From the Guidelines
Pheochromocytomas are considered malignant only in the presence of metastasis, as defined by the presence of tumor cells in tissues where chromaffin cells are not normally found, such as lymph nodes, liver, lungs, or bone, as stated in the 2012 ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of adrenal cancer 1.
Definition of Malignancy
The definition of malignancy in pheochromocytomas is crucial for determining the prognosis and treatment plan. According to the guidelines, malignant pheochromocytomas/paragangliomas are defined by the presence of metastasis 1. This means that the presence of metastasis is the only definitive way to determine if a pheochromocytoma is malignant.
Risk Factors for Malignancy
While there are no reliable histological features that can definitively predict malignancy in the absence of metastasis, certain risk factors may suggest a higher likelihood of malignancy. These include:
- Larger tumor size (greater than 5-6 cm)
- Extra-adrenal location (paragangliomas)
- Certain genetic mutations (particularly SDHB mutations)
- Elevated levels of certain biochemical markers like methoxytyramine
Treatment and Management
All pheochromocytomas should be considered potentially dangerous regardless of whether they are benign or malignant, as they all can produce excess catecholamines (adrenaline and noradrenaline) that can cause life-threatening hypertensive crises. Complete surgical removal is the standard treatment for both benign and malignant pheochromocytomas, with appropriate preoperative alpha-blockade (typically phenoxybenzamine or doxazosin) followed by beta-blockade to control symptoms and prevent complications during surgery 1.
Follow-up and Surveillance
Patients who underwent successful surgery for non-metastatic pheochromocytoma/paraganglioma are at risk of malignant recurrence and require long-term clinical and biochemical follow-up, as recommended in the guidelines 1. This includes regular intervals of clinical assessment, biochemical testing, and imaging studies to monitor for signs of recurrence or metastasis.
From the Research
Definition and Incidence of Malignant Pheochromocytoma
- Pheochromocytomas are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla 2.
- Approximately 10% of pheochromocytomas are malignant 3, 4, 5, 6, 2.
- The annual incidence of pheochromocytoma is 2 to 8 per million adults, with a peak frequency observed between 30 and 40 years of age 2.
Diagnosis of Malignant Pheochromocytoma
- The diagnosis of malignancy is based on neoplastic recurrence or the presence of metastasis in organs that lack chromaffin tissue 2.
- Criteria for malignancy include the invasion of neighboring organs, a large tumor, the presence of lymphadenopathy on imaging, or fixation on scintigraphy 2.
- The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) system can predict patients at risk for recurrence, with a score of ≥6 indicating a high risk of malignancy 3.
Clinical Characteristics and Treatment
- Hypertension is a constant finding in approximately 94% of patients with pheochromocytoma 4.
- The most common accompanying manifestations are headache, perspiration, and palpitations 4.
- Treatment options for malignant pheochromocytoma include debulking surgery, targeted radiation therapy with (131)I-MIBG, and chemotherapy 5, 6.
- Novel targeted therapies, such as somatostatin analogues and tyrosine kinase inhibitors, have shown promising results in the treatment of malignant pheochromocytoma 6.
Prognostic Factors
- The main prognostic factors of malignant pheochromocytomas are a large tumor volume, the existence or number of visceral metastases, and the presence of a mutation in the SDHB (Succinate dehydrogenase B) gene 2.
- High levels of chromogranin A may indicate tumor mass and malignancy, and can be used to monitor response and relapse 6.