Surgery for Cushing Syndrome What is the surgery for Adrenal (ACTH-independent) Cushing’s syndrome? There are eight well recognized techniques by which a surgeon can remove an adrenal gland or adrenal tumor. The specific technique used will be dictated in large part by the situation at hand. It is absolutely crucial that your adrenal surgeon is comfortable with all possible techniques of adrenal surgery since a customized, individual approach will give the best possible outcome. You need an operation that is tailor-made for you and your tumor. Most tumors (>95%) can now be removed using minimally invasive techniques such as the Posterior Retroperitoneoscopic Adrenalectomy (PRA) or the Mini-Back Scope Operation, or less frequently the Laparoscopic Trans-Abdominal Adrenalectomy (LTA) approach, with or without the hand-port. Large tumors (>12 cm) and tumors which are suspected or known to be malignant, especially if they are invading surrounding structures such as the kidney, liver, spleen, pancreas, bowel, or major vessels such as the inferior vena cava (IVC) are almost never removed by minimally invasive operations, rather an open standard technique is required. Mini-Back Scope Operation The Mini-Back Scope Operation is the preferred technique in >95 % of adrenal surgery cases for both uni- and bilateral Adrenal (ACTH-independent) Cushing’s syndrome. Here are the top beneficial reasons of this scope surgery: • The operation is the safest. There is less mobilization (i.e. dissection of surrounding structures). This leads to less risk of injury to surrounding structures such as the kidney, liver, spleen, pancreas, bowel, or major vessels such as the inferior vena cava; IVC. You want the safest possible operation. Dr. Carling has never had an injury to surrounding structures. • The operation is much faster than any other techniques. There is no value in a fast operation, per se. The operation needs to take as long as is required to get the job done. However, a fast operation means that your surgeons is experienced and knows what he/she is doing. It is not uncommon that an adrenalectomy that would take 2-4 hours at the most prestigious hospitals (yes, we are talking about the top 30 hospitals in the US News & World Report), can be performed by Dr. Carling in 20-30 minutes. Again, there is no value in a fast operation, per se. However, a faster operation means less time under general anesthesia. Although, general anesthesia is very safe, the longer time the patient is under general anesthesia, the greater risk of anesthesia-related complications such as nausea, vomiting, neurocognitive symptoms, blood clots, pulmonary embolism, urinary retention (emptying the bladder), infections and in some cases long-term effects on cognition and memory. • The surgeon does not need to enter the intra-abdominal cavity. This means that even for patients with previous operations on the abdomen, the surgeon does not need to deal with adhesions (scar tissue). Intra-abdominal scars (known as adhesions) may be from previous operations such as bariatric surgery (gastric band, sleeve gastrectomy, gastric bypass), gallbladder surgery (cholecystectomy), liver surgery, stomach surgery, bowel surgery of any kind (colectomy, appendectomy, etc) or any previous kind of gynecological operations (Caesarian section, hysterectomy, etc). Also, this means you are not at risk of developing future intra-abdominal scars (known as adhesions) which can lead to problems with small bowel obstruction (SBO). Also, you will not develop an ileus. • The risk of developing a postoperative, incisional hernia (breakdown or weakness of the abdominal wall muscles) is much lower. • There is less postoperative pain. Many patients only take Tylenol (acetaminophen) or other over the counter (OTC) medications after the operation. Very few patients need strong pain-killers. • The patients can go home faster. The typical patient would spend less <23 hours in the hospital. • The recovery is faster. You may return to work within days. You can start your hobbies, and exercises a lot faster, whether you engage in walking, running, biking, gym exercises, yoga, weightlifting, skiing, tennis, golf or any other work-outs. • The cosmetic outcome is exceptional and superior to any other technique. • There is no blood loss in this operation. Yes, it is true. Watch Dr. Carling’s surgical videos and you can see that there is no blood loss. There is less blood loss when Dr. Carling performs a Mini-Back Scope Operation compared to when you have your annual blood tests by your primary doctor. Dr. Carling has never, ever in his entire career had to order a blood transfusion. • For patients requiring bilateral adrenalectomy, there is no moving, flipping and turning the patient around during the operation. This is better for the patients and the entire operating room staff. Partial (or cortical-sparing) adrenalectomy Sometimes it is preferable and possible to remove the adrenal tumor without removing the remainder of the adrenal gland. This is called partial (or cortical-sparing) adrenalectomy. The purpose of leaving a portion of the adrenal gland is to avoid adrenal insufficiency (not enough adrenal hormones leading to the requirement to take hormonal supplements). This is especially important to know for some candidates with less common causes of ACTH-independent Cushing’s syndrome that are the familial and sporadic forms of bilateral macronodular (BAIMAH) and micronodular adrenal hyperplasia with its pigmented variant also referred to as primary pigmented nodular adrenocortical disease (PPNAD). Patients with BAIMAH and PPNAD can be excellent candidates for partial (cortex-sparing) adrenalectomy, and should have their operations performed at the highest-volume adrenal surgery center, as possible. For optimal results, there are some crucially important concepts (3) the patient needs to understand. The ability to perform partial (or cortical-sparing) adrenalectomy is dependent on 1) The type of tumor the patient has. 2) The size of the tumor, as well as its relationship to the adrenal vein, and other structures such as the inferior vena cava. 3) The key is to preserve sufficient normal adrenal cortex tissue (often 30% of one adrenal gland; or 15% of both glands) and at the same time not compromise the surgical resection margin (i.e. potentially spilling tumor cells that may lead to recurrence). Important to know, both benign (for instance, pheochromocytoma) and malignant adrenal tumors can grow back (so called recurrence) if not resected accurately. Partial (or cortical-sparing) adrenalectomy allows for resection of adrenal tumor(s), while preserving un-affected adrenal tissue to prevent adrenal insufficiency. This is especially important in patients affected with bilateral adrenal tumors, typically pheochromocytomas, as well as those with adrenal metastasis. The Mini-Back Scope Operation allows for a minimally invasive approach to adrenal gland resection compared to the more traditional laparoscopic transabdominal adrenalectomy (LTA) and open approaches. The Mini-Back Scope Operation technique is ideal to address patients with bilateral disease and can utilized in patients with for instance bilaterally pheochromocytomas in the setting of multiple endocrine neoplasia 2A (MEN2A), von Hippel Lindau (VHL) syndrome, or in patients who have had previous adrenal surgery. Watch Dr. Carling perform a partial (or cortical-sparing) adrenalectomy here. Partial (or cortical-sparing) adrenalectomy is an invaluable option for patients with genetic syndromes associated with pheochromocytomas. These syndromes include MEN2, VHL, and neurofibromatosis type 1 (NF1), as well as others. Approximately 40-80% of patients with either MEN2A or VHL will develop bilateral pheochromocytomas and these tumors are usually benign. As such, cortical sparing adrenalectomy can remove affected tissue, while leaving behind enough tissue to prevent adrenal insufficiency with minimal risk of recurrence. Typically, >90% of patients who are thought to be good candidates for partial adrenalectomy (based on preoperative imaging) will be able to undergo it. It is very important to realize the above mentioned 3 concepts: The ability to perform partial (or cortical-sparing) adrenalectomy is dependent on 1) What type of tumor the patient has. 2) The size of the tumor, as well as its relationship to the adrenal vein, and other structures such as the inferior vena cava. 3) The key is to preserve sufficient normal adrenal cortex tissue (often 30% of one adrenal gland; or 15% of both glands) and at the same time not compromise the surgical resection margin (i.e. potentially spilling tumor cells that may lead to recurrence). Important to know, both benign (for instance pheochromocytoma) and malignant adrenal tumors can grow back (recurrence) if not resected accurately. Thus, in about 10% of cases, the intraoperative findings may be such that a partial adrenalectomy is the wrong operation. Dr. Carling will not compromise the surgical resection margin putting his patients at risk of the disease coming back. This is where experience and excellent surgical judgement plays a huge role. In cases where partial adrenalectomy is performed for bilateral adrenal tumors, >90% of patients do not require steroid supplementation (Prednisone, hydrocortisone, etc). This means that >90% of patients undergoing partial bilateral adrenalectomy can be saved from developing adrenal insufficiency. In most cases with bilateral tumors, we would completely resect the entire adrenal gland on one side and then perform a partial resection on the other side. However, this has to be individualized in each scenario. The key to prevent adrenal insufficiency is to save at least 30% of one gland, or a total of 15% of both adrenal glands. Watch Dr. Carling perform a partial (or cortical-sparing) adrenalectomy here. What is the surgery for Adrenocortical Adenomas Causing overt Cushing’s syndrome? Again, unilateral adrenalectomy is the only curative therapy for these patients. Again, the Mini-Back Scope Operation is the preferred technique in >95 % of adrenal surgery cases for Adrenocortical Adenomas Causing overt Cushing’s syndrome. When performed by experienced adrenal surgeons, unilateral adrenalectomy (read about scope surgery here) is curative in nearly 100% of adults and children with cortisol producing adrenal adenomas. In patients with ACTH-independent Cushing’s syndrome due to functional adrenal adenomas (this is the cortisol is so excessively elevated from the tumor), recovery of normal function of suppressed hypothalamus, pituitary, and contralateral adrenal gland may be delayed. Therefore, the patients often require glucocorticoid replacement therapy for several months after curative adrenalectomy. This is very important to understand and we will work with your endocrinologist so you have a crystal-clear plan for weaning off your hormone replacement after surgery. A dose of 100 mg of hydrocortisone every 8 h intravenously may be administered over the first 24-h with the first dose given after induction of anesthesia. A rapid taper follows over a few days until hydrocortisone can be given by mouth. Recovery of HPA axis can be evaluated by measuring serum cortisol level with blood samples obtained before the morning hydrocortisone dose (every 3 months), followed by an ACTH stimulation test starting when the level is 7.4 μg/ dl (200 nmol/l) or more. The axis has recovered if the baseline or stimulated level is approximately 18 μg/dl (500 nmol/l) or greater. Patients with cortisol levels below 5 μg/dl (138 nmol/l) should remain on glucocorticoids (hydrocortisone) until retested in 3–6 months. In the literature, patients with Cushing’s syndrome have a greater (more than tenfold) risk of developing venous thromboembolism (blood clots, pulmonary embolism), when undergoing surgery, and perioperative hypercoagulability prophylaxis is recommended. Again, this is why you want the most experienced, safe and efficient surgeons doing your adrenalectomy. It is not uncommon that an adrenalectomy that would take 2-4 hours at the most prestigious hospitals (yes, we are talking about the top 30 hospitals in the US News & World Report; If they add robot assisted approaches you may add 1-3 hours), can be performed by Dr. Carling in 20-30 minutes. Again, there is no value in a fast operation, per se. However, a faster operation means less time under general anesthesia. Although, general anesthesia is very safe, the longer time the patient is under general anesthesia, the greater risk of anesthesia-related complications such as nausea, vomiting, neurocognitive symptoms, blood clots, pulmonary embolism, urinary retention (emptying the bladder), infections and in some cases long-term effects on cognition and memory. Dr. Carling has never had a case of blood clots, pulmonary embolism after adrenalectomy. What is the surgery for overt Cushing’s syndrome Caused by Adrenocortical Carcinoma? Complete surgical excision of localized adrenocortical carcinoma causing Cushing’s syndrome with locoregional lymphadenectomy in cases with locally advanced disease (R0 resection) is the mainstay of potentially curative approaches. That means, in plain language, you have one shot of having a perfect operation, where all cancer is removed, without spillage, and you have a chance of cure. Because of this, Dr. Carling will plan your operation meticulously, and utilize any of the 8 different surgical approaches to the adrenal (read more here about adrenal surgery approaches) to give you the best chance of having a curative operation. However, more than half of the patients who have undergone complete removal of the tumor are destined to have disease recurrence, often with metastases. In cases of recurrent adrenocortical carcinoma with localized or low tumor burden, a second operation may be effective in improving survival if the time to first recurrence was >12 months Despite improved survival reported in patients with resectable oligometastatic disease, prognosis in advanced inoperable cases is poor with a 5-year overall survival being <15%. Read more about adrenocortical carcinoma here. What is the surgery for ACTH-Independent Bilateral Adrenal Disease? The less common causes of ACTH-independent Cushing’s syndrome that are the familial and sporadic forms of bilateral macronodular (BAIMAH) and micronodular adrenal hyperplasia with its pigmented variant are also referred to as primary pigmented nodular adrenocortical disease (PPNAD). Adrenalectomy is again the potentially curative treatment. Again, the Mini-Back Scope Operation is the preferred technique in >95 % of adrenal surgery cases for both uni- and bilateral Adrenal (ACTH-independent) Cushing’s syndrome. This is especially important to know for some candidates with less common causes of ACTH-independent Cushing’s syndrome that are the familial and sporadic forms of bilateral macronodular (BAIMAH) and micronodular adrenal hyperplasia with its pigmented variant also referred to as primary pigmented nodular adrenocortical disease (PPNAD). Patients with BAIMAH and PPNAD can be excellent candidates for partial (cortex-sparing) adrenalectomy and should have their operations performed at the highest-volume adrenal surgery center, as possible. Occasionally, partial (cortex-sparing) adrenalectomy or unilateral adrenalectomy is not possible or inadvisable in these cases, because of some risk of disease recurrence. A complete bilateral adrenalectomy sometimes (but rarely) may have to be performed and will inevitably cause permanent adrenal insufficiency requiring a lifelong mineralocortioid and glucocorticoid replacement therapy (usually hydrocortisone 15 ± 3 mg in the morning and 5±2 mg in the evening with fludrocortisone 100 μg/day). Before discharge patients should be switched to 0.5 mg of dexamethasone daily for confirming cure, and UFC and diurnal serum cortisol must be measured 24- and 48-h after dexamethasone initiation. Undetectable serum cortisol (<1 μg/dl) and UFC (<1.3 μg/24-h) is considered biochemical evidence of cure. Prior to discharge, patients and patients’ family members should be thoroughly educated on adrenal insufficiency signs and symptoms including instructions on “sick day” dose adjustment 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 as described in detail in information prepared by the National Institutes of Health Clinical Center. Again, this is very important to understand and we will work with your endocrinologist so you have a crystal-clear plan for weaning off your hormone replacement after surgery. When is adrenal surgery for “failed” ACTH-dependent Cushing’s syndrome, Cushing’s Disease? Cushing’s disease (CD) is the consequence of chronic exposure to glucocorticoids due to a pituitary adenoma secreting ACTH. It comprises a large spectrum of signs and symptoms that cause an increased morbidity and mortality, and deterioration in quality of life (QoL). The first-line treatment option is surgical resection of the adenoma. Dr. Carling editorial note: The surgeons of the Carling Adrenal Center are the most world’s expert surgeons of adrenal tumors and disease. That is what we do. We do not perform surgery on the brain, or pituitary gland. However, if you have Cushing’s disease due to an ACTH producing pituitary tumor, you can always contact us, and we will direct you to a high-volume surgeon who does pituitary surgery (usually a neurosurgeon). You want the most expert pituitary surgeon do your operation! Similar as adrenal surgery, pituitary surgery is tricky and requires significant expertise and experience. However, 31% of patients with Cushing’s 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. This is a big problem. Then the second-line treatment options sometimes have to be complete bilateral adrenalectomy. The goal is to remove any cells in the body that can overproduce the toxic cortisol. 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. Again, the Mini-Back Scope Operation is the preferred technique in for “failed” ACTH-dependent Cushing’s syndrome, Cushing’s Disease. Prior to discharge, patients and patients’ family members should be thoroughly educated on adrenal insufficiency signs and symptoms including instructions on “sick day” dose adjustment 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 as described in detail in information prepared by the National Institutes of Health Clinical Center. Again, this is very important to understand, and we will work with your endocrinologist so you have a crystal-clear plan for weaning off your hormone replacement after surgery. What is the role of surgery (Mini back scope adrenalectomy) for Subclinical Cushing’s syndrome? KEY POINTS • Subclinical Cushing’s syndrome is more clinically significant as previously postulated. • Diagnosis of the syndrome is somewhat cumbersome, but possible. • As most patients present with “adrenal incidentalomas”, a thorough biochemical work-up by both a dedicated endocrinologist and endocrine surgeon is necessary for optimal outcome. • Given the low rate of complications, we (and most knowledgeable medical and surgical endocrinologists) recommend minimally invasive adrenalectomy (scope adrenalectomy, see here) in patients with biochemically proven or even suspected Subclinical Cushing’s syndrome who are appropriate surgical candidates. Indications for Surgery in Subclinical Cushing’s syndrome In the current era of evidence-based medicine the long-term complications of incidentally discovered adrenal adenomas remains virtually unknown. Therefore, the overall management of these tumors remains empiric. Given the overall questionable long-term effects of incidentally identified adrenal masses, there are broadly two clinical options, surveillance versus resection. Although studies so far are relatively small, about 10-15 % of patients with subclinical Cushing’s syndrome prove a progression to overt Cushing’s syndrome at one year of follow-up. In patients undergoing adrenalectomy, most studies to date demonstrate that surgically treated subjects identified an improvement of hypertension, diabetes, obesity and dyslipidemia (poor blood fat levels), as well as glucose metabolism and lowered body weight. Adrenalectomy has proven to ameliorate the biochemical abnormalities associated with subclinical Cushing’s syndrome, but its long-term effects have yet to be completely elucidated. Nonetheless, patients with subclinical Cushing’s syndrome have a higher incidence of hypertension, obesity, decreased bone density and metabolic syndromes. Importantly, adrenalectomy has been demonstrated to decrease the cardiovascular risk factors associated with subclinical Cushing’s syndrome. Another study identified elevated risk factors for cardiac disease, finding patients with subclinical Cushing’s syndrome to have increased fasting glucose levels, cholesterol and triglycerides when compared to matched controls. Multiple studies have identified a positive patient benefit from early adrenalectomy in reversing these potentially devastating systemic comorbidities. In general, a low threshold for surgical resection (read about scope adrenalectomy here) in patients with biochemically proven or suspected subclinical Cushing;-‘s syndrome or those that have an overall size greater than 4 cm lesions is advised in expert hands, given the low morbidity and mortality associated with minimally invasive adrenalectomy (Read about the Mini-Back Scope Operation here). Given the subclinical nature of subclinical Cushing’s syndrome, it remains extremely difficult to accurately determine clinical improvement, yet patients should be monitored and continued on a short steroid course until they have proven an intact HPA axis according to previously established protocols. Given the significant proportion of subjects who experience deterioration in biochemical indices and disease progression, and the unknown impact of chronic hypercortisolemia on health outcomes, contrasted with the high cure and low complication rates after minimally invasive adrenalectomy, render surgery a very attractive first option in patients with biochemically proven or even suspected subclinical Cushing’s syndrome whom are appropriate surgical candidates.