Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation‒Positive Child

Abstract

Context Inactivating germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are linked to pituitary adenoma predisposition. Here, we present the youngest known patient with AIP-related pituitary adenoma. Case Description The patient presented at the age of 4 years with pituitary apoplexy and left ptosis with severe visual loss following a 1-year history of abdominal pain, headaches, and rapid growth. His IGF-1 level was 5× the upper limit of normal, and his random GH level was 1200 ng/mL. MRI showed a 43 × 24 × 35‒mm adenoma with suprasellar extension invading the left cavernous sinus (Knosp grade 4). After transsphenoidal surgery, histology showed a grade 2A sparsely granulated somatotropinoma with negative O6-methylguanine-DNA methyltransferase and positive vascular endothelial growth factor staining. Genetic testing identified a heterozygous germline nonsense AIP mutation (p.Arg81Ter). Exome sequencing of the tumor revealed that it had lost the entire maternal chromosome-11, rendering it hemizygous for chromosome-11 and therefore lacking functional copies of AIP in the tumor. He was started on octreotide, but because the tumor rapidly regrew and IGF-1 levels were unchanged, temozolomide was initiated, and intensity-modulated radiotherapy was administered 5 months after surgery. Two months later, bevacizumab was added, resulting in excellent tumor response. Although these treatments stabilized tumor growth over 4 years, IGF-1 was normalized only after pegvisomant treatment, although access to this medication was intermittent. At 3.5 years of follow-up, gamma knife treatment was administered, and pegvisomant dose increase was indicated. Conclusion Multimodal treatment with surgery, long-acting octreotide, radiotherapy, temozolomide, bevacizumab, and pegvisomant can control genetically driven, aggressive, childhood-onset somatotropinomas.

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

“…Antiangiogenics has been used in other less common brain tumors. Results obtained with bevacizumab and sorafenib are contradictory and no recommendation about its use can be established [ 100 , 101 , 102 ]. Sunitinib combined with sirolimus, thalidomide, and vorinotad reduced choroid plexus carcinoma size without side effects in one case report [ 103 ].…”

Management of Aggressive Pituitary Tumors – A 2019 Update

“…He thereby remained progression-free during the follow-up of 8 years. Dutta et al presented a 4-year old boy with a giant somatotroph adenoma due to a germline AIP mutation, with immediate progress of a large tumor remnant after surgery [75]. The patient was immediately treated by temozolomide 180 mg/m 2 (5/28 d for 38 months), followed 3 months later by fractionated radiotherapy and initiation of bevacizumab 5-10 mg/kg every 2 weeks (for 35 months), with clear tumor shrinkage but continuous GH excess (intermittently treated by octreotide LAR and/or pegvisomant).…”

The role of the tumour microenvironment in the angiogenesis of pituitary tumours

“…However, research specifically studying the role of the different elements of the TME in the modulation of PitNET neovascularisation is scarce [24], contrasting with the extensive data available for other cancers [25][26][27]. Exploring this further within the context of the complex TME interactions may provide invaluable insights in PitNET pathophysiology and therapeutic advances for aggressive PitNETs, particularly with the employment of anti-angiogenic drugs, such as bevacizumab (an antivascular endothelial growth factor (VEGF) monoclonal antibody) [28,29], or check-point inhibitors [30][31][32]. In this study, we aimed to characterise the role of various TME elements underlying pituitary tumour angiogenesis, focusing on infiltrating immune cells and the PitNET-derived cytokine network.…”