by Brooke Swearingen, M.D. and Beverly M.K. Biller, M.D.
NECC Newsletter MGH Neuroendocrine Center Bulletin Vol 9, Issue 1, Fall/Winter 2003
ACTH Secreting Pituitary Tumors - A Patient Guide
1. What is Cushing's syndrome?
Cushing's syndrome refers to the physical and emotional difficulties caused by an elevated cortisol level. Features of excess cortisol include weight gain, especially centrally, fatigue, easy bruisability, excess hair growth (termed hirsutism), susceptibility to infection, depression, menstrual irregularities in women, decreased libido and erectile dysfunction in men, high blood pressure, diabetes, and weak and brittle bones (osteoporosis). Many of these are non-specific, meaning that people who have them usually do not have Cushing's syndrome. Most patients who do have Cushing's syndrome have some, but not all, of these features. There is a characteristic appearance in many patients who have excess cortisol which includes a round, reddened face, excess fat pad in the back of the neck ("buffalo hump"), excess fat in the collarbone area, central weight gain, primarily in the abdomen, with relative thinning of the arms and legs, and abdominal stretch marks. In the majority of cases, it can be cured, with improvement in all of these features
2. What are the causes of Cushing's syndrome?
The normal production of cortisol involves three parts of the body. An area in the brain, called the hypothalamus, produces a hormone called corticotropin releasing hormone (CRH). This hormone travels via blood vessels to the pituitary gland, located just below the brain, and triggers release of adrenocorticotropic hormone(ACTH). The ACTH travels through the bloodstream and when it reaches the adrenal glands, which lie above each kidney, cortisol is released. Cushing's syndrome can be caused in several ways. The most common cause is actually a side effect of the medical use of glucocorticoids (steroids) to treat many conditions. However, Cushing's syndrome can result from a tumor somewhere in the body which is overproducing either cortisol, or the hormone which triggers release of cortisol, ACTH. The most common tumor-related cause is a growth on the pituitary called a corticotroph adenoma. Cushing's disease refers specifically to the form of Cushing's syndrome which is due to a pituitary tumor. These are nearly always benign, and are typically small (less than 1 cm). The pituitary tumor makes too much ACTH, which causes the adrenal glands to overproduce cortisol. Other more rare causes of Cushing's syndrome can include excess production of cortisol by an adrenal tumor, or overproduction of ACTH by a tumor elsewhere in the body (termed ectopic Cushing's).
3. How is the diagnosis of Cushing's disease made?
The diagnosis is made through a comprehensive evaluation by an endocrinologist. This includes taking a detailed medical history, performing a physical examination, and obtaining laboratory and radiologic tests. These might include measurement of cortisol levels in the blood, urine, and/or saliva, blood ACTH levels, dexamethasone suppression testing and/or CRH stimulation testing. Imaging studies of the pituitary, such as head MRIs, will sometimes, but not always, show a pituitary tumor. Some tumors are so small (less than 1mm) that they do not show up on scans. To confirm a pituitary source for the excess ACTH, a procedure known as an inferior petrosal sinus catheterization is sometimes performed. This is a procedure which should be performed at centers specializing in this technique. The petrosal sampling involves measuring ACTH levels in blood draining from the pituitary gland. Small catheters are threaded up through the large veins in the leg until they reach small veins near the pituitary. If the endocrine tests indicate a pituitary source for the excess ACTH, transsphenoidal surgery is recommended even if the MRI does not show a tumor.
4. How is Cushing's disease treated?
The best treatment is almost always transsphenoidal surgery performed by a surgeon with extensive experience in pituitary tumor removal.
5. How is this surgery performed?
Most pituitary tumors can be removed transsphenoidally. The approach is through the sphenoid sinus, one of the facial air spaces behind the nose. Rarely, a craniotomy might be required, where the skull is opened to reach the tumor. There are three basic approaches to the sella, which is the bony cavity in the skull base where the pituitary gland is located. Many neurosurgeons now use a direct transnasal approach, cutting through the back wall of the nose to enter the sphenoid sinus. It is also possible to make an incision (cut) along the front of the nasal septum, and make a tunnel back to the sphenoid sinus. Finally, sometimes an incision is made under the lip, then passing through the upper gum, and entering the nasal cavity and then the sphenoid sinus.
6. How does the surgeon see the tumor?
The opening through which transsphenoidal surgery is performed is very small, about ½ an inch. Therefore, it is not possible to look directly at the surgical area or tumor. However, with modern technology there are tools for visualizing the area of the tumor through the small hole. This is done by using a high-powered operating microscope, or a fiberoptic endoscope. The operating microscope allows binocular vision (seeing with both eyes at once, allowing depth perception) with extremely high quality optics. This is very important for tiny tumors, like those responsible for Cushing's disease. The endoscope provides a wider field of view, but usually with monocular images (only one image which is flat, without depth) as seen on a television screen. At the Massachusetts General Hospital, a direct transnasal approach is used, whether we use the microscope or the endoscope, or both. With the direct transnasal approach, the need for postoperative nasal packing (bandaging in the nose) is minimized, regardless of whether the microscope or endoscope is used.
7. How is the tumor removed?
The tumor is usually soft and can be removed with small surgical instruments called curettes. In order to remove a large tumor through a small hole, the tumor itself has to be cut into small pieces. As the surgeon cores out the center of tumor, the peripheral margin of the tumor has to fall into an area that can be reached by the surgeon. In Cushing's disease, the tumor is usually small, often too small to be seen on an MRI scan. The surgeon has to dissect through the gland, taking multiple biopsies, to look for the tumor. If found, the tumor is removed with a small margin of normal tissue, to try to remove all of the abnormal area, but to preserve as much normal pituitary gland function as possible. It is important that the neuropathologist examining the specimens intra-operatively be experienced in the diagnosis of pituitary tumors, in order to aid the surgeon during the procedure. The pathologist examines biopsies during the operation, and can confirm whether adenoma has been found. If the tumor has grown beyond the pituitary, into the cavernous sinus or dura, it cannot be completely removed; and additional treatment (radiation, adrenalectomy or medication) will be required to achieve normal cortisol levels.
8. How should I choose a surgeon for my pituitary operation?
It has been shown that the success of surgery is dependent on the amount of experience the surgeon has at performing pituitary operations. Surgeons with the most experience generally have the highest rates of cure, meaning complete tumor removal. In addition, the rate of complications is lowest among experienced pituitary surgeons. Surgeons at major pituitary centers, such as the Massachusetts General Hospital Neuroendocrine Clinical Center, operate on patients with pituitary tumors every week.
9. What are the risks of the surgery?
The most common risk is damage to the normal pituitary gland. For macroadenomas (greater than 1cm) this happens between 5-10% of the time when the operation is performed by an expert pituitary surgeon. In Cushing's disease, where extensive dissection of the pituitary gland may be required to find a tiny tumor, hormone insufficiency may be caused in about 20% of cases. This means that new hormone replacement might be required after the surgery, possibly including thyroid hormone, cortisol, growth hormone, estrogen or testosterone. Damage to the posterior, or back portion, of the pituitary gland may produce a condition know as diabetes insipidus, which will lead to frequent urination and excessive thirst, since the kidneys will no longer adequately concentrate the urine. This can be controlled with a nasal spray or pill form of a medication called DDAVP. Permanent diabetes insipidus, meaning a need to take this medication long-term, occurs only 1-2% of the time after pituitary surgery.
10. Are there other more serious complications?
Yes, but they are very rare. There is a very small chance of damaging the carotid arteries which are located on either side of the pituitary. This is a potentially devastating complication which could lead to stroke or death. It occurs very infrequently, when the operation is performed by an expert pituitary surgeon, with an incidence of less than 1/1000 cases. There could also be post-operative bleeding into any residual tumor or into the sella, which could lead to worsening pressure on the optic nerves or chiasm and possible visual loss. This is also a very rare complication, but might require re-operation to remove the blood clot. A spinal fluid leak sometimes occurs because pituitary tumors are separated from the spinal fluid which bathes the brain by a very thin membrane. In order to prevent a spinal fluid leak, the tumor bed is packed with a small piece of abdominal fat taken from a tiny incision made in the abdominal skin. Despite this, spinal fluid leaks occur with an incidence of about 1%. If this happens, there is a risk of infection, called meningitis. If a spinal fluid leak occurs it may require a second operation to patch the leak and treatment with antibiotics. The risk of all complications is higher with less experienced surgeons.
11. How long does the operation take?
The procedure itself usually takes about three hours. Patients go to the recovery room for two to three hours after the surgery and are then admitted to the hospital floor. There is no need to stay in an Intensive Care Unit. Most patients are discharged from the hospital in just one or two days.
12. How will I feel after the surgery?
You will have a sinus headache and nasal congestion. This will gradually improve over a few weeks. You can take decongestants which will help these symptoms. It is common for patients undergoing transsphenoidal surgery to feel fatigued for two to three weeks after the surgery and this gradually improves. Patients with Cushing's disease often have a prolonged recovery from surgery as they are recovering from the effects of their disease, beyond just recovering from the surgery itself. If you are cured of your Cushing's disease, your postoperative cortisol levels will be quite low, and you will have the opposite problem from Cushing's syndrome, termed hypoadrenalism. This means that the body is not producing enough cortisol. This may cause symptoms such as fatigue, poor appetite, weight loss, headache, nausea, low energy, and weakness. Sometimes the skin peels, such as after a sunburn. You will actually require cortisol replacement, in the form of pills taken once or twice daily, until your own pituitary gland recovers. The endocrinologist managing your hormone replacement must walk a fine line between giving you too much cortisol replacement, which would prolong the effects of excess cortisol, versus giving you too little cortisol, which would make you feel unwell. Typically, the cortisol medication is started at a higher dose than the body would normally make, to minimize "steroid withdrawal" symptoms. Gradually, based on evaluations of the patient to assess recovery, the dose is reduced to replacement levels. Testing is performed to determine whether the pituitary-adrenal system is recovering. In the majority of patients, the system recovers 6 to 18 months after the surgical removal of the pituitary tumor. The cortisol replacement pills can then be stopped.
13. How long will I be out of work?
Most patients recover from the surgery in two to three weeks. Some people return to work sooner than that. As noted above, however, patients with Cushing's disease can have a prolonged period of recovery, so some patients are out of work longer.
14. How will we know if the entire tumor has been removed?
The endocrinologist will test your hormone levels after the surgery, including serum and urine cortisol levels. If you are cured, these levels should be very low and you will need to take a pill to replace cortisol until your own system recovers as noted above. Usually it is possible to determine if you are cured within one to two weeks of the surgery.
15. What is the chance of being cured?
The overall cure rate for Cushing's disease is between 80-90% when the operation is performed by an experienced pituitary surgeon.
16. What if I am not cured?
If residual tumor remains in an accessible location, your surgeon may recommend a second operation. Second operations carry a higher risk of damage to the normal pituitary gland and you have a higher likelihood of requiring long-term hormone replacement. If no further tumor can be removed, you may be referred for radiation therapy. This treatment is planned by a radiation oncologist. Single fraction radiosurgery (a single dose, given on one day) is effective in curing Cushing's disease in many cases and comes in several forms, including proton beam, gamma knife and LINAC. It may take one or more years before the radiation is effective. In the meantime, drugs to suppress cortisol secretion by the adrenal glands are used to control the effects of excess cortisol, while waiting for the radiation to become effective. In some cases, removal of both adrenal glands, termed bilateral adrenalectomy, may be advised. This does not treat the tumor directly, so your doctor will need to watch carefully for growth of the tumor with periodic head scans and ACTH levels.
17. Who will take care of me in the hospital and afterward?
At a major pituitary center, such as the Neuroendocrine Clinical Center at Massachusetts General Hospital, you will be managed by a team of physicians. This includes your neurosurgeon, a staff neuroendocrinologist and the residents, fellows and nurses who work with them. The team will follow you until you are returned to the care of your local endocrinologist and primary care physician. Endocrine follow-up is very important, to determine whether replacement of any of the hormones controlled by the pituitary (cortisol, thyroxine, estrogen/testosterone, growth hormone or vasopressin) is needed, as well as to adjust cortisol replacement until it is no longer needed.
18.What is the chance of the Cushing's disease coming back?
The chance of recurrence is small: only 5-10%. You should see an endocrinologist on a regular basis and more frequently if you have any concerns that the Cushing's disease might be returning.
19. What will improve if I am cured?
Virtually all of the physical and emotional problems associated with Cushing's disease resolve in the 1-2 years after cure in most patients.