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Purpose: Corticotroph tumor progression (CTP) or Nelson's syndrome (NS) can occur in patients with Cushing's disease (CD) following bilateral adrenalectomy. It has rarely been observed in patients treated with long-term medical therapy for persistent CD. Osilodrostat (LCI699) is a new steroidogenesis inhibitor of 11β-hydroxylase (CYP11β1) that induced remission of hypercortisolism in 86% of patients with refractory CD in the randomized placebo-controlled trial LINC-3 (NCT02180217)., Methods: A 40-year-old woman with persistent CD following transsphenoidal surgery was treated with osilodrostat in the LINC-3 trial and was followed with regular hormonal assessments and imaging of residual corticotroph tumor., Results: Under oral therapy with osilodrostat 10 mg twice daily, urinary free cortisol (UFC) normalized and clinical signs of CD regressed during therapy. However after 4 years of treatment, ACTH levels increased from 73 to 500 pmol/L and corticotroph tumor size increased rapidly from 3 to 14 mm, while UFCs remained well controlled. Surgical resection of an atypical tumor with weak ACTH expression and increased proliferative index (Ki-67 ≥ 8%) resulted in current remission but will require close follow-up., Conclusion: This case highlights the importance of monitoring ACTH and corticotroph tumor size in patients with persistent CD, either under effective treatment with steroidogenesis inhibitors or after bilateral adrenalectomy.

It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 μg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 μg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.

The simultaneous occurrence of a hypothalamic and sellar gangliocytoma with a pituitary prolactinoma is very rare. The explanation for such an association is not known. We describe the case of a woman who had a coexisting adjacent pituitary prolactinoma and gangliocytoma within the same sellar mass. The tumor cells of the gangliocytoma demonstrated expression of enkephalin, a product of proopiomelanocortin known to be a prolactin secretagogue. We postulate that in this patient there may be a link between gangliocytoma enkephalin and prolactin hypersecretion.