Head and Neck Paraganglioma in Pacak-Zhuang Syndrome

Jared S. Rosenblum, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Yasemin Cole, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Danielle Dang, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Pashayar P. Lookian, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Hussam Alkaissi, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, MD, USA.
Mayank Patel, Section on Medical Neuroendocrinology National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
Anthony J. Cappadona, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Abhishek Jha, Section on Medical Neuroendocrinology National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
Nancy Edwards, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
Danielle R. Donahue, Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
Jeeva Munasinghe, Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
Herui Wang, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Russell H. Knutsen, Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
Alberto S. Pappo, Division of Solid Tumor, St Jude Children's Research Hospital, Memphis, 38105, TN, USA.
Ronald M. Lechan, Division of Endocrinology, Diabetes & Metabolism, Tufts Medical Center, Boston, 02111, MA, USA.
Beth A. Kozel, Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
James G. Smirniotopoulos, Radiology, George Washington University, Washington DC, 20052, USA.
H Jeffrey Kim, Department of Otolaryngology, Georgetown University School of Medicine, Washington, 20007, DC, USA.
Alexander Vortmeyer, Clinical Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, 26202, IN, USA.
Markku Miettinen, General Surgical Pathology Section, National Institutes of Health, Bethesda, 20892, MD, USA.
John D. Heiss, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, MD, USA.
Zhengping Zhuang, Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.
Karel Pacak, Section on Medical Neuroendocrinology National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.

Document Type

Journal Article

Publication Date

1-17-2025

Journal

JNCI cancer spectrum

DOI

10.1093/jncics/pkaf001

Keywords

EPAS1; HIF-2α; carotid body; hypoxia-inducible factors; paraganglioma/pheochromocytoma; polycythemia

Abstract

Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Three patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and three had carotid artery malformations. Using high resolution ex vivo imaging and histology, we found that nine of ten adult mutant mice had carotid body tumors and six of eight had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in four of five mutant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. These findings 1) suggest HNPGL as a feature of PZS and 2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.

Department

Radiology

Link to Full Text

Share

COinS