Medullary thyroid carcinoma (MTC) is uncommon and accounts for only 5% of all thyroid cancers. MTC was first described in 1959 as a “peculiar” thyroid cancer with nonfollicular histology, amyloid-containing stroma, and a high incidence of lymph node metastases.1 MTC arises from the parafollicular, or calcitonin-secreting, C cells of the thyroid gland. C cells are neural crest cells that are derived embryologically from the ultimobranchial bodies and migrate to the thyroid gland. They are found throughout the thyroid but often concentrate in the uppermost third of the thyroid lobes; therefore, MTC usually originates in this region2 (Figure 6-1).

Approximately 25% of patients with MTC have the hereditary form of the disease, which results from germline activating missense mutations in the RET (REarranged during Transfection) proto-oncogene. The remaining 75% of patients with MTC have the sporadic form; however, somatic missense RET mutations may occur in up to 70% of the tumors in patients with sporadic MTC.3

RET is a 21-exon proto-oncogene located on chromosome 10q11.2. It encodes a receptor tyrosine kinase (RET) that functions as a signal transducer to regulate cell growth and survival.4 Germline RET mutations cause the multiple endocrine neoplasia type 2 (MEN2) syndromes, which are inherited in an autosomal dominant fashion.

There are three recognized subtypes of MEN2 (Table 6-1), all of which are characterized by a very high lifetime risk of MTC. MEN2A, or Sipple’s syndrome, is the most common subtype of MEN2 and accounts for 80% to 90% of all cases of hereditary MTC. It is characterized by MTC in more than 90% of patients, pheochromocytoma in about 50% of patients, and hyperparathyroidism in about 20% of patients.5 Rarely, MEN2A may be associated with cutaneous lichen amyloidosis (a pruritic plaque that develops on the skin overlying the scapula on the upper back; Figure 6-2)6 or Hirschsprung disease.7

The second MEN2 subtype, MEN2B, accounts for about 5% of MEN2 cases and is characterized by MTC in more than 90% of patients, pheochromocytoma in about 50% of patients, and characteristic physical features. These physical features include a thin, lanky (marfanoid) body habitus; increased joint mobility; decreased subcutaneous fat; corneal nerve hypertrophy; ganglioneuromatosis of the gastrointestinal tract with megacolon; and mucosal neuromas of the lips, tongue, and eyelids (Figure 6-3).8,9

The third MEN2 subtype, familial medullary thyroid cancer (FMTC), accounts for 5% to 15% of MEN2 cases and is defined by the presence of MTC only.10 However, because MTC is usually the first manifestation of MEN2, some patients with MEN2A may be initially misclassified as having FMTC if they are thought to have only MTC in the absence of adequate follow-up. This misdiagnosis results in a failure to screen for pheochromocytoma and hyperparathyroidism in these patients, which could have negative consequences, particularly if pheochromocytoma is present and not detected preoperatively. Thus, the classification of FMTC must adhere to strict guidelines. Some authors have advocated that only families with four or more cases of MTC, documented absence of pheochromocytoma and hyperparathyroidism, an adequate medical history, and long-term follow-up should be considered to have FMTC.5 Other authors are even more conservative and define an FMTC kindred by more than 10 carriers, multiple carriers or affected members over the age of 50 years, and an adequate medical history.11 Still other authors argue that FMTC should not be classified as a separate disease at all; instead, it should be considered a MEN2A variant with a greatly reduced penetrance of pheochromocytoma and hyperparathyroidism.

Childhood exposure to ionizing radiation is a well-established risk factor for thyroid cancer in general and accounts for 9% of thyroid cancers, although most are papillary thyroid cancers (PTCs). The only identified risk factor specific to MTC is a RET proto-oncogene mutation. Up to 10% of patients with presumed sporadic MTC actually harbor de novo germline RET mutations and thus represent the index cases of MEN2 kindreds.12 Because patients with sporadic and hereditary MTC are managed differently, genetic testing is essential in all patients who present with MTC.

Well-defined genotype–phenotype correlations exist in MEN2 patients. Specific RET mutations influence the MEN2 subtype, the age of disease onset, and the aggressiveness of MTC the patient will experience. Therefore, the specific RET mutation is used to determine the age at which a patient should undergo prophylactic thyroidectomy and whether screening for hyperparathyroidism or pheochromocytoma is necessary. The specific RET mutation also affects operative planning (extent of lymphadenectomy and intraoperative management of the parathyroid glands).

In 2001, an international conference of MEN experts published a consensus statement to help guide the management of patients with hereditary MTC according to their RET mutations.11 The authors classified the mutations into three levels based on aggressiveness of MTC (Table 6-2). Level 1 mutations are associated with the least aggressive form of MTC. There is significant variability in the age at onset of MTC associated with a level 1 mutation, so the timing of prophylactic thyroidectomy in carriers of these mutations is controversial; however, most experts recommend that carriers undergo prophylactic thyroidectomy by age 5 or 10 years. Level 2 mutations are associated with moderately aggressive MTC, and carriers of these mutations should undergo prophylactic thyroidectomy by age 5 years. Both level 1 and level 2 mutations give rise to MEN2A and FMTC, but there is considerable overlap between the mutations with regard to the phenotype displayed. Level 3 mutations are associated with the most aggressive form of MTC and result in the MEN2B phenotype. Prophylactic thyroidectomy in carriers with these mutations is recommended by age 6 months. However, it is usually quite difficult to make the diagnosis of MEN2B in the first few years of life, so prophylactic thyroidectomy should occur as soon as such a mutation is identified.

Patients who develop sporadic MTC or who represent an index case of MEN2A or FMTC may present as late as the fourth decade of life. Patients who represent index cases of MEN2B usually present with MTC within the first two decades of life. Unlike other thyroid neoplasms, which occur more often among women, MTC is equally prevalent in men and women.13

Patients with sporadic MTC and patients who represent index cases of hereditary MTC almost always present with a palpable neck mass. Hereditary MTC is often multifocal and bilateral.14 Approximately 15% of patients with MTC have symptoms of locally advanced disease at the time of presentation, including hoarseness, dyspnea, or dysphagia.13 Bone pain or systemic symptoms related to hypercalcitoninemia, such as flushing or diarrhea, may be present in 10% of patients13; in such cases, the clinician should suspect metastatic disease, which is usually to the liver, lung, or bone. Occasionally, metastases may develop in the brain or subcutaneous tissue.15 Patients with MEN2A or MEN2B may also present with symptoms of pheochromocytoma.13

Patients in known hereditary MTC kindreds are usually asymptomatic and are diagnosed by genetic testing and early screening. The disease is characterized by an age-related progression from a normal thyroid to C-cell hyperplasia to MTC,16 and these patients may lie at any point along this spectrum at the time of diagnosis.

Workup of Patients with Sporadic Medullary Thyroid Carcinoma or Index-Case Hereditary Medullary Thyroid Carcinoma

Obtaining a thorough history and physical examination is critical when evaluating patients with MTC. It is important to ask about voice changes, difficulty swallowing, increasing shirt size at the neck, flushing, diarrhea, and bone pain. Asking about kidney stones, pancreatitis, ulcers, osteoporosis, anxiety, tremor, panic attacks, “spells,” and so on may help to determine whether a patient has a personal history of primary hyperparathyroidism or pheochromocytoma. A detailed family history must also be obtained. Family members with kidney stones, pancreatitis, ulcers, or osteoporosis may have had primary hyperparathyroidism, and family members who died of an unknown cause or had significant hypertension (especially at a young age) may have had pheochromocytoma.

The physical examination should include an evaluation of the size and mobility of the neck mass, as well as its relationship to surrounding structures, keeping in mind that MTC tumors are often posterior and may be locally aggressive, invading the trachea, recurrent laryngeal nerve (RLN), and great vessels of the neck. The cervical lymph nodes should also be carefully examined. At the time of diagnosis, 80% of patients with palpable MTC have central compartment lymph node metastases, and 75% and 47% of patients have metastases to the ipsilateral and contralateral jugular nodes, respectively.17 Because cutaneous lichen amyloidosis may be associated with MEN2A, the skin overlying the upper back should be examined (see Figure 6-2). It is also important to note any physical features characteristic of MEN2B, particularly a tall, thin body habitus and neuromas of the tongue and eyelids (see Figure 6-3).

The diagnosis is established by cytologic evaluation of a fine-needle aspiration (FNA) biopsy of a nodule that is palpable or visible by ultrasonography. The presence of an elevated calcitonin level confirms the diagnosis; a recent study found that calcitonin levels of 100 pg/mL or above have a 100% positive predictive value for MTC.18 MTC also secretes carcinoembryonic antigen (CEA), and CEA levels may be a useful adjunct to calcitonin levels for determining the extent of disease. Neck ultrasonography is essential for obtaining anatomic information about the tumor or tumors and evaluating the central as well as lateral cervical lymph node compartments. Direct or indirect laryngoscopy should be performed to determine whether a locally invasive tumor has involved the RLN because this is important for operative planning and patient expectations.

Every patient who presents with MTC should undergo genetic counseling and then testing for a RET proto-oncogene mutation. Before undergoing genetic testing, patients should know how to interpret the results of genetic tests; understand the potential impact on health records and insurance; and realize the implications of positive results for other family members, particularly offspring. It is critical to identify MEN2 in patients before surgery for MTC because MEN2 patients may have additional neoplasms. Pheochromocytoma must be excluded in patients with MEN2A and MEN2B. Standard biochemical screening tests for pheochromocytoma include plasma-free metanephrine levels or 24-hour urine metanephrine and normetanephrine levels. Patients with elevated levels should undergo a dedicated adrenal-protocol computed tomography (CT) or magnetic resonance imaging (MRI) scan of the abdomen. It is of paramount importance that a pheochromocytoma be appropriately medically blocked and then resected before any neck operation is performed (although this may be done during the same anesthesia induction). MEN2A patients should also be screened for primary hyperparathyroidism before undergoing a neck operation for MTC. Measuring serum calcium and concomitant intact parathyroid hormone levels is an inexpensive, effective way to screen for primary hyperparathyroidism. If hyperparathyroidism is found, the parathyroid glands may be addressed at the same time as the initial cervical operation. However, most patients who are found to have MEN2A-related hyperparathyroidism are likely to have already undergone thyroidectomy with or without some level of neck dissection.