Case Report SDHB Gene Mutation in a Carotid Body Paraganglioma: Case Report and Review of the Paraganglioma Syndromes Laura A. Peterson, Maria Litzendorf, Matthew D. Ringel, and Patrick S. Vaccaro, Columbus, Ohio
Carotid body tumors represent the most common of head and neck tumors. They account for A, p. Arg230His. The patient was referred to thoracic surgery for excision of the mediastinal mass. After successful removal of the mass, the plasma-free metanephrines normalized to 0.52 and have remained normal for 13 months after surgery. He has been off of the doxasocin as well with no recurrence of hypertension or other symptoms.
DISCUSSION Carotid body tumors usually present as a painless slowly enlarging mass within the lateral neck.1,4,16 The doubling time of these tumors has been estimated to be 7.13 years with a median growth rate of 0.83 mm/year.17 As mentioned, very rarely do these tumors have a functional role.10e13 In most cases, the patient will present with mass effects causing dysphagia or deficits of the nearby cranial nerves and Horner syndrome.4,11 The mass in question is usually movable in the horizontal plan but limited in the vertical plane, which is also known as Fontaine sign. A bruit or thrill may be associated with the mass but the absence of these signs does not exclude a carotid body tumor. Bilateral involvement is uncommon but may be associated with familial cases.18 Carotid body paragangliomas are classified loosely according to the Shamblin criterion. In 1971, Shamblin created a three-stage classification system to grade the difficulty of resection in carotid body tumors.19 This is purely an operative classification. Type I tumors are defined as localized and easily resected. Type II tumors are adherent to or partially surrounding the carotid vessels. Type III carotid body tumors completely encase the carotid vessel. Approximately 70% of all carotid body tumors are defined as type II or type III thus increasing the risk for injury to the carotid vessels and cranial nerves during resection. Histologic classification of carotid body tumors is somewhat more standardized.
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Case Report 3
Fig. 2. (A) Neoplastic cells of paraganglioma negative for cytokeratin AE1/AE3; (B) cytoplasmic staining for marker synaptophysin; (C) cytoplasmic staining for neuroendocrine
marker chromogranin; and (D) S-100 positive sustentacular cells around the clusters of chief cells. (Magnification 400).
They uniformly have a zellballen or cell ball growth pattern with sustentacular cells at their periphery. Roughly 30% of all head and neck paragangliomas are associated with various tumor syndromes and are hereditary. In this case, the paraganglioma syndromes are of particular interest. Three syndromes have been classified: PGL 1, 3, and 4. PGL 1 is due to a mutations in the succinate dehydrogenase subunit D or (SDHD) gene on chromosome 11q23 which encodes the small cytochrome b subunit within the mitochondrial succinate dehydrogenase complex.20,21 Initially, germline missense or nonsense mutations in this SDHD gene were detected with a loss of heterozygosity of a second allele in tumor tissue. This prompted the belief that the SDHD gene behaves like a typical tumor suppressor gene requiring biallelic loss.20 However, further studies have demonstrated that the loss of heterozygosity may not always be required within the tumor tissue but may also be a feature of maternal imprinting such that only the transmission of the diseased paternal phenotype occurs.22 The exact molecular mechanisms involved in this genetic transmission to date are unknown. In PGL 3, there is a germline mutation in the SDHC gene on chromosome 1q21 that causes an autosomal dominant paraganglioma distribution type without the need for genetic imprinting of the secondary allele.23,24 In PGL 4, the SDHB germline mutation on
chromosome 1p36 is also distributed in an autosomal dominant fashion and is in and of itself a less-frequent cause of nonfamilial cases.25,26 Of the rare genetic cohort data available regarding these syndromes, SDHD and SDHB together appear to account for over 70% of head and neck paragangliomas with a positive family history and A with subsequent protein change p Arg230His has been described previously in familial reports of carotid body paragangliomas.27 This SDHB mutation has been shown to reduce penetrance because of unknown factors and therefore may not present in a standard autosomal dominant pattern of inheritance as expected28,29
CONCLUSIONS Carotid body paragangliomas are exceedingly rare vascular tumors that require careful consideration. Any patient who has a slow growing neck mass should be sent for evaluation at a center familiar with their treatment and evaluation. Surgical excision is the only curative treatment modality and should be undertaken with care by experience surgical teams. Approximately 90% of all hereditary head and neck paragangliomas are related to the
4 Case Report
paragangliomas syndromes PGL 1, 3, and 4. Because 8% of apparently sporadic paragangliomas are due to transmissible germline mutations, any patient who presents with a suspected carotid body paraganglioma should be considered for genetic testing. Whenever a mutation has been detected, information should be shared with the entire familial cohort so that carriers may be identified and timely counseling and medical treatment may be provided. REFERENCES 1. Boedeker CC, Ridder GJ, Neumann HPH, et al. Therapie und Behandlungsergebnisse zervikaler Paragangliome. [Diagnosis and management of cervical paragangliomas: the Freiburg experience]. Laryngorhinootologie 2004;83:585e92. 2. Schipper J, Boedeker CC, Maier W, et al. Paragangliome im Kopf-/Halsbereich Teil 1: Systematik und Diagnostik. [Paragangliomas in the head-/neck region. I: classification and diagnosis]. HNO 2004;52:569e75. 3. Persky MS, Setton A, Niimi Y, et al. Combined endovascular and surgical treatment of head and neck paragangliomasda team approach. Head Neck 2002;24:423e31. 4. Lee JH, Barich F, Karnell LH, et al. National cancer data base report on malignant paragangliomas of the head and neck. Cancer 2002;94:730e7. 5. Georgiadis GS, Lazarides MK, Tsalkidis A, et al. Carotid body tumor in a 13-year-old child: case report and review of the literature. J Vasc Surg 2008;47:874e80. 6. Lee KY, Oh YW, Noh HJ, et al. Extraadrenal paragangliomas of the body: imaging features. AJR Am J Roentgenol 2006;187:492e504. 7. Wang SJ, Wang MB, Barauskas TM, et al. Surgical management of carotid body tumors. Otolaryngol Head Neck Surg 2000;123:202e6. 8. Smit AA, Timmers HJ, Wieling W, et al. Long-term effects of carotid sinus denervation on arterial blood pressure in humans. Circulation 2002;105:1329e35. 9. Timmers HJ, Karemaker JM, Wieling W, et al. Baroreflex and chemoreflex function after bilateral carotid body tumor resection. J Hypertens 2003;21:591e9. 10. Sobol SM, Dailey JC. Familial multiple cervical paragangliomas: report of a kindred and review of the literature. Otolaryngol Head Neck Surg 1990;102:382e90. 11. Patetsios P, Gable DR, Garrett WV, et al. Management of carotid body paragangliomas and review of a 30-year experience. Ann Vasc Surg 2002;16:331e8. 12. Groblewski JC, Thekdi A, Carrau RL. Secreting vagal paraganglioma. Am J Otolaryngol 2004;25:295e300. 13. Koch CA, Rodbard JS, Brouwers FM, et al. Hypotension in a woman with a metastatic dopamine-secreting carotid body tumor. Endocr Pract 2003;9:310e4.
Annals of Vascular Surgery
14. Rodriguez-Cuevas S, Lopez-Garza J, LabastidaAlmendaro S. Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck 1998;20:374e8. 15. Astrom K, Cohen JE, Willett-Brozick JE, et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 2003;113: 228e37. 16. Pellitteri PK, Rinaldo A, Myssiorek D, et al. Paragangliomas of the head and neck. Oral Oncol 2004;40:563e75. 17. Jansen JC, van den Berg R, Kuiper A, et al. Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal. Cancer 2000;88:2811e6. 18. Wang SH, Chiu KM, Cheng PW. Bilateral carotid body paragangliomas. CMAJ 2011;183:E606. 19. Shamblin WR, ReMine WH, Sheps SG, et al. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg 1971;122:732e9. 20. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848e51. 21. Heutink P, van der Mey AG, Sandkuijl LA, et al. A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet 1992;1:7e10. 22. Van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, et al. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 1989;2:1291e4. 23. Slane BG, Aykin-Burns N, Smith BJ, et al. Mutation of succinate dehydrogenase subunit C results in increased O2 oxidative stress, and genomic instability. Cancer Res 2006;66:7615e20. 24. Niemann S, Becker-Follmann J, Nurnberg G, et al. Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am J Med Genet 2001;98:32e6. 25. Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178e83. 26. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49e54. 27. Cerecer-Gill NY, Figuera LE, Llamas FJ, et al. Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma. Clin Cancer Res 2012;16:4148e54. 28. McDonnell CM, Benn DE, Marsh DJ, et al. K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2004;61:510e4. 29. Solis DC, Burnichon N, Timmers HJ, et al. Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin Genet 2009;75:354e63.
Carotid body tumors represent the most common of head and neck tumors. They account for A, p. Arg230His. The patient was referred to thoracic surgery for excision of the mediastinal mass. After successful removal of the mass, the plasma-free metanephrines normalized to 0.52 and have remained normal for 13 months after surgery. He has been off of the doxasocin as well with no recurrence of hypertension or other symptoms.
DISCUSSION Carotid body tumors usually present as a painless slowly enlarging mass within the lateral neck.1,4,16 The doubling time of these tumors has been estimated to be 7.13 years with a median growth rate of 0.83 mm/year.17 As mentioned, very rarely do these tumors have a functional role.10e13 In most cases, the patient will present with mass effects causing dysphagia or deficits of the nearby cranial nerves and Horner syndrome.4,11 The mass in question is usually movable in the horizontal plan but limited in the vertical plane, which is also known as Fontaine sign. A bruit or thrill may be associated with the mass but the absence of these signs does not exclude a carotid body tumor. Bilateral involvement is uncommon but may be associated with familial cases.18 Carotid body paragangliomas are classified loosely according to the Shamblin criterion. In 1971, Shamblin created a three-stage classification system to grade the difficulty of resection in carotid body tumors.19 This is purely an operative classification. Type I tumors are defined as localized and easily resected. Type II tumors are adherent to or partially surrounding the carotid vessels. Type III carotid body tumors completely encase the carotid vessel. Approximately 70% of all carotid body tumors are defined as type II or type III thus increasing the risk for injury to the carotid vessels and cranial nerves during resection. Histologic classification of carotid body tumors is somewhat more standardized.
Vol.
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No.
-, -
2014
Case Report 3
Fig. 2. (A) Neoplastic cells of paraganglioma negative for cytokeratin AE1/AE3; (B) cytoplasmic staining for marker synaptophysin; (C) cytoplasmic staining for neuroendocrine
marker chromogranin; and (D) S-100 positive sustentacular cells around the clusters of chief cells. (Magnification 400).
They uniformly have a zellballen or cell ball growth pattern with sustentacular cells at their periphery. Roughly 30% of all head and neck paragangliomas are associated with various tumor syndromes and are hereditary. In this case, the paraganglioma syndromes are of particular interest. Three syndromes have been classified: PGL 1, 3, and 4. PGL 1 is due to a mutations in the succinate dehydrogenase subunit D or (SDHD) gene on chromosome 11q23 which encodes the small cytochrome b subunit within the mitochondrial succinate dehydrogenase complex.20,21 Initially, germline missense or nonsense mutations in this SDHD gene were detected with a loss of heterozygosity of a second allele in tumor tissue. This prompted the belief that the SDHD gene behaves like a typical tumor suppressor gene requiring biallelic loss.20 However, further studies have demonstrated that the loss of heterozygosity may not always be required within the tumor tissue but may also be a feature of maternal imprinting such that only the transmission of the diseased paternal phenotype occurs.22 The exact molecular mechanisms involved in this genetic transmission to date are unknown. In PGL 3, there is a germline mutation in the SDHC gene on chromosome 1q21 that causes an autosomal dominant paraganglioma distribution type without the need for genetic imprinting of the secondary allele.23,24 In PGL 4, the SDHB germline mutation on
chromosome 1p36 is also distributed in an autosomal dominant fashion and is in and of itself a less-frequent cause of nonfamilial cases.25,26 Of the rare genetic cohort data available regarding these syndromes, SDHD and SDHB together appear to account for over 70% of head and neck paragangliomas with a positive family history and A with subsequent protein change p Arg230His has been described previously in familial reports of carotid body paragangliomas.27 This SDHB mutation has been shown to reduce penetrance because of unknown factors and therefore may not present in a standard autosomal dominant pattern of inheritance as expected28,29
CONCLUSIONS Carotid body paragangliomas are exceedingly rare vascular tumors that require careful consideration. Any patient who has a slow growing neck mass should be sent for evaluation at a center familiar with their treatment and evaluation. Surgical excision is the only curative treatment modality and should be undertaken with care by experience surgical teams. Approximately 90% of all hereditary head and neck paragangliomas are related to the
4 Case Report
paragangliomas syndromes PGL 1, 3, and 4. Because 8% of apparently sporadic paragangliomas are due to transmissible germline mutations, any patient who presents with a suspected carotid body paraganglioma should be considered for genetic testing. Whenever a mutation has been detected, information should be shared with the entire familial cohort so that carriers may be identified and timely counseling and medical treatment may be provided. REFERENCES 1. Boedeker CC, Ridder GJ, Neumann HPH, et al. Therapie und Behandlungsergebnisse zervikaler Paragangliome. [Diagnosis and management of cervical paragangliomas: the Freiburg experience]. Laryngorhinootologie 2004;83:585e92. 2. Schipper J, Boedeker CC, Maier W, et al. Paragangliome im Kopf-/Halsbereich Teil 1: Systematik und Diagnostik. [Paragangliomas in the head-/neck region. I: classification and diagnosis]. HNO 2004;52:569e75. 3. Persky MS, Setton A, Niimi Y, et al. Combined endovascular and surgical treatment of head and neck paragangliomasda team approach. Head Neck 2002;24:423e31. 4. Lee JH, Barich F, Karnell LH, et al. National cancer data base report on malignant paragangliomas of the head and neck. Cancer 2002;94:730e7. 5. Georgiadis GS, Lazarides MK, Tsalkidis A, et al. Carotid body tumor in a 13-year-old child: case report and review of the literature. J Vasc Surg 2008;47:874e80. 6. Lee KY, Oh YW, Noh HJ, et al. Extraadrenal paragangliomas of the body: imaging features. AJR Am J Roentgenol 2006;187:492e504. 7. Wang SJ, Wang MB, Barauskas TM, et al. Surgical management of carotid body tumors. Otolaryngol Head Neck Surg 2000;123:202e6. 8. Smit AA, Timmers HJ, Wieling W, et al. Long-term effects of carotid sinus denervation on arterial blood pressure in humans. Circulation 2002;105:1329e35. 9. Timmers HJ, Karemaker JM, Wieling W, et al. Baroreflex and chemoreflex function after bilateral carotid body tumor resection. J Hypertens 2003;21:591e9. 10. Sobol SM, Dailey JC. Familial multiple cervical paragangliomas: report of a kindred and review of the literature. Otolaryngol Head Neck Surg 1990;102:382e90. 11. Patetsios P, Gable DR, Garrett WV, et al. Management of carotid body paragangliomas and review of a 30-year experience. Ann Vasc Surg 2002;16:331e8. 12. Groblewski JC, Thekdi A, Carrau RL. Secreting vagal paraganglioma. Am J Otolaryngol 2004;25:295e300. 13. Koch CA, Rodbard JS, Brouwers FM, et al. Hypotension in a woman with a metastatic dopamine-secreting carotid body tumor. Endocr Pract 2003;9:310e4.
Annals of Vascular Surgery
14. Rodriguez-Cuevas S, Lopez-Garza J, LabastidaAlmendaro S. Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck 1998;20:374e8. 15. Astrom K, Cohen JE, Willett-Brozick JE, et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 2003;113: 228e37. 16. Pellitteri PK, Rinaldo A, Myssiorek D, et al. Paragangliomas of the head and neck. Oral Oncol 2004;40:563e75. 17. Jansen JC, van den Berg R, Kuiper A, et al. Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal. Cancer 2000;88:2811e6. 18. Wang SH, Chiu KM, Cheng PW. Bilateral carotid body paragangliomas. CMAJ 2011;183:E606. 19. Shamblin WR, ReMine WH, Sheps SG, et al. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg 1971;122:732e9. 20. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848e51. 21. Heutink P, van der Mey AG, Sandkuijl LA, et al. A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet 1992;1:7e10. 22. Van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, et al. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 1989;2:1291e4. 23. Slane BG, Aykin-Burns N, Smith BJ, et al. Mutation of succinate dehydrogenase subunit C results in increased O2 oxidative stress, and genomic instability. Cancer Res 2006;66:7615e20. 24. Niemann S, Becker-Follmann J, Nurnberg G, et al. Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am J Med Genet 2001;98:32e6. 25. Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178e83. 26. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49e54. 27. Cerecer-Gill NY, Figuera LE, Llamas FJ, et al. Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma. Clin Cancer Res 2012;16:4148e54. 28. McDonnell CM, Benn DE, Marsh DJ, et al. K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2004;61:510e4. 29. Solis DC, Burnichon N, Timmers HJ, et al. Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin Genet 2009;75:354e63.
