Detection of interleukin-6 levels in serum and thyroid tissue of patents with papillary thyroid carcinoma and their significances / 吉林大学学报(医学版)

Objective: To investigate the relationship between interleukin-6 (IL-6) and papillary thyroid carcinoma (PTC), and to elucidate the role of IL-6 in the occurrence and development of PTC and its possible mechanism Methods: The serum levels of IL-6 were measured by ELISA method in 5 patients with PTC (case 1 group), 5 patients with Hashimoto thyroiditis (HT) complicated with PTC (case 2 group) and 5 normal persons (normal group). The thyroid tissues of 20 patients with PTC (PTC group), 15 patients with HT complicated with PTC (HT +PTC group) and 18 normal persons (control group) were collected. The positive expression rates of IL-6, IL-6 receptor (IL-6R), nuclear factor kappa-B (NF-κB) and RET/PTC proteins in thyroid tissue of the subjects in various groups were detected by immunohistochemistry (IHC) method; the relationships between IL-6, IL-6R and NF-kB, RET/PTC expressions were analyzed. Results: In the patients with PTC, the complex papillary hyperplasia of thyroid epithelial cells accompanying with ground glass like nuclei and nuclear sulcus and inclusions were seen; in the patients with HT complicated with PTC, in addition to the typical pathological changes of PTC, the diffuse lymphoid tissue infiltration accompanying with lymphoid follicle formation, and the coexistence of hyperplasia and atrophic thyroid follicular epithelium with eosinophic degeneration of thyroid epithelium and interstitial fibrosis were also found. The lobular structrure of normal thyroid tissue was found, and the follicular cells were in the same size The ELISA results showed that the serum IL-6 levels of the patients in PTC group and HT+ PTC group were higher than those in normal group (P<0. 05); the IHC results showed that the positive expression rates of IL-6, IL-6R, NF-κB, and RET/PTC in thyroid tissue of the patients in PTC group were higher than those in control group (P<0. 05). The expressions of IL-6, and IL-6R were positively correlated with the expressions of NF-kB and RET/PTC protein (P<0. 05). Conclusion: IL-6 may be involved in the occurrence and development of PTC through the RET/PTC-NF-B signal pathway.

Prevalência de tireoidite de Hashimoto em casos de carcinoma papilífero de tireoide / Prevalence of Hashimoto's thyroiditis in cases of papillary thyroid carcinoma

OBJETIVO: Avaliar a prevalência da coexistência entre tireoidite de Hashimoto em casos de carcinoma papilífero de tireoide. MATERIAL E MÉTODOS: Foi realizado um estudo retrospectivo a partir dos arquivos eletrônicos do Centro de Patologia de Curitiba ­ Hospital Nossa Senhora das Graças ­ Curitiba, PR, no qual foram analisados 139 laudos histopatológicos de pacientes submetidos a tireoidectomia com diagnóstico de carcinoma papilífero de tireoide, do período de dezembro de 2010 a maio de 2013. RESULTADOS: Os resultados mostraram uma prevalência do gênero feminino (80,6%) e uma média de idade dos pacientes de 43,5. A variante de carcinoma papílifero mais frequente foi o tipo clássico (47,5%) e a que foi mais associada com tireoidite de Hashimoto foi o tipo microcarcinoma (55%). CONCLUSÃO: A prevalência de tireoidite de Hashimoto entre pacientes com carcinoma papilífero foi de 39,6%, a mesma ocorreu mais em mulheres, a média de idade foi de 43,5 anos e o subtipo histológico de carcinoma papilar mais associado foi o microcarcinoma

AIM: To evaluate prevalence of Hashimoto's thyroiditis in cases of papillary thyroid carcinoma. MATERIAL AND METHODS: We conducted a retrospective study from the electronic files of the Centro de Patologia de Curitiba ­ Hospital Nossa Senhora das Graças - Curitiba, PR, analyzing 139 histopathological examinations of patients who were submitted by a thyroidectomy diagnosed with papillary thyroid carcinoma, from the time of December's 2010 to May´s 2013. RESULTS: The result has shown a prevalence of the female gender (80.6%), and an average age of 43.5. The papillary carcinoma variant of higher frequency was the classic type (47.5%), and the microcarcinoma type was the more associated (55%) with the Hashimoto´s thyroiditis. CONCLUSIONS: The prevalence of Hashimoto's thyroiditis in patients with papillary carcinoma was 39.6%, it was more in females, the average age was 43.5 years and the histological subtype of papillary carcinoma was the most associated is the microcarcinoma

Comparison of orthotropic models of RET/PTC1 rearrangement and BRAFV600E mutation papillary thyroid cancer cell lines in nude mice / 中华内分泌代谢杂志

Objective To observe and compare the different orthotopic models of papillary thyroid cancer ( PTC) cell lines of RET/PTC1 rearrangement and BRAFV600E mutation in nude mice. Methods Human PTC cell lines TPC-1, BHP5-16 and BHP2-7 were used. The genotypes of RET/PTC1 rearrangement and BRAFV600E mutation were determined by realtime-PCR and DNA sequencing analysis. The cells(2×105) were injected into the thyroid gland of nude mice. The nude mice were executed at 4th, 12th week, and then their thyroid tumors were removed and weighed. The levels of thyroid hormone were detected using chemiluminescent immunoassay. Results Both TPC-1 and BHP2-7 cells were identified as RET/PTC1 rearrangement by real time-PCR, and the expression of RET/PTC1 rearrangement in BHP2-7 cell was higher than that of TPC-1 cell. BRAFV600E mutation was found in BHP5-16 cell by DNA sequencing analysis, but was not found in TPC-1 and BHP2-7 cells. There were different characteristics in three orthotopic nude model groups. Tumorigenic rates of TPC-1 and BHP5-16 groups were 100%, but the growth of tumor was more rapid in BHP5-16 group than that in TPC-1 group, with more weight tumor. The changes of thyroid hormone levels in BHP5-16 group and TPC-1 group were the same, which were normal at 4th week and sharply decreased at 12 th week(P0. 05). Conclusions It showed difference in the orthotopic models of PTC cell lines of RET/PTC1 rearrangement and BRAFV600E mutation in nude mice. BRAFV600E mutation has obvious impacts on increasing tumorigenic rate and promotion of tumor growth in the orthotopic model. It should not be ignored that advanced thyroid tumor will lead to the destruction of thyroid function.

Analysis of the factors associated with clinicopathological characteristics of papillary thyroid carcinoma / 中华内分泌代谢杂志

Objective BRAFV600E mutation, RET/PTC rearrangement, and the concomitant of Hashimoto's thyroiditis(HT) could influence clinicopathological features of papillary thyroid carcinoma (PTC).This study is to investigate the distribution of three factors in PTC and to analyze their associations with clinicopathological characteristics.Methods Fine-needle aspiration samples were collected in a total of 122 conventional PTC patients, who were confirmed by surgery.The clinicopathological features were collected to analyze its association with different factors.BRAFV600E mutation and RET/PTC rearrangement were detected by pyrosequencing and Taqman-qPCR, respectively.Results BRAFV600E mutation was significantly correlated with an older age and a less coexistence with HT(P＜0.05).In contrast, RET/PTC rearrangement was more prevalent in young patients and was associated with the concomitant of HT(P＜0.05).In the age of ≥20 year and＜45 year groups, BRAFV600E mutation was significantly associated with extrathyroidal invasiveness.RET/PTC rearrangement was significantly associated with bilateral lymph node metastasis and the number of metastatic lymph node.Conclusions The distribution of three factors were different in PTC patients.In addition to the age at diagnosis, all of three factors should also be considered together to analyze the association of clinicopathological features of PTC.

Mutation Profile of Well-Differentiated Thyroid Cancer in Asians

Recent advances in molecular diagnostics have led to significant insights into the genetic basis of thyroid tumorigenesis. Among the mutations commonly seen in thyroid cancers, the vast majority are associated with the mitogen-activated protein kinase pathway. B-Raf proto-oncogene (BRAF) mutations are the most common mutations observed in papillary thyroid cancers (PTCs), followed by RET/PTC rearrangements and RAS mutations, while follicular thyroid cancers are more likely to harbor RAS mutations or PAX8/peroxisome proliferator-activated receptor gamma (PPARgamma) rearrangements. Beyond these more common mutations, alterations in the telomerase reverse transcriptase (TERT) promoter have recently been associated with clinicopathologic features, disease prognosis, and tumorigenesis in thyroid cancer. While the mutations underlying thyroid tumorigenesis are well known, the frequency of these mutations is strongly associated with geography, with clear differences reported between Asian and Western countries. Of particular interest is the prevalence of BRAF mutations, with Korean patients exhibiting the highest rate of BRAF-associated thyroid cancers in the world. Here, we review the prevalence of each of the most common mutations in Asian and Western countries, and identify the characteristics of well-differentiated thyroid cancer in Asians.

Clinical implications of rearrangements during transfection of papillary thyroid cancer (RET/PTC) 1,3 detected with FQ-PCR in fine-needle aspiration specimen of thyroid nodules / 中华内分泌代谢杂志

Objective To evaluate the clinical significance of rearrangements during transfection of papillary thyroid cancer (RET/PTC) 1,3 in fine needle aspiration (FNA) specimen from regional thyroid nodules by FQ-PCR.Methods Two hundred and eighty-five FNA samples were collected from patients with thyroid nodules during January 2012 to January 2013.RET/PTC1,3 rearrangements were detected with FQ-PCR.Results The frequencies of the RET/PTC1 and RET/PTC3 rearrangements in 285 FNA samples were 17.2％ (49/285) and 1.4％ (4/285),respectively.During 21.7 months of follow-up,19 (40.4％,19/47) RET/PTC1 positive patients were confirmed to have papillary thyroid carcinoma(PTC) after operation.In the patients with RET/PTC1 rearrangement PTC was found in Thy5 and Thy4 groups.In Thy 2 group,22.6％ cases with RET/PTC1 rearrangements developed PTC as compared with 3.2％ cases without it(x2 =6.667,P＜0.01).In addition,8.5％ (4/47) RET/PTC1 rearrangements emerged in benign lesions.Conclusions It is convenient and reliable to detect RET/PTC1,3 rearrangements by FQ-PCR using FNA samples.RET/PTC1 rearrangement frequently occurs in PTC,however it would be detected in benign lesions occasionally.

Cáncer de tiroides y síndromes polipósicos intestinales Síndrome de Gardner / Thyroid cancer and intestinal polyposis syndromes Gardner syndrome

Resumen Presentamos el caso de una mujer de 22 años de edad, evaluada debido a que en su historia familiar a su madre se le encontró carcinoma de colon sigmoide. A la paciente se le diagnosticó poliposis colónica, que resolvió tras remoción endoscópica de las lesiones. Se realizó estudio de nódulo tiroideo y se realizó tiroidectomía total encontrándose un carcinoma papilar de tiroides como diagnóstico definitivo. Hicimos una revisión de la literatura. (Acta Med Colomb 2013; 38: 182-185).

Abstract We report the case of a 22-year-old woman evaluated because in her family history his mother had a sigmoid colon carcinoma. The patient was diagnosed with colonic polyposis, which resolved after endoscopic removal of the lesions. We made the study of a thyroid nodule and performed total finding a papillary thyroid carcinoma as definitive diagnosis. (Acta Med Colomb 2013; 38: 182-185).

The correlation between BRAF mutations, RET/PTC rearrangements and platelet-derived growth factor B expression in papillary thyroid carcinomas / 中华内科杂志

Objective To investigate the prevalence of BRAF T1799A mutation and RET/PTC rearrangement in Qingdao and detect the expression of platelet-derived growth factor B (PDGF-B) in order to investigate the correlation between gene mutation and PDGF-B.Methods Fresh tissue from 48 papillary thyroid carcinomas (PTC) patients was examined for BRAF mutation RET rearrangements (RET/PTC1 and RET/PTC3) by PCR,followed by direct-sequence analysis.The expression of PDGF was analyzed by immunohistochemistry.Results Among the 48 patients,14 (29.2％) were micro PTC; 18 (37.5％) had BRAF T1799A mutations and 23(47.9％) had RET/PTC rearrangement.There were 17 (35.4％) cases of RET/PTC1 and 6 (12.5％) of RET/PTC3,with no multiple rearrangements.Both BRAF T1799A mutation and RET/PTC rearrangement were present in 6 (12.5％) cases of non-micro PTC.The level of PDGF-B expression in BRAF T1799A positive was higher than that in the negative,and the level of PDGF-B expression in RET/PTC3 was higher than that in RET/PTC1 (P ＜ 0.05).The more advanced neoplasm stage was,the stranger PDGF-B expression was.Conclusions The incidence of BRAF T1799A mutation and RET/PTC rearrangement is higher in Qingdao.BRAF T1799A mutation and RET/PTC3 rearrangement in patients suggests a poorer prognosis than the negative one.The BRAF T1799A mutation and RET/PTC3 rearrangement may strengthen the expression of PDGF-B.Both variations suggest a poor prognosis.

Synergistic growth inhibition of cancer cells harboring the RET/PTC1 oncogene by staurosporine and rotenone involves enhanced cell death.

TPC-1 is a highly proliferative thyroid papillary carcinoma-derived cell line. These cells express the RET/PTC1 fusion protein, whose isoforms are characterized in this work. The bacterial alkaloid staurosporine and the plant extract rotenone are death-inducing drugs that have an inhibitory synergistic effect on the growth of TPC-1 cells. We show that this synergism is accompanied by an enhancement of the induction of cell death. Staurosporine alone induces cell cycle arrest in G1, whereas rotenone induces arrest in G2/M. We suggest that this additive pressure may drive cells to die, resulting in the synergistic interaction of the drug combination. These data emphasize the potential use of the staurosporine plus rotenone combination as an anticancer tool.

20 years of RET/PTC in thyroid cancer: clinico-pathological correlations

The RET/PTC oncogene has been isolated almost twenty years ago. During these years, the research has given a final answer to several questions. In fact, it has been demonstrated that: a) RET/PTC is an early event in the process of thyroid carcinogenesis and has a critical role in the generation of the papillary carcinoma; b) RET/PTC activation is essentially restricted to the papillary histotype and to the Hürthle thyroid tumors; c) its incidence increases after exposure to radiations. However, some questions have not found a final answer yet: a) which is the real frequency of RET/PTC activation? Likely it is around 20 percent, but this point is still questionable; b) which other gene modifications are required to lead a thyroid cell carrying a RET/PTC oncogene to the malignant phenotype?, and c) is there any correlation between RET/PTC activation and clinical parameters? We hope that these questions will have a clear answer in the near future.

O oncogene RET/PTC foi isolado há quase 20 anos atrás. Durante esses anos de pesquisa várias questões foram solucionadas. Na verdade, já foi demonstrado que: a) o RET/PTC é um evento precoce no processo da carcinogênese da tiróide e tem um papel crítico na geração do carcinoma papilífero; b) a ativação do RET/PTC está restrita essencialmente ao histotipo papilar e aos tumores de Hürthle; c) sua incidência aumenta após a exposição à radiação. Entretanto, algumas questões permanecem ainda sem uma resposta final: a) qual é a real freqüência de ativação do RET/PTC? Provavelmente em torno de 20 por cento, mas este número ainda é questionável; b) quais outras modificações gênicas são necessárias para transformar uma célula tiroidiana que possui oncogene RET/PTC no fenotipo maligno?; e c) existe alguma correlação entre a ativação do RET/PTC e parametros clínicos? Esperamos que essas questões sejam solucionadas em futuro próximo.