March 2019 - Presented by Dr. Peter Conner (Mentored by Dr. Mirna Lechpammer)


Glioblastoma, IDH wild type (also known as primary glioblastoma), is a high-grade glioma with an aggressive and malignant behavior. Unfortunately, it is also one of the most common malignant brain tumors in adults. The incidence for Primary Glioblastoma tends to be higher in men than women (around 1.35:1), and generally higher in Caucasians versus other ethnicities. There are not many known risk factors for developing primary glioblastoma; however, exposure to ionizing radiation to the head and neck has an established increased risk of developing this tumor. Additionally, a very small proportion of primary glioblastomas are considered inherited in people with certain congenital tumor syndromes such as: Turcot syndrome, Li-Fraumeni syndrome, and Neurofibramtosis type 1.

The clinical history of this tumor can differ from person to person depending on the progression of their disease. Patients can present with vague symptoms such as headache, nausea and vomiting; however, as with our patient, one of the most common presenting symptoms is a seizure, and around half of all patients with Glioblastoma will develop seizures as their disease progresses. Other common presenting symptoms include behavioral and neurocognitive changes as well other neurological deficits like paralysis or aphasia. Glioblastomas are often located in the subcortical white matter and deeper grey matter of the cerebrum.   The tumor can arise in one hemisphere and then infiltrate into the contralateral hemisphere through the corpus callosum. Tumor spread is often rapid and aggressive. In some cases, when both hemispheres are affected, the tumor spread can appear symmetrical, leading to what is commonly called a “butterfly” glioma.

Macroscopically, Primary Glioblastomas are often quite large at the time of diagnosis.  They are often poorly delineated, with cut surfaces having variable colors such as a greyish periphery with central areas of yellowish necrosis. Additionally, they are can be stippled with hemorrhagic foci, seen as brown or red dot-like areas.

Histologically, Glioblastoma is one of the most polymorphic of all neoplasms and can display regional heterogeneity within a single tumor. In general, they are typically hypercellular and have poorly differentiated cells with nuclear atypia and mitotic activity. Two features that are essential for this diagnosis are necrosis and vascular proliferation. Another microscopic hallmark of IDH wild type Glioblastomas are foci of ischemic necrosis surrounded by palisading tumor cells.

Advancements in molecular testing have allowed more recent classifications by the WHO to incorporate these findings into pre-existing histologic parameters, such as dividing glioblastomas into IDH-wild type and IDH-mutant categories.  However, potentially unsurprisingly, molecular studies of glioblastomas have shown significant heterogeneity in terms of tumor clonality and development.  Nevertheless, some markers have been found to show promise in providing prognostic indicators and potential therapeutic targets. Firstly, Isocitrate dehydrogenase, specifically IDH1 mutations, have been found in high frequency with precursor lesions of secondary glioblastoma, while being very rare in de novo (or primary) glioblastoma, only occurring in <5% of cases, leading to the categorization described above.  Still, recent studies have shown that loss of another marker, alpha-thalassemia/mental retardation syndrome X-linked (ATRX); which is more common in IDH-mutant astrocytic tumors, such as secondary glioblastomas, and carries a more favorable prognosis and may potentially provide a therapeutic target.  A peptide containing mutant of IDH1, R132H, has been shown to be immunogenic, suggesting that a treatment could be produced for IDH-mutant glioblastomas. Two genes that have attracted some study as therapeutic targets are the Epidermal Growth Factor Receptor (EGFR) and Phosphatase and tensin homolog (PTEN).  EGFR gene amplification has been seen in around 35-45% of primary glioblastomas. PTEN mutations are seen in around 25-35% of primary glioblastomas and are thought to be involved in tumor cell proliferation, migration and invasion. PTEN mutations are almost exclusively in primary glioblastomas.  Unfortunately, both EGFR and PTEN mutations may lead to pro-oncogenic effects and increased treatment resistance to both chemotherapy and radiation. Yet, testing for mutations in PTEN and EGFRvIII could potentially identify patients that could be responsive to EGFR kinase inhibitors. Additionally, another gene known as telomerase reverse transcriptase (TERT), has shown that activating promoter mutations are seen in over 80% of primary glioblastomas. This gene is commonly lost or downregulated in brain, breast, and prostate cancer. Lastly, testing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is currently the only molecular marker for IDH wild type Glioblastoma that can provide an improved prognosis as having MGMT promoter methylation can indicate a better tumor response to alkylating and methylating chemotherapy.

While the definitive treatment for Primary Glioblastoma is aggressive surgical resection; the micro-invasive nature and potential location of the tumor makes it extremely difficult to achieve a full resection.  Individual tumor cells can be found several centimeters away from the main tumor and are likely causes of recurrence in some patients. Now, with standard treatment including neoadjuvant chemotherapy (ex. Temodar) and radiation, overall survival is somewhat improved; the expected median survival range is still around 15 months with less than 5-10% of patients surviving beyond 5 years after diagnosis.

In conclusion, although this is a common diagnosis of brain tumors in adults, this patient’s unique clinical history of alcohol withdrawal related seizures and recent binge drinking could have led doctors to potentially overlook critical testing which was instrumental in finding this diagnosis, which led to providing early and aggressive treatment that will hopefully significantly prolong her life had this gone further unnoticed.


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