Clinical Features Of

Most patients with MTC present in the fourth decade of life.10 Patients with sporadic MTC commonly present at an older age than patients with familial MTC and MEN type IIA. Most patients with MEN IIB are diagnosed within the first two decades of life.10 The

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Figure 3-7. The RET multicomponent receptor: the transmembrane RET recepetor bound to a coreceptor (growth factor receptors a1, -2, -4) anchored to the cell membrane by glycosylphosphatidyli-nositol (GPI) and the ligand (glia-derived neurotrophic factor, neur-turin, or persephin).

frequency of MTC is equal among both sexes, unlike other thyroid neoplasms, which have a female predominance. Almost all patients with sporadic MTC or index cases of familial MTC and MEN type IIA present with a thyroid mass, thyroid mass with cervical lymphadenopathy, and, less frequently, only cervical lymphadenopathy.310 Regional lymph node metastases are common and occur in up to 75% of patients with clinically evident MTC.29 Common sites of lymph node metastases are the central neck compartment lymph nodes: peritracheal and perithy-roidal nodes (level VI cervical lymph nodes) (Figure 3-8). Lymph node metastases also occur to the lateral cervical compartment and upper mediastinum (levels II, III, IV and VII) (see Figure 3-8). Because MTC usually occurs in the posterior-upper lobes of the thyroid gland, where most of the C cells reside, invasion into the trachea or recurrent laryngeal nerve or laterally into the jugular vein or carotid artery may be present. Rarely, patients with MTC may also present with diarrhea, flushing, or bone pain from tumor metastases or heavy tumor burden.10 Distant metastases from MTC to the liver, bone, and lung occur with late presentation or after initial treatment in

Figure 3-8. Cervical and mediastinal lymph node compartments. Level I = submental and submandibular nodes; level II = upper internal jugular chain nodes; level III = middle internal jugular chain nodes; level IV = lower internal jugular chain nodes; level V = spinal accessory and transverse cervical nodes; level VI = tracheo-esophageal groove nodes and perithyroidal nodes; and level VII = infraclavicular and upper anterior mediastinal nodes (thymic).

Figure 3-8. Cervical and mediastinal lymph node compartments. Level I = submental and submandibular nodes; level II = upper internal jugular chain nodes; level III = middle internal jugular chain nodes; level IV = lower internal jugular chain nodes; level V = spinal accessory and transverse cervical nodes; level VI = tracheo-esophageal groove nodes and perithyroidal nodes; and level VII = infraclavicular and upper anterior mediastinal nodes (thymic).

patients with persistent MTC. Unlike differentiated thyroid cancers of follicular cell origin, which trap radioiodine, localization of MTC distant metastases is difficult until gross disease has developed.

Hereditary MTC has an autosomal dominant pattern of inheritance and accounts for 25 to 50% of all MTC cases. Almost all patients who are RET germline mutation carriers develop at least CCH by 30 years of age.30 Familial MTC and MEN types IIA and IIB comprise the hereditary forms of MTC (Table 3-1). The MEN type IIA hereditary syndrome is composed of MTC, pheochromocytoma, and/or parathyroid neoplasms. About 50% of patients with MEN type IIA will develop pheochromocytoma, and up to 30% will develop hyperparathyroidism. Furthermore, some patients with MEN type IIA may have cutaneous lichen amyloidosis.31,32 Patients with MEN type IIB have MTC with or without pheochromocytoma and typical phenotypic features. These phenotypic features include mucosal neuromas on the distal tongue, intestinal ganglioneuromatosis, thickened lips, and a marfanoid body habitus. Familial MTC is a hereditary syndrome in which only MTC is observed without any of the other components of MEN type IIA. It remains unclear whether familial MTC is a distinct syndrome or a variant of MEN type IIA, in which there is a delayed manifestation of all of the components.

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