Paraganglioma

What is Paraganglioma?

Paraganglia are groups of cells that have their origin from the nervous system and are found both within the adrenal gland (an organ that sits on top of your kidneys) or outside of it. These cells can form rare and blood-rich tumors known as paragangliomas. Some people call them extra-adrenal pheochromocytomas when they are outside the adrenal gland, while others might refer to a pheochromocytoma inside the adrenal gland as an intra-adrenal paraganglioma.

Around 86% of these tumors located outside of the head and neck are of a type called ‘sympathetic’ and largely secrete a hormone called norepinephrine. This differs from the more specialized tumors found within the abdomen, neuroblastoma and pheochromocytoma, which primarily secrete another hormone, epinephrine. People with these sympathetic paragangliomas typically experience symptoms such as high blood pressure, rapid heartbeat, headache, and excessive sweating.

Sympathetic paragangliomas can occur anywhere along the route of the sympathetic nerves, from the base of the skull to the bladder and prostate. However, they are most commonly found at the junction of two veins in the abdomen or near an artery known as the inferior mesenteric artery.

Tumors that come from ‘parasympathetic’ cells are usually symptom-free and inactive. These are primarily located in the neck and the base of the skull along the route of certain nerves. Most of these paragangliomas come from a location called the carotid body in the neck, but some can also come from other areas. Only around 5% of these tumors secrete a type of hormones called catecholamines.

Paragangliomas usually appear as a single, non-cancerous tumor on one side of the body. Though rare, in about 1% of non-inherited and 20% to 80% of inherited cases, a person might have multiple tumors. These tumors are usually benign, but on rare occasions, they can turn malignant and spread to other parts of the body. Identifying these tumors early and completely removing them through surgery often cures the patient and has a good outlook. Finding out if the tumor has spread is the only sure way to understand how aggressive paragangliomas are.

Paragangliomas mainly occur spontaneously, but in 30% to 50% of cases, they can be inherited. Some inherited forms are related to certain genetic conditions and variations in specific genes. A tissue biopsy taken during surgery is typically used to confirm the diagnosis. However, the biopsy is not able to differentiate between pheochromocytomas and paragangliomas. Usually, the diagnosis is made based on the patient’s symptoms, assisted by imaging and pathological examination of the tumor.

What Causes Paraganglioma?

Paraganglia are special cells that come from neural crest cells, a group of cells that play a big role in the development of various body tissues. There are two types of paraganglia: sympathetic and parasympathetic. Sympathetic paraganglia, which are tasked with the body’s fight or flight response, are found in the adrenal gland, along the spine, and in nerves that control organs in the space behind the stomach and in the pelvic area. Parasympathetic paraganglia, which are involved in rest and digestion, are found along nerves in the neck and upper chest.

There are different types of parasympathetic ganglia including Jugulotympanic, Orbital, Vagal, Laryngeal, Subclavian, and those found in the Carotid and aortic bodies.

Tumors that grow from these paraganglia are called paragangliomas. Sometimes, these tumors can be related to specific family genes. Kids are more prone to these tumors if there’s a family history. Genes such as those responsible for different parts of the SDH enzyme complex are often involved.

Certain genetic syndromes also put people at a higher risk of developing these tumors. These syndromes include Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis type 1 (NF1), Von Hippel-Lindau disease (VHL), and Carney-Stratakis dyad.

Factors like living in high altitudes or illnesses that result in low oxygen levels, like cyanotic congenital heart disease and chronic obstructive lung disease, can boost the risk of these tumors, specifically those found in the carotid body.

The names of paragangliomas usually tell you their location. For example, Jugulotympanic paragangliomas are found in the ear. These tumors usually show up in women in their 50s and are on both sides in only about 10%-16% of cases. Around 10% of these tumors are inherited and can affect men and women equally. The inherited type often shows up earlier in life and is linked to changes on chromosome 11.

Risk Factors and Frequency for Paraganglioma

Paragangliomas, related to pheochromocytomas, are rare tumors diagnosed in between 500 to 1000 individuals in the US each year. The combined incidence rate of both types of tumors is 0.7 to 1.0 per 100,000 people annually.

These tumors typically appear in patients between their 30s and 50s, with an average age of diagnosis around 47. The location of the tumor can influence the age of diagnosis. For instance, those with tumors in their skull base and neck are often older, while those with abdominal tumors are usually younger, around 36. Moreover, it’s been observed that patients with hereditary paragangliomas often develop the tumors about 10 years earlier, typically in their early 30s.

• Paragangliomas, along with pheochromocytomas, are detected in 500 to 1000 individuals in the US yearly.
• The majority of patients are diagnosed between their 30s and 50s.
• The average age of diagnosis is 47 years old.
• Tumor location can influence the age of diagnosis, with abdominal tumors appearing at a younger age (around 36), and tumors in the skull base and neck appearing at an older age (around 43).
• Patients with hereditary paragangliomas tend to be diagnosed about 10 years earlier than those with sporadic tumors, typically in their early 30s.

Most paragangliomas are not cancerous. Malignant paragangliomas are extremely rare, with about 90 to 95 cases per 400 million people each year. For hereditary cases, paragangliomas affect males and females alike. However, sporadic tumors, which occur without a hereditary link, are more common in females, with a ratio of 3 to 1 compared to males.

Signs and Symptoms of Paraganglioma

Paragangliomas are typically slow-growing benign tumors that are highly vascular, which means they have a lot of blood vessels. The symptoms a person experiences depend on where the paraganglioma is located. Common signs of all paragangliomas include effects from the mass of the tumor and excess catecholamines, which are chemicals produced by nerve tissues. However, some paragangliomas don’t cause any noticeable symptoms and can be unexpectedly discovered during medical imaging or screenings.

Some possible symptoms include digestive bleeding, back or chest pain, coughing, difficulty breathing, nausea and vomiting after exercise. During a physical examination, signs that can allude to paragangliomas include a variety of issues such as hoarse voice due to paralyzed vocal cords, cranial nerve paralysis, restlessness, rapid heartbeat, heavy sweating, high blood pressure with irregular episodes, perspiration, cold and clammy skin, wide eyes, dry mouth, and goosebumps. Other symptoms may include slow heart rate, fainting as a result of the carotid sinus syndrome. Additionally, coughing up blood, difficulty swallowing, or chest pain can signal a condition called the superior venous sinus syndrome.

Regarding catecholamine excess, it’s most common feature is high blood pressure. These hypertension episodes could be constant or come and go, often reaching a peak. A majority of these episodes are accompanied by headache, fast heart rate and excessive sweating – symptoms known as “the classic triad”. If all three symptoms are present simultaneously, it implies a 90% likelihood of a catecholamine-secreting tumor. However, the chances of all three symptoms occurring at the same time is around 40%, and it’s quite rare if the tumor is located in the base of the skull or neck.

Patients who experience intermittent bouts of high blood pressure along with other classic symptoms are potentially dealing with a catecholamine paraganglioma. This is especially so when these symptoms are triggered by changing positions, feeling anxious, certain medications, doing physical activities or anything that increases pressure in the abdomen. It is worth noting that some patients with an SDHB-related mutation may have normal or even low blood pressure because they primarily produce the hormone dopamine.

• Other symptoms of a catecholamine excess could include a dry mouth, facial flushing, dilated pupils, restlessness, constipation, fatigue, tremors, feelings of panic or general weakness due to exhaustion.
• Certain symptoms such as fainting after urination or during sexual activity, high blood pressure, and blood in the urine, are classic signs of a bladder paraganglioma.
• Some patients may also experience orthostatic hypotension due to low blood plasma volume, a swollen optic disc in the eye, blurred vision, lightheadedness, weight loss, excess hunger, excessive thirst, mood swings, high blood sugar levels and losing weight.

When paragangliomas are located in the head and neck region, they are typically small tumors. Their small size generally leads to higher chances of successful surgical removal and better outcomes compared to larger tumors elsewhere.

Different types of paragangliomas may include Carotid body tumors, Jugulotympanic paragangliomas and Vagal paragangliomas. Certain rare cases include cervical paragangliomas originating near or in the thyroid gland or dura (outermost layer that surrounds the brain and spinal cord). Symptoms for these cases are based on the tumor’s location and could include neurological problems as a result of the tumor’s pressure.

Testing for Paraganglioma

When you are suspected to have a tumor that releases certain stress hormones, such as adrenaline, a number of tests can be performed to make the correct diagnosis. These tests can include looking at the biochemistry or genes of the tumor, as well as imagining studies to see where the tumor is located. In some cases, they may also test your urine over 24 hours or run a clonidine suppression test, which can help see how the tumor affects your hormone levels.

Before doctors can say for sure that you have a certain type of tumor called a pheochromocytoma or a paraganglioma, they need to see if your body is making too much of a particular kind of hormone called catecholamines. This is often done using a 24-hour urine test and some other lab tests. Certain medications or stressful events can lead to false-positive results, so it’s important for you to stop taking certain drugs two weeks before the test and to try to avoid stress.

To locate the tumor, doctors can use imaging tests such as CT scans or MRI scans. These tests are done using a special kind of dye, and some medications may be required beforehand to prevent serious complications. In some cases, if the CT or MRI scan cannot find the tumor, additional imaging tests may be needed, including scans of the head, neck, and chest or other specialized scans.

While a CT scan or MRI scan can often detect these types of tumors, sometimes doctors use other scanning techniques. For example, they might use a scan called an MIBG scan, which can identify tumors that aren’t seen on a CT or MRI scan. Other scans, such as PET scans, are also sometimes used.

Doctors can also perform genetic testing to see if you are predisposed to developing these types of tumors. Genetic testing can inform what to watch out for in the future, and if a genetic variant is found, it’s important for your close relatives to be tested as well.

The most definitive way to confirm the diagnosis is a biopsy, which is a procedure where a small piece of the tumor is removed and tested. Due to their high blood flow and the risk of hormone crisis, these tumors are typically removed in the same procedure as the biopsy. However, biopsies are usually avoided unless necessary because it can result in scarring at the biopsy site and there are other tests to establish diagnosis. The only confirmation of the malignancy can be determined by tumor deposits in abnormal tissues once removed.

About 20% of these tumors located outside of the adrenal glands are cancerous, and 10% of those in the adrenal glands are cancerous. Most of the tumors in the head and neck are not cancerous, and unfortunately, there’s no way to predict their behavior from clinical, tissue, or biochemical features. Once a tumor is removed or biopsied, tests that scan the whole body for other tumors or cancer spread may be done. Those with specific genetic variants which typically show secretive abdominal tumors have a higher rate of cancer and may need further evaluation for metastatic disease.

Treatment Options for Paraganglioma

The main treatment for paraganglioma and pheochromocytoma, two types of nerve tumors, is surgical removal. Nonetheless, if the surgery is not possible or if the tumor could not be entirely removed, radiotherapy (a treatment using high-energy rays) may be needed. It’s also important to manage blood pressure before the surgery to prevent a sudden, severe increase in blood pressure during the operation. This is largely dependent on the behavior of the tumor.

What else can Paraganglioma be?

When doctors are evaluating a patient’s symptoms, they have to consider different possibilities or diagnoses. Here are some conditions, grouped by type, that professionals might consider:

• Endocrine conditions:
• Pheochromocytoma
• Thyrotoxicosis
• Insulinoma
• Hypoglycemia
• Medullary thyroid carcinoma
• Cardiovascular conditions:
• Labile essential hypertension
• Positional orthostatic hypotension
• Carcinoid syndrome
• Pulmonary edema
• Syncope
• Orthostatic hypotension
• Cardiac arrhythmia
• Angina
• Renovascular disease
• Psychological conditions:
• Hyperventilation
• Vancomycin infusion reaction
• Anxiety and panic attacks
• Factitious disorder
• Somatization disorder
• Pharmacologic conditions:
• Sympathomimetic drug ingestion
• Recreational drug use (such as cocaine, phencyclidine [PCP], and lysergic acid diethylamide [LSD])
• Withdrawal from adrenergic inhibitors
• Monoamine oxidase inhibitor treatment combined with a decongestant
• Neurologic conditions:
• Autonomic neuropathy
• Migraine
• Cerebrovascular accident (stroke)
• Autonomic seizures
• Other conditions:
• Mast cell disease
• Recurrent idiopathic anaphylaxis

These are just potential diagnoses, and the suitable tests and investigations would be decided by a healthcare professional to confirm the specific condition.

Surgical Treatment of Paraganglioma

For small head and neck paragangliomas (a type of tumor) that are less than 1 cm and do not produce symptoms or hormone-related issues, doctors can monitor them without immediate treatment. These tumors grow very slowly, around 1 mm per year, and typically require a check-up scan every 6 months, then once a year if no changes occur. However, tumors found in areas outside the neck and head usually are not left untreated. Therapy might be needed for small tumors that cause issues, like tympanic paragangliomas (in the inner ear), jugular paragangliomas causing hearing loss, tinnitus, or facial nerve weakness, tumors causing compression on the brainstem, secretory tumors, tumors causing cranial nerve malfunctions, fast-growing tumors, malignant (cancerous) tumors, or simply if a patient prefers treatment.

The surgical approach to treat these tumors primarily relies on their location, size, and the overall health of the patient. Tumors that produce too many stress hormones (catecholamines) can be quite tricky to manage and necessitate extensive preparation before surgery. Patients with such tumors may require antihypertensive medications from at least a week before surgery to regulate blood pressure. Patients may also follow a high sodium diet and hydration regimen before the operation to avoid severe low blood pressure after removing the tumor.

In some cases, surgeons might use preoperative embolization (a procedure that diminishes blood flow to the tumor) for specific cases of hormone-producing head and neck paragangliomas, although this method’s utilization can vary. This procedure’s benefits include less blood loss during surgery, a shorter operation time, and a simpler tumor removal process. However, it does carry risks like strokes, blindness, cranial nerve damage, and in severe cases, death.

Radiation therapy is another treatment option for small, benign (non-cancerous) tumors that produce no hormones if surgery would harm critical nerve or blood vessel structures. This therapy can also be helpful for recurrent tumors after surgery.

During surgery, hormone release can result in unstable blood pressure and heart rate. Therefore, monitoring heart rate, blood pressure, and urine output is essential during operation. Surgeons will address significant changes in blood pressure promptly with suitable medications.

The surgical approach for paragangliomas usually involves minimally invasive endoscopic surgery, such as laparoscopic surgery. This method tends to have fewer complications, shorter operation times, and shorter hospital stays. That said, paragangliomas found in the thorax typically require a more traditional open surgery approach.
Surgically treating paragangliomas of the head and neck requires a multidisciplinary approach. Paragangliomas found in this area present their unique challenges and require detailed imaging to pinpoint the tumor’s exact location and size. In some cases, removal could cause nerve damage lower in the cranial area like facial palsy, hearing loss, hoarseness, and other nerve damage.

For pregnant patients with hormone-producing paragangliomas, doctors have to take special precautions due to concerns over fetal wellbeing and maternal surgical risks. These patients may choose to delay tumor resection until the second trimester or may opt for medical management throughout pregnancy and surgical resection after childbirth.

Postoperative complications following paragangliomas’ surgical removal can vary depending on the tumor’s location. For instance, resection of paragangliomas in the head and neck may result in cranial nerve deficits or strokes. Surgery in the abdomen or pelvic area might lead to bowel obstruction, bowel perforation, or organ failure. Resecting thoracic paragangliomas could cause pneumothorax (collapsed lung), chylothorax (fluid buildup in the chest), uncontrollable bleeding, esophageal perforation, or cardiac tamponade (pressure on the heart due to fluid buildup).

What to expect with Paraganglioma

Complete removal of a benign paraganglioma, which is a non-cancerous tumor that grows in certain cells of the nervous system, usually has a less than 10% chance of growing back, and it doesn’t affect overall life expectancy. The main focus for people having this benign tumor, especially in the head and neck area, is to maintain their quality of life. Those who have surgery to remove the tumor and retain normal neurological function carry a noticeable risk of surgical complications tied to lower cranial nerve deficits. This risk is especially present when compared to those who already had these deficits and had time to adapt.

Leaving out radiation therapy after partial tumor removal could lead to the tumor continuing to grow. Careful and continuous monitoring becomes vital as bigger tumors increase the risk of damage to the nerves. Patients with multiple tumors, genetic mutations, or cancer that has spread to other parts of the body pose the highest risk of the tumor growing back. Indeed, a significant number of these individuals, 65%, who originally presented with cancer that has spread, are likely to experience the return of such spread. Those with this form of cancer live an average of five years in a range of 34% and 60%. Typically, tumor recurrence happens around 5.5 years after diagnosis. Interestingly, 31% of people initially diagnosed with presumed non-cancerous disease may face a recurrence of their tumor, even 50 years after their first diagnosis. As a result, yearly lifelong monitoring is extremely important.

Possible Complications When Diagnosed with Paraganglioma

Paragangliomas are seldom seen tumors that develop in specific nerve cells that are part of our sympathetic nervous system, used for ‘fight or flight’ actions. While they usually grow slowly and do not often spread, they can cause health issues due to the overproduction of certain hormones like adrenaline.

Patients might face various health issues linked to these paragangliomas such as

• High blood pressure
• Heart-related problems
• Catecholamine crisis (a severe health problem due to sudden hormone surge)
• Orthostatic hypotension (a sudden drop in blood pressure when standing up)
• Heart attack risk
• Neurological symptoms (like headaches or vision issues)
• Endocrine dysfunction (issues with nearby organs or glands)
• Renal complications (like potential kidney issues)

While typically slow-growing and benign, these tumors might become malignant, spreading to other body areas, usually indicating a less favorable outlook. Managing these health issues involves a multi-layered approach, like surgery, radiation therapy, and medical management to control blood pressure and decrease the symptoms linked to the overproduction of hormones. Regular doctor visits and monitoring are critical to effectively handle potential complications, requiring patients to maintain close communication with their healthcare team.

Recovery from Paraganglioma

After having surgery to remove a tumor, some patients might need to go through rehabilitation to help them recover, depending on where the tumor was and any problems they might have after the surgery. Normally, if the tumor was removed using a procedure called an endoscopic tumor resection (a surgery done using a special tool called an endoscope), the patients don’t need a lot of rehabilitation and can leave the hospital sooner.

After surgery for a specific type of tumor called catecholamine-secreting paragangliomas, patients get special tests and images of their body within 3 months. The doctors want to make sure that they removed all of the tumor. They do this by looking to see if certain substances in the urine and blood are at normal levels and if the images of the patient’s body do not show any tumor. They usually do an imaging test called an MRI 3 to 4 months after the surgery.

If a patient had surgery to remove a paraganglioma in the head or neck and the doctors weren’t able to take everything out, the patient gets an MRI 8 to 12 weeks after the surgery, and then once a year for at least 3 years. After that, they get another image every other year for 6 years, and then every 3 years. If the tumor was the type that could make extra hormones in the body, the patient will have regular check-ups, blood pressure checks, and tests for hormone levels in the blood, every 6 to 12 months for the first 3 years after surgery. After that, they will have these checks and tests once a year or as needed by the doctor. If the patient’s pre-surgery imaging showed a high level of certain type of sugar (18-fluorodeoxyglucose or FDG) in the tumor, the patient will have regular PET scans (a type of image test) to keep an eye on it.

Patients with nonfunctioning paragangliomas (tumors that don’t make extra hormones) will have imaging and tests once a year at first, with the frequency decreasing over time, but they will continue these tests for their whole life. If these patients have a genetic predisposition syndrome (a condition in their genes that makes them more likely to get certain diseases), they will continue to have blood tests for hormone levels once a year. If the hormone levels in their blood start to rise, doctors will do imaging of their chest, stomach, and lower body parts to see if there are any new changes.

Preventing Paraganglioma

Pheochromocytomas and paragangliomas are rare kinds of tumors that form in the nerve tissue. Pheochromocytomas originate in the adrenal gland, a small organ located above the kidneys. Paragangliomas, on the other hand, develop outside the adrenal gland, anywhere along the nerves or blood vessels in areas like the neck, chest, belly, and pelvic area. While these tumors are generally not cancerous, they can sometimes be.

Some of these tumors produce excessively high levels of hormones called catecholamines. This overproduction can lead to symptoms such as headaches, high blood pressure, heart palpitations, and excessive sweating. These symptoms can show up unexpectedly or may be triggered by events like childbirth, injuries, or the stress of having surgery or anesthesia.

There are certain genetic conditions, like MEN 2A and 2B, NF1, Carney-Stratakis dyad, and changes in SDH genes, that make a person more likely to develop these sorts of tumors. That’s why people who’ve been diagnosed with a paraganglioma should undergo genetic testing. If they test positive for these genetic risks, their close family members can also be tested and treated if necessary, before the condition gets worse.

To diagnose these tumors, doctors start by checking the levels of catecholamines in the patient’s body. They might also do imaging studies like CT scans, MRIs, or radionucleotide scans that can help provide a detailed view of the tumors. After the diagnosis, the patient’s treatment could involve close observation, surgical removal, or radiation therapy. If the tumors are producing catecholamines, they are typically removed to prevent dangerously high blood pressure, which can lead to life-threatening conditions such as stroke, irregular heartbeat, and heart attack. But complete removal can be challenging because these tumors often have a rich supply of blood vessels and might be near important nerves.

Patients preparing for surgery might need to eat a high-salt diet, drink more fluids, and take certain blood pressure medications. These measures help prevent problems like excessively high blood pressure during surgery and low blood pressure afterward. Lastly, after a paraganglioma is treated, it’s important for patients to continue getting regular checks, including blood or urine tests and imaging studies. This kind of regular monitoring will depend on the patient’s situation, and factors like the type and location of the tumor.