Best Post of September 2012: DecisionDx-GBM: Should every glioblastoma patient be getting this test?

The next in our Best of the Month Series is from September 12, 2012. It's worth revisiting the question of whether or not genetic testing of brain tumors is appropriate in patients who are not on research studies:

What does the neuropathology community think of DecisionDx-GBM? This is a product offered by Castle Biosciences, based in Phoenix, AZ. DecisionDx-GBM is a gene expression profile test developed at The University of Texas M. D. Anderson Cancer Center for the purpose of increasing the accuracy of the prognosis and predicted responsiveness of glioblastoma multiforme to first line radiation plus temozolomide. The test is able to distinguish GBM tumors with a proneural phenotype (tumor signature) from those with a mesenchymal / angiogenic phenotype. Patients with a proneural phenotype tumor who are treated with first line radiation plus temozolomide experience a significantly longer median survival (over 7 years) compared to those patients with a mesenchymal / angiogenic phenotype tumor (approximately 1 year). According to the company website, the assay has been fully validated and has been available for clinical use since 2008. A study is ongoing to determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit from the addition of bevacizumab to temozolomide and radiotherapy. DecisionDx-GBM is also currently being incorporated into a number of other prospective and retrospective studies.

Is DecisionDx-GBM covered by insurance? Castle Biosciences states that the test receives reimbursement from a number of commercial insurance companies, and appeals to the Administrative Law Judge level for Medicare have resulted in favorable decisions for full payment. Should a patient need to pay out-of-pocket for this test, I could not find on the website what the cost would be.

Should we as neuropathologists recommend the use of this profile? Here is a an example of the kind of report that is generated when one orders the panel of 12 genes (3 of which are for control) upon sending a block of paraffin-embedded fixed tissue to the company. I would be interested in hearing people's opinions regarding this product, and whether there are others on the market which might be comparable. Please post!

How do you calculate a brain tumor's MIB-1 index?

Elizabeth J. Cochran, MD

I was recently contacted by the affable Elizabeth Cochran, MD  asking if I would post a query regarding MIB-1 counts on brain tumors. Does anyone know if there is a standardized approach to this?  Please tell us your approach to MIB-1 quantification in the comment section. Dr. Cochran takes an approach based on an article she had read in Human Pathology some time ago, summarized as follows:

1. Examine control section stained with MIB-1 antibody to confirm that the stain worked.

2. Survey the slide of the case to be counted to find the area(s) that have the most stained nuclei.

3. Put reticule in right eyepiece of microscope.

4. Place the area identified in #2 under the reticule at 40x power.

5. Using the hand held counter, count all the immunoreactive nuclei within the entire grid.

6. Count all nuclei that touch the right and bottom outer border of the grid, but NOT the nuclei that touch the upper and left borders.

7. Record this number in the lab book.

8. Count all nuclei present within one vertical column of the grid.  This column should be randomly chosen.

9. Record this number in the lab book.

10. Count all nuclei present within one horizontal column of the grid.  Again this column should be randomly chosen, and recorded in the lab book.

11. Again, be sure to count all nuclei that touch the right and bottom outer border of the grid, but NOT the nuclei that touch the upper and left borders

12. Repeat this procedure for at least two more high power fields on the section that contains the most numerous immunostained nuclei and record all values in the lab book.

 13. Calculate the MIB-1 proliferative index as follows:

                a. For each of the fields counted: Add all of the nuclei counted in each row and column from each field and multiple by five.  Divide the number of the immunostained nuclei counted in that field by the calculated sum of all of the nuclei in that field.

                b. The total number of all cells counted in all fields should be > 1000.  If it is substantially less than 1000, count another field, as described above.

                c. Calculate the average of the three fields and  record the proliferative index in the lab book.

An oddball sellar region mass

In the last post, it was noted that Dr. Peter Burger presented a series of sellar region "oddball lesions" at the recent USCAP meeting. The esteemed Dr. Mark Cohen was good enough to provide photographs (above) of one particular lesion that was discussed at the meeting: an osteolipoma of the tuber cinereum. Thank you, Dr. Cohen!

Dr. Thomasina Bailey reviews pituitary session at recent USCAP meeting

A guest post from Thomasina Bailey, MD:

 I spent Saturday night, March 9,  up late in Baltimore at the AANP session at USCAP.  The talks focused on sellar lesions. The panel consisted of  Drs. Lopez, Kleinschmidt-DeMasters, and Burger.  Dr. Lopez  from UVA gave a really great overview of sellar lesions focusing in on pituitary adenomas.  She discussed the things that are clinically significant in the work-up of pituitary adenomas along with the controversies over atypical adenomas and carcinomas of the pituitary.  At the end of her talk, she listed her own WHO classification of pituitary adenomas giving a comparison to meningioma WHO grading.

The next lecture was given by Dr. Kleinschmidt-DeMasters of University of Colorado on What’s New in Inflammatory Pituitary Lesions, Pituicytomas, Spindle Cell Oncocytomas,  and Craniopharyngiomas. During this hour numerous cases were reviewed. Of particular interest was the clinical pathological correlation of pharmacological treatment and the development of hypophysitis.  As she referenced articles and cases she called out audience members who were their authors. During the course of the talks there was a lot of audience interaction when comparing and contrasting use of certain antibodies.

The icing on the cake was Dr. Burger's talk on oddball lesions of the sellar region. He started off the talk by noting that no one will probably ever see in their practices the entities he was about to share. He called on the audience including some of his former fellows for their thoughts. The last case was of special interest because he sited a case report from 1855.  He talked about going to Welch Library to find the journal and then went off on an enjoyable tangent about Dr. Welch being the first pathology chair at Hopkins. Spending a Saturday night at a science talk was super geeky, but I love neuropathology and the pathology history lesson was a bonus.  It was neat to think about all the really great neuropathologists sitting in the audience as well as at the podium. I just wish Dr. Perry had sung a  little bit in the beginning!

Review by Dr. Mark Cohen of "Neuropathology: A Volume in the High Yield Pathology Series", edited by Yachnis and Rivera-Zengotita

Mark L. Cohen, MD

I am honored to present a guest post by the inimitable Dr. Mark Cohen of the illustrious Case Western Reserve University. Dr. Cohen not only reviews a great new neuropathology textbook, but illustrates yet again why he is widely known as the Maxwell Smart of Neuropathology.

(Not really) Full disclosure

Self-annihilating conflicts of interest, as follows:

1. Long-standing professional relationship with unbridled admiration for lead editor Tony Yachnis, both as a person and as a pathologist (he's not the Moderator of the world-famous Diagnostic Slides Session of the American Association of Neuropathologists, as well as their President-Elect, for nothing).
2. I have contributed to several publications that compete within the same niche, and from which I have amassed a small fortune (recently enabling me to purchase new windshield wipers for my ‘99 Corolla).

Several weeks ago, I received the following teaching evaluation from an anonymous medical student: "One of the worst lecturers that I had the misfortune of experiencing in medical school. Powerpoints were poorly constructed in terms of high yield content...”. So, when our host Dr. Moore blogged about the impending publication of Neuropathology: A Volume in the High Yield Pathology Series, I sprinted to my laptop to pre-order a copy.

Anthony T. Yachnis, MD, MS

The book arrived safely last night (albeit buried in several inches of snow), and I was not disappointed. Best described as Text-Atlas, it weighs in at 351 pages, which is roughly half that of both Perry & Brat’s Practical Surgical Neuropathology and Prayson’s Neuropathology, second edition. In addition, it represents something of a revolutionary approach in that it was primarily written by trainees in pathology, neuropathology, dermatopathology, hematopathology and neurosurgery. This team-based approach (a testament to Captain Tony’s coaching skills) has produced a neuropathology text “of the people, by the people, and for the people”, as well as resulting in a textbook which is remarkably up to date (including such topics as Natalizumab-related PML). In addition to an introduction to basic neuropathological reactions, subjects covered include developmental disorders (both malformative and acquired), cerebrovascular disorders, trauma, brain tumors, infectious diseases, neurodegenerative disorders, demyelinating diseases, toxic/metabolic disorders, and neuromuscular disorders. For a book of this size, the scope of the topics covered is remarkably comprehensive, and they are extensively, if not exhaustively, illustrated. The pictures, especially the gross photographs, are of uniformly high quality (which appears to be maintained in the on-line version, unlike another high-profile textbook I reviewed a few years ago). In addition to the beautifully photographed gross specimens, pictures include histochemistry, immunohistochemistry, and neuroimaging, as appropriate. The vast majority of the photographs are reproduced at 3.25 x 2.5 inches, which is more than adequate to appreciate the features described in the figure legends. With rare exceptions, arrows are not included within the photomicrographs (which I feel is appropriate, but has gotten me in trouble with certain journals, publishers, and students). As is the practice within this series of textbooks, as well as in many other currently published pathology books, the text is entirely bulleted (a practice which I personally dislike, but which is executed quite well here). Another feature that the reader should be aware of is that (no doubt as part of the philosophy of “high-yield pathology”) there are no references.

Marie Rivera-Zengotita, MD

As an academic neuropathologist, do I have criticisms? (Do bears sh...?). Besides minor quibbles with organization (I probably would have included Natilizumab-associated PML within the Infections section rather than as part of multiple sclerosis) and such Talmudic issues as whether brain invasive meningiomas are truly atypical or not really atypical, but still WHO Grade II, I think that the improvements that I would suggest are largely outside the purview of the authors and editors. Specifically, the titling typography and design layout is nothing short of hideous, and, although the pictures are of adequate size, the presence of many nearly blank pages certainly makes me wish that those spaces had been filled by larger format photographs. In addition, a few of the topics are presented sans photographs, which detracts somewhat from the flow of the textbook (although the authors had the good sense of not trying to illustrate mixed oligoastrocytomas). All in all, however, I think that the book succeeds in its aspirations of presenting "high yield neuropathology".

The editors hope that the volume will be useful for trainees in pathology, neurology, neurosurgery, neuroradiology, neuro-oncology and related fields; as well as being a practical reference for practicing pathologists -- including neuropathologists requiring quick access to the field. As I was reading through the text, I kept this in mind, and triaged these groups as follows:

1. Neurology and neurosurgery residents should run, not walk, to order a copy, as Board examinations are near at hand, and this book provides a perfect study guide for preparation. Neuropathology fellows should also obtain a copy for studying, although at this moment they have time to walk to their laptops or bookstore.
2. Neuroradiologists and anatomic pathologists should obtain a copy to keep as a quick reference
3. Neuro-oncologists will probably gravitate towards more specialized textbooks (such as the recent addition to the Diagnostic Pathology series edited by PCB et al.)
4. As far as practicing neuropathologists go, I think we all need a copy as we generally find ourselves in one of two situations:
1. A private practice or group setting without instantaneous access to literature databases. For this group, I think the book fulfills its goal as a quick access to diseases with which we may have become unacquainted during our time in practice.
2. A large academic medical center with broadband access to literature databases. In this position, our quick access will generally be on-line. On the other hand, we should all have a copy to lend to clinical rotators as an expression of our great goodwill. (Another minor weakness of the book is that there is no RFID device by which we can geolocate our books once they have left our offices. On the other hand, the included on-line access assures that even as our copies disappear, we will still have access from our computers).

Unfortunately, while I feel this book will definitely help to guide me in the revision of my medical student lectures, it is by itself not appropriate for medical student study. To paraphrase Jack Nicholson as Col Nathan R. Jessup, USMC in A Few Good Men: You want high yield? You can’t handle high-yield!

Luckily, for those who can handle the truth, Neuropathology: A Volume in the High Yield Pathology Series will provide a valuable and lasting resource.

A Primer on Perinatal Telencephalic Leukoencephalopathy

In my last post, it was correctly pointed out by two astute readers that the Netter figure demonstrating brain malformations included an entity which is NOT a brain malformation: perinatal telencephalic leukoencephalopathy (PTL). PTL results from a perinatal hypoxic insult and is not a malformation per se, as the term "malformation" should really be reserved for anatomic abnormalities resulting from developmental defects. The cerebral white matter in the fetus and neonate is particularly susceptible to injury as it is metabolically highly active. Ischemia of the germinal matrix, subependymal region, and periventricular white matter can lead to periventricular leukomalacia that may even calcify and result in periventricular mineralization (1). At its most extreme, PTL may take the form of hemispheric multicystic leukomalacia in which the cerebral hemispheric white matter is replaced by multiloculated cysts separated by strands of fibroglial tissue.(2)

References:
1. Fuller, Gregory N. and Goodman, J. Clay. Practical Review of Neuropathology. Lippincott 2001. Page 315.
2. Haberland, Catherine. Clinical Neuropathology: Text and Atlas. Demos Publishing 2007. Page 303.

Brain Malformations