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

Background/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.

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Journal
Cancers
Published
2026-10-30
DOI
https://doi.org/10.3390/cancers18213505
Primary Topic
Thyroid Cancer Diagnosis and Treatment
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article
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article

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

Paolo Del Rio, Nicolò de Manzini, Angela Pezzolla, Marco Raffaelli et al.
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Cancers
Thyroid Cancer Diagnosis and Treatment
article

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

Paolo Del Rio, Nicolò de Manzini, Angela Pezzolla, Marco Raffaelli, Luca Sessa, Nadia Innaro, Petra Makovac, Maurizio Iacobone, Piermarco Papini, Rita Laforgia, Barbara Mullineris, Stella Bernardi, Manuela Mastronardi, Gian Luigi Canu, Esther Diana Rossi, Chiara Dobrinja, Mario Testini, Giuseppa Graceffa, Darío Gregori, Federico Cappellacci, Emanuela Traini, Elena Bonati, Angela Gurrado, Giovanni Docimo, Maria Grazia Chiofalo, Francesco Pennestrì, Rita Gervasi, Loredana De Pasquale, Marco Bononi, Fabio Medas, Leonardo Rossi, Gabriele Materazzi, Carmela De Crea, Grégorio Scerrino, Giacomo Di Filippo, Pietro Giorgio Calò, Marco Stefano Demarchi, Giovanni Lazzari, Daniele Gasparini, Eleonora Morelli, Eduardo Mercelo Iervolino
article en

Abstract

Background/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.

CancersVol. 18(21)
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), University of Verona (IT), University of Parma (IT), University of Padua (IT), University of Trieste (IT), University of Cagliari (IT), University of Milan (IT), Policlinico Umberto I (IT), Agostino Gemelli University Polyclinic (IT), Azienda Ospedaliera Universitaria Integrata Verona (IT), Ente Ospedaliero Cantonale (CH), Ospedale di Cattinara (IT), Saint Camillus International University of Health and Medical Sciences (IT), University Hospital of Geneva (CH), Azienda Ospedaliero-Universitaria di Modena (IT), Ospedale Regionale di Mendrisio (CH), Azienda Ospedaliera Universitaria Università degli Studi della Campania Luigi Vanvitelli (IT), Fondazione Istituto G. Giglio di Cefalù (IT), Azienda Ospedaliero-Universitaria "Renato Dulbecco" (IT), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" di Palermo (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Azienda Sanitaria Universitaria Integrata di Trieste (IT), Città della Speranza Foundation (IT), Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo (IT), Azienda sanitaria universitaria Giuliano Isontina (IT), University of Bari Aldo Moro (IT), Sapienza University of Rome (IT), University of Palermo (IT)
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Thyroid Cancer Diagnosis and Treatment
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