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Meta-Analysis
. 2026 Jan 21;111(2):580-590.
doi: 10.1210/clinem/dgaf584.

Metastatic Disease in Phaeochromocytomas and Paragangliomas in Various Genotypes-A Systematic Review and Meta-analysis

Louise Kirkegaard Svendsen  1 , Åse Krogh Rasmussen  1 , Marianne Christina Klose  1 , Jesper Krogh  2 , Ulla Feldt-Rasmussen  1
Affiliations
Meta-Analysis

Metastatic Disease in Phaeochromocytomas and Paragangliomas in Various Genotypes-A Systematic Review and Meta-analysis

Louise Kirkegaard Svendsen et al. J Clin Endocrinol Metab. .

Abstract

Background: Paragangliomas and phaeochromocytomas (PPGLs) are rare neuroendocrine tumours with 10% to 20% of patients developing metastatic disease. The tumors exhibit a high degree of heritability, and pathogenic genetic variants have been associated with metastases.

Objective: We aimed to investigate the association between the genotype of PPGL patients and their risk of metastatic disease, adjusting for time.

Methods: A systematic search was conducted in PubMed and Embase. The primary outcome was the rate of metastatic disease per 100 followed patient-years analyzed through meta-analyses.

Results: A significantly increased rate of metastatic disease per 100 followed patient-years was observed in all pathogenic germline variants included in the analyses, compared to the group with no identified variant. The group with no variant had a rate of 1.55 per 100 patient-years. SDHA, SDHC, SDHD, VHL, RET, NF1, and MAX had rates of 13.73, 6.27, 2.03, 2.34, 1.91, 4.11, and 9.66, respectively. The rate of SDHB is not presented as statistical heterogeneity exceeded 75%. The pathogenic somatic variant EPAS1 showed a rate of 3.82. Cluster-divided meta-analyses resulted in rates of 4.41 and 3.0 for cluster 1 and cluster 2, respectively. Meta-regression analysis revealed a 2.3-fold higher rate for the SDHB variant compared to the other cluster 1 variants.

Conclusion: We present associations between genotype and metastatic disease in PPGL patients. Our results indicate that patients harboring a pathogenic genetic variant have a higher rate of metastases compared to patients with no identified variant. High heterogeneity in several analyses suggests that further large cohort studies are needed.

Keywords: genotype; meta-analysis; metastasis; paraganglioma; pheochromocytoma; systematic review.

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Figures

Figure 1.
Figure 1.
PRISMA flowchart.
Figure 2.
Figure 2.
Distribution of pathogenic variants in all paragangliomas and phaeochromocytomas patients. n = total number of pathogenic germline/somatic variants across all included studies.
See this image and copyright information in PMC

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