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Abstract

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Declaration of Interests
  6. References

Sympathetic paragangliomas are autonomic nervous system tumors associated with dysregulation of intracellular oxygen metabolism. Exposure to high altitudes is reported to activate the production of catecholamines in the sympathoadrenal system. We describe an individual with a paraganglioma complicated by a catecholamine crisis that occurred on the summit of Mount Kilimanjaro.


Case Report

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Declaration of Interests
  6. References

A 59-year-old man was diagnosed in 2004 with a norepinephrine-producing, right atrial paraganglioma in a tertiary hospital in the United States. Genetic testing was negative for germline point mutations and large deletions in the genes encoding subunits B and D of the mitochondrial complex II succinate dehydrogenase enzyme (SDHB and SDHD). No metastases were found at initial presentation. The tumor was surgically removed, after which the patient remained normotensive and asymptomatic for 3 years. During this time, the patient's plasma and urinary catecholamine and metanephrine levels were normal.

In 2007, the patient climbed Mount Kilimanjaro (19,340 ft; 5895 m) in Tanzania with the help of an experienced guide. The patient had received a pre-travel medical evaluation and was felt not to have active medical conditions or symptoms that would have prevented him from making the trip. Plasma normetanephrines had been measured 8 months prior and were reported as normal. The ascension to the Uhuru Peak (the summit of Mount Kilimanjaro) took 6 days. After reaching the summit, he developed palpitations, throbbing headaches, diaphoresis, tremulousness, anxiety, panic attacks, and intense oppressive chest pain. He did not experience nausea, vomiting, anorexia, or altered mental status.

The patient was taken to a local hospital, where his symptoms persisted. His blood pressure was 180/110 mm Hg, and his pulse rate was over 100 beats per minute. A myocardial infarction was ruled out. A 24-hour urine collection revealed normetanephrine excretion of 10,563 µg/24 hour (normal, <900 µg/24 h). The patient was treated with alpha and beta blockers, and he underwent an abdominal computed tomography study that showed lesions suggesting metastases in the liver, pelvic bones, and intra-abdominal/intrapelvic lymph nodes.

After returning to the United States, a biopsy of a pelvic bone mass (Figure 1) confirmed metastatic paraganglioma. For a year, the patient was treated with 16 cycles of cyclophosphamide, vincristine, and dacarbazine (CVD). Although tumor size did not respond to systemic treatment, his catecholamines decreased. For 6 months he was observed off treatment. Ultimately, a progressive rise of plasma catecholamines was identified, and CVD chemotherapy was reinitiated 4 months later. Early this year, the patient had symptomatic and radiographic progression of disease with the appearance of new metastases in the lungs and the skeleton. The patient initiated systemic therapy using the oral tyrosine kinase inhibitor sunitinib for 2 months. Unfortunately, his clinical condition deteriorated due to meningeal paragangliomatosis and he expired.

image

Figure 1. The arrows show multiple pelvic bone metastases. Biopsy from these lesions confirmed metastatic paraganglioma.

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Discussion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Declaration of Interests
  6. References

We hypothesized that exposure to low oxygen pressure due to high altitude triggered a sympathetic reaction in this patient, who released an excessive amount of catecholamines from a subclinical metastatic paraganglioma.

It is well known that exposure to high altitudes challenges the human body because of the extremely strenuous conditions and the associated hypobaric hypoxia.1 Hypoxia can elicit complex responses in the body. The output of chemoreceptors and baroreceptors increases, which in turn increases sympathetic outflow.2,3 Catecholamines are then released from the adrenal medulla and the peripheral sympathetic ganglia to preserve metabolic homeostasis by increasing oxygen delivery through high cardiac output, redistribution of blood flow, and alteration of local metabolism in vital organs.2 Many studies have emphasized the role of the autonomic nervous system, especially sympathetic activation, in adaptation to high altitude exposure.4 Measuring urine catecholamines in 11 healthy men who had climbed a 14,107 ft (4300 m) peak, Mazzeo and colleagues5 found increased urinary excretion of norepinephrine and a correlation between increased arterial norepinephrine concentrations and increased vascular resistance. A later study confirmed these results in a group of healthy women.6 Pheochromocytomas (tumors localized in the adrenal gland medulla) and paragangliomas (tumors localized outside the adrenal gland medulla) are rare, highly vascular tumors originated in the paraganglia of the autonomic nervous system. Although the respiratory and cardiovascular responses to hypoxia have never been investigated in patients with pheochromocytomas and paragangliomas, it is reasonable to assume that the release of catecholamines by these tumors could be subject to normal physiological regulation. Evinger and colleagues7 have demonstrated an increased expression of tyrosine hydroxylase, the rate-limiting enzyme of the catecholamine synthesis pathway, and an increased activation of the epinephrine synthesizing gene phenylethanolamine N-metyltransferase (PNMT) in mouse pheochromocytoma cells under hypoxic conditions. Kumar and colleagues8 have also demonstrated that the release of norepinephrine from PC-12 cells in conditions of low partial pressure of oxygen (less than 40 mm Hg) is very much increased than under conditions of normoxia.

Tumors that originate from the sympathetic paraganglia in the mediastinum, abdomen, or pelvis are associated with excessive catecholamine metabolism, whereas paragangliomas of the head and neck are not. Regardless of tumor location, abnormalities in oxygen metabolism seem to play a major role in the development of these tumors. In humans, many pheochromocytomas and paragangliomas occur in association with inactivating germline mutations of the SDHB, SDHC, and SDHD genes.9 The resulting mitochondrial dysfunction has been linked to tumorigenesis by the activation of hypoxia-inducible factor-1 alpha and the overexpression of the proangiogenic, tumor growth, and apoptosis resistance pathways. Our patient was negative for SDHx germline mutations. Genetic testing for VHL mutations was not offered. When the patient presented with this tumor, he was older than 50 years of age and gene testing for VHL is not recommended in individuals older than 50 years old. Additionally, VHL heart paragangliomas are extremely rare, and the patient's radiographic studies did not demonstrate other more prevalent tumors such as hemangioblastomas, kidney tumors, cyst, or other tumors associated with this disease. RET testing was not offered as MEN2 is only associated with adrenal tumors but not with paragangliomas (extra-adrenal tumors). The biochemical phenotype in this syndrome is characterized by excessive secretion of epinephrine. Our patient's tumor mainly produced norepinephrine. Nevertheless, there is a belief that a substantial percentage of sporadic tumors is a consequence of oxygen metabolism abnormalities;10 in fact, many sporadic head and neck paragangliomas are found in people who live at high altitudes.11

Finally, it has been well recognized that the manipulation of pheochromocytomas and paragangliomas during surgery could predispose to a catecholamine crisis. This is one of the reasons why patients with pheochromocytomas and paragangliomas should be prepared with a combination of alpha- and beta-receptor blockers before surgery. It is possible, therefore, that a mechanical stimulation of the patient's lesions by strenuous exercise might have been a contributing factor leading to a catecholamine crisis.

To the best of our knowledge, this is the first case of a malignant paraganglioma unmasked by exposure to a high-altitude environment and its attendant low oxygen pressure. This uncommon case illustrates the importance of a proper medical evaluation including careful review of past medical history in any individual planning to ascend to a high altitude. High altitude is associated with an elevation of sympathetic activity, which may worsen preexisting conditions such as systemic hypertension, coronary artery disease, arrythmias, obstructive pulmonary disease, and others. In individuals with a catecholamine-secreting tumor, exposure to a high-altitude environment may induce or exacerbate a catecholamine crisis. Travelers with a history of pheochromocytoma or paraganglioma or a hereditary predisposition for such tumors should be advised on the hazards of a trip to high-altitude locations. We believe that these individuals would benefit from a comprehensive biochemical and radiographic evaluation before they travel. Any identifiable tumor should be appropriately managed prior to any elective travel that might put the patient's health at risk.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Declaration of Interests
  6. References

The authors state they have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Declaration of Interests
  6. References