What is the association of paraganglioma (paraganglionic neuroendocrine neoplasm)?

From the Guidelines

Paragangliomas are most commonly associated with genetic syndromes, particularly mutations in succinate dehydrogenase (SDH) genes, and their management should prioritize a multidisciplinary approach considering the risk of tumor multifocality and bilaterality. The association of paraganglioma with genetic syndromes is well-established, with approximately 40% of cases having a hereditary basis 1. The most significant genetic associations include mutations in SDH genes, particularly SDHB, SDHC, SDHD, and SDHA, which follow an autosomal dominant inheritance pattern. Von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis type 1 are also associated with paragangliomas.

Key considerations in the management of paragangliomas include:

• Genetic testing to identify hereditary syndromes and guide screening of family members
• Biochemical testing for catecholamines and imaging studies for diagnosis
• Treatment options such as surgical resection, radiation therapy, and targeted medications for symptom management
• A multidisciplinary approach to balance surgical intervention with medical and radiotherapeutic approaches, especially in patients with SDHD pathogenic variants 1

A watchful waiting approach is often appropriate to characterize tumor behavior in patients with SDHD pathogenic variants, and referral to specialized high-volume medical centers is recommended. This approach prioritizes minimizing harm and allows for tailored management based on tumor behavior and patient characteristics 1. In contrast to older guidelines that may have suggested more aggressive treatment approaches, recent evidence supports a more conservative approach in selected cases, highlighting the importance of staying up-to-date with the latest clinical guidelines and research findings 1.

In terms of specific treatment options, 131I-MIBG therapy should be considered as a first-line approach in patients with a good uptake of 123I-MIBG and unresectable, progressive pheochromocytoma/paraganglioma or symptomatic patients 1. Additionally, cyclophosphamide- and dacarbazine-based regimens combined with vincristine (CVD) or doxorubicin (CVDD or CDD) are the best-studied chemotherapy regimens for paragangliomas 1. However, the choice of treatment should be individualized based on patient characteristics, tumor behavior, and genetic background.

From the Research

Association of Paraganglioma

The association of paraganglioma is a complex topic that involves various clinical settings and genetic factors. Some key points to consider include:

• Paragangliomas are rare tumors that arise from extra-adrenal paraganglia, and their diagnosis and management require a multidisciplinary approach 2.
• These tumors can be diagnosed in various clinical settings, including signs and symptoms related to catecholamine hypersecretion, mass effect symptoms, incidental finding on imaging, or family screening for hereditary paraganglioma 2.
• Paragangliomas that hypersecrete catecholamines may cause signs and symptoms identical to those in patients with hyperfunctioning adrenal pheochromocytoma, and biochemical documentation of catecholamine and fractionated metanephrine hypersecretion is essential for diagnosis 2.

Genetic Associations

Paragangliomas have been associated with several genetic syndromes, including:

• Multiple endocrine neoplasia type 2 (MEN 2) 3, 4, 5
• Von Hippel-Lindau disease (VHL) 3, 4, 5
• Neurofibromatosis type 1 (NF 1) 3, 4, 5
• Paraganglioma syndromes type 1,3, and 4, which are caused by mutations in the succinate dehydrogenase (SDH) gene subunits 3, 6
• The Carney triad, which is a rare syndrome that involves paragangliomas, gastrointestinal stromal tumors (GISTs), and other tumors 6

Clinical Implications

The association of paraganglioma with these genetic syndromes has important clinical implications, including:

• The need for genetic testing in all patients with paraganglioma to identify potential germline mutations 2, 3, 4, 5
• The importance of family screening for hereditary paraganglioma and other associated tumors 2, 5
• The need for regular follow-up and surveillance to detect and treat metachronous paraganglial and extraparaganglial tumors 5