A Blustery Wind of Change

Correspondence:

Editor‐in‐Chief, Brain Pathology

Arie Perry, MD

University of California, San Francisco (UCSF)

Department of Pathology, Division of

Neuropathology

505 Parnassus Avenue, #M551, Box# 0102

San Francisco, CA 94143

Ph: 415‐476‐5236 or 415‐476‐4961

Fax: 415‐476‐7963

E‐mail: Arie.Perry@ucsf.edu

President

Prof Herbert Budka

Institute of Neuropathology

University Hospital Zürich

Schmelzbergstrasse 12

CH‐8091 Zürich

Switzerland

E‐mail: herbert.budka@meduniwien.ac.at

Secretary General

Dr David Hilton

Department of Cellular and Anatomical

Pathology

Derriford Hospital

Plymouth PL6 8DH

United Kingdom

Fax: +44‐175‐2763590

E‐mail: davidhilton@nhs.net

Treasurer

Prof Markus Tolnay

Institute of Pathology, Division of

Neuropathology

Schoenbeinstrasse 40

CH‐4003 Basel

Switzerland

Fax: +41‐61‐265‐3194

E‐mail: mtolnay@uhbs.ch

Project Secretary

Dr Homa Adle‐Biassette

Inserm U676, Université Paris Diderot

Hôpital Robert Debré

48 Bd Sérurier

75019 Paris

France

Fax: +33‐1‐40031995

E‐mail: homa.adle@inserm.fr

Although possibly first coined in 458 B.C. by Aeschylus, who said “Zeus at last may cause our ill winds to change”, the modern “wind/winds of change” catchphrase is commonly ascribed to a 1960 speech by British Prime Minister, Sir Harold Macmillan in Cape Town, South Africa that included: “The wind of change is blowing through the Continent. Whether we like it or not, this growth of national consciousness is a political fact” (http://www.phrases.org.uk/bulletin_board/28/messages/103.html). In the same vein, whether we like it or not, a blustery wind of change is blowing through our daily neuropathology practice and we must therefore, bend in its path and not be too rigid, else we risk breaking. Since the last revision of the World Health Organization (WHO) classification scheme in 2007, there have been extraordinary advances in our understanding of tumor biology at the clinicopathologic, genetic/genomic, cytogenetic, epigenetic, and transcript/protein expression levels, such that it is now widely accepted that there are probably at least 4–6 distinct glioblastoma and 4 distinct medulloblastoma molecular subtypes 1, 2, 3. Whether each molecular subgroup has a well‐defined clinical or therapeutic significance remains in question, although in some, the answer is already yes. Still others are inspiring new targeted therapy strategies and the next generation of “molecular diagnosis” based clinical trials.

Due to these new realities, it is now obvious that for a growing range of tumors, histopathology is no longer sufficient for guiding patient management by itself. Keeping up with these increasingly rapid advances creates both exciting opportunities and practical challenges as we strive to balance our desire to provide the latest cutting edge molecular diagnostics with the need to maintain stability in diagnostic nomenclature over time and adjust to realities of available local resources, testing costs, ease of applying different lab techniques, indeterminate sensitivities/specificities, QA/QI requirements, and financial reimbursements. As one can imagine, these all vary tremendously among medical centers, not only based on practice types within a single country, but across different regions across the globe.

In order to start specifically addressing how molecular data should be incorporated into future brain tumor classification and grading schemes similar to that already being done in hematopathology, an international “WHO's Next?” meeting involving roughly 25 molecularly oriented tumor neuropathologists is scheduled for May 1–3, 2014 in Haarlem, the Netherlands, sponsored in part by the International Society of Neuropathologists (ISN) and made possible through generous support from the STOPbraintumors Foundation, a non‐profit Dutch organization dedicated to raising awareness and funds for brain tumor research. The organizers (David Louis, Pieter Wesseling, Arie Perry) and program committee (Peter Burger, David Ellison, Guido Reifenberger, Andreas von Deimling) have posed the major question, “How can non‐histological (molecular, imaging, clinical) criteria be used to enhance typing and grading of human brain tumors?”, along with the following four sub‐questions for discussion:

1. What is the relationship between diagnosis and grade? Can tumor type and grade be separated from one another, as occurs in other (non‐brain) tumor types? Also, should the grade reflect natural history or likely prognosis after therapy?

2. How does one make recommendations about the use of molecular testing? Is it required or optional? If optional, how does one formulate diagnoses to demonstrate this variability clearly? If required, does molecular diagnosis become incorporated into overall diagnosis or added as an extra level to histological diagnosis? Does one make recommendations about the type of test to use or specific cut‐off levels?

3. How does one formulate diagnoses if some institutions use molecular tests and others do not? If one uses molecular parameters to classify tumors, what does one call tumors with a classic histological appearance but not the defining molecular feature? What does one do with a tumor that has the defining molecular features of one tumor type, but the histologic appearance of another? How does one classify a tumor with an unexpected but diagnostic mutation/profile?

4. Should one recommend the use of radiology and clinical parameters for typing and grading—keeping in mind that we already occasionally use such features for classification (e.g., location to diagnose medulloblastoma)?

The ultimate goal of this meeting is to generate a white paper that provides guidelines to address these questions, accompanied by specific examples that could potentially be implemented in the next WHO scheme.

Stay tuned for further weather forecasts on this changing wind.