Cushing's disease is a rare subtype of Cushing’s syndrome caused by a benign (noncancerous and slow-growing) pituitary tumor that overproduces adrenocorticotropic hormone (ACTH), leading to excessive cortisol production by the adrenal glands. This condition disrupts normal cortisol rhythms and can cause serious complications and early death if left untreated.
Treatment for Cushing’s disease usually involves surgical removal of the adrenal gland, a transsphenoidal adenomectomy, to remove the pituitary tumor.
Surgery is often the primary (first-line) treatment for Cushing's Disease because it directly addresses the root cause of the condition—a pituitary tumor that secretes excess adrenocorticotropic hormone (ACTH). This minimally invasive procedure has a high success rate in experienced hands.
This article describes the surgical options available for treating Cushing's Disease, including a discussion of their benefits, risks, and outcomes to empower patients and practitioners with what to expect on the healing journey from Cushing’s disease.
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Understanding the Need for Surgery for Cushing's Disease
Patients diagnosed with Cushing’s disease are often offered surgery as a primary treatment. The goal of therapy is to normalize cortisol levels as soon as possible, and surgery to remove the ACTH-secreting tumor.
The Role of Surgery in Cushing's Disease
Surgery is often required in Cushing's disease to remove the pituitary tumor that is causing excess cortisol production. Surgical removal of the tumor can effectively reduce the overproduction of adrenocorticotropic hormone (ACTH), which normalizes cortisol levels.
Transsphenoidal surgical removal of the pituitary tumor is considered a first-line approach for Cushing’s disease treatment in children and adults because it targets the root cause of the condition, making it the most definitive treatment for achieving long-term remission.
Surgery is most effective when performed by an experienced surgeon. Successful resection can lead to remission in a significant proportion of patients.
When Surgery is Recommended
Surgery is recommended once a diagnosis of Cushing's disease has been confirmed through laboratory testing and the tumor has been located using imaging techniques.
MRI imaging is used to detect pituitary adenomas, especially microadenomas (a tumor less than 10 mm). When the diagnosis is confirmed, and the tumor localized, surgery offers the best chance of curing the disease and normalizing cortisol levels, which alleviates symptoms and reduces the risk of the severe complications associated with Cushing's disease.
Severe complications of Cushing’s disease include cardiovascular issues; metabolic complications including type 2 diabetes mellitus and dyslipidemia; osteoporosis and increased fracture risk; higher risk of infections; mental health issues; increased risk of blood clots; and muscle weakness.
The decision to proceed with surgery on the patient’s overall health and their ability to undergo the procedure. Surgery is most effective when the tumor is small, non-invasive, and clearly identifiable, as this increases the chances of a successful outcome.
Goals of Surgical Treatment
The primary goals of surgical treatment in Cushing's disease are to normalize cortisol levels and reduce the wide range of symptoms caused by hypercortisolism, such as weight gain, high blood pressure, and mood disturbances.
By reducing cortisol to normal levels, surgery also prevents serious complications, including cardiovascular disease, osteoporosis, and diabetes, thereby improving the patient's overall quality of life and long-term health outcomes.
Surgical Options for Cushing's Disease
The primary surgical option for Cushing’s disease is direct removal of the ACTH-secreting pituitary adenoma. When this is not possible, alternate procedures may be considered.
Transsphenoidal Surgery
During transsphenoidal surgery, the nasal passage is used to access and remove pituitary tumors. It is a minimally invasive approach that avoids the need for a craniotomy (a craniotomy is a surgical procedure that involves temporarily removing a portion of the skull to access the brain).
The procedure includes tumor removal, with care taken to avoid damage to surrounding structures, and is followed by reconstruction of the surgical site to prevent complications like cerebrospinal fluid leaks.
This procedure is best suited for patients with small, noninvasive pituitary adenomas causing Cushing’s Disease that are clearly visible on MRI.
Success Rates and Outcomes
Transsphenoidal adenectomy has high success rates, especially when performed by experienced surgeons.
After surgery, a patient’s hypothalamic-pituitary-adrenal (HPA) axis may need time to normalize. Successful surgery is indicated by postoperative serum cortisol levels dropping below 55 nmol/L (2 μg/dL). Patients who achieve remission often require glucocorticoid (GC) replacement until their HPA axis recovers.
However, postsurgical hypocortisolism is considered a good sign. Patients with postsurgical hypocortisolism followed by full adrenal recovery have a very low risk of recurrence. However, those without this complete recovery, especially if their circadian rhythm remains abnormal, are at a higher risk of recurrence.
Immediate post-surgical symptom relief is often observed as hypercortisolism typically resolves quickly. However, long-term symptom relief depends on the person returning to healthy (normal) cortisol levels.
Remission and recurrence rates can vary depending on multiple factors including tumor size, resectability, and the clinical picture of Cushing’s disease. Median rates of remission are given by one source as 77.9%, and median recurrence rates as 11.5%.
Risks and Complications
There are risks associated with surgery, including hypopituitarism and potential complications such as electrolyte disturbances and meningitis from infection. Cerebrospinal fluid (CSF) leaks have also been known to occur.
Potential post-surgical hormonal deficiencies require hormone replacement, so postoperative hormone levels should be monitored.
Postoperative management includes close monitoring for CSF leakage, infection, and monitoring of cortisol levels to assess remission and detect any potential recurrence.
In cases where surgery is not curative or feasible, guidelines suggest considering second-line treatments such as repeat surgery, radiation therapy, or medical therapy.
Adrenalectomy
Adrenalectomy involves the surgical removal of one or both adrenal glands, typically performed through either laparoscopic (minimally invasive) or open surgery. Laparoscopic surgery is the gold standard for adrenal gland removal, which is less invasive and has a faster recovery time than open surgery.
Adrenalectomy is recommended for patients with adrenal tumors or adrenal hyperplasia (an increase in normal, noncancerous cells of the adrenal cortex, causing increased hormone production and adrenal enlargement). Both of these conditions can cause Cushing’s syndrome, leading to excessive cortisol production.
Success Rates and Outcomes
Adrenalectomy is effective in normalizing cortisol levels. However, if the patient undergoes bilateral adrenalectomy (both adrenal glands are removed), the patient will require lifelong hormone replacement therapy, including glucocortiocoids and mineralocorticoids.
Risks and Complications
The risks of laparoscopic adrenalectomy include potential injuries to the liver, spleen, pancreas, duodenum, and inferior vena cava. Liver injuries can occur during retraction, and vena cava trauma might cause severe bleeding, sometimes requiring conversion to open surgery.
Other possible complications are pleural injuries and pneumothorax.
The risks of open adrenalectomy include surgical site infections, which were the most common complication, followed by pulmonary issues like atelectasis and pneumonia. Other significant complications can include deep venous thrombosis, retroperitoneal hematoma, and sepsis.
Nelson Syndrome is a condition that can develop after bilateral adrenalectomy for Cushing's disease. It is characterized by the growth of a residual pituitary adenoma, elevated adrenocorticotropic hormone (ACTH) levels, often exceeding 300 pg/mL, and hyperpigmentation (darkening) of the skin due to increased ACTH production.
After surgery, careful hormone management and monitoring are needed to avoid complications related to adrenal insufficiency. Patients who undergo bilateral adrenalectomy will require close monitoring lifelong.
Ectopic ACTH Tumor Resection
Description of the Procedure
Some tumors called neuroendocrine tumors (NETs), are made up of neuroendocrine cells that make hormones in response to nervous system signals. These tumors constantly release an excessive amount of hormones into the bloodstream.
NETs can develop in various parts of the body, most commonly in the gastrointestinal tract, pancreas, and lungs. They may be benign or malignant and very aggressive.
Some NETs in locations like the pancreas, GI tract, and lungs can secrete ACTH, producing Cushing's syndrome completely independent of the pituitary gland.
Neuroendocrine tumor resection involves surgically removing neuroendocrine tumor completely. This may involve partial removal of surrounding tissues or organs to achieve clear margins (the absence of cancer cells at the outer edge of tissue removed during tumor excision, indicating that the tumor has been completely removed and reducing the risk of recurrence).
NET surgical removal can be minimally invasive (laparoscopic) or open surgery, depending on the tumor's size, location, and involvement of adjacent structures.
Postoperative care involves monitoring for complications like wound infections, bleeding, and abscesses and managing hormone-related symptoms.
Success Rates and Outcomes
Success of the surgery depends on the neuroendocrine tumor location and the feasibility of complete removal. When possible, surgery is considered a cornerstone treatment for NETs, and significant symptom relief is possible if the tumor is fully excised.
Risks and Complications
Risks vary based on tumor location and surgical complexity. Accurate preoperative imaging and meticulous surgical planning are critical for reducing complications.
Pre-Surgical Evaluation and Preparation
Patients can expect a comprehensive evaluation of their condition before the decision to move forward with surgery.
Diagnostic Imaging
Diagnostic imaging including MRI, CT scans, and other technology are commonly used to accurately locate neuroendocrine tumors. These imaging modalities help determine the size, shape, and precise location of the tumor, as well as its relation to surrounding tissues, aiding in effective surgical planning.
Hormonal Assessment
Before surgery, hormonal assessments are conducted to measure cortisol levels and/or other hormones that might be produced by a NET. This helps in understanding the tumor's impact on the patient's endocrine system and guides surgical and postoperative management.
Preparing for Surgery
Preparation involves patient education about the surgical process, potential risks, and realistic expectations for outcomes.
Pre-operative care includes optimizing the patient's health, conducting necessary tests, and planning for post-surgical recovery, ensuring a safer and more effective procedure.
Post-Surgical Care and Recovery
Immediately following the surgical procedure, the focus is on monitoring cortisol levels, managing pain, and ensuring early mobilization to reduce the risk of complications such as blood clots or infections.
Other considerations include sodium and thyroid testing. A follow-up MRI is also recommended within 1-3 months of the procedure to determine the new baseline and monitor for recurrence.
Hormone Replacement Therapy
Hypocortisolemic patients should be placed on glucocorticoid replacement after surgery. Regular follow-up with morning cortisol and ACTH stimulation tests helps determine when to safely discontinue glucocorticoid therapy.
Patients who have undergone bilateral adrenalectomy (removal of both adrenal glands) will usually require lifelong steroid replacement therapy to compensate for lost hormone production. Regular follow-ups are necessary to adjust hormone levels and ensure proper management.
Long-Term Monitoring and Follow-Up
Regular check-ups are essential to monitor for tumor recurrence or other complications. Ongoing strategies are needed to manage long-term health and maintain quality of life post-surgery.
Risks, Benefits, and Considerations of Surgery
Any surgical procedure carries risks and the possibility of benefit, which in this setting can be curative. Considerations for a surgical procedure to cure Cushing’s disease include:
Potential Benefits of Surgery
Effective Reduction or Normalization of Cortisol Levels
Surgery is a primary treatment for Cushing’s disease that targets the removal of the ACTH-secreting tumor, which helps normalize cortisol levels and alleviates the symptoms of hypercortisolism.
Potential for Symptom Relief and Improved Quality of Life
Successful surgery can lead to significant symptom relief, including weight loss, reduced blood pressure, improved mood, and lower risks of serious complications like cardiovascular disease, osteoporosis, and diabetes.
This generally results in a better overall quality of life and long-term health outcomes.
Risks and Complications
Detailed Discussion of Risks Specific to Each Surgical Option:
- Transsphenoidal Surgery: risks include hypopituitarism, electrolyte disturbances, meningitis, cerebrospinal fluid leaks, and potential hormonal deficiencies requiring replacement therapy.
- Adrenalectomy: potential complications involve injury to nearby organs, risk of infections, bleeding, deep vein thrombosis, and the need for lifelong hormone replacement if both adrenal glands are removed.
- Ectopic ACTH Tumor Resection: complications depend on tumor location and may include wound infections, bleeding, and hormonal imbalances. Accurate preoperative imaging and careful surgical planning are critical.
Importance of Choosing an Experienced Surgical Team
The success of surgical treatment and the reduction of risks significantly depends on the experience and skill of the surgical team. Higher success rates and fewer complications are seen with experienced surgeons.
Making an Informed Decision
Considerations for Patients When Deciding on Surgery
Patients should consider the potential benefits of achieving long-term remission and symptom relief against the risks associated with surgical complications and recovery. The patient’s overall health, tumor characteristics, and potential for recurrence should guide the decision-making process.
Importance of Discussing All Options with a Healthcare Provider
Patients should discuss their condition, surgical options, potential risks, and alternatives (such as repeat surgery, radiation, or medical therapy) with their trusted healthcare provider. This allows for a well-informed decision that aligns with the patient's health goals and preferences.
Adjunctive (Post-Operative) Treatments
Medications
Medications, used as alternatives or adjuncts to surgery, focus on controlling cortisol production and alleviating symptoms:
- Adrenal Steroidogenesis Inhibitors: drugs like ketoconazole, metyrapone, and osilodrostat inhibit enzymes involved in cortisol synthesis. They effectively lower cortisol levels but can cause side effects such as gastrointestinal issues, liver enzyme elevation, and adrenal insufficiency.
- Somatostatin and Dopamine Receptor Agonists: pasireotide and cabergoline are pituitary-directed treatments that reduce ACTH secretion by targeting pituitary receptors. Pasireotide can normalize urinary cortisol and shrink tumors but may cause hyperglycemia (elevated blood glucose). Cabergoline lowers cortisol and tumor size but can lead to impulse control disorders.
- Glucocorticoid Receptor Antagonists: mifepristone blocks cortisol action, improving hyperglycemia and weight gain symptoms. It does not lower cortisol levels.
Radiation Therapy
Radiation therapy (RT) is used when surgery is insufficient or tumors are aggressive.
RT can achieve biochemical remission and control tumor growth but often leads to hypopituitarism, requiring lifelong monitoring for tumor recurrence and hormone deficiencies.
Combination Approaches
Combination therapies are often needed for effective control, especially in severe hypercortisolism or when monotherapy fails.
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Key Takeaways
Summary of Surgical Options:
- Transsphenoidal Surgery: A minimally invasive procedure through the nasal passage to remove the pituitary tumor, considered the first-line treatment due to its effectiveness in normalizing cortisol levels and achieving long-term remission.
- Adrenalectomy: Involves the removal of one or both adrenal glands, used when the pituitary surgery is not feasible or fails. This approach effectively reduces cortisol but requires lifelong hormone replacement.
- Ectopic ACTH Tumor Resection: Targets ACTH-secreting neuroendocrine tumors outside the pituitary gland. Success depends on complete tumor removal, which may require complex surgical planning.
Many patients achieve remission and significant symptom relief following surgery, leading to improved quality of life. It's crucial to seek care from experienced specialists who can provide the most effective treatment and manage potential complications.
Managing Cushing’s Disease effectively requires a team of specialists including endocrinologists, neurosurgeons, and oncologists. A collaborative approach ensures comprehensive care, personalized treatment plans, and better outcomes for patients.
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