PPGL: Types, Genetic Insights, and Treatment Approaches

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, often leading to excessive catecholamine production. Some cases present with classic symptoms like hypertension, while others remain undiagnosed until incidental detection or genetic screening. Their rarity and diverse presentations make diagnosis and management challenging.

Advances in genetics, imaging, and targeted therapies have improved the understanding of PPGLs. Identifying hereditary mutations is crucial for guiding treatment and assessing familial risk. Early recognition and intervention can prevent complications and improve outcomes.

Types Of Pheochromocytomas And Paragangliomas

PPGLs are classified based on anatomical location. Pheochromocytomas arise in the adrenal medulla, while paragangliomas develop in extra-adrenal sites along the sympathetic or parasympathetic nervous system. Recognizing these distinctions is key to accurate diagnosis and treatment.

Adrenal Tumors

Pheochromocytomas, arising in the adrenal medulla, secrete catecholamines like epinephrine and norepinephrine, causing episodic hypertension, palpitations, and sweating. While most are benign, 10–15% show malignant potential, often indicated by metastases in the liver, lungs, or bones.

Genetic mutations such as VHL, RET, and NF1 are linked to hereditary pheochromocytomas, associated with von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. Genetic testing helps stratify patients based on hereditary risk and malignancy potential.

Surgical resection is the primary treatment, with laparoscopic adrenalectomy preferred for its improved recovery outcomes. Preoperative alpha-adrenergic blockade is essential to prevent hypertensive crises during surgery.

Extra-Adrenal Tumors

Paragangliomas arise outside the adrenal glands and are classified based on location within the sympathetic or parasympathetic nervous system. Sympathetic paragangliomas, found in the abdomen, thorax, or pelvis, often secrete norepinephrine and cause symptoms similar to pheochromocytomas. Parasympathetic paragangliomas, typically in the head and neck, are usually non-secretory and present as slow-growing masses.

Mutations in SDHB, SDHC, and SDHD genes are strongly linked to hereditary paraganglioma syndromes, with SDHB mutations associated with aggressive tumor behavior and metastatic potential.

Treatment depends on tumor location, functionality, and genetic background. Surgery is preferred for localized tumors, while metastatic cases may require radiopharmaceutical treatments or targeted therapies. Long-term follow-up is essential for detecting recurrence or progression.

Rare Subtypes

Some PPGLs exhibit unique characteristics. Composite pheochromocytomas contain elements of other neuroendocrine tumors, such as ganglioneuroma or neuroblastoma, complicating diagnosis and biochemical evaluation.

Pediatric and syndromic pheochromocytomas, often linked to hereditary conditions like Carney-Stratakis syndrome, have a higher genetic predisposition compared to sporadic adult cases, emphasizing the need for genetic counseling and early screening.

Malignant PPGLs, though uncommon, pose management challenges. The presence of metastases at diagnosis defines malignancy, requiring a multidisciplinary approach that may include surgical debulking, systemic therapies, and radiopharmaceutical treatments like 177Lu-DOTATATE. Research into targeted therapies, including HIF2α inhibitors and SDH-related treatments, continues to expand options for aggressive cases.

Genetic Profiles

Genetic discoveries have reshaped PPGL diagnosis and treatment. About 40% of cases are linked to germline mutations, making them among the most heritable neuroendocrine tumors. Somatic mutations also contribute to sporadic cases, adding complexity to their genetic landscape.

Germline mutations fall into key pathways influencing tumor behavior. The hypoxia-inducible factor (HIF) pathway, including VHL, EPAS1, and SDH mutations, drives tumorigenesis by affecting metabolism and angiogenesis. VHL mutations, common in von Hippel-Lindau syndrome, lead to HIF stabilization and tumor formation. EPAS1 (HIF2A) mutations contribute to abnormal catecholamine synthesis, particularly in syndromic cases. SDHB mutations carry the highest malignancy risk.

Kinase signaling pathways also play a role. RET mutations define multiple endocrine neoplasia type 2 (MEN2), predisposing individuals to pheochromocytomas alongside medullary thyroid carcinoma. NF1 mutations, linked to neurofibromatosis type 1, disrupt RAS-MAPK signaling and drive tumor growth.

Next-generation sequencing has identified additional mutations such as ATRX and TP53, associated with metastatic potential. Methylation profiling has further distinguished benign from malignant tumors, offering potential biomarkers for prognosis. Integrating genomic analysis into clinical practice enhances diagnostic accuracy and treatment decisions.

Biochemical Markers

Biochemical evaluation relies on detecting catecholamine metabolites, which provide insights into tumor activity. Given the episodic nature of catecholamine secretion, direct measurements can be unreliable. Instead, metanephrines—O-methylated catecholamine metabolites—are preferred for their stability and diagnostic accuracy.

Plasma free metanephrines and urinary fractionated metanephrines are the gold standard. Plasma assays offer over 97% sensitivity, with metanephrine and normetanephrine levels correlating with tumor type. Pheochromocytomas predominantly produce epinephrine and metanephrine, while extra-adrenal paragangliomas favor norepinephrine and normetanephrine.

Dopamine and its metabolite 3-methoxytyramine are key markers, particularly in SDHB-mutated paragangliomas, which often exhibit dopamine secretion. Elevated 3-methoxytyramine levels indicate a higher malignancy risk.

Imaging Approaches

Accurate localization of PPGLs guides surgical planning and metastatic assessment. Initial imaging typically involves computed tomography (CT) or magnetic resonance imaging (MRI). CT, particularly with contrast, is the first-line choice for adrenal lesions due to its high resolution, while MRI is preferred for extra-adrenal and head and neck paragangliomas due to superior soft tissue contrast.

Functional imaging plays a central role in tumor characterization. 68Ga-DOTATATE PET/CT, targeting somatostatin receptors, is highly effective for detecting SDHB-mutated paragangliomas and metastatic disease. 18F-FDG PET/CT is valuable for aggressive, metabolically active tumors, particularly those with SDHB mutations.

Clinical Features

PPGL presentation varies, from classic symptoms of catecholamine excess to incidental findings. Hypertension, either sustained or paroxysmal, is the most common sign, often accompanied by headaches, tachycardia, and sweating. These symptoms stem from intermittent catecholamine surges, which can be triggered by stress or certain medications.

Beyond cardiovascular effects, PPGLs can impact metabolism, leading to glucose abnormalities and increased diabetes risk. Neurological symptoms, including anxiety, panic attacks, and tremors, may also occur. In metastatic or large tumors, mass effect symptoms like abdominal pain or cranial nerve deficits may dominate. Given these diverse presentations, a high index of suspicion is necessary, particularly in patients with resistant hypertension or a family history of hereditary syndromes.

Surgical And Pharmacological Therapies

Surgery remains the definitive treatment for localized PPGLs. Laparoscopic adrenalectomy is preferred for benign adrenal pheochromocytomas due to its minimally invasive nature, while open surgery is required for large, extra-adrenal, or invasive tumors. Preoperative alpha-adrenergic blockade with phenoxybenzamine or doxazosin is essential to prevent hypertensive crises. Beta-blockers are introduced only after adequate alpha blockade.

For metastatic or unresectable cases, systemic therapies are critical. Radiopharmaceutical treatments like 177Lu-DOTATATE and 131I-MIBG target somatostatin receptor-expressing or noradrenaline transporter-positive tumors. Tyrosine kinase inhibitors like sunitinib have shown promise in slowing tumor progression, particularly in SDHB-mutated cases. While chemotherapy remains an option, its efficacy is limited, highlighting the need for ongoing research into novel treatments.

Associated Endocrine Syndromes

PPGLs frequently occur in hereditary endocrine syndromes. Multiple endocrine neoplasia type 2 (MEN2), caused by RET mutations, predisposes individuals to pheochromocytomas, medullary thyroid carcinoma, and hyperparathyroidism. These tumors are often bilateral, requiring careful surgical planning.

Von Hippel-Lindau (VHL) syndrome, linked to VHL mutations, includes adrenal pheochromocytomas alongside renal cell carcinoma and hemangioblastomas, necessitating regular surveillance.

Neurofibromatosis type 1 (NF1) and hereditary paraganglioma-pheochromocytoma syndromes further highlight the genetic complexity of these tumors. NF1-associated pheochromocytomas tend to be less aggressive, while SDHB-mutated paragangliomas carry a higher metastatic risk. Lifelong monitoring is essential, as tumors may develop in multiple locations over time. Advances in genotype-phenotype correlations continue to refine screening, risk assessment, and treatment strategies.