Tuesday, April 21, 2015

The Tumor Biomarker Series: MGMT

MGMT stands for O6-methylguanine-DNA methyltransferase. I must admit that this is my favorite biomarker only because of its cool mechanism of action.  The standard chemotherapy for gliomas is temozolomide, which acts by cross-linking DNA through alkylating multiple sites including the 06 position of guanine. Crosslinking at this site is reversed by the DNA repair enzyme MGMT. Thus, low levels of MGMT activity by GBM cells is associated with enhanced response to alkylating agents such as temozolomide. To a large degree, the activity level of MGMT is determined by the methylation status of the gene's promoter. MGMT can be epigenetically silenced by hypermethylation. About half of all GBMs are epigenetically silenced in this manner and are therefore more susceptible to the alkylating action of temozolomide.  The methylation status of MGMT can be assessed by PCR-based testing. In addition to predicting better response to temozolomide, investigators have shown that epigenetic gene silencing of MGMT is a strong predictor of prolonged survival independent of treatment.

Thursday, April 16, 2015

The Tumor Biomarker Series: TP53

A few month ago, the College of American Pathologists released a Template for Reporting Results of Biomarker Testing of Specimens from Patients with Tumors of the Central Nervous System. Therefore, I thought it would be a good idea to review as succintly as possible the various tumor biomarkers one could use to interrogate CNS tumors. Not all neuropathologists would agree as to which ones, if any, are essential. So, comments are most welcome! The first biomarker I'd like to address is TP53, mainly because I have doubts about it's utility -- except for cases where there is a question regarding whether or not an oligodendroglial component is present. However, immunohistochemical p53 testing is performed on virtually all high-grade astrocytomas at many institutions. Here's a summary of the CAP consensus description of the TP53 test:

Found in a majority of high-grade astrocytic tumors, TP53 mutation is rare in oligodendrogliomas. Mutation of TP53 is highly correlated with IDH mutation. As a surrogate for testing the actual TP53 mutation, p53 immunohistochemistry is typically performed. As for the utility of this test, the CAP template makes the following statement: "[T]here is a strong association between IDH1 mutation and TP53 mutation in diffuse astrocytomas and this combination of mutations is helpful in distinguishing astrocytomas from oligodendrogliomas."

My feeling is that if you have a histomorphologically classic pure astrocytic neoplasm, there is no need for p53 immunohistochemistry. And, yet, you almost always see p53 immunohistochemistry results on reports for classic glioblastomas, anaplastic astrocytomas, and infiltrative astrocytomas. I just don't get it. Even in cases where you have a question about the presence of an oligodendroglial component, testing for IDH1 mutation and 1p/19q deletion would be more helpful than testing for IDH1 and TP53. I would love to hear from people who could dissuade me of this opinion regarding the utility of p53 immunohistochemistry. Feel free to enter comments below.

Tuesday, April 14, 2015

Best Post of November 2014: Robin Williams had Lewy Body Diesease

The next in our "Best of the month" series is from November 18, 2014:

Robin Williams

The official cause of Robin Williams' death, released Friday by the Marin County coroner, was ruled

Williams had long battled alcoholism, drug addiction and depression, but in November 2013 he was diagnosed with Parkinson's disease, according to his widow, after noticing a tremor in his left arm and difficulty moving on his left side as early as 2011.

Now a redacted pathology report from the autopsy on Williams' body has been made public and mentions "Diffuse Lewy body dementia,". Given that Dementia with Lewy Bodies can involve vivid visual hallucinations, it has now been speculated that perhaps such hallucinations may have lead to Williams' death.

Media reports, quoting anonymous "family sources," state that Williams' family believes that Lewy body disease was a critical "triggering" factor in his suicide. If so, this would be an unusual manifestation of the disease. Suicides have not been linked specifically to the hallucinations of Lewy Body Disease in the past.

Dennis Dickson, MD
"The use of the term dementia in the neuropathology report should not be inferred to mean that dementia was observed during life," warns Dennis Dickson of the Mayo Clinic in Jacksonville, who says he reviewed the neuropathology report.

"Mr. Williams was given a clinical diagnosis of (Parkinson's) and treated for motor symptoms. The report confirms he experienced depression, anxiety and paranoia, which may occur in either Parkinson's disease or dementia with Lewy bodies," Dickson said.

Wednesday, March 25, 2015

The asinine reason why the name JCD was converted to CJD

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 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 of hubris, 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 in his 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.

Monday, March 9, 2015

Peto's Paradox: why elephants don't get brain cancer

I was recently informed by a second-year medical student that elephants rarely, if ever, get brain cancer -- or other malignancies for that matter. This statement seemed illogical. If every living cell has a chance of becoming cancerous, massive animals like elephants and whales - by virtue of the fact that they have so many more cells -- should have a greater risk of developing cancer than do humans or mice. But, when I looked into it, it turns out that the student was right! A January 2013 article in Nature points out that across species, the occurrence of cancer does not show a correlation with body mass.

The lack of correlation between body mass and cancer risk is known as Peto's Paradox, after epidemiologist Richard Peto of Oxford University in the UK, who noted it in the 1970s. Evolutionary biologists think that it results from larger animals using protective mechanisms that many smaller animals do not.

Evolutionary biologists say that evolution does not always favor tumor-suppressor genes. Although these mechanisms could reduce cancer mortality in any animal, they may come at a cost — reduced fertility, in the case of one research group's model. The result is that for intermediate-sized animals, the evolutionary cost of having many tumor suppressor genes is greater than the benefits of cancer protection they offered. In other words, it is better for the population, evolutionarily, to tolerate more deaths from cancer rather than investing in more costly mechanisms to avoid cancer development. But for massive animals, the cancer avoidance cost of having many tumor suppressor genes is worth it since giant beasts tend to produce few offspring per animal.

Another theory to explain Peto's Paradox is that large animals generate fewer reactive oxygen species resulting from a lower basal metabolic rate and therefore have a lower chance of a suffering a genetic mishap.

Researchers around the world are trying to find the mechanism of Peto's Paradox with hope that it can be shed light on cancer prevention and treatment in humans.

Tuesday, February 17, 2015

The Perils of Crossing Boundaries in the Interstate Practice of Neuropathology: Real of Imagined?

A provocative article entitled Crossing Boundaries: A Comprehensive Survey of Medical Licensing Laws and Guidelines Regulating the Interstate Practice of Pathology appeared in March of last year in the American Journal of Surgical Pathology (Am J Surg Pathol 2014;38:e1–e5) which addressed recent judicial interpretations of interstate medical licensure laws. These legal developments are relevant to neuropathologists insofar as we, as a small group of sub-specialists, not uncommonly serve as consultants on surgical cases from outside of our own state. Recent legal judgements have found pathologists guilty of malpractice and even the criminal practice of medicine without a license. Given these recent developments, authors MC Hiemenz, ST Leung, and JY Park surveyed the licensure requirements and laws regulating the interstate practice of pathology. The authors then grouped states according to similarities in legislation and medical board regulations. The survey determined that states define the practice of pathology on the basis of geographic location of the patient at the time of the surgery.  Thirty-two states and the District of Columbia allow for a physician with an out-of-state license to perform limited consultation to a physician with an in-state license. However, five states prohibit physicians from consulting out of state unless they themselves hold a license in that state. Other states have limited restrictions, such as requiring that the consultation itself occur within the state.  The authors conclude that pathogists who either send cases out to consultants in other states or who serve as consultants to out-of-state pathologists should familiarize themselves with the medical licensure laws of the states from which they either send or receive cases. In a November 2014 letter to the editor, Edward O Cousineau, JD, deputy executive director of the Nevada State Board of Medical Examiners, wrote that "the representations in the article, related to how Nevada law applies to out-of-state licensed specialists, are erroneous". In the article, Nevada was represented as being in the category which allows for an out-of-state licensed physician to practice medicine in consultation with an in-state licensed physician, with the additional stipulation that the consultation must occur within the state boundaries. Mr. Cousineau, in representing the Nevada Board, stated that Nevada allows out-of-state consultations without the stipulation that the consultation must occur within state boundaries. Given Nevada's response to the survey, it may be that more states allow out-of-state consultation than the article indicates. Unfortunately, however, the article have resulted in the unnecessary restriction of certain out-of-state consultations by cautious department chairs

Please comment if you have been impacted by these state licensure issues when either consulting out of state or seeking a consultation from an out-of-state neuropathologist. I'm sure your colleagues would be interested in hearing your story.

Tuesday, February 3, 2015

Best Post of October 2014: Release of new edition of Greenfield's expected this month

The next in our "Best of the month" series is from October 2, 2014.  Since the original post, there's been an update on the price from Amazon: you save 9% if you pre-order the book. I had it listed in October at $778.35. Now, Amazon is listing it at $635.43. Here's the original post:

My secret agent intercepted this communication

Editors: Seth Love, Arie Perry, James Ironside, Herbert Budka
Title: Greenfield's Neuropathology 9e
ISBN: 9781444166934
Publisher: Taylor & Francis
Estimated pub date: 20 February 2015
Estimated extent: 2000pp
Print run: 2000 copies
Listed on Amazon for only $778.35!!!!!!

Monday, January 5, 2015

Dr. Pierluigi Gambetti steps down as director of national prion surveillance center

Pierluigi Gambetti, MD
Dr. Pierluigi Gambetti has stepped down as director of the National Prion Disease Pathology Surveillance Center. In a letter to members of the American Association of Neuropathologists, Dr. Gambetti writes:

"I will be resigning as Director of the National Prion Disease Pathology Surveillance Center effective January 1, 2015. I will continue to be associated with the Center in an advisory position and as consultant for special cases. Dr. Jiri Safar, Associate Professor of Pathology and Neurology at Case Western Reserve University, will be the new director."

Dr. Gambetti goes on to state that the NPDPSC "will remain unchanged", continuing to coordinate autopsies on suspected prion disease cases. Dr. Mark Cohen will continue to have primary responsibility for the histologic and immunohistochemical assessment of cases.