Is the increase in Adrenocorticotropic Hormone (ACTH) levels not indicative of corticotroph tumor progression?

Increased ACTH Levels and Corticotroph Tumor Progression

Elevated ACTH levels alone are not sufficient to diagnose corticotroph tumor progression, as they may reflect loss of cortisol feedback inhibition rather than actual tumor growth, particularly in patients on adrenal-targeting medications. 1

Understanding ACTH Elevation After Treatment

• Increased ACTH levels can occur after bilateral adrenalectomy (BLA) or during treatment with steroidogenesis inhibitors due to disruption of the normal cortisol feedback mechanism 1
• Long-term corticotroph tumor progression is a concern in 25-40% of patients after BLA within 5-10 years 1
• With adrenal-targeting agents, ACTH elevation may occur due to interruption of the ACTH-cortisol feedback loop, but this doesn't necessarily indicate tumor growth 1

Monitoring and Diagnosis of Tumor Progression

• Serial pituitary imaging is essential for confirming actual tumor progression, as ACTH levels alone are insufficient 1
• After BLA, plasma ACTH and serial pituitary imaging should be monitored starting 6 months after surgery 1
• For patients on medical therapy (steroidogenesis inhibitors), MRI is typically recommended 6-12 months after initiating treatment and repeated every few years depending on the clinical scenario 1
• More frequent evaluation is necessary if there is clinical suspicion of corticotroph tumor progression 1

Interpreting ACTH Elevation

• ACTH has a short half-life and levels fluctuate naturally, so isolated measurements may not necessarily reflect tumor growth 1
• Significant and progressive ACTH elevations may portend new tumor growth and indicate the need for MRI evaluation 1
• In a documented case, a patient on osilodrostat showed ACTH increase from 73 to 500 pmol/L with tumor growth from 3 to 14 mm over 4 years, despite well-controlled urinary free cortisol levels 2

Management Considerations

• If progressive increase in tumor size is confirmed on imaging, treatment approach should be reassessed 1
• Most cases of corticotroph tumor progression can be managed with surgery, radiotherapy, or medical therapy 1
• A subset of aggressive tumors will continue to grow and require more intensive monitoring and management 1
• Some "silent" corticotroph tumors may have the potential for ACTH secretion leading to hypercortisolemia at a later stage 3

Important Pitfalls to Avoid

• Misinterpreting ACTH elevation as tumor progression without confirmatory imaging 1
• Failing to distinguish between feedback-related ACTH elevation and actual tumor growth 1
• Overlooking the possibility that some corticotroph adenomas may transform to a more aggressive phenotype over time 3
• Not recognizing that some tumors may secrete ACTH precursors that are detected by clinical assays but have limited biological activity 4

Conclusion

While elevated ACTH levels warrant close monitoring, they must be interpreted in the context of serial imaging to confirm actual tumor progression. The combination of significantly rising ACTH levels AND tumor growth on imaging is required to definitively diagnose corticotroph tumor progression.