The age of onset and aggressiveness of MTC may vary considerably, depending on the clinical situation. Sporadic MTC is unilateral and unifocal in the majority of cases, whereas MTC in the MEN type II syndromes is usually bilateral and multifocal. MTC in MEN type IIA usually appears in late childhood or in the teenage years. In FMTC, the tumors are indolent and appear later in life, whereas MTC in MEN type IIB presents in infancy or early childhood, with gross evidence of cancer present in children as young as 6 months of age.
The prognosis of MTC is associated with disease stage at the time of diagnosis. Numerous studies of patients with MEN type IIA who are treated for MTC have demonstrated a direct corre lation between early diagnosis and cure of the disease. Patients with MEN type IIA and FMTC have a completely normal outward appearance. In these patients, the diagnosis of MTC has been made through screening efforts (measurement of calcitonin levels or RET gene mutation testing), undertaken because of other affected family members, or by detection of a thyroid nodule on physical examination. Over 50% of patients with MEN type IIB have normal parents, and the diagnosis in these de novo cases is not usually made until a mass is discovered in the neck. Very rarely, the diagnosis is made earlier by an astute clinician, who notes the characteristic phenotype. Most index cases of MEN types IIA and IIB and FMTC present with a thyroid mass, which is identified as MTC either on biopsy or at the time of thyroidectomy. Palpable cervical lymphadenopathy is present in over 50% of patients who present with palpable MTC, and microscopic metastases are present in 85%. Respiratory complaints, hoarseness, and dysphagia can be seen in about 13% of patients. Approximately 12 to 20% of patients with palpable MTC present with evidence of distant metastatic disease.314 Relatively few index cases of MEN type II present with clinical pheochromo-cytoma or hyperparathyroidism.
Twenty-five percent of all patients who present with MTC have MEN type IIA or IIB or FMTC. Because of this, we feel that genetic testing should be considered in all patients with MTC. An in-depth family history with close attention to any relatives with severe hypertension or thyroid and adrenal tumors is essential. A careful review of systems to identify any evidence of symptomatic pheochromo-cytoma or hyperparathyroidism should be conducted. The caregiver should also note any pheno-typic physical characteristics that might suggest MEN type IIB. If a RET mutation is found on genetic screening, all family members are tested for the same mutation. Patients found to have a mutation in the RET proto-oncogene should undergo biochemical testing for pheochromocytoma prior to operation if possible. Failure to identify a pheochro-mocytoma in a patient who undergoes thyroid surgery can have disastrous consequences as induction of anesthesia may cause a catechol surge with resultant malignant hypertension and cardiac events.
Thyroid C cells and MTC cells secrete calcitonin, which has been an invaluable marker for the presence of disease in screening and follow-up settings. Peripheral serum levels of this hormone are measured by radioimmunoassay. Over 30% of patients with MTC have normal basal levels of calcitonin. Therefore, provocative calcium-pentagastrin-stimulated calci-tonin tests are routinely performed. The gastric hormone pentagastrin stimulates calcitonin secretion and is widely used (with or without additional calcium infusion) as a secretagogue in provocative cal-citonin stimulation tests. The development of immunoradiometric assays has greatly improved the sensitivity and specificity of the provocative calci-tonin stimulation test.
Routine stimulated calcitonin testing, however, has several disadvantages. First, the test is very uncomfortable; patients often complain of nausea, diaphoresis, agitation, and urinary urgency. Historically, members of MEN type II kindreds at risk of inheriting the diseases were screened at early ages, usually around 5 years of age, and required annual testing until the age of 45. It is understandable, therefore, why compliance was often poor, especially among adolescents and young children. Second, because the disease is inherited in an autosomal dominant fashion, 50% of at-risk patients will never develop disease and would be spared the expense and inconvenience of routine scheduled testing if a definitive genetic test were applied. Third, calcitonin testing only detects the presence of existing disease and requires sufficient tumor mass to produce elevations of plasma calcitonin levels. On the other hand, routine genetic testing identifies RET mutation carriers earlier and more reliably than biochemical testing and obviates the need for continued testing in individuals found to be unaffected. Stimulated calcitonin testing remains important, however, in the follow-up of patients treated for MTC.
Genetic screening of all individuals within a known MEN type II kindred is the standard of care. If patients from a kindred with a known mutation are shown not to have inherited the mutation, they need no further follow-up. Controversy exists over the management of patients found to have a RET mutation with no clinical or biochemical evidence of dis ease. At present, we recommend in-depth genetic counseling and encourage prophylactic thyroidectomy in childhood for carriers of the mutant gene. The near-complete penetrance of MEN type II manifesting as MTC, combined with the morbidity and mortality associated with the tumor, warrants surgery before the tumor can be detected biochemically. In a study by Wells and colleagues, seven MEN type IIA kindreds were evaluated by genetic screening.15 Twenty-one patients had RET mutations and were offered prophylactic thyroidectomy. Thirteen patients opted for surgery and all were found to have either C-cell hyperplasia or foci of MTC on pathologic examination. Of these 13 patients, only 7 had abnormal calcium-pentagastrin-stimulated calcitonin testing preoperatively. Recent studies have shown that 10% of patients diagnosed by abnormal biochemical testing had metastatic MTC despite diligent screening.16
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