PHEOCHROMOCYTOMA and paraganglioma are neuroendocrine tumors rarely diagnosed in pediatric patients.1,2The incidence of malignant pheochromocytoma and paraganglioma in childhood is approximately 0.02 cases per million every year.3,4Coincidental intraoperative diagnosis of pheochromocytoma involves very high mortality rates, reaching 50%.5We present a case of coincidental diagnosis of pediatric metastatic malignant paraganglioma during an elective surgical procedure. The evaluation and management of pheochromocytoma and paraganglioma are discussed.
A 14-yr-old girl weighing 46 kg was scheduled for an elective excision of a skull lesion from her right forehead. Her medical history and results of the physical examination were unremarkable, and her American Society of Anesthesiologists physical status score was 1. General anesthesia was induced with 2 mg intravenous midazolam, 100 μg fentanyl, 150 mg propofol, and 30 mg rocuronium. An endotracheal tube with internal diameter of 6.5 mm was placed without difficulty, after which a right supraorbital nerve block was performed. Noninvasive blood pressure measurements at this time were approximately 130/80 mmHg. Just after the beginning of surgery, blood pressure measurements increased to 180/110 mmHg. Heart rate remained 85 beats/min. Blood pressure measurements in the other arm were not different. Because additional opiates and an increased concentration of the volatile anesthetic did not decrease blood pressure, an arterial line was inserted to allow direct blood pressure monitoring. The continuous invasive measurements revealed paroxysmal hypertensive/hypotensive episodes, ranging between 270/170 mmHg and 70/40 mmHg, repeated approximately every 5 min (fig. 1). Another attempt to control blood pressure with a remifentanil infusion did not have a significant effect. The surgical team was notified about the patient's hemodynamic status immediately after the hypertensive crisis was identified, before placement of the arterial line. It was decided to complete promptly the planned short surgery, after which the patient was awakened and extubated. Results of a gross postoperative neurologic examination were normal. In the postanesthesia care unit, the patient's blood pressure continued to show the same pattern seen during surgery. The patient was transferred to the pediatric intensive care unit for additional evaluation and treatment.
Important issues to consider in this case include the following:
What Is the Differential Diagnosis of Pediatric Hypertension?
The estimated prevalence of pediatric hypertension is 1–2%.2Adrogué and Sinaiko6reported a hypertension prevalence of 1% in junior high-school aged children. The most common reason for teenage hypertension is early-onset primary hypertension.2,7Secondary etiologies are listed in table 1, with the most common causes in teenagers being pharmacologic agents, renal disease, renovascular disorders, and several endocrine diseases (most commonly hyperthyroidism and Cushing disease, and rarely pheochromocytoma or carcinoid tumors).2,7,8Most of these etiologies are characterized by continuously high blood pressure, not the cyclic pattern seen in our patient.
What Measures Should Be Considered in Face of a Hypertensive Crisis?
A hypertensive crisis may be related to anesthesia, surgery, or (as in the current case) disease. Identification of the cause is crucial. Communication between the anesthesiologist and the surgeon is essential. Surgery should be halted when it involves handling of sensitive areas (e.g ., brainstem). The anesthesiologist should first rule out the most obvious etiologies, such as inadequate depth of anesthesia, analgesia, or preoperative preparation. Basic measures, such as deepening the level of anesthesia, should be taken immediately. Initial pharmacologic measures to control blood pressure should be executed. If blood pressure remains inadequately controlled, a prompt response is needed to minimize the morbidity associated with such crisis: an arterial line should be considered as well as vasoactive drugs and expert consultation. The next action is team decision-making: should surgery be completed as planned, shortened to a minimum, or stopped promptly? The importance and urgency of the surgical procedure should be weighed against the risks of intraoperative hypertensive crisis and the wish to wake the patient and evaluate his neurologic status. It seems that no hypertensive crisis resembles the other and there are no suitable algorithms.
Pheochromocytoma and Paraganglioma: What Are They?
Paragangliomas are relatively rare tumors originating from chromaffin cells of the autonomic nervous system. Pheochromocytomas are a subgroup of paragangliomas located in the adrenal medulla, whereas other paragangliomas are located anywhere outside the adrenal, usually either in the head and neck region or in the abdomen. The estimated incidence of pheochromocytoma and paraganglioma is less than 0.3 cases per million per year. Approximately 10–20% of the tumors are diagnosed during childhood. Most of them are benign, and the incidence of malignant tumors in the pediatric population is estimated as 0.02 per million per year.1–4,9Risk factors for malignancy in children include extraadrenal location, size greater than 6 cm, and apparently sporadic occurrence (as opposed to familial or genetic forms).10These tumors are responsible for approximately 1% of pediatric secondary hypertension.1,11
Pheochromocytomas usually secrete one or more of the three catecholamines epinephrine, norepinephrine, and dopamine, as well as their metabolites (metanephrine, normetanephrine, and methoxytyramine, respectively). Paragangliomas can originate from the sympathetic or parasympathetic ganglia. The former usually are functional, secreting tumors, whereas the latter are mostly nonsecreting. Functional paragangliomas, also known as sympathetic, can secrete the same catecholamine profile as pheochromocytomas, with norepinephrine being the most common.12Most abdominal paragangliomas are functional. Nonfunctional paragangliomas, also referred to as parasympathetic, usually are located in the head and neck region.
What Are the Clinical Manifestations of Pheochromocytoma and Paraganglioma?
Most clinical signs and symptoms are the result of constant adrenergic activation. The paroxysmal “attacks” are caused by an enormous release of catecholamines, reaching plasma concentrations more than 1,000 times normal values.12The major clinical signs and symptoms are listed in table 2.1,9,10,13,14Nonsecreting, nonfunctional tumors cause symptoms of space occupation and mass effects.
Evaluation of Suspected Pheochromocytoma and Paraganglioma
Diagnosis of suspected pheochromocytoma and paraganglioma includes a biochemical profile, radiologic evaluation, and nuclear imaging. The biochemical profile is composed of catecholamine and metanephrine concentrations in the blood and urine, respectively.15The biochemical profile usually can differentiate epinephrine-secreting tumors from norepinephrine-secreting ones because the former will show epinephrine, norepinephrine, and their metabolites, and the latter will show mostly norepinephrine and normetanephrine. Dopamine-secreting tumors are rare, and might be suspected when a tumor consistent with pheochromocytoma is found, but symptomatology does not include hypertension.3,16,17These tumors are mostly extraadrenal, and usually are discovered incidentally or because of symptoms of mass effects. In these rare cases, the biochemical profile should include dopamine and its metabolites (homovanillic acid and methoxytyramine), which usually are found to be increased in the plasma.16
The radiologic evaluation usually is made with a computed tomography scan or a magnetic resonance study; both modalities have similar sensitivity and specificity.11,13,17–19The radiologic evaluation is completed with the use of functional imaging. The most common nuclear imaging uses 123I-labeled metaiodobenzylguanidine scanning, the sensitivity of which approaches 100%.4,11,15,18Other options include positron-emission tomography scans using different radioactive isotopes, such as 18F-labeled dihydroxyphenylalanine, 18F-labeled fluorodeoxyglucose, and others.18The tumor cells will absorb these isotopes if they metabolize catecholamines; thus, functional imaging can reveal small foci of disease that do not appear on regular computed tomography or magnetic resonance scans. However, nonfunctional tumors may not be seen on functional imaging because they do not produce hormones. Some researchers argue that localization of tumor with nuclear imaging should not be routine but rather used only for selected cases of suspected metastases.19,20
Diagnostic Evaluation in the Current Case
A focused history taken immediately after surgery from the patient and her parents revealed that she had experienced recurrent episodes of intermittent headaches and dizziness during the several previous months. Physical examination revealed orthostatic hypotension. Blood pressure Holter monitoring showed numerous tachycardic and hypertensive episodes. Plasma electrolytes, renal function testing, and abdominal sonography did not suggest any renal or renovascular pathologies. Thyroid function, plasma renin, and atrial natriuretic peptide concentrations also were within normal range. Urine catecholamine concentrations were markedly high, and plasma concentrations of epinephrine and dopamine were normal, whereas the norepinephrine concentration was eight times the normal plasma concentration; all of these suggested pheochromocytoma as the etiology for the patient's hypertensive episodes.
The hormonal profile was found to suggest catecholamine excess, and radiologic imaging was done. Abdominal computed tomography scanning showed two large masses in the right retroperitoneum (shown and described in fig. 2).
Nuclear imaging was performed using an 123I-labeled metaiodobenzylguanidine scan 1 month after the initial surgery. Pathologic uptakes were found in the right middle abdomen, in the third right rib, and in the left femur (fig. 3). The higher mass near the celiac trunk did not absorb 123I-labeled metaiodobenzylguanidine. A biopsy from the femoral mass was done with local anesthesia and confirmed the diagnosis of metastatic malignant paraganglioma.
What Are the Treatment and Prognosis of These Tumors?
The definitive treatment of pheochromocytoma and paraganglioma is surgical removal of the tumor. The prognosis of benign tumor excision is excellent. With advancement in preoperative medical treatment, perioperative mortality has declined to less than 1% when surgery is undertaken by experienced anesthesiologists and surgeons.17,18,21–23With malignant disease, only 30% of patients survive after 10 yr.10Survival rates correspond to the metastasis site, with bone metastases being associated with better prognosis than liver or lung involvement.18Radiotherapy, chemotherapy, and radioactive 123I-labeled metaiodobenzylguanidine have all been reported as adjunct treatments to tumor debulking surgery, but none has shown remarkable efficacy.
How Should the Patient Be Prepared for Surgery?
Medical preoperative preparation is targeted mainly at minimizing the effects of possible massive catecholamine release during induction of anesthesia and manipulation of the tumor.3,17,24This is based mainly on α-adrenergic blockade.23The most common drug used to prevent α receptor activation is phenoxybenzamine, an irreversible noncompetitive α receptor blocker.13,21The main disadvantage of phenoxybenzamine is the possible prolonged hypotension after surgery caused by the sustained vasodilation.13,17,22,25Another option to prevent α receptor activation is the use of reversible α blockers, such as doxazosin and prazosin, which are shorter-acting and competitive α1antagonists.19,22,26α-Methyltyrosine is an inhibitor of the synthesis of catecholamines in the chromaffin cells and thus can lessen the adrenergic tone through another pathway.22,25,27,28α receptor blockade results in vasodilation, relative hypovolemia, and orthostatic hypotension. Tachycardia (either from catecholamine excess or from α receptor blockade) can be treated by addition of β blockade, but it is essential to remember that medical treatment should never be started with β blockers before sufficient α blockade because of the risk of unopposed α receptor activation.12,17,22,25Hypovolemia should be corrected using dietary loading or intravenous supplementation of sodium and fluids, with a target hematocrit of 30%.12,22,25Treatment endpoints are controlled blood pressure (according to age), lack of hypertensive episodes, mild orthostatic hypotension, normal ST segment and T wave on electrocardiogram, lack of ventricular premature beats, and presence of nasal congestion.5,17,24,25It should be mentioned that some authors maintain there is no advantage in the accepted complex medical preparations and say that, with the currently available monitoring devices and potent vasoactive agents, patients can safely undergo surgery and blood pressure can be controlled without any preparation or with simple routine antihypertensive drugs, such as calcium channel blockers.11,29,30
Preparation of Our Patient
In addition to fluid and sodium enrichment, medical preparation included phenoxybenzamine (50 mg/day) and propranolol (60 mg/day). This treatment was initiated once diagnosis was fairly established and was continued until surgery. Under this treatment, the patient's blood pressure was 100–110/60–70 mmHg with mild orthostatic hypotension. Electrocardiogram showed normal sinus rhythm of 60–70 beats/min without any evidence of arrhythmia. The patient reported nasal congestion, and laboratory results showed normal hemoglobin and glucose concentrations.
Course of the Second Operation: Excision of the Tumor
The definitive operation was conducted 3 months after the initial, elective surgery. An arterial line was placed before induction of anesthesia. Sodium nitroprusside and phentolamine infusions were prepared. Intravenous induction was performed by titration of midazolam (3 mg), propofol (200 mg), fentanyl (100 μg), and vecuronium (8 mg). Tracheal intubation with a 6.5-mm inner diameter tube was performed easily. During the excision of the first retroperitoneal mass, marked hemodynamic instability was seen, necessitating the use of both phentolamine and nitroprusside. Excision of the second retroperitoneal mass was characterized by hypotension treated with phenylephrine and eventually with norepinephrine infusion. This suggested that the second mass was nonsecreting, a fact that was not certain until that point. Nevertheless, the need for intraoperative vasopressor support after tumor resection is not uncommon, especially if preoperative preparation of the patient included long-acting antihypertensive agents, such as phenoxybenzamine. At the end of surgery, the patient was transferred to the pediatric intensive care unit while still mechanically ventilated and with norepinephrine support of 1.33 μg · kg−1· min−1. She was extubated and weaned from norepinephrine the following day. The blood pressure measurements of this surgery are shown in figure 4. The rest of her recovery was uneventful, and she was discharged home a few days later. She is being evaluated and scheduled for excision of the two skeletal metastases in the femur and rib.
This case presents the complexity of evaluating, diagnosing, and treating the rare entity of malignant, metastatic paraganglioma in the pediatric population. As mentioned, the coincidental intraoperative diagnosis of this pathology, as occurred in our case, is associated with a high mortality rate. As noted in our case, despite seemingly satisfactory medical preparation, the intraoperative course was characterized by hemodynamic instability necessitating aggressive vasoactive treatment. The need for or usefulness of preoperative pharmacologic preparation has been questioned by some clinicians, who say that the use of modern potent intravenous vasoactive drugs to control blood pressure makes preoperative medical preparation both unnecessary and potentially harmful in respect to its postoperative influence. A series of more than 60 patients with pheochromocytoma showed no difference in outcome between the 34 patients treated with α receptor blockers and the 29 who were not.29Ross11and Ulchaker et al .30describe series of more than 100 patients, of whom only 20–40% received α receptor blockers, and most others were treated with calcium channel blockers. Interestingly, 30% of patients were not medicated at all before surgery. Both reports describe noninferior results for these groups and conclude that, because potent vasoactive agents are available for use intraoperatively, the need for aggressive preoperative use of α receptor blockers no longer exists. It should be noted that all three series cited come from a single center and probably describe the same patient group. This approach needs to be thoroughly investigated before being adopted as the standard of care for pheochromocytoma.
Our case also presents the issue of surgery and anesthesia in an oncologic patient. Data from recent studies suggest that anesthetic techniques may affect cancer recurrence and long-term survival.31,32Several mechanisms of action have been reported, such as the influence of regional anesthesia, volatile anesthetics, and opioids on cell biology, immune responses, stress response and angiogenesis, and the possible interactions between anticancer medications and anesthesia or perioperative complications.33This issue is still far from being settled, and additional research is needed to confirm these interactions and their clinical significance.