The fascinating history of papillary thyroid carcinoma nuclei: revelation of two nuclear morphologies—“Classical papillary” and “papillary‐like”, with different pathobiologic characteristics

Abstract The nucleus of papillary thyroid carcinoma (PTC) has had a fascinating history since its early descriptions by Lindsay in 1960 and his designation of follicular variant papillary thyroid carcinoma (FVPTC) as a subtype of follicular carcinoma (FC). Later, Chen and Rosai revived the awareness of FVPTC and aligned this neoplasm with PTC. From this era, PTC became a nuclear diagnosis and was expanded to include FVPTC, even when noninvasive and encapsulated. However, this practice was prone to interobserver variability. The main issue centered on the interpretation of two types of nuclei: the widely accepted “classical papillary nucleus” with well‐developed features such as nuclear pseudoinclusions and grooves and the other “papillary‐like nucleus” with subtle and delicate nuclear features. Subsequently, some individuals recognized papillary‐like nucleus in most follicular‐patterned neoplasms and diagnosed them as FVPTC, whereas others diagnosed them as follicular adenoma. In the 2000s, noninvasive, encapsulated FVPTC was recognized as an indolent entity, and later relabeled as noninvasive follicular thyroid neoplasm with papillary‐like nuclear features. Molecular analyses revealed two main families of drivers for PTC, BRAF V600E or BRAF V600E –like mutations, which aligned with classical papillary nucleus, papillary architecture, and conventional PTC outcomes, and RAS or RAS ‐like mutations that were associated with papillary‐like nucleus, follicular architecture, and follicular‐patterned neoplasm outcomes. The story has come full circle, and the recent proposal to incorporate FVPTC into follicular adenoma is in keeping with Lindsay’s original concept. By the current understanding, these nuclei are classified better by molecular associations.