Systematic Review

Incidence of Pheochromocytoma and Paraganglioma Over 70 Years

Abdul Rahman Al Subhi; Veronica Boyle; Marianne S. Elston

Disclosures

J Endo Soc. 2022;6(9) 

In This Article

Abstract and Introduction

Abstract

Context: Pheochromocytomas and paragangliomas (PPGLs) are known to be rare. However, there is scant literature reporting their epidemiology, particularly whether the diagnosis of PPGL has increased with advances in medical imaging and biochemical and genetic testing.

Objective: The primary objective of this systematic review was to determine the annual incidence of PPGLs and change over time.

Design: A systematic review was performed. Medline, Embase, PubMed, and Web of Science Core Collection databases were searched to identify studies reporting PPGL incidence. Studies were eligible for inclusion from the database's inception until August 30, 2021.

Results: A total of 6109 manuscripts were identified; 2282 duplicates were excluded, and a further 3815 papers were excluded after abstract and/or full text review. Twelve studies were included in the final review. The incidence of PPGL ranged from 0.04 to 0.95 cases per 100 000 per year. Incidence increased over time, from approximately 0.2/100,000 individuals in studies performed before 2000, to approximately 0.6/100,000 in studies undertaken after 2010. The mode of diagnosis changed over the same time period, with more patients diagnosed from incidental imaging findings, and fewer at autopsy or from symptoms.

Conclusion: The annual incidence of PPGL has increased over time. Much of this increase is likely from incidental identification of tumors on imaging. However, the epidemiology of PPGL remains understudied, in particular, in associations with altitude, ethnicity, and genetics. To improve early detection and management guidelines, these gaps should be addressed.

Introduction

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from the chromaffin cells of the autonomic nervous system.[1] Pheochromocytomas (PCCs) originate from the adrenal medulla, whereas paragangliomas (PGLs) arise from extra-adrenal paraganglia.[2] Paragangliomas are divided into 2 subtypes: sympathetic paragangliomas, occurring along the sympathetic trunk, and head and neck paragangliomas (HNPGL); the latter named because the majority of parasympathetic paragangliomas arise in the head and neck region.[2]

Detailed epidemiological studies on PPGLs are scarce, with most conducted before the era of modern imaging and improvements in biochemical analysis. One of the oldest and most frequently cited studies, by Beard et al of patients from Rochester, Minnesota, with PPGL identified from 1950 to 1979, reported an annual PPGL incidence of 0.95/100,000.[3] In comparison, incidence rates reported in other studies from a similar time period were far lower, between 0.04 and 0.21/100,000,[4–7] suggesting that either Rochester had an unusually high incidence of PPGL or that PPGLs may be underdiagnosed in other centers.

Over the past 5 decades, there have been significant advances in clinical medicine. For example, there is now widespread availability of high-resolution anatomical imaging and a variety of functional imaging options including longstanding techniques such as I-123 metaiodobenzylguanidine scintigraphy, and more recent positron emission tomography scanning options including 18F-fluoro-2 deoxy-D-glucose, 18-F-flurodihydroxyphenylalanine, and gallium-68 Dotatate.[8,9] The sensitivity of biochemical detection has also improved with the development of assays for the detection of catecholamine metabolites.[10] With these advances, improved detection of PPGL is expected, and therefore higher incidence rates compared with those reported in the past century.[11]

Particularly over the past 2 decades there have been marked advances in our knowledge of the genetics of PPGL.[12,13] An increased number of germline susceptibility genes have been identified, genetic testing is more widely available, and there is an increased awareness of the importance of screening those with a known PPGL susceptibility gene. Nearly one-half of patients with PPGL harbor a germline mutation in 1 of the PPGL susceptibility genes.[13,14] Patients with a genetic predisposition often present younger and, particularly if identified from surveillance because of a known familial germline mutation, are more likely to be asymptomatic compared with those with sporadic tumors.[9] However, geographical differences in availability and uptake of screening and the presence of founder mutations in certain regions, such as the "Black Forest" VHL mutation,[15] the SDHx Dutch founder mutations,[16] and the Trentino SDHD mutation,[17] may result in different epidemiological patterns.

A clear understanding of the epidemiology of PPGLs is needed, especially with the recent advances in screening and investigation methods. Additionally, studying the epidemiology of the disease can help determine whether changes to the current guidelines are needed. The primary objective of this systematic review was to determine the annual incidence of PPGLs and determine any change in incidence over time.

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