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Treatment Options for Recurrent Cushing’s Disease


A patient who has been treated for a pituitary tumor is always at risk for recurrence of the tumor; this risk is usually small, but real. There is no way to predict in whom or when a pituitary tumor will recur. This statement is not made to frighten a patient, but to emphasize the need for continued regular medical care and follow up so that a recurrence can be detected early and treated promptly. The reported risk of recurrence of a pituitary adenoma varies according to the type of tumor and the length of follow up. In general, most tumors recur within 5 to 6 years of initial pituitary surgery, but recurrence has been reported 25 years after initial treatment, again emphasizing the need for long term follow up. The recurrence rate in patients with Cushing’s disease varies between 12% and 15%.

Multimodality Treatment

In the ideal situation, a pituitary tumor can be removed completely by an expert pituitary neurosurgeon and the patient is free of the problem forever. Unfortunately, this is not always the case. While pituitary adenomas are benign (not cancer), they may, and do, cause ongoing problems for some patients that require several treatments. Since many pituitary tumors are large and invade structures that are not accessible to the neurosurgeon, called invasive tumors, it is apparent before the first operation that a patient may require additional treatment after surgery. Even when the entire tumor is removed, if the tumor recurs, there is a role for more than one treatment to address the problem (a recurrent tumor may be more “aggressive” than the original tumor). So, what is “multimodality treatment”? This involves a stepwise use of combined therapies to control the problem and to hopefully produce a resolution of the problem (no excessive hormone production by the tumor, no tumor growth). To achieve these goals, some patients require surgery, medical treatment and pituitary radiation. This is usually the case in patients who have a large and invasive tumor, but may also apply to the patient who has a recurrence of the original tumor.

Why do pituitary tumors recur?

Even with successful surgery (remission of hormone over production and/or no visible tumor on the post operative MRI scan), the most likely reason that a tumor recurs is that a few tumor cells that cannot be seen, even with the operating microscope, remain. Over time, these cells grow and divide and produce a new tumor. It is important to emphasize that even when all visible tumor is removed, there may be a few remaining cells in the area of the original tumor or in an area that cannot be removed surgically (tumor cells invading the bone [sellar bone] below the pituitary, invading the membrane [dura] around the pituitary, and/or invading the cavernous sinus [area on each side of the pituitary that contains the artery that provides blood to the front part of the brain and nerves that control eye movements]).

Patients who have had surgery and/or radiation for a pituitary tumor often have loss of pituitary hormone production requiring hormone replacements, including growth hormone. The possible role of growth hormone replacement and the frequency of tumor recurrence has been questioned. This has been monitored for over 16 years. Surveillance studies of patients receiving growth hormone replacement have shown that the risk of tumor recurrence in patients treated with growth hormone is no greater than the risk of tumor recurrence in patients who were not treated with growth hormone.

How is tumor recurrence detected?

In a patient with a hormone producing tumor, the patient usually experiences some or all of the symptoms that were present at the original diagnosis. A patient with a history of Cushing’s disease often reports mood changes, depression, difficulty sleeping, weight gain, fatigue, facial hair growth, loss of hair from the head, thinning of the skin, bruising, new diabetes or worsening of diabetes control and/or increased blood pressure. In the early stages of recurrence of Cushing’s, the physical changes may be minimal, but the patient is aware of feeling “different”. In my 25 years of practice, I have learned, from patients, that the patient is usually correct about these symptoms, even if the initial hormone tests are normal. With time, the blood, salivary and urine tests become abnormally elevated. Treatment cannot be initiated until abnormal test results are obtained.

Does post-operative pituitary radiation prevent tumor recurrence?

Yes and no. Post-operative pituitary radiation reduces the risk of tumor recurrence, but does not guarantee that a tumor will not recur. Several studies have shown that post-operative pituitary radiation lowers the risk of re-growth of a pituitary tumor; however, any form of pituitary radiation may cause loss of normal pituitary hormone production, requiring hormone replacement(s).

What are the treatment options for a recurrent tumor?

Treatment of a recurrent tumor depends on the location and/or size of the tumor and, ultimately, the patient’s preference after carefully considering all options. In general, the treatments include another pituitary operation, pituitary radiation and/or medications to control hormone over production or bilateral adrenalectomy. If the recurrent tumor causes loss of vision, the most effective treatment is an immediate second operation; there is no other treatment that offers the possibility of improvement of vision.


If there is a visible tumor on the MRI scan that is not extending into the cavernous sinus (beyond the large artery that provides blood to the front part of the brain and not within the reach of the neurosurgeon), a second operation offers the possibility of immediate improvement, particularly if there is hormone overproduction (Cushing’s, acromegaly, prolactinoma). In patients with Cushing’s disease the reported success rate with the first operation ranges from 80% to 90%; the reported success rate with a second surgery is approximately 50%. Sometimes with a recurrent tumor, a more extensive removal of the gland is performed in an attempt to provide the best possible outcome. The success of pituitary surgery is directly related to the experience and expertise of the neurosurgeon.

Pituitary Radiation

All forms of pituitary radiation require time (often months to years) to be effective; there is no immediate effect. This is an important consideration in patients who have a hormone-producing tumor (Cushing’s disease, acromegaly, prolactinoma) because, until the radiation becomes effective, the patient has the ongoing effects of excessive hormone production. There is no way to predict when or if the radiation treatment will lower hormone overproduction to normal. Additionally, an expected effect of pituitary radiation is loss of normal pituitary hormone production (radiation affects both the tumor and the normal pituitary gland) requiring hormone replacement(s). The risk of loss of pituitary function increases over time after radiation treatment which means that regular hormone tests are necessary to detect the need for hormone replacement(s). Although loss of normal pituitary function is not desirable, all of the important hormones can be replaced. A benefit of pituitary radiation is control of tumor growth; pituitary radiation reduces, but does not guarantee, the risk of tumor growth. If a patient decides to have pituitary radiation, medical treatment to lower excessive hormone production is also given to control the problem while waiting for a beneficial effect of the radiation; the medication is discontinued every 6 months and hormone tests are measured to see if the radiation has become effective.

Medical Treatment

There are no consistently proven medications that reduce pituitary tumor production of ACTH (the pituitary hormone that causes the adrenal glands to produce excessive cortisol). However, there are medications that act on the adrenal glands to reduce cortisol production (ketoconazole, metyrapone). However, these medications do not address the pituitary problem and without pituitary radiation, there is the risk of continued growth of the pituitary tumor. Medical treatment may cause side effects: any medication may lower cortisol to below normal causing adrenal insufficiency (too little cortisol production) – emphasizing the need for very close monitoring of blood and urine cortisol levels and adjustment of the medication dose to avoid adrenal insufficiency. Ketoconazole may cause abnormalities in liver tests, which means that liver tests should be measured before treatment and regularly when the patient is taking this medication. If liver tests become abnormal, ketoconazole is stopped immediately. Metyrapone may cause fatigue, nausea and vomiting, usually depending on the dose. If this occurs, the dose may have to be reduced.

Bilateral adrenalectomy

Successful removal of both adrenal glands results in immediate loss of cortisol production requiring life-long replacement of cortisol (hydrocortisone or prednisone) and another adrenal hormone to maintain normal sodium and potassium balance (medication: Florinef). Bilateral adrenalectomy is usually the “last resort” treatment for patients who cannot tolerate medical treatment to control excessive cortisol production while awaiting a beneficial effect of pituitary radiation. Removal of the adrenal glands without addressing the source of the problem (the pituitary gland) causes the risk of further growth of the pituitary tumor. This is called “Nelson’s syndrome” named after the physician who first described this condition. Nelson’s syndrome developed in patients who did not have pituitary radiation. Approximately one-third of patients with Cushing’s disease who have the adrenal glands removed (and no pituitary radiation) develop Nelson’s syndrome. Pituitary radiation reduces the risk of developing Nelson’s syndrome. Features of Nelson’s syndrome include an increase in the blood ACTH level (hormone produced by the pituitary tumor), darkening of the skin and pituitary tumor growth. The high ACTH levels are not harmful medically, but the accompanying darkening of the skin may be disturbing to the patient. The main concern is continued growth of the pituitary tumor; if this occurs, the patient may require another pituitary surgery or radiation.

Summary and Conclusions

Recurrence of a pituitary tumor is obviously distressing to the patient and the physician. If a patient has a recurrence of the tumor, prompt treatment is necessary to reduce the adverse effects of excessive hormone production, to remove or control the tumor, to replace deficient hormones and to restore the patient to a productive life. This is possible and quite probable, but may require several types of treatments.

Author: Dr. Mary Lee Vance, MD (Spring, 2005)

Editor’s Note: Dr. Mary Lee Vance is a Professor of Medicine and Neurosurgery at the University of Virginia Health Sciences Center in Charlottesville, Virginia. Dr. Vance has been involved in the treatment of pituitary tumors and Cushing’s Disease for many years.


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