Overview

A paraganglioma is a rare tumour that arises from a particular kind of nerve cell found all over the body. These special nerve cells, called chromaffin cells, have vital functions within the body, such as regulating blood pressure.

When chromaffin cells become abnormal, they can form growths called tumours. When these tumours occur in the adrenal glands they are called pheochromocytomas. If the tumours arise elsewhere in the body they are called paragangliomas.

Paragangliomas are most often benign. However, a minority of them can become malignant and metastasise to other regions of the body. They are uncommon tumours and can develop at any age, but have most commonly been found in adults between 30 and 50 years. The cause of most tumours is unknown, although many paragangliomas result from mutations of genes that are passed from parent to child. The cells of paraganglioma often secrete catecholamines, such as the hormone adrenaline, responsible for the fight-or-flight response. This may bring about fits of hypertension, tachycardia, sweating, headaches, and even tremors.¹

Types 

Paragangliomas are categorised based on their locations.²

Caroid paragangliomas 

It presents with an expanding and pulsing mass. These benign paragangliomas appear as simple, isolated lesions and will have relatively few symptoms. These tumours usually appear in the neck but can extend into the space between the head and the neck. Other common symptoms related to paragangliomas are pains, hoarseness, fainting, difficulties swallowing, eye disturbances, and immobilisation of the tongue.

Cervical paragangliomas

They cause palsy, are slow-growing tumours, and may extend into the skull base. Differentiation between tumours affecting the vagus from those involving the carotid artery may not be easy.

Jugular paragangliomasThese are usually large and appear with paralysis of the fourth, fifth, and 11th cranial nerves. The symptoms vary: they can cause double vision if they paralyse the fourth nerve, some numbness of the face if it disturbs the fifth nerve paralysis, and if the tumour affects the 11th cranial nerve one may find it difficult to move his shoulder. When the tumour extends beyond the jugular foramen, it may involve the 12th cranial nerve, which can produce paralysis and/or weakness in the tongue.

Secretory paragangliomas

It may occur in up to one in eight patients and can present with release of catecholamines. Symptoms include headaches, hypertension or high blood pressure, palpitations, excessive sweating, and anxiety. Treatment may be hard because the paraganglioma would be jarred by it, prompting them to release some hormones.

Temporal paragangliomas 

It may present with any one symptom or several among the following: hearing loss, rhythmic, thumping in the ear, face paralysis, otorrhea, pain, vertigo, ear bleeding, lower cranial nerve paralysis, nausea and vomiting, loss of vision, headache, and change in behaviour.

Vagal paragangliomas

It may also cause paralysis of the lower cranial nerves, including the 10th cranial nerve, which might cause paralysis of the diaphragm; paralysis of the 12th cranial nerve with resultant paralysis of the tongue, problems in swallowing, and rising shoulder.

We consider them all as temporal paragangliomas since, in many instances, it is quite problematic to decide whether the tumour is of a purely jugular or of a tympanic origin.

Causes

The exact causes of most cases of paraganglioma are unknown, and the cancers seem to develop on their own. In 25-35% of people with paraganglioma, there is a concerning inheritance that in some way influences the development of the disease including:

• Multiple endocrine neoplasia 2 syndrome, types A and B
• Von Hippel-Lindau (VHL) disease²
• Neurofibromatosis type 1 (NF1)
• Hereditary paraganglioma syndrome
• Carney-Stratakis dyad³
• Carney triad (paraganglioma, gastrointestinal tumours, and pulmonary chondroma)⁴

Accordingly, the National Cancer Institute reports that mutations currently in more than 20 genes have been identified to predispose individuals to the development of pheochromocytomas and paragangliomas.

If the patient's paraganglioma is not part of a hereditary syndrome, the tumour is said to be nonsyndromic. Women are more commonly affected than men in cases with nonsyndromic paragangliomas.

Sign and symptoms

Most paragangliomas are benign neoplasms, hypervascular and slow-growing.

Symptoms depend on specific locations. Since most are a result of tumour mass effect and excess catecholamines, the rest may not present symptoms because they were incidentally found. This usually happens when imaging radiographically or during the screening of known carriers with pathogenic variants. These include excess perspiration, uncontrollable episodic hypertension, diaphoresis, cold and clammy skin, dilated eyes, dry mouth, and sometimes piloerection (goosebumps).⁵

The other potential clinical manifestations are upper gastrointestinal bleeding, back or chest discomfort, cough, dyspnea, nausea induced by exertion, and vomiting. Until very recently, examination usually demonstrated evidence of sympathetic overdrive or mass effect, including but not limited to hoarseness due to vocal cord paralysis, cranial nerve paralysis, restlessness, and tachycardia. Other symptoms could be diaphoresis, uncontrolled episodic hypertension, perspiration, cold and clammy skin, dilated eyes, dry mouth, and sometimes piloerection. Bradycardia and syncope may be seen with carotid sinus syndrome. Hemoptysis (coughing up blood), dysphagia (swallowing problems), or chest pain may be associated with superior venous sinus syndrome 

Catecholamine excess

The most common feature of catecholamine excess is hypertension, continuous or intermittent often paroxysmal (sudden recurrence). These episodes commonly present with the classic associated symptoms of headache, palpitations, and profuse sweating (the classic triad). If all three elements are present simultaneously, a catecholamine-secreting tumour can be diagnosed with specificity of 90% by a healthcare professional. However, the occurrence of these symptoms manifesting at the same time is a percentage likelihood of roughly 40% and is highly unlikely if the tumour is originating from the skull base or neck.

Intermittent episodes of hypertension in association with other classic symptoms, especially provoked by one or more of the following:  changes in the upright posture, anxiety, medications, exercise, and manoeuvres that increase intra-abdominal pressure. Less commonly, patients with a mutation related to the SDHB gene may produce dopamine, leading to normal blood pressure or even hypotension.

Classically, these are related to the constellation of hypertension, hematuria (blood in urine), and signs and symptoms of catecholamine excess with micturition or sexual activity. Indeed, one of the hallmark symptoms seen with a bladder paraganglioma is syncope upon micturition. Other symptoms of catecholamine excess include but are not limited to xerostomia or dry mouth, facial flushing, mydriasis or dilated pupils, restlessness or fidgetiness, constipation, fatigue, tremors, panic-like symptoms, and generalised weakness due to exhaustion. They may also show up with the symptoms of orthostatic hypotension owing to low plasma volume, headache, papilledema, blurred vision, dizziness, weight reduction, polyphagia, polydipsia, mood changes, hyperglycemia, and loss of weight.⁵

Diagnosis

Following is the diagnosis with tests and procedures for paraganglioma:

• Physical examination: An examination of the body to check for general signs of health, such as high blood pressure, and medical history, taking into consideration family medical history relating to endocrine problems
• 24-hour urine test: A test in which urine is collected for 24 hours to measure the amount of adrenal hormones in it. Higher-than-normal amounts of certain catecholamines in the urine may indicate paraganglioma
• Blood catecholamine studies: These tests measure the level of catecholamines in the blood. Other substances that are produced by the breakdown of these hormones are also measured. An above-normal amount of certain catecholamines in the blood may indicate paraganglioma
• Imaging studies: MRI, CT scan,and PET scan
• Genetic counseling and testing

Treatment

Treatment options are based on the site of the paraganglioma as well as whether or not it has spread to other parts of the body and whether it is causing excessive production of hormones that may contribute to signs and symptoms.

The treatment for paraganglioma is usually surgical. If the cells of the paraganglioma produce hormones, then it would be required to block the hormones before treatment. In some cases, that is also achieved via medications. Other treatments may be considered if the paraganglioma cannot be entirely taken out during an operation and if it spreads to other body parts.

Treatments that can help manage symptoms, if one has a paraganglioma causing symptoms due to excess adrenal hormones, may include:

• Alpha-blockers for blood pressure management
• Beta-blockers which help maintain a normal heart rate
• Medicine that blocks the effect of the excess hormones made by the adrenal gland(s)
• Surgical excision of the tumour
• Radiation therapy
• Chemotherapy

Ablation therapyTargeted therapy: This treatment may be an option for an individual with a paraganglioma that spreads to other parts of the body.

If the paraganglioma appears to be growing slowly and isn't causing signs and symptoms, the doctor may recommend that immediate treatment isn't necessary. Instead, the doctor may recommend monitoring the condition during regular follow-up appointments.

Prognosis

The outlook remains dependent on several factors, which include:

• Where in your body the tumour is and how large it is?

If it is a case of cancer and the tumour has already spread to other parts of your body.

• Is the tumour surgically resectable and, if so, how much of the tumour has been surgically removed?

Individuals with a small paraganglioma that has not metastasised to any other parts of the body have an approximately 95%-five-year survival rate. Five-year survival rates for individuals with a paraganglioma that has recurred or metastasised range between 34% and 60%.  

These are also the cases of malignant paraganglioma tumours that did not metastasise out of the primary site but infiltrated the local tissue in such a way that it was impossible to resect it surgically. In these cases, the excess release of adrenaline and noradrenaline becomes dangerous, and symptomatic treatment is hard to put into practice. 

If benign or malignant paragangliomas are not treated, they may lead the excess secretion of adrenaline and noradrenaline to severe and dangerous complications. The complications may result in:

• Cardiomyopathy is a primary disease of your heart muscle
• Myocarditis is an inflammation of your heart muscle
• Cerebral haemorrhaging, uncontrolled bleeding in your brain 
• Pulmonary oedema, fluid buildup in your lungs 
• Myocardial infarction (heart attack)
• Stroke
• Coma
• Death

Summary

Paragangliomas are neoplasias originating from a type of nervous cell that pervades the human body. They can be benign or malignant. Most of the reported cases involved adults between 30 and 50 years of age. The symptoms often vary depending on the site of the tumour. Common manifestations include palpable hypertension, tachycardia, diaphoresis (excessive sweating), headache, and trembling. Diagnosis usually involves physical examination, urine analysis, blood tests, and imaging studies. The treatment options vary but usually include surgery, medications to manage the hormonal secretion, and complementary therapy such as radiation and chemotherapy. The prognosis is based on the size and diffused area of the tumour and the response to treatment. In a few or untreated cases, paragangliomas may become extremely critical, leading to heart disease, stroke, and death.