Abstract :
Medullary carcinoma of thyroid (MCT) accounts for 4-10% of thyroid cancers. It occurs in sporadic ( 75-80%) or hereditary ( 20-25%) form. Prognosis is better in the hereditary form. Hereditary form occurs as part of multiple endocrine adenomata 2 (MEN 2) syndrome, a MEN 2A (MCT, parathyroid hyperplasia and pheochromocytoma), and MEN 2B (MCT, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, Marfanoid habitus) or as familial MCT (FMC). MEN 2B runs a more aggressive course than MEN 2A or FMC. Relative proportions of MEN 2A :FMC: MEN 2B: approximate 65:20:15. Hereditary MCT is transmitted in an autosomal dominant pattern. The gene for MEN 2 has been mapped to chromosome 10 q 11.2 and has been identified as ret proto-oncogene. Ret proto-oncogene codes for a putative receptor kinase containing a cysteine-rich extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain. The gene appears involved in development/differentiation of neural crest tissues. Missense germline mutations of the ret proto-oncogene altering cysteine residues in exon 10 or 11 are found in about 95% patients with MEN 2A and over 70% patients with FMC; mutation affects codon 634 in most cases ( 67%) and codon 609, 611, 618 or 620 in others. About 95% of MEN 2B families have mutation in exon 16 affecting codon 918. Germline mutation seen in MEN 2B have also been detected in about 20-40% of patients with sporadic MCT; several other cases show somatic mutations in the tumor. The mutated ret alleles are genes demonstrating constitutive activation of the ret kinase. Ret mutations are also found in 40% of families with Hirschsprung disease. Traditionally, screening for MCT has involved measurements of calcitonin before and after stimulation with pentagastrin and/or calcium. Since elevated calcitonin may not be observed for several years, there is often a delay in the diagnosis of MEN 2. Recent studies have demonstrated that direct DNA analyses identifies mutations of MEN 2 or FMC in a reliable and cost effective manner. This permits early diagnosis of MEN 2 and a markedly improved prospect of a surgical cure. Some have advocated prophylactic thyroidectomy in infants demonstrating germline mutations for MEN 2B. Subjects with germline mutations of MEN 2A may also undergo prophylactic thyroidectomy in early childhood and thus, avoid ravages of a subsequent invasive, recurrent or metastatic MCT. Treatment of MCT remains total thyroidectomy with lymph node dissection. External irradiation and chemotherapy offer little in its treatment.
