Postoperative Evaluation of Patients with Cushing’s Disease.

From Lewis S. Blevins Jr, MD  –  One of the greatest challenges facing medical practitioners is in the recognition and diagnosis of Cushing’s syndrome and disease. As if this not sufficiently difficult, an even greater challenge and awaits the physician in charge of the postoperative evaluation and management of patients who have undergone surgery for Cushing’s disease. It can be rather difficult to determine which patients have been rendered disease-free after surgery, which ones require continued observation without intervention, and when to initiate additional treatment. I have learned that the best approach is to proceed in a systematic fashion working through a series of questions. I will try to relate my approach to postoperative patient so that you can share this with your physician and discuss any relevant issues.

Was the preoperative diagnosis correct?   In every patient, I first reviewed the preoperative imaging and laboratory studies to discern whether I retrospectively, and agree with the diagnosis of pathologic hypercortisolism and Cushing’s disease. I even go back and question my very own decision making process.   This review states to stage so that I may properly evaluate pathology results, postoperative imaging, and relevant laboratory results in the context of how the patient is doing after surgery.

How does the patient look and feel? Most patients who have been rendered disease-free after surgery will have a period of adrenocortical insufficiency necessitating steroid replacement. Since most steroid regimens are, effectively, best considered as replacement, attempting to provide an equivalent of “normal” daily steroid exposure, most patients, having had hypercortisolism prior to surgery, and do not feel very well at their 6-12 week visits. Some of them have what we term “steroid withdrawal” characterized by weakness, fatigue, joint aches and pains, etc.   Usually, the plethora recedes rather quickly after successful surgery.   So, if the patient says that she feels spectacular than I’m concerned that she is either on too much steroid or has not been rendered disease-free. If the plethora persists then I also have a level of concern about the relative success of surgery.   Some endocrinologist like to treat patients with double or triple the usual steroid replacement dosage so that they avoid steroid withdrawal symptoms. I do not subscribe this practice because it simply delays recovery. Further, I have seen some patients come back to clinic looking more cushingoid as result of their medication than they did prior to surgery for their underlying disease process!

What did the pathologist see?   The pathology report is instrumental in the postoperative evaluation. The finding of an ACTH immunopositive pituitary tumor confirms the preoperative diagnosis.   Lack of the tumor does not always mean that there was not a tumor present because, sometimes, these tumors are lost at the time of surgery in the suction device used during the surgical procedure.   Thus, it is also important to know what the neurosurgeon was able to see at the time of surgery.   Further, lack of pathology could be related the fact that some of these tumors are located on the pituitary stalk or in the cavernous sinuses and may not have been visualized at the time of surgery in a manner that would permit their successful removal. Also, unfortunately, some with the syndrome of ectopic ACTH hypersecretion due to tumors elsewhere have undergone pituitary explorations and will have negative pathology. Remission rates are definitely higher in patients when tumors are identified at the time of examination of resected tissue. One study showed the surgical failure rate to be 47% when no tumor was identified by the pathologist versus 17% when tumors were found in the surgical specimens.


What does the MRI show? It is essential to compare the preoperative and postoperative MRI studies side by side. Doing so allows one to examine the boundaries of the original tumor and to determine whether it was completely resected by evaluating the entire tumor bed on the postoperative MRI. Patients who have residual tumor have not obviously been rendered disease-free. Unfortunately, some patients who have undergone a complete resection to still will have residual disease because many of these tumors are microscopically invasive and residual cells may be left behind.    For example, one study showed that 8% of Cushing’s microadenomas are invasive whereas 62% of macroadenomas that produce ACTH are invasive. To complicate matters, these microscopic invasions are usually so small as to not be seen on MRI studies of the pituitary. In these cases, biochemistry is extremely important in determining those patients who require close follow-up and additional treatment.


What do the laboratory studies show? Most would agree that serum cortisol levels less than 2 mcg/dL within a few days of surgery indicate that a patient may be in remission.   However, 25% of patients with cortisol levels higher than that will ultimately enter remission. I tend to wait 6 weeks to fully assess whether or not patient’s have been rendered disease-free.   Interestingly, in those patients with low or undetectable cortisol levels after surgery, approximately 8% will go on to develop recurrent disease. The most likely explanation for this observation is that those patients had microscopic invasive disease that, immediately after surgery, did not produce enough ACTH to maintain a normal adrenal function, thus resulting in adrenal insufficiency, and that, over time, the microscopic disease progressed to produce sufficient amounts of ACTH to cause recurrent hypercortisolism. Here is my general approach:

  • Cortisol levels greater than 8 mcg/dL almost always indicate persistent disease. In those patients, I usually do not treat of postoperative steroids and I evaluate 24 hr urine cortisol excretion rates 6 weeks after surgery.   If they are hypercortisolism if they may need additional treatment. Further evaluation and treatment decisions are based on MRI and laboratory as well as pathology results.
  • Cortisol levels less than 2 mcg/dL usually indicate remission. I treat those patients with replacement doses of dexamethasone (0.25-0.375 mg daily). I reassess serum cortisol levels 36 hours after withholding dexamethasone at 3 month intervals. When the cortisone levels are greater than 8 mcg/dL I proceed with a low dose ACTH stimulation test. If they pass the test (cortisol level greater than 18 mcg/dL) then I discontinue steroids and follow periodic 24 hr urine cortisol levels at 3 month intervals for the first year, then at six-month intervals for a year or 2, then annually thereafter. We do know that the duration of the requirement for steroid replacement is associated with the likelihood of long-term remission. For example, those patients who require steroids for less than 6 months will probably have recurrent disease whereas those who require steroids for one year or more will likely remain in remission. The longest time from successful surgery to recurrence in my practice is about 14 years. This observation indicates that patient’s do indeed require lifelong followup.
  • Cortisol levels between 2 mcg/dL and 8 mcg/dL require careful followup. Some of these patients will develop frank adrenocortical insufficiency indicating they are in remission while others will maintain normal levels for a long period of time, and others will become hypercortisolemic within a year.   Usually, I will discontinue steroid supplementation in this subset of patients and check a 24-hour urine cortisol. In those with hypercortisolism I proceed with further evaluation and management with the assumption that have not been rendered disease-free. Those patients with normal 24 hr urine cortisol excretion rates are usually followed to discern whether the cortisol levels fall or rise in whether or not the “normal” cortisol levels and affect the patient adversely in any way. Occasionally, I will check a salivary cortisol profile to determine whether those with “normal” cortisol levels have altered secretion of cortisol indicating that they have tumoral ACTH production rather than normal pituitary ACTH production driving cortisol production.   Those with “tumoral profiles” deserve treatment sooner rather than later. Dexamethasone suppression tests, dexamethasone-suppressed CRH stimulation tests, and other dynamic tests are often useful to identify those patients who have residual disease.


One of the most important things that I have learned in regards to evaluating and managing patients with Cushing’s disease is that mistakes can be minimized by not rushing to make a judgment about diagnosis and treatment. It is best to take time and reassess at 3 month intervals rather than to prescribe expensive and life altering treatments.   Things will usually sort themselves out over a short period of time….. a period of time it may be associated with some discomfort or suffering on the patient’s part, but the period of transition will be less than would be the suffering as a consequence of complications of surgery, radiation, medical therapy, etc. It is also important not to take short cuts in the evaluation of preoperative and postoperative patients suspected of having Cushing’s disease. The goals are to alleviate suffering, cure diseases, but also to “first do no harm.”


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