The new WHO Classification of Tumors affecting the Central Nervous System

	Neuroepithelial tumors
	Non-neuroepithelial tumors
	Astrocytic lineage tumor grading systems
	Mutations leading to astrocytic tumors
	Reference
	Links to other information on tumors affecting the central nervous system

In 1993 the WHO ratified a new comprehensive classification of neoplasms affecting the central nervous system. The classification of brain tumors is based on the premise that each type of tumor results from the abnormal growth of a specific cell type. To the extent that the behavior of a tumor correlates with basic cell type, tumor classification dictates the choice of therapy and predicts prognosis. The new WHO system is particularly useful in this regard with only a few notable exceptions (for example all or almost all gemistocytic astrocytomas are actually anaplastic and hence grade III or even IV rather than grade II as designated by the WHO system). The WHO classification also provides a parallel grading system for each type of tumor. In this grading sytem most named tumors are of a single defined grade. The new WHO classification provides the standard for communication between different centers in the United States and around the world. An outline of this classification is provided below.

 Neuroepithelial Tumors of the CNS

1. Astrocytic tumors [glial tumors–categories I-V, below–may also be subclassified as invasive or non-invasive, although this is not formally part of the WHO system, the non-invasive tumor types are indicated below. Categories in italics are also not recognized by the new WHO classification system, but are in common use.
   1. Astrocytoma (WHO grade II)
      1. variants: protoplasmic, gemistocytic, fibrillary, mixed
   2. Anaplastic (malignant) astrocytoma (WHO grade III)
      1. hemispheric
      2. diencephalic
      3. optic
      4. brain stem
      5. cerebellar
   3. Glioblastoma multiforme (WHO grade IV)
      1. variants: giant cell glioblastoma, gliosarcoma
   4. Pilocytic astrocytoma [non-invasive, WHO grade I]
      1. hemispheric
      2. diencephalic
      3. optic
      4. brain stem
      5. cerebellar
   5. Subependymal giant cell astrocytoma [non-invasive, WHO grade I]
   6. Pleomorphic xanthoastrocytoma [non-invasive, WHO grade I]
2. Oligodendroglial tumors
   1. Oligodendroglioma (WHO grade II)
   2. Anaplastic (malignant) oligodendroglioma (WHO grade III)
3. Ependymal cell tumors
   1. Ependymoma (WHO grade II)
      1. variants: cellular, papillary, epithelial, clear cell, mixed
   2. Anaplastic ependymoma (WHO grade III)
   3. Myxopapillary ependymoma
   4. Subependymoma (WHO grade I)
4. Mixed gliomas
   1. Mixed oligoastrocytoma (WHO grade II)
   2. Anaplastic (malignant) oligoastrocytoma (WHO grade III)
   3. Others (e.g. ependymo-astrocytomas)
5. Neuroepithelial tumors of uncertain origin
   1. Polar spongioblastoma (WHO grade IV)
   2. Astroblastoma (WHO grade IV)
   3. Gliomatosis cerebri (WHO grade IV)
6. Tumors of the choroid plexus
   1. Choroid plexus papilloma
   2. Choroid plexus carcinoma (anaplastic choroid plexus papilloma)
7. Neuronal and mixed neuronal-glial tumors
   1. Gangliocytoma
   2. Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos)
   3. Ganglioglioma
   4. Anaplastic (malignant) ganglioglioma
   5. Desmoplastic infantile ganglioglioma
      1. desmoplastic infantile astrocytoma
   6. Central neurocytoma
   7. Dysembryoplastic neuroepithelial tumor
   8. Olfactory neuroblastoma (esthesioneuroblastoma)
      1. variant: olfactory neuroepithelioma
8. Pineal Parenchyma Tumors
   1. Pineocytoma
   2. Pineoblastoma
   3. Mixed pineocytoma/pineoblastoma
9. Tumors with neuroblastic or glioblastic elements (embryonal tumors)
   1. Medulloepithelioma
   2. Primitive neuroectodermal tumors with multipotent differentiation
      1. medulloblastoma
         1. variants: medullomyoblastoma, melanocytic medulloblastoma, desmoplastic medulloblastoma
      2. cerebral primitive neuroectodermal tumor
   3. Neuroblastoma
      1. variant: ganglioneuroblastoma
   4. Retinoblastoma
   5. Ependymoblastoma

1. Tumors of the Sellar Region
   1. Pituitary adenoma
   2. Pituitary carcinoma
   3. Craniopharyngioma
2. Hematopoietic tumors
   1. Primary malignant lymphomas
   2. Plasmacytoma
   3. Granulocytic sarcoma
   4. Others
3. Germ Cell Tumors
   1. Germinoma
   2. Embryonal carcinoma
   3. Yolk sac tumor (endodermal sinus tumor)
   4. Choriocarcinoma
   5. Teratoma
   6. Mixed germ cell tumors
4. Tumors of the Meninges
   1. Meningioma
      1. variants: meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, clear cell, chordoid, lymphoplasmacyte-rich, and metaplastic subtypes
   2. Atypical meningioma
   3. Anaplastic (malignant) meningioma
5. Non-menigothelial tumors of the meninges
   1. Benign Mesenchymal
      1. osteocartilaginous tumors
      2. lipoma
      3. fibrous histiocytoma
      4. others
   2. Malignant Mesenchymal
      1. chondrosarcoma
      2. hemangiopericytoma
      3. rhabdomyosarcoma
      4. meningeal sarcomatosis
      5. others
   3. Primary Melanocytic Lesions
      1. diffuse melanosis
      2. melanocytoma
      3. maliganant melanoma
         1. variant meningeal melanomatosis
   4. Hemopoietic Neoplasms
      1. malignant lymphoma
      2. plasmactoma
      3. granulocytic sarcoma
   5. Tumors of Uncertain Histogenesis
      1. hemangioblastoma (capillary hemangioblastoma)
6. Tumors of Cranial and Spinal Nerves
   1. Schwannoma (neurinoma, neurilemoma)
      1. cellular, plexiform, and melanotic subtypes
   2. Neurofibroma
      1. circumscribed (solitary) neurofibroma
      2. plexiform neurofibroma
   3. Malignant peripheral nerve sheath tumor (Malignant schwannoma)
      1. epithelioid
      2. divergent mesenchymal or epithelial differentiation
      3. melanotic
7. Local Extensions from Regional Tumors
   1. Paraganglioma (chemodectoma)
   2. Chordoma
   3. Chodroma
   4. Chondrosarcoma
   5. Carcinoma
8. Metastatic tumours
9. Unclassified Tumors
10. Cysts and Tumor-like Lesions
    1. Rathke cleft cyst
    2. Epidermoid
    3. Dermoid
    4. Colloid cyst of the third ventricle
    5. Enterogenous cyst
    6. Neuroglial cyst
    7. Granular cell tumor (choristoma, pituicytoma)
    8. hypothalamic neuronal hamartoma
    9. nasal glial herterotopia
    10. plasma cell granuloma

A number of grading systems are in common use for tumors of astrocytic lineage (i.e. astrocytomas, anaplastic astrocytomas and glioblastomas). Grades are assigned solely based on the microsopic appearance of the tumor. The numerical grade assigned for a given tumor, however, can vary depending on which grading system is used as illustrated by the following table. Thus, it is important to specify the grading system referred to when a grade is specified. The St. Anne/Mayo grade has proven to correlate better with survival than the previously common Kernohan grading system. It can only be applied to invasive tumors of astrocytic lineage; it is otherwise similar to the WHO grading system.

 Grading of astrocytic tumors

WHO designation	WHO grade*	Kernohan grade*	St. Anne/Mayo grade	St. Anne/Mayo criteria
pilocytic astrocytoma	I	I	excluded	–
astrocytoma	II	I, II	1	no criteria fulfilled
			2	one criterion: usually nuclear atypia
anaplastic (malignant) astrocytoma	III	II, III	3	two criteria: usually nuclear atypia and mitosis
glioblastoma	IV	III, Iv	4	three or four criteria: usually the and/or necrosis

Molecular studies have identified some of the genetic changes that underlie the pathologic differences among astrocytic tumors; progression in tumor grade is associated with an ordered accumulation of mutations (Fig. below). Approximately 33% of low grade infiltrating astrocytomas (St. Anne/Mayo grade 2) have mutations detected in the p53 gene on chromosome 17p. Anaplastic astrocytomas (grade 3)-whether found in preexistent low grade astrocytomas or detected de novo-have a similar incidence of p53 mutations but, in addition, show a loss of heterozygosity on chromosome 19q in more than 40% of cases. Progression from astrocytoma to anaplastic astrocytoma also involves mutations in other tumor suppressor genes including the retinoblastoma gene on chromosome 13q. Finally, glioblastomas have the same incidence of these genetic aberrations and in addition 70 percent have lost heterozygosity for chromosome 10 and one third have amplification of the epidermal growth factor receptor gene. Many of these correlations have been defined largely through work in the MGH Molecular Neurooncology laboratory.

Molecular genetic alterations in infiltrative astrocytic tumors . The genetic aberrations identified accumulate in a fixed percentage of tumors at each stage of malignancy. The proportion of tumors with mutations characteristic of less anaplastic tumors remains constant as anaplasticity increases. Thus, astrocytic tumors vary with respect to the subset of these mutations which are detected. Neoplastic cells are clonal. Abbreviations: LOH = loss of heterozygosity, p = short arm of chromosome, q = long arm of chromosome, Rb = retinoblastoma gene, EGFr = epidermal growth factor receptor.

Per maggiori informazioni, tra cui le linee guida (2023) Italiane dell’ISS

Tatter SB , Wilson CB, Harsh GR IV. Neuroepithelial tumors of the adult brain. In Youmans JR, ed. Neurological Surgery, Fourth Edition, Vol. 4: Tumors. W.B. Saunders Co., Philadelphia, pp. 2612-2684, 1995.

Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathology 3:255-68, 1993.

Lopes MBS, VandenBerg SR, Scheithauer BW. The World Health Organization classification of nervous system tumors in experimental neuro-oncology. In A.J. Levine and H.H. Schmidek, eds. Molecular Genetics of Nervous System Tumors Wiley-Liss, New York, pp. 1-36, 1993. Linee guida dell’ ISS (2023) sul trattamento dei tumori cerebrali