Anaplastic Astrocytoma: Advanced Neuroimaging, Pathophysiology, Diagnosis, and Treatment Insights from a 43-Year-Old Case Study

Keywords: anaplastic astrocytoma, glioma, brain tumor MRI, magnetic resonance spectroscopy, diffusion tensor imaging, brain cancer treatment, neuroimaging, glioma diagnosis, WHO grade III astrocytoma, brain tumor prognosis

Introduction

Anaplastic astrocytoma (AA) is a malignant, diffusely infiltrating astrocytic tumor classified as WHO grade III under the 2021 World Health Organization (WHO) classification of central nervous system tumors. It represents an aggressive stage in the astrocytoma spectrum, bridging the gap between low-grade diffuse astrocytomas and glioblastomas (WHO grade IV). Despite advances in neuroimaging and molecular diagnostics, the management of AA remains challenging due to its infiltrative growth, molecular heterogeneity, and high recurrence potential.

This article provides a comprehensive overview of pathophysiology, epidemiology, clinical presentation, imaging findings, differential diagnosis, and treatment of anaplastic astrocytoma. It also features an illustrative case study of a 43-year-old male patient, integrating MRI, DTI, and MRS findings for educational and clinical insight.

Case Presentation

A 43-year-old male presented with three weeks of progressive neurological deficits, including right-sided facial weakness, limb weakness, and word-finding difficulty. He had no significant past medical history. A non-contrast CT scan performed in the emergency department revealed a mass-like lesion in the left cerebral hemisphere.

Clinical Findings

Right upper and lower limb weakness
Expressive language difficulty
No seizures or prior neurological history

Initial Imaging

Figure 1. MRI Axial Non-Contrast – shows a mass-like enlargement of the left corona radiata with FLAIR hyperintensity extending toward the internal capsule and thalamus.

The lesion displayed patchy multifocal enhancement on post-contrast MRI and restricted diffusion on DWI, consistent with a high-grade glioma.

Advanced Neuroimaging Findings

Magnetic Resonance Spectroscopy (MRS)

Figure 2. MRS Spectrum – reveals elevated choline (Cho) peaks with reduced N-acetylaspartate (NAA) and creatine (Cr) levels.
This metabolic profile (↑Cho / ↓NAA, ↓Cr) indicates increased membrane turnover and neuronal loss, characteristic of high-grade astrocytomas.

Diffusion Tensor Imaging (DTI)

Figure 3. DTI Tractography – shows marked disruption of white matter tracts within the posterior limb of the left internal capsule. Fractional anisotropy (FA) maps demonstrate signal reduction, suggesting tumor infiltration and corticospinal tract degeneration.

Perfusion-Weighted Imaging (PWI)

Although not shown in this case, perfusion MRI in AA typically reveals increased relative cerebral blood volume (rCBV), indicating neovascularization, a hallmark of malignant transformation.

Pathophysiology

Anaplastic astrocytoma arises from astrocytes, star-shaped glial cells responsible for maintaining neuronal homeostasis, the blood–brain barrier, and synaptic support. In AA, genetic mutations disrupt these regulatory functions, promoting uncontrolled proliferation, invasion, and resistance to apoptosis.

Molecular Mechanisms

According to the 2021 WHO classification, molecular profiling is central to AA diagnosis:

IDH1/2 mutations: Present in 70–80% of adult AAs; associated with better prognosis.
ATRX loss: Suggests astrocytic lineage.
TP53 mutation: Commonly coexists with IDH mutation.
1p/19q codeletion: Its absence distinguishes AA from oligodendroglioma.
MGMT promoter methylation: Predicts response to alkylating chemotherapy (temozolomide).

AA often evolves from low-grade diffuse astrocytoma (WHO grade II) through stepwise genetic progression. Approximately 75% of AAs arise from pre-existing low-grade lesions, while 25% are de novo.

Tumor Microenvironment

The tumor microenvironment is characterized by hypoxia-induced angiogenesis, microglial activation, and extracellular matrix remodeling, which together promote infiltration across white matter tracts and complicate complete surgical resection.

Epidemiology

Anaplastic astrocytoma accounts for approximately 4% of all malignant CNS tumors. The annual incidence is fewer than 1 per 100,000 population, with a male-to-female ratio of 3:2. The peak incidence occurs between 40 and 50 years of age.

Risk Factors

Genetic syndromes: Li-Fraumeni syndrome (TP53 mutation), neurofibromatosis types 1 and 2, and tuberous sclerosis.
Environmental factors: Ionizing radiation exposure, especially during childhood.
No clear link with viral infection or chemical carcinogens has been consistently demonstrated.

Clinical Presentation

The clinical features of AA depend on tumor location and size. Symptoms usually evolve over weeks to months, reflecting the subacute nature of its progression.

Common Manifestations

Focal neurological deficits: weakness, aphasia, or visual field loss.
Seizures: observed in up to 40% of patients.
Cognitive decline and behavioral changes.
Headache and nausea: due to raised intracranial pressure.

In this case, the patient’s right-sided weakness and language difficulty correlated with a lesion in the left corona radiata and internal capsule, affecting corticospinal and language pathways.

Neuroimaging Features

Conventional MRI

AA typically appears as:

T1-weighted: hypointense relative to white matter
T2/FLAIR: hyperintense, often with heterogeneous signal intensity
Contrast enhancement: patchy or ring-like; indicates breakdown of the blood–brain barrier
Mass effect and edema: variable, depending on tumor volume

Figure 4. MRI Post-Contrast – demonstrates irregular enhancement within the left deep white matter extending into the thalamus and midbrain, consistent with infiltrative high-grade glioma.

Advanced MRI Techniques

1. Diffusion Tensor Imaging (DTI):
Depicts microstructural disruption of white matter. Reduced FA and abnormal color-coded directionality reflect fiber disorganization and infiltration.

2. Perfusion-Weighted Imaging (PWI):
Increased rCBV and rCBF (relative cerebral blood flow) due to neovascular proliferation.

3. MR Spectroscopy (MRS):
Cho/NAA ratio elevation (>2.0) suggests high cellular turnover. Lactate and lipid peaks may indicate necrosis and hypoxia.

4. Diffusion-Weighted Imaging (DWI):
Restricted diffusion areas correlate with high tumor cellularity.

Differential Diagnosis

Cerebral metastasis – Usually multiple lesions with well-defined margins; peritumoral edema is more pronounced.
Tumefactive demyelination – May mimic glioma on MRI but lacks elevated Cho and has open-ring enhancement.
Subacute infarction – Shows restricted diffusion but lacks mass effect or prolonged enhancement.
Other gliomas – Differentiation from glioblastoma (grade IV) relies on histologic evidence of necrosis and microvascular proliferation.

Diagnosis

Definitive diagnosis requires histopathological and molecular analysis following stereotactic biopsy or surgical resection.

Histologic Features

Nuclear atypia and pleomorphism
Mitotic activity
Absence of necrosis (distinguishes from glioblastoma)
Increased cellularity with astrocytic morphology

Molecular Criteria (WHO 2021)

Marker	Diagnostic Relevance
IDH mutation	Defines subtype (IDH-mutant vs. IDH-wildtype)
ATRX loss / TP53 mutation	Supports astrocytoma lineage
1p/19q codeletion	Excludes oligodendroglioma
MGMT methylation	Predicts better chemotherapeutic response

Treatment

Management of AA is multimodal, integrating surgery, radiation, and chemotherapy, tailored to molecular subtype and patient performance status.

1. Surgical Resection

Goal: maximal safe resection while preserving neurological function.
Intraoperative DTI tractography aids in delineating tumor margins and sparing eloquent pathways.
Extent of resection strongly correlates with survival.

2. Radiotherapy

Standard dose: 59.4–60 Gy in 1.8–2.0 Gy fractions.
Often combined with concurrent or adjuvant chemotherapy.

3. Chemotherapy

Temozolomide (TMZ) remains the mainstay, particularly in MGMT-methylated tumors.
Alternative regimens: Procarbazine, Lomustine, Vincristine (PCV regimen) for recurrent disease.
Clinical trials are evaluating IDH inhibitors, PARP inhibitors, and immunotherapy.

4. Emerging Therapies

Tumor Treating Fields (TTF): electric-field therapy to disrupt tumor mitosis.
Vaccine and cellular therapies: under investigation for IDH-mutant gliomas.
Precision medicine approaches: gene sequencing to identify actionable mutations.

Prognosis

Despite aggressive therapy, AA carries a guarded prognosis.

Factor	Influence on Outcome
Age <50 years	Favorable
Extent of resection	Major survival determinant
IDH mutation / MGMT methylation	Better prognosis
Karnofsky Performance Score (KPS)	Predicts tolerance and survival

Survival

Median overall survival: 2.5–3 years
5-year survival rate: ~28%
Progression to glioblastoma occurs in most cases within 2–3 years.

Karnofsky Performance Scale

A functional scoring system to assess patient independence:

100 – Fully active, no symptoms
80 – Normal activity with effort
50–70 – Requires occasional assistance
10–30 – Disabled, requires special care
0 – Death

Quiz Section

Question 1. Which MRI sequence best highlights the infiltrative lesion in anaplastic astrocytoma?

A. Brainstem T1
B. Cortical grey matter
C. Subcortical white matter
D. Thalamus

Question 2. In MR spectroscopy of anaplastic astrocytoma, which metabolite pattern is most characteristic?

A. Normal NAA, Cr, and Cho peaks
B. Reduced NAA and Cr; elevated Cho
C. Reduced Cho and increased NAA
D. Elevated lactate with normal Cho

Question 3. Which molecular alteration is most predictive of better prognosis in anaplastic astrocytoma?

A. TP53 mutation
B. IDH1 mutation
C. ATRX loss
D. EGFR amplification

Answer & Explanation

1. Answer: C. Subcortical white matter. Explanation: FLAIR images show diffuse hyperintensity within subcortical white matter, typical of infiltrative gliomas.

2. Answer: B. Reduced NAA and Cr; elevated Cho. Explanation: This reflects increased membrane turnover (↑Cho) and neuronal loss (↓NAA), typical of high-grade gliomas.

3. Answer: B. IDH1 mutation. Explanation: IDH-mutant AAs are associated with longer survival and better response to therapy compared to IDH-wildtype forms.

Conclusion

Anaplastic astrocytoma represents a critical juncture in glioma progression, bridging low-grade and glioblastoma phenotypes. Comprehensive diagnosis integrating advanced MRI (DTI, MRS, perfusion) and molecular profiling (IDH, ATRX, MGMT) is essential for prognosis and treatment planning. While current multimodal therapy improves survival, molecular-targeted and immunotherapeutic strategies hold promise for the next generation of personalized neuro-oncology.

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