What causes a pheochromocytoma to form in the adrenal glands? 

A pheochromocytoma is a rare, usually non-cancerous tumour that develops in the adrenal glands, which are small organs located on top of each kidney. These tumours form in the adrenal medulla, the inner part of the gland responsible for producing hormones that regulate the body’s response to stress. While the exact reason why a specific individual develops a pheochromocytoma is not always clear, research has identified several genetic mutations and inherited conditions that play a significant role in their formation. Understanding the origin of these tumours is essential for managing the symptoms caused by the overproduction of adrenaline and noradrenaline. 

What We’ll Discuss in This Article 

• The function of the adrenal medulla in hormone production. 

• The role of genetic mutations in tumour development. 

• Inherited syndromes associated with pheochromocytoma. 

• The process of tumour formation in the adrenal glands. 

• Distinctions between sporadic and hereditary cases. 

• When to seek medical advice for related symptoms. 

The role of the adrenal medulla in hormone production 

To understand why a pheochromocytoma forms, it is necessary to look at the specific cells within the adrenal glands. The adrenal glands are divided into two main parts: the outer cortex and the inner medulla. The medulla is made up of specialised cells called chromaffin cells. These cells are part of the sympathetic nervous system and are responsible for producing and releasing catecholamines, which include adrenaline (epinephrine) and noradrenaline (norepinephrine). These hormones are vital for the fight or flight response, helping to increase heart rate, blood pressure, and blood sugar levels during times of stress. 

A pheochromocytoma begins when these chromaffin cells start to grow uncontrollably, forming a mass or tumour. Because the tumour is composed of hormone producing cells, it often continues to secrete large amounts of catecholamines into the bloodstream. This overproduction is what leads to the characteristic symptoms of the condition, such as high blood pressure, palpitations, and sweating. Unlike normal adrenal tissue, which releases hormones in response to specific triggers from the nervous system, the tumour cells often release these hormones sporadically or continuously, leading to unpredictable spikes in symptoms. 

The formation of these tumours is a complex biological process. In most cases, the growth is benign, meaning it does not spread to other parts of the body. However, even a non-cancerous pheochromocytoma can be life threatening if the hormone levels are not controlled. Pheochromocytomas are rare tumours of the adrenal glands that can cause high blood pressure. The pressure exerted by the tumour on surrounding tissues is less of a concern than the systemic effects of the hormones it produces. 

Genetic factors and inherited syndromes 

One of the most significant advancements in medical understanding of pheochromocytoma is the recognition of the role of genetics. It is now estimated that a significant proportion of these tumours are linked to inherited genetic mutations. If a person carries a mutation in certain genes, their chromaffin cells are more likely to undergo the changes that lead to tumour formation. This is why clinicians often recommend genetic testing for anyone diagnosed with a pheochromocytoma, as it can have implications for both the patient and their close relatives. 

Several specific inherited syndromes are known to increase the risk of developing these tumours. One of the most common is Multiple Endocrine Neoplasia type 2 (MEN 2). People with this condition have a high likelihood of developing tumours in various endocrine glands, including the thyroid and the parathyroid, in addition to the adrenal glands. Another condition is von Hippel-Lindau (VHL) disease, which causes tumours and cysts to form in various parts of the body, including the brain, spinal cord, and kidneys. Genetic testing is often offered to people with pheochromocytoma to see if it’s caused by an inherited condition. 

Neurofibromatosis type 1 (NF1) is another genetic disorder associated with an increased risk, though pheochromocytomas are less common in NF1 than in MEN 2 or VHL. Additionally, mutations in the succinate dehydrogenase (SDH) genes, which are involved in the body’s energy production processes, have been identified as a major cause of hereditary pheochromocytomas and related tumours called paragangliomas. These genetic links suggest that for many patients, the tumour forms because of a pre-existing “blueprint” in their DNA that predisposes certain cells to abnormal growth. 

Sporadic vs hereditary tumour formation 

While genetic factors are prominent, many cases of pheochromocytoma are classified as “sporadic.” This means the tumour occurs by chance, without a clear family history or a known inherited genetic mutation. In sporadic cases, the mutation that triggers the tumour growth happens only within the tumour cells themselves during the person’s lifetime, rather than being present in every cell of the body from birth. These are often referred to as somatic mutations. 

The distinction between sporadic and hereditary cases is important for clinical management. Hereditary tumours often appear at a younger age and are more likely to affect both adrenal glands. They also carry a higher risk of recurrence after surgery. Sporadic tumours, on the other hand, typically occur in older adults and usually involve only one adrenal gland. Despite these differences, the underlying mechanism of cell overgrowth in the adrenal medulla remains the same: a disruption in the normal signals that regulate cell division and hormone secretion. 

Researchers continue to investigate what triggers somatic mutations in sporadic cases. Environmental factors, lifestyle, and other non-genetic influences are being studied, but as of now, no single external cause has been definitively linked to the formation of these tumours. This makes regular health check ups and monitoring of blood pressure particularly important, as early detection of the symptoms caused by the tumour is often the first step toward a diagnosis. 

The process of cellular transformation 

The actual transformation of a normal chromaffin cell into a tumour cell involves several stages of molecular changes. For a tumour to form, the cell must bypass the natural checkpoints that prevent excessive growth. In many pheochromocytomas, this happens because of changes in the pathways that control how cells respond to oxygen levels or how they process energy. When these pathways are disrupted, the cell may “think” it is in a state of low oxygen (hypoxia), even when oxygen levels are normal. This false signal triggers the cell to grow and divide rapidly. 

Another common pathway involved in the formation of these tumours is the “kinase signaling” pathway. This pathway acts like a switch that tells a cell when to grow. Mutations in genes like RET (associated with MEN 2) or NF1 keep this switch in the “on” position. As a result, the chromaffin cells continue to multiply, eventually forming a visible mass within the adrenal gland. This mass then begins to function independently of the rest of the body’s regulatory systems. 

As the tumour grows, it develops its own blood supply to sustain its high metabolic activity. This process, known as angiogenesis, allows the tumour to grow larger and ensures that the hormones it produces have direct access to the bloodstream. The combination of uncontrolled cell growth and autonomous hormone production is what makes pheochromocytoma a unique and challenging clinical condition. The complexity of these cellular changes highlights why specialised care is necessary for those suspected of having an adrenal tumour. 

Distinguishing pheochromocytoma from paraganglioma 

When discussing the causes of tumours in the adrenal glands, it is often necessary to mention paragangliomas. While a pheochromocytoma forms specifically within the adrenal medulla, a paraganglioma is a closely related tumour that forms in the nerve tissues outside of the adrenal glands, often along the major blood vessels in the abdomen, chest, or neck. Both types of tumours arise from the same type of precursor cells and can produce similar hormones. 

The causes of paragangliomas are very similar to those of pheochromocytomas, with a strong emphasis on genetic mutations, particularly the SDH gene mutations. In fact, some genetic syndromes can cause both types of tumours to form in the same individual. The location of the tumour is the primary factor that determines whether it is called a pheochromocytoma or a paraganglioma. If the tumour is in the adrenal gland, it is a pheochromocytoma; if it is elsewhere, it is a paraganglioma. 

Conclusion 

A pheochromocytoma forms due to the abnormal growth of chromaffin cells in the adrenal medulla, frequently driven by genetic mutations. These tumours are significant because they overproduce stress hormones, leading to symptoms like high blood pressure and palpitations. While many cases occur sporadically, a large number are linked to inherited syndromes, making genetic screening an important part of the care pathway. Early identification and management are crucial to prevent cardiovascular complications. If you experience severe, sudden, or worsening symptoms, call 999 immediately. 

Authority Snapshot 

This article provides an overview of the causes and mechanisms of pheochromocytoma formation for educational purposes. It was developed by the Medical Content Team and reviewed by Dr. Stefan Petrov to ensure clinical accuracy and adherence to UK standards. The content is strictly aligned with NHS and NICE guidance regarding the diagnosis and management of rare adrenal tumours to ensure patient safety.