Clinicopathological Predictors of Recurrence in Papillary Thyroid Carcinoma

A retrospective cohort study was conducted with the aim of evaluating the risk of recurrence in relation to age (cut-off: 55 years), sex, tumor diameter, histological subtype (aggressive vs non-aggressive), vascular invasion, capsular invasion, muscular invasion, the presence of thyroiditis, multifocality and overall stage.

For each patient, demographic and clinicopathological data were collected, including age, sex, type of surgery (total thyroidectomy ± central/lateral neck dissection), histological subtype of PTC, presence of thyroiditis (as defined by histological examination), vascular invasion, capsular invasion (histological involvement of the thyroid capsule), muscular invasion (defined as gross extrathyroidal extension limited to the prethyroid strap muscles), tumor multifocality (presence of two or more distinct PTC foci, whether ipsilateral or contralateral to the dominant tumor) , lymph-node status, TNM classification, and final pathological stage (assigned according to the 8th edition of the AJCC TNM classification system). Recurrence and disease-specific mortality were also evaluated. Recurrence was defined as any biochemical or structural evidence of disease arising after the achievement of an initial disease-free status. For patients who developed recurrence, follow-up ended at the time of recurrence, which was considered the event endpoint.

Surgical management included hemithyroidectomy in patients with indeterminate cytology, and total thyroidectomy in cases with multinodular goiter or cytological findings suspicious for or diagnostic of malignancy, according to the cytological classification and clinical guidelines in force at the time of treatment. Patients with TIR 4 or TIR 5 cytology underwent concomitant central compartment lymph node dissection (CLND), whereas patients with TIR 3b cytology or multinodular goiter did not. Lateral neck dissection was performed in all patients with radiological evidence of lymph node metastases. Postoperative management and follow-up were conducted in accordance with the international and national guidelines in force during the study period. Routine follow-up included serial serum thyroglobulin measurements and neck ultrasonography. Postoperative treatment included radioiodine therapy in patients with aggressive histological subtypes and/or advanced stage disease. All patients received suppressive therapy with levothyroxine sodium for a minimum of 5 years.

All histopathological examinations were performed by a dedicated endocrine pathologist with more than 10 years of experience. Histological subtypes of PTC were categorized as aggressive (solid, columnar cell, diffuse sclerosing, hobnail and tall cell subtypes - PTC-sol, PTC-col, PTC-sc, PTC-h and PTC-t.c, respectively) or non-aggressive (classic, follicular, oncocytic, Warthin-like, and ossifying subtypes - PTC-c, PTC-f, PTC-onco, PTC-W, and PTC-oss, respectively), according to established morphological criteria. Tumor size, based on histological examination, was stratified into three categories: ≤1 cm, >1-2.5 cm, and >2.5 cm.

Statistical analysis Categorical variables were expressed as absolute and relative frequencies. The association between clinicopathological variables and recurrence was initially evaluated using Pearson's chi-squared test or Fisher's exact test, as appropriate. Tumor diameter was analyzed as a categorical variable with three levels (≤1 cm, >1-2.5 cm, and >2.5 cm). The significance threshold was set at p < 0.05. To identify independent predictors of recurrence, a multivariable logistic regression model was constructed including age group (<55 vs ≥55 years), sex, tumor diameter, histological subtype (aggressive vs non-aggressive), vascular invasion, capsular and/or muscular invasion, thyroiditis, multifocality, and AJCC stage. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.

To assess the association between concomitant thyroiditis and the histopathological features of papillary thyroid carcinoma (PTC), patients with histologically confirmed thyroiditis were compared with those without thyroiditis. The following pathological variables were evaluated: multifocality, capsular invasion, muscular invasion, vascular invasion, lymphatic invasion, tumor size (<2.5 cm vs ≥2.5 cm), and disease stage (I-II vs III-IV).Categorical variables were reported as counts and percentages and compared using Pearson's χ² test or Fisher's exact test, as appropriate. Associations between thyroiditis and tumor characteristics were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). To account for multiple comparisons, p values were adjusted using the Holm sequential procedure. Holm-adjusted p values <0.05 were considered statistically significant.

Survival analysis was performed using the Kaplan-Meier method, and differences in disease-free survival between groups were assessed with the log-rank test. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and their 95% CIs for recurrence. Variables included in the multivariable Cox models were selected a priori based on clinical relevance and univariable results. A secondary Cox regression analysis was restricted to events occurring within the first five years of follow-up. No significant differences were observed between the results of the 5-year and 10-year analyses.