Hiroto Yamashita

Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma

In patients with thyroid papillary carcinoma, age and the presence or absence of distant metastasis are regarded as the main prognostic factors. However, the histologic characteristics of thyroid papillary carcinoma that develops distant metastasis have not yet been clarified.

Familial nonmedullary thyroid carcinoma characterized by multifocality and a high recurrence rate in a large study population.

First-degree relatives of persons with thyroid cancer are known to be at relatively high risk for the disease. To better understand the clinicopathologic characteristics of familial nonmedullary thyroid carcinoma (FNMTC), we carried out a retrospective study in which we identified individuals treated at our institution who had at least one first-degree relative with the disease. We used data obtained from our patient records to compare the features of 258 cases of the disease with the features of sporadic papillary or follicular thyroid carcinoma in another group of patients. The 258 patients represented 154 families and were selected from among 6458 patients with papillary or follicular thyroid carcinoma who underwent thyroidectomy between 1946 and 2000. Compared to the patients with sporadic disease, the FNMTC patients were more likely to have intraglandular dissemination (28.5% vs. 40.7%; p < 0.0001) and multiple benign nodules (29.8% vs. 41.5%; p <0.0001). There were no significant differences between the two types of patients in terms of gender, age, tumor diameter, adhesion to or invasion of the surrounding tissues, macroscopic metastasis observed at surgery, histology, presence of single benign nodules, presence of chronic thyroiditis, microscopic metastasis, or rate of lymph node metastasis. Recurrence was statistically frequent in the FNMTC patients compared with that in the sporadic disease patients (16.3% vs. 9.6%; p = 0.0005), and the disease-free survival rate was significantly poorer in the FNMTC patients (p = 0.0041 by the Wilcoxon test and p <0.0001 by the log-rank test). No significant difference in the overall survival rate was found between the two groups. Multivariate analysis by Cox’s proportional hazards method showed FNMTC to be an independent predictor of shorter disease-free survival (risk ratio 1.88; confidence interval 1.35–2.54; p = 0.0003). Locoregional recurrence in the ipsilateral or contralateral lymph nodes and contralateral thyroid lobe was significantly more frequent in the FNMTC patients than in the sporadic disease patients, whereas no difference was found regarding distant metastases. We conclude that FNMTC is a clinically distinct entity with an aggressive nature. Because of the frequent presence of benign nodules, multifocality, and high rate of locoregional recurrence, total or near-total thyroidectomy with modified radical neck dissection in FNMTC patients is recommended.

Somatic Mutations in RET Exons 12 and 15 in Sporadic Medullary Thyroid Carcinomas: Different Spectrum of Mutations in Sporadic Type from Hereditary Type

Germline mutations in the RET proto‐oncogene are responsible for multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Point mutations or in‐frame deletions of exons 10, 11, 13, 14 and 16 are associated with sporadic medullary thyroid carcinoma (MTC). To understand further the role of the RET gene in sporadic MTC, we examined mutations in exons 12 and 15 of RET in patients with sporadic MTC. DNAs were extracted from 39 formalin‐fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes. DNA sequencing was used to identify mutations in exons 12 and 15 of RET. In this study, one novel somatic mutation was found in exon 12 and five novel mutations or deletions were found in exon 15. Of the patients with mutations, one had an in‐frame 12‐bp deletion (nt. 2625‐2636), one had point mutations in both codons 884 and 908, and the remaining three had point mutations in codons 748, 876 and 901, respectively. Together with our previous identification of somatic mutations in exons 10, 11, 13, 14 and 16, somatic alterations were found in 10 out of 39 (25.6%) sporadic MTCs. There was no association of RET gene mutations with tumor recurrence or prognosis. These results suggest that mutations occur frequently in the RET coding region in addition to the previously reported mutation hot spots, and there is a different spectrum of mutations between sporadic and hereditary MTC.

Thyroid Cancer Associated with Adenomatous Goiter: An Analysis of the Incidence and Clinical Factors

We evaluated the incidence of thyroid cancer in patients with adenomatous goiter and investigated the clinical factors distinguishing patients with occult thyroid cancer, defined as a tumor size smaller than or equal to 10 mm, from those with clinical thyroid cancer, defined as a tumor size larger than 10 mm. Of 835 patients with histologically confirmed adenomatous goiter, 256 (30.7%) also had thyroid cancer, being occult in 137 patients and clinical in 119 patients. There was no correlation between the maximum size of the thyroid cancer tumor and the age of the patient, and the percentage of patients with thyroid cancer in each group was not influenced by age. There were no significant differences in age, sex, the serum concentrations of free triiodothyronine, free thyroxine, thyrotropin, and thyroglobulin, or the urinary iodine creatinine ratio. The frequency of calcified lesions being detected by ultrasonography (US) and/or neck X-ray in the patients with clinical thyroid cancer was significantly greater than that in those with occult cancer at 83%vs 57%, respectively (P<0.0001). This study disclosed a high prevalence of thyroid cancer associated with adenomatous goiter, and the results suggest that a considerable number of associated carcinomas remain occult. The detection of calcification in the thyroid gland is one of the surgical indications for patients with adenomatous goiter.

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.

Technetium-99m tetrofosmin for parathyroid scintigraphy: a direct comparison with 99mTc-MIBI, 201Tl, MRI and US

The aim of this study was to evaluate the efficacy and role of technetium-99m tetrofosmin for the detection of abnormal parathyroid glands to be referred for surgical treatment. Twenty-eight consecutive patients, including 25 primary and 3 secondary cases of hyperparathyroidism, were evaluated. 99mTc-tetrofosmin/99mTc-pertechnetate subtraction scintigraphy (TF/Tc) was performed on all patients, and the results were directly compared with those of 99mTc-methoxyisobutylisonitrile (MIBI)/99mTc-pertechnetate subtraction scintigraphy (MIBI/Tc), 201Tl/99mTc-pertechnetate subtraction scintigraphy (Tl/Tc), magnetic resonance imaging (MRI) and ultrasonography (US). In cases of single-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 63.2%, 68.4%, 57.9%, 55.6% and 63.2%, respectively. In cases of multi-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 41.7%, 41.7%, 37.5%, 58.3% and 54.2%, respectively. In cases of parathyroid adenoma, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 68.8%, 75.0%, 68.8%, 62.5% and 75.0%, respectively. In cases of parathyroid hyperplasia, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 40.7%, 40.7%, 33.3%, 53.8% and 48.1%, respectively. It is concluded that, for the detection of abnormal parathyroid glands, 99mTc-tetrofosmin is as useful as 99mTc-MIBI and is more useful than 201Tl.

Effect of Combining Ultrasonography and Ultrasound-Guided Fine-Needle Aspiration Biopsy Findings for the Diagnosis of Thyroid Nodules

OBJECTIVE To assess the accuracy of ultrasonography and cytology in predicting malignancy in thyroid nodules. DESIGN Prospective open study. SETTING Thyroid centre, Japan. SUBJECTS 329 nodules in 309 patients examined by a new ultrasound scanner and ultrasound-guided fine-needle aspiration biopsy. INTERVENTIONS Comparison of ultrasonographic, cytological, and combined diagnosis with the histological diagnosis. MAIN OUTCOME MEASURES Sensitivity, specificity, and accuracy of each diagnostic method. RESULTS The sensitivity, specificity, accuracy were 84%, 87%, 85% for cytological diagnosis, and 82%, 91%, and 87% for ultrasonographic diagnosis. By using ultrasonographic diagnosis when cytological specimens were inadequate or gave false negative results, the sensitivity, specificity, and accuracy went up to 89%, 91%, and 90%, respectively. We could not diagnose follicular carcinomas accurately by combined cytology and ultrasonography. CONCLUSION The combination of ultrasonography and cytology improves the accuracy of diagnosis of thyroid nodules, but is less effective with follicular tumours.

CERVICAL THYMOMA and INCIDENCE OF CERVICAL THYMUS

A case of cervical thymoma in a 51‐year‐old female is reported. The tumor was located on the left side of the anterior neck just beneath the left lower lobe of the thyroid gland and there was no connection to the mediastinal thymus gland. It was well encapsulated and lobulated on the cut‐surface. Histologically, the tumor showed a mixed proliferation of lymphocytes and epithelial cells. Mitoses were frequently seen. Several tiny fragments of ectopic thymic tissue were found around the tumor. Cervical thymic tissue, considered to be the original site of the cervical thymoma, was studied and found macroscopically in 12 out of 657 patients with Basedows disease (1.8%).

Mutational Analysis of the APC Gene in Cribriform-Morula Variant of Papillary Thyroid Carcinoma

IntroductionFamilial adenomatous polyposis (FAP) is an inherited autosomal dominant syndrome caused by germline mutations in the adenomatous polyposis coli (APC) gene. Papillary thyroid cancer is one of the extracolonic manifestations of FAP. A characteristic histologic feature of this type of thyroid tumor is the cribriform-morula variant of papillary thyroid carcinoma (CMVPTC).MethodsTo investigate roles of the APC and β-catenin genes in the development of CMVPTC, we examined germline and somatic mutations of these genes in a female patient with CMVPTC and FAP. The patient had undergone total colectomy at the age of 19 years and total thyroidectomy at age 25 years.ResultsNumerous tumors were disseminated in both lobes of the thyroid gland, and histopathologic examination revealed typical CMVPTC. DNA was extracted from peripheral blood leukocytes and 12 CMVPTC tumors, and exons 1–15 of the APC gene and exon 3 of the β-catenin gene were examined. A germline mutation was detected in exon 13 of the APC gene, and this mutation generated a premature stop codon. Six somatic mutations (922delC, 1602delA, 1821delT, 1920delG, 2706del20, 2804insA) were found in the CMVPTC specimens. All mutations were truncating mutations in the N-terminus of the APC protein. Loss of heterozygosity was not observed in the remaining tumor tissues without somatic APC mutations. There were no mutations of the β-catenin gene in peripheral blood leukocytes or 12 CMVPTC specimens.ConclusionsThese results suggest that APC mutations play an important role in the development of CMVPTC and occur predominantly in the 5′ side of the APC gene between codons 308 and 935.

Vitamin D status in Japanese patients with hyperparathyroidism: Seasonal changes and effect on clinical presentation

The disturbance of vitamin D metabolism plays an important role in determining the clinical presentation of hyperthyroidism. We studied 72 patients (65 women, 7 men) with primary hyperparathyroidism (pHPT). Clinical presentation, biochemical indices, and bone mineral density (BMD) were compared in three patient groups classified according to their serum 25-hydroxyvitamin D (25OHD) levels: 23 patients whose 25OHD level was <25 nmol/L comprised the low group, 26 whose level was 25 to 40 nmol/L made up the intermediate group, and 23 whose level was > 40 nmol/L comprised the high group. The mean serum calcium level was 10.8 ± 0.9 mg/dl, and the mean weight of the resected parathyroids was 684 ± 749 mg. The mean serum 25OHD level was 36.5 ± 16.3 nmol/L (normal 25–100 nmol/L). Levels were below normal in 23 patients (32%). No between-group differences existed for clinical presentation, biochemistry, or BMD. Only differences in mean patient age were statistically significant between groups. Vitamin D deficiency is common among Japanese patients with pHPT, but the effects of HPT on clinical, biochemical, and densitometric indices are not pronounced. Our study population was at an early stage of pHPT, so the vitamin D deficiency may not be associated with the effects of HPT.