Tumors of Central Nervous System ( Neuro-oncology)

               TUMORS  OF  CENTRAL  NERVOUS  SYSTEM

                                           Dr. VKS Gautam

It is very important to use authentic terms for the cns tumors and have an overall view about all the tumors of the central nervous system. Various nomenclatures and classifications are used for description. Therefore, it is imperative to know what is most authentic and easiest way to remember. The pathological classification of cns tumors is the most common and most practical way of nomenclature and classification of such tumors.

CNS tumors, especially gliomas, contrary to the other cancers of the body , cannot be classified like Benign or Malignant or  Cancer and Non cancer or like Benign lesion of the Breast ( Fibroadenoma) and Cancer of the breast ( Ca Breast) , or Benign Prostrate Hyperplasia (BPH) and Cancer of the Prostrate. On the contrary, the Gliomas or Astrocytomas are classified on the basis of features of neoplasia- like cellular atypia, nuclear proliferation, vascular proliferation & necrosis. So, there is a grading of neoplasia. Cushing and Bailey classification was an earlier effort to classify brain tumors.  World Health Organization ( WHO) classification of  tumors of central nervous system is a comprehensive,  authentic and up to date source of reference. I have made an effort to create an outline and curtail the details so that any doctor can have an overview of all the tumors of CNS. The details of all such tumors should  be read in conjunction with the radiological findings which is more interesting and easy.

About a century back Harvey Cushing published his work on brain tumors.
World Health Organization Classification of the Central Nervous System , fourth edition (WHO 2007), lists more than 120 types of brain tumors. This is broadly a histopathological classification.

How to understand about brain tumors?  We are very much familier with the nomenclature used in the older classifications . A comprehensive WHO classification of CNS tumors helps in understanding the characterstics of the brain tumors . So, while describing these tumors, for a better understanding,  older terms in conjuction with newer terms should be used.

GLIOMA is the commonest primary brain tumor. Glioma arises from glial cells. Since glial cells are far more in number than neuronal cells, it will be easy to understand the fact that gliomas are more common. Glial cells comprise of astrocytes, oligodendrocytes, ependymal cells so the gliomas can further be subclassified as astrocytoma ( commonest type of glioma ), oligodendroglioma and ependymoma.  According to WHO classification, these tumors can further be subclassified on the basis of features of malignancy ( microvascular proliferation, cellular atypia, mitotic activity , necrosis ) from grade I, II, III and IV.

AS neuronal cells are less in number than glial cells it is easy to remember that tumors like NEURONAL  & MIXED NEURONAL GLIAL TUMORS are less common , and relatively benign tumors . Gangliocytoma ( WHO grade I ) and ganglioglioma ( WHO grade I or III ) are well differentiated tumors composed of neoplastc mature appearing neurons alone ( gangliocytoma) or neoplastic ganglion cells combined with glioma cells ( ganglioglioma).  Dysplastc gangliocytoma of the cerebellum ( Lhermitte-Duclos disease, WHO grade I ) is associated with Cowden syndrome in 50 % cases.  Central Neurocytoma & extraventricular neurocytoma ( WHO grade II ) are low grade neoplasms of young adults.  Paraganglioma of the filum terminale ( WHO grade I ), Papillary glioneuronal tumor ( WHO grade I ) are surgically curable tumors.  Dysembryoplastic neuroepithelial tumors ( DNT; WHO grade I ) is a low grade quasihamartomatous tumor that occurs in childrenand young patients with history of long standing resistant seizures.

Summary of the WHO Classification of CNS Tumors ( 2007) for comprehensive but easy to recapitulate the overview of CNS tumors

1. Tumours of neuroepithelial tissue

1.1. Astrocytic tumours

        

        Pilocytic astrocytoma  & Subependymal giant cell astrocytoma (WHO grade I)

       

        Pilomyxoid astrocytoma & Pleomorphic xanthoastrocytoma (WHO grade II)

        

         Diffuse astrocytoma (WHO grade II) 

                        Variants:  protoplasmic,   gemistocytic,   fibrillary,  mixed

       

         Anaplastic astrocytoma (WHO grade III)

        

         Glioblastoma (WHO grade IV)

                                         a. Giant cell glioblastoma

                                         b. Gliosarcoma

    

          Gliomatosis cerebri (WHO grade III)

1.2. Oligodendroglial tumours

                 Oligodendroglioma (WHO grade II)

                 Anaplastic oligodendroglioma (WHO grade III)

1.3. Oligoastrocytic tumours

                 Oligoastrocytoma (WHO grade II)

                 Anaplastic oligoastrocytoma (WHO grade III)

1.4. Ependymal tumours

                 Subependymoma &  Myxopapillary ependymoma (WHO grade I)

                 Ependymoma (WHO grade II)

                 Anaplastic ependymoma (WHO grade III)

1.5. Choroid plexus tumours

                     Choroid plexus papilloma (WHO grade I)

                     Atypical choroid plexus papilloma ( WHO grade II)

                     Choroid plexus carcinoma (WHO grade III)

1.6. Other neuroepithelial tumours

                   Astroblastoma (WHO grade I)

                  Chordoid glioma of the third ventricle (WHO grade II)

                  Angiocentric glioma (WHO grade I)

1.7. Neuronal and mixed neuronal-glial tumours

                    Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos),

                    Desmoplastic infantile astrocytoma/ganglioglioma,

                    Dysembryoplastic neuroepithelial tumour, 

                    Gangliocytoma ,

                    Ganglioglioma

                    Papillary glioneuronal tumour

                    Rosette-forming glioneuronal tumour of the fourth ventricle, & 

                    Paraganglioma are WHO grade I tumors.

                    Central neurocytoma & Extraventricular neurocytoma , Cerebellar liponeurocytoma   (WHO grade II)

                    Anaplastic ganglioglioma (WHO grade III)

                                 

1.8. Tumours of the pineal region

               Pineocytoma (WHO grade I)

               Pineal parenchymal tumour of intermediate differentiation (WHO grade II, III)

               Pineoblastoma (WHO grade IV)

               Papillary tumors of the pineal region (WHO grade II, III)

1.9. Embryonal tumours

              Medulloblastoma (WHO grade IV)

              Medulloblastoma with extensive nodularity (WHO grade IV)

              Anaplastic medulloblastoma (WHO grade IV)

              CNS Primitive neuroectodermal tumour (WHO grade IV)

              CNS Neuroblastoma (WHO grade IV)

              Atypical teratoid/rhabdoid tumour (WHO grade IV)

2. Tumours of cranial and paraspinal nerves

              Schwannoma (WHO grade I)

              Neurofibroma (WHO grade I)

              Perineurioma (WHO grade I, II, III)

              Malignant peripheral nerve sheath tumour (MPNST) (WHO grade II, III, IV)

3. Tumours of the meninges

3.1 Tumours of meningothelial cells

 Meningioma

                   Variants ( Subtypes ): meningothelial,  fibrous (fibroblastic),  transitional (mixed),  psammomatous,  angiomatous,  microcystic,  secretory,  clear cell,  chordoid,  lymphoplasmacyte-rich, and  metaplastic

 

 Atypical meningioma (WHO grade II)

 Anaplastic meningioma (WHO grade III)

3.2 Mesenchymal tumours

 Lipoma , Angiolipoma ,Liposarcoma,  Leiomyoma,  Leiomyosarcoma, Solitary fibrous tumour ,  Fibrosarcoma , Rhabdomyoma, Rhabdomyosarcoma,Chondroma , Chondrosarcoma,  Osteoma,Osteosarcoma, Osteochondroma, Angiosarcoma, Kaposi Sarcoma, Ewing Sarcoma - PNET 

 Malignant fibrous histiocytoma

 Hibernoma

 Haemangioma 

 Epithelioid hemangioendothelioma

 Haemangiopericytoma & Anaplastic haemangiopericytoma (WHO grade III)

3.3 Primary melanocytic lesions

                      Diffuse melanocytosis

                      Melanocytoma 

                      Malignant melanoma 

                      Meningeal melanomatosis 

3.4 Other neoplasms related to the meninges

                     Haemangioblastoma (WHO grade I)

4. Tumors of the haematopoietic system

                       Malignant Lymphomas

                        Plasmocytoma

                        Granulocytic sarcoma

5. Germ cell tumours

                             Germinoma

                             Embryonal carcinoma

                             Yolk sac tumour

                             Choriocarcinoma

                             Teratoma

                             Mixed germ cell tumours

6. Tumours of the sellar region

                                Craniopharyngioma (WHO grade I)

                                Granular cell tumour (WHO grade I)

                                Pituicytoma (WHO grade I)

                                Spindle cell oncocytoma of the adenohypophysis (WHO grade I)

7. Metastatic Tumours


The 2016 WHO Classification of CNS Tumors
The most recent and updated classification of CNS tumors is published by WHO in year 2016.
The new classification uses both molecular parameters and histological features, so, it is a combined genotype and phenotype classification. Previous classifications were mainly based on the microscopic histological features, immunohistochemical expressions and putative cell of origin of the tumors.
Over the past few decades there had been a better understanding of the genetic basis of tumorigenesis. The use of integrated phenotypic and genotypic parameters for the  CNS tumor classification  adds a level of objectivity in the diagnostic process leading to greater diagnostic accuracy as well as improved patient management and more accurate determination s of prognosis and treatment response.
So, the new classification proposed by WHO incorporates genetically defined entities and restructured the entire classification of tumors of central nervous system  into the molecular era. Certain terms had been added and some old terms had been deleted into the new classification.
The nosological shift to a new classification based on both phenotype and genotype.

The most recent and updated classification of CNS tumors is 2016-WHO classification.

WHO (2016) Classification of Tumors of Central Nervous System

In year 2016, for the first time, the World Health Organization ( WHO) classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities. Major restructuring has been done in diffuse gliomas, medulloblastomas and other embryonal tumors. It has added newly recognized neoplasms, and has deleted some entities, variants and patterns that are no longer have diagnostic and/or biological relevance.

Summary of changes in new classification

• Major restructuring of diffuse gliomas, Medulloblastomas, other embryonal tumors & incorporation of genetically defined entities
• The term “primitive neuroectodermal tumor” is removed
• Incorporation of a genetically defined ependymoma variant - RELA fusion positive
• 
  
  Addition of
            Newly recognized entities, variants and patterns have been added:
                            1.  IDH-wildtype and IDH-mutant glioblastoma 
                            2. Diffuse midline glioma, H3 K27M–mutant
                            3. Embryonal tumour with multilayered rosettes, C19MC-altered
                            4. Ependymoma, RELA fusion–positive
                            5. Diffuse leptomeningeal glioneuronal tumor
                            6. Anaplastic PXA
                            7. Epithelioid glioblastoma  
                             8. Glioblastoma with primitive neuronal component
                             9. Multinodular and vacuolated pattern of ganglion cell tumor
  Deletion of
              Gliomatosis cerebri
              Protoplasmic and fibrillary astrocytoma variants
              cellular ependymoma variant
              Primitive Neuroectodermal tumor
  
  

• Addition of Brain invasion as a criterion for atypical meningioma
• Restructuring of solitary fibrous tumor and hemangiopericytoma ( SFT/HPC) as one entity
• Expansion & clarification of entities included in of Nerve sheath tumors, with addition of hybrid nerve sheath tumors & separation of melanotic schwannoma from other schwanomas
• Expansion of entities included in hematopoietic/lymphoid tumors of the CNS ( lymphomas & histiocytic tumors)
                       
                                     NEW CLASSIFICATION
  Diffuse astrocyic and oligodendroglial tumors

• Diffuse astrocytoma, IDH-mutant
                          Gemistocytic astrocytoma, IDH-mutant

•  Diffuse astrocytoma, IDH-wildtype
•  Diffuse astrocytoma, NOS
• Anaplastic astrocytoma, IDH-mutant
• Anaplasticastrocytoma, IDH-wildtype
• Anaplastic astrocytoma, NOS

• Glioblastoma, IDH-wildtype
                       Giant cell glioblastoma
                       Gliosarcoma
                       Epitheloid glioblastoma

• Glioblastoma, IDH-mutant
• Glioblastoma, NOS

• Diffuse midline glioma, H3 K27M-mutant
• Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
• Oligodendroglioma, NOS
  
  

• Anaplastic Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
• Anaplastic oligodendroglioma, NOS
  
  

• Oligoastrocytoma, NOS
• Anaplastic Oligoastrocytoma, NOS
  Other astrocytic tumor

• Pilocytic astrocytoma
                   Pilomyxoid astrocytoma

• Subependymal giant cell astrocytoma
• Pleomorphic xanthoastrocytoma
• Anaplastic pleomorphic xanthastrocytoma
  Ependymal tumors

• Subependymoma
• Myxopapillary ependymoma
• Ependymoma
                  Papillary ependymoma
                  Clear cell ependymoma
                  Tanycytic ependymoma

• Ependymoma, RELA fusion-positive
  Anaplastic ependymoma
  Other gliomas

• Choroid glioma of the third ventricle
• Angiocentric glioma
• Astroblastoma
  Choroid plexus tumors

• Choroid plexus papilloma
• Atypical choroid plexus papilloma
• Choroid plexus carcinoma
  Neuronal & mixed Neuronal-glial tumors

• Dysembryoplastic neuroepithelial tumor
• Gangliocytoma
• Ganglioglioma
• Anaplastic ganglioglioma
• Dysplastic cerebellar gangliocytoma ( Lhermitte-Duclos disease)
• Desmoplastic infantile astrocytoma and ganglioglioma
• Papillary glioneuronal tumor
• Rosette forming glioneuronal tumor
• Diffuse leptomeningeal glioneuronal tumor
• Central neurocytoma
• Extraventricular neurocytoma
• Cerebellar liponeurocytoma
• Paraganglioma
  Tumor of the Pineal region

• Pineocytoma
• Pineal parenchymal tumor of intermediate differentiation
• Pineoblastoma
• Papillary tumor of pineal region
  Embryonal tumors
  Medulloblastoma, genetically defined
                         Medulloblastoma, WNT activated
                         Medulloblastoma, SHH-activated and T53-mutant
                         Medulloblastoma, SHH-activated and T53-wildtype
                         Medulloblastoma,  non-WNT/non SHH
                                  Medulloblastoma,  group 3
                                  Medulloblastoma, group 4
  Medulloblastoma, histologically defined
                         Medulloblastoma, classic
                         Medulloblastoma, desmoplastic/nodular
                         Medulloblastoma with extensive nodularity
                         Medulloblastoma, large cell/anaplastic
  Medulloblastoma NOS

• Embryonal tumor with multilayered rosettes, C19MC-altered
• Embryonal tumor with multilayered rosettes, NOS
• Medulloepithelioma
• CNS Neuroblastoma
• CNS ganglioneuroblastoma
• CNS embryonal tumor, NOS
• Atypical teratoid/ rhabdoid tumor
• CNS embryonal tumor with rhabdoid features
  
  
  Tumors of cranial and paraspinal nerves
  Schwannoma
            Cellular Schwannoma
            Plexiform Schwannoma
            Melanotic Schwannoma
  Neurfibroma
            Atypical neurofibroma
            Plexiform neurofibroma
  Perineurioma
  Hybrid nerve sheath tumors
  Malignat peripheral nerve sheath tumor
              Epitheloid MPNST
              MPNST with perineurial differentiation
  
  
  Meningioma

• Meningioma
• Meningothelial meningioma
• Fibrous meningioma
• Transitional meningioma
• Psammomatous meningioma
• Angiomatous meningioma
• Microcystic meningioma
• Secretory meningioma
• Lymphoplasmacyte-rich meningioma
• Metaplastic meningioma
• Chordoid meningioma
• Clear cell meningioma
• Atypical meningioma
• Papillary meningioma
• Rhabdoid meningioma
• Anaplastic ( malignant) meningioma 
  
  
  Mesenchymal, Non-meningothelial tumors

• Solitary fibrous tumor/hemangiopericytoma
• Hemangioblastoma
• Hemangioma
• Epitheloid hemangioendothelioma
• Angiosarcoma,
• Kaposi Sarcoma,
• Ewing sarcoma/ PNET
• Lipoma
• Angiolipoma
• Hibernoma
• Liposarcoma
• Desmoid type fibromatosis
• Myofibriblastoma

•  Inflammatory myofibroblastic tumor
• Benign fibrous histiocytoma
• Leiomyoma
• Leiomyosarcoma
• Rhabdomyoma
• Rhabdomyosarcoma
• Chondroma’
• Chondrosarcoma
• Osteoma
• Osteochondroam
• Osteosarcoma
  Melanocytic tumors

• Meningeal melaonocytosis
• Meningeal melanocytoma
• Meningeal melanoma
• Meningeal melanomatosis
  Lymphoma

• Diffuse large B-cell lymphoma of the CNS 
• Immunodeficiency-associated CNS lymphoma
                            AIDS-related diffuse large B-cell lymphoma
                            EBV-positive diffuse large B-cell lymphoma, NOS
                            Lymphomatoid granulomatosis 

• Intravascular large B-cell lymphoma 
• Low-grade B-cell lymphoma of the CNS 
• T-cell & NK/T cell-lymphoma of the CNS 
• Anaplastic large cell lymphoma , ALK-positive 
• Anaplastic large cell lymphoma , ALK-negative 
• MALT lymphoma of the dura
  Histiocytic tumors

• Langerhans cell histocytosis
• Erdheim-Chester disease
• Rosai-Dorfman disease
• Juvenile xanthogranuloma
• Histiocytic sarcoma
  Germ cell tumors

• Germinoma
• Embryonal carcinoma
• Yolk sac tumor
• Choriocarcinoma
• Teratoma
                   Mature, Immature

• Teratoma with malignant transformation
• Mixed germ cell tumor
  Tumors of the sellar region
  Craniopharyngioma
               Admantinomatous craniopharyngioma
               Papillary craniopharyngioma
  Granular cell tumor of sellar region
  Pituicytoma
  Spindle cell oncocytoma
  Metastatic tumors
  
  
  
  
  
  
  
  
  
  
          
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

Sources
Review article
The World Health Organization  classification of tumors of the central nervous system: a summary. David N. Louis, et al. Acta Neuropathol ( 2016) 131:803-820