5 Core Messages • Medullary thyroid carcinoma (MTC) constitutes 4 to 8% of all thyroid malignancies. • In general 20% of the MTCs are inherited (mainly in the form of multiple endocrine neoplasia type 2A [MEN2A], MEN2B, and other familial MTC syndromes); the remaining cases are sporadic. • Clinical appearance of the MTC is similar to differentiated thyroid cancers, but typical tumor location being the upper poles of the thyroid lobes. • Looking for adrenal abnormalities is mandatory in all patients with a suspected and/or confirmed MTC. • Surgery (total thyroidectomy with at least bilateral level VI compartmental lymph node dissection) is the only curative treatment for MTC. • In general 10-year disease-specific survival rate in patients with MTC approaches 75%. The first description of medullary thyroid carcinoma (MTC) was presented in 1906 by Jaquet; the described case was defined as “malignant goiter with amyloid” having distant metastases.1 In the second half of the 20th century the MTC was precisely defined as distinct thyroid malignancy (Laskowski in 1958, Hazard et al in 1959, and Williams et al in 1966).2–4 MTC constitutes 4 to 8% of all thyroid carcinomas; commonest being papillary thyroid carcinoma (60 to 80%) and follicular thyroid carcinoma (10 to 20%).5,6 MTC arises from calcitonin-secreting parafollicular C cells that constitute approximately 1% of all thyroid cells. C cells of the thyroid gland develop from the neural crest and belong to the neuroendocrine family of cells which are spread widely in the human body. The neuroendocrine cell system is called disseminated neuroendocrine system (DNS).6 Within the thyroid gland neuroendocrine cells are mainly located in the upper portions of both thyroid lobes, and that is why MTC are usually found around the upper poles of the thyroid gland. The typical microscopic change leading to MTC starts from C-cell hyperplasia (CCH), progresses to early invasive medullary carcinoma, which subsequently turns into an invasive MTC. The presence of CCH within thyroid is typical for inherited form of MTC (i.e., multiple endocrine neoplasia type 2 [MEN2] syndrome).6 Histologically MTC is composed of spindle-shaped or rounded cells with numerous fibrous septa and separated by amyloid deposits (amyloid deposits in MTC were described by Jaquet in 1906).1 The tumor is usually ill defined and nonencapsulated with macroscopic invasion into adjacent tissues. Positive immunohistochemical staining for calcitonin, carcinoembryonic antigen (CEA), and amyloid help establish diagnosis of MTC. Pearl • Medullary thyroid carcinoma is usually located in the upper poles of the thyroid lobes because this is where the relative number of parafollicular C cells is the highest. MTC occurs mainly sporadically (70 to 80%), but it could also follow autosomal dominant pattern of inheritance of the disease (i.e., there is a 50% risk for offspring of a carrier to inherit the disease).6 Inherited variant of MTC presents clinically as MEN2 syndrome. In absolute numbers MEN2 is a rare disease: 1 in 30,000 is affected.6 MEN2 virtually always consists of familial appearance of MTC (MTC is a core feature of MEN2) often coexisting with other neoplasms and includes three principal types5–7: 1. MEN2A (described in 1961 by Sipple [Sipple syndrome]; approximately 55% of all MEN2 cases)—MTC is found in all cases of the MEN2A type (100% of patients), pheochromocytoma (adrenal locations in 50 to 70% of patients, other locations rare), and hyperparathyroidism (25% of patients). 3. Familial medullary thyroid carcinoma (FMTC; approximately 35 to 40% of all MEN2 cases)—MTC (100% of patients) and—by definition—no pheochromocytoma or other tumors (due to late appearance of pheochromocytoma in MEN2A); this definition is difficult to use in advance, and therefore most families with FMTC are initially managed, observed, and treated as MEN2A families). In early 1990s RET (REarranged during Transfection) proto-oncogene germline mutations have been identified in nearly all studied MEN2A, FMTC, and MEN2B patients, however, there are still some families with typical features of MEN syndrome but no identifiable (so far) RET mutation. Germline mutations in RET gene result in abnormally overactive RET protein in all tissues, in which it is expressed (somatic mutations in RET gene are observed in 50% of sporadic MTC cases and are limited to C cells only). Since the identification of RET proto-oncogene mutations, all individuals at risk or suspected of having MEN2A or MEN2B syndrome should ideally have mutational analysis for the RET gene as early as possible. Presymptomatic diagnosis based on genetic tests leads to prophylactic surgery (see the section on “Surgical Prevention of Medullary Thryoid Carcinoma in Multiple Endocrine Neoplasia Type 2 Syndrome”). The clinical appearance of MTC is usually not different from the presentation of patients with differentiated thyroid carcinomas (see Chapter 3, Differentiated Thyroid Carcinomas). If clinically symptomatic, MTC typically presents as solitary, unilateral thyroid nodule, in the upper poles of the thyroid lobe (where the concentration of C-cells is the highest). Sporadic forms of MTC usually develop in the fifth or sixth decade of life. Contrary to that, the hereditary MTC (in MEN2 patients) usually presents at younger age (third or fourth decade of life or even earlier) and presents as multiple, bilateral nodules in the upper poles of the thyroid lobes. Unlike differentiated thyroid cancer, MTC prevalence is almost equal in both the genders.5,8 Pearl • MTC prevalence in men and women is almost equal (unlike differentiated thyroid cancer). The clinical evaluation of patients with MTC is virtually the same as for patients with differentiated thyroid cancers (see Chapter 3 Differentiated Thyroid Carcinomas). The important clinical feature of MTC is that 50 to 75% of patients present initially with metastatic cervical adenopathy. Tumors often grow quickly and presents with compressive symptoms; tracheal compression is seen in approximately 15% of the MTC cases at the time of initial presentation.3 Fine-needle aspiration biopsy (FNAB) (usually sonographically guided) is generally deemed sufficient to confirm the diagnosis of MTC. FNAB is a cost-effective tool, with low risk of procedure-related complications. There are ambiguities referred to FNAB use in follicular thyroid neoplasms, but in MTC, FNAB provides excellent accuracy (> 90%) with low false-negative outcomes (< 5%). The FNAB can be successfully performed with optimal results for tumors with 1 to 4 cm diameter (< 1 cm it is difficult to sample, and > 4 cm it is uncertain if appropriate portion of the tumor had been sampled).9 In general, the algorithm for the management of thyroid nodules presented in Chapter 3 is applicable when facing a patient with thyroid nodule and clinical features suggesting MTC. To diagnose MEN2A (or MEN2B), the only certain way is to confirm RET mutation or to identify typical feature of MEN2A (or MEN2B, respectively) also in first-degree relatives of the patient. Alternatively at least two typical clinical features of MEN2A in the individual are required to clinically diagnose MEN2A. For making a clinical diagnosis of MEN2B a preponderance of the classical clinical features of this syndrome in the individual is required. The diagnosis of FMTC requires exclusion of pheochromocytoma in at least two generations of the affected family.5 If the MTC is microscopically confirmed, clinical staging should follow. Staging divides patients into prognostic groups to support clinical decisions on optimal treatment strategy. Current tumor-node-metastasis (TNM) staging system (as updated by American Joint Committee on Cancer Staging in 2010) is presented in Tables 5.1 and 5.2. Pearl • Appropriate clinical staging is a mandatory first step in the assessment of the patient. The initial staging will form the basis for the assessment of treatment outcomes. • Virtually all MTCs secrete calcitonin, but rarely there may be odd cases with normal calcitonin level.
Medullary Thyroid Carcinoma I
Histogenesis
Genetics
Clinical Picture
Diagnosis and Staging
