The impact of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on the diagnosis of thyroid nodules

More than 70 years ago, Prof. Pierre Masson, a renowned French-Canadian pathologist (1880–1959), advised us that “No classification is more difficult to establish than that of thyroid carcinomas…Of all cancers, they teach, perhaps, the greatest lessons of humility to histopathologists.” Almost 70 years later, the recent evidence-based reclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), has demonstrated that this problematic is still ongoing. For about 30 years, it was wrongly assumed that the encapsulated FVPTC behaved and spread like its classical counterpart and, therefore, that it should be treated likewise. As such, the renaming of a malignant entity as a nonmalignant (albeit not benign) neoplasm has contributed to optimizing patient care by deescalating treatment and follow-up for an indolent neoplasm, decreasing medical expense and complications possibly caused by further treatment including radioactive iodine, and reassuring patients with this diagnosis. At the same time, NIFTP has significant implications not only for the practice of thyroid cytopathology but also for surgical pathology and for molecular tests, creating significant new challenges. NIFTP has rigorous histopathologic diagnostic criteria, including papillary-like nuclear features, and submission of the entire tumor capsule and content is required to exclude both invasion and presence of papillary structures. Cytologically, because of the morphological overlap with other follicular neoplasms and with papillary thyroid carcinoma (PTC), most NIFTP are diagnosed into one of the indeterminate Bethesda categories (III–V) and can be adequately triaged for surgery. From a molecular view, NIFTP are most often characterized by RAS-type mutations, similar to other follicular-patterned lesions, and molecular testing can be helpful to suggest NIFTP preoperatively. In this review, we focus on the impact of NIFTP on the diagnosis of thyroid nodules.