Predictive impact of metastatic lymph node burden on distant metastasis across papillary thyroid cancer variants.

BACKGROUND While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histologic features on predicting distant metastases at initial presentation. METHODS Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma (WDPTC), diffuse sclerosing variant (DSV), tall cell variant, poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC)) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. RESULTS Overall, M1 prevalence at disease presentation was 3.6% (n=1,717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC (1.0%), DSV (2.3%), tall cell (4.1%), PDTC (17.4%), ATC (38.4%) (p 10 LN+ (5.5%) (p<0.001)) and LN ratio (p<0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (OR 1.06 [1.05-1.08], p<0.001) and tall cell variants (OR 1.04 [1.02-1.07], p<0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95-1.10], p=0.52; PDTC, OR 1.00 [0.98-1.02], p=0.66; ATC, 1.00 [0.98-1.02], p=0.97). CONCLUSIONS Progressive nodal burden independently escalates the risk of distant metastasis in well-differentiated and tall cell variants of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher-risk patient groups.