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There are four major types of clinical MTC’s.
MTC may be sporadic or hereditary. Hereditary
MTC is transmitted as an autosomal dominant
trait and may be either transmitted alone (FMTC)
or as part of a Multiple Endocrine Neoplasia
(MEN) type 2A or 2B syndrome (Table 1).
Table 1: Clinical syndromes associated with MTC
Sporadic medullary thyroid carcinoma Patients with sporadic MTC usually present with a palpable thyroid nodule. Neck lymph-node metastases are detected in at least 50 % of patients and may reveal the disease. Metastases outside the neck, in liver, lungs or bones are initially present in 20 % of cases. In the presence of a thyroid nodule, several clinical features such as its location in the upper third of a lobe and a spontaneous pain that is increased by palpation, may prompt the clinician to suspect a MTC. Also, in a third of cases, and more frequently in patients with a large tumor burden, a syndrome of diarrhea and flushes exist. Fine-needle biopsy has made it possible to diagnose MTC prior to surgery. When performed, positive immunohistochemical staining for CT will confirm the diagnosis. Virtually all patients with clinical MTC have elevated basal serum CT concentrations, and serum CT measurement proved to be more reliable than fine-needle biopsy 24. Multiple endocrine neoplasia type 2A MEN-2A is a syndrome associating MTC, pheochromocytoma and hyperparathyroidism. C-cell disease In patients with MEN-2A, the age-specific prevalence of MTC is related to the sensitivity of the detection methods 25–28. Pentagastrin stimulates calcitonin secretion, and is the most sensitive test for the detection of C cell disease. Clinical MTC is rarely observed in gene carriers before the age of 10; its prevalence increases with age, and is 25 % at age 13 and about 70 %at age 70. The pentagastrin stimulation test is positive in about 20 % of gene carriers at 10 years of age; positivity increases with age, attaining 50 % at age 13, 65 % at age 20 and 95 % at age 30. At present, genetic testing is performed before the age of 6 years in all subjects at risk. Pheochromocytoma Pheochromocytoma occurs in 10 % to 60 % of MEN-2A gene carriers depending on the mutation, usually after the age of 10 years. When a pheochromocytoma is discovered in a member of a family carrying the gene, the disease is classified as the MEN-2A syndrome. In prospectively screened families, the diagnosis of clinically significant adrenal medullary disease invariably follows the diagnosis of C-cell disease. Almost all pheochromocytomas are located in the adrenal gland, and very few cases have been observed in the retroperitoneal region. It is bilateral in 50 % of cases, but often after an interval of several years. There is histological progression from adrenal medullary hyperplasia to pheochromocytoma which is almost always benign. Clinical symptoms (intermittent jitteriness, headaches, palpitations, increased sweating, sense of anxiety) fluctuate. Hypertension is rarely present at an early stage. Therefore, pheochromocytoma should be routinely screened for by measuring either plasma concentration or urinary excretion over 24 hours of metanephrines and normetanephrines. If biochemical tests are abnormal, 123 I-meta-iodobenzylguanidine (MIBG) scinti-graphy may demonstrate abnormal uptake in one or both adrenal glands. At an early stage, ultrasonography, CT or MRI scanning may not reveal an adrenal mass. Hyperparathyroidism Hyperparathyroidism occurs in 10 to 25 % of known MEN-2A gene carriers with a codon 634 mutation, usually after the third decade of life. It often consists of parathyroid hyperplasia, with one or more adenomas in older patients. Hyperparathyroidism develops slowly and is usually mild and should be screened for by measurement of serum ionised calcium and PTH 1-84 once a year, throughout life. Other abnormalities A pruritic and pigmented papular lesion of the skin on the upper portion of the back has been observed in patients of some MEN-2A families. This lesion is a form of cutaneous lichen amyloidosis and is called notalgia 18 Hirschsprung’s disease has been observed in rare families with MEN-2A 19. Familial medullary thyroid carcinoma A number of FMTC families have been described in which hereditary MTC was the only manifestation observed. Clinical presentation of MTC at a later age and with a relatively more favorable prognosis as compared to MEN-2A have been reported in families with mutations in exons 13 or 14 9. Whether FMTC represents a separate syndrome or a variant of MEN-2A in which the genetic component is modified to delay the onset of the array of manifestations typifying the MEN-2A syndrome, remains obscure. Multiple Endocrine Neoplasia type 2B MEN-2B is a syndrome associating MTC, pheochromocytoma, ganglioneuromatosis, marfanoid features and skeletal abnormalities. Hyperparathyroidism is practically never observed in this syndrome 29. MTC associated with MEN-2B is generally more aggressive than its MEN-2A counterpart. It occurs early in life, usually before the age of 10 years, and is frequently associated with extension beyond the thyroid capsule and with lymphnode and distant metastases. Pheochromocytomas are identified early in about half of the individuals presenting this syndrome and are frequently bilateral. Ganglioneuromatosis includes mucosal neuromas occurring on the distal portion of the tongue, in thickened lips, throughout the intestinal tract and eventually in the urinary tract. Gastro-intestinal disorders include colonic cramping, obstructive symptoms, and diarrhea. Hypertrophy of corneal nerves is frequent.Marfanoid features include long, thin extremities, an altered upper-to-lower body ratio and ligament hyperlaxity. Skeletal abnormalities are frequent, including slipped femoral epiphysis, pectus excavatum and a characteristic facies. |
