Low-Grade and High-Grade Gliomas

Shikher ShresthaNINAS

Low-Grade Gliomas – Management Perspective

Previously considered reliable diagnostic strategies – MRI and biopsy:vary substantially w.r.t. specificity, sensitivity and sampling error

Predictive values for patient survival:

volumetric tumor burdenextent of resection – greater resection reduces

malignant transformation ratetumor eloquence – determining resectability

LGG-associated seizures – key determinant of quality of life

New innovations and controversy: chemotherapy and molecular therapeutics

Epidemiology..

LGG – 15% of all primary adult brain tumors

Typically affects younger age groups (40s-60s)

Particular predilection for the insula and supplementary motor area

Most common symptom at presentation: seizure (80%)

Only definitive risk: exposure to ionizing radiation

Hereditary factor – no substantial role; though may be associated with NF-1 and Li-Fraumeni syndrome

15-20% patients with NF-1: LGG affecting the optic nerves, optic chiasm and hypothalamus (optic pathway glioma)

Etiology: largely unknown and multifactorial – genetic, infectious, immunological

Association between drinking water and brain tumor:chlorinated sources (cholroethane)nitrate/nitrite contamination

Adults with LGG/HGG – 1.5-4 fold less likely than controls to have allergies

inverse relationship between IgE and glioma riskelevated IgE in patients with glioma favors an approximate 8

months longer survival

Classification..

Gliomas classified according to predominant cell type

Graded based on presence or absence of necrosis, mitotic figures, nuclear atypia and endothelial cell proliferation

LGG = Grade I and Grade II lesions

WHO grade II astrocytoma: cellularity moderately increased and occasional nuclear atypia: BUT mitosis, endothelial proliferation and necrosis absent

3 histological subtypes of astrocytoma

Fibrillary Astrocytoma Most frequent variantlow cellularity with minimal nuclear atypiaexpresses intermediate GFAP positivity

Gemistocytic Astrocytoma plump, glassy, eosinophilic cell bodies of angular shape; consistently express GFAP

more prone to malignant transformation

Protoplasmic Astrocytoma rarest histological subtypesmall bodied astrocytes with few processesscant GFAPmucoid degeneration and microcystic formation

common

Oligodendrogliomas..

Show a monotonous pattern on low power with occasional nodules of higher cellularity

Nuclei are round and regular, and clear perinuclear halos are present in most paraffin embedded specimens

Typical “fried egg” appearance – formalin fixation artifact and therefore, not seen in frozen sections, smears, or rapidly fixed specimen

Oligoastrocytomas..

Ill-defined, prone to subjectivity, and based on an unproven concept of dual differentiation of astrocytoma and oligodendrogliomas as neoplastic processes

Mixture of cells resembling both oligodendroglioma and astrocytoma

No standardized immunohistochemisty or molecular panels to distinguish it from other LGGs

Clinical Presentation..

Seizure – most common presenting sign – 80% - due to superficial localization

Headache, lethargy, personality change

Depends on the location of tumor

Edema, hemorrhage, tumor mass effect

Features of raised ICP and ventricular obstruction

Prognostic Factors..

Age at the time of diagnosis inversely correlated with time to progression

age related impairment of DNA repair mechanismsacquisition of mutations promote rapid progression

Clinical presentation: Neurologically intact patients presenting with isolated seizures have better performance status and overall prognosis

LGG preoperative prognostic scoring systemUniversity of California at San Francisco (UCSF)Prognostic score based on the sum of points assigned to each of the following factors (1 point per factor):

location of tumor in presumed eloquent cortex

Karnofsky performance scale (KPS) score 80 or less

Age more than 50 yrs

Maximum diameter of tumor > 4cm

Low risk tumors are grade 0 or 1 and high risk tumors are grade 4

This scoring accurately predicted OS and PFS of LGG patients

Median survival Oligodendroglioma (better): 15 years

Astrocytoma: 10 years

Larger tumors, non lobar gliomas and tumors that cross the midline: short survival and high rate of malignant transformation

Proliferative index and contrast enhancement – inversely related to LGG outcome

Prognosis based on KPS and contrast enhancement..

4 categories of patients in distinct prognostic classes:

Younger patients (18-40 yrs) with a good performance status (KPS >or= 70) have a median survival of more than 10 years

Younger patients with a poor performance status (KPS <70) and older patients >40 yrs with good performance status and no contrast enhancement had a median survival of > 7 yrs

Older patients with a good performance status and contrast enhancement had a median survival <4yrs

Older patients with poor performance status- median survival of 12 months

EORTC (European Organization for Research and Treatment of Cancer) Prognostic scoring system..Adverse Factors:

Age > 40 yrsAstrocytic tumor typeTumor size > 6cmTumor crossing the midlineNeurological deficit at diagnosis

Favorable prognosis: no more than 2 of the adverse factors median survival of 7.7 yrs

3 – 5 adverse factors median survival of 3.2 yrs

Diagnostic Imaging..

MRI1.5 T MRI – the gold standard

T1 weighted – homogenously isointense to hypointense

T2 weighted – hyperintense

Epicenter of low grade astrocytoma – white matter

Oligodendroglioma – can be more superficial and occasionally expand to adjacent gyrus

contrast enhancement uncommon – 25-50% of oligodendrogliomas can have

Calcifications – 20% of lesionslow T1 and low T2 signals

Vasogenic edema and mass effect – uncommon due to slow growing nature of tumor

Rarely, large LGGs involve 3 or more lobes – GLIOMATOSIS CEREBRI

DTI (Diffusion tensor Imaging): specification of functional tract deflection

helpful for preoperative planning and intraoperative neuronavigation

can dictate the limit of resection

Functional MRI (fMRI) – for identification of functional pathways

too imprecise for complex functions like language mapping with sensitivity and specificity of 81 and 53% only

Direct intraoperative stimulation mapping – gold standard

Intraoperative MRI – real time guidance; localization of tumors and their margins

encouraging results in terms of achieving greater extent of resection

Structural MRI has a false positive rate as high as 50%

Misleading imaging features likely due to intrinsic heterogeneity of LGGs

Physiological MRI like MRS (magnetic resonance spectroscopy)demonstrates pockets of high-grade populations nested within the

tumor stroma

implication: stereotactic biopsies planned using MRS guidance to target putative high-grade components in non enhancing tumors

Diffusion weighted MRI (DWI) – measures microscopic molecular movement of water in tumor tissue

reflects varying levels of structural alterations, tumor cellularity and vasogenic edema

acquiring data with gradients in 3 directions allow calculation of ADC and in 6 or more directions allow the calculation of ADC and FA (Fractional anisotropy)

Proton MRS imaging (1HMRS) – identifies distribution of cellular metabolite levels

5 classes of molecules: N-acetylaspartate (NAA), free choline and choline containing compounds including phosphocholine and glyecerophosphocholine (Cho), Creatine and Phosphocreatine (Cr); Lactate (Lac); and Lipid (Lip)

LGG – dominant Cho peak – increased membrane synthesis

low NAA – decreased neuronal elementsno quantifiable lipid or lactate – absence of

necrosis or hypoxia

Normalized creatine/phosphocreatine levels – significant prognostic factor for progression free survival and malignant progression free survival

MRS – discriminate radiation necrosis from tumor progressionmonitor treatment progress

Relative cerebral blood volume (rCBV) – derived from dynamic susceptibility weighted perfusion contrast enhanced MRI (DSC-MRI)

correlates with tumor behavior and patient survivalspecifies regional tumor vascularity and expression of VEGF

most astrocytomas demonstrate slightly higher rCBV than normal tissue – 1.5

increase in rCBV further indicates evolution of more aggressive tumor

low grade oligodendrogliomas have paradoxically high rCBV

PET (Positron Emission Tomography)

FDG PET - LGGs are hypometabolic in contrast to HGGs, which are hypermetabolic

uptake of radiolabeled amino acids is increased in ~2/3 rd of LGG

18 F-FET PET (using tyrosine) – used in LGG for predicting outcome

Surgery and the Value of Extent of Resection..

More extensive surgical resection: more favorable life expectancy

influences malignant transformation

Special considerations: Malignant Transformation..

Malignant degeneration carries dramatically worse prognosis

Documented incidence of transformation: 17-73% over 15 yrs

Median interval for transformation: 2.1-10.1 years

Several recent studies have examined malignant transformation in the context of extent of resection risk of progression increases with tumor burden

Greater preoperative tumor volume significantly associated with shorted malignant progression free survival

Larger tumor at presentation have inherent faster growth rate, thus recur faster

Tumor growth rate study in 143 patients showed

median survival of 5.16 yrs – with growth rate of 8 mm per year or more

median survival of 15 yrs – with growth rate less than 8 mm per year

Sequential measurement of LGG volume allows accurate determination of growth rates and identification of patients whose tumors are at high risk for early transformation

Aggressive resection has the ability to manipulate the natural history – favors earlier intervention and argues against the validity of a simple biopsy procedure or wait and watch approach

Mapping Functional Pathways..

MRI neuronavigational techniques not only facilitate greater resection, but embedding DTI-based tractography can prevent inadvertent resection of adjacent subcortical pathways

Offers – maximal tumor resection with minimal morbidity

Intraoperative motor mapping can safely identify corridors for resection, as well as define the limits of tumor resection

Prediction of cortical language sites through classic anatomical criteria is inadequate because of individual variability of cortical organization, distortion of cerebral topography from tumor mass effect, and the possibility of functional reorganization through plasticity mechanism

The capacity for the brain to reorganize itself is critical for the process of functional recovery in patients following CNS injury

More progressive lesion like LGG can induce large-scale functional reshaping

That is why, slow infiltrative LGGs within the eloquent areas often do not induce detectable neurological deficits

When functional tissue is located within the tumor nidus, the standard surgical principle of debulking tumor from within is not always safe

Intraoperative stimulation mapping in the resection of eloquent LGGs is associated with an improvement in overall survival

Adjuvant Treatment..

Chemotherapy

Recent studies – “upfront chemotherapy” – ie, immediately following resection of a newly diagnosed LGGs

either procarbazine/CCNU/vincristine (PCV) or temozolomidePhase II trials provide little conclusive evidence in terms of OS

measuring response in absence of contrast enhancement is a challenge

in select cases- temozolomide associated with improved quality of life, better seizure control and longer progression-free survival

true advantage of upfront chemotherapy compared to initial radiotherapy is currently under investigation

For patients with bulky disease and neurological deficit, this is a reasonable strategy prior to implementation of radiotherapy

Temozolomide (methylating agent) best responders are:

patients with oligodendrogliomas and mixed oligoastrocytomas

1p/19q loss of heterozygosity

EORTC – reported 50% response rate for recurrent oligodendrogliomas

progressive and recurrent LGGs have overall response rate of 30% and a progression free rate of 56.7 %

No advantage of PCV when radiotherapy (54 Gy) compared to radiotherapy followed by 6 cycles of standard dose of PCV

Radiation therapy:

EORTC – advantage for immediate postoperative radiotherapy in terms of progression free survival (5.3 yrs compared with 3.4 yrs) but not for OS

higher dose of radiation (>45-50 Gy) have failed to demonstrate an improved outcome and are associated with increased late toxicity

high risk or progressive tumors have been randomized between primary radiotherapy or primary chemotherapy with low dose temozolomide for up to 1 year (12 cycles) – ongoing EORTC

Possibility of SRS beyond fractionated radiotherapy – no data exist to support this strategy beyond small, retrospective case series.

High Grade Gliomas..

GBM may arise from 2 distinct pathways

SECONDARY or TYPE I GBM:

develop in younger patients (5th to 6th decades)

tumors progress from lower grade (II or III) astrocytic tumors

time to progression ranges from months to decades

contain p53 mutations, especially involving codons 248 and 273 or G:C A:T mutations at CpG sites

PRIMARY or TYPE II:

develop in older individuals (6th to 7th decade)

have shorter clinical history (less than 3 months)

arise de novo without any evidence of a lower grade percursor

relatively high frequencies of EGFR amplifications, PTEN deletion, and CDKN2A (p16) loss

Pathology..

Heterogenous cellular composition – fibrillary, gemistocytic and occasional giant cells

Neoplastic fibrillary astrocytes – enlarged, elongated to irregularly shaped hyperchromatic nuclei with scant cytoplasm and variable GFAP immunoreactive processes

Mucin rich microcystic space

Oligodendroglial component if – significant fraction of cells have round uniform cells with sharp nuclear membranes and bland chromatin

Multimodal Management..

HGGs – poor prognosis, rapidly progressive and resistant to therapy

Infiltrative nature – majority recur within 2 cm of their original location

Median survival: 1 year for GBM, 2 years for anaplastic astrocytoma and 5 years for anaplastic oligodendroglioma

First option in management: Surgery – required for histological diagnosis

may entail biopsy or more aggressive resection

Radiotherapy: treatment with the greatest evidence base(increase in median survival from 3-4 mo to 9-10 mo)

Glucocorticosteroids: reduction of peritumoral edemaimprovement in neurological symptoms and survival

Chemotherapy: single agent or multiagent regimens

metaanalysis of chemotherapy in HGG – overall improvement of 2 months in median survival to 12 mo.

not clear whether the survival reflects a useful period of good quality of life

in grd III glioma – 2 RCTs – no increase in survival with PCV

Temozolomide: prolongs survival and time to progression without a significant risk of early adverse events

most effective in young and fit patients with debulking surgery

The Value of Extent of Resection..

No general consensus in the literature regarding the efficacy of extent of resection in improving patient outcome

Only patient age and tumor histological type – identified as reliable predictors of prognosis

Effect of glioma resection in extending tumor-free progression and patient survival remains unknown

Microsurgical resection a controversial value besides histological diagnosis and decompressing tumor mass effect

Among 16 studies, 11 demonstrated significant survival benefit with greater extent of resection

Mean survival following GTR vs STR in HGG studies differed by nearly 3 months

Lack of class I evidence prevents the establishment of convincing criteria guiding either low- or high-grade glioma extent of resection

Extent of resection is based on functional nature of the tissue

Effect of extent of resection for different ages and histological subtypes must be established

The question of impact of surgical resection on patient survival must be asked in the context of current prognostic factors (1p/19q and MGMT methylation status) and in the context of specific adjuvant therapy regimens

Thank you!!!