Subependymal giant cell astrocytoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Overview

Subependymal giant cell astrocytoma is believed to arise from a subependymal nodule present in the ventricular wall of a patient with tuberous sclerosis. Genes involved in the pathogenesis of subependymal giant cell astrocytoma include TSC1 and TSC2. Subependymal giant cell astrocytoma is almost exclusively associated with tuberous sclerosis complex, which is an autosomal dominant disorder. On gross pathology, subependymal giant cell astrocytoma is characterized by a large, fleshy, well-circumscribed intraventricular mass in the wall of the lateral ventricle near the foramen of Monro, that does not invade into the periventricular parenchyma. On microscopic histopathological analysis, subependymal giant cell astrocytoma is characterized by three types of cells (fibrillated elongated spindle cells, swollen gemistocytic-like cells, and giant ganglion-like cells) with nuclear pseudoinclusions and rosettes, perivascular inflammatory cells, and glassy eosinophilic cytoplasm. Subependymal giant cell astrocytoma is demonstrated by positivity to tumor markers such as GFAP, vimentin, S-100, neurofilament, and synaptophysin.

Pathophysiology

Pathogenesis

• Subependymal giant cell astrocytoma is believed to arise from a subependymal nodule present in the ventricular wall of a patient with tuberous sclerosis.
• Subependymal giant cell astrocytoma has both glial and neuronal components.
• The various risk factors that may lead to the transformation of a subependymal nodule into a subependymal giant cell astrocytic tumor include:
  • Diameter above 5 mm
  • Incomplete calcification at the perimonro region
  • Enhancement after gadolinium administration

Subependymal giant cell astrocytoma	Subependymal nodule
Large-sized	Small-sized
Tumor mass grows in size	Remains stable in size
Mass effect	No mass effect
Located in the caudothalamic groove	Located in the ependymal lining of the lateral ventricles along the caudate nucleus
No calcification	Calcification present
Contrast enhancement present	Nonenhancing lesions

• Subependymal giant cell astrocytoma is a major cause of tuberous sclerosis complex-related morbidity and mortality during the pediatrics age, as it is seen in 10 to 20% of these patients.

Genetic

• Development of subependymal giant cell astrocytoma is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of subependymal giant cell astrocytoma include:

• TSC1
• TSC2

• Both the genes, TSC1 and TSC2, are tumor suppressor genes.
• TSC1 is located on chromosome 9q34 and TSC2 is located on chromosome 16p13.
• Protein products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, form a heterodimer that suppresses the mammalian target of rapamycin (mTOR), a major cell growth and proliferation controller. In tuberous sclerosis complex (TSC), increased mTOR activation leads to disorganized cellular overgrowth, abnormal differentiation, increased protein translation, and the formation of tumors.
• Other genes that may be involved in the pathogenesis of subependymal giant cell astrocytoma include:
  • ANXA1
  • GPNMB
  • LTF
  • RND3
  • S100A11
  • SFRP4
  • NPTX1

Associated Conditions

• Subependymal giant cell astrocytoma is almost exclusively associated with tuberous sclerosis complex, which is an autosomal dominant disorder.
• These are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis patients.

Gross Pathology

• On gross pathology, subependymal giant cell astrocytoma is characterized by a large, fleshy, well-circumscribed intraventricular mass in the wall of the lateral ventricle near the foramen of Monro, that does not invade into the periventricular parenchyma.
• Subependymal giant cell astrocytoma typically arises at the caudothalamic groove adjacent to the foramen of Monro.
• Other common intracranial sites associated with subependymal giant cell astrocytoma include:

• Fornix
• Hypothalamus
• Basal ganglia
• Genu of the internal capsule

Gallery

• 
  _{Gross specimen of subependymal giant cell astrocytoma showing a large fleshy mass in the midline and producing marked dilatation of the lateral ventricles.}

Microscopic Pathology

On microscopic histopathological analysis, subependymal giant cell astrocytoma is characterized by:

• Pleomorphic multinuleated eosinophilic cells
• Elongated streams of tumor cells with abundant cytoplasm
• Clustered cells arranged in a perivascular pseudopallisading pattern

• Three types of cells
  • Fibrillated elongated spindle cells
  • Swollen gemistocytic-like cells
  • Giant ganglion-like cells with nuclear atypia
• Nuclear pseudoinclusions and rosettes
• Perivascular inflammatory cells (lymphocytic infiltrate)
• Calcification
• Vesicular nuclei
• Nuclear pseudoinclusions
• Glassy eosinophilic cytoplasm
• Elongated cells in a fibrillary background
• Abundant mast cells
• Endothelial proliferation
• Necrosis

According to the WHO classification of tumors of the central nervous system, subependymal giant cell astrocytoma is classified into a WHO grade I tumor.

Gallery

• 
  _{Typical histology of subependymal giant cell astrocytoma with differentiated giant cells.}

Immunohistochemistry

Subependymal giant cell astrocytoma is demonstrated by positivity to tumor markers such as:

• GFAP (50%)
• Vimentin (100%)
• S-100 (100%)
• Neurofilament (ganglionic component)
• Synaptophysin (ganglionic component)
• TTF-1
• MIB-1 (1-5%)
• MAP-2
• Class III beta-tubulin
• Calbindin 28-kD
• Somatostatin
• Met-enkephalin
• 5-hydroxytryptamine
• Beta-endorphin
• Neuropeptide Y
• Serotonin
• Neuron-specific enolase
• Substance P
• Neural cell adhesion molecule

Gallery

• 
  _{Immunohistochemistry staining of a supependymal giant cell astrocytoma showing positivity to GFAP.}

References

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