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Pheochromocytoma in Childhood

Pheochromocytoma, Childhood

Pheochromocytoma arises from the chromaffin cells in the medulla of the adrenal glands. It produces, stores, metabolizes, and secretes catecholamines, thereby provoking hypertension. Pheochromocytoma is generally diagnosed in adulthood, even if its development is associated with hereditary cancer predisposition syndromes such as multiple endocrine neoplasia and neurofibromatosis. Accordingly, pheochromocytoma in childhood is a rare entity.


Presentation

Hypertension is the clinical hallmark of pheochromocytoma in childhood. Conversely, this type of tumor accounts for <2% of pediatric cases of hypertension, and other, much more common causes should be ruled out when evaluating a child with elevated blood pressure [1] [2]. Secondary hypertension is most frequently diagnosed in preadolescent children suffering from renal disorders [3]. Nephropathies may be associated with nausea, vomiting, edema formation, hematuria, and alterations in the urine volume, while none of these symptoms is to be expected in pheochromocytoma patients. Similarly, chest pain and dyspnea on exertion, as described by the hypertensive patient with cardiovascular disease, are not characteristic for pheochromocytoma. Palpitations may be reported in either case. Adolescence implies an increased risk for primary hypertension, which is often related to obesity or a family history of hypertension, and while these are not exclusion criteria for endocrine hypertension, excess catecholamines are likely to provoke further symptoms, such as flushing, diaphoresis, and tachycardia. Pheochromocytoma patients frequently claim headaches, may suffer from anxiety and may lose weight [4] [5]. It is to be kept in mind that pheochromocytoma in childhood may not cause any symptoms at all and constitute an incidental finding. Above a threshold diameter, the tumor may be palpable as an abdominal mass, irrespective of its biochemical profile. Then, it's also likely to cause pain.

Pheochromocytoma in childhood may not be an isolated finding. The majority of pediatric patients presenting with pheochromocytoma suffers from a hereditary disorder favoring tumor development and growth. Accordingly, clinical findings may comprise a variety of signs of these pathologies:

  • In multiple endocrine neoplasia type 2, pheochromocytoma usually follows the development of medullary thyroid carcinoma, which has a higher penetrance [6]. Medullary thyroid carcinoma may cause flushing and chronic, watery diarrhea.
  • Neurofibromatosis type 1 is typically associated with neurofibromas, café-au-lait spots, axillary freckling, Lisch nodules, optic gliomas, and abnormalities of the bone and central nervous system.
  • Von Hippel-Lindau disease should be considered in patients presenting with hemangioblastoma of the retina or central nervous system or clear cell renal cell carcinoma.
  • Hereditary paraganglioma-pheochromocytoma syndromes additionally predispose to the development of extra-adrenal paraganglioma. They may arise in the sympathetic or parasympathetic nervous system. Extra-adrenal paragangliomas tend to release dopamine and norepinephrine instead of norepinephrine and epinephrine. Besides local mass effects, their clinical presentation is largely similar.
Falling
  • Twelve (63%) patients had postural fall in blood pressure, ten (53%) had abdominal pain, four (21%) had visual blurring, and three (16%) each had palpable abdominal mass and significant weight loss at presentation.[ncbi.nlm.nih.gov]
Asymptomatic
  • All patients are asymptomatic and have normal urinary catecholamines 15 to 51 months after operation. Because of the frequency of multiple tumors in familial pheochromocytoma, different diagnostic techniques were employed.[ncbi.nlm.nih.gov]
Dyspnea
  • Similarly, chest pain and dyspnea on exertion, as described by the hypertensive patient with cardiovascular disease, are not characteristic for pheochromocytoma. Palpitations may be reported in either case.[symptoma.com]
Abdominal Mass
  • Twelve (63%) patients had postural fall in blood pressure, ten (53%) had abdominal pain, four (21%) had visual blurring, and three (16%) each had palpable abdominal mass and significant weight loss at presentation.[ncbi.nlm.nih.gov]
  • Above a threshold diameter, the tumor may be palpable as an abdominal mass, irrespective of its biochemical profile. Then, it's also likely to cause pain. Pheochromocytoma in childhood may not be an isolated finding.[symptoma.com]
Chronic Watery Diarrhea
  • Medullary thyroid carcinoma may cause flushing and chronic, watery diarrhea.[symptoma.com]
Chest Pain
  • Similarly, chest pain and dyspnea on exertion, as described by the hypertensive patient with cardiovascular disease, are not characteristic for pheochromocytoma. Palpitations may be reported in either case.[symptoma.com]
Axillary Freckling
  • Neurofibromatosis type 1 is typically associated with neurofibromas, café-au-lait spots, axillary freckling, Lisch nodules, optic gliomas, and abnormalities of the bone and central nervous system.[symptoma.com]
Flushing
Freckles
  • Neurofibromatosis type 1 is typically associated with neurofibromas, café-au-lait spots, axillary freckling, Lisch nodules, optic gliomas, and abnormalities of the bone and central nervous system.[symptoma.com]
Suggestibility
  • Vena caval sampling for catecholamines confirmed all adrenal tumors but suggested additional tumors not verified at operation in two of three patients.[ncbi.nlm.nih.gov]
  • ., diameters 6 cm, may similarly suggest malignancy. Otherwise, neither histological nor immunohistochemical nor molecular markers have been defined to reliable distinguish malignant from benign pheochromocytoma.[symptoma.com]
Hematuria
  • Nephropathies may be associated with nausea, vomiting, edema formation, hematuria, and alterations in the urine volume, while none of these symptoms is to be expected in pheochromocytoma patients.[symptoma.com]

Workup

The workup is based on a thorough anamnesis, including the medical history of the index patient and information regarding the occurrence of hypertension or neoplasms in the family. Historical data may largely facilitate the relation of pheochromocytoma - which still does require diagnostic confirmation - to cancer predisposition syndromes. What's more, the identification of a child as a carrier of pathogenic mutations predisposing to pheochromocytoma and other types of tumors should prompt their inclusion in a long-term surveillance program, since these cases are associated with particularly high risks of malignancy and recurrence [7]. In line with anamnestic and clinical data, pheochromocytoma patients should be tested for mutations in genes RET, NF1, VHL, SDHB, SDHC, and SDHD, and, according to more recent discoveries, SDHAF2, TMEM127, KIF1β, and MAX [5].

The gold standard for the diagnosis of pheochromocytoma is the measurement of fractioned or free metanephrines in plasma and urine samples [1] [2]. The respective tests have a sensitivity of almost 100% for the diagnosis of sympathetic chromaffin tumors [6]. Different secretion profiles may allow for the biochemical distinction between adrenal or extra-adrenal tumors. Only adrenal neoplasms comprise the enzyme phenylethanolamine N-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Accordingly, extra-adrenal paragangliomas are unlikely to release epinephrine or its metabolite metanephrine [1]. In pheochromocytoma patients, plasma and urine levels of catecholamines released by the neoplasm tend to be elevated >4-fold above the reference range. Chromogranin A is another marker of pheochromocytoma; it is attributed high specificity, and its concentration may even correlate with the size of the neoplasm. If biochemical findings are within reference ranges despite strong clinical suspicion, the respective analyses should be repeated after a symptomatic episode. Due to the availability of non-invasive alternatives and the inherent risk of sudden catecholamine release, biopsies are to be omitted [2].

Furthermore, imaging studies are to be conducted to precisely locate the primary tumor, to identify potential metastases, and to prepare the surgical removal of all tumor tissue [1]. Metastasation is a clear sign of malignancy, with metastases most frequently developing in the lymph nodes, lungs, liver, and bones. Large tumor size, i.e., diameters >6 cm, may similarly suggest malignancy [8]. Otherwise, neither histological nor immunohistochemical nor molecular markers have been defined to reliable distinguish malignant from benign pheochromocytoma [5]. Imaging techniques such as sonography, computed tomography, or magnetic resonance imaging should also be employed to evaluate the contralateral adrenal gland: Patients with a genetic predisposition to pheochromocytoma development may present with bilateral tumors. Positron emission tomography with F18-fluorodeoxyglucose and MIBG scintigraphy are based on the functionality of tumor cells and are realized to detect metastatic lesions in the skeleton [1] [2].

Treatment

Definitive treatment comprises the surgical resection of the primary tumor and any metastatic lesions. To avoid hypertensive crises in the pre- and intraoperative course and to compensate for reflex tachycardia, affected children should be pretreated with alpha- and, subsequently, with beta-adrenergic receptor antagonists [1]. Because tyrosine is the precursor of catecholamines, tyrosine hydroxylase inhibitors may be administered instead of or complementary to adrenergic receptor antagonists. Within days before the surgical intervention, oral salt loading via increased dietary intake, sodium chloride tablets, or intravenous saline infusion is suggested for blood volume expansion to prevent severe postoperative hypotension [8]. Besides hypotension, hypoglycemia is the most dreaded postoperative complication. Particularly close monitoring for postoperative hypotension is recommended for patients who have been treated with long-acting drugs, such as phenoxybenzamine [2].

Patients undergoing bilateral adrenalectomy will become dependant on glucocorticoid and mineralocorticoid replacement. A cortical-sparing approach may be taken to avoid such dependency on replacement therapy, but may be difficult to carry out and possibly implies an increased risk of recurrence. Data regarding these issues are scarce [2].

With regard to patients diagnosed with irresectable metastatic pheochromocytoma in childhood, palliation may be achieved with medical therapy including the administration of somatostatin analogs, [131I]MIBG, chemotherapeutics, and bisphosphonates, with radiotherapy, and radiofrequency ablation [2].

Prognosis

The clinical behavior of pheochromocytoma in childhood appears to be more aggressive than in the adult population. Metastatic disease, in turn, is related to higher catecholamine production, more severe symptoms, and higher morbidity and mortality [5]. Nevertheless, pheochromocytoma is primarily considered a benign condition, and high rates of cure are achieved in patients diagnosed with early-stage disease: The prognosis for a completely resected tumor is excellent [4] [7]. According to a study on pheochromocytoma and paraganglioma in childhood, the mean survival time of patients with malignant tumors has been estimated at 13 years [8]. Similar rates have been described elsewhere and indicate long-term survival to be likely [5], but they also demonstrate that the majority of cancer patients eventually succumbs to the disease.

Etiology

Pheochromocytoma in childhood may arise sporadically or be related to cancer predisposition syndromes such as multiple endocrine neoplasia type 2, neurofibromatosis type 1, von Hippel-Lindau disease, and hereditary paraganglioma-pheochromocytoma syndromes. About 80% of pediatric cases are related to genetic disorders, not all of which are defined as syndromes or diseases [7]. Besides the mutations accounting for the aforementioned diseases, the development of pediatric pheochromocytoma may also be related to alterations in tumor suppressors TMEM127 and KIF1β, and transcription factor MAX [5].

Epidemiology

The overall incidence of pheochromocytoma has been estimated at 1 per 100,000 inhabitants. Few of these tumors are diagnosed in pediatric patients, and the majority of pheochromocytoma diagnosed in minors is benign. According to a British tumor register, the annual incidence of malignant pheochromocytoma in childhood is as low as 0.02 per million [2]. Both boys and girls may be affected by benign or malignant pheochromocytoma of childhood [4].

Sex distribution
Age distribution

Pathophysiology

There are at least two pathways to pheochromocytoma development [5]:

  • On the one hand, tumorigenesis may be associated with the accumulation and stabilization of hypoxia-inducible factor α. This type of pheochromocytoma is referred to as cluster 1. It displays a pseudohypoxic phenotype, i.e., it presents a hypoxic signature under normoxic conditions. Pseudohypoxia favors angiogenesis and is frequently related to mutations in genes VHL (von Hippel-Lindau disease) and SDHx (hereditary paraganglioma-pheochromocytoma syndromes). Cluster 1 tumors preferentially release norepinephrine and are more prevalent in the pediatric population than those assigned to cluster 2.
  • On the other hand, cluster 2 comprises tumors with mutations in genes RET (multiple endocrine neoplasia type 2), NF1 (neurofibromatosis type 1), TMEM127, KIF1β, and MAX. These mutations result in the activation of RAS/RAF/MAPK and PI3K/AKT/mTOR pathways and increased expression of genes involved in adrenergic metabolism.

Sporadic pheochromocytoma may feature properties of both clusters [1].

Prevention

The majority of pediatric pheochromocytomas is related to genetic disorders, and our knowledge regarding mutations predisposing to the development of tumors is growing rapidly [7]. Accordingly, more and more families harboring such mutations are offered genetic counseling and testing for pathogenic mutations. Children who test positive should be included in long-term surveillance programs with frequent follow-ups so that adrenal tumors can be detected at an early, resectable stage. This proactive approach has been proven to significantly augment the likelihood of curative resection and to increase survival rates [8].

Summary

Pheochromocytoma in childhood is a rare neoplasm of the adrenal gland. It is histogenetically related to other pediatric malignancies of the sympathetic nervous system, including the more common neuroblastoma and ganglioneuroblastoma, and forms part of the family of neuroendocrine tumors [1]. Pheochromocytoma is characterized by the excessive production of catecholamines like norepinephrine and epinephrine, which have strong effects on the cardiovascular and metabolic systems. According to the activity of tumor cells, patients may present paroxysmal or permanent symptoms, namely hypertension, perspiration, palpitations, and headaches [5]. Facial pallor and flushing may also be observed.

The causes of pheochromocytoma in childhood cannot always be related to preexistent conditions, but comprehensive genetic studies usually yield conclusive results: The majority of patients with pediatric pheochromocytoma is found to carry mutations that predispose to tumor development. Thus, molecular biological studies should be part of any workup of pheochromocytoma in childhood, and long-term surveillance should be planned according to the genetic findings. The direct management of pediatric patients is similar to adults and primarily consists in the surgical resection of the affected adrenal gland [2]. If degenerated tissue can be removed in its entirety, patients have an excellent prognosis.

Patient Information

Pheochromocytoma is a type of tumor that originates from the medulla of the adrenal glands. It is most commonly diagnosed in the adult patient, with pheochromocytoma in childhood being a rare entity. The majority of affected children carries pathogenic mutations favoring the development of pheochromocytoma and other tumors, e.g., mutations related to multiple endocrine neoplasia type 2, neurofibromatosis type 1, or von Hippel-Lindau disease.

Under physiological conditions, the adrenal medulla produces and releases catecholamines like epinephrine and norepinephrine, and functional tumor cells may do the same. Catecholamines have strong effects on the cardiovascular and metabolic systems, and they play major roles in the clinical presentation and workup of pheochromocytoma. Children with pheochromocytoma often suffer from hypertension, and they tend to claim palpitations and headaches. Perspiration, facial pallor, and flushing may also be observed. The release of catecholamines may vary over time, so symptoms may occur in a paroxysmal or permanent manner.

The metabolites of epinephrine and norepinephrine may be detected in plasma and urine samples obtained from affected children, with the respective analyses being the gold standard for the diagnosis of pheochromocytoma. The precise location of the tumor, its size, and extension, as well as the possible presence of metastases, are clarified with diagnostic imaging. Most pediatric pheochromocytomas are benign. They don't form metastases and can be surgically removed in their entirety. The respective patients have an excellent prognosis.

References

Article

  1. Bholah R, Bunchman TE. Review of Pediatric Pheochromocytoma and Paraganglioma. Front Pediatr. 2017; 5:155.
  2. Waguespack SG, Rich T, Grubbs E, et al. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010; 95(5):2023-2037.
  3. Luma GB, Spiotta RT. Hypertension in children and adolescents. Am Fam Physician. 2006; 73(9):1558-1568.
  4. Ludwig AD, Feig DI, Brandt ML, Hicks MJ, Fitch ME, Cass DL. Recent advances in the diagnosis and treatment of pheochromocytoma in children. Am J Surg. 2007; 194(6):792-796; discussion 796-797.
  5. Santos P, Pimenta T, Taveira-Gomes A. Hereditary Pheochromocytoma. Int J Surg Pathol. 2014; 22(5):393-400.
  6. Pacak K, Del Rivero J. Pheochromocytoma. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.
  7. Bausch B, Wellner U, Bausch D, et al. Long-term prognosis of patients with pediatric pheochromocytoma. Endocr Relat Cancer. 2014; 21(1):17-25.
  8. Pham TH, Moir C, Thompson GB, et al. Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center. Pediatrics. 2006; 118(3):1109-1117.

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Last updated: 2019-07-11 20:17