Registration and Abstract Submission for 19th International Congress of Neuropathology (ICN2018 Tokyo) now open

The organizing committees for the 19^th International Congress of Neuropathology (ICN2018 Tokyo) have announced that registration and abstract submission for the meeting have officially opened as of Wednesday, February 7, 2018.  ICN2018 Tokyo will take place September 23-27, 2018.  For more information, click here.

Meningioma involved by mantle cell lymphoma

70-year-old female with a right frontal lobe mass. Before the meningioma presented itself, the patient already carried the diagnosis of mantle cell lymphoma on peripheral blood analysis.

meningioma

lymphoma

Best Post of December 2017: A message from American Association of Neuropathologists President Elizabeth Cochran

The next in our "Best of the Month" series is form Monday, December 18, 2017. Good to be reminded of the upcoming meeting:

Louisville, KY AANP members are already prepping for the 94th Annual Meeting, to be held in Louisville, KY, June 7-10, 2018.  Annual Meeting registration and the abstract submission site have launched, and the call for DSS cases has been sent. We are looking forward to seeing you in Kentucky!

TBI Linked to Increased Dementia Risk Over Several Years

The following is adapted from a recent post on practiceupdate.com:

Traumatic brain injury (TBI) is associated with persistently increased risk of dementia, according to a study published online Jan. 30 in PLOS Medicine.

Anna Nordström, M.D., Ph.D., and Peter Nordström, M.D., Ph.D., both from Umeå University in Sweden, tracked dementia and TBI diagnoses among all 3,329,360 individuals in Sweden

The correlation was strongest in the first year after TBI (odds ratio, 3.52) and persisted at >30 years (odds ratio, 1.25). A weaker association with dementia was seen for single mild TBI versus more severe TBI or multiple TBIs (odds ratios, 1.63 versus 2.06 and 2.81, respectively). Among sibling pairs with discordant TBI status, TBI correlated with increased risk of dementia diagnosis (odds ratio, 1.89).

"The risk of dementia diagnosis decreased over time after TBI, but it was still evident >30 years after the trauma," the authors write.

Best Post of November 2017: Choroidal hemangioma in a patient with Stuge-Weber Syndrome

The next in our "Best of the Month" series is from Monday, November 6, 2017:

Sclera is at bottom of picture; retinal pigment epithelium is at top right. Between them is choroid with cavernous hemangioma

Uveal Melanoma: The Basics

The uvea of the eye is a vascular tunic comprised of the iris, ciliary body, and choroid. Located between the sclera and the retina, the uvea contains dendritic pigmented melanocytes which have the potential to give rise to malignant melanoma. Patients with choroidal melanoma typically present as adults with painless monocular vision loss, while a cataract or glaucoma may be the presenting feature of an anterior segment melanoma. Approximately half of patients with choroidal and ciliochoroidal melanomas eventually die from their tumors. Prognosis is better in cases localized to the iris, presumably because they are recognized earlier.

Uveal melanom on right, melanin pigment in middle, and atropic retina on left

Most uveal melanomas produce at least some melanin pigment. For amelanotic cases, confirmatory immunohistochemical stains for melanoma, such as SOX10 and HMB45, may be helpful. Many uveal melanomas perforate Bruch membrane, enter the subretinal space, and invade the retina (see image), resulting in cystic atrophy of the overlying retina.

Although a small percentage of melanomas diffusely infiltrate the uvea, the vast majority are well-circumscribed. The presence of distinct margins allows for accurate assessment of tumor size. Measurement of largest tumor diameter (LTD) at the base has prognostic significance. 

Histologic assessment of uveal melanoma requires subtyping based on the predominance of particular morphologic cell types: spindle type A, spindle type B, and epitheloid. This cytomorphologic subtyping schema is known as the modified Callender classification, after a system originated in 1931 by Dr. George Russel Callender and then modified in 1978. Spindle type A cells have elongated nuclei, inapparent nucleoli, scant cytoplasm, and indistinct cell borders. Spindle type B cells have oval nuclei with identifiable nucleoli and moderate cytoplasmic volume. Epithelioid cells are larger, with rounded nuclei, prominent nucleoli, and distinct cell borders. Patients with pure spindle tumors have the best prognosis. Indeed, tumors composed entirely of spindle A cells are better classified as benign spindle cell nevi. On the other end of the spectrum, tumors composed purely of epithelioid cells have the worst prognosis. Those with a mix of spindle and epithelioid cell types, which represent the majority of cases, have an intermediate prognosis.

In addition to basal LTD and cytologic phenotype, other histologic features shown to have some negative prognostic implication include: lymphocytic infiltration, macronucleoli, elevated mitotic count, looping vascular networks, and extrascleral extension.

Although the histomorphology of cutaneous and uveal melanomas can be similar, genetic tumorigenesis differs. Early mutations in BRAF characterize cutaneous melanoma while mutations in GNAQ and GNA11 are typical of uveal melanomas. Chromosomal and genetic features also impact prognosis. Monosomy for chromosome 3 indicates a worse prognosis. Gene expression profiling using RT-PCR has emerged as a method of stratifying patients according to risk for metastatic death, and has been reported to be prognostically superior to clinical and histopathologic features. Uveal melanomas naturally cluster into two groups according to expression of thirteen different genes. Class 1 melanomas tend not to metastasize, while Class 2 melanomas have a high risk of metastasis. Not unexpectedly, Class 2 tumors tend to exhibit epithelioid cytomorphology and monosomy for chromosome 3. Elevated expression of the PRAME (preferentially expressed antigen in melanoma) gene on chromosome 22 is an additional indicator of increased risk for metastasis. Increased PRAME expression has been shown to identify the small percentage of Class 1 uveal melanomas that metastasize as well as indicate a shorter time to metastasis for Class 2 tumors.

Therapeutic options such as brachytherapy and focused radiation may obviate the need for enucleation in smaller tumors. For those who undergo enucleation, long-term surveillance includes monitoring liver enzymes as well as hepatic imaging, as the liver is the metastatic site first discovered in 80% of cases. More than half of patients who have metastatic uveal melanoma die within one year.

Choroidal ganglioneuronal hamartoma in an NF1 patient

Thanks to Dr. Ahmed Gilani (pediatric pathology fellow at the University of Colorado) for providing me with slides of an enucleation specimen from a patient with Von Recklinghausen Neurofibromatosis (NF-1). The specimen exhibits a region of choroidal expansion with hamartomatous neuroglial tissue. Distributed throughout this choroidal expansion are non-pigmented ovoid bodies, which have a delicately laminated appearance reflecting the presence of concentric Schwann cell processes. One might conceive of these choroidal expansions as cousins of iridic Lisch nodules.

Choroidal expansion in an enucleation specimen from a child with NF1

Ganglion-like cells within the choroidal expansion

Ovoid body within choroidal expansion

What is amyloid?

The following is adapted from Phenomena, the Phenopath newsletter, Winter 2018 (21:1):

Rudolph Virchow, introduced the term “amyloid” to refer to extracellular deposits in human tissues that exhibited a positive blue-violet staining reaction to iodine and dilute acid. Based on this reaction, Virchow mistakenly identified these aggregates as composed of starch (amylum is Latin for starch).  Subsequent microscopic studies have shown that amyloid deposits exhibit an affinity for Congo red dyes, which also yield a property known as “dichroic birefringence” in which crossed polarizing filters produce apple-green birefringence. In the 20th century, X-ray diffraction analysis revealed amyloid to be composed of fibrils ordered in a beta pleated sheet conformation. Using the criteria of “congophilia,” dichroic birefringence, and fibrillar morphology, more than 30 biochemically distinct forms of amyloid have been identified, many associated with unique clinical syndromes. Examples of protein that can form an amyloid configuration include: immunoglobulin light chain, amyloid A, beta-amyloid, transthyretin, apolipoprotein A-I, lysozyme, and fibrinogen A α-chain. Identification of the amyloid protein can have important diagnostic, prognostic, and therapeutic implications.

Sural nerve in a case of amyloid neuropathy: congophilic amyloid circled

Today's Google Doodle Honors Neurosurgeon Wilder Penfield

Quoted from KN Smith of Forbes:

Today's Google Doodle celebrates the 127th birthday of Canadian neurosurgeon Wilder Penfield, who developed a groundbreaking epilepsy treatment called the Montreal Procedure.

In the 1930s, while working as a neurosurgeon at the Montreal Neurological Institute at McGill University, Penfield had a patient who reported smelling burned toast just before her seizures. He realized that he could use that hallucinatory scent to pinpoint the part of the brain that was seizing - and put a stop to it.

With the patient wide awake, but under local anesthetic, he used electrodes to stimulate parts of her exposed brain, asking her what she felt, saw, heard, or smelled each time. When she declared, "I smell burned toast!" Penfield determined that he must have found the center of her epilepsy. It worked; he removed a small piece of brain tissue from the spot, and the woman never had a seizure again. Penfield and his colleagues published a paper on the method in 1951, and since then it has helped bring relief to many epilepsy patients.

Of course, there are many different kinds of epilepsy, and the Montreal Procedure doesn't work on all of them, but it made a significant difference for a large number of people. And Penfield performed the procedure more times than any other neurosurgeon working at the time. In the process, he assembled a detailed map of where sensory and motor functions happen in the brain, and which areas of the brain receive input from, or send output to, which parts of the body. He also discovered that using an electrode to stimulate the temporal lobes, in particular, can produce very vivid sensory memories - such as the smell of burned toast.

Penfield died in 1976, after a lifetime spent doing what he described as "the best way to make the world a better place."

Endolymphatic Sac Tumor in an Elderly Man

Papillary architecture is typical for this entity

The patient is not known to have Von Hippel Lindau Syndrome, which can be associated with this tumor. According to Expert Path, the differential diagnosis for endolymphatic sac tumor is middle ear adenoma, middle ear adenocarcinoma, metastatic renal cell carcinoma, metastatic papillary thyroid carcinoma, paraganglioma, choroid plexus papilloma, and ceruminous adenoma.

Guest Post from Dr. Mike Lawlor: Audentes Announces Positive Interim Data from First Dose Cohort of ASPIRO, a Phase 1/2 Clinical Trial of AT132 in Patients With X-Linked Myotubular Myopathy

Dr. Mike Lawlor

Regular contributor Mike Lawlor, MD, PhD passed this development along from the X-linked myotubular myopathy clinical research front:

Audentes Therapeutics has released an interim data update on the ASPIRO gene therapy clinical trial for X-linked myotubular myopathy.  In the 4^th quarter of 2017, three patients were given a single dose of an adeno-associated virus containing the human myotubularin gene.  To quote the press release:

"The early AT132 efficacy data observed in our first dose cohort of patients have exceeded our expectations," stated Dr. Suyash Prasad, Senior Vice President and Chief Medical Officer of Audentes. "At the 12-week timepoint, Patient 1 has improved from a severely compromised baseline to achieve a CHOP-INTEND score and maximal inspiratory pressure that are approaching the ranges normally seen in healthy children.  Importantly, Patient 1 has also attained several age-appropriate developmental milestones within this time period, including head-control, rolling over and sitting unassisted.  While still early in the trial, we view these initial efficacy data as a promising indicator of the potential for AT132 to bring meaningful benefit to patients and families living with this devastating disease."

On the safety side of things, Audentes reported a total of six adverse events (AEs) reported in ASPIRO, two of which were determined to be serious adverse events (SAEs). Per the press release, “Both SAEs occurred in Patient 3, the first of which was a hospitalization one week post-administration due to pneumonia and was deemed not treatment-related. Patient 3 was also hospitalized at week 7 post-administration due to a gastrointestinal infection and elevated troponin levels, the latter of which was deemed probably treatment-related and is responding to treatment with intravenous steroid administration and supportive care.”

On the pathology side of things, it will be a while before biopsies are evaluated or analyzed, as the trial design incorporated extensive strategies to keep the study pathologists blinded to timepoint, treatment group, and even whether a given sample belongs to a study patient.  Hopefully I’ll have the opportunity to share some of the pathology data at the 2019 AANP meeting.

The complete press release can be found at: http://investors.audentestx.com/phoenix.zhtml?c=254280&p=irol-newsArticle&ID=2324833