Immunohistochemistry remains an indispensable tool in diagnostic surgical pathology. In parathyroid tumours, it has four main applications: to detect (1) loss of parafibromin; (2) other manifestations of an aberrant immunophenotype hinting towards carcinoma; (3) histogenesis of a neck mass and (4) pathogenetic events, including features of tumour microenvironment and immune landscape. Parafibromin stain is mandatory to identify the new entity of parafibromin-deficient parathyroid neoplasm, defined in the WHO classification (2022). Loss of parafibromin indicates a greater probability of malignant course and should trigger the search for inherited or somatic CDC73 mutations. Aberrant immunophenotype is characterised by a set of markers that are lost (parafibromin), down-regulated (e.g., APC protein, p27 protein, calcium-sensing receptor) or up-regulated (e.g., proliferation activity by Ki-67 exceeding 5%) in parathyroid carcinoma compared to benign parathyroid disease. Aberrant immunophenotype is not the final proof of malignancy but should prompt the search for the definitive criteria for carcinoma. Histogenetic studies can be necessary for differential diagnosis between thyroid vs. parathyroid origin of cervical or intrathyroidal mass; detection of parathyroid hormone (PTH), chromogranin A, TTF-1, calcitonin or CD56 can be helpful. Finally, immunohistochemistry is useful in pathogenetic studies due to its ability to highlight both the presence and the tissue location of certain proteins. The main markers and challenges (technological variations, heterogeneity) are discussed here in the light of the current WHO classification (2022) of parathyroid tumours.
Keywords: Ki-67; WHO classification; atypical parathyroid tumour; calcium-sensing receptor; immunohistochemistry; multiglandular parathyroid disease; p27; parafibromin; parathyroid adenoma; parathyroid carcinoma; tumour microenvironment.