Immunohistochemical surrogate for IDH1 mutation

Quoted highlights on IDH mutation IHC from: Tanboon J, Williams EA, and Louis DN. The Diagnostic Use of Immunohistochemical Surrogates for Signature Molecular Genetic Alterations in Gliomas. J Neuropathol Exp Neurol Vol. 75, No. 1, January 2016, pp. 4–18:

- IDH1 and IDH2 mutations are mutually exclusive events and indicate one of the early processes in gliomagenesis, before TP53 and ATRX mutations in astrocytic tumors, and before 1p/19q codeletion, CIC, and FUBP1 mutations in oligodendroglial tumors

- IDH mutations exist in at least 70% of diffuse gliomas, particularly World Health Organization (WHO) grade II and III astrocytomas, oligodendrogliomas, and secondary glioblastomas, and are rarely present in other types of brain tumors

- Clinically, patients with either IDH1 orIDH2 mutations are younger and have a better prognosis in terms of both overall survival and progression-free survival compared to patients carrying wild-type IDH

- Intriguingly, recent studies reveal similar age of onset and little differences in clinical outcome among IDH-mutant tumors previously classified as grade II and grade III astrocytomas by WHO 2007 criteria

- The “good effect” of having IDH mutation also applies to glioblastomas since patients with IDH-mutant glioblastomas have better clinical outcomes compared to those with grade III astrocytomas having wild-type IDH...

- The presence of IDH mutations may argue in favor of a diagnosis of anaplastic glioma over primary glioblastoma given that the latter typically does not harbor the mutation

- The most useful antibodies detect the common mIDH1 R132H mutation, which is present in 90% of IDH-mutant gliomas

- Immunohistochemistry for mIDH1 R132H clone H09 shows 88%–100% concordance rate with IDH1 R132H mutational status determined by DNA sequencing

The Diagnostic Use of Immunohistochemical Surrogates for Signature Molecular Genetic Alterations in Gliomas

David N. Louis, MD

The January 2016 issue of the Journal of Neuropathology and Experimental Neurology features a helpful review article entitled The Diagnostic Use of Immunohistochemical Surrogates for Signature Molecular Genetic Alterations in Gliomas. The review article-- authored by Drs. Jantima Tanboon, Erik A. Williams, and David N. Louis -- summarizes the current experience using immunohistochemistry of glioma samples to identify mutations in IDH1, TP53, ATRX, histone H3 genes, BRAF, EGFR, MGMT, CIC, and FUBP1 as well as guidelines for prudent use of DNA sequencing as a supplemental method. In subsequent posts, I will summarize the key points in this review to make the information easily searchable for readers to use in the future as needed.

Did King Henry VIII suffer from chronic traumatic encephalopathy?

Thanks to Dr. Doug Shevlin for alerting me to the following article recently posted on phys.org:

Henry VIII may have suffered repeated traumatic brain injuries similar to those experienced by football players and others who receive repeated blows to the head, according to research by a Yale University expert in cognitive neurology.

"It is intriguing to think that modern European history may have changed forever because of a blow to the head," said Arash Salardini, behavioral neurologist, co-director of the Yale Memory Clinic and senior author of the study.Traumatic brain injury explains the memory problems, explosive anger, inability to control impulses, headaches, insomnia—and maybe even impotence—that afflicted Henry during the decade before his death in 1547, according to a paper published online the week of Feb. 1.

The English monarch is best known for his dispute with the Catholic Church over his desire to annul his first marriage to Catherine of Aragon and marry Ann Boleyn. The affair led to the English Reformation and the creation of the Church of England. Henry would marry six times—and execute two of his wives.

Research assistants Muhammad Qaiser Ikram and Fazle Hakim Saijad analyzed volumes of Henry's letters and other historical sources to document his known medical history and events that may have contributed to his ailments. Their findings confirm conjecture by some historians that jousting injuries caused later health and behavioral problems.

Henry suffered two major head injuries during his 30s. In 1524, a lance penetrated the visor of his helmet during a jousting tournament and dazed him. A year later, he was knocked out when he fell head-first into a brook he was trying to vault across with a pole. However, said the researchers, the English monarch's increasingly unpredictable behavior may have been triggered by an accident during a jousting match in January of 1536 when a horse fell on Henry, causing him to lose consciousness for two hours.

"Historians agree his behavior changed after 1536,'' said Salardini, noting that descriptions of Henry during his youth portrayed an intelligent and even-tempered young man who made wise military and policy decisions. His behavior in the later years of his life became notoriously erratic: He was forgetful and prone to rages and impulsive decisions.

In 1546, for instance, he was assuring his sixth wife Catherine Parr, that he would not send her to the Tower of London when soldiers arrived to arrest her. He launched into a tirade against the soldiers, having forgotten that he had given that order the day before.

Other occasional side effects of traumatic brain injury are growth hormone deficiency and hypogonadism, which may lead to metabolic syndrome and impotence, respectively. Despite the womanizing reputation of his youth, Henry had difficulty completing sexual intercourse as far back as his marriage to his second wife, Ann Boleyn, in 1533, some evidence suggests.

Other ailments attributed to Henry—such as syphilis, diabetes, or Cushing Syndrome, a condition marked by weight gain and obesity—seem less likely in light of the available evidence, said the study's authors, noting that traumatic brain injury best explains most of his behavioral abnormalities.

Best Post of October 2015: Chromothripsis!

The next in our "Best of the Month" series comes from October 1, 2015:

The next edition of the World Health Organization Classification of Tumors of the Central Nervous System will feature a new, separate ependymoma subtype: RELA fusion-positive ependymoma. RELA fusion refers to the juxtaposition of the RELA gene (the principle effector of NF-кB signaling which controls DNA transcription and cell survival) to the poorly characterized C11orf95gene. Fusion of these two genes is brought about by chromothripsis, a term first coined in 2011 that literally means "chromosome shattering". Chromothripsis occurs when chromosomal segments first fragment into many pieces and then get stitched back together in random order by DNA repair processes. Seen in the setting of some malignancies, chromothripsis in a particular segment of chromosome 11 can result in C11orf95-RELA fusion, which in turn drives oncogenic NF-кB signaling in ependymoma.

Chromothripsis (literally meaning "chromosomal shattering") can drive oncogenesis

Although chromothripsis is a novel model for oncogenesis, it does not necessarily contradict more established models of progressive cancer development as there is no definitive proof that chromothripsis has to occur as a single catastrophic event. Nevertheless, this is a fascinating area of research which will undoubtedly yield more insights into the progression of at least a subset of cancers.

Best Post of September 2015 -- Guest Post: How to make your own Mercado Brain Cutting Device

The next in our Best of the Month Series comes from September 22, 2015:

Today I am fortunate to host a guest blogger, Dr. Juan Mercado, who is a neuropathology fellow at the University of Alabama at Birmingham under the guidance of Drs. Robert Hackney and Kenneth Fallon. Dr. Mercado studied music from a young age and went to a specialized school of music in San Juan, Puerto Rico; but during college he decided to exchange music for medicine and attend the University of Puerto Rico School of Medicine. He has not, however, abandoned his creative approach to the subject matter at hand; in this case, cutting autopsy brains. His guest post follows:

Juan J. Mercado, MD (neuropathology fellow at UAB 2015-17)

A while ago, as a pathology resident, I was temporarily in charge of organizing the weekly brain cutting activity. During this event I always felt a little bothered by the unpredictability and irregularity that occurred with each cut and the variability of results with each different person trying to pursue the same goal.  I decided to do some research trying to find more information about how braingrossing examination was done in different places. To my amazement, I found out about a brain tissue bank in the United Kingdom that performed their coronal sections with the help of a tool. This tool enabled them to create perfect fine cuts every time to perform a complete meticulous evaluation. After knowing about this, I was highly motivated to perform a DIY project. As I optimistically anticipated, the results were excellent. I made the tool using materials that I could easily find in any hardware store. This new and improved tool could now be made by anyone interested in having the same results.  

Materials:

·        White durable cutting board: the bigger the better (Fig. 1)

Figure 1

·        Straight cabinet handles: they come in different diameters, meaning a different brain slice thickness can be created depending on this diameter. Also they come in different lengths. Choose a length proportionate to the size of the cutting board you select. These bars always come with the screws included. (Fig. 2)

Figure 2

·        Drill: to make four holes 

·        Rubber O-ring washers: not necessary, but I use them just for the preservation of the tool, preventing liquids or tissue to enter in the drilled holes (Fig. 3)

Figure 3

·        Rubber chair legs (to elevate the board from a surface and to hold its placement) (Fig. 4)

Figure 4

With the above materials you can create the basic version that will permit you to create cuts of only one predetermined thickness based on the diameter of the bar you select. You can also have an add-on to be able to do thinner cuts with the same board, but it is not necessary. 

How it works:

After detaching the brainstem via an axial cut through the midbrain and then making the first brain coronal section cut through the middle of the mammillary bodies, proceed as usual making coronal sections but with the help of the tool

The bars aligned in the way pictured (Fig. 5) serve to hold in place any brain size firmly while cutting. Use a rigid knife sliding it above the bars as a guide. In this way the thickness of the brain sections will be the same as the diameter of the bars 

Figure 5


Advantages

·        Always the same results, not relying on the experience of the person cutting the brain -- meaning standardization.

·        Homogeneous leveled slices. Option of creating thin slices help in a more meticulous evaluation.

·        When a pathologic finding is present, such as a big intraparenchymal hemorrhage that normally disintegrates the brain slice if performed by normal technique; it does not happen with this tool.

·        Better pictures.

·        It is a lot faster and the cuts are perfect. Less time cutting, more learning and teaching.

See for yourself…

        Add-on(s): Optional (need a saw)

A thinner cutting board cut to fit within the two bars. The diameter of the bar minus the thickness of this board will be your new brain slice thickness, making the same board practical for two different thicknesses.

Thanks, Dr. Mercado. I have often thought about how nice it would be to have a tool that could simplify and standardize braincutting. I am hoping he builds a limited-edition series of these devices and sells them at the next AANP meeting. Since I am not particularly mechanically inclined, I would be the first in line to purchase what I am hereby dubbing "The Mercado Brain Cutting Device"!

Cerebellar dentate neuron undergoing grumose degeneration in a case of progressive supranuclear palsy

Bodian stain

New chair of University of Louisville Department of Pathology is also the new chair of the CAP Neuropathology Committee

Drs. Dan Brat (left) and Eyas Hattab (right)

The College of American Pathologists' Neuropathology Committee has a new chair: Dr. Eyas Hattab. He replaces Dr. Dan Brat in that role. Dr. Hattab also has recently been named chair of the department of pathology at the University of Louisville. He'll be a great asset to both the CAP and the University of Louisville in his new leadership roles. Best of luck, Eyas!!

Guest Post by Mark Cohen and Jeffrey Negrey: Assistance needed for national prion surveillance!

An important request from Dr. Mark Cohen and Jeff Negrey on behalf of the National Prion Disease Pathology Surveillance Center (NPDPSC):

The NPDPSC serves the United States as the national testing site and repository for tissue samples from suspected cases of prion disease (CJD and others). We accept any autopsy tissues for free-of-charge prion testing. With proper tissue procurement, we are able to diagnose with certainty whether or not prion disease is present; and if so, exactly which form and subtype of prion disease (sporadic vs. familial vs. variant) the patient has. Tissue samples are then stored indefinitely and shared with qualified researchers and institutions around the globe.

In order to provide accurate surveillance of prion diseases in the United States, the NPDPSC needs to test CNS tissue. Patients often pass away in non-hospital settings, and even for those who die in hospital, there is ever-increasing reluctance among medical institutions to perform post-mortem examination on patients if CJD is even considered a possibility. Therefore, the NPDPSC offers financial and logistical assistance to families with loved ones suffering from suspected prion disease to obtain a brain-only autopsy and subsequent testing for CJD free of charge to the surviving family (including transportation to-and-from a regional autopsy site if needed). These procedures are coordinated with the nearest approved regional site willing to perform these procedures.

NPDPSC Staff

Our national network is a group of public and private autopsy providers located across the country. Sometimes procedures are performed in hospital settings; other times they are performed in mortuary settings prior to final arrangements. We are always looking to add autopsy and mortuary professionals to our network. We encourage all hospitals and medical centers to send us tissue samples from possible prion disease cases as part of our mission to identify and contain potential outbreaks of prion disease. However, we also are willing to reimburse individuals or institutions who accept brain autopsy requests on our behalf. We arrange transport of the patient to a pre-designated autopsy site and provide free-of-charge shipping materials for sending tissue.

If you, or someone you know, would like to join our national network of autopsy providers, please contact Jeff Negrey for further information (phone 216-368-1290 or email jtn8@case.edu).

Best Post of August 2015: College of American Pathologists Neuropathology Committee meets

The next in our "Best of the Month" series is from August 15, 2015:

I am delighted to be in Chicago this weekend meeting with my wonderful colleagues on the College of American Pathologists Neuropathology (CAP-NP) Committee. We are making plans for a SAM-eligible educational product that will update you on the 2015 iteration of the World Health Organization Classification of Tumors of the Central Nervous System. The new WHO book is set to be published in October of this year; and we on the committee are making plans to create a CD to be issued a year from now designed to keep you in the loop regarding the latest in CNS tumor classification. This weekend's meeting also marks the end of Dr. Dan Brat's tenure as CAP-NP chairman. Dr. Brat will  be replaced by the illustrious Dr. Eyas Hattab at the helm of the CAP-NP Committee. After a long day at work today on the CAP-NP educational product, committee members retired to Smith and Wollensky Steakhouse for some well-deserved nourishment before returning to finish up our work tomorrow. In addition to Drs. Brat, Hattab, and myself, current committee members include Drs. Bill Hickey,Joe Ma, Roger McLendon, Matthew Schneiderjan, Aaron Wagner, Cynthia Welsh, and junior member Matthew Cykowski. (Additional note: the next CAP-NP meeting is just a couple of weeks away when we meet at in Key Largo, Florida.)

Rania Hattab (wife of Dr. Eyas Hattab) and Dr. Joe Ma enjoy a morsel of chocolate cake at tonight's CAP-NP dinner

Outgoing CAP-NP committee members Dr. Dan Brat and Dr. Cynthia Welsh will be sorely missed

Verocay body in a brachial plexus Schwannoma

Verocay body (nuclei palisading around an anuclear zone)

Jose Juan Verocay (1876-1927) [Figure 1] was a Uruguayan physician who trained and worked for most of his adult life in Europe in the late nineteenth and early twentieth century.

Figure 1

Photograph of Jose Juan Verocay (circa 1915)

He was born on June 16, 1876 in the town of Paysandu in Uruguay to immigrant parents. His father Silvino Verocay, was from the Tirol region in southern Austria and his mother Rosalia Garrone, was from the dolomite region of northern Italy and the family name is possibly derived from the town of Verocai which is near Cortina D’Ampezzo located in the Dolomitic Alps in north-eastern Italy. (From Joshi R., Learning from Eponyms: Jose Verocay and Verocay bodies, Antoni A and B areas, Nils Antoni and Schwannomas. Indian Dermatology Online Journal 2012 Sept-Dec; 3(3): 215-219.)

Best Post of July 2015: Medulloblastoma Markers

The next in our "Best of the Month" series is from July 17, 2015:

Four subgroups of medulloblastoma have been defined based on genetic alterations:

Wingless (WNT) - WNT medulloblastomas display monosomy 6 and most show nuclear accumulation of the WNT pathway protein beta-catenin, which serves as a useful immunohistochemical screen for this group. Medulloblasomas with more than 50% nuclear staining for beta-catenin have been shown to have WNT pathway activation, whereas those with only focal nuclear staining do not. Overall survival for WNT medulloblastomas are dramatically longer than those of other subtypes, and clinical practices surrounding the treatment of this subtype reflects this better prognosis.

Sonic Hedgehog (SHH) - SHH medulloblastomas often show a nodular/desmoplastic histopathology and are associated with a better prognosis in younger children and infants. 9q deletion is characteristic, and MYCN amplifications are occasionally noted. GAB1 is expressed in the cytoplasm of nearly all SHH medulloblastomas but not in other groups and can be detected imunohistochemically, making it a valuable SHH-group marker.  Targeted therapies directed at this subgroup have been established and are entering clinical practice.

"Group 3" - Group 3 medulloblastomas have the worst overall prognosis, have a high incidence of large cell/anaplastic histology, and are very frequently metastatic. This group contains the vast majority of MYC amplified tumors, with MYC amplification being a strong negative prognostic factor. It has been suggested that Group 3 tumors should perhaps be re-named MYC medulloblastomas, but wide agreement has not been reached on this designation. Group 3 tumors occur more commonly in males than females, and are found in infants and children, but almost never in adults.

"Group 4" - Group 4 medulloblastomas classically harbor isochromosome 17q; but as the molecular pathogenesis of this group is not currently clear, the generic name "Group 4" remains the consensus designation. Although isochromosome 17q is also seen in Group 3 tumors, it is much more common in Group 4. KCNA1 has been suggested as an immunohistochemical marker for this group, but this requires validation.  The only other notable cytogeneic change seen in Group 4 tumors is loss of X chromosome, which is seen in 80% of females with this tumor subtype. Group 4 patients have an intermediate prognosis, similar to patients with SHH tumors.

In conclusion, the worst prognosis is associated  with Group 3 medulloblastoma; Group 4 and SHH have an intermediate prognosis; and WNT medulloblastoma tends to have the best prognosis.