The Changing Paradigm of Head and Neck Paragangliomas: What Every Otolaryngologist Needs to Know

Background: Recommendations regarding head and neck paragangliomas (HNPGL) have undergone a fundamental reorientation in the last decade as a result of increased understanding of the genetic and pathophysiologic basis of these disorders. Objective: We aim to provide an overview of HNPGL and recent discoveries regarding their molecular genetics, along with updated recommendations on workup, treatment, and surveillance, and their implications for otolaryngologists treating patients with these disorders. Results: SDHx susceptibility gene mutations, encoding subunits of the enzyme succinate dehydrogenase (SDH), give rise to the Hereditary Pheochromocytoma/Paraganglioma Syndromes. SDHA, SDHB, SDHC, SDHD, and SDHAF2 mutations each result in unique phenotypes with distinct penetrance and risk for variable tumor development as well as metastasis. Genetic and biochemical testing is recommended for every patient with HNPGL. Multifocal disease should be managed in multi-disciplinary fashion. Patients with SDHx mutations require frequent biochemical screening and whole-body imaging, as well as lifelong follow-up with an expert in hereditary pheochromocytoma and paraganglioma syndromes. Conclusion: Otolaryngologists are likely to encounter patients with HNPGL. Keeping abreast of the latest recommendations, especially regarding genetic testing, workup for additional tumors, multi-disciplinary approach to care, and need for lifelong surveillance, will help otolaryngologists appropriately care for these patients.

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Malignant Head and Neck Paragangliomas in SDHB Mutation Carriers

Otolaryngology ◽

10.1016/j.otohns.2007.01.015 ◽

2007 ◽

Vol 137 (1) ◽

pp. 126-129 ◽

Cited By ~ 78

Author(s):

Carsten Christof Boedeker ◽

Hartmut P. H. Neumann ◽

Wolfgang Maier ◽

Birke Bausch ◽

Jörg Schipper ◽

...

Keyword(s):

Head And Neck ◽

Molecular Genetic ◽

Gene Mutations ◽

Distant Metastases ◽

High Rate ◽

Body Region ◽

Sdhb Mutation ◽

Sdhd Gene ◽

Mutation Carriers ◽

Head And Neck Paragangliomas

OBJECTIVE: Three of four paraganglioma syndromes (PGLs) have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D ( SDHD) gene, PGL 3 is caused by SDHC gene mutations, and PGL 4 is caused by SDHB gene mutations. The objective of this study was to investigate whether PGLs are associated with malignant head and neck paragangliomas (HNPs). STUDY DESIGN AND SETTING: Through November 2005, we screened 195 HNP patients for mutations of the genes SDHB, SDHC, and SDHD. RESULTS: We detected 5 SDHC, 13 SDHB, and 45 SDHD gene mutations. In seven SDHB mutation carriers, there were distant metastases. No signs of metastases were found in SDHC and SDHD patients. One patient with a sporadic HNP presented with locally metastatic disease. CONCLUSIONS: SDHB mutations are associated with a high rate of malignant HNPs. SIGNIFICANCE: In SDHB patients, a three-body region imaging and scintigraphy or DOPA-PET must be performed to exclude metastases.

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Tumor detection rates in screening carriers with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1545 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1545-1545

Author(s):

Samantha Greenberg ◽

Michelle Jacobs ◽

Heather Wachtel ◽

Amanda Anson ◽

Luke Buchmann ◽

...

Keyword(s):

Screening Program ◽

Tumor Detection ◽

Whole Body ◽

Prior History ◽

Whole Body Imaging ◽

Detection Rates ◽

Expert Recommendation ◽

Increased Risk ◽

History Of ◽

Biochemical Testing

1545 Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.

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Identification of a Signaling Axis HIF-1α/MicroRNA-210/ISCU Independent of SDH Mutation That Defines a Subgroup of Head and Neck Paragangliomas

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2410 ◽

2012 ◽

Vol 97 (11) ◽

pp. E2194-E2200 ◽

Cited By ~ 32

Author(s):

Anna Merlo ◽

Sandra Bernaldo de Quiros ◽

Pablo Secades ◽

Iriana Zambrano ◽

Milagros Balbín ◽

...

Keyword(s):

Head And Neck ◽

Target Genes ◽

Parasympathetic Nervous System ◽

Expression Patterns ◽

Tumor Development ◽

Immunohistochemical Analysis ◽

Iron Sulfur Cluster ◽

Iron Sulfur ◽

Signaling Axis ◽

Head And Neck Paragangliomas

Background: Head and neck paragangliomas (HNPGLs) are rare tumors associated with the parasympathetic nervous system. Most are sporadic, but about one third result from germline mutations in succinate dehydrogenase (SDH) genes (SDHB, SDHC, SDHD, SDHA, or SDHAF2). Although a molecular connection between SDH dysfunction and tumor development is still unclear, the most accepted hypothesis proposes a central role of the pseudohypoxic pathway. SDH dysfunction induces abnormal stabilization of the hypoxia-inducible factors (HIFs) that regulate target genes involved in proliferation, apoptosis, angiogenesis, and metabolism. The involvement of these pathways in the development of sporadic HNPGLs is presently unknown. Objective: To get some insights into the hypoxic/pseudohypoxic molecular basis of HNPGLs, we attempted to define the gene, microRNA (miRNA), and HIF-1α expression patterns that distinguish tumors from normal paraganglia tissue. Design: Genome microarray and TaqMan low-density arrays were used to analyze gene and miRNA expression, respectively, in 17 HNPGL tumor tissues and three normal human carotid bodies. Twelve HNPGLs were used for validation of data. HIF-1α, SDHB, and iron-sulfur cluster scaffold protein (ISCU) protein expression was analyzed by immunohistochemistry. Results: We found activation of a canonical HIF-1α-related gene expression signaling only in a subset of HNPGLs from patients that did not harbor germline or somatic SDH mutations. The pseudohypoxic signature consisted in the overexpression of both HIF-1α-target genes and the HIF-1α-inducible miRNA, miR-210, and down-regulation of the miR-210 target gene, ISCU1/2. A decreased level of the iron-sulfur-containing protein SDHB was found by immunohistochemical analysis performed in two of these tumors. Conclusions: Collectively, this study unveiled a putative signaling axis of HIF-1α/miRNA-210/ISCU in a subset of HNPGLs that could have an impact on SDHB protein stability by a mechanism independent of SDH mutations, thus providing a foundation to better understand the functional interplay between HIF, miR-210, and mitochondria and its relevance in the pathogenesis of HNPGLs.

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Clinical aspects of SDHx-related pheochromocytoma and paraganglioma

Endocrine Related Cancer ◽

10.1677/erc-08-0284 ◽

2009 ◽

Vol 16 (2) ◽

pp. 391-400 ◽

Cited By ~ 87

Author(s):

Henri J L M Timmers ◽

Anne-Paule Gimenez-Roqueplo ◽

Massimo Mannelli ◽

Karel Pacak

Keyword(s):

Head And Neck ◽

Susceptibility Gene ◽

Clinical Aspects ◽

Apoptosis Resistance ◽

Neuronal Precursor Cells ◽

Positron Emission ◽

Genes Encoding ◽

Head And Neck Paragangliomas ◽

Chromaffin Tissue

Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [18F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.

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