Synchronous Differentiated Thyroid Carcinoma in Non-Invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Prevalence, Pathological Profile, and Limits of Pre-Operative Risk Prediction in a Multicentre Cohort
Chiara Dobrinja, Manuela Mastronardi, Stella Bernardi, Elena Bonati, Marco Bononi, Pietro Giorgio Calò, Gian Luigi Canu, Federico Cappellacci, Maria Grazia Chiofalo, Loredana De Pasquale, Carmela De Crea, Marco Stefano Demarchi, Paolo Del Rio, Giacomo Di Filippo, Giovanni Docimo, Daniele Gasparini, Rita Gervasi, Giuseppa Graceffa, Angela Gurrado, Maurizio Iacobone, Eduardo Mercelo Iervolino, Nadia Innaro, Rita Laforgia, Giovanni Lazzari, Petra Makovac, Gabriele Materazzi, Fabio Medas, Eleonora Morelli, Barbara Mullineris, Piermarco Papini, Francesco Pennestrì, Angela Pezzolla, Marco Raffaelli, Esther Diana Rossi, Leonardo Rossi, Gregorio Scerrino, Luca Sessa, Mario Testini, Emanuela Traini, Nicolò de Manzini, Dario GregoriBackground/Objectives: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was reclassified as a non-malignant entity in 2016 to reduce overtreatment. A proportion of NIFTP-containing glands nonetheless harbour a synchronous differentiated thyroid carcinoma (DTC). We quantified its prevalence and pathological profile and assessed whether routinely collected pre-operative variables identify affected patients. Methods: A multicentre retrospective cohort of 1185 adults with NIFTP confirmed at second histological review, operated on between 2017 and 2023 in 22 centres. The outcome was a synchronous DTC in the surgical specimen. A weighted random forest and an elastic-net logistic regression based on 13 pre-operative predictors were evaluated with 20-times repeated five-fold cross-validation, with all data-driven steps nested within training folds, and with leave-one-centre-out and temporal validation. Results: A synchronous DTC was present in 61 patients (5.1%; 95% CI 4.0–6.6; 6.2% after review of the stored reports), with marked between-centre variation (none recorded in eight centres). Fifty-eight carcinomas (95%) were pT1a; none had gross extra-thyroidal extension or nodal metastasis (nodes examined in 27 patients), and none met the 2025 American Thyroid Association criteria mandating a more extensive operation. No pre-operative variable differed between groups after multiplicity adjustment. The cross-validated AUROC was 0.56 (95% CI 0.47–0.65) for the random forest and 0.58 (0.48–0.67) for the elastic net; the within-centre concordance was 0.48 and the temporal-validation AUROC 0.39, and decision-curve analysis showed no net benefit over default strategies. Conclusions: About one in twenty NIFTP-containing specimens harbours a synchronous DTC, usually a low-risk papillary microcarcinoma. Routinely available pre-operative variables do not identify these patients; management should be guided by the pathology of the carcinoma itself.