Molecular Predictors for Advanced Papillary Thyroid Carcinoma Recurrence.

Despite its indolent course, one-third of the papillary thyroid carcinoma (PTC) cases relapses, which directly impact on the quality of patients' lives. The molecular predictors of recurrence of PTC are poorly defined. We aimed at evaluating the long-term (10-20 years) prognostic value of aggressiveness markers in advanced PTC. To this end, immunohistochemistry for BRAFV600E, Estrogen receptor α, Progesterone receptor, Ki-67, and E-cadherin were performed in 53 primary advanced PTC from an up to 20 years follow-up patients from a well-characterized Brazilian cohort. Categorical data were summarized using frequencies and groups were compared using Chi-squared and Fisher's exact tests. The expressions of the aggressiveness markers were associated with clinical-pathological data using the single-covariate logistic regression analysis. The Kaplan-Meier method with the Log-rank and Peto tests was used to estimate the probability of PTC-free survival. Persistence and recurrence (active disease) were associated with age (≥55 years), tumor size (>2 cm), extrathyroidal extension, local aggressiveness, macroscopic lymph node metastasis, and TNM stage at initial treatment. The BRAFV600E mutation status was associated with extrathyroidal extension, local aggressiveness, and inversely associated with distant metastasis at initial treatment. All progesterone receptor-positive patients had active disease and displayed a shorter time of PTC-free survival than the negative ones using the Kaplan-Meir analysis (p = 0.001, Log Rank; p = 0.005, Peto). Loss of E-cadherin expression was associated with an increase in the probability of active disease (OR = 3.75). BRAFV600E could be useful as a biomarker of local aggressiveness, while PR positive and E-cadherin loss of expression could predict the recurrence of advanced PTC.

NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells.

BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. METHODS: The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990-1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). RESULTS: NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. CONCLUSIONS: In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.

Predictors for papillary thyroid cancer persistence and recurrence: a retrospective analysis with a 10-year follow-up cohort study.

OBJECTIVE: We aimed to determine outcome predictors of papillary thyroid cancer (PTC) persistence and recurrence, separately. CONTEXT: The factors contributing to either persistence or recurrence of PTC are poorly defined, as both outcomes are usually evaluated together. DESIGN AND PATIENTS: In this 10-year follow-up cohort study, 190 PTC patients were evaluated (18-85 years old; registered from 1 January 1990 to31 December 1999 at a Brazilian Cancer Care referral Hospital). After initial surgery, we examined persistence (disease detected up to 1 year), recurrence (disease detected after 1 year) and PTC-free status (disease absence during follow-up). MEASUREMENTS: Outcome predictors were modelled using multinomial logit regression analysis. RESULTS: The univariate analysis showed that persistence and recurrence were significantly associated with lymph node metastasis (OR = 12·33; OR = 2·84, respectively), local aggressiveness (OR = 5·22; OR = 3·35) and extrathyroidal extension (OR = 5·07; OR = 7·11). Persistence was associated with male sex (OR = 3·49), age above 45 years old at diagnosis (OR = 1·03), macroscopic lymph node metastasis (OR = 5·85), local aggressiveness (OR = 5·22), each 1-cm tumour size increase (OR = 1·34), a cancer care referral hospital as the place of initial surgery (OR = 2·3), thyroidectomy or near total thyroidectomy(OR = 3·03) and neck dissection (OR = 3·19). Recurrence was associated with the time of radioactive iodine ((131) I) therapy (OR = 3·71). After data modelling, persistence was associated with macroscopic lymph node metastasis (OR = 6·17), 1-cm increases in tumour size (OR = 1·30) and thyroidectomy or near total thyroidectomy (OR = 3·82), while recurrence was associated with surgery at referral hospital (OR = 3·79). CONCLUSIONS: The best predictors of persistence were tumour size and macroscopic lymph node metastasis; when the initial surgery is of quality, the recurrence depends more on tumour's biology aspects.