Indian Pediatrics 2002; 39: 51-57  

Pheochromocytoma in Children and Adolescents: An Institutional Experience

From the Departments of Endocrine Surgery and Endocrinology*, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India.

Correspondence to: Dr. S.K. Mishra, Professor and Head, Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India.

E-mail: [email protected]

Manuscript received: March 19, 2001;

Initial review completed: May 1, 2001;

Revision accepted: June 13, 2001.

Pheochromocytoma (PCC) is a rare tumor of childhood. Several characteristics of PCC in children distinguish them from their adult counterparts. In contrast to adults, children with PCC have a higher incidence of bilaterality, a higher association with the multiple endocrine neoplasia (MEN) syn-dromes, and a lower incidence of malignant neoplasms(1). It is an uncommon yet a significant cause of correctable hypertension in children, first described by Kremmer in 1936(2). The similarity that exists between pheochromocytoma in children and adults includes modes of presentation and methods of diagnosis and treatment. We present an audit of 5 cases of PCC in children treated at our center over 10 years period.

Medical records of 13 children with functional adrenal tumors managed at our hospital between June 1990 and January 1999 were reviewed. Four children had functional adrenal medullary tumors and one had paraganglionoma. Demographic data, clini-cal features, biochemical and localization studies, operative details and follow-up records were studied. Besides routine pre-operative work-up, diagnostic tests included estimation of 24-hours urinary catechol-amines (free catecholamine or metaneph-rines). Tumors were localized with abdominal ultrasonograpy (USG) and/or abdominal CT scanning.

Preoperative preparation was carried out by alpha blockade and expansion of the intra-vascular volume over period of three weeks. All children underwent laparotomy via an anterior trans-peritoneal route under close preoperative monitoring. Adrenalectomy was performed in four and excision of extra-adrenal tumor in one case. Intra-operative fluctuations of blood pressure were taken care by intravenous sodium nitroprusside, esmolol, adrenaline and crystalloid/colloid. Patients were kept for 24 hours electively in intensive care room.

Operative findings, tumor size and weight were recorded. Patients were discharged once the stitches were removed and post operative drug (antihypertensives) requirements were stabilized. The children were followed up 3 monthly twice, 6 monthly during subsequent 1 year, and annually thereafter. On follow-up visit, biochemical test (24 hour urinary metanephrine) and if required, imaging studies were carried out.

During the study period, 5 children of PCC were managed at our center. Median age was 10-years (range 3-16 years). Of the five children with adrenal PCC, four were boys and one girl. Median duration of illness was 14 months (range 3-36 months). Classical clinical triad of headache, palpitation and sweating was present in three cases while two of the three symptoms of triad were present in the remaining two cases. Hypertension was the commonest presenting feature (100%). There was no family history of PCC or other familial syndromes associated with PCC in these cases. Case 4 had high grade fever of long duration associated with sweating but no chills. In association he had grade IV protein energy malnutrition, severe constipation and focal right-sided seizures with secondary generalization followed by unconsciousness. He also had history of headache and vomiting. He had been treated for tuberculous abdomen at an outside hospital. At the time of admission he was hypertensive (190/104 mm Hg in right upper limb, 180/100 mm Hg in left upper limb), unconscious (E4V1M1 on Glasgow coma scale) and anemic. Both pupils were dilated. Right side fundus examination showed papilledema and bilateral plantars were extensor. Clinical findings of these cases are summarized in Table 1. The 24-hours urinary metanephrine done in four cases was raised (3-56 folds), while one had raised 24 hour urinary catecholamines. Abdominal ultrasonogram and computerized scanning was done in four cases for localization. In addition, MRI was done in one case. Head CT scanning was done in 2 cases with neurological complications. The child who presented with hemiplegia had evidence of hemorrhage in right basal ganglion and external capsule, while the child with convul-sions had post-ictal edema alone. Investiga-tion findings and tumor characteristics are summarized in Table II.

Table II__Pheochromocytoma: Investigation Findings and Tumor Characteristic

The children were prepared with alpha-blockers (phenoxybenzamine in one, prazosin in rest). The time required to achieve effects of alpha blockade ranged from 10-22 days (mean 12 days). The dosages of prazosin required to achieve blockade were 15, 13, 12 and 12 mg and Phenoxybenzamine 60 mg respectively. Beta-blocker (propanolol, 40 mg) was required in Cases no 3 and 5. All cases required calcium channel blockers and angiotensin converting enzyme inhibitor (ACE inhibitor) in addition to alpha-blocker since blood pressure control was not adequate despite high doses of alpha-blockers. It is interesting to note that all the symptoms got ameliorated with alpha-blockade in the fourth case. All cases were explored through anterior transperitoneal route. Three left sided and one right-sided adrenalectomies were performed. The patient with extra-adrenal tumor located in the para-aortic region close to lower pole of the kidney had undergone excision of the tumor with biopsy from a nodule in liver. Contralateral adrenal gland and ectopic sites were found to be free of tumor on exploration in all cases. Patients were kept in intensive surgical care unit for 24 hour after the operation. Post-operative period was uneventful.

On histological examination, all 4 tumors were reported as adrenal medullary tumors, consistent with the diagnosis of PCC. There was no evidence of malignancy. However, case no. 4 was reported malignant extra-adrenal pheochromocytoma in view of the metastatic nodule in the liver.

The child with hemiplegia improved considerably with conservative treatment and had grade 4 to 4/5 muscle power in various muscle groups at the time of discharge. All four children of PCC had normal urinary metanephrine level post-operatively and on subsequent follow up visits but they all required antihypertensives for control of persistent blood pressure though in reduced doses. Post-operative urinary metanephrine (7-10 d post-op) was higher than normal though it had fallen from the pre-operative level in the child with malignant pheo-chromocytoma. Case No. 1 had no clinical or investigative evidence of recurrent disease 63 months after surgery. He has not reported for past 4 years since then. The remaining three children were last seen 37, 21 and 9 months after surgery with no evidence of recurrence with normal urinary metanephrines level. The patient with malignant disease developed a metastasis in the left tibia.

PCC is a rare cause of hypertension in childhood, accounting for less than 1% of all hypertensive children(1-5) and affects boys twice as often as girls. Dorairajan and colleagues(6) have retrospectively reviewed 162 cases of endocrine based hypertension and reported an incidence of 48.7% of pheochromocytoma. In a referral hospital based study, 4.4.% cases of pheochromo-cytoma were responsible for hypertension(7).

Two thirds of PCC are situated in adrenal medulla. Hypertension is sustained in 88% of children with PCC, and clinical features include headache, sweating, nausea and vomiting, visual disturbances, abdominal pain, polyuria and polydipsia, convulsions and acrocyanosis(3). Noradrenaline and adre-naline hypersecretion account for symptoms such as palpitation, sweating, tremors, etc. In children, 5-10% of PCC are malignant(3).

In contrast to adults, children with PCC have a higher incidence of bilaterality, a higher association with the multiple endo-crine neoplasia (MEN) syndromes, and a lower incidence of malignant neoplasms(3). In our series classical clinical triad of headache, sweating and palpitation was present in three cases while two of the three symptoms of triad were present in rest two cases. One patient had the triad of headache, sweating and nausea which is a more commonly described triad in children(3). In our short series of 5 children with PCC, one (20%) had PCC at extra-adrenal site. In a report from a southern India hospital (n = 30), the overall incidence of extra-adrenal tumor was 26.6%. The age of the youngest patient in adrenal group reported was 13 years while in extra-adrenal group it was 14 years(8). No bilaterality or multifocality was present in the adrenal PCC. All the four children with adrenal PCC in our series had sustained hypertension, a finding which is consistent with other series. In patients with a positive biochemical diagnosis, initial imaging modality advisable is a combination of whole body 131I-MIBG scan and abdominal MRI or CT scan with 3 mm section in the region of adrenals. 131I-MIBG scanning is very helpful in localization of adrenal, extra-adrenal, metastatic and ectopic sites of these tumors and in total removal of this potentially curable cause of hypertension(9). This radio-pharma-ceutical was not routinely available at our institute till recently, hence, 131I-MIBG scan-ning could not be performed in our study.

Alpha-receptor blockade is the corner-stone of preoperative preparation of patient with PCC. It is important that alpha blockade be achieved before embarking on any opera-tive or invasive procedure on the patient. Phenoxybenzamine, an irreversible alpha-receptor antagonist is the conventional drug of choice. Adequate alpha blockade is heralded by appearance of postural hypo-tension, dry mouth, stuffy nose and sedation. Prazosin, a short acting selective alpha-2 adrenoceptor antagonist is preferred over phenoxybenzamine in recent times because of lesser post-operative hypotension associated with this drug, which was the main drawback with alpha blockade using phenoxybenzamine. However, it is rapidly displaced by high amount of catecholamines released from a PCC in response to stress or due to direct handling. We have used phenoxybenzamine in the initial one child but in other four patients prazosin was used since phenoxybenzamine was not easily available. We have found prazosin equally good drug for pre-operative preparation. Additional drugs like calcium channel blockers and ACE-inhibitors were used in all the cases to control the blood pressure.

Complete surgical excision of adrenal and/or extra-adrenal PCC results in cure of hypertension in most children(3,4). Persistent post-operative hypertension may result due to incomplete removal of tumor in the primary site, unidentified multi-focal disease at adrenal or extra-adrenal sites, and local residual malignant or metastatic PCC. In all these conditions, the urinary catecholamine and metanephrine would remain high, unlike our 4 patients of PCC, who remained hypertensive post operatively. Causes for persistent post-operative hypertension with-out catecholamine hypersecretion include reno-vascular hypertension, as was in one of our patients, irreversible vascular changes caused by prolonged hypertension due to delay in seeking medical attention, as could be in the remaining three cases, and high set baro-receptors. If urinary metanephrine level is normal, suitable antihypertensive drugs are used for control of blood pressure. Besides pharmacological treatment, 131I-MIBG therapy can offer some palliation in inoperable and metastatic cases(9,10). We could not offer this therapy to one of our patient with extra-adrenal malignant disease in view of poor financial status. Like most endocrine tumors, conventional histological features are inaccurate in predicting the biological behavior of the PCC. Presence of metastatic disease at non-chromaffin sites, such as lymph nodes, liver, etc. or a major vascular and capsular invasion and tumor thrombi can only be considered diagnostic of malignant nature. These cases require a careful life long follow up to identify and manage a recurrent malignant or meta-chronous multifocal disease, which can manifest long after the primary management. If a patient is found to have raised cate-cholamines or metanephrines during follow up, appropriate imaging by CT scan and 131I-MIBG scan are useful in identifying recurrent or metastatic disease(3,10). A suggested algorithm for the diagnosis and management of pheochromcytoma is depicted in Fig. 1.

Contributors: AKM and AM evaluated the patient data and drafted the manuscript. GA and AA gave the concept and revised the draft. VB was the treating pediatric endocrinologist and revised the article. SKM was responsible for surgical treatment of most of the patients, giving the concept and reviewed the manuscript. He will act as the guarantor for the manuscript.

Funding: None.

Competing interests: None stated.

Fig1. Algorithm for the diagnosis and Management of Pheochromocytoma

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