The Best Cushing’s Disease Surgery and Treatment
The Best Surgery and Treatment Options for Cushing's Disease
We perform more bilateral total adrenal operations (BLA) for “failed” Cushing’s Disease than any institution in the United States.
- What is “failed” Cushing’s Disease?
- What is bilateral total adrenal surgery (BLA)?
Cortisol production by the adrenal glands is under the control of the pituitary (a small endocrine gland located in the brain right behind your eye). When a pituitary tumor secretes too much ACTH (adrenocorticotropic hormone), it causes the otherwise normal adrenal glands to produce too much cortisol. This type of Cushing's syndrome is termed Cushing's disease.
The first-line treatment for Cushing’s disease is pituitary surgery to remove the tumor. When pituitary surgery works (70%), it is great! However, about 1/3 will never be cured in the first place or the tumor grows back (recurrence). This is “failed” Cushing’s Disease. Don’t despair! There are other treatment options.
In these patients, removing all cortisol-producing cells (total bilateral adrenalectomy) is often the best option. The goal is to remove all cells of the adrenal glands, which overproduce the toxic levels of cortisol.
The Mini-Back Scope Operation (MBSA) is the best adrenal operation for “failed” ACTH-dependent Cushing’s syndrome, termed Cushing’s disease. Do not go through the belly to get to the adrenal glands!
Learn more about adrenal surgery and the Mini-Back Scope Adrenal Operation (MBSA).
Here I will discuss:
- Pituitary surgery for Cushing's disease
- Bilateral total adrenalectomy (BLA) for Cushing's disease
- Pituitary radiation for Cushing's disease
- Medications for Cushing's disease
1) Pituitary surgery for Cushing's disease
The first-line treatment option is surgical resection of the ACTH producing pituitary adenoma. Transsphenoidal surgery is the most common procedure for removing the pituitary tumor. Rather than opening the skull in a traditional craniotomy, the neurosurgeon reaches the tumor through the nasal passages and the sphenoid sinus. This less-invasive approach allows the neurosurgeon to avoid important brain structures by accessing the pituitary gland from underneath the brain. When surgical resection of the ACTH producing pituitary adenoma works, it is a great treatment and the patients do very well. The main predictive factors for the outcome of pituitary surgery involve patient and tumor features, presurgical imaging, surgical and pathological findings, and surgical features. You need to have the most experienced neurosurgeon perform this operation (Dr. Carling operates on the adrenal, not the pituitary)
However, 32% of patients with Cushing disease will require a secondary treatment option, either due to a failure by a first pituitary surgery to control the symptoms or due to recurrence of cortisol hypersecretion. Remember, too much cortisol is very toxic to the body. This is a big problem.
Figure 1. Transsphenoidal pituitary surgery is the most common procedure for removing the ACTH producing pituitary tumor causing Cushing’s disease. Note, this operation is performed by a neurosurgeon. Dr. Carling and the Carling Adrenal Center do not perform pituitary surgery.
Despite an average immediate success rate of 78%, pituitary surgery is associated with a long-term failure, including the immediate relapses and the late recurrences, in an average of approximately 32%, (25% of patients with a microadenoma and 50% of patients with a macroadenoma).
If the Cushing’s disease comes back, repeat pituitary surgery can be considered, especially in case of well-defined, small, and noninvasive residual tumors. However, repeat surgery is associated with a lower success rate, due to a lower immediate remission rate with a similar recurrence rate, and a higher prevalence of hypopituitarism (meaning the production of other pituitary hormones is damaged).
2) Bilateral total adrenalectomy (BLA) for Cushing's disease
Many recent studies have shown that bilateral adrenalectomy is an increasingly used and essential treatment option when pituitary surgery is no longer an option. Compared to other options such as radiation or medical treatment, bilateral adrenalectomy lowers morbidity and mortality rates, as well as improves quality-of-life.
Figure 2. Dr. Carling at the Carling Adrenal Center performing a bilateral adrenalectomy (BLA) via the Mini-Back Scope Adrenalectomy (MBSA) approach in a patient with “failed” Cushing’s Disease and Cushing’s syndrome.
Bilateral adrenalectomy is associated with definitive disease cure in the vast majority of patients with Cushing’s Disease. It is important to note, that Dr Carling has never had a recurrence. Recurrences do happen, though, especially if the adrenal surgeon is inexperienced. The reason the disease comes back is that not the entire adrenal gland was removed. This operation must be performed perfectly. If adrenal cells are left behind or spilled, they can grow back (remember, the ACTH is still high and will stimulate any adrenal cell to grow and multiply). That is why the operation is called bilateral TOTAL adrenalectomy. All cells need to b totally removed. This is a procedure you do want to travel to the best center in the world for. At other institutions, the disease recurrence rate may be up to 12% of cases.
The major advantage of bilateral adrenalectomy is the rapid and definitive control (100% in Dr. Carling’s experience) of the clinical syndrome of Cushing’s Disease together with the rapid reversal of the comorbidities. Adrenal surgery prevents the clinical complications associated with the mortality of Cushing’s Disease. Naturally, the downside (and intended goal) of bilateral adrenalectomy is the development of permanent adrenal insufficiency. Patients need to be on lifelong glucocorticoid (hydrocortisone) and mineralocorticoid (Florinef) replacement therapy to prevent a life-threatening adrenal crisis. Nelson syndrome, or pituitary tumor progression, represents the most important risk after bilateral adrenalectomy. Nelson syndrome is defined as the association of expanding pituitary mass and high circulating ACTH concentrations after bilateral adrenalectomy in patients with Cushing’s Disease. This is rare, but your endocrinologist will watch for this following adrenal surgery.
Patients having undergone bilateral adrenalectomy (BLA) require special attention and must have a booked follow up appointment with their endocrinologist before surgery. Patients and their family members need to know about adrenal insufficiency signs and symptoms including instructions on “sick day” dose adjustment of hydrocortisone and when and how to use emergency hydrocortisone injection. Patients should be provided with medical alert bracelets and hydrocortisone sodium succinate vials for emergency use. This is particularly important to understand, and we will work with your endocrinologist, so this is addressed prior to surgery. You should have this all lined up prior to surgery.
3) Pituitary radiation for Cushing's disease
The results of the studies on radiotherapy for Cushing’s Disease demonstrate that it is associated with disease control in about 60% of patients. The studies on the use of radiotherapy in Cushing’s disease indicate that radiotherapy can be an effective second-line treatment for patients who have undergone unsuccessful pituitary surgery, especially in invasive and/or aggressive tumors. However, radiotherapy is nowadays generally used as a third-line treatment after unsuccessful surgery and the lack of effectiveness of, or presence of intolerance to, medical therapy, which is presently often considered before radiotherapy. The use of radiotherapy as first-line therapy has become an even rarer event with the incremental number of choices of medical treatments.
The main drawbacks of pituitary radiotherapy
- The time elapsing between the administration and complete efficacy of the treatment (it takes a long time to work)
- The complications, the most common of which is the hypopituitarism (damage to surrounding cells, leading to lack of production of other pituitary hormones) that occurs in a great majority of patients and develops a long time after radiotherapy.
Figure 3. Stereotactic radiotherapy for Cushing’s disease is less commonly used due to reduced efficacy, and complications.
4) Medications for Cushing's disease
Medical therapy for Cushing’s disease includes three categories of drugs: 1) adrenal-directed drugs, which block cortisol production from the adrenal gland; 2) pituitary-directed drugs, which inhibit ACTH secretion from the tumor and, secondarily, cortisol production; and 3) glucocorticoid receptor-directed drugs, which peripherally block the activation of the glucocorticoid receptors
Figure 4. The 3 classes of drugs and their targets of action in the treatment of Cushing’s disease.
Medical treatment is presently used in different situations, including:
- Presurgical treatment aimed at improving the clinical picture of patients before surgery
- Postsurgical treatment in case of unsuccessful pituitary surgery
- Bridging treatment before, bilateral adrenal surgery
- Bridging treatment before, during, and after the administration of radiotherapy, while awaiting its definitive effects
- Primary treatment in case of severe disease when no other options are available
As with all medications, there exist various levels of efficacy, side-effects and costs.
Additional Resources:
- Learn more about the Carling Adrenal Center
- Learn more about Dr. Tobias Carling
- Learn more about our sister surgeons at the Norman Parathyroid Center, Clayman Thyroid Center and Scarless Thyroid Surgery Center
- Learn more about the Hospital for Endocrine Surgery
References:
Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing's Disease. Endocrine Reviews. 2015 Aug;36(4):385-486