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.
EricksonDKudvaYCEbersoldMJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001;86(11):5210-5216.
2.
MannelliMCastellanoMSchiaviF, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94(5):1541-1547.
3.
TaiebDKaliskiABoedekerCC, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014;35(5):795-819.
4.
WilliamsMD.Paragangliomas of the head and neck: an overview from diagnosis to genetics. Head Neck Pathol. 2017;11(3):278-287.
5.
ShamblinWRReMineWHShepsSGHarrisonEGJr.Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg. 1971;122(6):732-739.
6.
TischlerAS.Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med. 2008;132(8):1272-1284.
7.
OldringDFischU.Glomus tumors of the temporal region: surgical therapy. Am J Otol. 1979;1(1):7-18.
8.
JacksonCGGlasscockME3rdHarrisPF.Glomus tumors. Diagnosis, classification, and management of large lesions. Arch Otolaryngol. 1982;108(7):401-410.
9.
ArtsHAFaganPA.Vagal body tumors. Otolaryngol Head Neck Surg. 1991;105(1):78-85.
10.
MyssiorekDHalaasYSilverC.Laryngeal and sinonasal paragangliomas. Otolaryngol Clin North Am. 2001;34(5):971-982, vii.
11.
PapathomasTGde KrijgerRRTischlerAS.Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments. Semin Diagn Pathol. 2013;30(3):207-223.
12.
LendersJWDuhQYEisenhoferG, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
13.
FishbeinL.Pheochromocytoma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am. 2016;30(1):135-150.
14.
NeumannHPHYoungWFJrEngC.Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381(6):552-565.
15.
RednamSPErezADrukerH, et al. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23(12):e68-e75.
16.
El-NaggarAK.What Is New in the World Health Organization 2017 Histopathology Classification?Curr Treat Options Oncol. 2017;18(7):43.
17.
WilliamsMDTischlerAS.Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas. Head Neck Pathol. 2017;11(1):88-95.
18.
JafriMWhitworthJRattenberryE, et al. Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. Clin Endocrinol (Oxf). 2013;78(6):898-906.
19.
MooreMGNettervilleJLMendenhallWMIsaacsonBNussenbaumB.Head and neck paragangliomas: an update on evaluation and management. Otolaryngol Head Neck Surg. 2016;154(4):597-605.
20.
Smith-BindmanRKwanMLMarlowEC, et al. Trends in use of medical imaging in US health care systems and in Ontario, Canada, 2000-2016. JAMA. 2019;322(9):843-856.
21.
LangermanAAthavaleSMRangarajanSVSinardRJNettervilleJL.Natural history of cervical paragangliomas: outcomes of observation of 43 patients. Arch Otolaryngol Head Neck Surg. 2012;138(4):341-345.
22.
IvanMESughrueMEClarkAJ, et al. A meta-analysis of tumor control rates and treatment-related morbidity for patients with glomus jugulare tumors. J Neurosurg. 2011;114(5):1299-1305.
23.
PapaspyrouKMannWJAmedeeRG.Management of head and neck paragangliomas: review of 120 patients. Head Neck. 2009;31(3):381-387.
24.
WillenSNEinsteinDBMaciunasRJMegerianCA.Treatment of glomus jugulare tumors in patients with advanced age: planned limited surgical resection followed by staged gamma knife radiosurgery: a preliminary report. Otol Neurotol. 2005;26(6):1229-1234.
25.
JansenTTGTimmersHMarresHAMKunstHPM. Feasibility of a wait-and-scan period as initial management strategy for head and neck paraganglioma. Head Neck. 2017;39(10):2088-2094.
26.
CarlsonMLSweeneyADWannaGBNettervilleJLHaynesDS.Natural history of glomus jugulare: a review of 16 tumors managed with primary observation. Otolaryngol Head Neck Surg. 2015;152(1):98-105.
27.
CosettiMLinstromCAlexiadesGTessemaBParisierS.Glomus tumors in patients of advanced age: a conservative approach. Laryngoscope. 2008;118(2):270-274.
28.
PrasadSCMimouneHAD’OrazioF, et al. The role of wait-and-scan and the efficacy of radiotherapy in the treatment of temporal bone paragangliomas. Otol Neurotol. 2014;35(5):922-931.
29.
KunzelJIroHHornungJ, et al. Function-preserving therapy for jugulotympanic paragangliomas: a retrospective analysis from 2000 to 2010. Laryngoscope. 2012;122(7):1545-1551.
30.
WannaGBSweeneyADCarlsonML, et al. Subtotal resection for management of large jugular paragangliomas with functional lower cranial nerves. Otolaryngol Head Neck Surg. 2014;151(6):991-995.
31.
WannaGBSweeneyADHaynesDSCarlsonML.Contemporary management of jugular paragangliomas. Otolaryngol Clin North Am. 2015;48(2):331-341.
32.
HeestermanBLde PontLMHVerbistBM, et al. Age and tumor volume predict growth of carotid and vagal body paragangliomas. J Neurol Surg B Skull Base. 2017;78(6):497-505.
33.
FarrHW.Carotid body tumors: a 40-year study. CA Cancer J Clin. 1980;30(5):260-265.
34.
JacksonCG.Glomus tympanicum and glomus jugulare tumors. Otolaryngol Clin North Am2001;34(5):941-970, vii.
35.
BacciuAMedinaMAit MimouneH, et al. Lower cranial nerves function after surgical treatment of Fisch Class C and D tympanojugular paragangliomas. Eur Arch Otorhinolaryngol. 2015;272(2):311-319.
MoeKSLiDLinderTESchmidSFischU.An update on the surgical treatment of temporal bone paraganglioma. Skull Base Surg. 1999;9(3):185-194.
38.
SannaMJainYDe DonatoGRohit, LaudaLTaibahA.Management of jugular paragangliomas: the Gruppo Otologico experience. Otol Neurotol. 2004;25(5):797-804.
39.
LamblinEAtallahIReytESchmerberSMagneJLRighiniCA.Neurovascular complications following carotid body paraganglioma resection. Eur Ann Otorhinolaryngol Head Neck Dis. 2016;133(5):319-324.
40.
Luna-OrtizKRascon-OrtizMVillavicencio-ValenciaVGranados-GarciaMHerrera-GomezA.Carotid body tumors: review of a 20-year experience. Oral Oncol. 2005;41(1):56-61.
41.
MakeieffMRaingeardIAlricPBonafeAGuerrierBMarty-AneC.Surgical management of carotid body tumors. Ann Surg Oncol. 2008;15(8):2180-2186.
42.
MetheetrairutCChotikavanichCKeskoolPSuphaphongsN.Carotid body tumor: a 25-year experience. Eur Arch Otorhinolaryngol. 2016;273(8):2171-2179.
43.
JacksonRSMyhillJAPadhyaTAMcCaffreyJCMcCaffreyTVMhaskarRS.The effects of preoperative embolization on carotid body paraganglioma surgery: a systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2015;153(6):943-950.
44.
LiJWangSZeeC, et al. Preoperative angiography and transarterial embolization in the management of carotid body tumor: a single-center, 10-year experience. Neurosurgery. 2010;67(4):941-948; discussion 948.
45.
TexakalidisPCharisisNGiannopoulosS, et al. Role of preoperative embolization in carotid body tumor surgery: a systematic review and meta-analysis. World Neurosurg. 2019;129:503-513.e502.
46.
Abu-GhanemSYehudaMCarmelNNAbergelAFlissDM.Impact of preoperative embolization on the outcomes of carotid body tumor surgery: a meta-analysis and review of the literature. Head Neck. 2016;38(suppl 1):E2386-E2394.
47.
CobbANBarkatADaungjaiboonW, et al. Carotid Body Tumor Resection: Just as Safe without Preoperative Embolization. Ann Vasc Surg. 2018;46:54-59.
48.
GartrellBCHansenMRGantzBJ, et al. Facial and lower cranial neuropathies after preoperative embolization of jugular foramen lesions with ethylene vinyl alcohol. Otol Neurotol. 2012;33(7):1270-1275.
49.
ColeJMBeilerD.Long-term results of treatment for glomus jugulare and glomus vagale tumors with radiotherapy. Laryngoscope. 1994;104(12):1461-1465.
50.
LarnerJMHahnSSSpauldingCAConstableWC.Glomus jugulare tumors. Long-term control by radiation therapy. Cancer. 1992;69(7):1813-1817.
51.
SkolyszewskiJKorzeniowskiSPszonJ.Results of radiotherapy in chemodectoma of the temporal bone. Acta Oncol. 1991;30(7):847-849.
52.
SahyouniRMahboubiHMoshtaghiO, et al. Radiosurgery of glomus tumors of temporal bone: a meta-analysis. Otol Neurotol. 2018;39(4):488-493.
53.
ShapiroSKellermeyerBRamadanJJonesGWisemanBCassisA.Outcomes of primary radiosurgery treatment of glomus jugulare tumors: systematic review with meta-analysis. Otol Neurotol. 2018;39(9):1079-1087.
54.
PatelNSCarlsonMLPollockBE, et al. Long-term tumor control following stereotactic radiosurgery for jugular paraganglioma using 3D volumetric segmentation. J Neurosurg. 2019;130:379-387.
55.
FishbeinLMerrillSFrakerDLCohenDLNathansonKL.Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450.
56.
ChaseWH.Familial and bilateral tumours of the carotid body. J Pathol Bacteriol. 1933;36(1):1-12.
57.
BaysalBEFerrellREWillett-BrozickJE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science2000;287(5454):848-851.
58.
FishbeinLNathansonKL.Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet2012;205(1-2):1-11.
59.
ElseTGreenbergSFishbeinL.Hereditary paraganglioma-pheochromocytoma syndromes. In: AdamMPArdingerHHPagonRA, et al. (eds). GeneReviews((R)). Seattle, WA: University of Washington; 1993. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1548/
60.
PasiniBStratakisCA.SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med. 2009;266(1):19-42.
61.
van der TuinKMensenkampARTopsCMJ, et al. Clinical aspects of SDHA-related pheochromocytoma and paraganglioma: a nationwide study. J Clin Endocrinol Metab. 2018;103(5):438-445.
62.
BauschBSchiaviFNiY, et al. Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncol. 2017;3(9):1204-1212.
63.
BennDEZhuYAndrewsKA, et al. Bayesian approach to determining penetrance of pathogenic SDH variants. J Med Genet. 2018;55(11):729-734.
64.
AndrewsKAAscherDBPiresDEV, et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55(6):384-394.
65.
JochmanovaIWolfKIKingKS, et al. SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. J Cancer Res Clin Oncol. 2017;143(8):1421-1435.
66.
RickettsCJFormanJRRattenberryE, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat2010;31(1):41-51.
67.
RijkenJANiemeijerNDJonkerMA, et al. The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers. Clin Genet. 2018;93(1):60-66.
68.
van HulsteijnLTDekkersOMHesFJSmitJWCorssmitEP.Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. J Med Genet. 2012;49(12):768-776.
69.
LendersJWPacakKWaltherMM, et al. Biochemical diagnosis of pheochromocytoma: which test is best?JAMA. 2002;287(11):1427-1434.
70.
JaspersonKWKohlmannWGammonA, et al. Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Fam Cancer. 2014;13(2):257-265.
71.
JanssenIBlanchetEMAdamsK, et al. Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma. Clin Cancer Res2015;21(17):3888-3895.
72.
JanssenIChenCCTaiebD, et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. J Nucl Med. 2016;57(2):186-191.
