Nuclear inclusions and pseudoinclusions: friends or foes of the surgical pathologist?

Abnormal substances in the nuclei that can be observed by light microscopy are often broadly referred to as nuclear inclusions. Although their recognition in the appropriate clinicopathological settings can aid in the diagnosis of some disease entities and tumor types, they can also be a source of error. There are 2 morphologically distinct types of inclusions with different mechanisms of formation and diagnostic significance, including bona fide nuclear inclusions and nuclear pseudoinclusions. Bona fide nuclear inclusions result from accumulation in the nuclei of viral particles, cytoplasmic materials (such as surfactant, immunoglobulin, and glycogen), biotin, nuclear lamins, or polyglutamine. Some of them are diagnostically helpful, such as surfactant inclusion, which can support the pulmonary origin of an adenocarcinoma, whereas others may be misleading, such as biotin inclusion, which can be mistaken for herpes infection. Nuclear pseudoinclusions, which represent invaginations of cytoplasm into the nucleus, are delimited by the nuclear membrane. Although not totally specific, they are particularly common in papillary thyroid carcinoma, meningioma, and usual ductal hyperplasia of the breast and hence may aid in the diagnosis of these entities. Nuclear pseudo-pseudoinclusions, which are artefactual bubbles in the nuclei that mimic nuclear pseudoinclusions or clear nuclei, can lead to misdiagnosis of follicular adenoma or hyperplastic nodule as papillary thyroid carcinoma.