PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1109-1117 (doi:10.1542/peds.2005-2299)
ARTICLE |
Pheochromocytoma and Paraganglioma in Children: A Review of Medical and Surgical Management at a Tertiary Care Center
Departments of a General and Pediatric Surgery
b Endocrinology, Mayo Clinic, Rochester, Minnesota
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ABSTRACT |
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OBJECTIVE. The aim of this study was to review our institutional experience managing pheochromocytomas and paragangliomas in children.
METHODS. A retrospective chart review of the Mayo Clinic database from 1975 to 2005 identified 30 patients <18 years of age with histologically confirmed pheochromocytoma or paraganglioma.
RESULTS. There were 12 patients with pheochromocytomas and 18 with paragangliomas. The most common presenting symptoms were hypertension (64%), palpitation (53%), headache (47%), and mass-related effects (30%). Nine patients (30%) had a genetic mutation or documented family history of pheochromocytoma or paraganglioma. Fourteen patients (47%) had malignant disease, whereas 16 (53%) had benign disease. Logistic analysis showed that statistically significant risk factors for malignancy were (1) paraganglioma, (2) apparently sporadic, as opposed to familial, pheochromocytoma or paraganglioma, and (3) tumor size of >6 cm. Surgical resection was performed for 28 patients (93%), with perioperative mortality and major morbidity rates of 0% and 10%, respectively. Resection achieved symptomatic relief for 25 patients (83%). All patients with benign disease appeared cured after resection. For patients with malignant disease, the 5- and 10-year disease-specific survival rates were 78% and 31%, respectively, and the mean survival time was 157 ± 32 months.
CONCLUSIONS. The incidence of malignant pheochromocytoma/paraganglioma was high in children (47%), particularly those with apparently sporadic disease, paraganglioma, and tumor diameters of >6 cm. Patients with a known genetic mutation or familial pheochromocytoma/paraganglioma were more likely to achieve resection with negative microscopic margins and had improved disease-specific mortality rates. Surgical resection remains the treatment of choice for pheochromocytoma and paraganglioma.
Key Words: pheochromocytoma • paraganglioma • children • surgery
Abbreviations: VMA—vanillylmandelic acid • HVA—homovanillic acid • MIBG—meta-iodobenzylguanidine
Pheochromocytoma and paraganglioma are exceptionally rare neoplasms in children. Both tumors develop from neural crest cell lineage, stain positive for chromaffin, and produce catecholamines, including dopamine, norepinephrine, and epinephrine. Tumors that originate from the adrenal medulla are defined specifically as pheochromocytomas, whereas tumors located in extraadrenal positions are termed paragangliomas. Although well described for the adult population,1–4 diagnosis and treatment of these rare tumors are characterized poorly in the pediatric literature.5–8 A clear understanding of the clinical characteristics and biochemical behavior of these tumors is essential for clinicians to differentiate them from more-common childhood neoplasms such as neuroblastomas and Wilms' tumors.9 Failure to differentiate these tumors may lead to dire consequences during surgery, resulting from hemodynamic lability brought about by catecholamine surges in the absence of proper perioperative 
- and ß-adrenergic receptor blockade. Furthermore, advances in anatomic and functional imaging, improved biochemical detection,10, 11 and early detection with genetic markers, such as the succinate dehydrogenase complex subunit B (SDHB), D (SDHD), and C (SDHC) genes, von Hippel-Lindau (VHL) gene, and RET protooncogene, have influenced perioperative management strategies for these tumors profoundly.12, 13
We sought to review our institution's experience managing pheochromocytomas and catecholamine-secreting paragangliomas in children, (1) to summarize the epidemiologic and clinical presentations of these patients, (2) to assess the utility of laboratory and imaging studies, (3) to evaluate the efficacy of medical, surgical, and chemotherapeutic treatment outcomes, (4) to identify the prognostic factors for poor outcomes, and (5) to review the emerging role of genetic evaluation and its impact on outcomes. Clinical presentations and management outcomes for children with pheochromocytomas and paragangliomas were compared with data for adult historical control subjects.
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METHODS |
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We performed an institutional review board-approved, retrospective review of the Mayo Clinic Rochester medical database, surgical database, and tumor registry, to identify children (<18 years of age) with the diagnosis of pheochromocytoma or paraganglioma between June 1975 and June 2005. Thirty patients were identified; the diagnoses for all patients were confirmed histologically through hematoxylin and eosin staining and immunostaining. Thirty-three primary tumors were removed. Follow-up monitoring was accomplished through recent clinic visits or mail correspondence. Patients were monitored until they died or we lost contact with them. Follow-up data were available for 27 patients (90%) as of June 2005, with a mean follow-up time of 117 ± 18 months (range: 4–318 months).
Epidemiologic data, clinical presentations, treatment information, pathologic results, and treatment outcomes were collected through detailed chart review. With respect to malignant classification, no specific pathologic findings reliably distinguish malignant from benign tumors or predict tumor aggressiveness.14–16 In this study, tumors were classified as malignant when (1) distant metastases were present, (2) the tumor was unresectable because of regional invasion of vital structures such as the spinal cord or great vessels, or (3) the tumor recurred regionally or distantly after initial resection with tumor-negative microscopic margins.15, 16
For the purpose of recurrence analyses, the time of recurrence was set to 0 months for patients who presented initially with unresectable tumors or incomplete tumor resection. Symptom resolution after surgery or chemotherapy was tabulated for each patient; the degree of resolution of the presenting symptoms was categorized as either incomplete or complete.
Statistical analyses were performed with the JMP statistical package (SAS Institute, Cary, NC). Student's t test or analysis of variance was used to evaluate statistical differences between groups, with P < .05 being considered statistically significant. The Kaplan-Meier method was used to analyze recurrence and survival outcomes. The log-rank test was used to assess survival differences between groups (ie, benign versus malignant). Logistic regression analysis was used to stratify risk factors for malignancy. SEM is used to express value uncertainty, unless specified otherwise.
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RESULTS |
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Clinical Presentation and Diagnosis
Typically, patients presented in their teenage years (mean age: 14.7 ± 0.5 years), with equal numbers of boys and girls (male/female ratio: 1:1). Table 1 summarizes the presenting complaints and diagnostic evaluations of the 30 children with pheochromocytoma or paraganglioma. Nine patients (30%) were diagnosed as having pheochromocytoma or paraganglioma on the basis of mass-effect symptoms (abdominal pain and distention or back pain) or an incidental mass in imaging studies. In addition to these presenting complaints, 17 patients (57%) had associated secondary symptoms (eg, perspiration, flushing, nausea, vomiting, or diarrhea).
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Urinary 24-hour excretion of fractionated catecholamines (dopamine, norepinephrine, and epinephrine), metanephrine, normetanephrine, vanillylmandelic acid (VMA), and homovanillic acid (HVA) was used for 28 patients (93%), to diagnose or to confirm preoperatively the presence of catecholamine-secreting tumors. Tumor size was not associated with the degree of hormonal secretion (P > .05). Urinary 24-hour excretion studies were not performed for 2 patients with cervical paragangliomas; both patients presented with a neck mass. Two patients (both normotensive) had incorrect preoperative diagnoses of neuroblastoma. For these 2 patients, only VMA and HVA levels were examined, and both were elevated. Perioperative blood pressure for these 2 patients remained in the high-normal range.
The anatomic imaging method of choice was computed tomography, but MRI was used frequently to evaluate the extent of invasion into the spinal canal and involvement of the major vessels. When used, computed tomography and MRI detected a retroperitoneal mass in 95% of the studies. Functional imaging with radioactive meta-iodobenzylguanidine (MIBG) scintigraphy was ordered frequently, to rule out metastatic disease, to assess tumor avidity for MIBG, and to predict whether the tumor would respond to therapeutic doses of [131I]MIBG. More recently, functional imaging with [18F]fluorodeoxyglucose-positron emission tomography has been performed with increasing frequency, in conjunction with computed tomography, to detect metastatic disease, to evaluate tumor recurrence, and to assess tumor responses after chemotherapy. There was an insufficient number of imaging studies to allow a definitive statement regarding the sensitivity of MIBG scintigraphy or [18F]fluorodeoxyglucose-positron emission tomography for this patient cohort.
Table 2 summarizes the genetic features, malignancy characteristics, and locations of the primary tumors. Nine patients (30%) were found to have a documented family history and/or genetic mutation (listed specifically in Table 2). Twenty-one patients (70%) with pheochromocytomas or paragangliomas lacked a family history for catecholamine-secreting tumors, and their tumors were classified as apparently sporadic cases (not confirmed with negative genetic testing results). The incidence of malignancy among the children was 47% (n = 14) in this study, which was different from data for our adult historical control subjects (10%–30%).2, 17, 18 Twelve children (40%) had pheochromocytomas and 18 (60%) had paragangliomas. Most paragangliomas (14 of 18 paragangliomas; 78%) occurred along the sympathetic ganglion chain (ie, para-aorta and para-inferior vena cava at the level of the renal hilum and organ of Zuckerkandl). Less commonly, paragangliomas were found in the neck near the carotid bifurcation and the posterior mediastinum (n = 4 of 18; 22%).
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Treatments and Tumor Pathologic Features
Most (n = 22; 76%) of the 28 children undergoing surgery were diagnosed preoperatively as having a catecholamine-secreting pheochromocytoma or paraganglioma, and they underwent preoperative blockade with an
-adrenergic receptor blocker followed by a ß-adrenergic receptor blocker (Table 3). Patients also received treatments to increase intravascular volume (ie, high-sodium diet, sodium chloride tablets, and intravenous saline solution). Seven patients (24%) who underwent surgery did not receive preoperative - and ß-adrenergic receptor blockade because the preoperative diagnosis of paraganglioma was not entertained; 3 patients (10%) with cervical paragangliomas presented with neck masses and 4 patients (13%) with retroperitoneal paragangliomas presented with incidental or symptomatic masses without classic catecholamine-related symptoms, such as hypertension, palpitation, headache, or facial pallor. Of these 4 patients with retroperitoneal paragangliomas, 2 had elevations of 24-hour urinary VMA and HVA levels, whereas the 24-hour urinary VMA and HVA levels for the remaining 2 patients were normal. The patients with elevated VMA and HVA levels were thought to have neuroblastomas, but hypertensive symptoms did not occur during the perioperative period.
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Table 3 summarizes the surgical, chemotherapeutic, and radiotherapeutic treatments for the 30 children. Twenty-eight patients (93%) had resectable disease, whereas 2 patients (7%) were deemed to have unresectable disease, as judged with imaging studies (n = 1) or findings during surgical exploration (n = 1). Seven patients (23%) with malignant disease received chemotherapy, in either primary, neoadjuvant, and/or adjuvant mode. The indications for chemotherapy included the presence of metastatic disease (in imaging studies or operative findings), recurrence of disease after resection, positive nodal involvement, and positive gross or microscopic margins. Chemotherapeutic regimens varied widely during the study period but usually involved the following agents: cyclophosphamide, vincristine, dacarbazine, etoposide, cisplatin, samarium, and [131I]MIBG. An equal number of patients (n = 7; 23%) with abdominal paraganglioma received radiotherapy, as either intraoperative radiotherapy (n = 2) or external-beam radiotherapy (n = 5) in conjunction with surgery and/or chemotherapy. Indications for radiotherapy were to control local disease for patients with positive gross margins (n = 2) and to palliate symptoms resulting from vertebral metastasis (n = 5). The mean radiation dose was 4400 ± 40 cGy.
Table 4 summarizes the pathologic findings. The mean maximal diameter of malignant tumors was clearly larger than that of benign tumors (8.6 ± 1.3 cm versus 4.5 ± 0.4 cm; P = .004) (Fig 1). With respect to completeness of resection, negative gross and microscopic margins were achieved for 23 patients (77%) and 19 patients (63%), respectively. Therefore, 4 patients (13%) had negative gross margins but positive microscopic margins.
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Genetic testing for germline mutations of the RET protooncogene and the SDHD and SDHB genes became clinically available only recently; therefore, evaluation was performed for only 5 patients, whose results are presented in Table 4. Molecular genetic testing was completed for an additional 3 patients and was negative for mutations in the VHL and neurofibromatosis type 1 genes. DNA ploidy analysis was performed for only 5 patients. All 5 patients had seemingly benign disease, and the tumors from these patients showed aneuploid DNA patterns.
Treatment Outcomes
Table 5 summarizes the treatment outcomes after surgery, with or without chemotherapy and radiotherapy. Twenty-five patients (83%) reported partial or complete resolution of their presenting symptoms, specifically hypertension, palpitation, headache, and regional pain. Partial resolution meant that the patients still required medication to control blood pressure or pain but at lower doses. Surgery was particularly effective in alleviating or curing catecholamine-induced symptoms or mass-effect symptoms (25 of 28 surgical patients). Patients who had persistent symptoms were those with unresectable primary tumors (n = 2) and extensive bony vertebral involvement (n = 3) causing spinal cord compression. Seven patients (23%) had positive gross margins and thus persistent disease. Of those who underwent resection and had negative microscopic margins, 3 patients (16%) experienced recurrence. Including those with persistent disease after the initial resection, the mean time to symptomatic recurrence was 24 ± 8 months (range: 0–103 months). Significantly, surgery was accomplished with a 30-day perioperative mortality rate of 0% and a major morbidity rate of 11% (n = 3). The major morbidities were as follows: 1 patient developed small-bowel obstruction that required reexploration, 1 patient experienced postoperative ileus, radiation-induced enteritis, and long-term ureteral obstruction, and 1 patient required blood transfusion (6 units of packed red blood cells).
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Figures 2 and 3 depict the impact of microscopic margin status and malignancy status on survival rates. Both factors had statistically significant effects on survival rates. Table 5 presents disease-specific survival data for patients with malignant and benign disease. In this study, long-term survival for patients with malignant pheochromocytoma or paraganglioma was evident, but eventually most patients succumbed to their disease within 15 years after presentation. We also performed a subgroup survival analysis to evaluate the effect of chemotherapy on survival times, evaluating disease-specific survival times for patients with malignant disease who underwent surgical resection only versus those who underwent surgery and chemotherapy (neoadjuvant or adjuvant). Survival analysis showed that patients who underwent surgery and received chemotherapy fared far worse. However, there was an insufficient number of patients in the study to control for selection or stage biases.
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Table 6 summarizes the odds ratio for the listed risk factors. Statistically significant risk factors for the development of malignant disease included (1) paraganglioma (odds ratio: 9.99; P = .013), (2) apparently sporadic disease (ie, negative status for mutation and/or familial diseases) (odds ratio: 6.00; P = .049), and (3) tumor size of >6 cm (odds ratio: 5.40; P = .033). The higher incidence of malignancy among paragangliomas resulted in a significantly shorter mean disease-specific survival time for paraganglioma, compared with pheochromocytoma (165 vs 269 months; P = .007). The contribution of genetic status to decreasing malignancy risk was examined more thoroughly, specifically, whether patients with a known genetic mutation or familial form of pheochromocytoma/paraganglioma had tumors that were more resectable because of earlier tumor detection. Figure 4 shows the tumor size distribution and microscopic margin status of patients with familial versus sporadic occurrence of pheochromocytoma or paraganglioma. Tumor sizes in familial cases trended to be smaller (P = .084). Resection with negative microscopic margins was achieved in a significantly higher percentage of familial cases, compared with apparently sporadic pheochromocytoma/paraganglioma cases (89% vs 52%; P = .043).
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DISCUSSION |
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Limitations
Pheochromocytomas and paragangliomas are exceedingly rare in children and therefore are poorly described in the pediatric literature. The retrospective nature of this study is subject to limitations and bias, including changes in the diagnostic and therapeutic approaches during the study period and selection biases inherent in a tertiary referral center study. For example, some of the more-modern laboratory studies and genetic evaluations were not available or were not performed for all of our patients. This has limited our ability to draw conclusions regarding the incidence of hereditary pheochromocytoma and paraganglioma. The study was performed at a tertiary referral center and, although we cannot exclude referral bias completely, we think that the higher incidence of malignancy seen in the studied population most likely reflects a truly higher malignancy rate for children, compared with adults. This is supported by the fact that the incidence of malignancy for our patient population (<18 years of age) was higher than that for adults who were treated at the same tertiary referral center. Despite these limitations, however, the study contains one of the largest case series on pheochromocytoma and paraganglioma in children and has one of the longest follow-up periods.5, 19–21 Herein we discuss the study results with emphasis on findings that are unique to children and we provide an update on the management of pheochromocytoma and paraganglioma in children.
Clinical Presentation and Diagnosis
The 3 most common symptoms of pheochromocytoma and paraganglioma in children were hypertension, palpitation, and headache, similar to the presentation in adults.15, 22 Evaluation of hypertension in children entailed a focus on secondary causes, which included ruling out catecholamine-secreting pheochromocytoma and paraganglioma. Among children, paraganglioma may present as a symptomatic or incidental retroperitoneal mass and may be mistaken for the more-common neuroblastoma. Factors contributing to the diagnostic uncertainty regarding paraganglioma versus neuroblastoma include their similarity in location, histologic features, and ability to secrete hormones. In particular, these neoplasms are found commonly in the retroperitoneum, have similar histologic features because of their common origin from neural crest cells, and are capable of secreting VMA and HVA. An important distinction between paraganglioma and neuroblastoma is that paraganglioma can produce physiologically active catecholamines (ie, dopamine and norepinephrine). In evaluation of a child with possible neuroblastoma, VMA and HVA levels in urine are measured routinely; however, frequently the analyses of 24-hour urine samples do not include analyses of fractionated catecholamines or fractionated metanephrines. VMA and HVA levels are often elevated in paraganglioma as well as neuroblastoma; therefore, measurements of only VMA and HVA levels are inadequate to distinguish these neoplasms. Failure to recognize paraganglioma can have dire consequences because of inadequate preoperative - and ß-adrenergic receptor blockade. For this reason, we recommend that patients who present with the presumptive diagnosis of neuroblastoma and have any symptoms suggesting catecholamine excess should undergo 24-hour urinary measurements of fractionated catecholamines and fractionated metanephrines, in addition to VMA and HVA.
Treatments and Tumor Pathologic Features
In this case series, there were 3 notable differences for children, compared with adults, with pheochromocytoma or paraganglioma. First, the malignancy rate among children was higher than typical adult malignancy rates, that is, 47% vs 10% to 30%.1, 23, 24 Second, more children had an underlying genetic mutation or familial pheochromocytoma/paraganglioma, compared with the adult population, that is, 30% vs 10% to 20%.25, 26 Third, there was a higher percentage of paragangliomas among children, compared with adults, that is, 60% vs 10% to 40%.1, 2 Despite the higher incidence of malignancy, the combined 5-year disease-specific survival rate for children with pheochromocytoma or paraganglioma was more favorable than that for adults, that is, 
90% vs 40% to 60%.2, 24, 27, 28 Factors contributing to the favorable outcomes for children might be that (1) tumors were detected at an earlier stage, (2) tumors in children were biologically less aggressive, and (3) surgical resection was pursued aggressively for children.
With respect to tumor pathologic features, tumor size of >6 cm was clearly a risk factor for malignancy (Fig 1) and affected the survival rate adversely. Similarly, positive microscopic margins portended recurrence and poor survival rates (Fig 2). Therefore, surgery with the goal of achieving negative microscopic margins is crucial for cure. Of interest was the survival outcome of patients with negative gross margins but positive microscopic margins, specifically, whether there was survival benefit in removing gross disease without complete microscopic clearance. Identification of only 4 patients with such margins did not allow for subgroup survival analysis.
Treatment Outcomes
The vast majority of patients underwent surgical resection, a testament to our aggressive surgical approach. Study results show that surgical resection of pheochromocytoma and paraganglioma is the most effective treatment to achieve cure, to alleviate symptoms, and to prolong survival.14, 29 The 10-year disease-specific survival rates were 81% for all patients and >30% for patients with malignant tumors. Eighty-three percent of the patients experienced partial or complete resolution of their presenting symptoms after resection. Importantly, surgical resection was performed safely, as indicated by a mortality rate of 0% and a low morbidity rate. Patients should have frequent follow-up evaluations, because a recurrence rate of 16% was observed even for patients with initially negative microscopic margins.
Genetic testing for pheochromocytoma and paraganglioma is proving to be essential in the evaluation of patients.30 Accumulating evidence suggests that (1) cases of pheochromocytoma or paraganglioma presenting at a younger age are associated with familial multiple endocrine neoplasia 2 or von Hippel-Lindau disease, (2) cases with malignancy or paraganglioma have a greater association with SDHB mutations,31–33 and (3) as many as 24% of cases of pheochromocytoma with an apparently sporadic presentation may have germline mutations in one of the RET, VHL, SDHD, or SDHB genes.34, 35 Moreover, routine testing may show that the apparently sporadic cases actually have germline mutations and these patients represent index cases for their families. Our study suggests that genetic evaluations, through either genetic testing or pedigree analysis, and frequent follow-up assessments made it possible to detect tumors at an earlier, resectable stage (Fig 4). This proactive approach has a significant impact on survival rates. Curative resection was accomplished more frequently for patients with genetic mutations or familial pheochromocytoma or paraganglioma. Furthermore, genotype-phenotype correlations, as well as proteomic markers,36, 37 may provide a quantitative assessment of malignant tendency, with prophylactic resection being warranted for patients at high risk.25, 38, 39 This tactic has precedent for patients with multiple endocrine neoplasia 2A, for whom prophylactic total thyroidectomy is warranted to prevent the development of medullary thyroid cancer.
Results indicated that the main risk factors for the development of malignant tumors in children included (1) tumor size of >6 cm, (2) apparently sporadic occurrence of pheochromocytoma or paraganglioma (as opposed to the familial forms or cases with known mutations), and (3) paraganglioma. Of course, factors that increase the risk of malignant disease portend shorter survival times, as shown in Fig 3.
Medical management controlled catecholamine-induced symptoms successfully for patients with unresectable disease. Survival analysis showed that patients who received chemotherapy had worse outcomes, compared with those who did not receive chemotherapy. However, these poor outcomes clearly represented a selection bias because of inadequate randomization (ie, only patients with positive tumor margins or unresectable disease received chemotherapy). Available data from the adult literature suggest that the response to chemotherapy is limited.40, 41 Radiotherapy was partially effective in relieving pain resulting from bony metastases (n = 5 of 7). As with chemotherapy, there was an inadequate number of patients for assessment of survival benefits free from the effect of selection bias.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Pheochromocytomas and paragangliomas are rare in children and, compared with these tumors in adults, are more likely to be malignant. It is crucial to distinguish paragangliomas from the more-common childhood retroperitoneal neuroblastomas. Tumors of >6 cm confer significant malignancy risk. Surgical resection, with appropriate perioperative management of catecholamine-related symptoms, remains the treatment of choice, to achieve cure, to prolong survival, and to provide palliation of symptoms. Surgical resection with negative microscopic margins is essential for achieving long-term survival and cure. Genetic analysis may have a significant impact on the management of these neoplasms, by facilitating earlier diagnosis and identification of patients at high risk for malignancy.
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FOOTNOTES |
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Accepted Apr 19, 2006.
Address correspondence to William F. Young, Jr, MD, Department of Endocrinology, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 Second St SW, Rochester, MN 55905. E-mail: wyoung{at}mayo.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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