Association between circadian rhythm disruption and the risk of malignancy in patients with thyroid nodules: a...

The rising incidence of thyroid cancer (TC) underscores the need to identify modifiable risk factors for malignancy in patients with thyroid nodules. The role of circadian rhythm disruption (CRD), a pervasive modern lifestyle factor, in TC is poorly understood. We aimed to investigate the association between cumulative CRD and the risk of malignancy and aggressiveness in patients with thyroid nodules.

We conducted a hospital-based, propensity score-matched study involving 2,541 patients who underwent thyroidectomy for thyroid nodules between 2016 and 2019. A novel cumulative circadian rhythm disruption index (cCRDI), integrating sleep insufficiency, shift work history, chronotype/mid-sleep timing, and dietary irregularity, was calculated from preoperative questionnaires. The primary outcome was the definitive postoperative histopathological diagnosis (benign vs. malignant). Propensity score matching (PSM) (1:1) was performed to balance baseline confounders (e.g., age, sex, BMI, TSH levels, and autoimmune status), yielding a cohort of 850 matched pairs (1,700 patients). Conditional logistic regression was used to assess the association between cCRDI and malignancy.

In the matched cohort, a strong, dose-dependent relationship was observed. Compared to the No CRD group, the adjusted odds ratios (aOR) for malignancy were 1.58 (95% CI: 1.15-2.15) for Low CRD, 1.85 (95% CI: 1.30-2.62) for Moderate CRD, and 2.95 (95% CI: 2.05-4.25) for High CRD (P for trend < 0.001). Restricted cubic splines confirmed a non-linear association with accelerating risk at higher cCRDI scores (P for non-linearity = 0.008). Crucially, increasing CRD severity was independently associated with aggressive clinicopathological features, including multifocality, extrathyroidal extension (ETE), and a dramatic increase in lymph node metastasis (LNM) (69.4% in High CRD vs. 29.3% in No CRD, P < 0.001). High CRD remained the strongest independent predictor for LNM in multivariable analysis (aOR = 4.21, 95% CI: 2.90-6.10, P < 0.001).

Cumulative CRD is independently associated with both the presence of malignancy and the aggressive progression of TC in patients with thyroid nodules. Assessing a patient's circadian health might have potential utility as a novel, modifiable factor for risk stratification and may underscore the importance of lifestyle interventions in the clinical management of thyroid nodules.