Genetics and the clinical approach to paragangliomas

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Paragangliomas (PGLs) require accurate malignancy risk assessment for clinical management.
• Malignancy suspicion dictates workup and surgical approach for adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas.
• Current clinical practice lacks a standardized algorithm integrating location, family history, and genetic testing for PGL risk stratification.

Purpose of the Study:

• To analyze gene mutation data in paragangliomas and contextualize findings for clinical application.
• To evaluate the correlation between specific gene mutations and the risk of malignancy in PGLs.
• To determine the utility of mutation analysis in preoperative risk assessment for PGLs.

Main Methods:

• Systematic literature search of PubMed using "paraganglioma genetics" yielded 1,821 articles.
• Selection and analysis of 37 articles, with 9 ultimately included in the study.
• Germline mutation status and specific gene mutations (SDHB, VHL, RET, SDHD, NF1, SDHC) were analyzed in relation to PGL characteristics and malignancy.

Main Results:

• Germline mutations were identified in 24% (599/2,487) of PGL patients.
• Mutations in SDHB (30.2%), VHL (25%), RET (19.4%), and SDHD (18.4%) were most prevalent.
• Malignancy rates varied significantly by PGL location and mutation status, with higher risks in certain E-PGLs (thoraco-abdominal) and SDHB mutations.

Conclusions:

• Mutation analysis provides critical preoperative information for assessing malignancy risk in both A-PGL and E-PGL.
• Exclusion of a mutation significantly lowers the probability of malignancy, particularly in E-PGL.
• Mutation testing should be considered in the workup of all E-PGL lesions to guide clinical management.