Best Post of April 2015 - The Tumor Biomarker Series: BRAF

The next in our "Best of the Month" series comes from Tuesday, April 28, 2015:

BRAF gene (v-Raf murine sarcoma viral oncogene homolog B)

BRAF+ IHC (correlates with V600E mutation) in ganglioglioma

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.

Juvenile psammomatoid ossifying fibroma in 22-year-old male with eyelid droop

This lesion was arising from the nasal sinuses but was growing into the anterior skull base and pushing into the left orbitofrontal region. At first low-power glance, I thought it was a bread-and-butter psammomatous meningioma. But it revealed itself when targeted with a 20X objective lens:

Brain Tumor Rhapsody by Dr. Arie Perry

Arie Perry, MD

I have written about Dr. Arie Perry's incredible musical talent before, and how he has applied it to neuropathology education. Well, he's brought that talent to a whole new level through a collaboration with the San Francisco Bay Area's vocal ensemble Musaic.  With Virchow as his muse, Arie outlines major biomarkers in the diagnosis of CNS tumors. This magnum opus is called Brain Tumor Rhapsody, and its Dr. Perry's first-ever educational music video.This is an epic musical and neuropathological achievement! Many thanks to Dr. Gabrielle Yeaney of the Cleveland Clinic for alerting me to this remarkable video. Check it out on YouTube!

Gabrielle A. Yeaney, MD

Heterotopic neuron in a patient with epilepsy

The patient is a 22-year-old female with intractable epilepsy who underwent resection of an epileptogenic region of the left lateral temporal lobe. In addition to mild cortical dyslamination (not depicted) and Chaslin's subpial gliosis (pinkish band on top surface of brain in photomicrograph), there were an increased number of individual heterotopic neurons within the neocortical molecular layer. The heterotopic neuron pictured below is also disoriented, with its axon projecting tangentially rather than perpendicularly to the the pial surface.

Best Post of March 2015: The asinine reason why the name JCD was converted to CJD

The next in our "Best of the Month" series is from March 25, 2015.

Originally referred to as Jakob-Creutzfeldt disease (and believed by many to rightfully be called simply Jakob's disease), we now refer to this prion disease as Creutzfeldt-Jakob disease. Why? It all stems from a Dr. C. Joseph Gibbs, a colleague of D. Carleton Gajdusek's at the National Institutes of Health, who worked on this disease back in the 1960's. Here's the explanation, lifted from Nobel laureate Stanley Prusiner's Madness and Memory: The Discovery of Prions - A New Biological Principle of Disease:

"Alfons Jakob wrote a paper in 1921 describing several cases of progressive dementia with widespread neuronal loss in the brain. A year earlier, Hans Creutzfeldt had described the brain of a woman who died after a prolonged series of seizures. He found widespread vacuolation, but some medical scientists believe that his patient died of a seizure disorder complicated by hypoxic brain damage and doubt that she had what became known as CJD. So why did the named Jakob and Creutzfeldt become flipped in an important report on the disease, regarding the transmission to a chimpanzee? Twenty years passed before I found the answer, in conversation with Gibbs. 'When I was writing my first paper on the transmission of Jakob-Creutzfeldt disease to an ape,' he told me, 'I wanted to rename the disease Gibbs disease. I didn't think this would be acceptable to the scientific and medical communities, so I decided to reverse the names, because my first name is Clarence and my middle name is Joseph and my initials are C.J.' Thus did the diease become known as Creutzfeldt-Jakob disease, or CJD for short - a case of mind-boggling scientific mischief." 

Gibbs (left) and Gajdusek with a New Guinea kuru patient in 1972.

 
A remarkable case ofhubris, although from what I hear about Prusiner, he is not one to point fingers at those who grasp credit for the work of others.Gajdusek, also a Nobel prize winner, once wrote inhis diary the following about Prusiner:


""I never heard a word of original thought from you nor read such ideas in anything you authored for which I did not recognize immediately its source, which you always went out of your way to obscure. You a heretic? You a martyr? You a defender of unacceptable ideas? Bullshit! You shrewdly jumped onto a bandwagon of creative ideas and experimental work and shrewdly got on to the winning cart, proclaiming outrageously in press and media it was yours! I respect you less and less as your despicable game succeeds and you bask in your coveted fame."

But then again, Gajdusek himself, who died in 2008 at age 85, was no paragon of virtue.In the course of his research trips in the South Pacific to study kuru , Gajdusek had brought 56 mostly male children back to live with him in the United States, and provided them with the opportunity to receive high school and college education. He was later accused by one of these, now an adult man, of molesting him as a child. In fact, seven men testified in confidentiality about Gajdusek having had sex with them when they were boys.  Gajdusek was charged with child molestation in April 1996, based on incriminating entries in his personal diary and statements from a victim. He pleaded guilty in 1997 and, under a plea bargain, was sentenced to 12 months in jail. After his release in 1998, he was permitted to serve his five-year unsupervised probation in Europe. He never returned to the United States and ultimately died in Norway.

Chromothripsis!

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 C11orf95 gene. 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.