Institute of Basic Medical Sciences

IBMS

Glioblastoma Multiforme

Assignment submitted by:

Dr Mohammad Manzoor Mashwani,

M.Phil Scholar,

Subject: Histopathology

Assignment submitted to:

Dr Nuzhat Sultana Khattak,

Assistant Professor,

Histopathology,

IBMS, KMU

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Table of Contents

Introduction 3

Causes 3

Pathophysiology\ Pathogenesis 4 Clinical features 6

Diagnosis 7

Histopathology 8

Treatment 9

Prognosis 10

References 12

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Introduction

Gliomas:

1. Astrocytomas Infiltrating & Non-infiltrating2. Oligodendrogliomas3. Ependymomas

Diffuse astrocytoma (grade II/IV)Anaplastic astrocytoma (grade III/IV)Glioblastoma - GBM (grade IV/IV).

(The grade I/IV category is limited to pilocytic astrocytoma.)

Glioblastoma Multiforme. It is the most common malignant primary tumor of the brain. It is very aggressive, involving glial cells. GBM is 20% of all intracranial tumors and 52% of all tissue brain tumors. In North America and Europe incidence is two to three per hundred thousand.GBM incidence is only 2–3 cases per 100,000 people in Europe and North America. Of the 17,000 brain tumors in the USA per year, 60% are gliomas. GBM differ in location within the CNS, in age and sex distribution, in growth, in invasiveness, in histological features, in progression, & in response to therapy.

There are 2 variants of GBM:

1. Gliosarcoma 2. Giant Cell Glioblastoma.

GBM treatment can be Chemotherapy, radio surgery, radiation, corticosteroids, surgery, antiangiogenic therapy and gene transfer.

Prognosis is worst. Median survival time despite of multimodality treatment is fourteen months.

Causes

The exact cause is unknown but changes or loss of chromosome 17 & inactivation of p53 has a role.

Gender: Men are more affected than women.

Most cases are sporadic.

Viruses like CMV or SV40 may be the cause.

There is some association of GBM with polyvinyl chloride, radiation, malaria and lead exposure.

Age: above fifty years.

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Ethnicity: Asians, Caucasians

Pathophysiology /Pathogenesis

GBM have necrotizing tissues which are surrounded by anaplastic cells. This along with hyperplastic vessels distinguishes GBM from astrocytomas grade III.

Types of GBM:1. Classical GBM:

This type has extra copies of the EGFR gene in 97% of cases. They have higher expression of EGFR gene.

2. Proneural GBM: This type shows greater alterations in IDHI, TP53, & in PDGFRA.

3. Mesenchymal GBM:Alterations & mutations in Neurofibromatosis type 1(NF1).

4.

G BM can be primary or secondary. Primary GBM is sixty percent. These manifest de novo .

Secondary GBM is 40% develop in younger patients less than forty five years of age. Malignant transformation from a low to anaplastic astrocytoma requires one to ten years. There is genuine evidence which indicates that primary & secondary GBMs are distinct entities. Different genetic pathways involve in GBM.

Common genetic abnormalities are:

1. LOH: Loss of heterozygosity on arm 10q is the most common gene change for glioblastomas.This occurs in sixty to ninety percent of cases. This alteration is specific for GBM associated with poor survival.

2. p53:. The p53 gene deletes or alteres in 25-40% of GBM, more frequently in secondaryGBM.[6]

3. Epidermal growth factor receptor gene: It is involved in the control of cell proliferation. There is over expression as well as rearrangement of receptor. It is more common (40-50%) in primary GBM. EGFRvIII is a target for kinase inhibitors & peptide vaccines.[11, 12, 13, 14, 15, 16, 17]

4. MDM2: Overexpression or amplification of MDM2 is an alternative mechanism to escape from p53 -regulated control of cell growth. It binds to p53 and diminishing its activity.

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MDM2 overexpression is the 2nd most frequent (10-15%) gene mutation in GBM. This mutation is associated with a worse prognosis.[7]

5. Platelet-derived growth factor–alpha gene: This is a major mitogen for glial cells. It binds to plate-derived growth factor receptor. In secondary GBM it is typically overexpressed.

6. PTEN: It is also called MMAC &TEP1 encodes a TP located at 10q23.3. It is more frequently found in primary GBM.[14, 18, 19]

Rare mutations:

MAC1-E1 - A MAGE-E1 - A NRP/B – A

Additional alterations in primary GBM :

p16INK4A, p16 deletions (30-40%), & retinoblastoma (RB) gene.

Genetic alteration in 2ndary GBM:

LOH at chromosome arm 19q (50%),

RB protein alterations (25%),

PTEN mutations (5%).

GBM occur most frequently in the subcortical white matter (the cerebral hemispheres). The commonly affected sites are the temporal (31%), parietal (24%), frontal (23%), and occipital (16%) lobes.[20] The typical location is frontotemporal. Tumor infiltration commonly extends into the adjacent cortex /the basal ganglia. Glioblastoma Multiforme grow quickly, producing symptoms when become sufficiently large.

1. Some (< 10%) form slowly. These follow degeneration of low-grade astrocytoma/ anaplastic astrocytoma. These are common in younger patients and are called secondary Glioblastomas and are more common in younger. Mean age forty five versus sixty years.

GBM may extend into the meninges or ventricular wall, leading to high protein content in the CSF. Cancer cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. About half of GBMs are bilateral. GBM may take on a variety of appearances, depending on the amount of hemorrhage, necrosis, or its age.

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Clinical Features:

Clinical features largely depend on the location of the tumor than on its pathological characteristics.

Following are signs and symptoms found in Glioblastoma multiforme:

Headache

Personality change

Visual loss

Paralysis or sensory loss

Increased pressure inside skull

Headache frontal lobe tumor

Vomiting frontal lobe tumor

Impaired memory frontal lobe tumor

Intellectual disability frontal lobe tumor

Convulsions frontal lobe tumor

Paralysis on one side of body

Seizures parietal and frontal lobe tumor

Poor coordination temporal lobe tumor

Impaired speech

Personality changes frontal lobe tumor

Lack of emotion frontal lobe tumor

Reduced ability to interpret language temporal lobe tumor

Motor disturbance temporal lobe tumor

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Agraphia parietal lobe tumor

Paresthesia parietal lobe tumor

Loss of positional awareness of body parts parietal lobe tumor

Sensory changes parietal lobe tumor

Spatial disorientation parietal lobe tumor

Diagnosis

Biopsy is the gold standard.CT, MRI, stereotactic biopsy, craniotomy along with tumor resection

and microscopy are required to confirm the diagnosis.

A neurologic examination by the neurologist should be done if there signs and symptoms of increased pressure inside the skull that is signs of mental dysfunction, seizures, persistent headaches vomiting, and swelling of the eye.

To determine that whether the tumor is primary or secondary complete examination is necessary that is MRI, CT scan, and a chest X-ray. Magnetic Resonance Imaging finds low-grade astrocytomas earlier than computed tomography scan.

Following are some specialized tests which may be done depending on the clinical features:

Field of vision,

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The sharpness of vision &

Hearing.

Fluid examination may be done in case the above mentioned tests are not conclusive. Fluid that surrounds the brain and spinal cord is done.

Histopathology:

Macroscopy or Gross: Lesions are poorly delineated. The tumor mass consists of necrotic tissues. Necrotic tissue is surrounded by hypercellular tissue. Macroscopic appearance of the GBM from region to region is different. Some areas are yellow & soft, some areas are firm and white others show areas of cystic degeneration, hemorrhage and necrosis.

Microscopy: It is characterized by poorly differentiated, pleomorphic, neoplastic astrocytes. There is marked nuclear atypia & high mitotic activity. Necrosis & vascular or endothelial cell proliferation are important for diagnosis. Necrosis in GBM commonly occurs in a serpentine pattern in regions of hypercellularity. Cancer cells gather along the edges of the necrotic areas, producing a specific pattern known as pseudo-palisading. Vascular cell proliferation is has tufts of piled-up cells. These bulge into the lumen. Double layer is the minimal criterion for this feature. The glomeruloid body can be seen, which is a rounded structure formed by the tuft due to increased vascular cell proliferation. Vascular endothelial growth factor causes this vascular change. Hypoxia makes malignant astrocytes to produce VEGF.A small single biopsy may be deceivable because of different histological features in different areas.

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Treatment

Treatment of GBM is difficult due to the following factors:

The cancer cells are resistant to conventional therapies The brain is vulnerable to damage due to conventional therapy The brain has a limited capacity to repair itself Many drugs cannot cross the BBB to act on the tumor

Symptomatic therapy

Anticonvulsants & corticosteroids are used to relieve symptoms and improve neurological functions of the patient.

Palliative therapyIt improves quality of life and achieves a longer survival time. It includes chemotherapy, surgery and radiation therapy. Prognosis is strongly associated with gross total resection of tumor.

Surgery It is the 1st stage of treatment of GBM. After surgery a reduction of 99% occurs in tumor cells. It is better to remove more than 98% of tumors which has better survival rate.

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Surgery is used for the purpose of biopsy, to remove a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival. Recurrence is common despite total resection.

Radiotherapy

It is the main treatment after surgery. It increases the median survival time more than double. It can reduce the tumor size to 107 cells. The more precise and targeted three-dimensional conformal radiotherapy is sufficient. Radiation dose of 60–65 Gy is optimal for treatment.Chemotherapy

Temozolomide sensitize tumor cells to radiation and improves median survival.

Avastin (bevacizumab) reduced tumor size in some GBM patients. Bevacizumab reduces brain edema and consequent symptoms.

Gene transfer

It is a promising approach for fighting GBM. Trial for the potential treatment of GBM is continued.Protein therapeuticsAPG101 inhibits the invasive growth of GBM cells. It inhibits the binding of the CD95-Ligand to its cognate receptor which stimulates the invasive growth of the tumor cells. Thus, the inhibition of this interaction by APG101 reduces tumor cell migration. Immunotherapy

Relapse of GBM is due to the recurrence and persistence of tumor stem cells. A tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the GBM. Tests of different EGFR signaling patterns and their relationship to tumor stem cells are in progress to further assess this approach to treating GBM. Alternating electrical fieldsThese interfere with the division of cancer cells. It is a new approach to GBM treatment. AEF is being explored for the 1st time in the treatment of GBM. In an EFof given wavelength, cells attempting to divide will be destroyed. This treatment is optimal for brain tumors in that normal brain cells do not divide, but malignant cells within the brain divide. GBM patients treated with AEF wear electrodes attached to the device. Metabolic therapyMalignant cells are unable to use fats as an energy source. They are completely reliant on glucose, and glutamine for their energy. Healthy neurons use ketones as efficient energy sources. Removing carbohydrates from the diet starves the malignant cells without damaging the healthy neurons RecurrencesGBM usually reappears although disease free condition is achievable. Mostly it occurs within 3 cm of the original site but may occur in 10–20% cases at distant sites.

Prognosis

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Prognosis without treatment is three months survival and with treatment it is upto two years. Older patients have worse prognosis. Cerebral edema is the common cause of death.Karnofsky Performance Score and MGMT methylation are associated with longer survival. Patients with a methylated MGMT promoter have been associated with greater long-term benefit than patients with an unmethylated MGMT promoter..Patients who receive surgery, radiotherapy, and Temozolomide chemotherapy have long –term benefit.

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