Vestige of a choroidal melanoma

Only melanin and melanophages remain in an enucleation specimen from a patient successfully treated with brachytherapy for choroidal melanoma. The eye was enucleated not because of the tumor, but because it was blind and intractably painful in the aftermath of treatment.

Best Post of October 2016: Brain Cancer Surpasses Leukemia as #1 Pediatric Cancer Killer

The next in our "Best of the Month" series comes from October 18, 2016:

The following post appeared on the Johns Hopkins Neuropathology Blog last month. The author is Andrew Black:

New data from the CDC shows the mortality rates for pediatric cancers is in decline. A study published by the CDC found that during 1999–2014, the cancer death rate for patients aged 1–19 years in the United States dropped 20%. What is also changing are the type of patients dying. In 1999, leukemia was the leading killer of childhood cancer. That has been replaced by brain cancer. Numerous other trends were also observed in the study.

In both 1999 and 2014, more than one ­half of all cancer deaths among children and adolescents 1­-19 years old were attributable to either leukemia or brain cancer. 3 out of 10 cancer deaths among children and adolescents aged 1–19 years in 1999 were due to leukemia (29.7%), and 1 in 4 were due to brain cancer (23.7%). By 2014, these percentages reversed and brain cancer was the most common site, accounting for 29.9% of total cancer deaths.

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas

Ganesh Shankar of Brigham and Women's Hospital and colleagues recently published an article in Neuro-Oncology entitled Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Rhabdoid meningiomas are designated in the World Health Organization Classification of Tumours as high grade, despite the fact that only a subset follow an aggressive clinical course. To define genomic aberrations of rhabdoid meningiomas, the authors performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1–associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. The tumor suppressor gene BAP1 is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas. A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. The authors conclude that BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

MOC Exam Topic: Acute Hemorrhagic Leukoencephalopathy

First recognized as a discrete entity by Weston Hurst in 1941, acute hemorrhagic leukoencephalopathy (AHL) is a usually fatal disease characterized clinically by an abrupt onset of fever, neck stiffness, and neurological deficits, often progressing rapidly to seizures and coma. The presenting clinical picture is similar to that of acute disseminated encephalomyelitis (ADEM) but with a more fulminant course. At autopsy, the brain is swollen with multiple petechial hemorrhages centered in the white matter. Large foci of necrosis with cavitation may be present. The cerebral cortex and basal ganglia usually appear intact. Histologically, perivascular demyelinating lesions consist of ball or ring hemorrhages surrounding necrotic venules. There are cuffs of mononuclear cells and neutrophils. There is also substantial axonal injury in the affected areas. The lesions are indistinguishable from ADEM, but the extent of microvascular damage and therefore hemorrhage is is greater. An allergic mechanism is postulated.

FIGURE 3. A (H&E, 100×), B (LFB/PAS, 100×), and C (HAM-56 IHC, 400×). Light microscopic studies revealed thin sleeves of pallor surrounding small-caliber parenchymal blood vessels (A) which correspond to areas of demyelination on special stain (B). Macrophages stain strongly positive for macrophage marker HAM-56 (C). From Lann MA, et al. Am J Forensic Med Pathol. 2010 Mar;31(1):7-11.

Mister Mitochondrion

Best Post of September 2016 - Featured Neuropathologist: Karra A. Jones, MD, PhD

The next in our "Best of the Month" Series is from September 6, 2016:

Karra Jones, MD, PhD

From time to time on Neuropathology Blog, we profile a prominent neuropathologist. In the past, we've featured the likes of Craig Horbinski, Roger McLendon, and Jan Leestma. Today, we feature a rising star in the field: Karra A. Jones, MD, PhD. Having just moved to the University of Iowa from UCSD, Dr. Jones is poised to do great work at her new institution. Here's a short bio followed by a Q&A with the inimitable Dr. Jones:

Karra Jones grew up in Kansas City where she completed her M.D. and Ph.D. at the University of Kansas School of Medicine. Karra’s graduate work focused on the evaluation of muscle spindle innervation by large peripheral nerve fibers and proprioceptive abnormalities in diabetes. During her time at KUMC, Karra was inspired by the strong history of neuropathology in Kansas City started by the dearly missed John Kepes and continued by her amazing mentor Kathy Newell. Karra traveled to the West Coast in 2010 to train in combined anatomic pathology/neuropathology under Lawrence Hansen, Scott VandenBerg, Subhojit Roy, and Henry Powell at the University of California, San Diego. There she focused on brain tumor research with Scott VandenBerg and Steve Gonias and developed a clinical interest in neuromuscular pathology. She was fortunate to obtain additional training in muscle pathology at UCSD with Diane Shelton in The Comparative Neuromuscular Laboratory. Karra joined the staff at UCSD in 2014 where she headed the neuromuscular service, participated in the general neurosurgical service, collaborated with molecular pathology on brain tumor molecular testing protocols/testing, supervised a biomarker laboratory, and was a co-director of the tissue biorepository. Karra very recently returned to the Midwest to join the highly talented neuropathology group at the University of Iowa where she is very excited to be practicing alongside Steve Moore, Leslie Bruch, Pat Kirby, and Gary Baumbach. 

1. Why did you decide to become a neuropathologist?

I became interested in the neurosciences after spending a year as a research assistant at Emory University in the Department of Neurology prior to medical school. Then, during graduate school at KUMC, my interest in tissue morphology was peaked after spending hours each day under a confocal microscope staring at muscle spindle innervation (what a gorgeous thing!) While at KUMC, I was extremely lucky to have Kathy Newell take me on as a mentee, and after that I was hooked. Almost everyone in my family is an artist, and I often felt like the outsider in that regard. But I realized with pathology, and in particular the beauty of neuropathology, I was a different kind of artist in my own right. Examining, classifying, and photographing brain tumors, neuromuscular diseases, and neurodegenerative diseases seemed like the most fun I could ever have at work. And I continue to have fun every day as a neuropathologist. 

2. Name a couple of important professional mentors. Why were they important to you?
I already mentioned Kathy Newell – Kathy has been an amazing mentor throughout my training and early career even though I haven’t worked with her directly since medical school. She first inspired me to pursue neuropathology with her amazing eye, calm demeanor, and kind heart. She also taught me about the importance of a “Neuropathology Family” introducing me to John Kepes and encouraging me to work with B.K. DeMasters during my last year of medical school, which helped solidify my decision to pursue combined AP/NP training. Another very important mentor is Lawrence Hansen (although he would argue that mentor means “cross-dresser” as the word is derived from Homer’s Odyssey in which Athena assumes the form of Mentor.) Larry is one of the most talented teachers and morphologists I have ever had the opportunity to work with. His “Hansen-isms” are embedded in my brain for life and as a neuropathologist and educator I will forever pass them on to my fellows, residents, students and mentees. Not only is Larry an amazing teacher and mentor, but also he is a very good friend and human being. I was also extremely lucky to be mentored by Scott VandenBerg on brain tumor diagnosis, molecular testing, and basic science research. Without Scott’s influence, I wouldn’t be where I am today. 

3. What advice would you give to a pathology resident interested in doing a neuropathology fellowship?
Do it! Neuropathology is clearly the best of all pathology specialties. But in all seriousness, Neuropathology training will give you a highly desirable skill set that will prepare you for a large variety of career paths. There are many ways to “differentiate” as a neuropathologist – academic, private practice, research, clinical, tumors, neuromuscular, neurodegenerative, etc. So, prior to your NP training, try to think about what you would like to do as a career after it’s all said and done, but remember to always be flexible and allow yourself to change your mind (it happens in medicine quite often). Neuropathology can also be a good specialty to combine with others such as pediatric pathology and forensic pathology, making you a highly desirable job candidate for varied positions. Don’t be intimidated by the 2 year commitment of the NP fellowship. One extra year in training is nothing in the grand scheme of life and only prepares you even better for the day you click “finalize” on your first case (or it gives you more time to work toward getting grant funding before the clock starts ticking). Right now, there are many job openings in neuropathology – we need bright, motivated, and enthusiastic trainees to become the next generation of neuropathologists. 

4. What city would you like a future American Association of Neuropathologists meeting to be held and why?

I would love for the meeting to be held in San Francisco again. I love visiting the city and always look for excuses to return.

MOC Exam Topic: Status Marmoratus

The neurons of the infant caudate, putamen, thalamus, and globus pallidus are susceptible to damage by hypoxia-ischemia. In some extensive injuries, a marked gliosis occurs and, if the brain is actively forming myelin in that region, there is hypermyelination of the area with aberrant myelination of astrocytic processes. There is frequently also neuronal loss and mineralization of residual neurons. The resulting white, firm, marbled-appearing lesion is called status mamoratus. Thought to occur if a hypoxic insult happens before the age of 6 to 9 months, status marmoratus has been associated with complicated parturitions and acute febrile illness during the first year of life. Lesions in the basal ganglia occurring after the period of active myelination exhibit only gliosis associated with neuronal loss. (Source: Greenfield's Neuropathology, 8th Edition)

status marmoratus involving thalamus and basal ganglia

Subcortical Band Heterotopia

Calcifying Pseudoneoplasm of the Neuroaxis (CAPNON)

Approximately 59 cases of CAPNON have been reported in the literature, A non-neoplastic entity that can be found in either an intra-axial or extra-axial location, the pathogenesis of CAPNON is unclear but a reactive process has been favored. The outcome is generally considered to be excellent, with gross total resection typically curative. This case is somewhat unique in that it harbors adipose tissue.

Foci of calcification and fat are present in this midline example

Nodules of basophilic calcification

The calcifications have a chondromyxoid appearance

Surgery was complicated as the lesion encased the anterior cerebral arteries

References:

Aiken AH, Akgun H, Tihan T, Barbaro N, Glastonbury C. Calcifying pseudoneoplasms of the neuroaxis: CT, MR Imaging, and Histologic Features. American Journal of Neuroradiology 30 (2009) 1256-1260.

Duque SG, Lopez DM, de Mendivil AO, Fernandez JD. Calcifying pseudoneoplasms of the neuroaxis: Report of four cases and review of the literature. Clinical Neurology and Neurosurgery 143 (2016) 116-120.

White matter tract abnormalities seen in football players receiving subconcussive blows

A group out of Wake Forest in North Carolina just published an article entitled Subconcussive Head Impact Exposure and White Matter Tract Changes over a Single Season of Youth Football in the journal Neuroradiology. Head impact data were recorded by using the Head Impact Telemetry system and quantified as the combined probability risk-weighted cumulative exposure (RWEcp).
Twenty-five male participants were evaluated for seasonal fractional anisotropy (FA) changes in specific white matter tracts.There were statistically significant linear relationships between RWEcp and decreased FA in certain white matter tracts. This study found a statistically significant relationship between head impact exposure and change of white matter FA value of in the
absence of a clinically diagnosed concussion. This research supports work by Ann McKee and others hinting at histologic changes that can be incidentally observed at autopsy among young football players. (Thanks for Dr. Adam King for alerting me to this important article from the radiology literature.)

MOC Exam Topic: More on Aquaporin-4

My last post elicited two important comments on aquaporin-4. Since not all readers necessarily look at the comments, I am publishing them as a separate post here:

 Maria said...

Worth mentioning that [aquaporin-4] is the most well known target in Neuromyelitis Optica (NMO) and NMO spectrum disorders, since about 80% of patients with this syndrome will have circulating anti-aquaporin 4 antibodies. The IHC is useful when considering active NMOSD on a biopsy specimen by showing loss of staining (Neurology. 2015 Jan 13;84(2):148-58)

Agent86 said...

And one can only get so far without mentioning the glymphatic pathway..

Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.

Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane
R, Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology
after traumatic brain injury. J Neurosci. 2014 Dec 3;34(49):16180-93.

MOC Exam Topic: Aquaporin-4

Among the topics for the neuropathology maintenance of certification examination is aquaporin-4 (AQP-4). An important regulatory molecule in the maintenance of the proper flow of water across the blood-brain barrier, AQP-4 is the major water channel expressed within CNS astrocytic foot processes. Water flux across AQP4 is bidirectional.

Neuropathology Maintenance of Certification Topics

For those taking the maintenance of certification (MOC) examination at some point in the next few years, the American Board of Pathology (ABP) has published topics that may be covered in the examination. The examination consists of 150 multiple-choice questions, 50 of which are required to be in the a category designated "general neuropathology I". The remaining 100 questions can be from various categories which the examinee chooses (general neuropathology II, degenerative I & II, developmental/pediatric/congenital I & II, neoplastic I & II, and neuromuscular I & II). The ABP provides an MOC examination study guide to help examinees prepare for the exam. The following list is copied from the study guide and includes possible topics in the mandatory general neuropathology 50-question module:

 abnormal corticospinal tracts/pyramids
 leptomeningeal opacifications
 acute hemorrhagic leukoencephalopathy
 leukodystrophies
 anaplastic astrocytoma
 motor cortex; smear prep
 aquaporin-4
 multicystic encephalopathy
 astrocytomas; chemotherapeutic resistance
 multiple system atrophy
 axonal injury; IHC
 myxopapillary ependymoma
 borderzone hypoxic-ischemic damage
 orbital plate fractures
 cervical spinal cord tracts
 Pick disease
 CNS cysts
 pituitary gland histology
 CNS neoplasms; loss of heterozygosity
 postmortem artifacts
 CSF; metastatic tumors
 primary angiitis of the CNS
 deep (basal) nuclei; tracts
 ragged red fibers
 dermatomyositis
 retinal hemorrhage
 dysembryoplastic neuroepithelial tumor
 retinoblastoma
 fetal developmental; neuroanatomy
 skeletal muscle ultrastructure
 fibrillary astrocytoma
 spinal cord anatomy
 glioblastoma
 status marmoratus
 GM1 and GM2 gangliosidoses
 Steele-Richardson-Olszewski syndrome
 hereditary sensory-motor neuropathies
 substantia nigra
 Huntington disease
 tauopathies
 hypoxic injury
 TORCH infections
 infant developmental neuropathology; cerebellum
 tract degeneration
 infant spinal cord; sequence of myelination
 trinucleotide repeat disorders
 Lafora progressive myoclonic epilepsy
 vascular malformations

Registration for AANP meeting launches today

The countdown to the 93rd Annual Meeting of the American Association of Neuropathologists starts today with registration now officially open. The meeting will be held in Garden Grove, CA on June 8-11, 2017. Go to the AANP Website to register online!