) analysis to determine the presence markers such as Ctn, chromogranin, and CEA, and the absence of thyroglobulin. (B)
• Complete notation of the features of every MTC should follow the synoptic reporting guidelines of the College of American Pathologists Protocol for the Examination of Specimens from Patients with Carcinomas of the Thyroid Gland (www.cap.org). (B)
• In patients with MTC morphological examination of the entire gland is recommended to determine the presence of C-Cell hyperplasia (CCH) or multifocal neoplasia. (C)
• Thyroid nodules that are ≥1 cm in size should be evaluated by fine needle aspiration biopsy (FNA). FNA findings that are inconclusive or suggestive of MTC should have calcitonin measured in the FNA washout fluid and IHC staining of the FNA sample to detect the presence of markers such as Ctn, chromogranin, and CEA, and the absence of thyroglobulin. (B).
• Realizing that opinions of experts vary regarding the usefulness of measuring serum Ctn levels in patients with nodular goiters, the Task Force recommends that physicians decide whether the technique is useful in the management of patients in their clinic. (I)
• Patients presenting with a thyroid nodule on physical examination should have determination of serum levels of Ctn and CEA, and genetic testing for a RET germline mutation. The presence of a PHEO and HPTH should be excluded in patients with hereditary MTC.
• Ultrasound (US) examination of the neck should be performed in all patients with MTC. Contrast enhanced CT of the neck and chest, three-phase contrast-enhanced multi-detector liver CT, or contrast-enhanced MRI of the liver, and axial MRI and bone scintigraphy are recommended in patients with extensive neck disease and signs or symptoms of regional or distant metastases. These studies should also be conducted in all patients with a serum Ctn level greater than 500 pg/mL. (C)
• Neither FDG-PET/CT nor F-DOPA-PET/CT is recommended to detect the presence of distant metastases. (E)