Canine high-grade astrocytomas are currently distinct from human glioblastomas

Historically, the classification and grading of central nervous system neoplasms in domestic animals was based on the World Health Organization (WHO) guidelines for human central nervous system tumors. ⁵ Although the WHO grading system may provide a useful diagnostic framework, there is currently no evidence that it provides prognostically relevant information for domestic animals. For this reason, a classification and grading system for canine glioma was developed. ⁴ Under these species-specific guidelines, gliomas are classified as low-grade or high-grade oligodendrogliomas, astrocytomas, or undefined gliomas based on histology and immunohistochemistry. Although canine high-grade astrocytomas may be histologically diverse, they should not be referred to as glioblastoma or glioblastoma multiforme (WHO grade 4) under the current canine glioma classification system. ⁴

Glioblastoma is the most aggressive and lethal brain tumor of adult humans. ⁸ Although the term has been used in veterinary medicine because of the widespread use of the WHO guidelines, it carries specific biological and clinical implications in human medicine that do not fully translate to dogs, cats, or other animal species. ⁸ Because the human-specific definition of glioblastoma does not accurately represent the behavior, prognosis, or molecular features of canine high-grade astrocytomas, its current use in veterinary medicine is misleading and should be discontinued.

A primary reason for abandoning the term “glioblastoma” in veterinary medicine lies in the differences in tumor classification and grading. The human WHO criteria integrate histology with molecular alterations to determine tumor type and grade. ⁸ In veterinary medicine, canine gliomas are assessed by histology and immunohistochemistry, and classified as low- or high-grade tumors. ⁴ Using the human term “glioblastoma” bypasses the canine-specific glioma classification guidelines.

A second reason for abandoning the term “glioblastoma” in veterinary medicine is related to potential differences in tumor biology, prognosis, and treatment between dogs and humans. The proportion of tumors that are classified as astrocytoma versus oligodendroglioma is different between humans and dogs, which may suggest divergent pathways for oncogenesis and tumor progression. While approximately 75% of human gliomas are of astrocytic origin (including glioblastomas), and less than 50% of oligodendrogliomas are high-grade, 75% of canine gliomas are oligodendrogliomas, and most of these are high-grade. ⁴ Although canine high-grade astrocytoma and human glioblastoma can share key histologic features (particularly geographic necrosis and microvascular proliferation), their underlying molecular alterations may be distinct. Genetic alterations that are diagnostic for human glioblastoma, such as TERT promoter mutation, EGFR gene amplification, and/or +7/−10 chromosome copy-number changes, ⁸ have not been consistently identified in canine astrocytomas. There are some significant similarities between human and canine high-grade gliomas, such as aberrations in the TP53, RB1, and RTK/RAS/PI3K pathways, although specific genes and the frequency of mutations differ between the 2 species.^1,2 Canine gliomas have been reported to have losses in chromosomal regions syntenic to human 1p19q, containing tumor suppressor genes like CDKN2C and others,^1,2 but it is unknown if these translate to better prognosis and response to treatment in dogs as they do in humans. A critically important difference is that IDH1/2 hotspot mutations, which are foundational for patient stratification in human medicine, are extremely rare in canine tumors. Similarly, mutations in the TP53 pathway and CDK4 and CDK6 amplifications are rare in dogs in comparison to their human counterparts.^1,2 Therefore, applying the term “glioblastoma” to a canine glioma suggests an equivalence that is not accurate or proven. In addition, human glioblastoma is an aggressive tumor with a well-established prognosis based on clinical outcome data from hundreds of thousands of patients over many decades. ⁸ Canine high-grade astrocytomas may have variable clinical behavior and survival outcomes that are still not well-determined and may not consistently match those of human glioblastoma.^3,6 The term may therefore mislead clinicians and owners.

Finally, a glioblastoma diagnosis in humans is associated with specific treatment protocols that are not standard or directly translatable to dogs. The prevalence of specific epigenetic modifications relevant to the current human glioblastoma standard-of-care therapy temozolomide, such as MGMT promoter methylation, has been documented only in a small number of canine glioma cell lines in vitro. ⁷ Using the term could create inappropriate expectations for treatment strategies for client-owned animals.

We acknowledge that subsets of canine high-grade astrocytomas may have geographic necrosis and/or microvascular proliferation, histologic features historically associated with human glioblastoma. However, many others lack these features and are instead classified as high-grade based on marked cellular anaplasia and high mitotic activity, analogous to WHO grade 3 astrocytomas. Under current canine-specific guidelines, these tumors are grouped as high-grade astrocytomas to avoid the unverified prognostic assumptions inherent to the WHO classification system. We recognize that future prospective studies may identify biologically distinct subsets of canine high-grade astrocytomas with molecular and clinical features analogous to glioblastoma. Nevertheless, unless such equivalences are validated, applying the term “glioblastoma” to canine high-grade astrocytomas remains premature and potentially misleading because it implies a degree of prognostic and therapeutic predictability that has not been established in canine tumors.

Tumor classification and grading in domestic animals is shifting from reliance on human-centric diagnostic criteria toward species-specific guidelines. Using canine glioma classification and grading as an example, the use of terms like “glioblastoma” or “glioblastoma multiforme” in veterinary medicine should be recognized as inappropriate and potentially misleading. Canine high-grade astrocytomas differ from human glioblastoma in classification and grading criteria and likely in their molecular profile, prognosis, and therapeutic responses, despite the fact that there are similarities that allow spontaneous gliomas in dogs to be a useful model for many aspects of the human disease. Adopting species-specific classification and grading systems ensures more accurate diagnosis and clearer communication with clinicians and pathologists, avoiding the unverified assumptions inherent in applying human-centric labels to nonhuman patients. We hope that in time, the molecular pathology of canine glioma becomes better understood and its comparison to other domestic animals is done in an appropriate and scientifically validated manner. Future species-specific tumor classification and grading systems must aim to unveil and better understand the potential molecular drivers of carcinogenesis in domestic animals. The incorporation of molecular data will certainly generate a more nuanced and objective interpretation of different neoplasms and avoid the reliance on human classification systems that may not be translatable to nonhuman species.