DecisionDx-GBM: Should every glioblastoma patient be getting this test?

What does the neuropathology community think of DecisionDx-GBM? This is a product offered by Castle Biosciences, based in Phoenix, AZ. DecisionDx-GBM is a gene expression profile test developed at The University of Texas M. D. Anderson Cancer Center for the purpose of increasing the accuracy of the prognosis and predicted responsiveness of glioblastoma multiforme to first line radiation plus temozolomide. The test is able to distinguish GBM tumors with a proneural phenotype (tumor signature) from those with a mesenchymal / angiogenic phenotype. Patients with a proneural phenotype tumor who are treated with first line radiation plus temozolomide experience a significantly longer median survival (over 7 years) compared to those patients with a mesenchymal / angiogenic phenotype tumor (approximately 1 year). According to the company website, the assay has been fully validated and has been available for clinical use since 2008. A study is ongoing to determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit from the addition of bevacizumab to temozolomide and radiotherapy. DecisionDx-GBM is also currently being incorporated into a number of other prospective and retrospective studies.

Is DecisionDx-GBM covered by insurance? Castle Biosciences states that the test receives reimbursement from a number of commercial insurance companies, and appeals to the Administrative Law Judge level for Medicare have resulted in favorable decisions for full payment. Should a patient need to pay out-of-pocket for this test, I could not find on the website what the cost would be.

Should we as neuropathologists recommend the use of this profile? Here is a an example of the kind of report that is generated when one orders the panel of 12 genes (3 of which are for control) upon sending a block of paraffin-embedded fixed tissue to the company. I would be interested in hearing people's opinions regarding this product, and whether there are others on the market which might be comparable. Please post!

American Association of Neuropathologists Links of Interest

From the AANP's website:

• ACCME
• Alzheimer’s Association
• American Academy of Forensic Sciences
• American Academy of Neurology
• American Brain Tumor Association
• American Neurological Association
• Association of Pathology Chairs
• American Society for Clinical Pathology
• American Society for Investigative Pathology
• Canadian Association of Neuropathologists
• College of American Pathologists
• CAP links to SAMS
• European Confederation of Neuropathological Societies
• International Society of Neuropathologists
• National Institutes on Aging
• National Institute of Neurological Disorders and Stroke
• National Prion Disease Pathology Surveillance Center
• Society for NeuroOncology
• Society for Neuroscience
• USCAP

Best Post of March 2012: Spinocerebellar Ataxia Type 6 autopsy photographs

The next in our "Best of the Month" series is from March 19, 2012:

On the left is the brain of an 82-year-old patient with a diagnosis of spincocerebellar ataxia, type 6 (SCA6). On the right is the brain of a 96-year-old "control" patient with Alzheimer disease:

Note comparative diminution of the cerebellum in the SCA6 patient.  Here's a closer look at the cerebellum:

SCA6 is one several autosomal dominant cerebellar ataxias. SCA6 results from a CAG trinucleotide repeat expansion in the CACNA1A gene on chromosome 19p.

A case of renal cell carcinoma metastatic to a meningioma

A 74-year-old woman with a history of a seizure disorder had been followed for several years with a stable and unsymptomatic left parasagittal dural-based brain tumor presumed to be a benign meningioma. Recently, though, the lesion increased in size and hemorrhaged, leaving her significantly paretic on the right side. Neurosurgery thereupon performed a craniotomy for tumor removal. Intraoperative frozen section diagnosis was meningioma. But, upon receipt of the permanent sections, I was impressed by the staghorn vessels at low power and hemangiopericytoma immediately came to mind.

Staghorn vessels prominent in region below dot marks

Psammoma body consistent with original impression that this was simply a meningioma

Whirled architecture consistent with meningioma

I was obviously dealing with a meningioma, but something else was going on in that area featuring the staghorn vessels. This region exhibited a different histomorphology:

Clear cells

High-power view of clear cell portion of specimen

This dual morphology puzzled me. I then discovered that back in 2003 the patient had undergone a radical nephrectomy for renal cell carcinoma. Surgical margins of the nephrectomy specimen were free of tumor. I retrieved the 2003 nephrectomy specimen, which looked quite similar to the clear cell portion of the brain tumor:

Nephrectomy specimen from 2003 showing renal cell carcinoma, clear cell type

I thereupon went back to the brain tumor specimen and did some immunohistochemical stains, including RCC for suspected renal cell carcinoma metastasis:

Positive RCC Immunohistochemistry

I had a case of renal cell carcinoma metastatic to a meningioma! Such a case had been reported in the literature before:

Han, HS, et al. Metastatic renal cell carcinoma in a meningioma: a case report. J Korean Med Sci. 2000 October 15 (5):593-597.

Here's case number two!

Follow-up: The patient received radiation to the tumor bed and is recovering.

Does anyone recognize this guy at his recent Oberlin College 50th Reunion?

Thanks to the ever-vigilant Dr. Mark Cohen for providing this photograph.

Start packing your bags: Next AANP meeting is in Charleston, SC

The 2013 Annual Meeting of the American Association of Neuropathologists will be held June 20-23, 2013 in Charleston, SC at the Charleston Place Hotel.

The Charleston Place Hotel in Charleston, South Carolina

Best Post of February 2012: Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

The next in our "Best of the Month" series is from February 24, 2012. To read the comments engendered by Dr. Eberhart's question, go to the original post.

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:

Hi Brian,

I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.

"Chasing The Dragon": A Cause of Toxic Spongiform Leukoencephalopathy

My favorite case from the 2012 AANP Diagnostic Slide Session in Chicago last month featured an autopsy slide from the brain of a 25-year-old man with a history of polysubstance abuse found unresponsive at a New Year's Eve party. Toxicology screening was positive for methadone, lorazepam, and cocaine. The patient died after three weeks in the intensive care unit. Attendees were provided glass slides in advance of the session demonstrating the following findings:

Low Power: Marked white matter pallor

High Power: White matter virtually replaced by lipidized macrophages

Presenter Joshua Menke, MD of The Mayo Clinic (Rochester, MN) revealed that white matter damage was diffuse, including infratentorial structures. The subcortical U-fibers were relatively spared and myelin was disproportionately affected as compared to axons, as demonstrated in these photomicrographs from Dr. Menke's presentation:

LFB stain on left and neurofilament stain on right

Discussants included Drs. Tessa Hedley-Whyte, Craig Horbinski, Mark Cohen, and others. Before the diagnosis was revealed, Dr. Horbinski stated that he thought Delayed Hypoxic Leukoencephalopathy might be the best fit for this case. Dr. Cohen pointed out that Delayed Hypoxic Leukoencephalopathy tends spare the infratentorial regions, while the white matter damage is more diffusely distributed in toxic leukoencephalopathy. This case was ultimately revealed to be that of Toxic Spongiform Leukoencephalopathy.

Toxic leukoencephalopathy can be caused by a range of insults including radiation, chemotherapy, and drugs of abuse. Among the drugs of abuse that have been shown to cause toxic leukoencephalopathy are toluene, ethanol, cocaine, 3,4-methylenedioxy-methamphetamine, intravenous heroin, inhaled heroin pyrolysate, and psilocybin (Ref: Filley & Kleinschmidt-DeMasters NEJM 2001). Toxic spongiform leukoencephalopathy is a clinicopathologic entity first associated with the inhalation of pyrolysate heroin vapors, a practice which had its origins in Hong Kong in the 1950's and which came to be known colloquially as "chasing the dragon". Users typically "chase the dragon" by placing heroin on a creased piece of tin foil over a flame. As the drug sublimates, the user inhales the fumes. The pathophysiology of this form of leukoencephalopathy has not been clearly elucidated, but is thought to be related to a direct toxic effect of heroin on oligodendrocytes.

The Intrepid Dr. Mike Lawlor reports on job opportunities discussed at recent AANP meeting

Here's a report from Michael Lawlor, MD, PhD summarizing the job opening updates that came out of last weekend's AANP annual meeting in Chicago. I have updated the job listings on this site to reflect Dr. Lawlor's up-to-date information: 

Hi Everyone,

Dr. Mike Lawlor

As a component of the AANP Trainee Luncheon, we attempted to contact all of the institutions with job postings on the Neuropathology Blog site, and invited them to talk about their positions at the luncheon.  There have been an exceptional number of jobs filled over the past 6 months, so our roster of potential presenters changed considerably over time.  Based on my conversations with people, here is an update on several of the jobs currently posted on the site.

1.       Brigham and Women’s Hospital: Their search for applicants is currently closed.

2.       Case Western Reserve University:  Mark Cohen spoke about this position for a few minutes, which sounds like an excellent opportunity for a research-oriented neuropathologist that wants to spend a minority of their time on clinical work.  I would highly recommend contacting Mark to discuss this position, if you’re in the market for a job.

3.       Mayo Clinic, Stanford University, and UCSF:  These positions remain open, but these institutions are each looking for an experienced neuropathologist who would immediately be able to take on a considerable clinical load.

6.      University of Chicago:  This position remains open, and I think that the link fell off the blog site for a short time (or I missed it).  It looks like it’s back up now, and Peter Pytel confirmed that they’re still looking for people.

7.       University of Manitoba: This position remains open, and Marc del Bigio was able to provide me with some information on it.  This information can all be found on the link to this position, so I won’t repeat it.

8.       University of Wisconsin - Madison:  There had previously been two postings on the blog site, which turned out to be two different “flavors” of descriptions for the same job.  There is one job open at UW-Madison and they have interviewed several promising candidates, but the job currently remains open.

9.       University of Calgary- This job had previously been posted here on the website, but it looks like it has disappeared over the past few months.  The job actually remains open, though, and Jim Wright and Jeff Joseph sent me a lot of information on it.  It looks like the job could involve a combination of clinical, teaching, and research opportunities.  Researchers could either develop their own program or fit into their collaborative neuroscience community, and preference will be given to applicants with interests in neurodegenerative diseases, neuromuscular diseases, inflammatory diseases, or developmental brain disorders.  Jeff Joseph also sent a beautiful picture taken from his backyard to show off some of the scenery of Calgary, and it definitely looks like a breathtaking area.  For more information, feel free to contact Jeff Joseph (jtjoseph@ucalgary.ca) or Jim Wright (jim.wright@cls.ab.ca).

Two additional notes that might be useful to people:

1.        One speaker from the pharmaceutical community mentioned that a lot of biotech/pharmaceutical industry jobs for pathologists are actually posted on veterinary pathology websites.  If you’re interested in pursuing such a position, you may want  to widen your search to these sites.

2.       I talked briefly about the NIH Loan Repayment Program, which provides student loan repayment for projects on which the investigator spends >50% effort on the project.  These are one or two year grants, and the submission process is very reasonable.  For anyone that has student loans, I’d encourage you to check these awards out at their website and contact them for more details.  This is a wonderful program and the people involved in it are extremely supportive and responsive.

Good luck to everyone!

-Mike Lawlor

Thank you, Mike. And if anyone in the neuropathology community has further updates on the job listings (additions, deletions, etc.), please let me know and I'll make the necessary changes.

AANP 2012: Dr. Michael Norenberg talks about the multifunctionality of astrocytes



Dr. Norenberg on "Why the Brain Fails when the Astrocyte Ails"

The University of Miami's Michael Norenberg is currently talking about the functions and physiology of astrocytes. The forgotten function of astrocytes is that they are involved in the synaptic communication between neurons and are an active participant in modulating the neuron-neuron interaction. Dr. S. Ramon y Cajal speculated on this active participation of the astrocyte in the synapse with regard to sleep many decades ago. So, although not a new concept, the concept of expanded functionality of astrocytes has gained scientific support in recent years.

Neuropathologists party hard at this evening's AANP annual reception

L to R: Drs. Heather Sumner and T. David Bourne

Drs. Mark Cohen, T. David Bourne, and Mahtab Tehrani

L to R: Drs. Edward Stopa, William Taylor, and Qian Wu