A 61-year-old legal assistant presented to the Endocrinology Clinic with symptoms and signs of cortisol excess. She was found to have extremely aggressive Cushing's disease with recurrence and regrowth within the left cavernous sinus despite two trans-sphenoidal debulking surgeries, three treatments with radiotherapy, two cycles of Temozolomide in conjunction with Ketaconazole and Metyrapone and finally bilateral adrenalectomies. Dosage of medical treatment was limited by adverse side-effects. Pituitary histology was concerning with a high mitotic-count and an elevated Ki67 of 12%. It stained weakly for ACTH, but not for prolactin or Programmed-Cell-Death-1 ligand (PDL-1). She progressed to develop left sided ptosis, a below knee deep venous thrombosis and new fragility vertebral fractures. Retrospective immunohistochemistry staining of her pituitary tumour revealed mismatch repair gene (MMR) mutations, and negative staining for Epithelial Growth Factor Receptor (EGFR). With limited treatment options remaining, she is being considered for PD1-inhibitor and possibly tyrosine-kinase inhibitor therapies.
PD-L1 expression has been measured in pituitary tumours with reports that functional tumours are more likely to express PD-L1, and therefore respond to PD1-inhibitors than non-functional tumours(1). PD1-inhibitors have also been reported to be effective in PD-L1 negative tumours staining for MMR mutations(2). Finally, a large proportion of ACTH-secreting adenomas express EGFR. Tyrosine-kinase inhibitors bind to the tyrosine-kinase domain of EGFR and deactivates EGFR activity(3).
This case highlights firstly the significant morbidity in Cushing's disease. Secondly, in persistent/recurrent Cushing's disease, treatment has largely involved the use of steroidogenic inhibitors, whose therapeutic efficacy has often been limited by adverse effects. Therefore, there remains the need for more effective systemic medical therapies that can target the residual pituitary tissue. PD1- and tyrosine-kinase inhibitors are novel classes of therapy that may be considered in functioning pituitary tumours. However, the role of immunohistochemistry in predicting treatment response in pituitary tumours requires further study.