Adrenal tumours

Essentials

  • Adrenal tumours are usually discovered incidentally in association with other imaging (incidentaloma).
  • They are most often benign, inactive adenomas, i.e. glandular tumours not requiring follow-up or treatment.
  • Nevertheless, such a finding should be further investigated because it may also represent a tumour requiring treatment, such as an adrenocortical carcinoma, phaeochromocytoma, hormone-secreting adenoma or metastasis of some other malignant disease.
  • Adrenal tumours may secrete cortisol, aldosterone, adrenaline or noradrenaline and, rarely, also androgens or oestrogens, in which case the tumour is often an adrenocortical carcinoma.
  • A tumour may also be found when
    • investigating the aetiology of a disease involving a hormonal excess
    • staging a malignant disease
    • screening because of hereditary susceptibility.

Symptoms

  • Most tumours are asymptomatic.
  • The symptoms may be either local (pain, obstruction, bleeding) or due to agents secreted into the circulation by the tumour.

Diagnostic investigations

  • Small, hormonally inactive adrenal tumours that are considered to be benign based on imaging do not require surgical treatment or follow-up.
  • The hormonal activity of adrenal tumours can be assessed based on laboratory tests (check also reference values of the local laboratory).
    • 1 mg dexamethasone test
      • Results exceeding 50 nmol/l suggest cortisol hypersecretion.
      • Hypercortisolism can be confirmed by measuring 24-hour urinary cortisol excretion and salivary cortisol at midnight.
    • Serum adrenaline and noradrenaline metabolites
    • If a patient has hypertension and a hypokalaemic tendency, the aldosterone to renin ratio in plasma should be defined.
      • A serum aldosterone to plasma renin ratio > 30 and serum aldosterone > 300 pmol/l suggest aldosterone hypersecretion.
  • The primary radiologic investigation is unenhanced computerized tomography (unenhanced CT).
    • A homogeneous tumour with a density below 10 Hounsfield units (HU) is benign regardless of its size; follow-up by imaging is not necessary.
    • A tumour exceeding 4 cm that is inhomogeneous or has a density exceeding 20 HU should be removed due to risk of malignancy.
    • Tumours over 4 cm with a density of 10–20 HU, or smaller than 4 cm with a density exceeding 20 HU, should be followed up by imaging in 6–12 months.
  • Adrenal biopsy should be considered if the adrenal tumour is suspected of being a metastasis of some other cancer and phaeochromocytoma has been biochemically excluded.
    • Biopsy is not recommended for the diagnosis of adrenal carcinoma, because the carcinoma could metastasize through the biopsy route.
    • Adrenal metastases of other malignant tumours can typically be confirmed by a FDG-PET scan.

Treatment

  • If an adrenal tumour is found to be hormonally active or cannot be confirmed as benign by imaging, the treatment plan should be drawn up by a multiprofessional team including a radiologist, an endocrinologist, gastrosurgeon and oncologist, at least. The patient’s age, functional capacity and other diseases should be taken into account.
    • Hormonally active adrenal tumours are removed in most cases.
    • Imaging is used to assess the risk of malignancy (size, density; see above ) and consequently to define any surgical treatment or follow-up.
  • Tumours less than 6 cm in size with no local invasion are removed by laparoscopy or retroperitoneoscopy.
  • Invasive tumours larger than 6 cm and metastatic tumours are removed by laparotomy.
  • In Cushing’s syndrome, hypercortisolism suppresses the pituitary-adrenal axis.
    • Before surgery, good control of any concomitant diseases, particularly hyperglycaemia (insulin), hypertension and hypokalaemia (spironolactone) should be ensured.
    • Antithrombotic prophylaxis should be considered before surgery already. It should be started no later than 6 h after surgery and continued for 4 weeks.
    • After successful surgery, patients always need hydrocortisone replacement, 10–12 mg/m2 (for a normal-weight adult, 20 mg/day) divided into 2–3 doses.
  • In patients with phaeochromocytoma, catecholamine hypersecretion may lead to a hypertensive crisis or other circulatory catastrophe. In addition, it carries a risk of cancer. See .
    • The patient’s overall situation permitting, surgical treatment is therefore always indicated.
    • Before surgery, patients need preliminary treatment.
  • In hyperaldosteronism, venous catheterization of the adrenal glands is used to see whether aldosterone is secreted from just one adrenal gland or both of them.
    • Before surgery and to the extent possible, blood pressure should be controlled to a level of < 140/90 mmHg and any hypokalaemia should be corrected.
    • While waiting for surgery, the patient can take 12.5–100 mg spironolactone daily.

Follow-up

  • Adrenal tumours found to be benign by imaging or after surgery do not require follow-up.
  • Adrenocortical carcinoma is treated in specialized hospital oncology units.
    • In most cases, cooperation between an oncologist and an endocrinologist is needed, because the treatment of the tumour will cause adrenocortical suppression.
  • Preliminary treatment of hormonally active tumours, ensuring biochemical recovery, and follow-up are done at an outpatient endocrinology clinic.
    • After the excision of a cortisol-secreting adrenal tumour, it should be ensured that hypercortisolism and postsurgical adrenocortical suppression have been corrected.
      • Adrenocortical suppression will continue for an average of 18 months.
      • Adrenal suppression can be considered corrected when plasma cortisol levels measured before morning medication are at about the middle of the reference range.
    • Four to six weeks after removing an aldosterone-secreting adrenal tumour, serum aldosterone and plasma renin, potassium, sodium and creatinine should be defined and the need for antihypertensive medication should be assessed.
      • Surgical treatment of unilateral hypersecretion will correct hypokalaemia in nearly all patients.
      • Hypertension will resolve in 30–60% of patients, and even in the rest control of hypertension will improve significantly.
      • If histological examination of the surgical specimen shows hyperplasia, the need for an aldosterone receptor antagonist should be assessed because the disease is probably bilateral.
    • Biochemical healing of phaeochromocytoma is assessed at an outpatient endocrinology clinic, and the patients are followed up lifelong; see below .

Phaeochromocytoma

  • A tumour originating from the adrenal medulla that produces, stores, metabolizes and secretes catecholamines.
    • It may produce both adrenaline and noradrenaline but noradrenaline production predominates in most cases.
  • Incidence 0.8/100,000
  • May occur at any age but most commonly between the ages of 40 and 50 years.
  • As many as 40% of phaeochromocytomas are hereditary.
    • In patients with familial phaeochromocytoma (MEN2 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, gene disorders affecting the succinate dehydrogenase enzyme), bilateral phaeochromocytoma is common.
  • The secretion of catecholamines (adrenaline and noradrenaline) may cause many kinds of symptoms.
    • Constant or intermittent hypertension
      • Blood pressure is elevated in 95% of patients with phaeochromocytoma.
      • Phaeochromocytoma is the cause of elevated blood pressure in about 0.6% of patients with hypertension.
    • Paroxysmal headaches, sweating and palpitation are the classic triad of symptoms.
      • Other typical symptoms include tremor, pallor, orthostatic hypotension, panic attacks, nausea and diabetes in a slim person.
    • Phaeochromocytoma may cause a hypertensive crisis, ventricular arrhythmia, myocardial infarction, cerebrovascular accident, takotsubo cardiomyopathy (Takotsubo cardiomyopathy), pulmonary oedema or aortic dissection occurring spontaneously or triggered by delivery, anaesthesia or an intervention.
  • The diagnosis is based on increased concentrations of serum adrenaline and noradrenaline metabolites.
    • Concentrations that are within the reference range exclude phaeochromocytoma.
    • If clinical symptoms strongly suggest phaeochromocytoma, the serum noradrenaline metabolites test should be repeated after resolution of the paroxysmal symptom.
    • False positive findings are common in the elderly. The accuracy of plasma catecholamine measurements is only 77% in patients over 60 years. If a false positive finding is suspected, catecholamines in 24-h urine (including metanephrine and normetanephrine) should be determined.
  • A biochemically confirmed tumour can be located by contrast enhanced CT or, alternatively, by MRI.
    • If functional imaging is needed, 18F-FDOPA-PET-CT or 68Ga-DOTANOC-PET-CT are be used.
    • Metaiodobenzylguanidine (123IMIBG) imaging is not done before surgery but only when planning 131I-MIBG treatment of metastatic disease.
  • The patient’s overall situation permitting, surgical treatment of phaeochromocytoma is always indicated because hypersecretion of catecholamines may lead to a hypertensive crisis or other vascular accident and because phaeochromocytoma involves a risk of cancer.
  • The aim of presurgical treatment is to normalize blood pressure, heart rate and blood volume and to prevent uncontrolled fluctuation of blood pressure during surgery.
    • The effect of catecholamines can be prevented by using the long-acting alpha 1 and alpha 2 blocker phenoxybenzamine.
    • Phenoxybenzamine treatment is usually started no less than 14 days before surgery at a dosage of 10 mg twice daily. The dose is increased every 3 days until sufficient response or until adverse effects prevent further increase.
  • After surgery, biochemical healing of phaeochromocytoma is confirmed at an outpatient endocrinology clinic.
    • A gene panel test with genes known to predispose to phaeochromocytoma is recommended for all patients.
    • About 10% of phaeochromocytomas are malignant, but this cannot be assessed based on clinical, biochemical or histological features. Therefore, only metastasized tumours are classified as malignant.
    • Due to the possibility of recurrence, all patients should be followed up for the rest of their lives.

References

1. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2023;189(1):G1-G42  [PMID:37318239]
2. Nazari MA, Hasan R, Haigney M, et al. Catecholamine-induced hypertensive crises: current insights and management. Lancet Diabetes Endocrinol 2023;11(12):942-954  [PMID:37944546]
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