Correspondence *Watkins 3, Room 4-330, Kingston General Hospital, 76 Stuart Street, Kingston, ON K7L 2V7, Canada

Email houldenr@post.queensu.ca

The case

A 40-year-old man was referred to our clinic for the management of recurrent paragangliomas. He was intellectually challenged, secondary to phenylketonuria, which was detected on newborn screening; he was, therefore, unable to give a complete history.

Research into the patient's family history revealed that his mother had died at 39 years of age of metastases from a carotid body tumor.¹ Autopsy revealed metastases in her liver and intestinal tract compatible with malignant paraganglioma. At 19 years of age, the patient had developed headaches, hypertension, and episodic lightheadedness. Elevated catecholamine excretion was revealed by 24 h urine collections, and a CT scan revealed a tumor arising from the right adrenal gland. The patient underwent surgical exploration at this time and during the operation a tumor superior to the right kidney was excised, along with the right kidney and 5 cm of the wall of the inferior vena cava. The adrenal gland was left intact and seemed normal. Pathology of the tumor was compatible with an extra-adrenal paraganglioma. Postoperatively, the patient was well until 39 years of age when he developed episodes of headache and palpitations.

On presentation to our clinic, the patient was found to be hypertensive with a blood pressure averaging around 160/100 mmHg. He had elevated norepinephrine:creatinine, metanephrine:creatinine, and vanillylmandelic-acid:creatinine ratios that were revealed after 24 h urine collections (Table 1). With the exception of changes compatible with his previous surgery, a CT scan of the abdomen was unremarkable. ¹³¹I-labeled meta-iodobenzylguanidine (MIBG) scanning with imaging from the base of the skull to the base of the bladder at 24, 48, and 74 h revealed two paragangliomas: a 3 cm lesion in the mid abdomen and a 2 cm lesion 6 cm inferior to it (Figure 1).

Figure 1 ¹³¹I-labeled meta-iodobenzylguanidine scanning showing abdominal paragangliomas (arrows) in the patient described (anterior view)

 

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Table 1 Results of the patient's 24 h urine collections before and after treatment

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The patient was treated preoperatively for 6 weeks with 20 mg doxazosin daily, 200 mg labetalol daily, 120 mg diltiazem twice daily, and 250 mg metirosine (also known as metyrosine) three times daily. His symptoms resolved and his blood pressure was 120/85 mmHg lying down, and 100/70 mmHg when he stood upright. Salt-loading was not provided. After 5 weeks of drug therapy, 24 h urine collection revealed reduced epinephrine:creatinine and vanillylmandelic-acid:creatinine ratios (Table 1). Surgery was performed with excision of two para-aortic paragangliomas that measured 3.3 cm by 2.2 cm by 1.5 cm and 1.0 cm by 0.8 cm by 0.7 cm. Histology revealed that the tumor nodules were relatively well circumscribed with a fibrous capsule of variable thickness. Epithelioid cells had moderately abundant amphophilic cytoplasm, and round-to-oval vesicular nuclei that were arranged in solid clusters with interconnecting trabeculae, within a richly vascularized, loose connective tissue stroma. There was moderate nuclear pleomorphism with rare giant cells. Mitotic activity was low, with only a rare mitotic figure identified. There was no tumor necrosis or angiolymphatic channel invasion (Figure 2).

Figure 2 Histology of the para-aortic paragangliomas from the patient described

The sample was stained with hematoxylin phloxine saffron (magnification 400).

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The lesions were felt to be recurrent paragangliomas rather than node metastases because no lymphoid tissue was seen. The right adrenal gland was excised and was found to have a normal histology. In addition, a 1.2 cm ganglioneuroma next to the right adrenal gland was excised. Histology of the ganglioneuroma revealed a haphazard proliferation of S100 positive spindle cells associated with rare ganglion cells that seemed mature.

The patient had persistently elevated norepinephrine:creatinine, epinephrine:creatinine, metanephrine:creatinine, and vanillylmandelic-acid:creatinine ratios 6 weeks after surgery (Table 1). Uptake of ¹³¹I MIBG near the mediastinum was revealed by ¹³¹I MIBG scintigraphy performed 4 months postoperatively. A review of his initial MIBG scan revealed that this uptake had been present at that time, but was not detected by the radiologist. A CT and MRI scan revealed a 5.5 cm by 3.0 cm by 4.5 cm mass in the interatrial septum causing compression and displacement of the superior vena cava, right pulmonic vein, and left atrium (Figure 3).

Figure 3 Different views of the MRI scan of interatrial septum paraganglioma in the patient described

(A) Coronal T1 weighted image of the chest demonstrating interatrial septum paraganglioma. (B) Axial T2 weighted image of the chest demonstrating interatrial septum paraganglioma with diffuse increased signal intensity. (C) Coronal T2 weighted image of the chest demonstrating interatrial septum paraganglioma with diffuse increased signal intensity.

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The patient was started on 10 mg phenoxybenzamine twice daily, 200 mg labetalol daily, 120 mg diltiazem twice daily, and 250 mg metirosine four times daily. After 4 weeks of drug therapy, 24 h urine collections revealed an epinephrine:creatinine ratio of 8.3 nmol/mmol, a norepinephrine:creatinine ratio of 498.4 nmol/mmol, and a metanephrine:creatinine ratio of 2.07 mol/mmol (Table 1). Surgery was performed with excision of a 5.5 cm by 4.0 cm by 3.5 cm paraganglioma involving both atria. Pathology revealed a similar morphology to that of the tumor described in the previous surgery. Most of the atrial tissue was excised and required patch reconstruction. The patient had normal epinephrine:creatinine, norepinephrine:creatinine, metanephrine:creatinine, and vanillylmandelic-acid:creatinine ratios 6 weeks postoperatively (Table 1).

The patient was screened for hereditary paraganglioma. Genetic testing for succinate dehydrogenase complex, subunit B (SDHB) gene mutations was performed because of the history of an extra-adrenal paraganglioma. A previously unpublished mutation (c.600G>T; p.Trp200Cys) was identified by sequence analysis. This heterozygous nucleotide change of guanine to thymidine at the third nucleotide of codon 200 in exon 6 in one copy of SDHB causes an amino acid change of tryptophan to cysteine.

Given the possibility that the patient might have experienced malignant rather than recurrent paragangliomas, and that he might have nonfunctional tumors, MRI scanning of the neck, thorax, abdomen, and pelvis was performed, but no evidence of a tumor was found. In the future, 6-[¹⁸F]fluorodopamine PET scanning will be performed to search for metastases, and, if negative, this will be followed by ¹¹¹In pentetreotide scanning. In terms of follow-up, MRI and CT scanning every 6–12 months will be carried out to search for nonfunctional tumors. Physical examination with annual measurements of blood pressure and levels of urinary catecholamines and metanephrines will also be undertaken. If these procedures suggest a recurrence of paraganglioma, ¹²³I MIBG scanning will be performed.

Discussion of diagnosis

Paragangliomas are tumors derived from the parasympathetic and sympathetic nervous systems.² The sympathetic-associated paragangliomas arise from the adrenal medulla or from the sympathetic ganglia that extend along the paravertebral axis from the neck to the abdomen and pelvis. These tumors are usually functionally active and secrete either catecholamines or metanephrines. The parasympathetic-associated paragangliomas arise in the head and neck region and middle mediastinum, and are usually nonfunctioning. The term pheochromocytoma is commonly used for a tumor located in the adrenal gland.

There are several documented, hereditary pheochromocytoma and paraganglioma disorders, and recent reports have suggested that up to 27.4% of all cases of pheochromocytoma and paraganglioma are associated with gene mutations.^{3, 4, 5} All cases of hereditary pheochromocytoma and paraganglioma disorders display an autosomal dominant inheritance pattern with variable penetrance. The prevalence of pheochromocytomas in cases of hereditary pheochromocytoma and paraganglioma disorders is 10–20% in patients with von Hippel–Lindau disease, approximately 40% in patients with multiple endocrine neoplasia type 2A and 2B, and 0.1–5.0% in patients with neurofibromatosis type 1.⁶

There are four types of familial paraganglioma (PGL) syndromes that have been identified with mutations in the SDH genes that encode subunits of the heterotetrameric SDH complex. SDH is involved in oxidation of succinate to fumarate in the Krebs cycle and provides electrons to the mitochondrial electron transport chain.⁷ PGL type 1 is associated with germline mutations in the succinate dehydrogenase complex, subunit D gene (SDHD),⁸ PGL type 4 is associated with mutations in SDHB,⁹ PGL type 3 is associated with mutations in the succinate dehydrogenase complex, subunit C gene (SDHC),¹⁰ and the susceptibility gene for PGL type 2 remains unidentified.

An international cohort study, published in 2006, included 49 patients with SDHB or SDHD mutations.¹¹ This study revealed that SDHD mutations (PGL type 1) are associated with multifocal head and neck paragangliomas, whereas SDHB mutations (PGL type 4) are associated with extra-adrenal disease and malignancy.¹¹ Although a number of germline mutations have been reported,¹² the patient we describe seemed to have a previously unpublished SDHB mutation. SDHB encodes an iron-sulfur protein catalytic subunit of the SDH complex. The mechanism by which the mutations cause tumors remains to be elucidated. Hypotheses include mitochondrion-mediated failure of apoptosis or activation of the angiogenesis pathway.¹³ Several groups have recently demonstrated the link between succinate and activation of the angiogenesis pathway by prolyl hydroxylase hydroxylation.¹⁴Our case is also unusual because the patient presented with elevated epinephrine excretion in the urine. Most patients with paragangliomas caused by SDHB mutation have only elevated norepinephrine levels.¹¹

Genetic testing should be considered for patients diagnosed with pheochromocytoma and functional paraganglioma. Most case series have been too small to identify precisely an upper age limit for genetic testing in patients with a sporadic presentation; however, it seems that most patients with a germline mutation are typically younger than 55 years of age.³ For patients with apparently sporadic pheochromocytoma or functional paraganglioma tumors, genetic testing for SDHB mutations and von Hippel–Lindau disease should be performed first and, if negative, screening for SDHD and SDHC gene mutations should then be performed.³ For individuals presenting with head and neck paragangliomas, testing for SDHD mutations should be performed first.¹⁵ For patients found to have malignant paragangliomas, testing for SDHB mutations should be the initial screen.¹¹ For patients with a family history of pheochromocytoma or paraganglioma, a syndromic presentation, or both, the appropriate genetic screening for von Hippel–Lindau disease, multiple endocrine neoplasia type 2 (caused by a mutation in the RET proto-oncogene), and neurofibromatosis type 1 should be performed. If the results of genetic testing are positive, genetic counseling and testing of relatives should be offered.

Treatment and management

Several studies have suggested that patients who are carriers of the SDHB mutation (PGL type 4), like the patient we describe, are more likely to develop extra-adrenal pheochromocytomas (abdominal or thoracic) and malignant disease.^{5, 11, 15} It is unclear whether our patient's recurrent paragangliomas were metastases or primary tumors. The WHO defines malignant pheochromocytomas and paragangliomas as metastatic disease at sites where chromaffin tissues are not usually present.² Metastatic sites include the lungs, bones, liver, and lymph nodes. Malignant tumors are typically larger, have a higher mitotic count, have extensive local or vascular invasion and express fewer peptides on immunohistochemical studies compared with benign tumors. For our patient, the paragangliomas have been in locations normally associated with chromaffin cells and the histology has not been highly suggestive of malignant disease. Clonality studies on paraffin sections from the patient's pathology specimens might help distinguish whether our patient experienced recurrent paragangliomas or metastases.^{16, 17} To search for metastases, 6-[¹⁸F]fluorodopamine PET scanning or ¹¹¹In pentetreotide somatostatin receptor scintigraphy is indicated.¹⁸ The patient will be required to undergo an annual monitoring program with a physical examination and measurement of blood pressure and levels of urinary catecholamines and metanephrines. If these procedures suggest a recurrence of his paraganglioma, ¹²³I MIBG scanning should be performed. As the patient might develop nonfunctional tumors, however, he should also undergo CT scanning, MRI scanning, or both, of the neck, thorax, abdomen, and pelvis every 6–12 months.

If an isolated tumor is found in the future, our patient will probably be offered resection. If the tumor(s), however, are felt to be nonresectable because of the location or number, combination cytotoxic chemotherapy, ¹³¹I MIBG treatment, or both, would be considered, since these therapies have been shown to palliate symptoms and to be associated with prolongation of survival.¹⁹

The patient's brother has been offered genetic screening. If this individual is found to have the same SDHB mutation, the authors would recommend that he undergo a monitoring program that consists of a careful evaluation of his history and a physical examination with annual measurements of blood pressure and levels of urinary catecholamines and metanephrines. Biennial imaging (e.g. neck, thorax, abdomen, and pelvis), by CT scanning, MRI scanning, or both, should also be performed.

Conclusion

This case outlines the clinical course of a patient with a familial disorder associated with pheochromocytoma. Specifically, the patient was diagnosed with PGL type 4 with a previously unpublished mutation in SDHB. The case highlights the importance of offering targeted genetic testing for the SDHB gene mutations to a patient with multiple, extra-adrenal paragangliomas and a maternal history of malignant paraganglioma. It also illustrates the importance of identifying patients with germline SDHB mutations, as these patients are at a high risk of developing malignant disease.

References

1. Titcombe AF and Wellington JL (1962) Carotid body tumour. CMAJ 87: 810–812 | ChemPort |
2. DeLellis RA et al. (2004) Pathology and genetics of tumours of endocrine organs. In World Health Organization Classification of Tumours, 138–159 (Eds Kleihues P and Sobin LE) Lyon, France: IARC Press
3. Amar L et al. (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 34: 8812–8818 | Article |
4. Neumann HP et al. (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346: 1459–1466 | Article | PubMed | ISI | ChemPort |
5. Gimenez-Roqueplo AP et al. (2003) Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 63: 5615–5621 | PubMed | ISI | ChemPort |
6. Yeo H and Roman S (2005) Pheochromocytoma and functional paraganglioma. Curr Opin Oncol 17: 13–18 | Article | PubMed | ISI |
7. Eng C et al. (2003) A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3: 193–202 | PubMed | ChemPort |
8. Baysal BE et al. (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848–851 | Article | PubMed | ISI | ChemPort |
9. Astuti D et al. (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69: 49–54 | Article | PubMed | ISI | ChemPort |
10. Muller U et al. (2005) SDHC mutations in hereditary paraganglioma/pheochromocytoma. Fam Cancer 4: 9–12 | Article | PubMed | ChemPort |
11. Benn DE et al. (2006) Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 91: 827–836 | Article | PubMed | ISI | ChemPort |
12. Bayley JP et al. (2005) The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med Genet 6: 39–44 | Article | PubMed | ChemPort |
13. Gimenez-Roqueplo AP et al. (2002) Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 87: 4771–4774 | Article | PubMed | ISI | ChemPort |
14. Esteban MA and Maxwell PH (2005) HIF, a missing link between metabolism and cancer. Nat Med 11: 1047–1048 | Article | PubMed | ChemPort |
15. Neuman HP et al. (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292: 943–951 | Article | PubMed | ISI | ChemPort |
16. Jin Y et al. (1996) Clonal chromosome abnormalities in two chemodectomas. Genes Chromosomes Cancer 15: 178–181 | ChemPort |
17. Baylin SB et al. (1976) Clonal origin of inherited medullary thyroid carcinoma and pheochromocytoma. Science 193: 321–323 | Article | PubMed | ChemPort |
18. Ilias I and Pacak K (2004) Anatomical and functional imaging of metastatic pheochromocytoma. Ann NY Acad Sci 1018: 495–504 | Article | PubMed | ChemPort |
19. Sisson JC et al. (1999) Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy. Am J Clin Oncol 22: 364–370 | Article | PubMed | ISI | ChemPort |

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Subject areas under which this article appears: Adrenal gland (including endocrine hypertension) | Genetics