Review ArticleThe Genetic Basis of Pheochromocytoma and Paraganglioma: Implications for Management
Section snippets
Background
The incidence of pheochromocytoma and paraganglioma is quite low, with <2000 cases each year in the United States, with an annual incidence rate of 0.8 per 100,000 person-years.6 For paraganglioma, despite representing only about 20% of ChT, urologic surgeons should also be familiar with their management, as 85% of these tumors are located in the abdomen and pelvis.7
Despite the WHO dividing ChT into 2 types, many experts still split paragangliomas into head and neck paragangliomas and
Clinical Presentation
Patients with symptomatic pheochromocytomas and paragangliomas frequently report hypertension, sweats, palpitations, anxiety, headaches, tachycardia, and tremors. However, with current imaging, 20%-30% of these tumors are incidentally detected.9 Pheochromocytomas can be found in approximately 1 in 5000 patients evaluated for hypertension and in the workup of 1 in 20 adrenal incidentalomas. Although baseline catecholamines may be elevated, at least about half of patients can present with
Clinical Evaluation
The initial workup for a pheochromocytoma and paraganglioma includes biochemical testing to document excessive catecholamine production (Supplementary Figure 1). Clinicians have the option of performing either, or both, plasma or urinary testing.11 The optimal testing strategy remains to be determined, as the sensitivity and specificity of each test vary. Many clinicians choose to screen patients with what is currently the most sensitive test, plasma free metanephrines.12 There is complexity in
Von Hippel-Lindau
Von Hippel-Lindau (VHL) is an autosomal dominant hereditary condition characterized by the development of tumors in a number of organs, including retinal angiomas, central nervous system hemangioblastomas, pancreatic cysts and neuroendocrine tumors, renal cell carcinomas, epididymal cystadenomas, and pheochromocytoma and paraganglioma (Fig. 1). The incidence of this disorder is approximately 1 in 35,000 individuals. Linkage analysis in families with VHL localized the region of interest to 3p.28
Genetic Testing
The consensus from the First International Symposium on Pheochromocytoma was that although genetic testing should be considered in patients with a ChT, the current costs may preclude testing of some patients for all recognized genes.11 Clinicians must be very thoughtful in selecting genetic testing and for which particular genes. In patients who do not present with a known hereditary condition, clinicians should look for the additional characteristics of one of the common associated syndromes,
Surgical Management
The surgical management of a paraganglioma and pheochromocytoma has traditionally involved complete excision and/or total adrenalectomy. In patients with bilateral, multifocal, or hereditary pheochromocytoma syndromes, partial adrenalectomy has emerged as an option to preserve adrenal function.82-87 Patients who have permanent need for adrenal replacement with steroids and mineralocorticoids face long-term consequences, such as hypertension, diabetes, osteoporosis, and weight/body habitus
Conclusion
ChT are rare tumors derived from neural crest tissue and are divided into 2 categories, pheochromocytomas and paragangliomas. Well-described hereditary syndromes such as VHL, NF1, and MEN2 are a common cause of these tumors; however, recently more than a half dozen potential novel pheochromocytoma and paraganglioma syndromes have been reported. Currently, 35% of “sporadic” pheochromocytomas are found to have a hereditary component; therefore, clinicians who manage these patients need to be
References (29)
- et al.
Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3
Genomics
(1990) Lloyd RHPEC: Pathology and Genetics of Tumors of Endocrine Organs
(2004)- et al.
Pheochromocytoma and functional paraganglioma syndrome: no longer the 10% tumor
J Surg Oncol
(2005) - et al.
Germ-line mutations in nonsyndromic pheochromocytoma
N Engl J Med
(2002) - et al.
Genetic testing in pheochromocytoma or functional paraganglioma
J Clin Oncol
(2005) - et al.
Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127
Endocrinology
(2011) - et al.
Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979
Mayo Clin Proc
(1983) - et al.
Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients
Clin Cancer Res
(2009) - et al.
Extraadrenal retroperitoneal paraganglioma: clinical, pathologic, and CT findings
AJR Am J Roentgenol
(1990) - et al.
Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma
Eur J Endocrinol
(2009)
Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma
Ann Intern Med
Preoperative management of the pheochromocytoma patient
J Clin Endocrinol Metab
Biochemical diagnosis of pheochromocytoma: which test is best?
JAMA
Drugs and pheochromocytoma—don't be fooled by every elevated metanephrine
N Engl J Med
Cited by (36)
EDITORIAL COMMENT
2023, UrologyLong term outcomes for patients with von Hippel-Lindau and Pheochromocytoma: defining the role of active surveillance
2021, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Individuals affected with von Hippel-Lindau (VHL) are at risk for the development tumors in multiple organs, including spine and/or brain and/or retinal hemangioblastomas, pancreatic neuroendocrine tumors, endolymphatic sac tumors, bilateral clear cell renal cell carcinoma, papillary cystadenoma of the epididymis and broad ligament, and pheochromocytomas [1, 2].
Diagnostic Pathology: Endocrine
2018, Diagnostic Pathology: EndocrineHereditary Kidney Cancer Syndromes and Surgical Management of the Small Renal Mass
2017, Urologic Clinics of North AmericaCitation Excerpt :If left unidentified, these extrarenal tumors can complicate surgery by causing intraoperative issues, such as hypertensive crisis. Catecholamine and metanephrine testing (either of the urine or plasma) should be performed preoperatively in these patients to rule out a potential pheochromocytoma/paraganglioma.68,84 In some patients, intervention may be indicated in both kidneys, which can make surgical planning complex.
Educational Case: Pheochromocytoma
2018, Academic PathologyCitation Excerpt :Many patients are asymptomatic with the lesion discovered during imaging workup for an abdominal condition or at autopsy.4 Each of the above hereditary syndromes, involving mutations in the succinate dehydrogenase gene, must be considered when evaluating a patient with a pheochromocytoma and/or paraganglioma.1-4,6-12 Patients presenting at an early age with these neoplasms should be screened for mutations involving the succinate dehydrogenase gene.
Financial Disclosure: The authors declare that they have no relevant financial interests.