Tuesday, April 28, 2015

The Tumor Biomarker Series: BRAF

Aberrant constitutive activation of BRAF tends to be seen in cerebellar and midline pilocytic astrocyomas whereas the activating point mutation at BRAF V600E is more likely to be seen in cerebral examples. The V600E point mutation is also observed in other low-grade gliomas and glioneuronal neoplasms, including approximately two-thirds of pleomorphic xanthoastrocytomas, and lower percentages of ganglioglioma, desmoplastic infantile ganglioglioma, dysembrioplastic neuroepithelial tumor, and papillary craniopharyngioma. Although less common, diffusely infiltrative gliomas including glioblastoma, particularly the epithelioid variant, may also demonstrate the V600E point mutation -- making this biomarker potentially less useful as a diagnostic tool in distinguishing low-grade gliomas from high-grade ones.

Tuesday, April 21, 2015

The Tumor Biomarker Series: MGMT

MGMT stands for O6-methylguanine-DNA methyltransferase. I must admit that this is my favorite biomarker only because of its cool mechanism of action.  The standard chemotherapy for gliomas is temozolomide, which acts by cross-linking DNA through alkylating multiple sites including the 06 position of guanine. Crosslinking at this site is reversed by the DNA repair enzyme MGMT. Thus, low levels of MGMT activity by GBM cells is associated with enhanced response to alkylating agents such as temozolomide. To a large degree, the activity level of MGMT is determined by the methylation status of the gene's promoter. MGMT can be epigenetically silenced by hypermethylation. About half of all GBMs are epigenetically silenced in this manner and are therefore more susceptible to the alkylating action of temozolomide.  The methylation status of MGMT can be assessed by PCR-based testing. In addition to predicting better response to temozolomide, investigators have shown that epigenetic gene silencing of MGMT is a strong predictor of prolonged survival independent of treatment.

Thursday, April 16, 2015

The Tumor Biomarker Series: TP53

A few month ago, the College of American Pathologists released a Template for Reporting Results of Biomarker Testing of Specimens from Patients with Tumors of the Central Nervous System. Therefore, I thought it would be a good idea to review as succintly as possible the various tumor biomarkers one could use to interrogate CNS tumors. Not all neuropathologists would agree as to which ones, if any, are essential. So, comments are most welcome! The first biomarker I'd like to address is TP53, mainly because I have doubts about it's utility -- except for cases where there is a question regarding whether or not an oligodendroglial component is present. However, immunohistochemical p53 testing is performed on virtually all high-grade astrocytomas at many institutions. Here's a summary of the CAP consensus description of the TP53 test:

Found in a majority of high-grade astrocytic tumors, TP53 mutation is rare in oligodendrogliomas. Mutation of TP53 is highly correlated with IDH mutation. As a surrogate for testing the actual TP53 mutation, p53 immunohistochemistry is typically performed. As for the utility of this test, the CAP template makes the following statement: "[T]here is a strong association between IDH1 mutation and TP53 mutation in diffuse astrocytomas and this combination of mutations is helpful in distinguishing astrocytomas from oligodendrogliomas."

My feeling is that if you have a histomorphologically classic pure astrocytic neoplasm, there is no need for p53 immunohistochemistry. And, yet, you almost always see p53 immunohistochemistry results on reports for classic glioblastomas, anaplastic astrocytomas, and infiltrative astrocytomas. I just don't get it. Even in cases where you have a question about the presence of an oligodendroglial component, testing for IDH1 mutation and 1p/19q deletion would be more helpful than testing for IDH1 and TP53. I would love to hear from people who could dissuade me of this opinion regarding the utility of p53 immunohistochemistry. Feel free to enter comments below.

Tuesday, April 14, 2015

Best Post of November 2014: Robin Williams had Lewy Body Diesease

The next in our "Best of the month" series is from November 18, 2014:


Robin Williams

The official cause of Robin Williams' death, released Friday by the Marin County coroner, was ruled

Williams had long battled alcoholism, drug addiction and depression, but in November 2013 he was diagnosed with Parkinson's disease, according to his widow, after noticing a tremor in his left arm and difficulty moving on his left side as early as 2011.

Now a redacted pathology report from the autopsy on Williams' body has been made public and mentions "Diffuse Lewy body dementia,". Given that Dementia with Lewy Bodies can involve vivid visual hallucinations, it has now been speculated that perhaps such hallucinations may have lead to Williams' death.

Media reports, quoting anonymous "family sources," state that Williams' family believes that Lewy body disease was a critical "triggering" factor in his suicide. If so, this would be an unusual manifestation of the disease. Suicides have not been linked specifically to the hallucinations of Lewy Body Disease in the past.

Dennis Dickson, MD
"The use of the term dementia in the neuropathology report should not be inferred to mean that dementia was observed during life," warns Dennis Dickson of the Mayo Clinic in Jacksonville, who says he reviewed the neuropathology report.

"Mr. Williams was given a clinical diagnosis of (Parkinson's) and treated for motor symptoms. The report confirms he experienced depression, anxiety and paranoia, which may occur in either Parkinson's disease or dementia with Lewy bodies," Dickson said.