The goal of this observational study is to identify demographic and clinicopathological factors associated with disease recurrence in adults with histologically confirmed papillary thyroid carcinoma (PTC) who achieved an initial disease-free status after primary treatment.

The main questions it aims to answer are:

Which demographic and clinicopathological characteristics are associated with an increased risk of PTC recurrence?

Researchers will compare patients who developed biochemical or structural recurrence with those who remained recurrence-free to assess the prognostic role of age, sex, tumor size, histological subtype, vascular invasion, capsular invasion, gross invasion of the prethyroid strap muscles, concomitant thyroiditis, multifocality, lymph-node status, and pathological stage.

As this is a retrospective study, participants will not undergo any study-specific intervention or additional procedure. Researchers will review existing demographic, surgical, pathological, treatment, and follow-up data from a prospectively maintained institutional database. Follow-up data include serial serum thyroglobulin measurements, neck ultrasonography, recurrence, and disease-specific mortality.

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.

Inclusion Criteria:

• histologically confirmed diagnosis of papillary thyroid carcinoma
• no history of previous neck surgery
• availability of complete clinical, pathological, treatment, and follow-up data;
• achievement of an initial disease-free status after primary treatment
• minimum follow-up of 60 months for patients who remained recurrence-free

Exclusion Criteria:

• histological diagnosis other than papillary thyroid carcinoma
• previous neck surgery
• incomplete clinical, pathological, treatment, or follow-up records
• follow-up shorter than 60 months in patients without recurrence
• biochemical or structural evidence of persistent disease after initial treatment

The study population consisted of adult patients treated for histologically confirmed papillary thyroid carcinoma at the Department of Surgery of Sapienza University of Rome, Policlinico Umberto I Hospital, between 2000 and 2018. Patients were identified from a prospectively maintained institutional database and had undergone primary surgical treatment and subsequent postoperative surveillance at the same tertiary referral center.