Shuji Fukata

Thyroid Cancer Detected by Ultrasound-Guided Fine-Needle Aspiration Biopsy

Abstract. A greater percentage of thyroid cancers can be detected by ultrasound-guided fine-needle aspiration biopsy (UG-FNAB) than by ordinary FNAB. A group of 678 patients were selected sequentially as having been diagnosed with benign nodules by the conventional FNAB method. We reexamined these patients by UG-FNAB and investigated the types of thyroid cancer that were missed by the conventional FNAB. Of the 678 patients diagnosed with benign nodules (using conventional FNAB), 571 (84.2%) demonstrated the same diagnosis when UG-FNAB was used. The remaining 107 patients (15.8%) studied were suspected of having a malignancy after UG-FNAB had been performed. Surgical specimen histology proved thyroid cancer in 99 of the 107 patients: 93 had papillary carcinoma, 4 had follicular carcinoma, 1 had medullary carcinoma and 1 had anaplastic carcinoma. Two drawbacks were noted when conventional FNAB was used: (1) cancer lesions difficult to palpate (n = 55) (e.g., small cancers with or without benign lesions or cancers associated with Hashimoto’s thyroiditis or Graves’ disease); and (2) palpable cancers with insufficient cell material for analysis (n = 44) (e.g., cystic carcinoma and cancers with calcified lesions. UG-FNAB is a powerful technique for detecting microcancers, cystic carcinomas, cancers associated with benign nodules, Hashimoto’s thyroiditis, or coarse calcifications.

p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thryroid cells

To understand the effects of ionizing radiation on thyroid cells, we investigated the role of p53 in mediating apoptosis and in DNA repair following in vivo and in vitro irradiation of thyroid cells. In vitro exposure of human thyroid cells to ionizing radiation of up to 5 – 8 Gy failed to induce apoptosis in primary cells. The same results were obtained when the thyroid gland was irradiated in the intact rat. To explore the mechanism of failure of the wild-type p53 in inducing apoptosis in thyroid cells, we investigated the expression of apoptosis-related genes, bax, bcl-2 and fas/APO-1 following irradiation or induction of temperature-sensitive p53. The expression of Bax, Bcl-2 and Fas/APO-1 in human primary cultured thyroid cells did not change after irradiation. To further confirm the results, we established a clonal cell line (tsFRO) in which a temperature sensitive p53 (Val138) expression vector was stably transfected to a thyroid carcinoma cell line lacking endogenous p53. Incubation of tsFRO cells at the permissive temperature for three days, however, did not induce apoptosis although G1 arrest was noted. Although enhanced expression of the bax mRNA level was observed, the expression of Bax, Bcl-2 and Fas/APO-1 protein did not change by shifting tsFRO cells to permissive temperature as well as irradiated primary cells. Furthermore, DNA end-jointing ability was examined by transfection of linearized luciferase plasmid into tsFRO cells. Increased luciferase activity occurred when the cells were cultured at the permissive temperature, indicating that the wild-type p53 enhances DNA end-jointing activity. Our results indicate that the wild-type p53 does not lead to apoptosis but facilitates DNA end-jointing in thyroid cells. These results may reflect specific responses in thyroid cells following irradiation.

Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves’ disease

Objective  Differentiation between destruction‐induced thyrotoxicosis and Graves’ thyrotoxicosis is important for selection of proper therapy. It is, however, often difficult to make this distinction without measurement of radioactive iodine uptake. We investigated the possibility that assessment of thyroid blood flow would allow differentiation between the two entities.

Gastrin-releasing peptide immunoreactivity in medullary thyroid carcinoma

Two cases of gastrin releasing peptide (GRP)‐producing medullary thyroid carcinoma are presented. Immunohistochemical examination revealed the presence of GRP‐like immunoreactivity (IR‐GRP) in the primary tumor tissues. High concentration of IR‐GRP was also demonstrated in extracts of the primary tumors by radioimmunologic means with use of a GRP‐specific antiserum. Chromatographic analysis showed that the immunoreactivity was composed of at least two molecular forms: one behaved as synthetic porcine GRP on Sephadex G‐50 gel filtration and the other as porcine GRP (14–27), a C‐terminal active fragment of GRP. The IR‐GRP was shown not to be attributed to bombesin‐like immunoreactivity. Substance P‐like immunoreactivity was not detected in the tumor tissues by either immunohistochemical or radioimmunologic means. This is, as far as the authors are aware, the first finding of IR‐GRP as an ectopic product in medullary carcinoma.

A Novel Homozygous Missense Mutation of the Dual Oxidase 2 (DUOX2) Gene in an Adult Patient with Large Goiter

OBJECTIVE To describe the first adult case of large goiter associated with a novel R1110Q mutation in the dual oxidase 2 (DUOX2) gene. She was initially euthyroid, and developed hypothyroidism later in her forties. DUOX2 is an essential enzyme in iodine organification of thyroid hormone biosynthesis. Only infant cases of congenital hypothyroidism due to mutations of the DUOX2 gene have been reported. Biallelic mutation of DUOX2 is thought to lead to total iodine organification defect. PATIENTS AND MEASUREMENT: This 57-year-old woman became first aware of goiter around the age of 20 years. Since the goiter had enlarged gradually, she consulted us at the age of 32 years. Goiter was soft, and thyroid function was normal. Antithyroid antibodies were negative. Both physical and mental development was normal. Three of her nine siblings and her mother had large goiters. At the age of 44 years, thyroid function demonstrated subclinical hypothyroidism. She started to take levo-thyroxine at a dose of 100 mug/day to reduce goiter. At the age of 56 years, goiter size remained the same. The perchlorate discharge rate was 72.8%, suggesting partial iodine organification defect. Thus, thyroid peroxidase (TPO) gene and DUOX2 gene were analyzed. RESULTS There was no mutation in the TPO gene, but a novel homozygous mutation (R1110Q) in the DUOX2 gene was identified. The same heterozygous mutation was detected in her two sons and two grandchildren. This mutation was not detected in 104 control alleles and was located at a site differing from any other reported mutations in the DUOX2 gene. CONCLUSIONS This homozygous missense mutation can be associated with thyroid dysfunction and goiter formation of an enlarged thyroid gland.

Serum concentrations of remnant‐like particles in hypothyroid patients before and after thyroxine replacement

objectives  Remnant‐like particles (RLPs) reflect chylomicron remnants and very‐low‐density lipoprotein remnants, which are most likely to be atherogenic particles. To investigate the effect of thyroxine replacement on the metabolism of RLPs in hypothyroidism, we measured serum concentrations of RLPs during an oral fat‐loading test in patients with hypothyroidism before and after thyroxine replacement.

Acute suppurative thyroiditis caused by an infected piriform sinus fistula with thyrotoxicosis

We report herein an unusual case of thyrotoxicosis caused by acute suppurative thyroiditis (AST) infected through a piriform sinus fistula (PSF). A 28-year-old man presented with pain over the thyroid gland and elevated serum thyroid hormone levels, a picture similar to subacute thyroiditis. A fine-needle aspiration biopsy from the left lobe showed neutrophil infiltration, and culture from the aspirate grew anaerobic peptostreptococcus. A neck computed tomography (CT) scan showed an abscess in the thyroid gland, and barium swallow revealed the presence of PSF. Appropriate antibiotic treatment ameliorated his symptoms of infection, followed by normalization of thyroid function. Three months later, he underwent fistulectomy and partial left lobectomy. The end of the PSF track was found in the left thyroid lobe. Thus infection of the thyroid gland through the infected PSF was likely the cause of supprative thyroiditis. The unusual clinical features of AST in this patient include the presence of severe thyrotoxicosis, relatively late onset (28-years-old) of infection despite the presence of congenital PSF, and the lack of acute inflammatory signs on the overlying skin of the thyroid gland. It is important to recognize this type of AST, since fistulectomy is required to prevent recurrent AST.

Papillary Carcinoma Obscured by Complication with Subacute Thyroiditis: Sequential Ultrasonographic and Histopathological Findings in Five Cases

BACKGROUND Subacute thyroiditis (SAT) has been rarely reported to coexist with thyroid carcinomas. The objective of the study was to assess sequential ultrasonographic and histopathological findings of SAT in the context of complicating thyroid carcinomas. METHODS Of 1152 patients with SAT who visited our thyroid clinic at Kuma Hospital from 1996 through 2006, 5 cases complicated by papillary carcinoma underwent surgical resection 3-16 months after SAT onset. Ultrasonographic examinations and thyroid function tests were performed in all patients at onset of SAT and just before surgery. Sequential histopathological features of regenerated thyroid and carcinoma involvement were evaluated. RESULTS Heterogenous areas with microcalcifications in the thyroid or lymphadenopathy in three patients were clues for the nodular involvement with papillary carcinoma on the initial ultrasonographic examination. In contrast, diffuse hypoechoic change in the thyroid in two patients made it impossible to differentiate nodular involvement from inflammatory lesion. Histopathological examination of surgical specimens showed granulomatous and fibrotic changes. These were present about 3 months from SAT onset, and residual fibrosis remained several additional months, in the condition of no inflammatory hypoechoic lesions. In the areas of papillary carcinoma overlapping with transient inflammatory involvement, some lymphocytes and fibrotic changes were present in the stroma of papillary foci, but no granulomatous formation was present in any sections. Continuity with fibrosis around regenerated follicular cells was absent. The degree of lymphoid infiltrate and fibrotic change in the papillary carcinoma was not dependent on periods between SAT onset and the resection. CONCLUSIONS SAT may produce ultrasound changes that obscure the coexistence of papillary carcinoma, but affects no lymphoid infiltrate and fibrotic changes involved in carcinoma throughout the clinical course. We recommend that patients with SAT have ultrasonography after they recover. Further workup, including cytological examination of hypoechoic regions, should be performed if they are present as measuring 1 cm or larger.

Diagnosis of follicular carcinoma of the thyroid : role of sonography in preoperative diagnosis of follicular nodules

The purpose of this study was to evaluate sonographic examination, as well as other clinical tests, for clarifying the parameters for predicting follicular carcinoma in follicular nodules of the thyroid. Nine hundred and ten consecutive patients with follicular nodules were pathologically classified as having follicular carcinoma (109 patients) or benign tumor (811 patients). Benign tumors included follicular adenoma (237 patients) and adenomatous thyroid nodules (574 patients). A case-control study was performed for follicular carcinomas and benign tumors. “Thyroglobulin 1000 ng/ml≦”, “cytology class 3≦”, and a “solid pattern”, “low-echoic level of internal echo”, and “jagged borders” of follicular carcinomas were found to be significantly higher than those of benign tumors. The sensitivities of a solid pattern (79.8%) and a low-echoic level (75.2%) were found to be relatively higher than those of other features and findings. The specificities of thyroglobulin 1000 ng/ml≦(84.0%), cytology class 3≦, and jagged borders (86.2%) were found to be relatively higher than those of other features and findings. We concluded that thyroglobulin 1000 ng/ml≦ and cytology class 3≦ in clinical features, and a solid pattern, low-echoic level, and jagged borders on sonography, indicated an increased risk of follicular carcinoma of the thyroid in follicular nodules.

Gene Rearrangement of Immunoglobulin as a Marker of Thyroid Lymphoma

Abstract. Thyroid lymphoma occurs most commonly in the thyroid gland in association with Hashimoto’s thyroiditis. Histologic findings occasionally cannot distinguish lymphoma from Hashimoto’s thyroiditis, which creates a serious problem of whether treatment should be initiated. For this study, we examined 33 lymphoma tissues and 10 thyroid tissues from patients with Hashimoto’s thyroiditis for the presence of gene rearrangement of immunoglobulin, which represents clonality of B-cell-derived tumors. Genomic DNA from thyroid tissues was digested with Bam H1 and Hind III restriction enzymes followed by electrophoresis. A Southern blot was performed with an IgH-JH probe or IgL-Jκ probe to detect gene rearrangement. Of the 33 lymphoma tissues, 27 (85%) showed gene rearrangement of immunoglobulin, whereas none of Hashimoto’s thyroiditis tissue showed gene rearrangement. Five patients with a positive histologic diagnosis of lymphoma showed a negative gene rearrangement and were treated as having lymphoma. We encountered one case of lymphoma (plasmacytoma) in which gene rearrangement (not histologic findings) was diagnostic. Gene rearrangement of immunoglobulin can be used to detect thyroid lymphoma, particularly when the histologic diagnosis is inconclusive. The sensitivity of detecting thyroid lymphoma by the Southern blot method was about 85% in the present series.