|Year : 2015 | Volume
| Issue : 3 | Page : 268-271
An uncommon cause of hypertension: Paraganglioma revisited
Babulreddy Hanmayyagari1, Sri Nagesh Voleti2, Mounika Guntaka3, Srinivas Sidduri4
1 Department of Medicine, KIMS, Narketpally, Nalgonda, India
2 Department of Endocrinology, Care Hospital, Banjara Hills, Hyderabad, India
3 Department of Biochemistry, Chalemeda Anadarao Medical College, Karimnagar, India
4 Department of Endocrinology, Gandhi Medical College, Secunderabad, Telangana, India
|Date of Web Publication||12-Jun-2015|
Flat No-A 904, Sri Sai Ram Towers, Beside Alwyn Colony Water Tank, Hafeezpet, Hyderabad - 500 049, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
A significant number of secondary hypertension could be due to endocrine etiology. The pheochromocytoma/paraganglioma (PGL) syndrome is one among them. We herein report a case of PGL in a young woman, who presented to us with hypertension and its reversal after surgical treatment. In this review, we also discussed in detail about this rare entity.
Keywords: Hypertension, paraganglioma, pheochromocytoma/paraganglioma syndrome (pheochromocytoma/paraganglioma)
|How to cite this article:|
Hanmayyagari B, Voleti SN, Guntaka M, Sidduri S. An uncommon cause of hypertension: Paraganglioma revisited. CHRISMED J Health Res 2015;2:268-71
|How to cite this URL:|
Hanmayyagari B, Voleti SN, Guntaka M, Sidduri S. An uncommon cause of hypertension: Paraganglioma revisited. CHRISMED J Health Res [serial online] 2015 [cited 2019 Oct 23];2:268-71. Available from: http://www.cjhr.org/text.asp?2015/2/3/268/158713
| Introduction|| |
Hypertension is a very common disorder in clinical practice, which significantly contributes to mortality and morbidity globally. Primary (essential) hypertension is the term applied when no cause for hypertension identified. It constitutes 95% patients of hypertension, , the rest of the cases are due to secondary hypertension, which arises due to an identifiable cause. The etiologies for secondary hypertension are diverse, including renal, endocrine, drugs, etc.
The endocrine causes of secondary hypertension include primary hyperaldosteronism, Cushing's disease, pheochromocytoma (PHEO), acromegaly, hyperparathyroidism, hypo, and hyperthyroidism.  It is important to identify secondary causes of hypertension due to endocrine disorders, because with appropriate intervention usually results in the amelioration or substantial improvement of the hypertension.
We herein report a case of secondary hypertension due to a paraganglioma (PGL) (extra-adrenal PHEO) and reversal of hypertension after surgical treatment, and then we will also briefly discuss about this rare entity.
| Case Report|| |
A 27-year-old female was referred to the Endocrinology Outpatient Department for the evaluation of hypertension. She was diagnosed to have hypertension on routine examination 1-month ago; her initial blood pressure recording was 200/120 mm of Hg and even on a combination therapy of telmisartan 40 mg twice daily and amlodipine 10 mg/day it was inadequately controlled with a blood pressure of 160/100 mm of Hg. She denied any history of paroxysms, polyuria, periodic paralysis, or symptoms suggestive of Cushing's syndrome. History was also negative for hypo/hyperthyroidism. No family history of hypertension was noted.
On examination, no neurocutaneous markers were found; her pulse rate was regular 100 beats/min, blood pressure of 160/100 mm of Hg in lying down position and 140/100 mm of Hg 2 min after standing. Systemic examination including the heart, lungs, central nervous system and gastrointestinal system was normal. There was no renal bruit heard over the abdomen.
Hemoglobin was 10.9% with a total leukocyte count of 6000/cumm, erythrocyte sedimentation rate was 10 mm, random blood sugar - 86 mg/dl, serum creatinine - 0.6 mg/dl and liver function tests, serum electrolytes were normal, T3 was 1.6 ng/ml, T4-9.2 μg/dl and TSH - 2.3 μIU/ml (0.3-5.5), ultrasonogram of the abdomen showed normal kidney size and echotexture. Two-dimensional echocardiogram and renal Doppler were normal. 24 h urinary metanephrine was 0.6 mg/day (0-1), nor metanephrine was 7,590 μg/day (0-600). Free plasma metanephrine was 17.70 pg/ml (0-90) and free plasma nor metanephrine 402 pg/ml (0-180). Computed tomography (CT) of whole abdomen with contrast suggested left para-aortic mass measuring 3 cm × 4.3 cm × 4.6 cm with heterogeneous contrast enhancement, is seen just caudal to the level of the left renal hilum most likely a PGL [Figure 1] and 123 I-metaiodobenzylguanidine (MIBG) scan also revealed solitary functional PGL [Figure 2].
|Figure 1: Contrast-enhanced computed tomography was showing paraganglioma|
Click here to view
|Figure 2: 123I-metaiodobenzylguanidine was showing solitary functioning paraganglioma|
Click here to view
The patient diagnosed to have secondary hypertension due to hormonally active solitary PGL. She was advised to take the liberal salt intake along with phenoxybenzamine at a starting dose of 10 mg/day, which then titrated until normalization of blood pressure. Once target blood pressure achieved, patient was started on Atenolol 25 mg twice daily for the associated tachycardia. After 2 weeks of this preparation, the patient underwent surgery with laparoscopic removal of the tumor under general anesthesia. Intra and postoperative period was uneventful. Histopathology of the tumor revealed a PGL without any features of malignant transformation. Post-operatively, the patient's blood pressure normalized; 2 weeks after postsurgery her 24 h urinary nor metanephrine was 116.53 μg/day (0-600) and free plasma nor metanephrine was 67.1 pg/ml (0-180), indicating successful removal of tumor.
The patient is presently doing well with maintaining normal blood pressure and on regular follow-up in Endocrinology Outpatient Department.
| Discussion|| |
Paraganglioma (extra-adrenal PHEO) is a neuroendocrine tumor, originating from embryonic neural crest cells. Sympathetic PGLs usually secrete catecholamines and are located in the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. Though they mimic PHEO clinically, differentiation is required for the evaluation of malignant risk and genetic testing. On the other hand, most parasympathetic PGLs are nonfunctional and located along the IX and X cranial nerves in the neck and at the base of the skull.
The majority of PGLs are sporadic in occurrence and approximately one-third to one-half , are associated with an inherited syndrome. Hereditary PGLs occur with following genetic syndromes, namely multiple endocrine neoplasia types 2A and 2B (MEN2), neurofibromatosis type 1 (NF1), von Hippel-Lindau (VHL), and Carney triad and some PGLs are associated with mutations in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. Most PGLs are solitary, but they tend to be multicentric in hereditary syndromes. 
The clinical presentation of these tumors can be either due to mass effect or related to excess catecholamine secretion. The diagnosis is made based on the physical examination, family history, biochemical testing, imaging modalities and molecular genetic testing. The first step in the evaluation of a suspected case of PHEO/PGL syndrome (PHEO/PGL) is biochemical confirmation of catecholamine excess status. This is done by 24-hour urinary vanillylmandelic acid, 24-h urinary fractionated metanephrines and serum catecholamines. Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations.  Biochemical phenotype may also be useful to predict the site and syndromic association, thereby helping in genetic testing. Predominantly epinephrine (metanephrine) secreting tumors are almost always located in adrenal glands and are commonly encountered with MEN-2 syndromes. Only norepinephrine (normetanephrine) secreting tumors arise either from the adrenal medulla or other sympathetic ganglia, which are located in the pelvis, abdomen and thorax along the paravertebral area. They are usually associated with VHL and SDH related syndromes. Isolated or co-secretion of dopamine (best assessed with plasma or urinary methoxytyramine) is associated with higher risk of malignancy.
Computed tomography or magnetic resonance imaging (MRI) is useful in tumor localization and also for tumor staging,  CT scan is preferred for its better spatial resolution of thorax, abdomen, pelvis, MRI is preferred in patients with metastasis and conditions where minimal radiation is required (e.g. pregnancy). MIBG scintigraphy is useful when CT or MRI is negative, to further characterize masses detected by CT or MRI and for the detection of additional tumors.  Newer positron emission tomography functional imaging with 18F-fluorodeoxyglucose, 3,4-dihydroxy-6-(18) F-fluoro-l-phenylalanine and [18F]-fluorodopamine are also available and promising in the management of PHEO/PGL syndromes with superior sensitivity for malignant PGLs than MIBG. 
Till date about 14 genes identified with the development of PHEO/PGL syndromes  (RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, EGLN1, HIF2A, H-RAS, and KIF1B). Currently, several authors have proposed genetic testing for all patients with PHEO/PGL syndromes. , Mutations in TMEM127, MAX, HIF2A, and SDHAF2are extremely rare and hence they should only be analyzed when patients are negative for the other gene mutations. 
Wide surgical excision is the gold standard treatment of PGL. Preoperative preparation with an alpha blocker, followed by addition of beta blocker is essential to improve outcomes.  Hypertensive crisis during the intraoperative period should be done with sodium nitropusside or phentolamine. Postoperative follow-up with a urinary Metanephrine assay is an important tool in predicting recurrence of the tumor. As with any endocrine tumors, distant metastasis is the only certain indicator of malignancy. 131 I-MIBG is used for patients in whom 123 I-MIBG scintigraphy is positive.  Chemotherapy is preferred in patients with negative 123 I-MIBG scintigraphy and in those with rapidly progressing tumors. 
Hence in summary, a high degree of suspicion is required for the diagnosis of endocrine hypertension, PHEO/PGL should be included in the differential diagnosis, though they have persistent hypertension without any paroxysmal symptoms, because excision of tumor mostly controls underlying hypertension and associated morbidity and mortality in these patients. We also stress the point that normetanephrine assay (or fractionated Metanephrines) must be included in the investigation as most of the practitioners write only urinary Metanephrines, which can potentially give false negative results in the diagnosis of PHEO/PGL syndromes. The limitation in this case study was that we have not carried out molecular genetic testing in our patient, due to financial constraints.
| References|| |
Carretero OA, Oparil S. Essential hypertension. Part I: Definition and etiology. Circulation 2000;101:329-35.
Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med 2003;139:761-76.
Sica DA. Secondary forms of hypertension. In: Hypertension. Philadelphia, PA: American College of Physicians; 2005. p. 167-88.
Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F, et al.
SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010;19:3011-20.
Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL. Inherited mutations in pheochromocytoma and paraganglioma: Why all patients should be offered genetic testing. Ann Surg Oncol 2013;20:1444-50.
Hamilton BH, Francis IR, Gross BH, Korobkin M, Shapiro B, Shulkin BL, et al.
Intrapericardial paragangliomas (pheochromocytomas): Imaging features. AJR Am J Roentgenol 1997;168:109-13.
Young WF Jr. Endocrine hypertension. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams Textbook of Endocrinology. 12 th
ed. Philadelphia, PA: Saunders Elsevier Inc.; 2011. p. 545-80.
Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, et al.
Pheochromocytoma: Recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 2007;3:92-102.
Havekes B, King K, Lai EW, Romijn JA, Corssmit EP, Pacak K. New imaging approaches to phaeochromocytomas and paragangliomas. Clin Endocrinol (Oxf) 2010;72:137-45.
Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2013;78:165-75.
Mannelli M, Castellano M, Schiavi F, Filetti S, GiacchèM, Mori L, 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;94:1541-7.
Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher ER, et al.
Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 2006;65:699-705.
Martins R, Bugalho MJ. Paragangliomas/Pheochromocytomas: Clinically oriented genetic testing. Int J Endocrinol 2014;2014:794187.
Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 2007;92:4069-79.
Gedik GK, Hoefnagel CA, Bais E, Olmos RA. 131I-MIBG therapy in metastatic phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2008;35:725-33.
Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, et al.
Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988;109:267-73.
[Figure 1], [Figure 2]