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von Hippel-Lindau (VHL) disease occurs secondary to pathogenic alterations of the VHL tumor suppressor gene, manifesting with cysts and tumors in multiple organ systems. VHL protein (pVHL) is a known downregulator of hypoxia inducible factor-1a (HIF1a). Loss of function of pVHL is associated with upregulation of the HIF1a pathway including carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). Paired box 8 (PAX8) is an important transcription factor regulator of mesonephric development. We investigated the role of immunohistochemistry in the assessment of CA9, GLUT1, and PAX8 expression in VHL disease-related lesions. Clinicopathologic information and archived pathology material from 5 patients with VHL disease were reviewed and evaluated for expression of CA9, GLUT1, and PAX8. The spectrum of VHL disease-related lesions included hemangioblastoma, endolymphatic sac tumor, pulmonary microcysts, pheochromocytoma, pancreatic neuroendocrine tumor and serous cystadenoma, renal cysts, renal cell carcinoma, and epididymal papillary cystadenoma. CA9 was expressed in all lesions and exhibited diffuse positivity (15/15 lesions, 100%; 5/5 patients), while GLUT1 expression was focal/weak or absent in some instances (strong positive: 12/15 lesions, 80%; 5/5 patients). PAX8 was expressed only in renal and epididymal lesions. CA9 and GLUT1 are consistently overexpressed in VHL disease-related lesions, reflecting upregulation of the HIF1a pathway. PAX8 is only expressed in genitourinary lesions, mirroring organ-specific differentiation. A combination of CA9 and GLUT1 immunostains is useful in screening lesions of patients with VHL spectrum manifestations, which may be targeted by the recently Food and Drug Administration-approved HIF-2a inhibitors., (Copyright © 2022 Elsevier Inc. All rights reserved.)