Thursday, June 30, 2016

Best Post of June 2016: Neuropathologist calls into question the capacity of small centers to adequately diagnose brain tumors in the molecular age

The next in our "Best of the Month" series comes from June 7, 2016:

With the emphasis on molecular diagnostics in the new WHO classification of tumors, an Austrian neuropathologist has called into question the capacity of smaller community hospitals, which don't have access to molecular techniques, to provide adequate diagnoses for many primary brain tumors. In an interview with the Science Daily website, Viennese neuropathologist Johannes Hainfellner (pictured) states: "Modern, advanced medical diagnosis of brain tumors relies heavily on the expertise of academic neuropathology. For this reason, smaller centers treating smaller numbers of cases and with standard pathology facilities without the benefit of university neuropathology have neither the requisite capacity nor the necessary routine." Hainfellner was a contributor to the new WHO book and has a research focus on biomarker validation and translation at the Medical University of Vienna.

Tuesday, June 28, 2016

Best Post of May 2016 -- MYB-QKI fusion: A novel alteration that may define and drive pediatric angiocentric glioma

The next in our "Best of the Month" series comes from May 12, 2016

Angiiocentric glioma
Angiocentric glioma is a rare form of pediatric low-grade gliomas (PLGG), first described in 2005, that arises in the cerebral cortex and shares histological features of astrocytomas and ependymomas. Until now, nothing was known of the genetic events underlying this tumor type. In a recent study published in Nature Genetics, Bhandopadhayay et al (see reference below) used whole genome sequencing and/or RNAseq to show that all seven angiocentric gliomas in their sample set harbored rearrangements in MYB, the most common being intrachromosomal deletions resulting in MYB-QKI gene fusions. QKI encodes the RNA-binding protein Quaking, which has been previously established as a tumor suppressor in glioblastoma. Analysis of 12 additional FFPE angiocentric glioma specimens revealed that all of these had alterations in MYB, with the MYB-QKI alteration being confirmed in six cases. The MYB-QKI gene fusion was not observed in any other PLGGs in the panel and therefore may specifically define angiocentric glioma. The MYB-QKI fusion protein was shown by mechanistic studies to drive expression of pro-oncogenic target genes. These data strongly support the concept that MYB-QKI fusions define angiogentric glioma and act as the oncogenic driver mutation in this tumor.

This post is adapted from "Highlights from the Literature", edited by Kenneth Aldape in the journal Neuro-Oncology 18(6), 761–763, 2016

Bhandopadhayay P, Ramkissoon LA, Jain P, et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet2016;48(3):273–282.

Monday, June 27, 2016

Best Post of April 2016: Zika virus isolated from fetal brain tissue

The next in our "Best of the Month" series is a post from April 8, 2016:

Cheng-Ying Ho, MD, PhD
Dr. Cheng-Ying Ho, neuropathologist at Children's National Medical Center in Washington DC, recently authored a report in the New England Journal of Medicine entitled Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. In this report, Dr. Ho and colleagues describe a case of a pregnant woman and her fetus infected with the Zika virus during the eleventh week of gestation. The fetus had a significantly decreased head circumference by the twentieth week of gestation. Given the grave prognosis, the mother elected to terminate the pregnancy at 21-weeks gestation. Postmortem analysis of the fetal brain revealed diffuse cerebral cortical thinning, a high Zika virus RNA load, detection of viral particles, and isolation of the Zika virus from brain tissue. This is the first report of Zika virus isolation from fetal brain tissue. This finding fulfills Koch's second postulate regarding the isolation of a pathogen from a diseased organism and therefore goes a long way toward strengthening the association between congential Zika virus infection and fetal brain damage. This is an important work from a rising star in the neuropathological firmament. As a fellow neuropathologist commented, Dr. Ho is "a very talented young investigator from whom you will be hearing a lot in the future".

Saturday, June 18, 2016

Peter Burger then and now

Yesterday's trainee luncheon at the annual meeting of the American Association of Neuropathologists featured the esteemed Dr. Barbara Crain and the inimitable Dr. Peter Burger reflecting on their illustrious careers. Dr. Berger displayed a picture of himself with colleagues from days gone by:
Peter Burger, Paul Kleihues, and Bernd Scheithauer (circa 1985)

Dr. Michael Punsoni and I had the opportunity to get a picture with Dr. Berger yesterday:

Michael Punsoni, Peter Burger, and me (June 17, 2016)

Thursday, June 16, 2016

American Association of Neuropathologists annual meeting is underway in Baltimore

Dr. Doug Anthony (in foreground) enjoys Special Course at
AANP meeting today
The 92nd Annual Meeting of the American Association of Neuropathologists opened today with a Special Course focusing on the neuropathology of chronic traumatic encephalopathy (CTE). Additionally, two sessions focused on updates to the most recent WHO Classification of CNS Tumors. The day opened with a presentation by Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Koroshetz addressed advances in optical instrumentation in the imaging of brain trauma and the way in which neuropathologists are pivotal in providing histologic correlation to what is seen on imaging. Next, Dr. David Brody from Washington University in St. Louis discussed radiologic/ pathologic correlations in traumatic axonal injury. Dr. Ann McKee followed with an overview of the latest consensus regarding the neuropathologic diagnosis of CTE. She explained that perivascular accumulation of phosphorylated tau is characteristic of the early stages of CTE. The later stages show evidence of tau accumulation in the medial temporal lobes and at the base of sulci in other regions of the neocortex. A break from the CTE theme came in the form of a presentation by Dr. David Louis on the new nomenclature of diffuse glioma diagnosis in the 2016 WHO Classification of CNS Tumors. The concept of an integrated, layered diagnosis involving histology, histologic grade, and molecular information was presented. Dr. Cynthia Hawkins followed with a discussion of changes in the way pediatric tumors are reported under the new WHO classification. Dr. Hawkins noted, for instance, that the term "primitive neuroectodermal tumor (PNET)" has been retired in favor of more updated terminology. After lunch, Dr. Dan Perl talked about his work on CTE among military personnel. Then, Dr. William Stewart discussed the pathophysiology of CTE and explained that, although tau accumulation is characteristic of CTE, the pathology is more complex and also involves beta amyloid and TDP-43 accumulation. The day concluded with a lively round table discussion involving Drs. McKee, Perl, and Stewart. In summary, the Special Course was an informative and exciting beginning to what will undoubtedly prove to be a magnificent annual meeting!

Tuesday, June 14, 2016

Amyloid neuropathy in a middle-aged man

Patient presented with bilateral leg weakness and numbness. EMG showed severe sensory motor axonal neuropathy.
Congo Red stain: amyloid aggregation is circled

Friday, June 10, 2016

Venues for upcoming annual meetings of the American Association of Neuropathologists announced

The 92nd annual meeting of the American Association of Neuropathologists takes place in Baltimore next week. Locations for the following three years have been announced:

2017 - Orange County, CA
2018 - Louisville, KY
2019 - Atlanta, GA

Maybe Dr. Roger McLendon's wish for a Tampa meeting will come true in 2020....

Thursday, June 9, 2016

Featured Neuropathologist: Roger McLendon, MD

Today I feature the inimitable Dr. Roger McLendon, director of neuropathology at Duke University. McLendon has made major contributions to the field in the area of molecular characterization of gliomas. He has also demonstrated a commitment to professional service, including his current work on the Neuropathology Committee of the College of American Pathologists. Check out this interview with one of the most influential neuropathologists practicing today.....

Roger McLendon, MD

1.    Why did you decide to become a neuropathologist?

When I was in college, I asked a buddy of mine who was in vet school what course should I take that would help me out in med school.  His answer was neuroanatomy.   I did not have a course available in neuroanatomy at Emory, so I went over to the med school and talked with a guy working in pain fibers.  He had a great project (using the old Fink-Heimer silver stain) that got me interested in the anatomy of the brainstem.  I followed that experience up in med school with a project working in muscle enzyme histochemistry with Dale Sickles.  I found the use of stains to identify things not seen before to be an exciting way to spend a career.  I have followed those experiences up with immunohistochemistry and FISH to see things in brain tumors.

2.    Name some important professional mentors. Why were they important to you?

Obviously my Duke colleagues and teachers have had huge impacts on my career.  I was tremendously fortunate to land at Duke at the same time as Drs. Stephen Vogel, Peter Burger, Darell Bigner, Doyle Graham, Barbara Crain, Edward Bossen, and Gordon Klintworth.  While I was at Duke, my co-fellows were Doug Anthony, Rod McComb, Gerald Campbell, and Sebastian Alston and visiting fellows included H.K. Ng and Felice Giangaspero.  Each one of these neuropathologists pushed each other to think clearly, regardless of age or faculty status, in a gentle and collegial fashion.  However, the opportunities that Darell Bigner made available to me have pushed my career far beyond my own early goals and to him I owe the biggest thanks.

3.    What do you predict the practice of neuropathology will be like 50 years from now?

In brain tumor surgery, it is undoubted that advances in microelectronics and photonics will allow greater localization and visualization of tumors and normal anatomy.  As a result, we will be receiving better characterized tumor samples that we will be expected to handle in more stringent fashions.  Fresh tissues will be submitted directly to pathology labs for culturing, cellular subset detection and quantitation, and tumoral microenvironmental analysis.  In the past, pathology has been ahead of therapeutics by 20 or more years because we could detect differences in tissues that no drugs could exploit.  However, I think that the largest advances will come in biological therapeutics that will push pathology to better understand the biological differences to be exploited in the tumor. As I discuss later on, the problem in diagnostic pathology will be in staying current with the rapidly changing “core knowledge”.  These issues will be have to be addressed by large group practices of neuropathologists who can provide consultations in all things neuropathologic.   In this way, esoteric testing will be made financially feasible, particularly among rare diseases. 

4.    What advice would you give to a pathology resident interested in doing a neuropathology fellowship?

If you want to have a successful academic career, be ready to give up on 75% of what you learn in your fellowship.  To succeed, you must focus; to focus in the future will mean going far beyond the confines of traditional pathology to learn new techniques in cell culture, -omics, microenvironmental manipulation including stem cells, and electronics that will be needed to measure and manipulate these factors.  I would be shocked to think a successful academic neuropathologist would be able to compete in the research arena and still sign out brain biopsies, muscles, nerves, eyes, and dementia autopsies.  However, outstanding diagnosticians will not got the way of the dinosaur.  We will still need outstanding, broadly trained diagnosticians, but I fear that what will be  considered to be “core knowledge” for the discipline may become overwhelming and yet, rapidly modified.  Keeping up will be a challenge. The challenge for departments will be to make room/share facilities for enough diagnostic pathologists who can handle each of these areas well

5.    What advice would you give to a neuropathology fellow about to embark on a search for his or her first job?

I recently heard a story about people planning their retirements.  The study said that a majority of people planning to retire focused on money issues while a majority of people who had been retired for 5 or more years focused on social issues.  In other words, happiness is ultimately not found in a paycheck, but in the people around you and the issues you are working on.  Therefore, look very closely at the people you will be working with.  I have been extremely fortunate to work with a great group of neuropathologists here at Duke who focused on areas that I was happy to let them focus on.  Christine Hulette loves dementia work, Anne Buckley loves muscles and nerves as well as ultrastructural studies and Tom Cummings is just a brilliant consultant in brain biopsies, eyes, and bone/soft tissue.  They have left me with time and energy to work with the Duke Brain Tumor Center researchers, the Brain Tumor Biorepository, and to look at brain biopsies.  Also get a chance to meet the clinicians you will be working with.  I once interviewed at a major medical center where the chief of oncology told me he had no interest in neuro-oncology (something important to know!)  Along these lines, I have had wonderful relationships with our neurosurgeons and neuro-oncologists and look forward to their continued success.

6.    In what city would you like a future American Association of Neuropathologists meeting to be held, and why?

The first issue you have to deal with is a June meeting and its weather.  Then you have to have a place that you can fly to relatively easily.  Then my choice leans heavily to being able to see a baseball game.  Finally food choices are important and having a wide variety of fish, fowl, and beef choices.  From this it comes down to either Denver or Tampa (Tropicana Field is enclosed) and my preference would be Tampa, because of its proximity to beaches, great airport, indoor baseball, and excellent restaurants.

Wednesday, June 8, 2016

Toward an integrated histomolecular diagnosis of supratentorial ependymoma

In an editorial in the July 2016 issue of Neuro-Oncology, Dr. Kristian W. Pajtler -- from the Department of Pediatric Oncology at the University Hospital, Heidelberg, Germany -- reflects on the fact that ependymomas are no longer considered a single disease entity regardless of location or molecular profile. Three ependymoma subgroups have now been identified in the supratentorial (ST) compartment. Pajtler writes: "One subgroup was enriched for World Health Organization (WHO) grade I tumors, and termed “molecular” subependymoma (ST-SE), while the other 2 were characterized by mutually exclusive prototypic fusion genes involving YAP1 and RELA, and named ST-EPN-YAP1 and ST-EPN-RELA, respectively." The RELA fusion ependymoma is notable because it is recognized as a separate diagnostic entity in the latest WHO classification of CNS tumors. Pajtler goes on as follows: "The study by Figarella-Branger et al. published in this issue of Neuro-Oncology focuses on supratentorial clear cell ependymoma... The authors report on a rare series of 20 supratentorial clear cell ependymomas that all share an additional histopathological attribute, the appearance of branching capillaries... Interestingly, nuclear immunostaining with a p65/RELA antibody was detected in all cases. The authors identified a causative C11orf95-RELA fusion using reverse transcriptase (RT)-PCR primers for the most common subtype, RELA fusion type I, in 19 of 20 samples... Based on these findings, the authors concluded that supratentorial ependymomas, phenotypically appearing as clear cell tumors with branching capillaries, represent a subset of the molecularly defined ST-EPN-RELA group. Figarella-Branger et al. are the first to report a correlation between a defined histological appearance of supratentorial ependymoma and a recently described distinct molecular subgroup. Interestingly, 10-year overall survival in patients with this histologically homogeneous RELA-positive series identified by immunohistochemistry and/or RT-PCR was better compared with survival rates in 122 patients with supratentorial ependymomas from a recent molecular classification study [Pajtler KW, et al Cancer Cell 2015;27(5):728-3] that were subgrouped according to their DNA methylation profiles as ST-EPN-RELA (72.2% vs 49%). At this stage, it is... difficult to infer whether RELA-positive clear cell ependymoma with branching capillaries represents a subset of histomolecularly defined tumors that have a more favorable outcome compared with the cellular subtype harboring the same fusion event... An integrative approach including routine testing for the RELA fusion as a diagnostic marker in histologically identified supratentorial ependymomas and in cases with diagnostic uncertainty or ambiguous features will undoubtedly facilitate and improve tumor classification.

Branching capillaries in supratentorial ependymoma from paper by Figarella-Branger et al.
"The study by Figarella-Branger et al has now set the stage to further explore if and to what extent distinct morphological appearances reflect biological subgroups of supratentorial ependymoma. Analyses of bigger cohorts are needed to confirm whether clear cell morphology with branching capillaries is always associated with ST-EPN-RELA tumors or if this histology might also occur in ST-EPN-YAP1 tumors. Specialties involved in the treatment of these tumor types should now move forward quickly to elicit the prognostic aswell as predictive impact of the molecular subgroups ST-EPN-RELA and ST-EPN-YAP1 in more detail. Integrated histomolecular analyses of supratentorial ependymomas from histopathologically and clinically well annotated international trial cohorts as well as from single series with long-term follow-up, as in the Figarella-Branger et al study, are essential to answer this question. An interconnection of tissue-based information with more precise diagnostic aids gained from novel, unbiased, and observer independent molecular analyses as well as data from imaging methods, including central pathology and radiological review, is required to finally converge at a refined diagnostic setting and improve treatment strategies for ependymoma. For RELA-positive ependymoma there is a good chance that this theory will be turned into action, since these tumors will be considered as an entity in the update of the WHO classification."

Tuesday, June 7, 2016

Neuropathologist calls into question the capacity of small centers to adequately diagnose brain tumors in the molecular age

With the emphasis on molecular diagnostics in the new WHO classification of tumors, an Austrian neuropathologist has called into question the capacity of smaller community hospitals, which don't have access to molecular techniques, to provide adequate diagnoses for many primary brain tumors. In an interview with the Science Daily website, Viennese neuropathologist Johannes Hainfellner (pictured) states: "Modern, advanced medical diagnosis of brain tumors relies heavily on the expertise of academic neuropathology. For this reason, smaller centers treating smaller numbers of cases and with standard pathology facilities without the benefit of university neuropathology have neither the requisite capacity nor the necessary routine." Hainfellner was a contributor to the new WHO book and has a research focus on biomarker validation and translation at the Medical University of Vienna.

Thursday, June 2, 2016

Chronic Traumatic Encephalopathy Brain Bank focuses on military personnel

C. Dirk Keene, MD PhD
The Seattle Times recently reported that a new brain bank, designated the Pacific Northwest Brain Donor Network, has been launched at the University of Washington. 

“We are going to study these brains to the full extent that we are capable,” said Dr. C. Dirk Keene, who leads the neuropathology core at UW Medicine. “They are so rare, so valuable and just so precious, and can give us so much information about what these exposures mean.”

Since the program started in March, researchers have acquired three brains. They include donations from one military veteran, a middle-aged man who had not been exposed to blast injury, and a military contractor, a woman, also middle-aged, who had worked in a war zone.

Neuropathology Blog is Signing Off

Neuropathology Blog has run its course. It's been a fantastic experience authoring this blog over many years. The blog has been a source...