The Tumor Biomarker Series: EGFR

Epidermal growth factor receptor (EGFR) is the most frequently amplified oncogene in astrocytic tumors (>40% or GBMs and 5-10% of anaplastic astrocytomas). EGFR is far more often amplified in de novo GBMs as compared to secondary GBMs. About one-half of those GBMs with EGFR amplification also have specific EGFR mutations (the vIII mutant), which produce a truncated receptor with constitutive activity. Both EGFR amplification and EGFRvIII mutant are mutually exclusive with IDH mutations. So, what is the utility of EGFR testing? First, astrocytomas with EGFR amplification tend to be of higher grade. So if, for example, the diagnostician is vacillating between a WHO grade II and a WHO grade III tumor, positive EGFR amplification status would favor the latter. Secondly, EGFR amplification can also help distinguish between a small cell GBM (which would potentially harbor the amplification) from anaplastic oligodendrogliomas (which do not exhibit the amplification).

"Bad Ass" CrossFitter and Neuropathologist Greg Fuller set to compete in kettlebell competition for brain cancer research

Elite Neuropathologist

Elite Athlete

It's no secret that Dr. Greg Fuller (pictured) is the fittest neuropathologist in the world. What his colleagues might not know is that he is the 67th fittest man in the world for his age class (60+). Greg's wife, Tina, describes him as a "bad ass CrossFitter". As a former owner of a CrossFit "box" myself, I know what it takes to achieve Greg's level in the Sport of Fitness. It requires true grit. There are many of us who would also consider Greg a "bad-ass neuropathologist" -- in the very best sense of that phrase. He's bringing together his love of fitness with his commitment to the study of CNS malignancies by participating in the Kettlebells For Brain Cells competition in Boerne, Texas on June 13. (So, he has a legitimate reason for not showing up at the concurrent AANP annual meeting. in Denver.) All proceeds from the competition will be going to the American Brain Tumor Association. The event is being organized by a brain tumor patient at MD Anderson Cancer Center, where Greg is Chief Neuropathologist. This is a shining example of a neuropathologist reaching out to a patient in a very personal way. Best of luck in the competition, Greg. Crush it!

The Tumor Biomarker Series: Ki-67

An immunohistochemical marker of cellular proliferation, the nuclear antigen Ki-67 is positive in cells that are actively engaged in cell cycle (i.e., not in G0). Results are expressed as a percent index of positively staining cells. Several studies have shows a correlation between Ki-67 indices in various astrocytomas, oligodendrogliomas, and mixed gliomas. Among grade II and grade III diffuse gliomas, the Ki-67 index provides prognostic value. However, investigations have consistently shown that Ki-67 proliferation indices have no prognostic value on patient outcomes for GBM. So, if you have an unmistakable GBM under your microscope, you are not practicing evidence-based parsimonious medicine by ordering Ki-67 immunohistochemistry on that tumor.  On the other hand, if you are debating between diagnosing a grade III or a grade IV astrocytoma, Ki-67 can be helpful in swaying your decision. The Ki-67 index is not used in the WHO grading system because of the high degree of technical variability between laboratories, making standardization difficult.

The Tumor Biomarker Series: ATRX

Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX) is a gene that encodes a protein involved in chromatin remodeling. ATRX mutations are a marker of astrocytic lineage among the IDH-mutant gliomas and are mutually exclusive with 1p/19q codeletion. Present in 57% of secondary GBMs, ATRX mutations are uncommon in primary glioblastomas. Nearly all diffuse gliomas with IDH and ATRX mutations also have TP53 mutation and are associated with the Alternative Lengthening of Telomeres (ALT) phenotype. Immunohistochemistry for ATRX demonstrates loss of protein expression in neoplastic cells harboring the inactivating mutations, while expression is retained within non-neoplastic internal controls (such as endothelial cells).

The Tumor Biomarker Series: PTEN and LOH of chromosome 10

Loss of heterozygosity (LOH) of chromosome 10 occurs in most GBMs and less frequently in grade II and III diffuse astrocytomas. The phosphatase and tensin (PTEN) gene at 10q23.3 has been most strongly implicated as a glioma-related tumor suppressor on chromosome 10q, with PTEN mutations identified in about 25% of GBMs and less frequently in grade III astrocytomas. Losses of chromosome 10 and mutations in PTEN are considered to be specific for astrocytic differentiation and are rare in oligodendrogliomas. They are also markers of high-grade progression and aggressive clinical behavior in astrocytomas.