Double faces of pheochromocytoma and paraganglioma—a review of integrated pathologic diagnosis

Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia. Both PCC and PGL (PPGLs) are included in neuroendocrine tumors (NETs) of dispersed neuroendocrine system. The most important issue on PPGLs for pathology has been how to differentiate malignant from benign PPGLs, and the previous articles concentrated on solving this difficult issue. However, the concept of PPGLs was dramatically changed by WHO Blue Book, 4th edition (2017), in which all PPGLs have some metastatic potential, therefore, the previous categories of benign and malignant PPGLs have been eliminated in favor of an approach based on risk stratification. This review article includes following issues; 1. historical review of PPGLs, 2. significance of Ki67 labeling index, 3. comparison of scoring system of PASS, GAPP, COPPS these were cited in WHO Tumour Classification 5th edition (2022) with explanation of each parameter, 4. immunohistochemical approach for histopathologic diagnosis using antibodies for neuroendocrine tumors, the specific markers for catecholamine synthesis such as tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) for sympathetic PPGL and choline acetyltransferase for parasympathetic PGL, and additional markers such as GATA3 and Phox2B for both sympathetic and parasympathetic PGL. Then markers for familial PPGLs such as SDHB for SDH-deficient PPGLs, CA9 for VHL, and MAX for MAX-related PPGL, and added Algorithm for diagnosis. The other familial type of MEN type2 and NF1 are discussed by some characteristic features in histology. Finally, rare types such as ACTH-producing PPGL, and dopamine-producing PPGL are discussed.