Nervous System Neoplasms: Classification & Grading

• Neoplasms of the nervous system and its coverings are discussed

Classification of Central Nervous System Neoplasms (WHO 2021, 5th ed.)

• Primary neoplasms include gliomas, glioneuronal, and neuronal neoplasms like astrocytoma, oligodendroglioma, glioblastoma, and ependymoma.
• Other primary neoplasms: pineal, cranial and paraspinal nerve, cerebral meninges, melanocytic, lymphoma, histiocytic, embryonal, germ cell, choroid plexus, mesenchymal non-meningothelial, and sellar region neoplasms.
• Metastatic neoplasms are those that spread to the brain or spinal cord parenchyma, and/or the meninges.

Grading of Cerebral Neoplasia (WHO 2021, 5th ed.)

• All neoplasms of the central nervous system are considered malignant in a clinical context but usually do not spread outside the nervous system.
• Histological grading predicts the biological behavior of a neoplasm.
• Grade 1 lesions have low proliferative potential.
• Grade 2 lesions have an infiltrative growth pattern, low proliferative activity, and often recur after treatment.
• Grade 3 lesions show histological evidence of malignancy, including nuclear atypia and a moderate rate of mitoses.
• Grade 4 lesions have a significant rate of mitoses, necrosis, and significant cellular and nuclear polymorphism.

Molecular Profile of Cerebral Neoplasia (WHO 2021, 5th ed.)

• Molecular (genetic) alterations, mutations are important for classification, prognosis, course, and treatment strategy of CNS neoplasms.
• These alterations are often specific and typical for some CNS neoplasia (adult and pediatric).
• Examples of molecular alterations: IDH1, IDH2-mutant vs. wildtype, p53 mutation, ATRX mutation, 1p/19q codeletion, and TERT mutation.
• IDH refers to isocitrate dehydrogenase.
• ATRX refers to alpha thalassemia mental retardation X-linked protein.
• TERT refers to telomerase reverse transcriptase.

Adult-Type Diffuse Glioma: Astrocytoma

• Commonly found in patients aged 30-40 years old.
• Most common localization is the supratentorial compartment, mostly frontal cerebral lobes.
• Microscopically, neoplastic cells are of astrocytic lineage.
• Grade 2: well-differentiated fibrillary glial cells in a diffuse pattern, monomorphic cells, round nuclei, and absent mitotic rate.
• Grade 3: increased cellular density, cellular and nuclear atypia, and some mitotic activity.
• Grade 4: prominent cellular atypia, high mitotic rate, necrosis, and microvascular proliferation.
• IDH-mutant / ATRX-mutant/p53-mutant.

Adult-Type Diffuse Glioma: Astrocytoma Molecular Profile

• Molecular profile of neoplasia (based on results of immunohistochemical reactions): IDH-mutant / ATRX mutant (loss) / p53 mutant.

Adult-Type Diffuse Glioma: Oligodendroglioma

• Most commonly located in the supratentorial compartment, mostly frontal cerebral lobes.
• Microscopically, neoplastic cells are of oligodendrocytic lineage.
• Round cells with well-defined cell membranes and clear cytoplasm around the central spherical nucleus.
• Frequent microcalcifications (calcospherites - irregular foci with laminated appearance).
• Grade 2: lower overall cellularity, low mitotic rate (Ki67 proliferation index <5%).
• Grade 3: higher overall cellularity, high mitotic rate (Ki67 proliferation index >10%).
• IDH-mutant / ATRX-wildtype / p53-mutant + 1p/19q deletion.

Adult-Type Diffuse Glioma: Oligodendroglioma Molecular Profile

• Molecular profile of neoplasia (based on results of immunohistochemical reactions + genetic testing): IDH-mutant / ATRX-wildtype/p53-mutant + 1p/19q deletion.

Adult-Type Diffuse Glioma: Glioblastoma

• Most common localization is the supratentorial compartment, mostly the cerebral hemispheres, with no lobar predominance.
• Peak incidence occurs for patients aged 55-85 years old.
• Microscopically, it contains neoplastic cells of any neural tissue precursor cells.
• Exhibits high cellularity, prominent cellular atypia, and polymorphism.
• The mitotic rate is high.
• Necrosis with perinecrotic palisading + microvascular (glomeruloid) proliferation.
• Grade 4.

Adult-Type Diffuse Glioma: Glioblastoma Molecular Profile

• Molecular profile of neoplasia (based on results of immunohistochemical reactions): IDH-wildtype / ATRX-mutant (loss) / p53-mutant.

Neoplasms of Meninges: Meningioma

• Originates from the dura mater.
• It is the most common adult primary CNS neoplasm.
• The margin between the neoplasm and unaffected tissue is usually clear (mostly grade 1).
• May have an invasive growth pattern and invade skull bones or cerebral tissue (grade 2, 3).
• Microscopically, there are 15 histological types; the most common are meningothelial, fibrous, and transitional.

Metastatic Neoplasms of Brain

• May be the first clinical manifestation of malignant neoplasm elsewhere.
• Most common metastases originate from pulmonary small cell carcinoma and adenocarcinoma, breast carcinoma, gastrointestinal carcinoma, and melanoma.
• General morphologic features include clear margins between neoplasm and unaffected tissue, between gray and white matter.
• Perifocal cerebral edema around the neoplasm and central necrosis are also typical.
• Carcinomatosis occurs in cerebral coverings.

Complications and Causes of Death

• Cerebral edema and cerebellar herniation with clinical neurologic symptoms of local injury/stroke.
• Paralysis and decreased motoric capacity may lead to bronchopneumonia.
• Deep vein thrombosis of legs and thrombic embolism to pulmonary arteries.
• Decreased general functions of individual → poor quality of life.

Neoplasms of Peripheral Nerves

• Benign neoplasms include schwannoma and neurofibroma.
• Malignant neoplasm of peripheral nervous sheath occurs in syndromes like neurofibromatosis (types Ist and IInd).
• Tuberous sclerosis causes multiple neoplasms of the nervous system and visceral organs with mental retardation.
• Von Hippel–Lindau disease is a congenital autosomal dominant disease with multiple neoplasms of the nervous system and visceral organs.

Schwannoma

• Affects peripheral and cranial nerves.
• Microscopically, it shows mixed areas of increased or decreased cellularity and a palisading pattern.

Neurofibroma

• Macroscopically, it is an encapsulated firm nodule with an exophytic growth pattern.
• Microscopically, it resembles fibrous tissue with small cells with elongated nuclei in a wavy pattern.

Tuberous Sclerosis

• Associated with tumors of the cerebral cortex.
• Multiple small tumors in periventricular areas.
• Depigmented skin areas and adenoma sebaceum.
• Renal angiomyolipoma.
• Cardiac rhabdomyosarcoma

Von Hippel-Lindau Disease

• Includes cerebellar and spinal cord hemangioblastoma.
• Leads to paraganglioma of the mediastinum, abdominal or pelvic areas.
• May include Pheochromacytoma, renal cell carcinoma, retinal angioma, and pancreatic neoplasms.