A Case of the Use of Genomic Signatures in the Diagnosis of Cushing Disease

Case Presentation: A 31 year-old female presented with headaches and left sided facial pain. On exam she was found to have a cranial nerve (CN) VI palsy and some Cushingoid features. MRI revealed a 2.5 cm sellar/suprasellar mass with left cavernous sinus invasion and extension into the superior orbital fissure and optic foramen. Her presentation was concerning for pituitary apoplexy. Due to the need for urgent intervention, her preoperative evaluation was limited but demonstrated elevated random cortisol levels and failure to adequately suppress cortisol with 4 mg dexamethasone (8 am cortisol 2.3 mcg/dL). She subsequently underwent endoscopic endonasal resection which revealed a large sellar, suprasellar tumor with visible normal pituitary pushed to the right side of the cavity. Intraoperative pathology revealed a pituitary adenoma with infarction. The majority of the specimen was necrotic tissue with viable cells staining positive for synaptophysin and negative for all pituitary hormones including ACTH. Whole exome sequencing (WES) of the patient's tumor and blood control showed a USP8 missense mutation. Postoperative MRI at 3 months showed no residual tumor. Patient had resolution of her CN VI palsy and noted a decrease in weight and improvement in acne, AM cortisol normalized, and the remainder of her pituitary hormones were normal.

One year following her surgery, she developed recurrent headaches and left sided facial pain during the first trimester of pregnancy. Soon after delivery, she developed double vision and a third nerve palsy. MRI then revealed a partially hemorrhagic enlarging mass in the left cavernous sinus. Given the rapid tumor expansion, she began radiation therapy and received a total of 52 GY. Her double vision resolved and imaging showed decrease in tumor size. Hormonal evaluation now revealed elevated Urine Free Cortisol, salivary cortisol, ACTH, and failure to suppress with dexamethasone. She was diagnosed with CD and was started on cabergoline but this was discontinued due to persistent hypercortisolism and replaced by pasireotide.

Discussion: Our case highlights the challenge in making an accurate diagnosis of CD. Clinically our patient's history was suspicious, but, since her tumor did not stain for ACTH and since her initial cortisol levels were obtained while on oral contraceptives, a diagnosis of CD was not initially confirmed. On subsequent testing, however, after tumor regrowth, evidence of hypercortisolism was unequivocal.

Mutations in USP8, a deubiquitinating enzyme, have been described in cases of CD. The mechanism for stimulating ACTH production is thought to be due to impaired EGF signaling and increased transcription of the POMC gene that encodes the precursor peptide of ACTH. The presence of USP8 mutation is thought to suggest a more aggressive adenoma with an increased probability of recurrence. In our patient, it appeared to correlate with the patient's course. Our patient's WES result revealing the USP8 mutation, which is only seen in CD, helped confirm the diagnosis of CD where biochemical and pathological methods had initially failed. Molecular diagnosis may become an important adjunct in the diagnosis and management of pituitary tumors as it has become in the field of neuro-oncology.

 

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No conflict of interest has been declared by the author(s).