Transsphenoidal Surgery for Cushing's disease

• Surgical Treatment of Cushing's Disease: The Lessons Learned
• Venous thromboembolism in patients with pituitary adenoma: UK multicentre cohort study
• Endoscopic endonasal surgery using indocyanine green fluorescence endoscope for Cushing's disease caused by mixed intrasellar gangliocytoma and adrenocorticotropin adenoma: illustrative case
• Outcomes of the Transsphenoidal Approach for ACTH-Secreting Pituitary Tumours and the Role of Postoperative ACTH in Predicting the Late Recurrence of Cushing's Disease: A Retrospective Analysis of 50 Cases
• Postoperative Initiation of Thromboprophylaxis in patients with Cushing's Disease (PIT-CD): a randomized controlled trial
• Prediction of remission and recurrence of Cushing's disease following transsphenoidal surgery (TSS): a single center, 20-year, retrospective series
• Pituitary surgery in New Zealand: A single neurosurgeon case series of 1,224 operations
• Challenges of Cushing's syndrome and bariatric surgery: a case report with literature review

Transsphenoidal surgery is the primary treatment for Cushing’s disease, as it directly targets the ACTH-secreting pituitary adenoma. The goal is to remove the adenoma to normalize cortisol levels. Here are the main indications for transsphenoidal surgery in Cushing’s disease:

1. Confirmed Diagnosis of Cushing’s Disease: Biochemical confirmation of ACTH-dependent Cushing’s syndrome, with elevated or inappropriately normal ACTH levels. MRI evidence of a pituitary adenoma or biochemical confirmation of a pituitary source when imaging does not show a tumor. Positive response to dexamethasone suppression testing: Partial suppression of cortisol with high-dose dexamethasone, supporting a pituitary source. 2. Presence of a Pituitary Adenoma: Microadenoma (tumor <10 mm): The most common cause of Cushing’s disease, where the adenoma is localized to the sella turcica. Macroadenoma (tumor >10 mm): Transsphenoidal surgery is also indicated for larger adenomas, although the surgery can be more complex, particularly if the tumor has invaded surrounding structures. 3. Failed or Inadequate Medical Management: Indicated when patients have persistent hypercortisolemia despite medical therapy (e.g., adrenal steroidogenesis inhibitors like ketoconazole or metyrapone). Surgery is considered curative, while medical therapy typically serves as a bridge or adjunct in cases where surgery is not feasible or delayed. 4. Severe Clinical Manifestations of Hypercortisolism: Patients with severe symptoms of Cushing’s syndrome (e.g., rapid weight gain, muscle weakness, severe hypertension, diabetes, osteoporosis) benefit from prompt transsphenoidal surgery to control cortisol levels and prevent further complications. Cardiovascular complications, such as uncontrolled hypertension or diabetes, increase the urgency for surgery to normalize cortisol. 5. Ectopic ACTH Source Excluded: Before proceeding with transsphenoidal surgery, it must be confirmed that the source of ACTH overproduction is the pituitary gland and not an ectopic source (e.g., small-cell lung cancer). This can involve inferior petrosal sinus sampling (IPSS) to confirm ACTH secretion from the pituitary when MRI findings are equivocal. 6. Tumor-Related Symptoms: Visual disturbances or neurological symptoms due to compression of the optic chiasm or other surrounding structures by a large or invasive pituitary tumor. Pituitary apoplexy (hemorrhage or infarction in the adenoma) leading to sudden headache, vision loss, or hormonal deficiencies may necessitate urgent surgery. 7. Subclinical Cushing's Disease (in some cases): Patients with subclinical Cushing’s disease and biochemically proven cortisol excess may benefit from surgery, particularly if they have associated complications such as osteoporosis, hypertension, or diabetes that are difficult to manage. 8. Recurrent or Residual Disease: Transsphenoidal surgery is indicated for patients with recurrent Cushing’s disease after an initial successful surgery, especially if repeat imaging shows a residual or recurrent tumor. Persistent hypercortisolism after initial surgery may also prompt a second transsphenoidal approach, depending on the location and size of the residual tumor. Summary of Indications: Biochemically confirmed Cushing’s disease with a pituitary adenoma. MRI evidence of a pituitary adenoma (microadenoma or macroadenoma). Inadequate medical management or persistent hypercortisolism. Severe clinical symptoms due to excess cortisol. Exclusion of ectopic ACTH production. Tumor-related symptoms such as visual disturbances or neurological deficits. Recurrent or residual disease after initial surgery. Transsphenoidal surgery remains the first-line treatment for Cushing’s disease, with a high chance of remission, particularly in patients with microadenomas.

Transsphenoidal surgery is the treatment of choice for most (medical therapy is inadequate as initial therapy since there is no effective pituitary suppressive medication). Cure rates are ≈ 85% for microadenomas but are lower for larger tumors.

Even with microadenomas, hemihypophysectomy on the side of the tumor is usually required for cure (the tumor is diffcult to completely extirpate) with attendant increased risk of Cerebrospinal fluid fistula. If this fails, consideration should then be for total hypophysectomy. Failure of total hypophysectomy prompts consideration for bilateral adrenalectomy (total hypophysectomy virtually eliminates risk of Nelson’s syndrome following adrenalectomy).

If no tumor is identified on pre-op MRI:

● Intraoperative ultrasound may help localize tumor in ≈ 70% of cases ¹⁾ but a specialized U/S probe is required

● if Inferior petrosal sinus sampling (IPS) sampling showed a lateralizing ACTH gradient: start with a paramedian incision on the side of the higher ACTH gradient; if no adenoma is encountered, the contralateral paramedian and then midline incisions are used to explore the pituitary gland

● if IPS sampling and MRI do not suggest tumor location: the gland is explored sequentially with 2 paramedian incisions and then a midline incision

● if the adenoma cannot be found, a hemihypophysectomy is performed on the side of higher ACTH levels if IPS sampling shows a lateralizing gradient, or on the side with more suspicious tissue on the frozen section. Total hypophysectomy is not routinely performed ²⁾.

The management of corticotroph adenomas with Cavernous Sinus Invasion remains a therapeutic challenge due to incomplete resection of invasive and/or a large adenoma. With the application of multiple techniques, approximately half of the patients could achieve gross total resection and biochemical remission via transsphenoidal surgery by experienced neurosurgeons. The extent of tumor resection and the number of operations were associated with surgical remission rate in corticotroph adenomas with CSI. If the remission was not achieved by surgery, other treatments including radiotherapy, medical therapy, and even bilateral adrenalectomy are required ³⁾.

Potts et al. conducted a single-center, retrospective review of all patients with Cushing's disease treated by a single neurosurgeon with endonasal transsphenoidal surgery. Accuracy of adenoma localization with CVS and dMRI was analyzed. Ninety-one consecutive patients were included. Pathology confirmed an adenoma in 66. Preoperative dMRI and CVS were performed in 40 and 37 patients, respectively, with 20 undergoing both studies. Surgical pathology was positive for adenoma in 31 dMRI patients, 25 CVS patients, and 13 who underwent both. Among patients with pathology confirming an adenoma, dMRI identified a lesion in 96.8 % and correctly lateralized the lesion in 89.7 %, while CVS correctly lateralized in 52.2-65.2 % (depending on location of sampling). Among patients with both studies, dMRI and CVS correctly lateralized in 76.9 and 61.5-69.2 %, respectively. Accuracy of CVS improved if only patients with symmetric venous drainage were considered. In this mixed population of Cushing's disease patients, dMRI was more accurate than CVS at localizing adenomas, supporting the use of advance MRI techniques in the work-up of Cushing's disease. CVS, however, remains an important tool in the workup of Cushing's syndrome ⁴⁾.

see Endoscopic endonasal approach for pituitary neuroendocrine tumor.

Patients with CD have significantly prolonged postoperative sinonasal QOL impairment following EEA compared to patients with non-functioning tumors, who normalize within 6 months. In CD patients, only morbidity in the facial domain, likely related to post-operative pain and nasal packing, improved over time, while the sleep domain was the most affected ⁵⁾.

To derive a clinical score from parameters that favor remission of Cushing's disease (CD) after pituitary surgery.

Methods: This is an analysis of 11 clinical, hormonal, and post-operative parameters that each favored remission in a cohort of 145 patients with CD treated by trans-sphenoidal surgery (TSS). Each parameter was designated as a categorical variable (presence/absence), and several favorable parameters present for each patient were calculated. From this, a median parameter score (clinical score) of the entire cohort was derived, which was then compared to the event of remission/persistence of CD.

Results: The median number of favorable parameters present in the entire cohort was 3 (0-7). The significant count of patients in remission increased with the increasing number of parameters. The receiver-operator characteristic curve showed that the presence of ≥3 parameters was associated with remission in CD with a sensitivity of 84.2% and a specificity of 80%. Patients with a clinical score ≥3 had significantly higher remission rates (88.9%) than those who had persistent disease (27.3%; P = 0.001).

Conclusion: A clinical score of ≥3 predicts remission in CD treated by TSS; however, it requires validation in other large cohorts. Rather than assessing individual parameters to predict remission in CD, an integrated clinical score is a better tool for follow-up and patient counseling ⁶⁾.

Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described.

Patients with CD with surgical remission and surgically treated NFPA.

Measurements: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine-free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests.

The cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed a higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%).

Limitation: The small sample of patients with autoimmune disease limited identification of independent risk factors.

Patients achieving surgical remission of CD have a higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. A family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger ⁷⁾.