Head and Neck Paragangliomas: An Update on the Molecular Classification, State-of-the-Art Imaging, and Management Recommendations

Abstract

Paragangliomas are neuroendocrine tumors that derive from paraganglia of the autonomic nervous system, with the majority of parasympathetic paragangliomas arising in the head and neck. More than one-third of all paragangliomas are hereditary, reflecting the strong genetic predisposition of these tumors. The molecular basis of paragangliomas has been investigated extensively in the past couple of decades, leading to the discovery of several molecular clusters and more than 20 well-characterized driver genes (somatic and hereditary), which are more than are known for any other endocrine tumor. Head and neck paragangliomas are largely related to the pseudohypoxia cluster and have been previously excluded from most molecular profiling studies. This review article introduces the molecular classification of paragangliomas, with a focus on head and neck paragangliomas, and discusses its impact on the management of these tumors. Genetic testing is now recommended for all patients with paragangliomas to provide screening and surveillance recommendations for patients and relatives. While CT and MRI provide excellent anatomic characterization of paragangliomas, gallium 68 tetraazacyclododecane tetraacetic acid-octreotate (ie, ⁶⁸Ga-DOTATATE) has superior sensitivity and is recommended as first-line imaging in patients with head and neck paragangliomas with concern for multifocal and metastatic disease, patients with known multifocal and metastatic disease, and in candidates for targeted peptide-receptor therapy. Keywords: Molecular Imaging, MR Perfusion, MR Spectroscopy, Neuro-Oncology, PET/CT, SPECT/CT, Head/Neck, Genetic Defects © RSNA, 2022.

Keywords: Genetic Defects; Head/Neck; MR Perfusion; MR Spectroscopy; Molecular Imaging; Neuro-Oncology; PET/CT; SPECT/CT.

Figure 1:

Overview of pheochromocytomas and paragangliomas by function, location, and cellular type. EA = extra-adrenal, HN = head and neck. (Reprinted, with permission, from University of Rochester, Rochester, New York © 2022; illustration by Nazdezhda D. Kiriyak.)

Figure 2:

Histopathologic analysis. (A, B) Type I chief cells in well-defined nests (* = zellballen) surrounded by type II sustentacular cells (arrows). (Hematoxylin-eosin stain; original magnification, [A] ×10 and [B] ×40.) (C) Type I chief cells (*). (Synaptophysin stain; original magnification, ×10.) (D) Type II sustentacular cells (arrow). (S100 stain; original magnification, ×10.)

Figure 3:

Summary of molecular clusters, as defined by their driver mutations, altered molecular pathways, and tumor types. CSDE1 = cold-shock domain containing e1, EA = extra-adrenal, EPAS1 = endothelial pas domain-containing protein 1, FH = fumarate hydratase, HN = head and neck, HRAS = HRas proto-oncogene, MAPK = mitogen-activated protein kinase, MAX = myc-associated factor X, MAML3 = mastermind-like 3, MEN2 = multiple endocrine neoplasia type 2, mTOR = mammalian target of rapamycin, MYC = myc proto-oncogene, NF1 = neurofibromatosis 1, PCC = pheochromocytoma, PGL = paraganglioma, RCC = renal cell carcinoma, RET = rearranged during transfection, SDH = succinate dehydrogenase, SDHAF2 = SDH complex assembly factor 2, TCA = tricarboxylic-acid, TMEM 127 = transmembrane protein 127, VHL = von Hippel Lindau, Wnt = wingless and Int-1. (Reprinted, with permission, from University of Rochester, Rochester, New York © 2022; illustration by Nazdezhda D. Kiriyak.)

Figure 4:

Relationship between tricarboxylic acid (TCA) cycle and pseudohypoxia pathways. Mutations of succinate dehydrogenase (SDH) and fumarate hydratase (FH) enzymes lead to stabilization of hypoxia inducible factor−α (HIFα), resulting in angiogenesis and cell proliferation. CoA = coenzyme A, FAD = flavin adenine dinucleotide, FADH₂ = 1,5-dihydro-flavin adenine dinucleotide, GDP = guanosine diphosphate, GTP = guanosine-5′-triphosphate, NAD = nicotinamide adenine dinucleotide, VHL = von Hippel Lindau. (Reprinted, with permission, from University of Rochester, Rochester, New York © 2022; illustration by Nazdezhda D. Kiriyak.)

Figure 5:

Typical imaging characteristics of head and neck paragangliomas. (A) Left carotid body paraganglioma on axial contrast-enhanced CT angiographic image, with splaying of internal carotid (arrowhead) and external carotid (arrow) arteries. (B) Right vagal paraganglioma on axial contrast-enhanced CT image, with anteromedial displacement of internal carotid artery (arrow) and posterolateral displacement of internal jugular vein (arrowhead). (C) Right jugular paraganglioma on axial T2-weighted MR image with intralesional flow voids. (D) Right jugulotympanic paraganglioma (arrowhead) on coronal noncontrast CT image extending into hypotympanum.

Figure 6:

(A) Axial contrast-enhanced T1-weighted MR image demonstrates vagal paraganglioma (arrowhead) with splaying of internal carotid artery and internal jugular vein. (B) Corresponding increased blood flow of the vagal paraganglioma (arrowhead) on arterial spin labeling perfusion.

Figure 7:

Axial T1-weighted dynamic contrast-enhanced perfusion MR image of bilateral jugular paragangliomas (arrows) with confirmed succinate dehydrogenase subunit B mutation, reveals (A) increased time to maximum enhancement, (B) high maximum signal-enhancement ratio (SER), and (C) low volume transfer constant (K^trans), a measure of capillary permeability. (D) MR spectroscopy image demonstrates elevated succinate (Su) at 2.4 ppm. Ch = choline, L = lipid or lactate.

Figure 8:

Multifocal head and neck paragangliomas. Right carotid body paraganglioma on (A) axial contrast-enhanced CT image and (B) digital subtraction angiographic image, with splaying of the internal (arrowhead) and external (arrow) carotid arteries in the shape of a lyre. (C) Image from gallium 68 tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) PET/CT following resection shows second initially missed left paraganglioma vagale with high DOTATATE avidity (red). (D) Axial contrast-enhanced CT image, in retrospect, helps confirm left paraganglioma vagale (arrow).

Figure 9:

History of head and neck paraganglioma status after resection and radiation with succinate dehydrogenase subunit D (SDHD) variant. Gallium 68 tetraazacyclododecane tetraacetic acid–octreotate (ie, DOTATATE) PET/CT images show (A) residual skull base paraganglioma (arrow) and (B) metastatic right level IIb lymph node (arrow).