Search

BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAF(V600E)-positive PTC.

Background: More than 80% of all thyroid cancers, the most common endocrine malignancy, are papillary thyroid cancer (PTC). It is well established that CITED1 (Cbp/p300 Interacting Transactivators with glutamic acid [E] and aspartic acid [D]-rich C-terminal domain) mRNA is characteristically overexpressed in PTC. Our previous study suggested a positive association of BRAF mutation with CITED1 overexpression. However, the mechanism of CITED1 expression in PTC remains to be elucidated. In the present study, we analyzed whether aberrant methylation of CITED1 gene promotes CITED1 overexpression in PTC., Method: CITED1 mRNA expression levels were analyzed by quantitative polymerase chain reaction in three PTC-derived cell lines, TPC1, K1, and KTC-1, and in surgically dissected PTC and surrounding normal tissues from 19 patients. The BRAF mutation status of the cells and clinical specimens was determined by direct sequencing. The methylation status of the deoxycitidine-phosphate-deoxyguanosine dinucleotides (CpGs) in the CITED1 promoter was analyzed by the bisulfite-sequencing method using genomic DNA. Finally, the expression of CITED1 mRNA in TPC1 cells, when subjected to pharmacological inhibition of methylation, was analyzed., Results: CITED1 mRNA was expressed at lower levels in TPC1 than in K1 and KTC-1 cells. A BRAF mutation was present in K1 and KTC-1 cells, but not in TPC1 cells. CITED1 promoter was hypomethylated in K-1 and KTC-1 cells, but not in TPC1 cells. In surgically dissected specimens, the mean expression level of CITED1 mRNA was 30-fold higher in PTC tissues than in normal tissues. CpGs in the CITED1 promoter were more heavily methylated in normal tissues than in PTC tissues. In PTC specimens without a BRAF mutation, two CpGs were more heavily methylated than in PTC specimens with the BRAF V600E mutation. Pharmacological inhibition of methylation in TPC1 cells by 5'-aza-2'-deoxycitidine resulted in increased expression of CITED1 mRNA., Conclusion: Hypomethylation of the CpGs in the promoter region of CITED1 is associated with higher expression of CITED1 mRNA in PTC tissues, consistent with the hypothesis that epigenetic regulation is involved in the overexpression of CITED1. This hypothesis is supported by pharmacologic inhibition studies in TPC1 cells.

The cysteine peptidase cathepsin B is important in thyroid physiology by being involved in thyroid prohormone processing initiated in the follicular lumen and completed in endo-lysosomal compartments. However, cathepsin B has also been localized to the extrafollicular space and is therefore suggested to promote invasiveness and metastasis in thyroid carcinomas through, e.g., ECM degradation. In this study, immunofluorescence and biochemical data from subcellular fractionation revealed that cathepsin B, in its single- and two-chain forms, is localized to endo-lysosomes in the papillary thyroid carcinoma cell line KTC-1 and in the anaplastic thyroid carcinoma cell lines HTh7 and HTh74. This distribution is not affected by thyroid stimulating hormone (TSH) incubation of HTh74, the only cell line that expresses a functional TSH-receptor. Immunofluorescence data disclosed an additional nuclear localization of cathepsin B immunoreactivity. This was supported by biochemical data showing a proteolytically active variant slightly smaller than the cathepsin B proform in nuclear fractions. We also demonstrate that immunoreactions specific for cathepsin V, but not cathepsin L, are localized to the nucleus in HTh74 in peri-nucleolar patterns. As deduced from co-localization studies and in vitro degradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.

Background: Monocyte chemotactic protein-1 (MCP-1) is a chemokine ligand that has been associated with aggressive behavior in breast and prostate cancer. The present study was performed to determine if there is a relationship between the expression of MCP-1 in papillary thyroid carcinoma (PTC) and factors indicative of aggressive behavior in this disease., Methods: The subjects of this study were 115 patients with PTC. MCP-1 expression was determined using a semiquantitative scoring system for immunohistochemical staining of MCP-1 in resected PTC samples. There were four levels of immunohistochemical staining intensity, and the population of cells that positively stained for MCP-1 was graded at four levels. The scores for the intensity of immunohistochemical staining for MCP-1 and for the percentage of cells that stained for MCP-1 were used to generate a range from 0 to 9 for scoring MCP-1 expression., Results: Positive staining for MCP-1 was observed in the cytoplasm of PTC cells and stroma cells in 79.2% of the specimens. Expression levels of MCP-1 in PTC cells were positively correlated with tumor size (p < 0.05) and lymph node involvement (p < 0.05). In addition, the expression of MCP-1 in PTC cells level was an independent predictive factor for recurrence of PTC in an analysis that included age, sex, tumor size, extrathyroidal infiltration, and lymph node involvement (p < 0.005)., Conclusions: MCP-1 expression in PTC may stimulate the aggressive behavior of this tumor or it may be a marker for aggressive behavior. Previous reports with non-thyroid tumor cells favor the hypothesis that MCP-1 expression promotes aggressive behavior in PTC.

BRAF (7q24) encodes a serine/threonine protein kinase, and its expression level varies in different tissues. Although a high prevalence of BRAF mutation has been suggested as an important event in thyroid tumorigenesis, little is known about the expression pattern of B-Raf in the thyroid. Thus, we examined the expression of B-Raf in various neoplastic and nonneoplastic thyroid tissues and compared it with BRAF mutational status. Normal and hyperplastic thyroid tissues showed focal and faint immunoreactivity for B-Raf, especially in cuboidal follicular cells of small follicles. In contrast, diffuse expression of B-Raf was observed in follicular adenomas and well-differentiated carcinomas. The missense point mutation BRAF(V600E) was identified in 42% (13/31 cases) of papillary carcinomas and 33% (5/15 cases) of undifferentiated carcinomas but not in normal thyroid tissues, nodular hyperplasia, follicular adenomas, or follicular carcinomas. The immunohistochemical expression of B-Raf did not correlate with BRAF mutational status. Moreover, Western blotting revealed that B-Raf expression in thyroid carcinoma cell lines was also independent of BRAF mutation. Serum or fibroblast growth factor-1 stimulation further activates ERK1/2 in heterozygous BRAF(V600E)-positive carcinoma cells as well as BRAF(V600E) mutation-negative carcinoma cells. In conclusion, heterogeneous focal expression of wild-type B-Raf in nonneoplastic tissues may play a role in the growth or functional activity of thyroid follicular cells. In contrast, diffuse expression of wild-type and/or mutant B-Raf may be involved in the tumorigenic process resulting in activation of the mitogen-activated protein kinase signaling pathway in cooperation with other genetic abnormalities and activation of ligand-receptor signaling pathways.

Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase (MAPK). Here, we show that FGF receptor 1 (FGFR1), which is expressed mainly in neoplastic thyroid cells, propagates MAPK activation and promotes tumor progression. In contrast, FGFR2 is down-regulated in neoplastic thyroid cells through DNA promoter methylation. Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway. These data unmask an epigenetically controlled FGFR2 signal that imposes precisely on the intragenically modified BRAF/MAPK pathway to modulate thyroid cancer behavior.

We report three radioiodine-resistant patients with metastatic papillary thyroid carcinoma administered docetaxel. Patient 1: Bi-weekly docetaxel was administered to a 67-year-old woman with clavicle, cervical lymph node and lung metastases that had progressed after external irradiation and radioiodine therapy. Stable disease was maintained for 18 months without elevation of serum thyroglobulin. Patient 2: Bi-weekly docetaxel was administered to a 72-year-old man with lung metastases that had progressed after radioiodine therapy. Stable disease was maintained for 14 months. Patient 3: Bi-weekly docetaxel was administered to a 58-year-old woman with lung metastases that had progressed after radioiodine therapy. Stable disease was maintained for 18 months with slight reduction of serum thyroglobulin. In all three patients, doubling time of tumor growth was revealed to be far prolonged after docetaxel administration without distinct adverse events. Since no effective systemic treatment has been established for radioiodine-resistant patients with metastatic papillary thyroid carcinoma,docetaxel therapy was supposed to be a viable alternative for them.

Purpose: This retrospective study analyzes the predictive factors after curative surgery for papillary thyroid carcinoma (PTC)., Methods: We analyzed 386 patients who underwent a curative operation for PTC in our hospital between 1977 and 1997, subject to the inclusion criteria., Results: According to univariate analysis, pathological lateral cervical lymph node involvement (P < 0.0001), dedifferentiation of the tumor (P < 0.002), male sex (P < 0.0001), a large tumor (P < 0.005), and an age of over 50 years (P < 0.05) were significant factors. Cox's proportional hazard model showed that a man (P < 0.05), aged over 50 years (P < 0.05), who had a large primary tumor (P < 0.05) with dedifferentiation (P < 0.05), and pathological lateral cervical lymph node metastasis (P < 0.005) was more likely to have recurrence of PTC., Conclusions: Determining whether lymph node metastasis exists could be useful for predicting recurrence in patients who have undergone curative resection of PTC.

Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nm. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH(2) terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.

To establish a molecular targeting therapy for anaplastic thyroid carcinomas, we studied the effect of the specific tyrosine kinase inhibitor, STI571, on anaplastic thyroid cancer cell lines highly expressing c-ABL ARO (mutated p53) and FRO (undetectable p53). These lines showed marked inhibition of cell growth after treatment with STI571. In contrast, the growth of papillary thyroid cancer cell lines that harbor wild-type p53 and have low levels of c-ABL was not affected by STI571. Fluorescent-activated cell sorting analysis revealed that STI571 treatment increased the fraction of FRO and ARO cells in S and G(2)/M phases, respectively, indicating induction of S and G(2)/M transition arrest. These changes were accompanied by inhibition of c-ABL phosphorylation/activation and increased expression of p21(cip1) in FRO and p27(kip1) in both FRO and ARO cells. Treatment with STI571 also led to reduction of cyclin A, B1, and CDC2 levels. The growth of FRO cells implanted into immunocompromised mice was significantly inhibited by STI571. Taken together, these results suggest that selective suppression of c-ABL activity by STI571 may represent a potential anticancer strategy for p53-mutated undifferentiated thyroid carcinomas.

A new thyroid cancer cell line, KTC-2, was established from the malignant pleural effusion of a patient with recurrent thyroid cancer associated with anaplastic transformation from thyroid papillary cancer. Karyotype analysis showed a mode of 109 chromosomes. Subcutaneous cell injections produced small regressing tumors in athymic or severe combined immunodeficiency disorders (SCID) mice. Histologic examination showed anaplastic tumor cells surrounded by prominent mononuclear cells. An expression of thyroglobulin, thyroid transcription factor-1, and PAX-8 but not thyroid peroxidase and thyrotropin (TSH) receptor was detected. Biochemical analysis revealed secretion of interleukin (IL)-6, parathyroid hormone-related protein (PTHrP), and granulocyte-macrophage colony-stimulating factor. All the cytokines are known to induce paraneoplastic syndromes in patients with anaplastic thyroid cancer. Our previous studies revealed that medroxyprogesterone acetate (MPA) reduces secretion of IL-6 and PTHrP from human breast cancer cells. To investigate the regulatory mechanisms of secretion of these cytokines, MPA was administered to the KTC-2 cells. MPA dose-dependently decreased the secretion and mRNA expression of IL-6 and PTHrP. Expression of androgen receptor and glucocorticoid receptor (GR) but not progesterone receptor was detected. Dexamethasone but not dihydrotestosterone and progesterone decreased IL-6 and PTHrP secretion. These findings suggest that MPA decreases IL-6 and PTHrP secretion as a glucocorticoid mediated by GR in the KTC-2 cells. This KTC-2 cell line may be a suitable model for developing new strategies against paraneoplastic syndromes caused by anaplastic thyroid cancer.

We report a unique case of metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia. A 48-year-old man was referred to our hospital for treatment of a thyroid tumor and right submandibular masses. A tumor, 2 cm in its largest dimension, was palpated in the right lobe of the thyroid gland. The masses in the submandibular region measured up to 3 cm in diameter. Each submandibular tumor had a cystic cavity containing slightly opaque fluid. Aspiration cytology of the thyroid established a diagnosis of papillary carcinoma. Aspirated material from the cystic cavity of one of the submandibular masses contained only keratinized material with a thyroglobulin level of 175 ng/ml. The patient underwent a total thyroidectomy with modified radical neck dissection. Microscopic examination of the resected specimen confirmed a diagnosis of papillary carcinoma of the thyroid, as well as well-differentiated squamous cell carcinoma with cystic changes in the submandibular lymph nodes. Focal immunoreactivity for thyroglobulin, combined with the absence of any other possible primary lesions in the head and neck region, suggested metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia.

Purpose: Angiogenesis is essential for tumor growth and is controlled by the balance between angiogenic and antiangiogenic factors. We studied the expression of angiogenic factors and antiangiogenic factors in papillary thyroid carcinoma., Experimental Design: We investigated immunohistochemically the expression patterns and levels of antiangiogenic factor and its receptor, thrombospondin-1 (TSP-1) and CD36, and four angiogenic factors, vascular endothelial growth factor (VEGF), VEGF-C, angiopoietin-2 (Ang-2), and Tie-2, in the primary tumors of 75 papillary thyroid carcinoma patients. We also examined the microvessel count (MVC), using CD31 staining., Results: VEGF expression strongly correlated with other angiogenic factors. The cytoplasm of cancer cells stained positive for all factors. Tie-2 and TSP-1 receptor also appeared in endothelia of microvessels. TSP-1 inversely correlated with the degree of invasion of the primary tumor to other adjacent organs and with MVC. A higher MVC correlated with poorer survival. To clarify the balance between angiogenic and antiangiogenic factors in the same tumor, we calculated the ratio of each angiogenic factor against TSP-1 as the antiangiogenic factor. The ratios VEGF/TSP-1, VEGF-C/TSP-1, and Ang-2/TSP-1 significantly correlated with a higher MVC. Furthermore, the ratios VEGF/TSP-1 and Ang-2/TSP-1 significantly correlated with the degree of infiltration., Conclusions: To the best of our knowledge, this is the first report demonstrating that the balance between angiogenic and antiangiogenic factors correlates with distinct invasion to other organs and neovascularization of papillary thyroid carcinoma.

Purpose: Four different factors have recently been identified in the vascular endothelial growth factor (VEGF)family, namely, VEGF-A, VEGF-B, VEGF-C, and VEGF-D. We investigated the expression of each VEGF gene in diseased thyroids using the multiplex reverse transcription-polymerase chain reaction (RT-PCR) method., Methods: The subjects were 61 patients (11 with Graves' disease, 41 with primary papillary carcinoma, and 9 with recurrent papillary carcinoma). A semiquantitative multiplex RT-PCR was designed to compare the RT-PCR products of each VEGF mRNA with beta-actin mRNA products to determine the relative expression., Results: VEGF-A and VEGF-B mRNA were expressed in all patients, VEGF-C mRNA was expressed in 58 (95.1%), and VEGF-D mRNA was expressed in 28 (46.0%). The expression of VEGF-D mRNA was significantly lower than that of the other VEGF mRNAs. The patients with papillary carcinoma and nodal involvement had significantly higher expression of the VEGF-C mRNA than those without nodal involvement. The expression of VEGF-C mRNA did not directly represent nodal involvement; however, the number of metastatic lymph nodes was positively correlated with the expression of VEGF-C mRNA in the primary tumor., Conclusions: To our knowledge, this is the first clinical study on VEGF-B, VEGF-C, and VEGF-D mRNA expression in diseased thyroids. Although VEGF-C mRNA expression was required for nodal involvement, we assume that other factors and mechanisms are also involved.

Background and Objectives: Differences in the expression levels of Thyroglobulin (Tg), Thyroid peroxidase (TPO) and thyrotropin receptor (TSH-R) in primary and recurrent specimens under a suppressive serum TSH condition were elucidated in 26 papillary carcinoma patients., Methods: Immunohistochemical detection was performed by use of each monoclonal antibody against Tg, TPO, and TSH-R. The staining concentrations of the three markers in each specimen were measured for comparison., Results: The mean staining concentrations of Tg, TPO, and TSH-R in the entire primary tumor were 103.92, 104.6 and 89.25, respectively. Five cases showed stronger expression of all the differentiation markers and eight cases showed weaker expression of all these markers in recurrent tissue than in primary tumors. The weaker expression of TSH-R at the recurrent site as compared with that at the primary site significantly demonstrated the shortness of the disease free interval or overall survival. There were significant differences between the death due to cancer and the weaker expression of TSH-R in the recurrent tumor as compared with that in the primary tumor., Conclusions: Under the TSH suppressive condition, the markers were not expressed uniformly among recurrent tumors. Even under that state, however, low expression of TSH-R in the recurrent tissue was strongly related to a poorer outcome in the patients., (Copyright 2000 Wiley-Liss, Inc.)

A new human thyroid carcinoma cell line, KTC-1, was established from the malignant pleural effusion of a recurrent thyroid carcinoma patient. Cytogenetic analysis revealed a normal karyotype, and no p53 mutation in exons 5-9 was detected. This cell line is tumorigenic in athymic nude mice. Histological findings by light and electron microscopy, such as the absence of follicular structures and the existence of intranuclear cytoplasmic inclusions and psammoma bodies, indicated transplanted tumors to be a poorly differentiated papillary thyroid carcinoma. A low expression level of thyroglobulin was detected by immunocytochemistry and RT-PCR. Messenger ribonucleic acid (mRNA) expression of thyroid transcription factor-1 and PAX-8 was also detected. No mRNA expression of TSH receptors, thyroid peroxidase, or Na+/I- symporter was detected. Interleukin-6 and leukemia inhibitory factor were secreted into the medium. These findings suggest this cell line to be functionally poorly differentiated. Moreover, all-trans-retinoic acid increased the mRNA expression of thyroglobulin and decreased both the mRNA expression and secretion of interleukin-6 and leukemia inhibitory factor while significantly stimulating growth. RT-PCR analysis of retinoic acid receptors (RARs) revealed that KTC-1 cells express a moderate level of RARalpha and -gamma, but a low level of RARbeta. This cell line may be useful for studying redifferentiation therapy for thyroid carcinoma.

Objective: To investigate the levels of expression of the sodium iodide symporter (NIS) and three differentiation markers (thyroglobulin (Tg), thyroid peroxidase (TPO) and thyrotrophin receptor (TSH-R)) in 35 patients with primary (n=31) or recurrent (n=4) papillary thyroid carcinoma, and to compare the findings with clinical data., Methods: We performed a multiplex semi-quantitative RT-PCR to analyse the relative levels of expression of Tg, TPO and TSH-R mRNAs, and a separate semi-quantitative RT-PCR for NIS mRNA., Results: Tg, TPO and TSH-R mRNAs were expressed in all the patients, whereas NIS mRNA was expressed in all but eight. Analysis of the expression of the differentiation markers in all patients showed a significant correlation among Tg, TPO and NIS. With regard to the relationship between the expression of each gene and the MACIS score, there was significant correlation only for the Tg gene (P<0.05)., Conclusions: The levels of expression of NIS mRNA correlated significantly with those of Tg and TPO mRNAs, but not with those of TSH-R mRNA. The relationship with clinical stage and prognostic score, however, varied among these differentiation markers.

We retrospectively analyzed the outcome for patients with locally invasive papillary carcinoma. The study group comprised 40 patients with locally invasive papillary thyroid carcinoma first diagnosed between 1981 and 1995. The enrolled patients were divided into two groups according to whether they underwent complete resection (n = 19) or not (n = 21). All patients were followed-up for a maximum of 206 months and a minimum of 33 months until 1998. There were no significant differences among these two groups with regard to age, sex, or tumor size. Recurrence of the disease was recognized in four patients in the complete resection group and ten in the incomplete group. There were no significant differences in the recurrence rate between both groups. Five patients from the incomplete resection group died of disease, and all patients from the complete resection group were alive. The percentage of surviving patients in the complete resection group was significantly higher than that in the incomplete group. The 15-year survival rates of the complete resection group and incomplete resection group were 100% and 74.2%, respectively. The 15-year survival rate of patients younger than 45 years in the incomplete resection group was 100%. The 15-year survival rate of the complete resection group was significantly higher than that of the incomplete group. In conclusion, complete resection without tumor residue should be performed for patients older than 45 years.

Mass screening for detecting both thyroid and breast cancer in adult women was carried out in Gunma Prefecture, Japan, between 1980 and 1986. The total number of subjects during the seven years was 152,651. The first screening was by inspection and palpation using experienced surgeons. Thyroid abnormalities were found in 5,902 subjects (3.9%) and 3,804 (2.5%) were required to attend a second examination. Thyroid carcinoma was detected in a total of 216 subjects, a detection rate of 0.14%. The detection rate for thyroid cancer was twice as high at the initial screening (0.19%) than that at subsequent periodic screenings (0.09%). Histological classifications of the detected thyroid cancers were: papillary carcinoma, 189 cases (87.5%); follicular carcinoma, 26 (12%); medullary carcinoma, 1 (0.5%). Eighty-seven percent of the thyroid cancers were asymptomatic at the time of screening. The tumor size were 2 cm or less in 126 patients (58.3%). Thyroid cancer detected by mass screening was revealed at an earlier stage and showed a significantly better survival rate compared to that of our usual outpatients. As differentiated carcinoma has been found at a higher incidence by mass screening, the program is useful for the early detection and treatment of thyroid cancer.