Revisiting Pre‐RAI MLR, PNI, and NRI Estimating Early and Higher Recurrence in Intermediate‐Risk DTC in Thyroidology

Dear Editor,

The retrospective analysis by Piticchio et al. [1] provides a compelling foray into the host‐immune landscape of differentiated thyroid carcinoma (DTC), specifically targeting the ‘grey zone’ of intermediate‐risk in thyroidology [2, 3, 4, 5, 6] published in volume 104 of Clinical Endocrinology. By elucidating the prognostic significance of the pre‐radioiodine (RAI) Monocyte‐to‐Lymphocyte Ratio (MLR), the authors address a critical gap in our ability to predict recurrence‐free survival using cost‐effective, routine haematological parameters. The primary merit of this study lies in its timing; by assessing systemic inflammatory indices after surgical recovery but before RAI therapy, the authors capture a unique immunological ‘snapshot’ that incorporates the host's response to residual microscopic disease. The finding that an MLR > 0.188 independently predicts a nearly fourfold increase in recurrence risk is statistically robust and clinically provocative. However, several methodological nuances warrant further deliberation to ensure these findings are translated accurately into clinical practice. Antecedently, the temporal convergence of blood sampling with profound iatrogenic hypothyroidism—secondary to levothyroxine withdrawal—merits scrutiny. As the authors correctly acknowledge, endogenous hypothyroidism can modulate circulating leucocyte counts and inflammatory cytokines, which raises an essential question: Does the elevated MLR reflect an intrinsic pro‐tumorigenic inflammatory state, or is it partly a surrogate for the metabolic stress of acute thyroid hormone deficiency? Comparing these results with cohorts prepared via recombinant human TSH (rhTSH), where euthyroidism is maintained, would be vital to isolating the tumour‐host interface from systemic metabolic shifts. Afterwards, the lack of prognostic value for nutritional indices like the Prognostic Nutritional Index (PNI) and Nutritional Risk Index (NRI) is insightful. It suggests that in the context of DTC—unlike aggressive gastrointestinal malignancies—the macro‐nutritional status remains largely preserved. This observation should encourage researchers to pivot towards more sophisticated markers of body composition or specific micronutrient profiles that may more subtly influence immune surveillance. Furthermore, while the association between circulating monocytes and tumour‐associated macrophages (TAMs) provides biological plausibility, the transition from peripheral blood counts to the complex tumour microenvironment remains largely speculative without concomitant immunohistochemical data. The ‘immunological disequilibrium’ suggested by a high MLR likely represents a weakened defence against quiescent neoplastic cells, but the definitive mechanisms remain to be unravelled. Consequently, the authors have provided a valuable compass for navigating the complexities of intermediate‐risk DTC. The MLR serves as a ‘sentinel’ of sorts, signalling which patients require more vigilant surveillance. However, until prospective, multicenter trials confirm these thresholds across diverse populations, the MLR should be viewed as a complementary piece of the prognostic puzzle rather than a standalone arbiter of clinical decision‐making. This issue merits further investigation. We thank Piticchio et al. [1] for their valuable study on pre‐RAI MLR, PNI and NRI estimating early and higher recurrence in intermediate‐risk DTC in Clinical Endocrinol, which is of interest to thyroidologists.

Author Contributions

Ilker Sengul: conceptualization, formal analysis, investigation, methodology, project administration, validation, visualization, writing – original draft, writing – review and editing. Demet Sengul: conceptualization, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data sets used and/or analysed during this study are available from the corresponding author upon reasonable request.