Pituitary Tutorial—Cushing's Disease (ACTH Tumors)

ACTH-producing pituitary tumors, AKA Cushing's disease

ACTH-producing tumors are probably the most maddening of the known pituitary tumors.

We will discuss:

History and physical examination
Laboratory and imaging tests which help in diagnosis
Differential diagnosis of high cortisol
Treatmentof this tumor
We will also mention some controversiesin the treatment of ACTH tumors

History and Physical Examination

ACTH tumors usually present with Cushing's Syndrome, typified by:

Characteristic pattern of fat deposition:
- Truncal obesity: fat deposition in the abdomen, very skinny limbs
- Buffalo hump: a fat pad developing in the area around C7
- Supraclavicular fat pads: where there was a hollow, there is a pillow
- Moon face: again, very characteristic rounding of facial outline
Hypertension and hypokalemia
Fatigue, irritability, depression, psychosis
Glucose intolerance, up to outright diabetes mellitus
Hirsutism
Purple striae of the trunk

The above is the typical and usual presentation of Cushing's disease. Two problems occur to bother your endocrinologist.

First, lots of other things present like this
Second, ACTH producing pituitary tumors may present with a variety of other clinical syndromes, the breadth and complexity of which really make you reconsider the Manichaean Heresy

Laboratory and imaging studies

Laboratory studies

Recall that cortisol has a nice diurnal variation, with peaks in the early AM, and a falloff in the PM. This is why we can get out of bed in the morning. ACTH producing tumors tend to level off this variation: your cortisol stays high always. However, a single random cortisol is not sufficient to decide anything:

If you are really concerned about Cushing's, do a 24 hour urine free cortisol.

Because you have too much cortisol circulating for too long, your total 24 hour urinary cortisol excretion increases. So you collect it and measure it (kinda like glycated hemoglobin to check diabetes mellitus). To do this test order:

Serum cortisol
24 hour urine collection for: free cortisol, 17-OH corticosteroids, creatinine

Your patient should be capable and willing to collect urine every time they urinate for 24 hours, else the test will be unreliable (particularly if they don't collect their evening cortisols which will be elevated in this disorder).

So much for screening tests. So you suspect an ACTH producing tumor now. Where from here?

The next step on this ladder is usually a dexamethasone suppression test. Dexamethasone is a very potent glucocorticoid which will feedback onto the pituitary gland (and tumor) and zap ACTH production, resulting in a decreased cortisol, usually. The test typically goes like this:

you give a PM dose of dexamethasone
you measure today and tomorrow's urinary free cortisols (2 days to get a trend)

The results and what they mean usually look like this:

Dexamethasone dose	cortisols suppressed?	meaning
lo: 2 mg	no	you're in the right ballpark: there is probably a problem, so do the hi-dose test now
hi: 8 mg	no	worry about an ectopic source of ACTH, like an adrenal tumor or APUD tumor of lung
hi: 8 mg	YES	probably an ACTH producing pituitary tumor

The problem with this test is that the dex suppression test is accurate only about 80% of the time.

Imaging studies

The best and first imaging study to be done is the MR with and without gadolinium enhancement. Really, folks, the days of the CT scan for diagnosing pituitary tumors are over. MR scanning, which drops bone out of the image, shows the tumor and its surrounding structures with exquisite detail. Small tumors are best appreciated on MR. You don't even catch any X-rays, they do it with magnets (really).

Realize that you can still have an ACTH producing pituitary tumor and have a negative MR. It takes an incredibly small volume of these cells to cause florid Cushing's disease. With negative MR scanning but a great story for ACTH-producing pituitary tumor, one can do an inferior petrosal sinus sampling with CRF stimulation to help decide this issue.

Petrosal sinus sampling is an invasive neuroradiological test, where the person comes in, gets catheters placed into both their petrosal sinuses (look it up). They then have ACTH levels measured from each petrosal sinus, as well as an ACTH sample from peripheral blood. Following this, they have an injection of CRF (corticotropin releasing hormone), which stimulates the pituitary gland (and tumor, if present) to pour out ACTH. Five minutes after injection of CRF, another sample is taken from each petrosal sinus and the peripheral blood. One then compare pre-CRF and post-CRF ratios of petrosal sinuses/peripheral blood. In ACTH producing pituitary tumors, the ratios typically shoot very high after CRF. This test is good to differentiate between pituitary/nonpituitary sources of ACTH, but is not very good at localizing pituitary tumors (i.e. not good at right VS left differentiation).

Differential diagnosis of ACTH pituitary tumors

Hypercortisolism can be caused by

ACTH-producing pituitary tumor, bien sûr
Hyperplasia or adenoma of the adrenal gland itself
ACTH producing tumor elsewhere (most are in lung)
Iatrogenic or patient-induced ingestion of corticosteroids
Depression can raise cortisols
Chronic alcoholism
Acute illness (remember Selye's stress response?)

Treatment of ACTH producing pituitary tumors

The mainstay of treatment for these tumors, particularly microadenomas, is surgery. However, recurrence rates seem to take a pretty linear trend, especially if followed out to around 10 years. This probably means that we should continue doing this surgery, but need to follow our postoperative patients at least 10 years.

Radiation therapy has its proponents and detractors. More recently, single-dose radiation, like gamma-knife and LINAC stereotactic radiosurgery has been tried and shows promise, particularly for recurrent tumors.

Unknowns/controversies in ACTH pituitary tumors

Among the controversies in the diagnosis and treatment of ACTH tumors are:

Can the patient have such a tumor if the clinical syndrome does not fit into the classic picture of Cushing's disease?
How do you confirm your diagnosis of ACTH pituitary tumor if you are suspicious?
What are the real long-term (10-15 year) results of surgery in ACTH microadenomas?
Should radiation therapy be used to treat these tumors? When? Ever?
How to deal with recurrent ACTH tumors after surgery? After RT?
Is total hypophysectomy ever indicated in treating these tumors? When?

Such questions provide grist for controversies during endocrinological and neurosurgical meetings.