Euy Young Soh

SURGICAL CONSIDERATIONS AND APPROACH TO THYROID CANCER

Patients with thyroid cancer can be safely treated by an experienced endocrine surgeon. More extensive initial surgery such as total or near-total thyroidectomy seems to decrease tumor recurrence and prolong life. When such operations can be done with minimal complications, we believe it is the treatment of choice because even low-risk patients have a 4% or 5% risk of eventually dying of thyroid cancer. If this risk of death from thyroid cancer can be decreased to 1% or 2% and the rate of serious complications is 1% or 2%, the authors believe total thyroidectomy is indicated. Most patients can be discharged within 1 day of total thyroidectomy.

Central Lymph Node Metastasis Is an Important Prognostic Factor in Patients with Papillary Thyroid Microcarcinoma

Papillary thyroid microcarcinoma (PTMC) has been increasing, without a consensus for the management of this condition. In the present study, we analyzed the clinicopathological features of patients with PTMC to examine the impact of initial therapy and establish appropriate treatment. A total of 2,018 patients with PTMC were enrolled at a single university hospital. Of them, 1,245 patients (61.8%) underwent total thyroidectomy, and 1,838 patients (91.3%) underwent central lymph node (LN) dissection. Five-and 10-yr recurrence rates were 3.2% and 4.6%, respectively. In univariate analysis, the prognostic factors for recurrence were N stage, the number of LN metastases, and extrathyroidal extension. However, multivariate analysis revealed LN metastases and N stage as the only significant prognostic factors after adjusting for confounding factors (P < 0.001). Additionally, multivariate analysis of a subgroup consisting of PTMC patients without N1b revealed the number of central LN metastases as the only significant factor. Therefore, intraoperative examination for central LN metastasis may discriminate high or low risk group.

The current status of endoscopic thyroidectomy in Korea.

We investigate the current status of endoscopic thyroidectomy in Korea. A representative questionnaire was sent to 21 members of the Korean Association of Endocrine Surgeons who were thought to be performing endoscopic thyroidectomy. All the reply letters were collected and analyzed. The response rate was 95%. A total of 1616 cases of endoscopic thyroidectomy were performed from the year 1998 to the year 2005. The patients included 71 men and 1545 women, with a mean age of 36.17 years. The mean operation time was 124.18 minutes and overall length of hospital stay was 4.31 days. Thyroid lobectomy and nodular hyperplasia were the most common procedures and prominent pathologic findings. Axillary approach was the most popular operative approach method. Gas insufflation and skin-lifting gasless method were used in 800 cases and 816 cases, respectively. Postoperative complication rate was 14.2%. Skin paresthesia was the most common complication. Conversion rate to conventional thyroidectomy was 2.2%. Korean experiences show that endoscopic thyroidectomy is a technically safe and feasible procedure. It is considered to be an important surgical tool that can be further progressed and that also has an excellent potential in a management of thyroid neoplasm.

VE1 Antibody Is Not Highly Specific for the BRAF V600E Mutation in Thyroid Cytology Categories With the Exception of Malignant Cases

OBJECTIVES We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the BRAF V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC). METHODS We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the BRAF mutation in these specimens matched with their corresponding histology. RESULTS Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%. CONCLUSIONS VE1 immunocytochemistry in thyroid FNAC as a screening test for BRAF mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases.

TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6.

B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E–induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E–induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E–induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E–induced papillary thyroid carcinogenesis.

B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40–70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.

Senescent tumor cells lead the collective invasion in thyroid cancer

Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC.

Cyclooxygenase-2 expression in human thyroid disease

Objectives: Cyclooxygenase (COX)-2, which is the inducible form of the COX enzyme for prostaglandin synthesis and a key mediator of epithelial cell growth, has been shown to be up-regulated in gastrointestinal cancers. Additionally, regular intake of other non-steroidal anti-inflammatory drugs (NSAID) is known to decrease the incidence of these cancers. Therefore, the goals of the present study were to determine the possible involvement of COX-2 in human thyroid diseases. Methods: We used immunohistochemical staining and Western blot analysis to characterize the expression of COX-2 proteins in thyroid tissues from 64 patients with thyroiditis, benign tumors, and malignant tumors with or without metastasis. Immunoreactivity scores were calculated by multiplication of the determined grades. Results: COX-2 proteins were not expressed in normal thyroid tissues. However, each type of tumor tissue showed intense bands of COX-2 protein expression in Western blot analyses, and the immunoreactivity scores were 7.67±1.17 (SD) for thyroiditis, 7.87±0.9 for benign tumors, 7.53±1.53 for follicular cancer, 7.63±1.11 for papillary cancer without metastasis, and 7.17±1.55 for papillary cancer with metastasis. No significant differences were found in the levels of COX-2 expression between different tumor tissue types. Conclusion: No significant correlations were observed between clinical and/or pathological characteristics of thyroid tumors and the intensity of COX-2 protein expression. In addition, we found no difference in COX-2 protein expression between thyroiditis and thyroid tumors. Thus, up-regulation of COX-2 protein synthesis in human thyroid diseases does not appear to be of clinical significance.

Desensitization in Normal and Neoplastic Human Thyroid Cell Lines

Abstract. Because some papillary thyroid cancers continue to grow when thyroid-stimulating hormone (TSH) levels are suppressed, we questioned whether desensitization (i.e., a decreased cAMP response to repeat stimulation with TSH) occurs in normal and neoplastic thyroid tissue. If desensitization does occur, is it similar or different in these human thyroid cells? Normal and papillary thyroid cancer cells from the same patient were cultured as we have previously described. Normal and neoplastic thyroid tissues responded to TSH (0.01–10.0 mU/ml) by increasing cAMP production and growth in a dose-dependent manner. In normal cells there was an 11-fold mean increase in cAMP production at 4 hours, and all thyroid cultures responded. In neoplastic cells cAMP production increased from 1.5-fold to 3.0-fold with a mean 2.0-fold increase at 4 hours. In normal thyroid cells the cAMP response to a second TSH stimulus (desensitization) decreased up to 75% (range 25–75%), and desensitization occurred in all normal thyroid cell cultures. In neoplastic thyroid cells, however, the cAMP response to a second TSH stimulus decreased up to 17% (range 0–17%); and desensitization occurred in only two of the five neoplastic thyroid cell cultures. Thus when normal thyroid and neoplastic cells from the same patients were studied, greater desensitization occurred in the normal cells (75% vs. 17%). These studies document that there is greater desensitization in normal tissue than in neoplastic thyroid tissue, which may account for the increased growth of thyroid neoplasms in the presence of ever-changing low levels of TSH.

Evaluation of the VE1 Antibody in Thyroid Cytology Using Ex Vivo Papillary Thyroid Carcinoma Specimens.

Background: Recently, VE1, a monoclonal antibody against the BRAFV600E mutant protein, has been investigated in terms of its detection of the BRAFV600E mutation. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in thyroid cytology samples is rarely performed, and its diagnostic value in cytology has not been well established. In present study, we explored VE1 immunoexpression in cytology samples from ex vivo papillary thyroid carcinoma specimens in order to minimize limitations of low cellularity and sampling/targeting errors originated from thyroid fineneedle aspiration and compared our results with those obtained using the corresponding papillary thyroid carcinoma tissues. Methods: The VE1 antibody was evaluated in 21 cases of thyroid cytology obtained directly from ex vivo thyroid specimens. VE1 immunostaining was performed using liquid-based cytology, and the results were compared with those obtained using the corresponding tissues. Results: Of 21 cases, 19 classic papillary thyroid carcinomas had BRAFV600E mutations, whereas two follicular variants expressed wild-type BRAF. VE1 immunoexpression varied according to specimen type. In detection of the BRAFV600E mutation, VE1 immunostaining of the surgical specimen exhibited 100% sensitivity and 100% specificity, whereas VE1 immunostaining of the cytology specimen exhibited only 94.7% sensitivity and 0% specificity. Conclusions: Our data suggest that VE1 immunostaining of a cytology specimen is less specific than that of a surgical specimen for detection of the BRAFV600E mutation, and that VE1 immunostaining of a cytology specimen should be further evaluated and optimized for clinical use.