Position paper from the Japan Thyroid Association task force on the management of low-risk papillary thyroid microcarcinoma (T1aN0M0) in adults.

The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.

Low insulin resistance after surgery predicts poor GH suppression one year after complete resection for acromegaly: a retrospective study.

Remission of acromegaly is defined as a nadir in GH <1.0 ng/mL during a 75-g oral glucose tolerance test (75gOGTT) and insulin-like growth factor-1 (IGF-1) normalization. Recently, a lower cut-off value for GH nadir (<0.4 ng/mL) has been proposed. We retrospectively evaluated the prevalence and clinical characteristics of postoperative cases with normalized IGF-1 levels and a GH nadir of 0.4-1.0 ng/mL one year after complete resection of GH-secreting pituitary adenoma (GHoma). We included 110 cases of acromegaly with complete adenoma resection, no preoperative treatment, preoperative glycosylated hemoglobin <6.5%, preoperative basal plasma glucose <126 mg/dL, GH nadir <1.0 ng/mL during a 75gOGTT, and normalized IGF-1 at the first postoperative year evaluation, whereupon patients were divided into two groups: control (GH nadir <0.4 ng/mL) and high GH (GH nadir >0.4 ng/mL). Clinical parameters, including measures of insulin secretion and resistance, were compared between groups. The high GH group included 10 patients (9.1%) and had a lesser level of insulin resistance immediately following surgery and at the first postoperative year evaluation. On single regression analysis, insulin resistance immediately following surgery was predictive of and correlated with the GH nadir at the first postoperative year evaluation. The GH nadir at the first postoperative year evaluation may be insufficient in patients with normalized IGF-1 with low insulin resistance immediately following complete resection of GHoma. Careful evaluation is needed to assess remission in such patients.

Ultrasonographic evaluation of parathyroid hyperplasia in multiple endocrine neoplasia type 1: Positive correlation between parathyroid volume and circulating parathyroid hormone concentration.

There are few reports on parathyroid ultrasonography of multiple endocrine neoplasia type 1 (MEN1). This study investigated the ultrasonographic features of parathyroid glands in 10 patients with MEN1 who underwent preoperative neck ultrasonography and parathyroidectomy between 2006 and 2010 at Toranomon Hospital. We retrospectively analyzed clinical features, laboratory and ultrasonographic data, and pathological diagnosis. A total of 38 parathyroid glands were surgically removed (three to five glands from each patient). All removed parathyroids were pathologically diagnosed as hyperplasia. Seven cases (70.0 %) had adenomatous thyroid nodules. Twenty-five enlarged parathyroid glands (65.8 %) were detected by preoperative ultrasonography with a detection rate of 81.8 % (9/11) and 59.3 % (16/27) for patients without and with adenomatous nodules, respectively. Total parathyroid gland weight and potentially predictable total parathyroid volume by preoperative ultrasonography were significantly correlated with preoperative serum intact parathyroid hormone (iPTH) concentration (R = 0.97, P < 0.001 and R = 0.96, P < 0.001, respectively). The equation used for prediction of the total volume by ultrasonography was 15 × iPTH (pg/ml) - 1,000 and that for total weight was 20 × iPTH (pg/ml) - 1,400. Although adenomatous nodules often coexisted with MEN1 and made identification of enlarged parathyroid glands by ultrasonography difficult, the positive correlation between the predictable parathyroid volume by ultrasonography and serum iPTH suggests that their measurement is useful in the preoperative detection and localization of enlarged parathyroid glands in patients with MEN1. Furthermore, the presence of parathyroid glands that should be resected can be predicted before surgery using the equation proposed here.

A large functioning parathyroid cyst in a patient with multiple endocrine neoplasia type 1.

A 62-year-old woman presented with a mass on the left side of the neck. Biochemical testing revealed primary hyperparathyroidism. Further, a prolactinoma was detected, and the patient's son and daughter also had primary hyperparathyroidism, indicating that the patient had multiple endocrine neoplasia type 1 (MEN1). Neck ultrasonography revealed several cystic nodules (≤ 30 mm) that appeared to be adenomatous. After parathyroidectomy with autotransplantation, the largest cystic mass, in the left lower thyroid lobe, was pathologically diagnosed as a functioning parathyroid cyst, and all laboratory data returned to normal. On genetic analysis of blood, we found a novel single base insertion (duplication) in exon 10 codon 552 of the MEN1 gene (c1659dupT) that creates an early stop codon. This is the first case report of a parathyroid cyst resulting from parathyroid hyperplasia in a MEN1 patient.

[Diagnostic imaging of thyroid tumor].

Recently, thyroid nodules are found frequently when other imaging test was performed, and selection of diagnostic methods and its handling have become a problem clinically. Although it is possible to differentiate the malignant tumor from benign one using B-mode ultrasound, it can be obtained more detailed information in combination of other modalities such as color Doppler and tissue elasticity imaging (elastography). The malignant B-mode findings are irregular shape, indistinct border, hypoechoic and inhomogeneous internal echo, and fine calcification. CT/MRI is useful to evaluate the extention of thyroid cancer to adjacent organs beyond the thyroid capsule. It is also useful to evaluate distant metastases to lung or brain of thyroid cancer. In nuclear medicine, 125I scintigraphy is used to measure thyroid uptake rate, 131I scintigraphy is used to investigate the distant metastasis of thyroid cancer. It is necessary to be careful that some false-positive cases exist in 18FDG-PET.

[Effects of thyrotropin-suppressive therapy in patients with well-differentiated thyroid carcinoma].

Patients with differentiated thyroid carcinoma are commonly treated long-term with thyrotropin (TSH)-suppressive thyroxine replacement therapy, which lead to a state of subclinical hyperthyroidism. Many studies including meta-analysis, there are increasing risk in the state of subclinical hyperthyroidism, especially in bone metabolism and cardiac dysfunction. Although there is a marked discrepancy in various therapeutic opinions between Japan and other countries, TSH suppressive therapy would be advisable to aim at TSH levels in the low normal range in low risk patients, whereas TSH levels should be suppressed in non-cured or high risk patients.

Distinct diagnostic criteria for ultrasonographic examination of papillary thyroid carcinoma: a multicenter study.

Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.

Primary aldosteronism presenting with an atypical aldosterone-renin ratio in the acute phase of cerebral hemorrhage.

The aldosterone-renin ratio (ARR) is considered to be the most reliable and sensitive screening parameter for primary aldosteronism (PA). However, little is known regarding how stroke influences the ARR. We herein present a case of a 35-year-old man who was ultimately found to have PA after diagnostic challenges. The patient showed an atypical ARR in the acute phase of cerebral hemorrhage. We therefore conclude that the ARR may be inappropriately decreased immediately after stroke in patients with PA, presumably due to sympathetic activation and the effects of medications. When diagnosing PA in patients with stroke, we suggest reevaluating the ARR in the stable phase.

Radiation exposure and the risk of pediatric thyroid cancer.

It has been more than three years since the unprecedentedly massive earthquake and tsunami struck eastern Japan on March 11, 2011, and the large accident occurred at the Fukushima Daiichi Nuclear Power Plant. To investigate the influence of radiation exposure, thyroid ultrasonography has been provided preliminarily for 360,000 children who lived in Fukushima Prefecture at the time of the accident. As of September 2013, 59 children had been diagnosed with thyroid cancer by fine-needle aspiration cytology, and 34 children had been treated surgically and ultimately diagnosed with papillary thyroid cancer. Here, I would like to describe the characteristics of pediatric thyroid cancer and typical thyroid images obtained by ultrasonography.

Ketoacidosis as the initial clinical condition in nine patients with acromegaly: a review of 860 cases at a single institute.

OBJECTIVE: Excess GH causes insulin resistance and impaired glucose metabolism. The objective of this study was to clarify the prevalence of ketoacidosis as the initial presenting symptom of acromegaly. DESIGN AND METHODS: Data were collected from 860 patients with acromegaly who underwent pituitary surgery at Toranomon Hospital over the last 32 years, between 1980 and 2011. RESULTS: Nine cases had ketoacidosis before being diagnosed with acromegaly, including seven males and two females with a mean +/- S.D. age of 38.8 +/- 14.2 years. Serum GH and IGF1 levels were 155 +/- 203 ng/ml and 9.86 +/- 0.68 SDS before pituitary surgery and 3.6 +/- 1.7 ng/ml and 3.72 +/- 3.40 SDS after surgery respectively. The maximum tumor diameter was 28.2 +/- 11.6 mm (ranging from 15 to 47 mm, n=8). None of the patients were diagnosed with diabetes mellitus (DM) nor were they positive for antibodies related to type 1 DM. A possible precipitating factor for ketoacidosis in six cases was excessive ingestion of sugar-containing soft drinks. All the cases had invasive pituitary adenomas. After pituitary surgery, plasma glucose levels were under control without requiring insulin in all cases. Furthermore, six patients did not need oral hypoglycemic agents. CONCLUSIONS: Approximately 1% of patients with acromegaly presented with diabetic ketoacidosis as their first clinical condition.

Impaired glucose metabolism in Japanese patients with acromegaly is restored after successful pituitary surgery if pancreatic {beta}-cell function is preserved.

OBJECTIVE: Impaired glucose metabolism is common in acromegaly, but it is not clear how glucose metabolism is impaired or what predicts its restoration after cure of the disease. To identify factors involved in the impairment of glucose metabolism in acromegaly, we evaluated clinical parameters before and immediately after surgical cure of the disease. DESIGN AND METHODS: We retrospectively analyzed clinical data of 92 consecutive Japanese patients with acromegaly who underwent successful pituitary surgery. Patients who had received medical therapy for acromegaly or insulin treatment for diabetes were excluded. We evaluated insulin resistance (IR) and pancreatic ß-cell function in addition to GH and IGF1 levels before and after surgery. Results In this study of Japanese patients with acromegaly, average body mass index (BMI) was 23.4, and no patient had a BMI>30. IR was involved in the impairment of glucose metabolism, which was restored upon surgical cure of acromegaly if ß-cell function was preserved. Insufficient ß-cell function did not improve after normalization of GH/IGF1 and was associated with impaired glucose metabolism before and after surgery. RESULTS: of receiver operating characteristic analysis of preoperative clinical parameters suggest that insulinogenic index (IGI) >0.50 best predicts restoration of normal glucose metabolism upon cure of acromegaly in Japanese patients. CONCLUSIONS: IR impairs glucose metabolism in acromegaly. Once ß-cell function is impaired, abnormal glucose metabolism persists even after cure of acromegaly. IGI>0.50 indicates that ß-cell function is preserved in non-obese Japanese patients with acromegaly.

GH deficiency in patients after cure of acromegaly by surgery alone.

OBJECTIVE: The aim of this study was to determine the frequency and characteristics of severe GH deficiency (sGHD) in patients after treatment of acromegaly by surgery alone. DESIGN AND METHODS: One hundred and eighty-six patients fulfilling the criteria for cure of acromegaly were examined by GH-releasing peptide-2 stimulation test or arginine stimulation test as well as oral glucose tolerance test (GTT). In addition, the Japanese adult hypopituitarism questionnaire was completed to determine the quality of life (QoL). RESULTS: sGHD was found in 17 patients (9.1%; the GH-deficient group), and not found in 169 patients (90.9%; the GH-sufficient group). There were no significant differences in preoperative serum GH levels, IGF1 levels, incidence of hyperprolactinemia, tumor volumes, or incidence of microadenoma between the two groups. Upon follow-up examination, IGF1 levels and Z-scores of IGF1 levels were significantly lower in the GH-deficient group than in the GH-sufficient group, whereas neither basal GH levels nor nadir GH levels during 75 g GTT were significantly different between the two groups. Moreover, sGHD patients had a substantially higher incidence of multiple pituitary failures (17.6 vs 2.4%) and dyslipidemia (60 vs 16.2%). sGHD patients had a substantially poorer condition-related QoL. CONCLUSIONS: This is the first large-scale, single-center, clinical study to evaluate sGHD in patients after cure of acromegaly by surgery alone. This study found that sGHD occurred in ~9% of patients and assessment of GHD by stimulation tests is critical after successful treatment of acromegaly by surgery.

Sunitinib induces hypothyroidism with a markedly reduced vascularity.

BACKGROUND: Sunitinib is a small molecule that inhibits receptor tyrosine kinases, including the vascular endothelial growth factor receptors, and exhibits antiangiogenic and antitumor activity. This molecule has also been reported to cause hypothyroidism at a high frequency, but the mechanism of this is unknown. SUMMARY: A 60-year-old woman was administered sunitinib for the treatment of metastatic renal cell carcinoma. One week later, she displayed overt hypothyroidism with an atrophic thyroid and a marked reduction in vascularity as determined by ultrasonography, despite high levels of thyrotropin. In contrast, during the off-periods in the sunitinib treatment cycles, the volume of her thyroid recovered with an increase in vascularity despite a low level of thyrotropin. These results suggest that thyroid function and volume may depend on the vascularity, which is negatively regulated by sunitinib. CONCLUSION: Our case study provides compelling evidence that sunitinib induces hypothyroidism by reducing blood flow via capillary regression and constriction.

Coincidence of multiple endocrine neoplasia type 2A with acromegaly.

Medullary thyroid carcinoma (MTC) occurs as a part of multiple endocrine neoplasia (MEN) type 2. Acromegaly, a pituitary adenoma, occurs as a part of MEN1. Rarely, MEN2 and MEN1 coexist in a single patient simultaneously. A 40-year-old man with a history of pituitary adenomectomy for acromegaly had a surgical resection of thyroid carcinoma clinically diagnosed as MTC. His mother, who had MTC and pheochromocytoma, had a germline mutation in the RET gene that could cause the subtype, MEN2A. Identification of gene mutations in RET and MEN1 were examined in the subject. The resected tumor was pathologically diagnosed as MTC. Genomic examinations revealed the RET mutation C634F, which was identical to the mutation of his mother, but no MEN1 gene mutation was found. Although the simultaneous occurrence of both MEN2A and sporadic acromegaly may be accidental, there is evidence to suggest a genetic interaction between MEN2 and acromegaly.

Hypoglycemic coma in a patient with anorexia nervosa coincident with acute exacerbation of liver injury induced by oral intake of nutrients.

A 33-year-old woman with anorexia nervosa was admitted because of severe malnutrition. Acute liver injury was observed soon after the beginning of oral intake. She was prohibited from eating for 10 days and treated with parenteral nutrition until liver dysfunction was improved. One week after resuming oral intake, she presented severe hypoglycemic coma along with acute exacerbation of hepatocytic injury. Clinical laboratory data suggest that insufficient gluconeogenesis in acute liver injury was involved in severe hypoglycemia. We should be careful of severe hypoglycemia in patients with anorexia nervosa after resuming oral ingestion when signs of liver damage are detected, although hypoglycemic coma is uncommon in anorexia nervosa.

Recurrence of primary hyperparathyroidism following spontaneous remission with intracapsular hemorrhage of a parathyroid adenoma.

A few patients with primary hyperparathyroidism (PHPT) have a chance of spontaneous remission by either infarction of or hemorrhage into or around the parathyroid adenoma. In most cases, biochemical derangements associated with PHPT are permanently improved after spontaneous remission. Here we report a case with a recurrence of PHPT 4 months after spontaneous remission with acute intracapsular hemorrhage of parathyroid adenoma. In the literature, only two cases have been reported to have experienced a recurrence of clinical features of PHPT after infarction but not hemorrhage of parathyroid adenomas. Thus, the spontaneous remission of biological derangements in PHPT upon hemorrhage or infarction of parathyroid adenoma could be temporary. One should carefully observe such patients thereafter.

Ultrasonographic findings of papillary thyroid carcinoma with Hashimoto's thyroiditis.

OBJECTIVE: Papillary thyroid carcinoma (PTC) sometimes occurs with Hashimoto's thyroiditis (HT). It is often difficult to differentiate between benign and malignant nodules in HT because HT varies greatly on ultrasonography. We aimed to characterize the ultrasonographic features of PTC with HT. PATIENTS AND METHODS: In this retrospective study, 2167 patient records (1897 women and 270 men) were examined for ultrasonographic features and thyroid autoantibodies between 1998 and 2002 at our university. Patients with Graves' disease, positive TSH receptor autoantibody (TRAb) or thyroid-stimulating antibody (TSAb) were excluded. PTC was diagnosed by pathological examination. RESULTS: Of the 1644 patients who were autoantibody negative (MCHA, TGHA, TgAb, TPOAb), 54 (3.3%) had PTC, while 29 (5.5%) of the 523 patients who were autoantibody positive had PTC. On ultrasonography, the frequency of dense calcification in patients with HT was significantly higher (P=0.0064) and frequency of psammoma bodies was less than PTC patients without HT (P<0.0001). On the other hand, PTC with HT had more irregular shapes and ill-defined edges of the borders with less hypoechogenecity and calcification than PTC without HT, but the difference was not significant. CONCLUSION: The frequency of psammoma bodies in PTC with HT was less, while dense calcifications were greater than in those of PTC without HT. Any type of ultrasonographic calcification features may represent a risk for PTC.

Diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography.

The aim of this study was to define the preoperative diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography (US). We compared the vascular pattern and the velocimetric parameters, such as peak systolic velocity (Vmax), end-diastolic velocity (Vmin), pulsatility index (PI), or resistance index (RI) between follicular adenoma (FA, n = 25) and follicular carcinoma (FC, n = 10) and analysed them by means of receiver characteristics curves (ROC). Of 10 patients with FC, 8 (80%) patients presented a moderate increase of intranodular vascularization using power Doppler US. In contrast, the majority (84%, 21 out of 25 cases) of FA cases showed only a peripheral rim of color flow even by power Doppler US. These color flow imagings by power Doppler US were suggested to be a reliable tool for the differential diagnosis of thyroid follicular tumor with a sensitivity of 87.5% and a specificity of 92%. In velocimetric analyses, the Vmax/Vmin ratios, PI, and RI were significantly higher in the patients with FC than those with FA (p<0.001, p<0.005, and p<0.001, respectively). By means of ROC, FC could be diagnosed with a cutoff value of ratio of PI (>1.35), RI (>0.78), and Vmax/Vmin (>3.79). The diagnostic efficiency evaluated by ROC curves were 0.898 for PI, 0.876 for RI, and 0.888 for Vmax/Vmin, respectively. In conclusion, the evaluation of the vascular pattern and the velocimetric parameters using pulsed and power Doppler ultrasound may provide important information that is useful in making correct differential diagnosis of malignant or benign thyroid follicular tumor preoperatively.

Increased expression of phosphorylated p70S6 kinase and Akt in papillary thyroid cancer tissues.

Although a number of abnormalities in oncogenes have been reported in thyroid neoplasms, little information is available on the signal transduction pathway involved in neoplastic thyroid cell growth. Both p70S6 kinase (p70S6K) and Akt are kinases downstream of phosphatidylinositol 3 kinase (PI3K). These kinases are phosphorylated and activated by growth factors including IGF-1, EGF/TGF-alpha, and HGF in thyroid cells. Since the receptors for these growth factors are reportedly overexpressed in human thyroid cancer, we hypothesized that the PI3K-mediated signalings are overactivated in thyroid cancers. Tumorous and adjacent normal tissues of 20 patients with papillary thyroid cancer were obtained at surgery, and expression of p70S6K and Akt were measured by Western blot. Expression of the protein levels of p70S6K was increased in tumor tissues (T) compared to normal thyroid tissues (N), and expression of phosphorylated p70S6K was also significantly increased in tumor than in surrounding normal tissues. Overexpression of p70S6K in tumor tissues was further confirmed by immunohistochemistry. Strong immunoreactivity in the cytoplasm of thyroid cancer cells was seen in the majority of cases, whereas little immunoreactivity was found in the surrounding normal portion. Expression of phosphorylated Akt (pAkt) was also significantly higher in tumor tissues. Phosphorylation of Bad (pBad), a substrate of Akt, was also increased in the tumor tissues in association with activation of Akt, and the T/N ratio for pAkt positively correlated to the T/N ratio for pBad. The data presented here demonstrate that both p70S6K and Akt are activated in the majority of human papillary cancer cells. Activation of these signalings may be involved in the progression of papillary carcinoma by stimulating cell proliferation and/or preventing apoptosis.