Noguchi Thyroid Clinic Research Articles

Low echogenicity of Hashimoto's disease could be useful in detecting early phase of thyroid lymphomas, especially diffuse large B cell lymphomas

BackgroundHashimoto's disease, characterized by low echogenicity on ultrasonography, is associated with thyroid lymphomas. Most thyroid lymphomas are diffuse large B cell lymphomas (DLBCLs) and mucosa-associated lymphoid tissue (MALT) lymphomas. DLBCLs have a worse prognosis than MALT lymphomas. This study aimed to evaluate the early signs, especially the low echogenicity, of Hashimoto's disease and thyroid lymphomas. MethodsThis retrospective cohort study was conducted at Noguchi Thyroid Clinic and Hospital Foundation. A total of 9008 cases were operated on between 2008 and 2016, of which 162 had operated with suspected thyroid lymphoma, because of low echogenicity and aspiration biopsy cytology. The final diagnosis revealed 28 Hashimoto's disease, 134 thyroid lymphomas (91 MALT lymphomas and 43 DLBCLs). The primary outcomes were clinicopathological characteristics including low echogenicity of the thyroid. Early signs of thyroid lymphomas, especially DLBCLs were also investigated. ResultsAge, echo pattern, echogenicity anti-thyroid peroxidase antibody (TPOAb) and lactate dehydrogenase (LDH) were significantly different between Hashimoto's disease and thyroid lymphomas. Echogenicity, echo pattern and age were significant early signs of thyroid lymphomas. Age, echogenicity, soluble interleukin-2 receptor (IL2R), lactate dehydrogenase (LDH), and the neutrophil-to-lymphocyte ratio were significantly different between MALT lymphomas and DLBCLs. Echogenicity, and IL2R were significant early signs of DLBCL. The ROC analysis of low echogenicity for thyroid lymphomas compared to Hashimoto's disease revealed that Area Under the Curve (AUC) was 0.80 and the ROC analysis for DLBCL compared to Hashimoto's disease and MALT lymphoma revealed that the AUC was 0.73. ConclusionsLow echogenicity of Hashimoto's disease could be a useful early sign of thyroid lymphomas, especially DLBCL. Data availabilityThe data that supports the findings of this study are available in the supplementary material of this article.

Recurrent laryngeal nerve palsy during surgery for benign thyroid diseases: Risk factors and outcome analysis

We investigated the risk factors for postoperative recurrent laryngeal nerve (RLN) palsy and related outcomes in patients with benign thyroid diseases. From 2008 to 2010, 844 thyroidectomies for benign thyroid diseases (benign nodules in 447; Graves' disease in 377; huge goiter attributable to Hashimoto thyroiditis in 20) were performed at Noguchi Thyroid Clinic and Hospital Foundation. The otolaryngologists screened all patients for the presence or absence of RLN palsy by laryngoscope, both pre- and postoperatively. When RLN palsy was present, the patients were checked periodically by laryngoscopy without additional drug therapy until the recovery of vocal cord palsy or loss of contact. A total of 1,374 nerves were at risk during the thyroid surgery (bilateral risk in 530, unilateral risk in 314). No patient exhibited a bilateral RLN palsy. Unilateral postoperative RLN palsies were found in 45 patients (benign nodules in 25, Graves' disease in 19, and Hashimoto thyroiditis in 1). The RLN was involuntarily amputated in five patients during the operation. The incidence of RLN palsy was 5.3% per patient and 3.3% per nerve. The incidence of RLN palsy was greater in patients who underwent complete unilateral thyroid lobe resection compared with partial resection of the lobe (P = .04). The occurrence of RLN palsy was associated with the need for reoperation caused by postoperative bleeding and the reduced weight of the thyroid remnant in Graves' disease (P = .04 and P = .03, respectively). Among 40 patients with RLN palsy and excluding 5 amputated patients, the RLN palsy resolved in 34 patients (85%) within 12 months after the procedure. The remaining 6 patients (15%) were considered to have permanent RLN palsies. Complete resection of the thyroid lobe and reoperation for postoperative bleeding are the risk factors for postoperative RLN palsy in patients with benign thyroid nodules. In Graves' disease, smaller weight of the residual thyroid tissue contributes to the occurrence of RLN palsy. Most RLN palsies that do not require amputation of the nerve resolve spontaneously within 12 months after surgery. In this study, the palsy remained in 1.3% (11/844) of patients.

Follicular thyroid cancer in children and adolescents: clinicopathologic features, long-term survival, and risk factors for recurrence

Children and adolescents represent 1-1.5% of all patients with thyroid cancer (TC). The vast majority of TC in children and adolescents is papillary TC; follicular TC (FTC) is exceedingly rare. In this study, we evaluate the clinical and pathological features of FTC in children and adolescents. We also report the risk factors for post-operative tumor recurrence and the associated outcomes. Twenty children and adolescents (under 21 years old) with FTC have been treated and followed at Noguchi Thyroid Clinic and Hospital Foundation since 1946. All patients underwent surgery (lobectomy, 11; subtotal thyroidectomy, 8; and total thyroidectomy, 1), and 8 patients received postoperative external beam radiation therapy. The incidence of FTC in children and adolescents was 1.9% among all FTC patients treated in our hospital. Histopathology revealed vascular and capsular invasion in 9 and 20 patients, respectively. The tumor recurrence rate in FTC with vascular invasion is significantly higher than in those without it (p = 0.038). No other factors were significant. Patients with recurrences were treated with completion thyroidectomy and ¹³¹I radioactive iodine therapy. There were no significant differences in the rates of disease-free survival or cause-specific survival when pediatric/adolescent FTC patients were compared to adults with FTC. FTC is very rare among children and adolescents, but the outcomes are similar to those observed among adults. Vascular invasion is poor prognostic indicator in pediatric/adolescent FTC patients.

The Surgical Strategy and the Molecular Analysis of Patients with Parathyroid Cancer

Parathyroid cancer is a rare endocrine tumor, and the prognostic factors for this cancer remain unclear. The standard therapy is en bloc resection of the primary tumor at the time of the initial operation. However, the clinical significance of prophylactic neck dissection (PND) in the management of parathyroid cancer has not yet been established. In this study, we investigated its clinical significance in patients with parathyroid cancer and the association of gene mutations with tumor progression. A total of 12 patients with parathyroid cancer were treated and have been followed at Noguchi Thyroid Clinic and Hospital Foundation since 1977. In all, 11 patients were treated with the initial surgery for the cancer, and 1 patient underwent surgery for a metastatic lung lesion. Somatic and germ-line mutations of the HRPT2 and MEN1 were examined by polymerase chain reaction and automated DNA sequencing. En bloc resections of thyroid tissue were performed in 10 patients, and 1 patient underwent only parathyroidectomy with limited resection of the thyroid gland. PND was performed in eight patients, and no lymph node metastases were found in the histological specimens. Six of the eight patients had no evidence of the disease, and two had recurring disease (neck lymph node and lung in one patient and local, lung, and brain in another). PND was not performed in three patients, two of whom had no evidence of the disease and one with recurrence at the site of a regional lymph node. There were no significant differences in disease-free survival and cause-specific survival between the patients who underwent PND and the patients who did not (P=0.98 and P=0.32, respectively). Among the 12 patients with parathyroid cancer, 1 had a germ-line mutation of the HRPT2 at exon 7, codon 234, CGA (Arg) to TGA (Stop), and 1 patient had a tumor-specific mutation at exon 1, nucleotide 34-37 delAACA. Two of the four patients with recurrent disease had an HRPT2 gene mutation. MEN1 gene analysis revealed one somatic missense mutation at exon 2, codon 121, GTC (Val) to GAC (Asp) in one patient. PND for patients with parathyroid cancer resulted in no evidence of lymph node metastasis and does not improve the prognosis. HRPT2 gene mutation may be associated with tumor recurrence.

Antithyroid Drug-Induced Agranulocytosis: How Has Granulocyte Colony-Stimulating Factor Changed Therapy?

This study examined whether granulocyte colony-stimulating factor (G-CSF) is beneficial for the treatment of antithyroid drug-induced agranulocytosis. From January 1975 to December 2001, 30,798 patients with Graves' disease were treated with antithyroid drugs at Noguchi Thyroid Clinic & Hospital Foundation. During this period, 109 patients (0.35%) were found to have agranulocytosis caused by antithyroid drugs. In the symptomatic group, the recovery time from agranulocytosis was significantly shorter after the introduction of G-CSF (5.5 +/- 3.5 days, n = 19) compared to the symptomatic group before its introduction (9.2 +/- 4.4 days, n = 37, p < 0.01). In the asymptomatic group, the recovery time from agranulocytosis was significantly shorter after the introduction of G-CSF (2.3 +/- 1.9 days, n = 15) compared to the asymptomatic group before the introduction of GCSF (5.4 +/- 4.3 days, n = 34, p < 0.05). However, G-CSF therapy was ineffective in severe cases with granulocyte count below 0.1 x 10(9)/L and symptoms. We recommend that G-CSF therapy should be applied only in asymptomatic patients and symptomatic patients with granulocyte count above 0.1 x 10(9)/L, and not for symptomatic patients with granulocyte count below 0.1 x 10(9)/L. In conclusion, G-CSF therapy shortens the period of recovery from antithyroid drug-induced agranulocytosis and benefits patients, except those with symptoms and a granulocyte count below 0.1 x 10(9)/L.

Invited critique

Hypotheses: After subtotal thyroidectomy with modified radical neck dissection of the affected side, nodal recurrence at the contralateral cervical side indicates a poor prognosis for patients with papillary thyroid cancer. Bilateral modified radical neck dissection is beneficial for patients at high risk for contralateral nodal recurrence. Design and Setting: Retrospective study of patients with papillary cancer who were treated surgically from January 1, 1970, through December 31, 1995, at the Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan. Patients: Patients (N =1776) had primary tumors greater than 10 mm in maximum diameter and underwent thyroidectomy and ipsilateral modified radical neck dissection with curative intent. Results: Thirty-two patients (1.8%) developed contralateral lymph node metastases during the mean follow-up period of 12.1 years. The risk factors for contralateral nodal recurrence were male sex, large primary tumor, tumor extension over the isthmus, extracapsular adhesion or invasion to surrounding tissues, and the presence of gross nodal metastasis at initial surgery. These patients had a greater number of distant metastases (31.1% vs 0.7%; P<.001) and a lower 10-year survival rate (83.7% vs 99.3%; P<.001) than patients without nodal recurrence. Conclusion: Bilateral modified radical neck dissection should be considered for patients with papillary carcinoma who show risk factors for contralateral nodal recurrence, as it could prevent a second operation and may improve their outcome.

Changing Trends and Prognoses for Patients With Papillary Thyroid Cancer—Invited Critique

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, ≥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 non-curative 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.

Papillary thyroid carcinoma: modified radical neck dissection improves prognosis.

To ascertain whether modified radical neck dissection offers a survival advantage for some subsets of patients with papillary cancer of the thyroid. A retrospective cohort study of 2966 patients curatively treated at the Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan, between 1946 and 1991. A center for the treatment of thyroid disease, where about 1400 thyroid operations are performed per year. 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. 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. 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.

Second Primary Neoplasms in Thyroid Cancer Patients

To determine risk patterns for second primary neoplasms after the occurrence of thyroid cancer, we conducted a retrospective cohort study of 3321 thyroid cancer patients who were operated and histologically confirmed at the Noguchi Thyroid Clinic and Hospital Foundation between 1946 and 1985. They were followed from the date of operation through the end of 1990 with an observation period from 45 to 5 years. The average observation period of the patients was 13.4 years and the follow‐up rate reached 98%. The standardized mortality ratio (SMR) was computed to assess possible risk increase by cancer site. In this computation, the time period less than 5 years after operation was omitted to reduce the influence of deaths related to the original thyroid cancer. A total of 103 deaths from malignant neoplasms other than thyroid cancer were observed during this time period (SMR=1.6, 95% confidence interval [CI]=1.3–2.0). Analyses of site‐specific cancer mortality revealed significantly elevated risks for the central nervous system (SMR=16.1, CI=5,2–37.6) and respiratory organs (SMR=2.6, CI=1.5–4.1). Based on a review of available medical records with histological findings, we concluded that the risk increases for these sites were most likely to be attributable to second primary neoplasms. Whether or not the patients had received radiotherapy was not significantly associated with elevated risk. Further investigations are needed to clarify the risk factors responsible for the above findings.

Small Carcinomas of the Thyroid

To determine the adequate extent of surgery for small carcinomas of the thyroid. Retrospective cohort study of 867 consecutive patients with small carcinomas of the thyroid (lesions < 10 mm in diameter) who were operated on at the Noguchi Thyroid Clinic, Oita, Japan, between 1965 and 1987. Mean follow-up was 12.8 years. A center for treatment of thyroid disease, where about 1400 thyroid operations are performed per year. Thyroidectomy was performed in patients with a preoperative diagnosis of Graves' disease, Graves' disease with nodules, solitary thyroid nodules, multinodular goiters, cysts, chronic thyroiditis and small carcinomas of the thyroid, in 394, 22, 136, 193, 18, 28, and 76 patients, respectively. Operations were conservative. Three patients who had adenomatous nodular goiters underwent total thyroidectomy. Modified radical neck dissection was performed in 66 patients. Of these 66 patients, 30 had grossly noticeable nodal metastases and 17 had microscopic metastases. Another 50 patients underwent selective lymph node excision, and 28 patients had nodal metastases. Recurrence from remnants of thyroid was seen in five patients. They were treated by surgery. Recurrence in lymph nodes was observed in five patients, and four of them were successfully treated. Recurrence in bone was observed in two patients; one with recurrence in the femur was successfully treated. Two patients died with recurrent cancer. Small carcinomas of the thyroid can be fatal. Total thyroidectomy is unnecessary. Modified radical neck dissection is unnecessary unless gross nodal metastases are present. Long-term follow-up is mandatory. A

Classification of papillary cancer of the thyroid based on prognosis.

Between 1965 and 1988 there were 2953 patients with papillary carcinoma treated at Noguchi Thyroid Clinic. Among them 761 patients were excluded because the primary tumor was < 10 mm in maximum diameter, the patient's age was > 80, or the patient underwent noncurative surgery. The remaining 2192 patients, 192 men and 2000 women, were analyzed. The mean follow-up period was 12.5 years. Total thyroidectomy, subtotal thyroidectomy, lobectomy with or without isthmectomy, and less than lobectomy were performed in 2.3%, 40.3%, 44.2%, and 13.2%, respectively. Modified radical neck dissection, partial node excision, and no node excision were performed in 77.8%, 6.4%, and 15.8%, respectively. Men and women were separately analyzed because their risk factors and prognosis were significantly different. Multivariate analysis was carried out according to Cox's regression hazard model. Independently significant factors affecting prognosis in men were aged and gross nodal metastasis; and age, gross nodal metastasis, tumor size, and number of adhered tissues or organs were the factors in women. Based on those risk factors patients were classified into three groups. For men, 65.6% were classified in the excellent group and their 10-year survival was 98.4%; 17.2% were classified as intermediate and 17.2% as poor with survival rates of 90.1% and 74.4%, respectively. For female patients 69.6% were classified in the excellent group, 18.6% in the intermediate group, and 11.9% in the poor group with 10-year survivals of 99.3%, 96.4%, and 88.8%, respectively.

Monitoring Antithyroid Therapy-Reply

In their comment, Sobel and Glick stated that the fact we were able to accumulate three patients with agranulocytosis in 1 year is somewhat surprising. We treated 1356 patients with Graves' disease while our granulocyte colony—stimulating factor study was carried out from July 1990 to August 1991. The incidence of antithyroid drug-induced agranulocytosis (granulocyte count, 9 /L) was 0.4% (six of 1356), which was the same as that (0.2% to 0.5%) reported previously. 1 Noguchi Thyroid Clinic (Beppu, Japan) is a special hospital for thyroid disease. About 1200 patients with Graves' disease per year visited this clinic from western Japan. As reported in our article, 2 from 1975 to 1987, 15 398 patients with Graves' disease were treated with an antithyroid drug in the Noguchi Thyroid Clinic. Of these, 55 (0.4%) were found to have agranulocytosis. We do not think that there is a discrepancy between our data and

Prognostic factors in primary lymphoma of the thyroid--a review of 74 cases

Prognoses and prognostic factors in 74 patients with primary lymphoma of the thyroid gland were analyzed. From 1968 to 1991, 74 patients with non-Hodgkin's lymphoma originating in the thyroid gland were treated at Noguchi Thyroid Clinic Hospital. Patients consisted of 53 females and 21 males, with a median age of 64.5 years. Survival curves were calculated by the Kaplan-Meier method and significance was tested by generalized Wilcoxon test. The overall 5-year and 10-year survival rates were 81.8% and 62.5%, respectively. The survival rate in stage II disease was significantly (P = 0.004) lower than that in stage I. By the LSG classification, there was no significant difference in survival curves between follicular lymphoma and diffuse lymphoma. Using the Working Formulation, there was no significant difference in survival curves between cases with low and intermediate grade histology. Histologic subtype of the tumor did not appear to be a significant determinant of prognosis. Patients with vocal cord paralysis had poorer survival rates than others (P = 0.001). Extrathyroidal spread of the tumor by direct soft tissue invasion had a distinctly adverse effect on prognosis.

Graves' Disease with Autoimmune Insulin-binding Antibody : Report of 12 Cases

In 1970, Hirata et al. first described a case of spontaneous hypoglycemia resulting from autoimmune insulin-binding antibodies in the serum.Until the Hirata report, it was generally accepted that insulin-binding antibodies were not been found in patients not treated with insulin.In fact, it was extremely rare to detect insulin-binding antibodies in patients who had not received insulin injections. Nevertheless, we recently demonstrated insulin-binding antibodies for endogenous insulin in twelve patients with Graves' disease. None of them had diabetes mellitus, but the following 2 cases had suffered from hypoglycemic attacksCase 1 E.T., a 23-year-old woman was admitted to the Noguchi Thyroid Clinic, on February 8, 1971, because of Graves' disease. In the early morning of March 1, the next day and three days later, she was found to have lost consciousness due to decreased venous glucose levels which ranged from 26 mg/dl to 36 mg/dl. Serum insulin levels after an ex-traction procedure with acid ethanol were extremely increased and ranged from 23,100/μU/ ml to 35,280/μU/ml during hypoglycemic attacks. Although she had never received an insulin injection, titers of insulin-binding antibodies determined as 125I-insulin-binding percent were from 70.5% to 82.5% in her sera. She had a subtotal thyroidectomy for Graves' disease on March 9. Two years after operation, insulin-binding antibodies were still detected in her sera, though 125I-insulin-binding percent and serum insulin levels gradually decreased since the hypoglycemic attacks.Case 2 Y.T., a 30-year-old woman, was given thiamazole for Graves' disease for three weeks. From February 20 to 28, 1970, drowsiness and pain in the extremities developed. At that time, levels of fasting blood glucose ranged from 41 mg/dl to 44 mg/dl, but neither insulin nor blood glucose levels after glucose administration were estimated. 4.0 mCi of radioiodine (131I) for Graves' disease was administered on March 14, 1970. Two years later due to hypoglycemic attacks, insulin-binding antibodies were demonstrated in her sera, although she did not receive insulin injections. The fasting blood glucose was normal as 99 mg/dl, but the glucose tolerance curve showed a diabetic pattern. The fasting insulin level was estimated at 130 μU/dl after the extraction procedure using acid ethanol. These results suggest that hypoglycemic attacks which occurred two years previously, were also due to the production of insulin-binding antibodies for endogenous insulin.In the sera of the remaining ten patients with Graves' disease not accompanied by hypoglycemia and who had never received insulin injections, insulin-binding antibodies were demonstrated. That is, 2.3% of Graves' disease patients had insulin-binding anti-bodies for endogenous insulin. In these cases, fasting blood glucose levels were within normal range, but fasting serum insulin increased and was estimated to be from 50 μU/ ml to 850 μU/ml. Glucose tolerance curves showed abnormal patterns, such as diabetic or oxyhyperglycemic patterns.As serum insulin levels increased after oral glucose administration, 125-insulin-binding percent decreased in all six patients who were examined by glucose tolerance test.It is interesting that all twelve of the patients were given thiamazole for Graves' dis-ease and demonstrated autoimmune insulin-binding antibodies. In three of these patient, insulin-binding antibodies were not detected before administration of thiamazole. From four to eight weeks after cessation of thiamazole administration, insulin-binding antibodies were decreased in the sera of five patients and were not detected in three patients.