CNS Neoplasms: WHO 2021 Classification

• Neoplasms that affect the nervous system and its coverings are a key area of study

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

• Primary neoplasms include gliomas, glioneuronal, and neuronal neoplasms like astrocytoma, oligodendroglioma, glioblastoma, and ependymoma
• Other primary neoplasms include pineal neoplasms (e.g., pineocytoma)
• Primary CNS neoplasms can include cranial and paraspinal nerve neoplasms
• Primary CNS neoplasms can include neoplasms of cerebral meninges (e.g., meningioma)
• Melanocytic neoplasms (e.g., melanoma) are primary CNS neoplasms
• Primary CNS neoplasms include lymphoma and histiocytic neoplasms (e.g., B-cell lymphoma)
• Embryonal neoplasms, for example, medulloblastoma and atypical teratoid/rhabdoid tumors, are primary CNS neoplasms
• Germ cell neoplasms such as teratoma fall under primary CNS neoplasms
• Primary CNS neoplasms are choroid plexus neoplasms (e.g., choroid plexus papilloma)
• Mesenchymal, non-meningothelial neoplasms are primary CNS neoplasms such as hemangioma and chondrosarcoma
• Neoplasia of the sellar region (e.g., craniopharyngioma) is also a primary CNS neoplasm
• Metastatic neoplasms spread to the brain, spinal cord parenchyma, and meninges

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

• All CNS neoplasms are considered malignant in a clinical context, but usually do not spread outside the nervous system
• Histological grading is a tool to predict the biological behavior of a neoplasm

General Principles of Grading Cerebral Neoplasms

• Grade 1 lesions have low proliferative potential
• Grade 2 lesions exhibit an infiltrative growth pattern and low proliferative activity, often recurring 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, such as mutations, are important for the classification, prognosis, course, and treatment strategy of CNS neoplasms
• Molecular alterations are specific and typical for certain adult and pediatric CNS neoplasias
• Examples of molecular alterations include IDH1/IDH2 mutations versus wildtype, p53 mutation, ATRX mutation, 1p/19q codeletion, and TERT mutation
• IDH stands for isocitrate dehydrogenase
• ATRX is alpha thalassemia mental retardation X-linked protein
• TERT is telomerase reverse transcriptase

Adult-Type Diffuse Glioma: Astrocytoma

• Patients with astrocytoma are predominantly 30-40 years old
• Astrocytoma most commonly localizes in the supratentorial compartment, primarily in the frontal cerebral lobes

Microscopic Features of Adult-Type Diffuse Glioma: Astrocytoma

• Neoplastic cells show astrocytic lineage
• Grade 2 astrocytomas have well-differentiated fibrillary glial cells in a diffuse pattern, monomorphic cells, round nuclei, and absent mitotic rate
• Grade 3 astrocytomas show increased cellular density, cellular and nuclear atypia, and some mitotic activity
• Grade 4 astrocytomas feature prominent cellular atypia, a high mitotic rate, necrosis, and microvascular proliferation
• IDH-mutant / ATRX-mutant / p53-mutant molecular profiles

Molecular Profile of Adult-Type Diffuse Glioma: Astrocytoma

• Molecular profile of neoplasia is based on results of immunohistochemical reactions
• IDH-mutant, ATRX mutant (loss), and p53 mutant profiles are common

Immunohistochemical Reactions

• Immunohistochemical reactions use IDH immunomarkers, showing cytoplasmic staining
• Immunohistochemical reactions use ATRX immunomarkers showing nuclear staining
• Immunohistochemical reactions use p53 immunomarkers showing nuclear staining

Adult-Type Diffuse Glioma: Oligodendroglioma

• Glioma most commonly localizes in the supratentorial compartment, mostly in the frontal cerebral lobes

Microscopic Features of Adult-Type Diffuse Glioma: Oligodendroglioma

• Neoplastic cells are of oligodendrocytic lineage
• Round cells have well-defined cell membranes and clear cytoplasm around the central spherical nucleus
• Frequent microcalcifications (calcospherites – irregular foci with laminated appearance)
• Grade 2 oligodendroglioma has lower overall cellularity and a low mitotic rate with a Ki67 proliferation index
• Grade 3 has higher overall cellularity, high mitotic rate (Ki67 proliferation index >10%)
• IDH-mutant, ATRX-wildtype, p53-mutant + 1p/19q deletion

Molecular Profile of Adult-Type Diffuse Glioma: Oligodendroglioma

• Molecular profile of neoplasia relies on immunohistochemical reactions and genetic testing
• It is IDH-mutant, ATRX-wildtype, and p53-mutant with a 1p/19q deletion

Molecular Analysis Techniques

• Fluorescent in situ hybridization identifies 1p deletion (left image) and 19q deletion (right image), with red signals indicating the "p" arm and green signals showing the "q" arm of the chromosome

Adult-Type Diffuse Glioma: Glioblastoma

• Glioblastoma most commonly localizes in the supratentorial compartment, mainly in the cerebral hemispheres, with no lobar predominance
• Peak incidence is for patients aged 55–85 years

Microscopic Features of Adult-Type Diffuse Glioma: Glioblastoma

• Glioblastoma displays neoplastic cells of any neural tissue precursor cells
• Glioblastomas exhibit high cellularity, prominent cellular atypia and polymorphism, and a high mitotic rate
• Glioblastomas have necrosis with perinecrotic palisading and microvascular (glomeruloid) proliferation

Molecular Profile of Adult-Type Diffuse Glioma: Glioblastoma

• IDH-wildtype / ATRX-mutant (loss) / p53-mutant

Neoplasms of Meninges: Meningioma

• Meningiomas originate from the dura mater and are the most common adult primary CNS neoplasm
• The margin between the neoplasm and unaffected tissue is typically clear (mostly grade 1)
• Meningiomas can have an invasive growth pattern to invade skull bones or cerebral tissue (grade 2, 3)

Microscopic Features of Meningioma

• The 15 histological types most commonly encountered are meningothelial, fibrous, and transitional

Metastatic Neoplasms of the Brain

• Metastatic neoplasms may be the first clinical manifestation of a malignant neoplasm elsewhere in the body
• The most common metastases come from pulmonary small cell carcinoma and adenocarcinoma, breast carcinoma, gastrointestinal carcinoma, and melanoma

General Morphologic Features of Metastatic Neoplasms

• Margins between neoplasm and unaffected tissue are clear
• They appear between grey and white matter
• Perifocal cerebral edema surrounds the neoplasm
• Central necrosis is usual
• Carcinomatosis of cerebral coverings is typical

Complications and Causes of Death in CNS Neoplasms

• Cerebral edema and cerebellar herniation
• Clinical neurologic symptoms of local injury
• Clinically presents as a syndrome of stroke
• Paralysis and decreased motoric capacity leading to bronchopneumonia
• Deep vein thrombosis from legs and thrombic embolism to pulmonary arteries
• Decreased general functions leading to poor quality of life

Neoplasms of Peripheral Nerves

• Benign neoplasms include schwannoma and neurofibroma
• Malignant neoplasms include malignant neoplasms of peripheral nervous sheath

Syndromes Associated with Peripheral Nerve Neoplasms

• Neurofibromatosis (Types Ist and IInd)
• Tuberous sclerosis (congenital disease leading to neoplasms, mental retardation)
• Von Hippel–Lindau disease (autosomal dominant disease causing multiple various neoplasms)

Schwannoma

• Schwannomas affect peripheral and cranial nerves
• Microscopically, they show mixed areas of increased/decreased cellularity and palisading patterns

Neurofibroma

• Neurofibromas are encapsulated firm nodules with an exophytic growth pattern
• Microscopically, they resemble fibrous tissue with small cells and elongated nuclei in a wavy pattern

Neurofibromatosis

• Neurofibromatosis presents in two types (Ist and IInd)

Tuberous Sclerosis

• Tuberous sclerosis presents with tubers of cerebral cortex
• Multiple small tumors in periventricular areas
• Depigmented skin areas
• Adenoma sebaceum
• Renal angiomyolipoma
• Cardiac rhabdomyosarcoma
• Facial nevus

Von Hippel–Lindau Disease

• Von Hippel-Lindau disease is associated with various neoplasms
• Cerebellar hemangioblastoma
• Spinal cord hemangioblastoma
• Paraganglioma of mediastinum, abdominal, or pelvic areas
• Pheochromocytoma
• Renal cell carcinoma
• Retinal angioma
• Pancreatic neoplasms