Brainstem gliomas (BSGs) account for approximately 20% of primary tumors of the central nervous system in pediatric patients; however, in adults, they are rare, and represent less than 2% of all neoplasms occurring at this site (Grimm and Chamberlain, 2013, Smith et al., 1998, Reyes-Botero et al., 2014, Theeler et al., 2015, Ramos et al., 2013).

Gliomas occurring in the brainstem are heterogeneous in both adults and pediatric patients and include tumors showing either a diffuse or circumscribed growth pattern.

Adult brainstem tumors are most frequently found in the pons (60%−63%), with occurrences also in the medulla oblongata (25%) and the midbrain (12%−15%). In up to 80% of cases, a combination of these brainstem regions is affected. Brainstem gliomas in adults typically have been subdivided based on clinical and radiographic characteristics into diffuse intrinsic, low-grade brainstem gliomas; focal, malignant brainstem gliomas; focal, tectal gliomas; and exophytically growing tumors (Eisele and Reardon, 2016; Guillamo, 2001). Despite similarities in clinical presentation and radiographic appearance, the prognosis varies widely between adult and pediatric brainstem gliomas (BSGs). These differences may reflect distinct histological and molecular features between age groups, regardless of the radiological tumor appearance, including lesion site and contrast enhancement. Given the challenging location and potential diagnostic uncertainty, the importance of surgical biopsy and pathologic confirmation cannot be overstated in guiding subsequent management decisions (Eisele and Reardon, 2016).

The only circumscribed glioma reported to occur in the brainstem is pilocytic astrocytoma (Yang et al., 2022), which is classified as grade 1 by the World Health Organization (WHO) (Louis et al., 2021) (Table 1). All the three types of so-called “adult-type” diffuse gliomas were reported in the brainstem of adult patients. Among these, glioblastoma (GBM) IDH-wildtype (classified as grade 4 by the WHO), is the most frequently occurring in the brainstem (Zhou et al., 2021), whereas IDH-mutant astrocytomas (grade 2, 3, or 4) are less common, and oligodendroglioma IDH-mutant and 1p/19q codeleted (grade 2 or 3) are exceptional at this site (Zhou et al., 2021, Hodges et al., 2015). Among the so-called "pediatric-type" low-grade diffuse gliomas, angiocentric glioma (WHO grade 1), diffuse astrocytoma MYB- or MYBL1-altered (WHO grade 1), and MAPK pathway-altered diffuse gliomas (which are currently considered as low-grade tumors) may rarely occur in the brainstem of children (Chan et al., 2017, Ryall et al., 2020), but epidemiological data in adults are currently lacking. With regard to pediatric-type high-grade diffuse gliomas, diffuse midline glioma H3 K27-altered, which is classified WHO grade 4 owing to its dismal prognosis (Kesari et al., 2008, Guillamo et al., 2001, Reithmeier et al., 2014), can also occur in the brainstem of adults (Zhou et al., 2021, Eschbacher et al., 2021, Manjunath et al., 2021). Nonetheless, epidemiological data are scarce owing to the recent description of this tumor type. Finally, diffuse pediatric-type high-grade glioma IDH- and H3-wildtype, classified as grade 4, has been identified in the brainstem in children (Korshunov et al., 2017), whereas epidemiological data in adults are not available.

Since the majority of BSGs in adults are high-grade, they are commonly regarded as aggressive and fatal diseases (Eisele and Reardon, 2016). Defining adequate treatment options for adult BSGs is extremely challenging, mainly because of their rarity and absence of prospective clinical trials. As a result, current therapeutic options for are limited.

Despite significant advancements in surgery and radiotherapy, the prognosis remains extremely poor, with a median overall survival (OS) of 24.1 months and 5-year OS rate of only 11.8% (Babu et al., 2014, Maxwell et al., 2018). Adult BSG prognosis is influenced by a wide range of factors, including clinical, radiological, surgical, and molecular factors. According to several studies, the presence of contrast enhancement or necrosis on magnetic resonance imaging (MRI) scans, as well as an infiltrative growth pattern, are strongly associated with poor prognosis and low survival rates (Kesari et al., 2008, Guillamo et al., 2001, Reithmeier et al., 2014). Additionally, older age has been linked to worse clinical outcomes, which may be attributed to a higher incidence of high-grade lesions (HGG) (WHO grade 3 and 4) in elderly patients than in younger patients.

The optimal management of adult BSG is debated and poorly defined (Babu et al., 2014, Faulkner et al., 2021, Leibetseder et al., 2022). Before the advent of MRI, BSGs were considered malignant and unresectable. In recent decades, with the advancement of neuroradiological, anesthesiological, neurophysiological and neurosurgical techniques, a growing number of investigations has demonstrated that focal lesions may benefit from surgical resection with favorable clinical outcomes. Considering the difficulty in planning prospective clinical trials, the role and the optimal schedule of both radiotherapy and chemotherapy in the treatment of adult BSGs remain unclear.

The purpose of this review was to provide an updated overview of treatments for adult BSGs, emphasizing the importance of interdisciplinary management. This study considers the primary pathological features and novel molecular stratification of BSGs and their prognostic value. Moreover, the roles of surgery, or radiotherapy and emerging targeted therapies in terms of safety and impact on OS have described. To ensure a rigorous and comprehensive analysis, we conducted a thorough systematic multidisciplinary review to summarize the results according to the class of evidence (CE) and the strength of recommendation (SR).