Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET

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The pathogenesis of thyroid carcinoma in Graves' goiter is still obscure and the methods for preoperative diagnosis of such carcinomas is not well established. We studied the incidence, clinical features, and pathological findings of thyroid carcinoma in Graves' goiter. From October, 1983 to September, 1985, a total of 739 patients with Graves' disease underwent subtotal thyroidectomy at Ito Hospital, Tokyo. All of these patients underwent roentgenography of the neck before surgery. Thyroid carcinoma was revealed in the resected specimen in 15 (2.0%) of 739 patients. During the same period, another 4 patients underwent surgery for thyroid carcinoma who had had Graves' disease previously and these 4 cases were included in the present study. The incidence of thyroid carcinoma associated with Graves' disease was 2.6% (19 of 743 cases). Histological examination revealed 15 papillary and 4 follicular carcinomas. The size of the carcinoma foci was 13.8 +/- 15.6 mm in diameter (range: 1-60 mm), 10 (52.6%) foci being 10 mm or greater. Invasive growth into the surrounding thyroid tissue was predominant and regional lymph node metastasis was noted in all 6 patients who underwent cervical dissection. Preoperative roentgenography revealed calcification in 5 (26.3%) of 19 cases. Our present study indicates that thyroid carcinoma in Graves' goiter may show markedly invasive growth with lymph node metastasis even though the primary tumor is small in size, and it is suggested that the detection of calcification may serve as a part of the diagnostic measures when the carcinoma focus is difficult to palpate in the diffusely-enlarged Graves' goiter.

We analyzed the results of ethanol sclerotherapy in 61 patients with cystic thyroid lesions which recurred after aspiration. Cytologic study showed all of the lesions to be benign. The patients were followed clinically and ultrasonically 1 month and 6 or more months after treatment. If the cystic lesions recurred, repeated treatment was offered. During the follow-up, 36 (59.0%) patients experienced no recurrence after the initial treatment and 5 (8.2%) patients received treatments 2 or more additional times. In 44 (72.1%) of the 61 patients, the cystic lesion almost disappeared or decreased in size, but in 17 (27.9%) patients it did not decrease. Four patients underwent surgery after the ethanol sclerotherapy. Although no severe complications were observed, there were complaints of slight pain in 12 patients, severe pain in 1 patient, and a drunken feeling in 1 patient. We consider instillation of ethanol into recurrent cystic lesions of the thyroid to be a simple, safe, economical, and effective treatment.

Eight-year follow-up evaluation and analysis of factors related to postoperative thyroid dysfunction were made in 216 patients with Graves' disease treated by subtotal thyroidectomy. The postoperative status of thyroid function were as follows according to hypersensitive TSH level: 65 patients (30.1%) were euthyroid, 25 (11.5%) had overt hyperthyroidism requiring treatment, 14 (6.5%) had subclinical hyperthyroidism with normal thyroid hormone and suppressed TSH, 21 (9.8%) were overt hypothyroid requiring thyroid hormone replacement and 91 (41.1%) had latent hypothyroidism without hormone replacement. In order to know factors related to postoperative thyroid function, age, sex, preoperative levels of TSH receptor antibody (TRAb), thyroid antibody titers, degree of lymphocyte infiltration, duration of medical treatment, weight of the resected thyroid tissue and weight of the remnant thyroid tissue were determined. No factor except thyroid remnant and antimicrosomal antibody titer was related to postoperative thyroid function. The weight of remnant should be less than 6 g to avoid recurrent hyperthyroidism. As recurrence of hyperthyroidism was observed more than 5 yr after surgery, long follow-up is needed.

Solid cell nests (SCN) are found within the thyroid parenchyma on routine clinical pathological examinations, but their histogenesis and clinical significance are still obscure. From November 1987 to May 1991, a total of 3,260 patients underwent thyroid surgery at Ito Hospital and SCN were noted in 42 (1.3%) patients. Serial sections of the specimens from these patients were studied morphologically and immunohistochemically. The location and growth pattern of SCN within the thyroid parenchyma were distinct from those of hyperplastic C-cells. SCN were located in the isthmus lobe in 1 patient and even in the pyramidal lobe in 3 patients. In another patient neoplastic proliferation of SCN was observed. Immunohistochemically, SCN were negative for neuron-specific enolase, chromogranin A, and S-100 protein. These findings strongly suggest that SCN are of endodermal origin and that they may be closely related to mucoepidermoid carcinoma of the thyroid gland.

The histogenesis and clinical significance of solid cell nests (SCN) of the thyroid are not fully understood. From August 1987 to December 1989 a total of 2544 patients with thyroid and parathyroid diseases underwent surgery at Ito Hospital, and SCN were revealed within the thyroid parenchyma in 21 (0.8%). Distribution of SCN was not limited to the upper one-third of the lateral lobe, and SCN were found even in the isthmus lobe. In 5 cases microcysts were also noted within SCN, and their content was thought to be acidic proteoglycan. Immunohistochemical study revealed that SCN were negative for thyroglobulin and calcitonin but positive for carcinoembryonic antigen. Thirteen of 21 cases showed positive immunostaining with cytokeratin. Scattered calcitonin-positive cells were noted around the SCN. It is suggested from these findings that SCN of the thyroid are closely related to certain cells of ultimobranchial body vestiges which may be not of neuroectodermal origin but of endodermal origin.