Best Post of November 2015: A 60-year-old woman with a left occipitotemporal brain lesion

The next in our "Best of the Month" series comes from November 18, 2015:

We were sent this case in consultation to rule out infiltrating neoplasm. The diagnosis is amyloid beta related angiitis (ABRA). In this case, no infarction was present in the specimen, but white matter rarefaction (the presumed pathologic correlate to the leukoaraiosis reported on imaging) is present.

Granulomatous vasculitis associated with pink hyaline material in vessel walls

The pink hyaline material is shown to be beta-amyloid by immunohistochemistry

White matter rarefaction (upper half of picture) correlating with leukoaraiosis seen on imaging

Request for updates on job listings

Among the most popular aspects of this blog is the job listings on the right side of the homepage. I try to keep it updated, with the valuable help of Sherry Miller (Dr. Doug Miller's wife). I would ask that if you are looking for a job and discover that one of the listings is no longer valid, please let me know so that I can delete it. Likewise, if there is opening you know about that is not listed, let me know about that as well so that I can add it. Thanks for your assistance in keeping the job listings on this site the most complete and updated list of available US neuropathology positions on the World Wide Web!

Featured Future Neuropathologist: Areli K. Cuevas-Ocampo, MD

Every so often, neuropathology blog posts a profile of a neuropathologist. This time, we feature a future neuropathologist, Dr. Areli K. Cuevas-Ocampo. We wish Areli the best of luck as she embarks upon a neuropathology fellowship at UCSF this summer...

SHORT BIO

I was born and went to Medical School in Cuernavaca Morelos, Mexico. After graduation I moved to Mexico City to train in Anatomic Pathology at the National Medical Center 21st Century, a program of the National Autonomous University of Mexico (UNAM). Because fellowships options in my country were limited, I thought about pursuing specialized training in the United States. I moved to Massachusetts in the summer of 2012 to start my AP/CP training at Baystate Medical Center/Tufts affiliated program. Toward the end of my PGY-2 year, I realized that neuropathology was the perfect fit for me and became more actively involved in the neuropathology activities at my program in addition to my service obligations like signing out neuropathology cases, participating in the organization of the monthly neuropathology interdepartmental conferences and brain cutting sessions for residents. During my 2^nd and 3^rd year of residency I attended and presented scientific posters at the AANP meetings in Portland OR and Denver CO, respectively. During my third year of residency, I became particularly interested in the molecular aspects of brain tumors and started (and currently am) working on a project involving ATRX tumor marker by IHC and its possible function as a surrogate marker for 1p/19q co-deletion. Currently I am the Junior Member of the CAP Neuropathology Committee. Upon completion of my AP/CP residency this summer, I will be starting my fellowship in neuropathology at the University of California in San Francisco.

WHY DID YOU DECIDE TO BECOME A NEUROPATHOLOGIST?

In spite of enjoying pretty much every subspecialty in pathology; the brain is the brain! I have always been interested in such a complex and intimidating organ as a whole: macroscopic, microscopic, and now molecular and genomic levels (and beyond). Obviously there are other subspecialties within neuropathology that I find intriguing as well. Since it is clear that molecular technologies are, and will be changing the way pathologists approach diseases and make diagnoses; l want to be a participant in this shift, helping with the incorporation of those changes into neuropathology and hopefully making contributions in the understanding of cancer biology of brain tumors and neurodegenerative conditions.

​NAME A COUPLE OF IMPORTANT PROFESSIONAL MENTORS. WHY WERE THEY IMPORTANT TO YOU?

I am very fortunate to have met many role models throughout my career, so it is difficult to mention only two. I am sure I will also meet inspiring mentors along the way, but at this moment I want to acknowledge Dr. Christopher Otis for whom I have a deep respect and admiration not only as a pathologist but as a person.  He has many attributes that makes him notable but I especially like his professionalism, competency, leadership and integrity. He inspires me to be better and to go the extra mile. The other crucial person in my career is Dr. Luis A. Moral, the staff neuropathologist at my program. He is not only a knowledgeable and competent neuropathologist but to me he has been a friend and a confidante, playing a crucial role in my fellowship election and being an advisor in my projects. Last but not least I would like to thank my former pathology colleagues and professors from Mexico who always believed in me and encouraged me to pursue my career goals, especially: Dr. Ignacio Felix, Dr. Enrique Blanco-Lemus, Dr. Guillermo Castellanos, Dra. Luz Ma. Gomez, Dr. Miguel Reyes-Mugica (who is the Chair of Pediatric Pathology at UPMC), Dr. Rodolfo Gatica-Marquina and Dr. Victor M. Sanchez-Fernandez.

​WHAT ADVICE WOULD YOU GIVE TO A PATHOLOGY RESIDENT INTERESTED IN DOING NEUROPATHOLOGY FELLOWSHIP?

As everything in life, you should pursue a career in neuropathology because that is what you like and what makes you happy. There are different paths you can follow in order to become a neuropathologist. In my case I took the longest one: the AP/CP -> NP track (6 years) since I found out that my true calling was neuropathology at the end of my 2^nd year of AP/CP residency. The other track is the researcher route, where you find most of the NP residents who also have a MD/PhD degree. They do 2 years of AP first and then 2 years of NP. The career opportunities for neuropathologists (coming from either track) are definitely there, but you need to be flexible in terms of relocation, not ruling out doing another fellowship or a post-doc and staying open to the possibility of covering other pathology services (like general surgical pathology) besides neuropathology once you get a job.

​WHAT CITY WOULD YOU LIKE A FUTURE AMERICAN ASSOCIATION OF NEUROPATHOLOGISTS MEETING TO BE HELD?  

In no particular order; I would include some of the states that I haven't visited yet: Alaska (Anchorage), Minnesota (Minneapolis), Utah (Salt Lake City), and Washington (Seattle).

Immunohistochemical surrogate for BRAF V600E mutation

Quoted highlights  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:

- The most common BRAF alteration is an activating mutation caused by a substitution of valine for glutamic acid at codon 600 (BRAF V600E) in exon 15.

- BRAF V600E status can be screened for using the mutation-specific BRAF V600E immunohistochemistry clone VE1... Only strong homogeneous unambiguous cytoplasmic staining should be interpreted as positive.

- While BRAFV600E can be found in a wide variety of brain tumors, BRAF fusions... are mostly limited to pilocytic astrocytomas (PAs).

- For tumor classification, aBRAF V600E mutation in a ganglion cell-rich lesion biopsied from infratentorial region favors ganglioglioma over PA.

- BRAF V600E mutations are present in pleomorphic xanthoastrocytoma (PXAs) with and without anaplasia (65%–70%), ganglioglioma (33%–60%), and [occasionally] PA, especially extracerebellar PA (6%–8%).

- In addition, BRAFV600E mutations are common in epithelioid glioblastomas (eGBM) (54%), which also tend to occur in children and relatively young adults.

- BRAF V600E mutations have also been reported in a small number of desmoplastic infantile astrocytomas, desmoplastic infantile gangliogliomas, and dysembryoplastic neuroepithelial tumors.

- A few diffuse astrocytomas in children and adults harbor BRAF V600E mutation; the tumors in adults show unusual histologic features such as partly circumscribed portions and spindle cells, and may associated with more favorable prognosis.

- Strong cytoplasmic staining patterns are often observed in PXA and eGBM; on the other hand, staining can be variable in glioneuronal tumors because BRAF can be diffusely positive in the tumor cell population or it can be limited to either a glial or neuronal component. For example, in ganglioglioma, mutant BRAF is predominantly expressed in neuronal tumor cells

- In glioneuronal tumors, BRAF V600E mutation is associated with activation of the mammalian target of rapamycin (mTOR) pathway, worse postoperative seizure outcome, and shorter recurrence-free survival.

Immunohistochemical surrogate for H3 K27M mutations

Quoted highlights on IHC mutational surrogates 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:

- K27M mutations in H3F3A [the gene encoding H3.3] and HIST1H3B [the gene encoding H3.1] occur in approximately 40%–80% of pediatric diffuse intrinsic pontine gliomas (DIPG) and 20% of nonbrainstem glioblastomas.

- The central role of these mutations in such tumors will result in these neoplasms being designated as “diffuse midline glioma, H3 K27M-mutant” in the 2016 WHO Classification of Tumours of the Central Nervous System

- The presence of K27M mutations in pediatric glioblastomas (including DIPG) is associated with shorter survival compared to the wild-type tumors... [T]he presence of K27M mutations can be used as a diagnostic marker and poor prognostic marker for pediatric high-grade astrocytoma.

- K27M mutations in both the H3.3 and H3.1 histones can be detected by immunohistochemistry using an anti-H3K27M antibody. Positivity can therefore be useful to establish a diagnosis of infiltrating glioma in lower-cellularity biopsies, and can be used to subtype and genotype these diffuse gliomas. 

- The pattern of positivity is nuclear, with positivity in most of the tumor cells; nontumor cell nuclei are negative.

Immunohistochemical surrogate for ATRX mutation

Quoted highlights on IHC mutational surrogates 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:

- Loss of nuclear staining for ATRX protein by immunohistochemistry has been used as a surrogate marker for ATRX mutations.

- Consistent and strongly positive staining in the nuclei of nonneoplastic endothelial cells and neurons is commonly used as internal positive controls.

- Unfortunately, there are no standard criteria (in terms of number of cells) for what constitutes loss of ATRX staining in gliomas.

- Because ATRX mutations are uncommon in IDH-mutant tumors with 1p/19q codeletion, it is suggested that ATRX, along with TP53 mutations, can be used as markers of astrocytic lineage.

- In adults, ATRX mutations have been reported either by sequencing or immunohistochemistry in 45%–67% of diffuse astrocytomas, 57%–73% of anaplastic astrocytomas, and 33%–57% of secondary glioblastoma; ATRX mutations are uncommon in primary glioblastoma (4%–7%)

- In children, ATRX mutations have been reported in 22% of pediatric diffuse intrinsic pontine gliomas and 48% of nonbrainstem high-grade gliomas in children;when ATRX mutation occurs in children, patients tend to be over 11 years old.

Immunohistochemical surrogate for TP53 mutation

Quoted highlights on IHC mutational surrogates 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:

- Because they are rare in nonneoplastic brain lesions, TP53 mutations can be used as a marker to differentiate glioma from gliosis.

- TP53 alterations ... are essentially mutually exclusive with 1p/19q codeletion.

- Tumorigenic TP53 mutations have been reported to be present in > 50% of gliomas with astrocytic features, including 59%–74% of diffuse astrocytomas, 53%–65% of anaplastic astrocytomas, and 62%–65% in secondary glioblastomas. In contrast, these mutations are less common in gliomas with oligodendroglial features (9%–44%), and in primary glioblastomas (23%–28%).

- Intense nuclear staining for p53 protein by immunohistochemistry in a substantial percentage of tumor cells has long been used as a surrogate marker for TP53 mutations. The underlying mechanism is abnormally elongated half-lives for the protein products of the most common TP53 mutations in gliomas. 

- Strong p53 nuclear positivity in > 10% of the tumor cells is the most accurate predictor for TP53 mutations in gliomas.

- Positivity of p53 immunohistochemistry staining can occur in [non-neoplastic] conditions of cellular stress, [causing false positive results].

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"!