What is phaeochromocytoma?
Phaeochromocytoma (pheochromocytoma in American spelling) is a rare neuroendocrine tumour that secretes high amounts of the catecholamines noradrenaline and, to a lesser extent, adrenaline.
Phaeochromocytomas arise from the adrenal medulla (85%) or from neural ganglia in the head and neck (15%). The latter are also termed paragangliomas.
Who gets phaeochromocytoma?
Phaeochromocytomas are rare. It is estimated that 2–8 cases are diagnosed per year in a population of one million people. The tumours have a higher prevalence in patients with hypertension (about 1–6 per thousand).
The mean age at diagnosis is 40 years, although phaeochromocytoma can occur at any age.
What causes phaeochromocytoma?
- 75% of phaeochromocytomas are sporadic.
- 25% are due to inherited genetic mutations.
The associated hereditary syndromes and genetic mutations include the following:
|Named disease||Affected gene||Inheritance||Clinical phenotype|
|Von Hippel-Lindau||VHL gene on chromosome 3p25||Autosomal dominant||Phaeochromocytomas (in 20% of cases), angiomatosis, renal clear cell carcinomas, renal cysts, primitive neuroectodermal tumours (PNET), retinal haemangioblastomas, pancreatic tumours, endolymphatical tumours, epididymal cystadenomas|
|Neurofibromatosis Type 1||NF1 gene on chromosome 17q11||Autosomal dominant||Phaeochromocytoma (in 1–3% of cases), neurofibromas, learning disabilities, scoliosis, kyphosis|
|Multiple Endocrine Neoplasia Type 2||RET gene on chromosome 10q11||Autosomal dominant||Bilateral phaeochromocytomas (in 50–80% of cases), medullary thyroid carcinoma, parathyroid adenoma|
|Succinate Dehydrogenase Protein Complex Genes Germline Mutations||SDHA gene on chromosome 5p15||Autosomal dominant||Paraganglioma, dilated cardiomyopathy, Leigh syndrome|
|SDHAF2 on chromosome 11q12||Autosomal dominant||Multifocal paraganglioma, no associated metastases|
|SDHB gene on chromosome 1p36||Autosomal dominant||Phaeochromocytoma, paraganglioma, Cowden syndrome, renal–cell carcinomas, gastrointestinal stromal tumours|
|SDHD gene on chromosome 11q23||Autosomal dominant||Phaeochromocytoma, paraganglioma, Carcinoid tumours, Cowden syndrome, gastrointestinal stromal tumours, deafness|
|TMEM127||TMEM127 gene on chromosome 2q11||Autosomal dominant||Bilateral phaeochromocytomas, and malignancy is infrequent|
|MAX||MAX gene on chromosome 14q23||Autosomal dominant||Malignant phaeochromocytomas|
10% of gene mutations are associated with malignancy (cancer).
What are the clinical features of phaeochromocytoma?
Symptoms of phaeochromocytoma are variable due to paroxysmal episodes of hormone release. They include:
- Sweating (hyperhidrosis)
- Paroxysmal hypertension
- Malignant hypertension
Malignancy is defined by the presence of distant metastases. Metastatic rates are 10–15% for phaeochromocytomas and 20–50% for paragangliomas. The most common metastatic sites are the skeleton, lungs, liver, and lymph nodes.
How is phaeochromocytoma diagnosed?
Phaeochromocytoma may be suspected from typical history and presence of hypertension on examination. The following investigations are performed.
- Plasma or 24-hour urinary catecholamines and metanephrines – if strongly elevated (> 3–4 times the normal range), the diagnosis of phaeochromocytoma is likely
- Chromogranin A – elevated in phaeochromocytoma
- Clonidine suppression test
- Genetic testing if there are multiple tumours or a family history of phaeochromocytoma. For solitary tumours in patients over 40 years of age without a family history, genetic testing is probably not necessary
- Magnetic resonance imaging (MRI) with gadolinium contrast shows a hyperintense mass in T2 phase. Infiltration of local organs and vessels can be better evaluated with MRI than with CT.
- Computed tomography (CT) with contrast. Benefits of CT are low cost, availability and high sensitivity (detection of lesion 0.5–1 cm). CT has low specificity for phaeochromocytoma.
Radionuclide imaging is used to determine functionality of the tumour and for follow-up.
- Iodine-123 metaiodobenzylguanidinescan (I23I–MIBG SPECT) has excellent specificity, and sensitivity of 90–100% in detection of small tumours > 1–2 cm. It can be used for planning MIBG therapy in metastatic disease.
- Positron emission tomography (PET) as PET-CT or PET-MRI with fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) has excellent specificity and sensitivity of 90–100% for 18F–DOPA in detection of small tumours > 1–2 cm. This has higher spatial resolution and a more selective, clearer radiotracer accumulation in phaeochromocytomas compared to 123I–MIBG SPECT. However, it is less widely available and is more expensive.
The criteria for malignancy are excessive hormone production and tumour size > 4–6 cm. Currently, there are no histological criteria for distinguishing benign and malignant tumours.
What is the treatment for phaeochromocytoma?
The management of patients with phaeochromocytoma should be performed by multidisciplinary teams of experienced endocrinologists, anesthesthetists and surgeons, to prevent perioperative complications and reduce morbidity.
Genetic counselling may be required.
Medical management of hypertension
- Alpha-blockers, eg phenoxybenzamine (long-acting), doxazosin (short-acting)
- B-blockers, eg atenolol – do not use without concurrent alpha-blockade due to risk of severe refractory hypertension
Surgical excision is the only curative treatment modality. Effective management of perioperative hypertension improves outcomes.
Laparoscopic surgery is generally preferred to open surgery. Note:
- Retroperitoneal “no touch technique” is better than transperitoneal approach
- Benefits of laparoscopy compared to open surgery include shorter hospital stay, less blood loss, faster recovery, better cosmetic results
- Risks: 5% are converted to open approach
- Contraindications to laparoscopy include tumours > 8 cm, malignancy, extreme obesity (BMI > 45)
Treatment of metastatic phaeochromocytoma is limited, with no curative treatment options.
Chemotherapy options for metastatic phaeochromocytoma include:
- Cyclophosphamide, vincristin, dacarbazine: 5–year survival is 30–60%
- Tyrosine kinase receptor inhibitors eg. sunitinib
- mTOR inhibitor eg, everolimus
Other treatment options for metastatic phaeochromocytoma are:
- Ablation procedures
- De-bulking surgery
What is the outcome for phaeochromocytoma?
Negative prognostic factors for phaeochromocytoma include:
- Older age
The prognosis is excellent for a completely resected sporadic phaeochromocytoma, which has a low risk of relapse or malignancy.
In inherited causes, one-third of patients with extra-adrenal disease experience recurrence.
- Annual follow-up is recommended for at least 10 years after surgery.
- Lifelong follow-up is recommended for those with extra-adrenal or familial phaeochromocytoma.
- Blood pressure and urinary catecholamines should be regularly monitored
- Imaging with CT and/or MRI may be undertaken every 2 years or so.