As astrocytes are the most plentiful cell in the human central nervous system (CNS), it is not entirely surprising that astrocytomas are the most common form of primary malignant brain tumors in both adults and children [1–3]. Lacking the ability to produce electrical depolarization, astrocytes are often described as star-shaped glial cells that support the function of neurons [4]. Astrocytes have a plethora of roles in the CNS, including blood-brain barrier (BBB) development and maintenance, water and ion regulation, influencing neuronal synaptogenesis, and stimulating immunological response [4, 5]. The exact function and morphology of the astrocyte may be primarily determined by the spatial domain the cell occupies within the brain and the surrounding population of astrocytes [6, 7].

The clinical presentation of astrocytoma symptoms is similar to most brain tumors with both focal and generalized neurologic signs. Focal symptoms include weakness, numbness, seizures, and aphasia, while generalized symptoms due to edema and increased intracranial pressure can cause headaches, vision deficits, and emesis [8, 9]. Diffuse headaches present at diagnosis in 50% of patients, with seizures observed in 20–40% of patients [10].

Radiation, chemotherapy, and surgical resection play a role in the medical management of both low- and high-grade astrocytomas to alleviate symptoms, improve prognosis, and prevent malignant transformation [11, 12]. By summarizing the current understanding of astrocytomas, this paper strives to consolidate and clearly explain the accepted medical and surgical management of this condition to better educate the reader.

Glioblastoma (GB) is both the most common astrocytoma and the most malignant, accounting for roughly 65% of astrocytomas [8, 13]. Based on 2003–2007 data gathered from region-specific populations over 40 years old, the age-adjusted incidence rate of astrocytic tumors per 100,000 is highest in Australia [9.58, 95% confidence interval (CI) = 9.30–9.86], Western Europe (8.45, 95% CI = 8.30–8.59), and Canada (8.26, 95% CI = 8.04–8.48), with lowest rates in Southeast Asia (1.91, 95% CI = 1.75–2.08) [14]. These trends in astrocytoma incidence based on the region are summarized in Figure 1.

When examining 244,808 patients with gliomas from 2000–2014, there was a higher incidence of astrocytomas in non-Hispanic whites compared to Hispanic whites (30% lower), blacks (52% lower), or Asians (52% lower) [15]. Overall, epidemiological studies have indicated an increased incidence of astrocytomas in males compared to female populations [16]. This sex preference is especially prominent in the development of GB, with an incidence 60% higher in both male children and adults [15–17]. Elevated levels of testosterone and activation of androgen receptors on cancer cells are believed to play significant roles in the increased incidence of male GB, while the protective benefit of progesterone and estrogen has also been theorized [18–20]. With the exception of low-grade pilocytic astrocytomas (PAs) that typically present in pediatric populations, the majority of astrocytomas are observed sporadically in adulthood after the age of 40 without a familial association [14, 21, 22]. While the mortality rate varies with different grades of astrocytomas and mutations present, GB has a median survival of 15 months with treatment and a 3-year survival rate of 3–5% [23]. There are numerous factors associated with improved overall survival rate, including female sex, younger age of diagnosis, lower comorbidity burden, presence of O⁶-methylguanine-DNA methyltransferase (MGMT) methylation in tumor genetics, reduced tumor size, single lesion, complete tumor resection, chemotherapy, and radiation treatment [24]. Although it could be explained by the patient population and socioeconomic elements, there appears to be a trend towards superior 30–90 day mortality and reduced readmission rates in academic research and high-volume facilities compared to community and integrated network cancer programs [24].

Therapeutic ionizing radiation exposure is one of the few environmental risk factors with a strong correlation with increased incidence of astrocytomas and other glioma formation [25]. Surprisingly, cigarette smoking and alcohol consumption have not been associated with higher rates of astrocytomas as observed in many other forms of cancer [26]. Although the risk factors of astrocytoma are poorly understood, germline genetic variants contribute significantly to the risk of developing gliomas like astrocytomas. For example, some genetic syndromes [Cowden, Lynch, Turcot, Li-Fraumeni, neurofibromatosis type 1 (NF1)] have been identified as potential risk factors. Conditional inactivation of NF1, phosphatase and tensin homolog (PTEN), and tumor protein p53 (TP53) tumor suppressor genes in murine models has induced the formation of malignant astrocytomas [27, 28]. Carlos-Escalante et al. [29] found an association between genetic variants in angiotensinogen (AGT, involved in angiogenesis), TP53 (tumor suppressor), and MGMT (DNA repair) and the risk of developing astrocytoma in a case-control study performed in 49 Mexican patients.

Another genetic association involves B-Raf proto-oncogene (BRAF) abnormalities, in which tandem duplication-rearrangements and BRAF V600E mutations are observed in PA and pleomorphic xanthoastrocytoma, respectively [30]. The most common glial tumor in children is PA. While sporadic cases are associated with BRAF rearrangements, 15–20% of children develop PA in the context of NF1 [31]. The most common tumor in NF1 patients is the optic pathway tumor, also known as optic glioma. Although these are rare tumors (2–5% of childhood brain tumors), up to 70% are associated with NF1 [32]. Most of these tumors are grade I PAs. These tumors form within the optic pathway and brainstem to then expand into the optic nerve, producing a fusiform mass [27, 33, 34].

Certain genetic markers have been associated with worse prognosis. Perdomo-Pantoja et al. [35] conducted a prospective study on 48 patients diagnosed with astrocytoma and proposed that the genetic variant AGT reference single nucleotide polymorphism 5050 (rs5050) GG-genotype can be detected safely and practically in blood/saliva samples and was identified as a risk factor for lower survival rates. Other genes [ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), cytochrome P450 family 19 subfamily A member 1 (CYP19A1)] have also shown an association with worse prognosis [36].

As astrocytomas, like all cancers, are the unregulated overgrowth of cells brought about by changes in genetic expression, genetics play a significant role in astrocytoma advent, evolution, and treatment [37]. While some cancer states are strongly linked to specific genes, such as Li-Fraumeni with TP53 and breast and ovarian cancers with breast cancer 1 (BRCA1)/BRCA2, other cancers, such as astrocytomas rest at the intersection of a combination of genes [38, 39]. Significant research on the genetics of astrocytomas focuses on isocitrate dehydrogenase 1 (IDH1) and MGMT.

IDH1 and IDH2 are genes that encode nicotinamide adenine dinucleotide phosphate (NADP⁺)-dependent IDHs which convert isocitrate to alpha-ketoglutarate [40, 41]. This activity plays a role in cellular processes affecting lipid synthesis, oxidative respiration, and signal transduction [42, 43]. The R132H mutation in IDH1 can lead to the transformation of alpha-ketoglutarate into 2-hydroxygluterate (2HG) [44]. Aberrations in IDH1/2 as well as the accumulation of 2HG have been linked to a multitude of cancers, including astrocytomas like GB [42, 44, 45]. While their presence is not ubiquitous in primary GB (5%), mutations in IDH1 are prevalent in secondary GB (80%) [46].

Extensive exploration into the link between IDH1 and gliomas has led to a deeper understanding of the influence of IDH1 on current treatments. Investigation of this relationship has also opened the door for targeted therapeutic interventions. Mutation of IDH1 has proven to be a strong prognostic indicator in gliomas [45, 46]. Studies have shown better responses to treatment and improved outcomes in patients with IDH1 mutated GB and anaplastic astrocytoma (AA) [46, 47]. Therapies targeting IDH1-specific mutations including hypomethylating agents, IDH enzyme inhibition, and vaccination are being investigated with promising early findings [42].

MGMT is another gene that’s been shown to influence patient response to treatment in astrocytoma. MGMT encodes a protein that repairs alkylated DNA via the transfer of a methyl group [48]. Temozolomide (TMZ) is an alkylating agent that has been a stalwart therapy in the treatment of astrocytoma [49]. As such, functional MGMT repairs damage caused by the alkylation of DNA by drugs like TMZ and can lead to drug resistance in tumors [50]. While the loss of function of MGMT via methylation is associated with different cancers, it is also associated with improved patient outcomes in the treatment of astrocytomas [48, 51, 52]. Studies have shown a significant association between methylated MGMT and longer survival as well as decreased tumor size over the course of treatment [51, 52]. Of note, there is no current consensus on the amount of methylation that distinguishes methylated from unmethylated MGMT. The mechanism of the improved outcome of TMZ treatment in MGMT-inhibited tumors is summarized in Figure 2 [53].

While the BBB normally restricts immune cell access to the brain, malignancy in the brain often creates a privileged environment where leukocytes are granted access [54]. Despite that, often times immune response in brain tumors is limited by patient immunodeficiency or immunological escape of the cancer [54]. Immunological escape is a phenomenon whereby tumors elude immune action [55]. There are a few forms of immune escape exhibited by astrocytomas, including the restriction of antigen presentation via the downregulation of major histocompatibility complex (MHC) expression [56]. Other methods include the facilitation of cell death in leukocytes by increasing Fas-ligand expression, and secretion of immunosuppressive cytokines like transforming growth factor-β (TGF-β), and interleukin-10 (IL-10) [57, 58]. As immunological escape and immune suppression increase the difficulty of treating astrocytomas, genetically modified immune cells and augmentation of the immune response are of particular interest in the treatment of astrocytomas [59]. Of note, these methods may run the risk of autoimmunity.

When examining GB mutation distribution based on sex, there appears to be a trend toward higher subclonal mutation burden in the majority of glioma subtypes of biological females over males [60]. Additionally, some mutations observed in astrocytomas appear to express some level of male or female preference. For example, mutations in the signaling pathway of mitogen-activated protein kinase (MAPK) tend to occur more often in the GB of biological female patients [60]. In the case of gliomas with mutations of the phosphoinositide 3-kinase (PI3K) pathway, these genetic changes occur more frequently in the helical domain for females and the kinase domain for males, demonstrating a sex preference for mutation location [61]. The increased mutation burden could be explained by increased mutations on the X chromosome, or potentially by different environmental exposures that may be more sex-specific.

As genetics play a significant role in the development and progression of astrocytomas, further investigation into the influence of specific genes may illuminate a pathway to better understand and more effectively treat the disease.

The grading of astrocytomas is based on histological observations and cellular markers [62]. The following presents a discussion on some of the most common locations for each lesion type and prognosis based on tumor grading. The grading type and location are summarized in Table 1.

Magnetic resonance imaging (MRI) maintains a significant role in the standard of care among patients diagnosed with astrocytomas, especially as MRI has evolved to incorporate functional, hemodynamic, metabolic, cellular, and cytoarchitectural modalities [93]. Malignant gliomas typically demonstrate strong contrast enhancement, peritumoral edema [evident on T2-fluid-attenuated inversion recovery (FLAIR) sequences], mass effects, heterogeneity, central necrosis, and intratumoral hemorrhage on conventional MRI [94–97]. In contrast, low-grade astrocytomas often present as well-defined homogeneous masses with little or no mass effect, vasogenic edema, or enhancement after contrast administration on conventional MRI [94–96]. Yet, distinguishing low-grade astrocytomas from high-grade astrocytomas and metastases using conventional MRI findings alone is not always possible, as overlapping features may persist [98, 99]. The distinctions that exist between high- and low-grade astrocytomas when observed on different MRI modalities are summarized in Table 2.

Within GB management, functional MRI (fMRI) has utility pre-operatively, particularly when resection may disrupt eloquent areas [97]. Notably, patients with tumors previously deemed unresectable have become candidates for a more aggressive surgical resection following the utilization of advanced MRI sequences and functional mapping. Diffusion tensor imaging (DTI) can assist in distinguishing between postoperative vascular damage and residual enhancing tumor [100, 101]. Serving a predictive role, DCE can pre-operatively measure contrast uptake, which may be associated with early disease progression [102]. Dynamic susceptibility contrast (DSC) can indicate tumor capillary permeability and neoangiogenesis, factors useful in characterizing glioma type, grade, and tumor recurrence after treatment [103].

In 2019, Bulakbaşı and Paksoy [104] utilized advanced MRI techniques including SWI, DWI, PWI, MRS, and fMRI to differentiate low- and high-grade gliomas. ADC is determined using DWI, rCBV is approximated using PWI, K^trans is determined using DCE, ITSS is calculated using SWI, and metabolic markers (i.e., Lip-Lac/ Cr and Cho/Cr) can be measured using MRS. Their study suggested low-grade gliomas have lower cellularity (high ADC), decreased angiogenesis (low rCBV), decreased capillary permeability (high K^trans), and decreased mitotic activity (Cho/Cr), thus supporting the use of advanced MRI techniques in the differentiation of astrocytomas [104]. Challenges in utilizing these advanced MRI techniques include the diversity of imaging equipment and techniques available, as standardization is currently lacking across facilities [104].

de Fatima Vasco Aragao et al. [99] evaluated the application of advanced MRI sequences using DWI, PWI, and MRS in differentiating PAs from high-grade astrocytomas. Their study suggested lower rCBV from PWI and higher ADC on DWI were suggestive of PAs, whereas higher Lip-Lac/Cr and Cho/Cr ratios on MRS favored high-grade astrocytomas [99, 104]. The accuracy of MRS in glioma grading is controversial, particularly as many studies have not included the broad range of low-grade gliomas (particularly PAs) [99]. Additionally, MRS patterns do not necessarily translate between adults and children, as is particularly notable in PAs [105].

Per a 1991 study by Krouwer et al. [106], as low as a 5% gemistocytic component within a patient’s astrocytoma is sufficient to negatively impact prognosis. In 2016, Simkin et al. [107] described the use of MRI in diagnosing gemistocytic astrocytomas. Specifically, gemistocytic astrocytoma evaluation should be considered in patients with heterogeneous cystic lesions that display contrast enhancement and partial FLAIR suppression [107]. Recent literature has emerged on the use of MRI to predict tumor grade in IDH-mutant astrocytomas and oligodendrogliomas [108]. Joyner et al. [108] suggest a positive association between contrast enhancement and the grade of astrocytomas as well as oligodendrogliomas. Additionally, their study suggests a negative association with ADC and a positive association with rCBV in predicting astrocytoma grade, but not oligodendroglioma grade [108].

Over the last 50 years, radiotherapy (RT) has been a key therapy in astrocytoma management, as an integral component of multimodal treatment alongside surgical and medical considerations [109]. Initial clinical trials in patients with malignant gliomas, including high-grade astrocytomas, utilized whole-brain RT (WBRT) in conjunction with surgical resection. The combination of WBRT using 5,000–6,000 rad in addition to surgical resection of malignant gliomas revealed significant survival benefit in comparison to surgical resection alone [110, 111]. Studies led by the Brain Tumor Study Group (BTSG) from the National Cancer Institute (NCI) examined the relationship between increasing WBRT dose titration and median survival [112]. Patients receiving doses of 5,000–6,000 rad demonstrated significantly longer median survival, compared to patients randomized to no radiation [112].

With the advent of more targeted approaches in radiation oncology such as stereotactic radiosurgery (SRS), new techniques, protocols, and recommendations have emerged for studying and treating astrocytoma. SRS differs from WBRT in numerous ways, but the most important distinction is the high degree of precision SRS has directed against cancerous lesions while sparing healthy tissue [113]. SRS typically refers to multisource cobalt-60 gamma radiation or linear accelerator (LINAC)-based photon therapy [114]. Radiation Therapy Oncology Group (RTOG) 93-05 trial evaluated the use of standard RT with TMZ compared to SRS with TMZ and results demonstrated comparable overall survival between both arms. PFS, complete and partial response rates did not significantly differ, but significantly higher toxicity was observed in the standard RT with TMZ arm [113, 115]. Like other focal regimens, SRS has not produced a significantly different survival advantage relative to standard RT [116]. Other roles for SRS may exist, such as salvage therapy for recurrent astrocytoma and as an adjuvant to systemic immunotherapy, but further elucidation of this role is necessary through pre-clinical studies and randomized controlled trials (RCTs) [117, 118].

Evidence-based guidelines for use of RT in treating high-grade astrocytoma have been established by the American Society for Radiation Oncology (ASTRO). Regarding ideal target volumes for RT against GB, ASTRO issued a “strong recommendation” for partial brain radiation therapy directed against brain areas with the highest recurrence risk, namely within 2 cm of the primary site [119]. This recommendation was supported by evidence indicating that partial brain RT did not decrease survival relative to WBRT [119]. Additionally, a “strong recommendation” was issued for two RT strategies for high-grade astrocytoma: (1)

Two-phase strategy utilizing RT against the primary target volume encompassing edema and gross residual tumor/resection cavity plus a boost target volume encompassing gross residual tumor/ residual cavity [119].

Guidelines issued by the European Association for Neuro-Oncology (EANO) present similar recommendations as ASTRO for various subtypes of astrocytoma. Depending on various prognostic factors, the mainstay radiation recommendation is focused RT with a 1–2.5 cm margin, with SRS suggested as an option in the recurrent setting to improve the delivery of therapy against cancerous lesions and sparing healthy structures [120].

Guidelines for RT for low-grade astrocytoma were examined and issued by the Spanish Society of Medical Oncology, regarding timing and dosage. Early RT demonstrated a significant increase in PFS, but no difference in overall survival. Based on level I evidence, high and low doses of radiation were demonstrated to be equivalent, with lower doses minimizing radio-necrosis and toxicity [121].

Despite survival benefits with multimodal management of astrocytomas, iatrogenic toxicities and adverse events do exist and afflict patients both short- and long-term. Among the various clinical trials cited in this review, RT-related toxicities and adverse events include but are not limited to infection, worsening neurologic status and late cognitive decline, and significantly worsening Karnofsky performance scores [115, 123, 143]. Related to the use of chemotherapies such as TMZ, toxicities and adverse events include, but are not limited to hematologic toxicities and myelosuppressive effects such as neutropenia, anemia, thrombocytopenia, and lymphopenia [115]. Other adverse effects include moderate-to-severe fatigue, deep vein thrombosis, pulmonary embolism, and severe pneumonia [115]. The use of bevacizumab in patients with GBs exhibited numerous toxicities such as hypertension, leukopenia, thromboembolic events, non-CNS, and CNS hemorrhage [144]. The combination of lomustine and bevacizumab demonstrated similar toxicities to other chemotherapies used to treat astrocytomas [145]. These toxicities include leukopenia, intracranial hemorrhage, serious thromboembolic events, hypertension, liver toxicity, and limited gastrointestinal side effects [145]. In patients that are candidates for re-irradiation due to recurrence, some studies have found rates of neurologic toxicity related to radiation necrosis ranging from 5–20% among patients following SRS, while others have found high rates of therapy tolerance and few adverse events [143, 146]. Overall, each treatment comes with its own unique risks and potential reduction in quality of life.

With unique intrinsic factors and a privileged microenvironment, astrocytomas continue to remain an elusive target for new therapeutic options. One of the reasons it has been challenging to develop new treatments for astrocytomas is the need to penetrate the BBB [192]. The BBB consists of a highly selective semipermeable border of endothelial cells, through which most conventional drugs cannot pass [193]. The selectivity of the BBB is one of the reasons that TMZ remains the standard chemotherapeutic agent in the treatment of astrocytomas. TMZ is able to cross the BBB due to its small size and lipophilic properties [194]. Two recent developments have shown promise in facilitating transport through the BBB [195, 196]. One of these is convection-enhanced delivery (CED), a technique in which a pressure gradient is generated at the tip of an infusion catheter allowing therapeutics to be delivered through the interstitial space into the CNS [195]. Since the development of CED in the 1990s, there have been many advancements over the years. Although CED in its current state has limited anti-tumor effects for astrocytomas, it may show promise in the near future with many current clinical trials seeking to improve the technique [197, 198]. Another method to cross the BBB employed by Gregory et al. [196] is nanoparticle technology. Researchers engineered a synthetic protein nanoparticle (SPNP) based on human serum albumin along with internalizing arginine-glycine-aspartic acid (iRGD) for cell penetration. An in vitro study using this SPNP against signal transducer and activator of transcription 3 inhibitor (STAT3i) in mice found that tumor regression and long-term survival were increased in mice with GB [196]. STAT3i downregulates signal transducer and activator of transcription 3 (STAT3), which impairs anti-tumor immunity and enhances tumor progression [196, 199]. As such, this technology shows promise for the treatment of high-grade astrocytomas.

Another challenge in developing new therapies for astrocytomas is the tumor microenvironment. Astrocytomas invade the CNS, an immune-privileged site. This has been a significant obstacle in the development of effective immunotherapies. In recent years, immunotherapy treatments such as chimeric antigen receptor (CAR)-T cell therapy, monoclonal antibodies against programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been approved by the FDA for the treatment of various cancers [200–202]. However, currently, there are no immunotherapy drugs approved by the FDA for the treatment of astrocytomas [203]. With current clinical trials that seek to improve the shortcomings of CAR-T cell, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies in regard to the treatment of astrocytomas, these immunotherapy drugs may show promise in the future. Additional immune checkpoints that are being explored as potential targets for treatment are cluster of differentiation 47 (CD47) and CD73 [203]. CD47 blockade has shown to be effective against GB in vitro and in animal models, however, clinical trials have not yet been conducted on this immunotherapy target [204]. CD73 pathway targeting agents are now reaching clinical trials and may prove successful as a target for immunotherapy [205]. Other immunotherapy options that are being developed for the treatment of astrocytomas are vaccine therapies including dendritic cell-based vaccines, heat shock protein vaccines, peptide vaccines, and viral-based vaccines [192].

Astrocytomas often have high recurrence rates and may be resistant to chemotherapy and radiation therapy. One of the reasons behind this high recurrence rate may be glioma stem cells (GSCs) which allow for tumorigenicity and stem-cell renewal [203]. Additionally, different types of astrocytomas present with molecular heterogeneity, making it difficult to develop targeted therapeutics [206]. Despite this molecular heterogeneity, targeted therapies may show promise against specific astrocytomas. As discussed previously, some astrocytomas have been found to contain the BRAF V600E mutation, with the highest rate of the mutation found in pleomorphic xanthoastrocytomas [30]. Studies evaluating the use of BRAF V600E kinase inhibitors in various astrocytomas have had interesting results [207, 208]. A basket trial by Kaley et al. [207] looking at the BRAF V600E kinase inhibitor vemurafenib found that patients with pleomorphic xanthoastrocytomas responded best to the drug, while patients with other astrocytomas had variable response. Unfortunately, high-grade astrocytomas tend to have low rates of the BRAF V600E mutation, which may limit the application of vemurafenib and other BRAF V600E kinase inhibitors to a subgroup of astrocytomas [209]. An additional targeted therapeutic that shows potential against high-grade astrocytomas is Erdafitinib, a tyrosine kinase inhibitor of fibroblast growth factor receptor 1–4 (FGFR1–4) [208]. This drug is currently in phase II clinical trials (NCT04083976). Inhibitors of the mutated form of IDH may also prove beneficial against astrocytomas that display this mutation. Potential therapeutics against astrocytomas with mutant IDH1 include AG-5198 and ivosidenib. Additionally, enasidenib may prove to be a potential therapeutic against astrocytomas with mutant IDH2 [206].

Staging based on physical and genetic characteristics, imaging, RT, chemotherapy, surgical management, and targeted therapies all serve an integral function in the understanding and management of astrocytomas. Genetic mutations and a variety of imaging modalities are playing an increasingly more important role in the staging and consideration of treatment approaches for astrocytomas. With the ever-increasing interest in targeting the mechanism of each mutation that drives tumor formation, genetic characterization and targeted therapies for astrocytoma treatment will likely continue to develop in conjunction with surgical and radiation therapy. While not always improving the speed and efficiency of surgery, the newest surgical techniques may dramatically improve the field of resection and most importantly improve mortality and quality of life.