Masakatsu Toda

Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas.

Germline mutations in the RET proto‐oncogene have been shown to be the underlying cause of multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Some cases of sporadic medullary thyroid carcinoma (sporadic MTC) are reported to have specific codon 918, 883 and 768 mutations of the RET gene in tumor tissues. We examined RET gene mutations in 40 Japanese cases who had previously undergone surgery for sporadic MTC. DNA extracted from formalin‐fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes was analyzed for mutations of exon 10, 11, 13, 14 and 16 of the RET gene by DNA sequencing and by mutation‐specific restriction enzyme analysis. Germline RET point mutations were found in six of 40 cases (15%), cysteine residues at codon 618 in two, codon 634 in three and valine residue at codon 804 in one, and were newly identified as heritable MTC. Of the remaining 34 sporadic MTC cases, four (12%) had tumor‐specific RET point mutations. Two were found in exon 16; one case showed an ATG to ACG (Met to Thr) mutation at codon 918, and the other showed two point mutations, ATG to ACG (Met to Thr) at codon 918 and GCA to GTA (Ala to Val) at codon 919 with loss of the wild‐type allele, suggesting that both alleles at the RET locus were altered. The other two were found in exon 13; one case showed a CCG to TCG (Pro to Ser) mutation at codon 766 and the other showed a silent mutation, GTC to GTT (Val) at codon 778 with loss of the wild‐type allele. There was no association of sporadic mutations with recurrence or prognosis in patients with sporadic MTCs. The low rate of somatic RET mutation at codon 918 in our sporadic MTC suggests that as yet unknown factors may be involved. Genetic alterations in both alleles may have an important role in a small fraction of sporadic MTCs.

Calcium and its regulating hormones in patients with graves disease: sex differences and relation to postoperative tetany.

OBJECTIVE To find out why female sex is the most important risk factor for tetany, as calcium and bone metabolism may differ between the sexes. DESIGN Prospective study. SETTING Thyroid centre, Japan. PATIENTS AND METHODS 45 men (mean age 35 years, SD 13) and 178 women (mean age 33 years, SD 12) with Graves disease treated by subtotal thyroidectomy. INTERVENTIONS Measurement of serum concentrations of intact parathyroid hormone (iPTH), calcium, electrolytes, 25-hydroxyvitamin D (25 (OH) D), and 1,25-dihydroxyvitamin D (1,25 (OH) 2D). MAIN OUTCOME MEASURES Mean values of these substances, together with reductions in serum calcium concentration, relative youth, increased alkaline phosphatase activity, large goitre, and increased serum TSH binding inhibitory globulin concentration. RESULTS Women had significantly lower calcium concentrations than men (mean (SD) 2.37 (0.13) compared with 2.43 (0.07), p = 0.003). Serum calcium concentrations correlated significantly with concentrations of 25 (OH) D (p < 0.001). 121 of the women (68%) compared with 13 (29%) of men had vitamin D deficiency as defined as 25 (OH) D < 25 nmol/l (p < 0.05). 15 patients (8%) developed tetany postoperatively compared with I man (2%, p = 0.2). CONCLUSION Women with Graves disease are more susceptible to calcium and vitamin D deficiency than men, which may account for the higher incidence of postoperative tetany among women with the disease.

Usefulness of endoscopic ultrasonography (EUS) in diagnosing esophageal infiltration of thyroid cancer

Pre-operative evaluation of esophageal infiltration is sometimes difficult in patients with advanced thyroid cancer even with recent imaging modalities. We evaluated the accuracy of endoscopic ultrasonography (EUS) in diagnosing esophageal infiltration of thyroid cancer. Twenty-nine patients with advanced thyroid cancer underwent EUS and other imaging examinations before surgery. The diagnostic accuracy of EUS was compared with that of magnetic resonance imaging (MRI) and esophagography based on pathologic findings in 27 of the 29 cases. EUS clearly demonstrated the 5-layer structure of the esophageal wall. EUS detected cancer invasion into the muscularis propria of the esophagus correctly in 8 of 10 patients diagnosed pathologically with muscular infiltration. EUS was significantly more accurate than MRI and esophagography (88.9% vs 63.0% and 66.7%, respectively). The specificity of EUS was also significantly better than the specificities of MRI or esophagography (94.1% vs 58.8% and 64.7%, respectively). The sensitivity, positive predictive value and negative predictive value of EUS tended to be better than those of MRI and esophagography. EUS is useful in evaluating the esophageal infiltration of thyroid cancer. This method has the further advantage of detecting the exact depth of cancer invasion into the esophageal wall.

Presymptomatic Detection and Treatment of Japanese Carriers of the Multiple Endocrine Neoplasia Type 2A Gene

DNA extracted from the peripheral blood leukocytes of 36 members of five families with multiple endocrine neoplasia (MEN) type 2A was analyzed for mutations of exons 10, 11, 13, 14, and 16 of theRET proto-oncogene by nonisotopic polymerase chain reaction-single-strand conformation polymorphism analysis and automated DNA sequencing. Germline mutations were found in all 9 of the affected individuals and in 6 of the 27 individuals of unknown status. A 70-year-old man who had been completely asymptomatic before genetic diagnosis underwent left adrenalectomy and total thyroidectomy, and was found to have pheochromocytoma and multifocal micromedullary thyroid carcinoma (MTC), A 32-year-old man and a 15-year-old boy, with elevated calcitonin levels detected by the C-cell-stimulation test, but no evident thyroid tumor, underwent total thyroidectomy. Histopathological diagnosis revealed multiple micro MTCs. A 7-year-old girl without evidence of a thyroid tumor or an elevated calcitonin level is being followed up. The remaining two subjects with an evident thyroid tumor and elevated calcitonin levels refused surgery. These results suggest that genetic screening for MEN type 2 afflicted family members can facilitate the presymptomatic detection of gene carriers. Thus, we must carefully evaluate whether immediate prophylactic total thyroidectomy is indicated for gene carriers of MEN 2A without an evident thyroid tumor or elevated calcitonin levels.