Adrenal Incidentaloma

Fig.1: Left adrenal incidentalomaAny adrenal tumour discovered incidentally, usually during investigation for something else unrelated to the adrenal gland, is called an incidentaloma. More recently they have also been called 'clinically inapparent adrenal masses'.

They were first described in the early 1980s. Imaging of the abdomen by CT scan and ultrasound is commonly done, and picks up unexpected adrenal masses in 4 to 5% of patients (Fig. 1). Around 7% of patients have an adrenal incidentaloma found during a post-mortem examination. The incidence appears to be increasing (and more closely approximating the postmortem rate) due to the ageing population and the more widespread use of CT scanning for investigation of a variety of abdominal conditions.

The incidence depends on patient age, being very uncommon in the young (0.5%), around 3% in middle age, and up to 10% in the elderly. The median diameter is about 3.5cm, it is bilateral in <15% and the male to female ratio tends to be equal.

The importance of investigation of these incidentalomas lies in finding the answers to 2 questions:

1. is the tumour functional (making hormones)? 

2. is the tumour malignant, and if so is it primary (such as adrenocortical cancer), or a metastasis (usually from breast, lung, kidney or melanoma)?

A high percentage (around 11%) of incidentalomas are in fact secreting hormones, producing small amounts of excess hormones below the level of detection, which can affect the patient, but without the well described symptoms of the adrenal hyperfunctioning syndromes, like Conn's or Cushing's syndromes.

Pathology

The majority of surgically removed incidentalomas are apparently non-functioning cortical adenomas, but there is a great variety in pathology, which to a certain extent depends on the size of the tumour. In the patient without a history of a previous malignancy, the common diagnoses are listed below, divided into benign, malignant and other categories:

If there is a history of cancer in the past, especially breast, lung, kidney or melanoma, the risk of an incidentaloma being a metastasis rises to nearly 50%. The adrenal is a common site in the body for spread of cancer from other areas, and metastases are often bilateral (affect both adrenals). 

The risk of an adrenal tumour being a primary adrenocortical cancer (ACC) increases with size, as shown below; for this reason, most adrenal surgeons like me recommend removal of adrenal lesions greater than 4 cm in diameter:

• <4cm 2% risk
• 4-6cm 6% risk
• >6cm 25% risk of ACC

Although the adrenal incidentaloma appears to be non-functioning, a large number of studies have shown high percentages of these patients in fact have subclinically functioning tumours, producing a variety of metabolic abnormalities.

In the largest Italian study, 9.2% had subclinical Cushing's (excess cortisol), 4.2% had a phaeochromocytoma, and 1.6% had an aldosterone-producing tumour. The most common of these, subclinical Cushing's syndrome, is associated with something called the 'metabolic syndrome', with the majority of patients having hypertension, impaired glucose tolerance or diabetes, obesity and abnormal lipids (fats) in the blood, and poor bone density, resulting in an increased risk of fractures. The significance of this syndrome in the longer term is not known, but the majority of patients will improve after adrenalectomy.

Investigation

The goals of investigation as mentioned above, are firstly to determine if the tumour is producing hormones, and secondly to rule out malignancy.

History & Examination

It is important to take a careful history from the patient, in particular:

• past history of malignancy
• family history of endocrine diseases / cancer syndromes
• history suggestive of the metabolic syndrome, such as hypertension, diabetes, obesity or osteoporosis
• symptoms suggestive of excess catecholamines, such as flushing, headache or sweating

Assessment of Function

• plasma metanephrines or 24 hour urinary catecholamines

• low-dose dexamethasone suppression test or late-night salivary cortisol +/- 24 hour urinary cortisol

If the patient is hypertensive, then these additional tests should be done:

• aldosterone-renin ratio

• serum potassium estimation

Assessment of Malignancy

• Fig. 2: Right adrenal myelolipoma, with very low densityCT scan  - malignant lesions tend to be larger (>5cm), irregular and may invade other structures; they also tend to grow steadily in size. On CT scan they tend to have delayed or poor washout of contrast. If the lesion has >60% relative washout and >40% absolute washout on CT, this indicates a benign lesion. Nearly all lesions smaller than 4 cm are benign. It is important to remember however, that CT underestimates the true size of the tumour by 16-47%.
  
  The use of modern intravenous contrast in phaeochromocytoma is now acceptable, with degranulation of the tumour and sudden release of catecholamines most unlikely.
  
  A standardized measure of XRay absorption known as the CT attenuation value, expressed in Hounsfield units (HU), may differentiate between benign and malignant lesions. A homogeneous mass with a smooth border, prompt washout and an attenuation value of less than 10 HU on unenhanced CT strongly suggests a benign adrenal adenoma (Fig. 2).
  

• MRI scan -  can be used if the CT is indeterminate. The T2 weighted scan is the most useful, with adenomas having low intensity, while metastases and phaeochromocytomas have high intensity.
• PET scan - can be useful, especially in the diagnosis of metastases from another cancer, and in fact in Australia is only funded for this use. It is highly sensitive in the diagnosis of metastases and adrenocortical cancer, with a resolution down to 4mm.
• FNA cytology - is rarely needed (or warranted), but may be useful for suspected metastases, but only after ruling out a phaeochromocytoma.

Management of Adrenal Incidentalomas

Several recent studies have shown that:

• a high percentage of adrenal incidentalomas are subclinically functioning

• a relatively high percentage of patients have pathological features like impaired glucose tolerance, hypertension, obesity and reduced bone mineral density

• after adrenalectomy, these features are significantly improved or resolve completely

Conservative management is recommended for those who have small tumours, no evidence of subclinical function, no associated symptoms and no evidence of malignancy. These patients need at least yearly followup to make sure the lesion is not growing in size or changing in function. The safest option would be to repeat the initial CT at 3-6 months.

In one study of 75 patients with incidentaloma the estimated risk for enlargement was 18%, and for hyperfunction was 9.5% over 5 years. After 10 years the risk had not changed much, with 22.8% enlargement risk but the same hyperfunction risk.

Surgery is recommended in all other cases, when the tumour is functional (making hormones), growing in size, has suspicious CT features, or if the tumour is greater than 3-4cm in diameter. Surgery is also the most cost effective treatment for adrenal lesions that are 4cm or more in diameter, but not once the patient is over 65, when surveillance tends to be more appropriate.

Adrenalectomy can almost always be performed by laparoscopic surgery, unless malignancy is suspected, when open operation is indicated.

Followup

Follow-up of patients with non-functional adrenal masses suggests that 5% to 25% of lesions increase in size by at least 1 cm, but the clinical significance of this increase in size is unknown. The risk of an adrenal incidentaloma transforming into a malignancy seems to be very rare.

It is unclear what percentage of patients will develop hormone overproduction during follow up, but it may be as high as 10% over 5 years. However, this is most unlikely if the tumour is 3 cm or less in diameter.

The long term natural history of adrenal incidentalomas is in fact largely unknown, and more studies are needed in this increasingly common finding.