Grading of diffuse astrocytic gliomas: Broders, Kernohan, Zülch, the WHO… and Shakespeare
The grading of diffuse astrocytic gliomas has been a critical topic in neuro-oncology for the past century, with the field using grading to estimate prognosis, guide clinical care, and engage in clinical and experimental studies to move the discipline forward. The question of how diffuse astrocytic gliomas are most accurately graded has, in turn, been the subject of considerable debate over the years. For example, a book published in 1989 catalogued the opinions of leaders at the time in brain tumor classification and grading . With respect to grading, they discussed the conceptual and practical debate between the histological/anaplasia (pioneered by Broders and then Kernohan) and clinical/biological (pioneered by Zülch and the WHO) approaches—with each side argued effectively by its respective leaders. Remarkably, it has been only 30 years since those lively discussions, and yet our insights into the biological basis of diffuse gliomas are now substantially more advanced, and we can now bring these insights to bear on the question of grading diffuse astrocytic gliomas, perhaps aligning these historical viewpoints. Moreover, we can propose steps to set the stage for a grading system that builds on the historical approaches in light of the advents of molecular typing of CNS tumors.
Historical aspects of astrocytoma grading
In the early decades of the twentieth century, Albert Broders, a pathologist at the Mayo Clinic, published four studies that compared the histological appearances of tumors to their normal tissue counterparts. In these articles, he postulated that their similarity could correlate with the likely behavior of the tumors. Tumors that appeared most similar to normal counterparts were considered less aggressive (lower grade) and considered to have better prognoses relative to tumors that looked dissimilar to the normal counterparts—i.e., they looked dissimilar as they became more anaplastic. Such grades reflected degrees of malignancy within a tumor type. This histological/anaplasia approach was extensively pursued at the Mayo Clinic and strategically popularized in scientific meetings at the time . Shortly thereafter, Broders’ colleague, Kernohan , extended this principle to the astrocytic gliomas, proposing a four-tier scheme. Over the next few decades, multiple others confirmed Kernohan’s concept of histological/anaplasia-based grading for at least the diffuse astrocytic tumors [1, 10].
However, in the 1970s, when the World Health Organization (WHO) began grading tumors, it took a conceptually different approach. Following the lead of Zülch , the WHO included grades for all tumors based on their expected clinical outcomes—i.e., as a general estimate of clinical malignancy. Zülch was a neurologist in addition to being a neuropathologist, and this may have influenced his emphasis on the overall clinical and biological approach, rather than the more strictly histopathological one started by Broders. An advantage of the clinical/biological approach was that it operated across tumor types rather than within a tumor type (for instance, all grade I tumors follow roughly similar courses, regardless of the histological type; all grade II tumors follow roughly similar courses, etc.), but as discussed below, this also produced challenges.
Conceptual question 1: should grading occur within individual tumor types or across tumor types?
While the Broders histological/anaplasia concept was a good one and one that achieved great popularity, Kernohan unfortunately included all astrocytomas (including pilocytic astrocytomas, i.e., not just the diffuse astrocytomas that existed in and progressed through a continuum). By doing so, he disturbed the concept that grade reflected a continuum with a tumor type, instead applying grade to disparate groups of tumors. Nonetheless, such an approach fit well with the WHO clinical/biological system of grading across different tumor types.
The distinction of grading within a tumor type versus across tumor types creates some practical challenges as well. Because the clinical/biological approach links grade to name, it limits the utility of assigning grades in CNS tumors. For example, glioblastoma is grade IV, and if there were different degrees of glioblastoma malignancy, there would not be a way to indicate this using the clinical/biological approach via WHO grades. Over the years, this approach has hampered attempts to use grades to demonstrate varied expected clinical behavior within tumor types. For example, in the Heidelberg discussions of 2006 that led to the 2007 CNS WHO classification, debate revolved around the alternative terms “anaplastic oligoastrocytoma, WHO grade IV” and “glioblastoma with oligodendroglioma component, WHO grade IV”—with the majority favoring the latter predominantly because it was deemed problematic to have both an “anaplastic oligoastrocytoma, WHO grade III” as well as an “anaplastic oligoastrocytoma, WHO grade IV”.
This strict approach, however, has not necessarily been applied to non-neuroepithelial tumors in the CNS WHO classifications. For example, the solitary fibrous tumor/hemangiopericytoma (SFT/HPC) has been given a “within tumor” grading system of 1–3 . This raises the possibility to do so for other nervous system tumors, including the diffuse astrocytic ones, and specifically begs the question of whether this flexibility can be applied to grading diffuse astrocytic gliomas relative to IDH mutation status (see below).
Conceptual question 2: are tumors with similar name entities sui generis or subtypes of a single entity?
What’s in a name? that which we call a rose
By any other name would smell as sweet
The question “What’s in a name?” pertains to the relationship of tumor names to tumor biology. Post-2016 CNS WHO, we have genetically distinct entities that have similar names, e.g., glioblastoma, IDH-mutant, and glioblastoma, IDH-wildtype. These tumors have similar names, of course, since they began as a single, histologically defined entity, glioblastoma. Thus, IDH-mutant and IDH-wildtype tumors (either diffuse astrocytoma, anaplastic astrocytoma, or glioblastoma) are genetically distinct but have common elements in their names and, unfortunately, it is the common elements (e.g., glioblastoma) with which people are familiar.
While the 2016 CNS WHO changed classification, the 2016 CNS WHO grading approach remains the same as it did before: it is Broders-like in that it is histological, but Zülch-like in that it is linked to prognosis more than just histological anaplasia. The central problem, therefore, is that, with the advent of genetically distinct tumor types, the grading system is now not enough linked to prognosis and is too linked to histological features of anaplasia. In other words, we are using the same histological features, but the prognostic importance of those features seems to be different depending on IDH status. In this regard, it is similar to looking at the traditionally defined role of mitoses in diffuse astrocytic gliomas versus oligodendrogliomas, in which they have been thought to have a different significance depending on the tumor type.
We believe that, post-2016 CNS WHO, it is important to consider tumor entities such as IDH-mutant anaplastic astrocytoma and IDH-wildtype anaplastic astrocytoma as different entities despite sharing a common historical name (anaplastic astrocytoma). If this opinion were widespread, it would be possible, even in a clinical/biological, WHO-type framework, to use different grades to describe these tumors if the field had data that their prognoses were different enough. In this context, the above quote from Shakespeare reminds us that we are more interested in the underlying biology of an entity, that names are conveniences (albeit important ones), and that the significance of names can vary with different perspectives—thus allowing them to change over time.
Conceptual question 3: should grading reflect natural history or behavior in light of current therapy?
In addition to the conceptual debate as to whether grade should be purely histological/anaplasia-based or be clinical/biological, there is the additional question of whether grading strictly reflects natural history of a neoplasm or whether it reflects a combination of natural history and likely behavior in response to the current treatment. For example, a CNS germinoma of the pineal gland is a highly aggressive neoplasm that, left untreated, progresses rapidly, leading to death of the patient in under a year (i.e., grade IV); on the other hand, with current radiotherapy, many germinoma patients can be cured of their disease (more like a grade I lesion). Most clinicians would prefer to maintain the high grade (IV) for such a tumor, since it encourages effective therapy—but this type of an approach treats grade as reflecting natural history only. This question becomes more complicated in how one then decides on grade for recently discovered brain tumor types, such as IDH-mutant glioblastoma. For this entity, there are essentially no “natural history” data, since nearly all patients in the developed world receive aggressive therapy for such a tumor. This begs the question: does this necessitate adapting a second type of grade that reflects current clinical/biological data? This was discussed in 2014 at the Haarlem meeting, but it was felt that having two parallel grading systems would be too confusing . But should therapies become more effective for many CNS neoplasms, we may have to develop such parallel grading systems.
WHO grading of diffuse astrocytic gliomas in the 21st century: before and after the 2016 CNS WHO
As we have shown elsewhere , changing the rules for classifying diffuse astrocytic gliomas by IDH status prompted a large shift in the clinical characteristics of patient groups with these tumor entities. As a result, for example, it appears prognostically inaccurate to assign the same WHO grade to IDH-mutant and IDH-wildtype grade II–III astrocytic gliomas. However, while the rules for classification were changed with the 2016 CNS WHO, the rules for grading remained largely untouched. In fact, suggestions to change grading were deliberated intensely at the 2014 Haarlem meeting, but consensus was not reached and a decision was made to keep grading linked only to histology . Again, at the 2015 WHO Working Group meeting in Heidelberg, it was felt that sufficient data were not available at the time to propose a novel grading system based on both histological and molecular genetic grounds .
Follow-up studies after the 2016 CNS WHO decisions have now also reported a marked reduction or complete abrogation of the prognostic power of the current diffuse astrocytic glioma grading criteria in relation to IDH status. For instance, the presence of mitotic activity—the major criterion for upgrading from grade II to III—has lost much of its power according to at least one study . Such findings have already begun to affect clinical practice. For instance, the authors of this manuscript have found it difficult to render the diagnosis of anaplastic astrocytoma, WHO grade III for a well-differentiated IDH-mutant tumor with no microvascular proliferation and no contrast enhancement on the sole basis of few mitotic figures, and such studies provide some affirmation for that discomfort. As a result, post-2016 CNS WHO, different institutions have taken different approaches to “soften” grading; for example, at one of our institutions (MGH), the neuropathologists add a note to reports on IDH-mutant diffuse astrocytic gliomas stating (e.g., for a grade III anaplastic astrocytoma) that “the behavior of this tumor may be more favorable than typical of historically and histologically defined anaplastic astrocytomas”.
The switch to an integrated histological-molecular classification for diffuse astrocytic gliomas has, therefore, resulted in IDH status-based entities that do not closely overlap with the historically and histologically defined entities that have had similar names. In addition, the grading criteria used to define the historically and histologically defined entities are likely not the same as those relevant to the 2016 CNS WHO entities. The post-2016 CNS WHO situation thus argues for a change of grading criteria to adapt to the novel classification system.
Grading post-2016 CNS WHO: practical questions to be addressed
From a practical point of view, data are required to address whether all IDH-mutant astrocytomas (either diffuse astrocytoma or anaplastic astrocytoma) should be assigned to WHO grade II and whether both IDH-mutant glioblastoma and IDH-wildtype glioblastoma should both be assigned to WHO grade IV or to different grades. To answer questions such as these, however, the field must confront some of the more conceptual questions posed above. For example, should the WHO shift to a more Broders-type system of grading within tumor types or does genetic typing provide a framework that makes this unnecessary? We would argue the latter: that the genetic framework makes this essentially unnecessary. A grade II IDH-mutant diffuse astrocytoma would not need to equate fully to a grade II IDH-wildtype diffuse astrocytoma, just as we do not attempt to equate the behavior of a grade 2 malignant peripheral nerve sheath tumor with that of a grade II diffuse astrocytoma: they are different tumor types. In this regard, it may be that our current knowledge that IDH-mutant glioblastoma is biologically different from IDH-wildtype glioblastoma allows us to break from the WHO historical tradition of equating a histological diagnosis (e.g., glioblastoma) with a single grade (e.g., WHO grade IV). Specifically, if one viewed IDH-mutant glioblastoma as a wholly different entity from IDH-wildtype glioblastoma (as the 2016 CNS WHO does), this would still retain the CNS WHO system of grading across entities—despite the presence of the word glioblastoma in both names. In this context, when it comes to names, it is useful to remember that both a Chihuahua and a Great Dane are dogs.
An extension to the above question is whether IDH-mutant glioblastoma should instead be termed grade IV IDH-mutant astrocytoma? In other words, if we believe that IDH-mutant high-grade astrocytomas exist in a Broders/Kernohan-like spectrum of malignancy, should nomenclature be adjusted to reflect that? In this situation, one would propose grading IDH-mutant astrocytomas in a continuum, from lower grade to higher grade, thus hearkening back to the Kernohan proposals for at least the IDH-mutant astrocytic gliomas.
“What’s past is prologue”
Shakespeare’s phrase from The Tempest, “What’s past is prologue,” has often been used to convey the sense that history necessarily leads us to today’s decisions. In this context, it seems to us that molecular classifications have created novel and distinct tumor entities that provide the opportunity to align the histological/anaplasia and clinical/biological approaches to CNS tumor grading. We are, unfortunately for some tumor types, left with similar words (like anaplastic astrocytoma) in the entity names for now, begging the question of whether new classifications will move even further away from such historical terms.
At the present time, data are accumulating to answer the above questions. Indeed, discussing this issue is one of the first tasks for the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) initiative [5, 6]. But how classification and grading approaches will change when therapies hopefully become more effective remains a subject for further debate in future years.
I am not so nice,
To change true rules for old inventions.
As we have reviewed, the grading of diffuse astrocytic gliomas has many “old inventions”. Nonetheless, it is our job to substitute what we are discovering (and will discover) as “true rules”.
Note For readers interested in the history of brain tumor classification and grading, the Field book  and the detailed chapter in Zülch’s 1986 textbook  are highly recommended. They are scholarly treatises that incorporate much pre-Internet era literature and, as such, represent important sources of valuable, less readily accessible information.
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