Avoiding overdiagnosis of parathyroid carcinoma.

The diagnosis of a non-metastatic parathyroid carcinoma requires the demonstration of invasive growth that defines malignancy. These include angioinvasion or vascular invasion (i.e., tumor penetrating the vessel wall and associated with thrombus or intravascular tumor cells intermixed with thrombus), lymphatic invasion, perineural (intraneural) invasion, and/or direct invasion into adjacent anatomical structures. However, the distinction of a pT1 disease (8th edition of UICC TNM staging system) which represents a localized disease (tumor confined to the parathyroid gland or showing minimal extra-parathyroidal soft tissue invasion without direct invasion into adjacent structures) often requires meticulous microscopic examination that couples multiple levels and biomarker studies. Although the diagnostic criteria of malignancy are clearly defined, the identification of harbingers of invasive growth and distinguishing them from their mimics can pose diagnostic challenges. Several artifacts and manipulations can simulate malignancy. For example, a prior biopsy, PTH washout, ethanol injection, or any form of surgical manipulation may result in fibrosis, crush (mechanical) artifacts, or tissue distortion, which can obscure histological details and mimic invasion. Peliosis-the presence of extravasated erythrocytes without an endothelial lining-may simulate vascular invasion. Other common mimics include mechanically displaced intravascular tumor cells unassociated with thrombus, which can occur at the time of specimen handling. Extension of the tumor into the adjacent irregular connective tissue or pseudo-capsule can be mistaken for invasive growth. Similarly, an intrathyroidal location of the parathyroid gland adds another layer of complexity. In such cases, the boundary between the parathyroid tissue and surrounding thyroid parenchyma may not be clearly discernible, making it difficult to determine whether there is genuine invasive growth into thyroid (pT2 disease, 8th edition of UICC TNM system) or simply anatomical proximity. In addition, parathyromatosis and contour irregularities associated with long-standing secondary or tertiary hyperparathyroidism are other challenging manifestations. Atypical parathyroid tumors (WHO 2022) should also be clearly delineated using appropriate criteria. In summary, pathologists must be aware of the potential pitfalls that may lead to overdiagnosis of parathyroid carcinoma. A consolidated diagnostic workup, which combines multiple levels and biomarkers, is necessary to ensure diagnostic accuracy in all parathyroid tumors. This review provides practical insights on these diagnostic difficulties, illustrating common artifacts and mimics. We also discuss the relevant clinical, histological, immunohistochemical, and molecular features associated with parathyroid carcinoma, with the goal of enhancing diagnostic accuracy.