Primary neuraxial central nervous system (CNS) tumors are different from other systemic tumors: in having a wider variety of prognostically distinct entities and variants thereof, different and more varied histopathology, molecular biology, behavior and response to anti-cancer therapy.

Unlike systemic tumors, primary CNS tumors generally do not metastasize, hence their prognosis is largely dependent on local progression and brain infiltration, and assessed by histologic type and grading. Outcome is also influenced by patient age, tumor site and quality and promptness of treatment. Judicious incorporation of evidence-based immunohistochemical (both extent and pattern of positivity) and molecular parameters, based upon improved insights in their pathobiology, are becoming vital to provide accuracy to histopathologic typing and grading (WHO). They are also important for prognostication and to facilitate optimization of targeted and individualized radiation and chemotherapy. Microsurgical resection is a cornerstone in their treatment. The limited resectability, especially in critical and eloquent areas, and the emerging trend of stereotactic biopsy necessitates optimized fixation and processing of all available excised tumor tissue (including suctioned tissue). It is desirable to interpret pathologic findings in the light of radiologic information. For example, a grade II or III astrocytic tumor on a tiny biopsy, in a radiologically large necrotic tumor with mass effect and high choline content, is most likely to be an under sampled GBM. Overall, these tumors require systematic evaluation, prognostic appraisal, and well-timed therapeutic interventions and follow up. Consequently the need for optimized, clinically relevant pathologic reporting towards the multi-disciplinary management of CNS tumors is an eminent responsibility of pathologists (CAP guidelines, data sets – www.cap.org).

It is noteworthy that statistically the most common primary brain tumors are the most aggressive ones, namely glioblastomas in adults and medulloblastomas in children. Glioblastomas can infiltrate brain tissue extensively and in a “stealth” manner as individual cells, thereby hindering disease control surgically, and show variable resistance to radiation and chemotherapy, explaining the lack of significant improvement of their median survival over the last few decades. Furthermore, even benign or low grade neuraxial tumors may cause significant morbidity and even mortality, if they infiltrate critical and eloquent areas of the brain and spinal cord or sometimes merely by the mass effect.

Histologic typing requires a step ladder approach virtually based upon a combination of histopathologic patterns and cell types (in the appropriate age and site). Identification of cell types, typically on histology, sometimes supported by GFAP staining pattern, contributes to lineage determination (astrocytic, oligodendroglial and ependymal for gliomas). Identification of histologic patterns within a lineage allows the pathologist to deduce a clinicopathologic prognostically distinct entity. For example, compact astrocytic areas with piloid morphology and Rosenthal fibers alternating with spongy microcystic areas with protoplasmic morphology and accompanying eosinophilic granular bodies (EGB) allows for a diagnosis of pilocytic astrocytoma, regardless of age and location of the tumor. Molecular classification is a further refinement in providing greater objectivity and distinction between entities and variants.

Histologic grading provides prognostic subgroups within broad lineage-based categories such as diffusely infiltrating gliomas, and assigns a prognostic code to distinct clinicopathologic entities. WHO grading system follows a 4-grade method in an increasing order of malignancy. Barring few limitations, it effectively translates into prognostication and management strategies for primary brain tumors. It is important to use as nearly diagnostic criteria as possible to identify grade I (to avoid over treatment) and grade IV (to avoid under treatment, and prevent CSF seeding as in PNET). There is greater subjectivity and room for judgment in grades II and especially III, largely due to progression of malignancy being a continuum and intratumoral heterogeneity.
Biologically, gliomas behave in two distinct ways, namely as either diffusely infiltrating or relatively circumscribed expansile growth. Majority of the diffuse fibrillary astrocytic (grades II through IV) and oligodendroglial tumors comprise the diffusely infiltrating group. Ependymomas, pilocytic astrocytomas, pleomorphic xantho-astrocytoma (PXA) and subependymal giant cell astrocytoma (SEGA) are usually circumscribed. Accordingly, the management strategies differ.

Low-grade gliomas represent a minority (about 11%) of the primary central nervous system (CNS) tumours and represent a challenging and controversial area in clinical neuro-oncology.

For accurate diagnosis of grade I tumors, the use of diagnostic criteria in the right clinical setting is vital. Most occur in the first two decades except myxopapillary ependymoma, neurocytoma and paraganglioma. Pilocytic astrocytoma (typically cerebellum, optic/hypothalamic), and myxopapillary ependymoma (filum/conus) are diagnosed on histopathology. For diagnosis of central neurocytoma (CN) (lateral/third ventricle), extraventricular neurocytoma (EVN)), dysembryoplastic neuroepithelial tumor (DNT) (cerebral cortical, usually temporal), ganglioglioma (throughout neuraxis, usually temporal), desmoplastic infantile astrocytoma (superficial cerebral), SEGA (lateral ventricle), paraganglioma (filum) and rosette-forming glial-neuronal tumor (RGNT) (posterior fossa), recognition of characteristic histopathologic patterns along with imunohistochemical confirmation, especially using synaptophysin and NeuN is recommended. This includes pattern analysis such as surface perikaryal (ganglioglioma) and glioneural element (DNT) staining with synaptophysin. In general, in grade I tumors, the correlation of rarely detected histologic anaplasia with clinical outcome are inconsistent. For example, in pilocytic astrocytoma, necrosis (infarct), microvascular proliferation (usually pericystic), and nuclear atypia (smudgy chromatin) are of no significance in absence of obvious anaplasia. However some pointers are worthy of consideration: MIB1 LI of >2% is a risk factor for recurrences in pilocytic and neurocytomas. When high MIB1 is associated with microvascular hyperplasia and palisaded necrosis in neurocytomas, the risk of recurrence is more in extraventricular and spinal than central neurocytoma. Mixed glial-neuronal neoplasm is a growing category: in its frequency due to regular use of immunohistochemical stains and better understanding of pathologists, as well as description of newer entities such as DNT, RGNT, EVN and others.

Most common grade II tumor is a diffuse fibrillary astrocytoma typically seen in supratentorial compartment. Prognostic factors for adult supratentorial WHO grade 2 astrocytomas are poorly defined. Multivariate analysis from a large prospective trial (EORTC 2002) showed that age >40 years, histology (absence of oligodendroglial component), tumor diameter >6 cm, tumor crossing the midline, and presence of neurologic deficit before surgery were unfavorable prognostic factors for survival.Low-grade gliomas represent a minority (about 11%) of the primary central nervous system (CNS) tumours and represent a challenging and controversial area in clinical neuro-oncology.

For accurate diagnosis of grade I tumors, the use of diagnostic criteria in the right clinical setting is vital. Most occur in the first two decades except myxopapillary ependymoma, neurocytoma and paraganglioma. Pilocytic astrocytoma (typically cerebellum, optic/hypothalamic), and myxopapillary ependymoma (filum/conus) are diagnosed on histopathology. For diagnosis of central neurocytoma (CN) (lateral/third ventricle), extraventricular neurocytoma (EVN)), dysembryoplastic neuroepithelial tumor (DNT) (cerebral cortical, usually temporal), ganglioglioma (throughout neuraxis, usually temporal), desmoplastic infantile astrocytoma (superficial cerebral), SEGA (lateral ventricle), paraganglioma (filum) and rosette-forming glial-neuronal tumor (RGNT) (posterior fossa), recognition of characteristic histopathologic patterns along with imunohistochemical confirmation, especially using synaptophysin and NeuN is recommended. This includes pattern analysis such as surface perikaryal (ganglioglioma) and glioneural element (DNT) staining with synaptophysin. In general, in grade I tumors, the correlation of rarely detected histologic anaplasia with clinical outcome are inconsistent. For example, in pilocytic astrocytoma, necrosis (infarct), microvascular proliferation (usually pericystic), and nuclear atypia (smudgy chromatin) are of no significance in absence of obvious anaplasia. However some pointers are worthy of consideration: MIB1 LI of >2% is a risk factor for recurrences in pilocytic and neurocytomas. When high MIB1 is associated with microvascular hyperplasia and palisaded necrosis in neurocytomas, the risk of recurrence is more in extraventricular and spinal than central neurocytoma. Mixed glial-neuronal neoplasm is a growing category: in its frequency due to regular use of immunohistochemical stains and better understanding of pathologists, as well as description of newer entities such as DNT, RGNT, EVN and others.

Most common grade II tumor is a diffuse fibrillary astrocytoma typically seen in supratentorial compartment. Prognostic factors for adult supratentorial WHO grade 2 astrocytomas are poorly defined. Multivariate analysis from a large prospective trial (EORTC 2002) showed that age >40 years, histology (absence of oligodendroglial component), tumor diameter >6 cm, tumor crossing the midline, and presence of neurologic deficit before surgery were unfavorable prognostic factors for survival. Presence of two factors identifies the low-riskEpendymomas (grade II) occur mainly in children in infratentorial compartment, in adults in spinal cord (most common glioma at the site, and associated with NF2 mutation), and supratentorially in either age group. Clear cell and tanycytic variants have predilection for supratentorial and spinal cord respectively. Ependymomas are diagnosed by perivascular pseudorosettes, and less common but more definitively by true ependymal rosettes/ canals in combination with cytologic features. Rosettes are less conspicuous in cellular and tanycytic variants. Adverse prognostic factors include children (especially <3 yrs), posterior fossa, incomplete resection, anaplasia (high cell density and brisk mitoses), MIB1 LI >4% and CSF seeding. Anaplastic ependymomas need to be differentiated from PNET.

High grade gliomas
Anaplastic astrocytoma, diagnosed by a combination of hypercellularity (regional), significant nuclear atypia and marked mitoses, but without prominent microvascular proliferation or necrosis. MIB1 LI is usually 6% or above.
Glioblastomas (grade IV) are typically diagnosed by prominent microvascular proliferation and necrosis with/without pseudopalisading in an anaplastic astrocytic tumor. They are of two main clinical-molecular types: Primary (95%) – seen in older age (mean 55 yrs), with rapid onset (<3 months), large tumors, central necrosis, ring enhancement, perifocal edema, and typically showing -9p (p16), +12q (CDK4 & MDM2) thus disrupting both p53 and Rb pathways, -10q (PTEN), and EGFR amplification (35%). Secondary type (5%), occurs in younger patients (mean 40 years), evolves from pre-existing low grade tumors (fibrillary/gemistocytic astrocytomas), and show loss of both p53 and Rb alleles, p16 promoter methylation, and -10q, but usually no amplification of EGFR or CDK4.

Favorable prognostic factors include age <50 years, higher post-op Karnofsky score, resection of contrast enhancing tumor, giant cells (hypertriploidy), oligo- component, classic capillary pattern, LOH 1p (10% cases), over expression of mitochondrial caspase activator, and promoter methylation based silencing of MGMT (a DNA repair gene). Unfavorable prognostic factors include post-operative residual tumor, large area of necrosis, glomeruloid pattern, high MIB-1 or DNA topoisomerase II alpha LI, increased quantitative angiogenic parameters (MVD), significant VEGF positivity, EGFR amplification, Her2/neu amplification, Neuropilin1 overexpression, combined PTEN and Rb1 pathway (p16, RB1, CDK4) mutations. Overall, the above molecular events contribute to infiltrative ability and resistance to radiation / chemotherapy, the two most important hindrances to longer survival in glioblastomas. Recently, a sizable subset of glioblastoma patients with MGMT promoter methylation reportedly responded better to radiation with/without temozolamide with improved 2-year survival. Selective anti-EGFR, anti-Her-2/neu and other similar molecularly targeted chemotherapeutic agents are also being evaluated for use in smaller subsets of glioblastomas.

Medulloblastomas, the most common pediatric brain tumor are characterized by embryonal round cell histology, Homer Wright rosettes, immunochemical expression of synaptophysin and nestin. Isochromosome 17q (50% cases), altered Wnt pathway, amplification of MYC and less often MYCN genes are known to occur. The typical t(11;22) with EWS/FLI1 fusion of peripheral PNET are usually absent. Two variants are of importance: (a) Desmoplastic (favorable prognosis), characterized by synaptophysin positive, reticulin poor and low MIB1 labelling differentiated nodules, separated by reticulin rich, high MIB1 labelling undifferentiated cells. Extensive nodular variant in infants similarly has a favorable course. (b) Anaplastic (unfavorable prognosis) shows association with MYCC/MYCN amplification. Age <3 years, supratentorial location (PNET), anaplastic variant, MYC amplification and metastatic tumor at presentation are unfavorable prognostic indicators. Desmoplastic variant and B-catenin nucleopositivity are thought to be favorable prognosticators.
In pineal parenchymal tumors, pineoblastomas and tumors of intermediate differentiation are potentially aggressive with risk of CSF seeding. The main prognostic factor is the extent of disease at diagnosis. Pineocytomatous rosettes with lobular growth characterize the differentiated pineocytomas which have favorable prognosis.

Atypical teratoid/rhabdoid tumor (ATRT) is a specific, usually pediatric, embryonal tumor showing diverse histology with rhabdoid, PNET (2/3rd cases), mesenchymal (1/3rd) and epithelial (1/4th) components. It is more common in infratentorial (typically invasive CP angle tumor) than supratentorial location. Typical genetic feature is deletion of chromosome 22 involving INI1 gene. Prognosis is uniformly grim (median survival <1 year).
In our experiences, evidence based approach was particularly helpful in (i) differential diagnosis of entities showing morphologic overlap such as PXA vs GBM, PNET vs ependymoma, PNET vs GBM, oligodendroglioma vs neurocytic tumors and others, (ii) identification of prognostically distinct variants, such as desmoplastic medulloblastoma, and (iii) prognostic and predictive indicators in individual cases.
In summary, evidence based guidelines enable the pathologists to diagnose specific clinicopathologic entities and variants of central nervous system tumors with greater accuracy, provide prognostic stratification, predictive parameters for targeted therapy, and prepare a foundation to readily incorporate newer advances.

References :
1. Cenacchi G, Giangaspero F. Emerging tumor entities and variants of CNS neoplasms. J Neuropathol Exp Neurol 2004; 63: 185-192.
2. Gupta M, Djalilvand A, Brat DJ. Clarifying the Diffuse Gliomas : An update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol 2005; 124: 755-768.
3. Kleihues P, Cavenee WK. Pathology and Genetics of Tumors of Nervous System. World Health Organization Classification of Tumors. IARC Press, Lyon, 2000, pp 1-148
4. Kreth F, Faist M, Rossner R, Volk B, Ostertag C. Supratentorial World Health Organization Grade 2 astrocytomas and oligoastrocytomas. A new pattern of prognostic factors. Cancer 1997; 79: 370-9.
5. Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW. Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 2004; 10: 5482-93.
6. Pignatti F, Bent MV, Curran D, Debruyne C et al. Prognostic Factors for Survival in Adult Patients With Cerebral Low-Grade Glioma. Journal of Clinical Oncology 2002; 20: 2076-2084.