MTC was first described by Jaquet in the German literature as ‘‘malignant goiter with amyloid’’ (6). In 1959, Hazard et al. (7) provided a definitive histological description, while Williams further suggested that MTC originated from the calcitonin (Ct)-secreting parafollicular C cells of the thyroid gland, which derive from the neural crest (8–10). Currently, MTC accounts for about 4% of all thyroid cancer cases in the United States (11). MTC presents worldwide as part of an autosomal dominant inherited disorder in about 20–25% of cases and as a sporadic tumor in the remainder (12–15).
Inherited MTC syndromes (multiple endocrine neoplasia type 2, MEN 2) affect approximately 1 in 30,000 individuals (16,17) and consist of MEN 2A (Sipple’s syndrome), familial MTC (FMTC), and MEN 2B. Interestingly, the founding de novo mutations have occurred exclusively on the paternal allele (18,19). Affected individuals initially develop primary C-cell hyperplasia (CCH) that progresses to early invasive medullary microcarcinoma, and eventually develop grossly invasive macroscopic MTC (20). Secondary CCH has been described with aging, hyperparathyroidism, hypergastrinemia, near follicular derived tumors, and in chronic lymphocytic thyroiditis (21). Familial CCH is a preneoplastic lesion as opposed to secondary CCH, which is associated with much less, if any, malignant potential (21). Although there is controversy surrounding the definition of CCH (22), its utility to identify or confirm MEN 2 has been essentially replaced by RET (REarranged during Transfection) protooncogene testing.
Sipple (23) published a case report and review of the literature that demonstrated the association of thyroid cancer with pheochromocytoma (PHEO) in 1961. Steiner et al. (24) associated the presence of primary hyperparathyroidism (PHPT) with the syndrome and introduced the term ‘‘multiple endocrine neoplasia 2.’’ Recent molecular evidence has demonstrated that the first description of PHEO in 1886 was a young woman with MEN2A (25). FMTC is a variant of MEN2A with multigenerational MTC without PHEO or PHPT. This variant was first categorized by Farndon and colleagues in 1986 (26). Initial descriptions of MEN 2B were recorded by Wagenmann in 1922 (27), Froboese in 1923 (28), and then Williams and Pollock in 1966 (29).
The RET gene was first identified in 1985 (30). In 1987, the genetic defect causing MEN 2A was located on chromosome 10 (31). In 1993 and 1994 it was demonstrated that MEN 2A and FMTC (16,17), and MEN 2B (32–34), respectively, were caused by germline RET mutations. Thus, a RET gene mutation occurring in the germline that results in expression of abnormally overactive Ret protein in all tissues in which it is expressed causes these specific inherited syndromes. Somatic RET mutations that occur later in life and are limited to C cells are present in 40–50% of sporadic MTCs (35–37).
The 10-year disease-specific survival of MTC is about 75% (11). Important prognostic factors that predict adverse outcome include advanced age at diagnosis, extent of primary tumor, nodal disease, and distant metastases (11,13,38–40). The current American Joint Committee on Cancer (AJCC) 6th edition TNM (tumor, node, metastasis) classification system (41) is shown in Table 4. Using a prior TNM classification system, 10-year survival rates for stages I, II, III, and IV are 100%, 93%, 71%, and 21%, respectively (40). Unfortunately, there has been no significant trend toward earlier stage of disease at diagnosis with just under half of the patients presenting with stage III or IV disease (11), and no significant increase in the survival of patients with MTC in recent decades (42,43)
Table 4. American Joint Committee on Cancer TNM Classification
|Primary tumor (T)|
|T0—No evidence of primary tumor|
|T1—Tumor 2 cm or less in greatest dimension limited to the thyroid (Supplementum to the 6th edition: T1a, tumor 1 cm or less; T1b, tumor more than 1 cm but not more than 2 cm)|
|T2—Tumor more than 2 cm, but not more than 4 cm, in greatest dimension limited to the thyroid|
|T3—Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extra-thyroidal extension (e.g. extension to sternothyroid muscle or perithyroid soft tissues)|
|T4a—Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve|
|T4b—Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels.|
|Regional lymph nodes (N) are the central compartment, lateral cervical, and upper mediastinal lymph nodes|
|NX—Regional lymph nodes cannot be assessed|
|N0—No regional lymph node metastases|
|N1—Regional lymph node metastases|
|N1a—Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)|
|N1b—Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes|
|Distant metastases (M)|
|MX—Distant metastasis cannot be assessed|
|M0—No distant metastasis|
|* T1, N0, M0|
|* T2, N0, M0|
|* T3, N0, M0|
|* T1, N1a, M0|
|* T2, N1a, M0|
|* T3, N1a, M0|
|* T4a, N0, M0|
|* T4a, N1a, M0|
|* T1, N1b, M0|
|* T2, N1b, M0|
|* T3, N1b, M0|
|* T4a, N1b, M0|
|* T4b, any N, M0|
|*Any T, any N, M1|
Sixth edition (41).