Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP ("pseudo-pseudoinclusions") are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin-negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo-pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo-pseudoinclusions.
Keywords: NIFTP; Papillary thyroid carcinoma; Pseudoinclusions; Thyroid; Ubiquitin.