Shinya Uchino

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.

Video-assisted thyroid lobectomy through a small wound in the submandibular area

BACKGROUND Endoscopic thyroidectomy has not gained wide acceptance because of the expertise required, the long operation time, the wide dissection, and the extra cost of specialized instruments. We developed a video-assisted hemithyroidectomy procedure that requires only one small incision at the upper neck. METHODS Hemithyroidectomy was performed through a 25 to 30 mm transverse incision made in the upper lateral neck for the treatment of benign thyroid nodule. No gas or external lift dissection was needed. RESULTS The mean age of 39 patients was 33.8 years. The tumor size ranged from 1.9 to 5.5 cm (mean 3.1 cm). All patients underwent total lobectomy without conversion to traditional cervicotomy. The mean operation time was 56 minutes (range 36 to 90). Follicular adenoma was the final pathologic diagnosis in 25 patients and adenomatous goiter in 14. Transient recurrent laryngeal nerve palsy was seen in 1 patient. CONCLUSIONS Our technique is safe, minimally invasive, less time consuming, and cosmetically excellent.

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

Background  A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism–jaw tumour syndrome (HPT‐JT).

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database

Objective  Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1.

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.

Comparison of parathyroid hormone levels from the intact and whole parathyroid hormone assays after parathyroidectomy for primary and secondary hyperparathyroidism

BACKGROUND Most commercial intact parathyroid hormone (intact PTH) assays cross-react with non-(1-84) PTH (likely 7-84 PTH). Using a whole-molecule PTH (whole PTH) assay that specifically measured only 1-84 PTH, we compared the kinetics of whole PTH and intact PTH after parathyroidectomy in patients with primary hyperparathyroidism (HPT) and secondary HPT. METHODS This study comprised 74 patients with primary HPT caused by a single adenoma and 18 patients with secondary HPT who underwent parathyroidectomy. Blood samples were drawn after anesthesia, just before excision of a single adenoma in primary HPT, and just before excision of the last parathyroid gland in secondary HPT, and at 5, 10, and 15 minutes after excision. The 7-84 PTH level was calculated by subtracting the whole PTH value from the intact PTH value. RESULTS There was a difference between the percentage of 7-84 PTH/intact PTH in plasma samples from patients with primary HPT and secondary HPT (28%+/-12% vs 35%+/-9%; P<.05). Plasma whole PTH decreased more rapidly than intact PTH after parathyroidectomy in patients in both the primary HPT (P<.0001) and secondary HPT groups (P<.0001). Decline of intact PTH was slower in patients with secondary HPT than in patients with primary HPT; however, there was no significant difference in the decline of whole PTH between the 2 groups. CONCLUSIONS The quick intact PTH assay is not used frequently during surgery in patients with secondary HPT; however, our results suggest that a quick whole PTH assay may be a more useful adjunct to parathyroidectomy in both secondary HPT and primary HPT.

Modified Radical Neck Dissection for Differentiated Thyroid Cancer: Operative Technique

Our standard surgical approach to patients with papillary thyroid cancer is subtotal thyroidectomy with modified radical neck dissection (MRND) on the affected side. MRND preserves the jugular vein, the sternocleidomastoid muscle, and the accessory nerve, effectively conserving function and cosmesis. Knowledge of the anatomy of the neck, precise staging, prognostic evaluation, and experience are needed for a surgeon to perform MRND. Radical neck dissection should not be performed unless the tumor invades the jugular vein and sternocleidomastoid muscle. Berry picking is not indicated for patients with thyroid cancer. The skin incision used is an extended collar incision. If lymph node metastasis is present at the upper bifurcation of the carotid artery, a modified MacFee incision is used. Taping of the carotid artery or sternocleidomastoid muscle is avoided unless the tumor invades these tissues. MRND is a safe procedure when performed by skilled, experienced surgeons.

Role of Cyclase Activating Parathyroid Hormone (1-84 PTH) Measurements During Parathyroid Surgery: Potential Improvement of Intraoperative PTH Assay

Summary Background DataQuick intraoperative parathyroid hormone assays are widely used as a guide to the adequacy of resection during parathyroid surgery. However, some authors have reported a 15% error rate of these assays because of the presence of false-positive and false-negative results. Recently the authors have found that most commercial intact PTH (iPTH) assays cross-react with non-(1-84) PTH (likely 7-84 PTH) and that the proportional levels of non-(1-84) PTH in patients were variable in a much wider range, accounting mostly for 20% to 60% of the immunoreactivity in samples obtained from hyperparathyroid patients. A cyclase activating PTH (CAP) measured by a novel immunoradiometric assay was shown to measure specifically 1-84 PTH. Using a CAP assay, the authors studied the rate of decline of CAP after parathyroidectomy and compared it with iPTH as measured by the Nichols intact PTH immunoradiometric assay. MethodsThis study comprised 29 patients with primary hyperparathyroidism (pHPT) caused by a single adenoma and 7 patients with secondary hyperparathyroidism (secondary HPT) who underwent parathyroidectomy. Blood samples were drawn after anesthesia, before excision of one enlarged parathyroid gland in pHPT and of the last gland in secondary HPT, and at 5, 10, and 15 minutes after excision. The 7-84 PTH level was calculated by subtracting the CAP value from the iPTH value. ResultsThe percentage of 7-84 PTH in iPTH in plasma samples was 27.5 ± 14.4% in pHPT and 39.6 ± 15.1% in secondary HPT. In pHPT patients the plasma CAP and iPTH value decreased to 23.4 ± 10.8 and 32.0 ± 11.3% of the preexcision level at 5 minutes, 10.6 ± 7.7 and 21.1 ± 8.8% at 10 minutes, and 8.5 ± 4.9 and 16.1 ± 6.8% at 15 minutes after removal of the enlarged gland, respectively. At 5 minutes, CAP levels of all 29 pHPT patients had decreased to less than 40% of the preparathyroidectomy level; however, 7 (24%) patients still had an iPTH level of more than 40%. In secondary HPT patients, CAP and iPTH values had dropped to 43.3 ± 20.2 and 66.1 ± 19.7% at 5 minutes, 28.6 ± 16.6 and 53.6 ± 18.1% at 10 minutes, and 14.2 ± 9.0 and 41.0 ± 12.9% at 15 minutes after removal of the last enlarged gland, respectively. At 10 minutes, CAP levels of all seven secondary HPT patients had decreased to less than 50% of the preexcision level; however, three (43%) patients still had an iPTH level of more than 50%. In pHPT and secondary HPT, the 7-84 PTH level had dropped to 57.4 ± 85.9 and 62.1 ± 84.9%, respectively, of the preexcision value 15 minutes after removal of the enlarged gland or glands. ConclusionsThe percentage of 7-84 PTH in iPTH in plasma samples varies substantially between patients with HPT. In both pHPT and secondary HPT, the plasma CAP value decreased more rapidly than iPTH after parathyroidectomy, depending on the amount of 7-84 PTH in circulation. These results suggest that the CAP assay may be a more useful adjunct to parathyroidectomy than the currently used iPTH assay.