Low-risk papillary microcarcinoma of the thyroid: A review of active surveillance trials.

Papillary microcarcinoma (PMC) of the thyroid is defined as papillary thyroid carcinoma (PTC) measuring ≤1 cm. Many autopsy studies on subjects who died of non-thyroidal diseases reported latent small thyroid carcinoma in up to 5.2% of the subjects. A mass screening study for thyroid cancer in Japanese adult women detected small thyroid cancer in 3.5% of the examinees. This incidence was close to the incidence of latent thyroid cancer and more than 1000 times the prevalence of clinical thyroid cancer in Japanese women reported at that time. The question of whether it was correct to treat such PMCs surgically then arose. In 1993, according to Dr. Miyauchi's proposal, Kuma Hospital initiated an active surveillance trial for low-risk PMC as defined in the text. In 1995, Cancer Institute Hospital in Tokyo, Japan, started a similar observation trial. The accumulated data from the trials at these two institutions strongly suggest that active surveillance (i.e., observation without immediate surgery) can be the first-line management for low-risk PMC. Although our data showed that young age and pregnancy might be risk factors of disease progression, we think that these patients can also be candidates for active surveillance, because all of the patients who showed progression signs were treated successfully with a rescue surgery, and none of them died of PTC. In this review, we summarize the data regarding the active surveillance of low-risk PMC as support for physicians and institutions that are considering adopting this strategy.

Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy.

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

Cytological features of solid variants of papillary thyroid carcinoma: a fine needle aspiration cytology study of 18 cases.

OBJECTIVE: Solid variants of papillary thyroid carcinoma (SV-PTC) are rare, and there have been few reports describing the cytological findings of such variants. METHODS: The cytological features of cellular specimens aspirated from 18 histologically confirmed SV-PTC cases were evaluated, retrospectively. RESULTS: Solid and small papillary clusters were observed in 14 (77.8%) and 13 (72.2%) cases, respectively. The incidences of large papillary clusters (11.1%) and sheet-like arrangements (11.1%) were low. Nuclear features were consistent with conventional PTC. The background was clean, and there were no colloid materials, foamy histiocytes, multinucleated giant cells, psammoma bodies, or necrotic materials. CONCLUSIONS: Solid clusters and small papillary clusters in conjunction with a clean background are diagnostic clues that indicate SV-PTC cytologically. It is thought that small papillary clusters reflect the micropapillary growth pattern seen within the lumen of middle-sized follicular structures. The presence of nuclear findings typical of conventional PTC and the absence of mitotic figures and necrotic materials are important for distinguishing SV-PTC from poorly differentiated carcinoma.

Diffuse sclerosing variant of papillary thyroid carcinoma: a study of fine needle aspiration cytology in 20 patients.

BACKGROUND: A diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a rare variant and reports describing the cytological findings are few. PATIENTS AND METHODS: We studied 24 cytological samples from thyroid fine needle aspirates of 20 patients with DSV-PTC. The specimens were taken from 14 non-nodular lesions and 10 nodules. RESULTS: All aspirates taken from both non-nodular lesions and nodules had sufficient cellularity. The carcinoma cells frequently (70-100%) appeared as solid cell balls and hollow balls, and showed a hobnail pattern, squamous differentiation, septate cytoplasmic vacuoles and large unilocular vacuoles. Most of the carcinoma cells seem to be taken from the lumen of dilated lymph vessels. Ground glass nuclear chromatin, intranuclear cytoplasmic inclusions and grooved nuclei were infrequent (50% or less). In the background, a large number of lymphocytes and abundant psammoma bodies were almost always seen. CONCLUSIONS: Cytological findings of DSV-PTC are as follows: (1) solid cell balls and/or hollow balls containing lymphocytes; (2) hobnail cells; (3) septate cytoplasmic vacuoles; (4) large unilocular vacuoles; (5) squamous differentiation; (6) abundant psammoma bodies; (7) lymphocytic background; and (8) the absence or relative lack of characteristic nuclear features of papillary carcinoma. When DSV-PTC is suspected by ultrasound examination, the aspiration cytology from a non-nodular area of the thyroid can led us to the diagnosis of the variant.

Identification of Hic-5 as a novel regulatory factor for integrin αIIbß3 activation and platelet aggregation in mice.

BACKGROUND: Integrin αIIbß3 plays key roles in platelet aggregation and subsequent thrombus formation. Hydrogen peroxide-inducible clone-5 (Hic-5), a member of the paxillin family, serves as a focal adhesion adaptor protein associated with αIIbß3 at its cytoplasmic strand. OBJECTIVES: Hic-5 function in αIIbß3 activation and subsequent platelet aggregation remains unknown. To address this question, platelets from Hic-5(-/-) mice were analyzed. METHODS AND RESULTS: Hic-5(-/-) mice displayed a significant hemostatic defect and resistance to thromboembolism, which were explained in part by weaker thrombin-induced aggregation in Hic-5(-/-) platelets. Mechanistically, Hic-5(-/-) platelets showed limited activation of αIIbß3 upon thrombin treatment. Morphological alteration in Hic-5(-/-) platelets after thrombin stimulation on fibrinogen plates was also limited. As a direct consequence, the quantity of actin co-immunoprecipitating with the activated αIIbß3 was smaller in Hic-5(-/-) platelets than in wild-type platelets. CONCLUSION: We identified Hic-5 as a novel and specific regulatory factor for thrombin-induced αIIbß3 activation and subsequent platelet aggregation in mice.

Deletion of thyrotropin receptor residue Asp403 in a hyperfunctioning thyroid nodule provides insight into the role of the ectodomain in ligand-induced receptor activation.

Somatic mutations of the TSH receptor (TSHR) gene are the main cause of autonomously functioning thyroid nodules. Except for mutations in ectodomain residue S281, all of the numerous reported activating mutations are in the TSHR membrane-spanning region. Here, we describe a patient with a toxic adenoma with a novel heterozygous somatic mutation caused by deletion of ectodomain residue Asp403 (Del-D403). Subsequent in vitro functional studies of the Del-D403 TSHR mutation demonstrated greatly increased ligand-independent constitutive activity, 8-fold above that of the wild-type TSHR. TSH stimulation had little further effect, indicating that the mutation produced near maximal activation of the receptor. In summary, we report only the second TSHR ectodomain activating mutation (and the first ectodomain deletion mutation) responsible for development of a thyroid toxic adenoma. Because Del-D403 causes near maximal activation, our finding provides novel insight into TSHR structure and function; residue D403 is more likely to be involved in the ligand-mediated activating pathway than in the ectodomain inverse agonist property.

Extent of hypoechogenic area in the thyroid is related with thyroid dysfunction after subacute thyroiditis.

OBJECTIVE: To gain an insight into risk factors for hypothyroidism after subacute thyroiditis (SAT), we examined the correlation between initial laboratory and ultrasonographic findings and sequential thyroid dysfunction among treatment modalities. PATIENTS: We reviewed retrospectively the medical records of 252 patients (26 men and 226 women) with SAT who consecutively visited our thyroid clinic at Kuma Hospital for at least 6 months from 1996 through 2004. RESULTS: Throughout the course, 135 patients (53.6%) developed transient or permanent hypothyroidism. Levels of TSH were most often elevated (greater than 5 IU/ml) 2 months after SAT onset regardless of treatment, and 97.0% of patients who showed transient or permanent hypothyroidism clustered within 6 months from onset. During follow-up, patients treated with prednisone (PSL) were more likely to have normal thyroid function than patients not treated or those receiving anti-inflammatory drug therapy. In patients who developed hypothyroidism with PSL treatment or without treatment, the rates of bilateral hypoechogenic areas (HEA) were 6-fold higher than those of unilateral HEA. Moreover, permanent hypothyroidism occurred in 5.9% of patients, and all patients with permanent hypothyroidism presented initially with bilateral HEA and had consequently small thyroid size with or without abnormal autoimmunity. CONCLUSIONS: The rates of thyroid dysfunction after SAT were significantly lower in patients receiving PSL. Extent of HEA in the thyroid, but not laboratory findings, may be a possible marker for developing thyroid dysfunction after SAT.

Increased expression levels of tensin3 mRNA in thyroid functional adenomas as compared to non-functioning adenomas.

Tensin3 is a member of tensin family which is localized in focal adhesion. In our previous study, a high level of tensin3 mRNA expression was observed in the thyroid but not in other tissues, thus, tensin3 gene was regarded as a novel thyroid-specific gene. The high expression level of tensin3 mRNA in normal thyroid tissue suggests some fundamental roles in thyroid functions. In fact, the expression level of tensin3 mRNA was low in most thyroid carcinomas and non-functioning thyroid follicular adenomas which do not produce thyroid hormone. In the present study, we measured the expression levels of tensin3 mRNA in twelve functional adenomas and compared the results with those in normal thyroid tissues, adenomatous goiters and non-functioning thyroid follicular adenomas. Tensin3 mRNA was expressed abundantly in all twelve functional adenomas at almost the same level as in normal thyroid tissues and adenomatous goiters, while its expression was significantly lower in non-functioning follicular adenomas. Considering these facts, an abundant expression of tensin3 mRNA is observed in tissues that produce thyroid hormone, which suggests some fundamental roles in basic thyroid functions.

Analgesic and chondroprotective effects of risedronate in osteoarthritis assessed by electroalgometry and measurement of collagen type II fragments in urine.

We evaluated the effect of the bisphosphonate, risedronate, on pain and cartilage metabolism in 33 patients with osteoarthritis of the knee, randomized into two groups. Group RC was treated with risedronate (2.5 mg/day) and calcium (900 mg/day); group C received calcium (900 mg/day) alone. Pain on exercise was estimated using a subjective visual rating scale (VRS) and an electroalgometric method of measuring decrease in skin impedance, previously shown to be indicative of pain. We measured urinary excretion of cartilage-specific collagen type II fragments as a marker of cartilage degradation. Multiple regression analysis revealed that pain alleviation as measured by skin impedance, but not VRS, was associated with a decrease in collagen fragment excretion. This suggests that, for pain evaluation, reduction in skin impedance may have a greater physiological basis compared with VRS-based evaluation. We consider that the chondroprotective and analgesic effects of risedronate may be related.

BRAF V600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas.

Frequency of a BRAF V600E mutation in anaplastic thyroid carcinoma, which is thought to be derived mainly from papillary carcinoma by multi-step carcinogenesis, is much lower than that in papillary carcinomas. To clarify this phenomenon, we analysed BRAF V600E mutation in 20 cases of anaplastic carcinoma and 13 accompanying differentiated carcinomas. Among twenty cases of anaplastic carcinomas, nine and four accompanied papillary and follicular carcinomas, respectively. BRAF V600E mutation was found in four (20%) cases. BRAF V600E mutation was found in three of nine (33.3%), none of four and one of seven (14.3%) anaplastic carcinomas with papillary carcinoma, follicular carcinoma and without differentiated components, respectively. All three papillary carcinomas accompanied by anaplastic carcinoma with a BRAF V600E mutation were also shown to have a BRAF V600E mutation. In summary, BRAF V600E mutation was occasionally observed in anaplastic carcinomas with papillary carcinoma, and the low frequency of BRAF V600E mutation in anaplastic carcinoma was thought to be due to the low frequency of anaplastic carcinomas with papillary carcinoma. These findings raise a question about the classical model of anaplastic transformation and suggest some roles of thyroid cancer stem cells in the generation of anaplastic carcinoma.

A review of 227 cases of small papillary thyroid carcinoma.

AIMS: To review differences in biological aggressiveness, clinical behaviors or selected surgical treatments between the PMC and the slightly larger PTC of 1.0

Two cases of subacute thyroiditis presenting in pregnancy.

Subacute thyroiditis (SAT) is an extremely rare cause of thyrotoxicosis in pregnant women. Untreated, thyrotoxicosis may result in complications, such as prematurity and congenital malformations in the fetus. We report two cases of first trimester subacute thyroiditis, one mild and one severe. The severe case, as demonstrated by laboratory and ultrasound findings, was successfully treated with prednisolone. In this case, it was thought that the benefits of pharmacological therapy outweighed the risk of potential teratogenesis by the medication. In contrast, the milder case was managed conservatively and resolved without treatment. These cases illustrate how laboratory and ultrasound findings can be used to determine whether treatment should be initiated and, once begun, if medication levels need to be adjusted. In both cases, the pregnancies resulted in healthy full-term infants.

Multiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in culture.

CCN2 consists of 4 distinct modules that are conserved among various CCN family protein members. From the N-terminus, insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1) and C-terminal cysteine-knot (CT) modules are all aligned tandem therein. The multiple functionality of CCN2 is thought to be enabled by the differential use of these modules when interacting with other molecules. In this study, we independently prepared all 4 purified module proteins of human CCN2, utilizing a secretory production system with Brevibacillus choshinensis and thus evaluated the cell biological effects of such single modules. In human umbilical vascular endothelial cells (HUVECs), VWC, TSP and CT modules, as well as a full-length CCN2, were capable of efficiently activating the ERK signal transduction cascade, whereas IGFBP was not. In contrast, the IGFBP module was found to prominently activate JNK in human chondrocytic HCS-2/8 cells, while the others showed similar effects at lower levels. In addition, ERK1/2 was modestly, but significantly activated by IGFBP and VWC in those cells. No single module, but a mixture of the 4 modules provoked a significant activation of p38 MAPK in HCS-2/8 cells, which was activated by the full-length CCN2. Therefore, the signals emitted by CCN2 can be highly differential, depending upon the cell types, which are thus enabled by the tetramodular structure. Furthermore, the cell biological effects of each module on these cells were also evaluated to clarify the relationship among the modules, the signaling pathways and biological outcomes. Our present results not only demonstrate that single CCN2 modules were potent activators of the intracellular signaling cascade to yield a biological response per se, while also providing new insight into the module-wise structural and functional relationship of a prototypic CCN family member, CCN2.

Restriction of dietary Iodine does not ameliorate the early effect of anti-thyroid drug therapy for Graves' disease in an area of excessive iodine intake.

The close relationship between iodine intake and the effects of anti-thyroid drugs (ATD) for Graves' disease (GD) has been well established. However, it remains unknown whether restriction of dietary iodine improves the effect of ATD. This study aimed to clarify this issue in Japanese patients with GD who routinely ingest large amounts of dietary iodine. We performed a prospective clinical study in 81 patients with newly diagnosed GD who were divided into an iodine restricted group and a control group. Urinary iodine, thyroid hormones and TSH receptor antibody were measured during the first 8 weeks of ATD therapy. Urinary iodine concentrations in the iodine restricted group were significantly lower than in the control group (p=0.043). However, there were no significant differences in the decrease of thyroid hormones and TSH receptor antibody between the two groups. Restriction of dietary iodine does not ameliorate the effect of ATD therapy for GD in an area of excessive iodine intake.

Expression of S100A2 and S100A6 in thyroid carcinomas.

AIMS: S100 calcium-binding proteins are known to play multiple roles in carcinoma development. In this study, we focused on two kinds of these proteins, S100A2 and S100A6, and investigated their expression in thyroid neoplasms. METHODS AND RESULTS: We investigated S100A2 and S100A6 expression in 141 thyroid neoplasms by immunohistochemistry. S100A2 was not expressed in normal follicles or follicular tumours, with one exception. Although 89.5% of papillary carcinoma were positive for S100A2, the expression was heterogeneous except in two cases. In anaplastic carcinoma, 78.5% of cases expressed S100A2 diffusely, while the remaining cases were negative. In normal follicles, S100A6 expression was always low, while 8.3% of follicular adenomas and 39.5% of follicular carcinomas showed increased expression. In papillary carcinomas, S100A6 expression was increased in 75% of cases, but in anaplastic carcinomas it was decreased, with only 14.3% showing high expression. CONCLUSIONS: The expression patterns of S100A2 and S100A6 in thyroid neoplasms are unique compared with those of other carcinomas, suggesting that: (i) S100A2 and S100A6 contribute to certain events in papillary carcinoma progression, and (ii) S100A2 expression is one of the biological characteristics of anaplastic carcinoma.

Papillary carcinoma of the thyroid in Japan: subclassification of common type and identification of low risk group.

AIMS: Papillary thyroid carcinoma (PTC) is classified into two subgroups-common type and other histological variants. Correlations between further subgrouping of the common type and patient prognosis are not well documented. AIMS: To introduce two novel histological parameters to characterise PTC-loss of cellular polarity and loss of cellular cohesiveness. To investigate a new subgroup of common type PTC with possible prognostic value. METHODS: In total, 213 patients with PTCs larger than 1 cm were studied. Histological characteristics of these PTCs, including tumour growth pattern, encapsulation, extrathyroidal invasion, loss of cellular polarity, and loss of cellular cohesiveness were examined and correlated with disease free survival (DFS). RESULTS: Multivariate analysis revealed that invasive growth of unencapsulated PTC, in addition to sex (male) and tumour size (>4 cm) were significant and independent parameters for poor DFS, whereas loss of cellular polarity and cohesiveness, old age (>60 years), extrathyroid invasion, and completeness of surgery were significant only in univariate analysis. PTCs that showed expansive growth and retained cellular polarity had a favourable course, with no recurrence and no cancer related deaths. In contrast, PTCs exhibiting loss of cellular polarity and/or invasive growth with no tumour capsule had a higher risk of recurrence. CONCLUSION: Cytological features alone cannot predict patient outcome in PTC. This study indicates for the first time that loss of cellular polarity and the tumour growth pattern are useful parameters for identifying the so called low risk group in common type PTC and in predicting patient outcome in terms of tumour recurrence and cancer related death.

Lower concentration of serum soluble CD8 in severe Hashimoto's disease.

To investigate the roles of soluble CD4 (sCD4) and CD8 (sCD8) in the severity of autoimmune thyroid diseases, we examined serum concentrations of sCD4 and sCD8 in various degrees of severity of Hashimoto's disease (HD) and Graves' disease (GD) by enzyme immunoassay. The serum concentration of sCD8 was lower in euthyroid patients with HD undergoing treatment for hypothyroidism (severe HD) than in untreated, euthyroid patients with HD (mild HD), but the sCD4 concentration did not differ between patients with severe and mild HD. The serum sCD8 concentration was negatively correlated with the proportion of CD25(+) cells in CD8(+) cells in patients with severe HD. Serum sCD4 and sCD8 concentrations did not differ between euthyroid patients with GD in remission and those with intractable GD. These results indicate that serum sCD8 is involved in the severity of HD, possibly by down-regulating the function of cytotoxic T cells.

Decrease of CD154 intensity on peripheral CD4+ T cells in autoimmune thyroid disease.

To clarify immunological differences among patients with Graves' disease (GD) and Hashimoto's disease (HD) at various levels of severity, we examined the expression of the CD154 molecules on peripheral T cells, which regulate B cell activation, B cell differentiation, and T-cell survival. We found decreases in the intensities of CD154 on peripheral CD4(+) cells from euthyroid patients with GD and HD, but we did not find any differences between patients with different disease severities. CD8(+) cells did not express CD154 molecules. Thus, CD154 expression on CD4(+) cells may be related to the pathogenesis of the autoimmune thyroid diseases, not to the disease severity.