Medical articles from Noguchi Thyroid Clinic and Hospital Foundation from 1998 to 1999
Major publications from 1998 to 1999
Noguchi Thyroid Clinic and Hospital Foundation
Surg Today 1999;29(9):862-7 Presymptomatic detection and treatment of Japanese carriers of the multiple endocrine neoplasia type 2A gene. Uchino S, Noguchi S, Sato M, Adachi M, Yamashita Hiroyuki, Watanabe S, Murakami T, Toda M, Murakami N, Yamashita Hiroto
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 the RET 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.
Jpn J Cancer Res 1999 Nov;90(11):1231-7 Somatic mutations in RET exons 12 and 15 in sporadic medullary thyroid carcinomas: different spectrum of mutations in sporadic type from hereditary type.
Uchino S, Noguchi S, Yamashita Hiroto, Sato M, Adachi M, Yamashita Hiroyuki, Watanabe S, Ohshima A, Mitsuyama S, Iwashita T, Takahashi M
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.
Cancer 1999 Sep 1;86(5):842-9 Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma.
Yamashita Hiroto, Noguchi S, Murakami N, Toda M, Yamashita Hiroyuki, Uchino S, Watanabe S, Kawamoto H
BACKGROUND: The majority of patients with thyroid microcarcinoma have a favorable prognosis. However, some patients may die from this tumor. Although the incidence of microcarcinoma is high, to the authors' knowledge no histologic risk factors have been identified. The objective of this study was to establish risk factors for patients with thyroid microcarcinoma. METHODS: The histologic findings for 1743 surgically excised thyroid microcarcinomas (<=10 mm in greatest dimension) and simultaneously obtained lymph nodes from 324 microcancer patients were reexamined to determine risk factors. Follow-up for the patients was 11.2 +/- 6.3 years (mean +/- standard deviation). These thyroid carcinomas were classified according to the World Health Organization Histological Classification system, and lymph node involvement was classified into two groups: those patients with extracapsular invasion of the lymph node metastasis (ECI) (62 patients) and those patients without (1681 patients). A Fisher exact test, an F test, univariate and multivariate proportional hazards regression analyses, and a Kendall correlation measurement were performed. RESULTS: No undifferentiated tumors were found among the microcarcinomas. During the follow-up period, 1643 of 1743 patients were alive without recurrence, 25 were alive with recurrence, 71 had died of thyroid-unrelated diseases including 2 patients with recurrence, and 4 had died of recurrent thyroid carcinoma. In total, recurrence was noted in 31 patients. Multivariate proportional hazards regression analysis revealed that the absence of Graves disease (risk ratio = 5) and the presence of ECI (risk ratio = 7) were significant risk factors for disease recurrence. Univariate analysis revealed that patient age and the presence of ECI were significant risk factors for thyroid carcinoma-related deaths. CONCLUSIONS: The presence of ECI of lymph node metastasis in patients with thyroid microcarcinoma was found to be a significant indicator of disease recurrence and a poorer prognosis. Copyright 1999 American Cancer Society.
Thyroid 1999 Apr;9(4):401-4. Signet ring cell adenoma of the thyroid with mucin predominance.
Yoshida J, Tanimura A, Yamashita Hiroyuki, Matsuo K
A 22-year-old male presented with a 1-year history of a right anterior neck mass. He did not have gastrointestinal cancer. Laboratory examination revealed an elevated serum thyroglobulin level of 120 ng/mL. The neck lesion showed poor uptake on 99mTc scan, but enhanced uptake on 201T1 scan. The patient underwent a hemithyroidectomy; the cut surface of the 7 x 3.5 cm lesion was solid and tanned orange. Postoperatively the serum thyroglobulin level decreased to 26 ng/mL. Microscopy of the tumor showed signet ring cells and microfollides, both of which were positive for mucicarmin and alcian Blue. A small percentage of the follicles were positive for thyroglobulin and periodic acid-Schiff. Our literature search detected 18 patients with signet ring cell lesions positive for thyroglobulin, but none had characteristics similar to ours showing predominance of mucin and poor staining for thyroglobulin.
M.P. (Medical Practice) 1999 Mar;16(3):491.
Ann Surg 1999 Feb;229(2):237-45 Postoperative tetany in Graves disease: important role of vitamin D metabolites.
Yamashita Hiroyuki, Murakami T, Noguchi S, Shiiba M, Watanabe S, Uchino S, Kawamoto H, Toda M, Murakami N
OBJECTIVE: To test the authors' hypothesis of the causal mechanism(s) of postoperative tetany in patients with Graves disease. SUMMARY BACKGROUND DATA: Previous studies by the authors suggested that postoperative tetany in patients with Graves disease occurs during the period of bone restoration and resulted from continuation of a calcium flux into bone concomitant with transient hypoparathyroidism induced by surgery. PATIENTS AND METHODS: A prospective study was carried out to investigate sequential changes in serum levels of intact parathyroid hormone (iPTH), calcium and other electrolytes, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and bone metabolic markers in 109 consecutive patients with Graves disease who underwent subtotal thyroidectomy. RESULTS: Preoperative serum iPTH levels negatively correlated with ionized calcium levels and positively correlated with 1,25(OH)2D or 1,25(OH)2D/25OHD. After the operation, there was a significant decline in levels of ionized calcium, magnesium, and iPTH. Serum iPTH was not detected in 15 patients after surgery. Four of these 15 patients, and 1 patient whose iPTH level was below normal, developed tetany. Preoperative serum ionized calcium levels were significantly lower, and iPTH levels were higher, in the 5 patients with tetany than in the 11 patients who did not develop tetany despite undetectable iPTH levels. The tetany group had significantly lower serum 25OHD levels and higher 1,25(OH)2D levels, and had increased 1,25(OH)2D/25OHD as an index of the renal 25OHD-1-hydroxylase activity than those in the nontetany group. These results suggest that patients with a high serum level of iPTH as a result of low serum calcium levels (secondary hyperparathyroidism) are susceptible to tetany under conditions of hypoparathyroid function after surgery. CONCLUSIONS: Postoperative tetany occurs in patients with secondary hyperparathyroidism caused by a relative deficiency in calcium and vitamin D because of their increased demand for bone restoration after preoperative medical therapy concomitant with transient hypoparathyroidism after surgery. Calcium and vitamin D supplements may be recommended before and/or after surgery for patients in whom postoperative tetany is expected to develop.
Arch Surg 1998 Oct;133(10):1058-65 Changing trends and prognoses for patients with papillary thyroid cancer.
Yamashita Hiroyuki, Noguchi S, Yamashita Hiroto, Murakami N, Watanabe S, Uchino S, Kawamoto H, Toda M, Nakayama I
OBJECTIVE: To analyze differences in the demographic backgrounds, and in treatments, prognosis, and risk factors of patients with papillary thyroid cancer operated on from 1965 to 1990, by dividing them into 3 chronological groups. DESIGN: Retrospective cohort study of 2423 patients with papillary thyroid cancer (tumor size, > or = 10 mm) who underwent curative surgery at the Noguchi Thyroid Clinic, Oita, Japan. SETTING: A center for the treatment of thyroid disease, at which about 1400 thyroid operations are performed per year. PATIENTS: There were 596 patients treated during from January 1, 1965, to December 31, 1973; 964 patients treated from January 1, 1974, to December 31, 1982; and 959 patients treated from January 1, 1983, to December 31, 1990. RESULTS: Of the 2519 patients treated, 96 were excluded from the study because they had undergone noncurative surgery. Therefore, the analyses are based on data for 2423 patients who underwent curative surgery. Three groups were defined as follows: group 1, underwent surgery during the period 1965-1973 (n = 577); group 2, underwent surgery during the period 1974-1982 (n = 924); and group 3, underwent surgery during the period 1983-1990 (n = 922). The mean age of the patients in group 1 was 42.4 years, in group 2, 45.0 years, and in group 3, 47.8 years. The mean tumor size was 30.4 mm, 26.5 mm, and 24.6 mm, respectively, for groups 1, 2, and 3. The 10- and 20-year disease-specific survival rates were significantly improved from group 1 (95.5% and 90.3%, respectively) to group 2 (97.8% and 93.9%, respectively), and the 10-year rate was significantly improved for group 3 (98.2%). In the multivariate analysis, age, sex, tumor size, and gross nodal metastasis were significant predictors of survival for group 1; however, only age and gross nodal metastasis were significant for group 3. CONCLUSIONS: Over time, papillary thyroid cancer has become diagnosed at an earlier stage, but the age of the patients at diagnosis is older. The disease-specific survival rate was significantly improved, mainly owing to earlier treatment, and the change in the risk factor profile for cancer mortality may be due to the changes in the demographic backgrounds and diagnostic and therapeutic modalities. These considerations derived from risk factor analysis should be considered for treating the patient and for the prediction of patient survival.
Endocrine J 1998 Aug;45(4):513-517 Post-operative thyroid status of patients with Graves' disease is determined by the responsiveness of thyrocyte to TSH under the present thyroid gland remnant.
Yamashita Hiroto, Noguchi S, Murakami N, Watanabe S, Kawamoto H
In order to determine whether thyrocyte responsiveness to TSH is correlated with post-operative thyroid status, thyrocytes obtained from 51 patients with Graves' disease were cultured for 3 days. This was followed by culture with 10 mU/mL of TSH (TSH group) or without TSH (control group) for 3 additional days. On the 8th culture day, the amount of thyroglobulin (Tg) secreted into the culture medium was assayed and the Tg ratio (amount of Tg from the stimulated group/amount of TG from the control group) was calculated. Log10 (the Tg ratio) was used for the statistic study. The post-operative status of the patient was determined based mainly on the serum concentration values of free T3 and T4 obtained between 5 and 16 months after surgery. Multivariate analysis revealed that among age, gender, TSH-binding inhibitory immunoglobulin (TBII) obtained before the surgery, estimated weight of the thyroid gland remnant, and Log10 (Tg ratio), only Log10 (Tg ratio) was statistically significant (P=0.008). When the Log10 (Tg ratio) value was small, most patients showed signs of as post-operative hypothyroidism, and as the value became larger as the number of euthyroid and/or hyperthyroid patients increased.
Thyroidology Clinical and Experimental 1998 Aug;10(4):41-50 Differentiated thyroid carcinomas in Japan: our own experience and review of the literature.
Noguchi S
Thyroidology Clinical and Experimental 1998 Aug;10(4):265-269 Diagnosis of thyroid follicular tuomrs using serum thyroglobulin.
Tahara K, Yamashita Hiroyuki, Noguchi S, Watanabe S, Uchino S, Murakami T, Toda M, Yamashita Hiroto, Murakami N
We evaluated the serum levels of thyroglobulin (Tg) in patients with histologically proven follicular tumors to assess the clinical value of Tg measurements in the differentiation between follicular thyroid cancer and adenoma and also analyzed the relationships between the serum values and several prognostic factors in patients with follicular cancer. Univariate analysis of age, gender, maximum tumor size and serum level of Tg to discriminate between benign and malignant, maximum tumor size and serum Tg levels were significant. In multivariate analysis, only the serum Tg level was significant. There were significant correlations between serum Tg levels and size of the follicular cancer tumor. The serum Tg level in patients with poorly-differentiated follicular cancer was significantly higher than in those with well-differentiated follicular cancer. Serum Tg is more useful for differentiation between follicular thyroid cancer and follicular adenoma than age, sex of the patient, and diameter of tumor. In follicular carcinomas, serum Tg tended to be higher along with the size and lower histologic differentiation of the cancer, which are considered to be significant prognostic factors.
Thyroidology Clinical and Experimental 1998 Aug;10(4):279-281 RET gene analysis of latent small medullary thyroid carcinoma associated with Graves' disease.
Uchino S, Noguchi S, Sato M, Adachi M, Yamashita Hiroyuki, Watanabe S, Murakami T, Toda M, Murakami N, Yamashita Hiroto
Small medullary thyroid carcinoma (small MTC) is occasionally found in cases with preoperative diagnosis of Graves' disease. To investigate the genetic status of these small MTCs, RET gene mutations in exons 10 through 16 were examined in 3 cases of latent small MTCs associated with Graves' disease. MTC tissues and peripheral blood leukocytes were analyzed in all cases. In one 37-year-old woman, germline mutation was found at codon 804 (GTG Þ ATG) resulting in a valine to methionine substitution, and this case was newly identified as hereditary MTC. The other two cases had no germline mutations. In one case, somatic point mutation was found at codon 634 (TGC Þ TGG) resulting in a cysteine to tryptophan substitution. Based on these results, genetic examination is indispensable in cases of latent small MTCs coupled with benign thyroid disease such as Graves' disease.
Thyroidology Clinical and Experimental 1998 Aug;10(4):289-292 Appearance of intranulear cytoplasmic invagination in cultured thyoid cells obtained from patients with Graves' disease.
Yamashita Hiroto, Noguchi S, Murakami N, Yasuoka Y, Wakiya S, Tanigawa Y, Sato M, Takenaga M, Maruta J
Thyrocytes obtained from patients with hyperthyroidism were cultured with and without TSH for 8 days. During this period, nuclear grooving and intranuclear inclusion were observed light-microscopically. A laser microscopic study revealed the presence of numerous cells with irregularly-indented and/or -outlined nuclei. A transmission electron microscopic study showed that these nuclear changes were due to intranuclear cytoplasmic invagination. This invagination was considered to be degenerative, because other findings suggesting degenerative change were found simultaneously, and the thyrocytes did not proliferate under the present culture conditions. Intranuclear cytoplasmic invagination has been considered to be a first step forming intranuclear cytoplasmic inclusion, which is one of the main diagnostic findings of thyroid papillary carcinoma. Therefore, the present study suggests that the intranuclear cytoplasmic inclusion process is not related to the malignant nature of these cells but is related to the degenerative process of the cells at least at its initial stage.
Thyroidology Clinical and Experimental 1998 Aug;10(4):293-296 Prediction of postoperative tetany in patients with Graves' disease: a prospective studay.
Yamashita Hiroyuki, Noguchi S, Shiiba M, Murakami T, Watanabe S, Uchino S, Kawamoto H, Toda M, Murakami N
We have recently reported the formula that can predict the risk for postoperative tetany in patients with Graves' disease after subtotal thyroidectomy. The aim of this study was to verify our formula of the prediction of postoperative tetany in Graves' patients prospectively. The subjects were 650 consecutive female patients with Graves' disease who underwent subtotal thyroidectomy between 1995 and 1996. The incidence of tetany was 4.9 % (32/650). A low log odds ratio for tetany resulted in an incidence of 0%, whereas a high log odds ratio resulted in an incidence of 12%. Calcium and vitamin D supplements during the preoperative period and/or after surgery may be useful for patients who are suspected to develop postoperative tetany based on the predictive risk values.
Jpn J Cancer Res 1998 Apr;89(4):411-418 Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas.
Uchino S, Noguchi S, Adachi M, Sato M, Yamashita Hiroyuki, Watanabe S, Murakami T, Toda M, Murakami N, Yamashita Hiroto
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 MTC. 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 small fraction of sporadic MTCs.
Thyroid 1998 Mar;8(3):197-202 Chronic thyroiditis as a favorable prognostic factor in papillary thyroid carcinoma.
Kashima K, Yokoyama S, Noguchi S, Murakami N, Yamashita Hiroyuki, Watanabe S, Uchino S, Toda M, Sasaki A, Daa T, Nakayama I
A subgroup of patients with papillary thyroid carcinoma (PTC) also has chronic thyroiditis (CT) as an associated disease of the thyroid. To assess the prognostic value of CT in patients with PTC, we reviewed the histological slides of 2225 patients with PTC who had undergone surgery between 1971 and 1992. Of the 2225 patients, 692 were excluded from the analysis because regional lymph nodes and/or nonneoplastic thyroid tissues were unavailable for histological assessment. The series included 281 patients with CT in nonneoplastic thyroid tissue and 1252 without CT. We performed statistical analyzes by the log-rank test and Cox's proportional-hazard method. Sixty-two (5.0%) of the 1252 patients without CT died of metastatic disease during the follow-up period and the relapse-free 10-year survival rate was 85%. By contrast, only 2 (< 1.0%) of the 281 patients with CT died, and their relapse-free 10-year survival rate was 95%. The difference between patients with CT and those without CT in terms of relapse-free and overall survival was statistically significant (p < 0.0001). Risk factors for unfavorable outcome were age 45 years or more, absence of psammoma bodies, and absence of CT (p < 0.0001), followed by vascular invasion (p = 0.0007), male sex (p = 0.0013), and metastasis to regional lymph nodes (p = 0.047). Multivariate analysis indicated that all of these factors with the exception of gender were independent factors in the final model for overall survival. Chronic thyroiditis in the nonneoplastic thyroid of patients with PTC is a powerful prognostic factor for both relapse-free and overall survival.
Arch Surg 1998 Mar;133(3):276-280 Papillary thyroid carcinoma: modified radical neck dissection improves prognosis.
Noguchi S, Murakami N, Yamashita Hiroyuki, Toda M, Kawamoto H
OBJECTIVE: To ascertain whether modified radical neck dissection offers a survival advantage for some subsets of patients with papillary cancer of the thyroid. DESIGN: A retrospective cohort study of 2966 patients curatively treated at the Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan, between 1946 and 1991. SETTING: A center for the treatment of thyroid disease, where about 1400 thyroid operations are performed per year. PATIENTS: Between 1946 and 1991, patients with papillary cancer whose primary tumor was 1 cm or larger and who were curatively treated were studied. Of the 2859 patients, 72.1% underwent modified radical neck dissection, 8.5% underwent partial node excision, and 19.4% underwent no node excision. RESULTS: A univariate analysis revealed a subset of patients who benefited from modified radical neck dissection. A multivariate analysis revealed that sex (P<.001), age at the time of the operation (P<.001), size of the primary tumor (P<.001), extrathyroidal invasion (P<.001), and the presence of nodal metastasis (P<.01) are significant risk factors. CONCLUSION: Patients with nodal metastasis, patients in whom the primary tumor invades beyond the thyroid capsule, and women older than 60 years can benefit from modified radical neck dissection.
Pathol Int 1998 Mar;48(3):184-190 Expression of splice variants of CD44 in thyroid neoplasms derived from follicular cells.
Gu J, Daa T, Kashima K, Yokoyama S, Nakayama I, Noguchi S
Isoform expression of CD44 in follicular carcinoma (FC) of the thyroid was analyzed by immunohistochemical staining and compared to the isoforms in follicular adenoma (FA) and papillary carcinoma (PC) of the thyroid. Variant isoforms of CD44 (CD44v) were detected in these neoplastic cells but not in non-neoplastic cells. CD44v6 was expressed in PC with nodal metastasis and also in FC at significantly higher frequencies than those in PC without metastasis and FA. The frequency of expression of CD44v3 was significantly higher in PC with nodal metastasis than in PC without metastasis. The reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blotting analysis revealed the presence of a transcript for a variant of CD44 that contained variant exon 6 in FA, FC and PC. DNA sequencing of the products of RT-PCR yielded three species of cDNA for CD44v. One of the cDNA corresponded to a transcript that contained variant exon 6. These results suggest that immunohistochemical staining and RT-PCR with Southern blotting analysis for CD44v6 might be a useful diagnostic tool for the differentiation of FC from FA and that the expression of CD44v3 and CD44v6 might be important for the development of nodal metastasis in cases of PC.
