Craniopharyngioma—An update on metabolic and cognitive complications and new therapy

Abstract

Craniopharyngiomas (CPs) are rare primary brain epithelial tumors arising in the suprasellar region from remnants of Rathke's pouch. About 50% originate at the level of the third ventricle floor, including the hypothalamus (HT). CPs are characterized by a low proliferation rate and symptoms due to mass effect and local infiltration and are managed primarily with surgery and radiotherapy. Gross total removal of a CP will reduce the recurrence rate but increases the risk of HT damage. Today, subtotal resection is the goal and will reduce the risk of HT damage. There are two histological subtypes of CP—adamantinomatous (ACP) and papillary CP (PCP)—that differ in their genesis and age distribution. ACPs are driven by somatic mutations in CTNNB1 gene (encoding β‐catenin), and PCPs frequently harbor somatic BRAF V600E mutations. There are also two phenotypes of outcome, the one with a rather good outcome without HT damage and the other with HT damage where recurrent operation with additional cranial radiotherapy results in HT obesity (HO), affecting psychosocial life and cognitive dysfunction. The group with HO suffers from metabolic syndrome, lower basal metabolic rate, and leptin and insulin resistances. There is currently no successful treatment for HO. The group with HT damage suffers from cognitive dysfunction with attention deficits, impaired episodic memory, and processing speed. Diffusion tensor imaging has shown significant microstructural white matter alteration in several areas important for cognition. Recently, complete or partial tumor response was shown to targeted therapy, with BRAF and Mekinist inhibitors for PCPs with BRAF V600E mutation.

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification

“…Some studies have suggested that EGFR regulates the mechanism of cellular senescence via excessive activation of RAS and the RAS-BRAF-ERK1/2 signaling axis (Shang et al 2020 ), providing new insights into the regulatory mechanism of EGFR , but further studies are needed to clarify the underlying mechanism of its direct influence. In craniopharyngiomas (CPs), specifically the papillary subtype (PCP), BRAF gene mutations are often detected, potentially leading to cognitive impairments and attention deficits (Erfurth 2023 ). More direct evidence comes from Emily Schroeder et al’s study ( 2016 ), which illustrated in patients with bipolar I disorder that reduced BRAF protein expression in olfactory neuroepithelial progenitor cells (ONPs) can induce apoptosis via the MEK/ERK signaling pathway.…”

Aerobic exercise interventions to address impaired quality of life in patients with pituitary tumors

“…However, even in cases of maximally safe surgical resection and biochemical normalization of pituitary function, several studies have demonstrated decreased activity levels and impaired aerobic adaptation to physical exercise [34][35][36]. While there have been many attempts to study various pharmacologic interventions to address the metabolic disturbances seen in craniopharyngioma patients with hypothalamic injury, there are a lack of data to address impaired quality of life in patients treated for craniopharyngioma with preserved hypothalamic function [37,38]. Given the evidence for decreased physical functioning, a tailored aerobic exercise intervention could be effective in optimizing activity levels and overall quality of life for these patients.…”