By Andrew D. Miller, DVM, Dipl. ACVP

The time has come for all of us to have an honest discussion about grading in our profession. No, I do not mean exam grades, but rather those provided by veterinary pathologists on biopsy samples of cancer procured from our animal patients.

Human cancer diagnostics are replete in tumor grading schemes, many of which are directly tied to patient outcome and/or response to therapy. However, veterinary medicine remains woefully behind in developing, validating, and applying grading schemes to cancer in our animal patients. We all want what is best for our patients, so how can we move our field forward and start better developing and utilizing grading schemes in cancer diagnostics?

Basic terminology

It is important to remember the difference between clinical staging and tumor grading.

Staging involves many different assessments to evaluate overall patient health, including physical examination findings, imaging, biopsy results, and blood work. All these results offer important clues and windows into the type of cancer, presence or absence of spread, and can be used to guide and predict therapy.

Tumor grading, on the other hand, is a deep dive into the tumor itself and the features that it has microscopically. For the neoplastic cells, features like atypia, multinucleation, bizarre nuclear, and cytoplasmic features have all been used to define variations in tumor grade. Additionally, extracellular features, such as tumor necrosis and lymphovascular invasion, have been incorporated into grading schemes.

Clinical staging and tumor grading are intimately tied together, each providing the other with important information for our patient assessment. Unfortunately, many of these features are subjective and their interpretation can vary widely across pathologists leading to inconsistent tumor grading and interpretative challenges for clinicians.

Grading schemes

Before we delve into ways that we can improve tumor grading and synergism between pathologists and clinicians, below is a review of some of the more common grading schemes used in veterinary medicine to illustrate challenges we currently face.¹ Unfortunately, large animals really get short shrift here, so this discussion will focus on more common canine and feline cancers.

• Cutaneous mast cell tumors. These are commonly seen in small animal practice, accounting for one of the most common primary skin tumors in dogs, and to a lesser degree, cats. An early attempt at grading canine cutaneous mast cell tumors dates to the 1970s, with modifications in the 1980s.² These early cutaneous mast cell tumor grading schemes utilized a three-tiered system that incorporated cellular features and tumor architecture to indicate a lower grade (grade I) or higher grade (grade III) mast cell tumor. Although not being widely validated beyond the initial publications, this grading scheme remains in use today, even if the vast majority of canine mast cell tumors fall into the intermediate (grade II) category.

Coincidentally, the biologic behavior of these grade II mast cell tumors is often the hardest to predict, leading to confusion and predictive challenges for clinicians. In part to address this confusion, a new canine cutaneous mast cell tumor grading scheme was produced about a decade ago, dividing the tumors into low- or high-grade.3 This system utilizes only the histologic features of the cells and is prognostically significant. Even though prognostic significance has been shown for the newer grading scheme, there remain differences between outcomes in the two grading schemes, and pathologists typically offer both in a biopsy report.

• Canine osteosarcoma. This is a devastating and debilitating disease with a markedly increased incidence in larger breed dogs. Two separate grading schemes for canine osteosarcoma exist in the veterinary literature. They both use similar histologic features, including tumor necrosis, pleomorphism, and mitotic count with one system incorporating amount of matrix and tumor cellularity into the grading scheme.¹

While these dual grading schemes remain utilized in veterinary medicine, a recent publication indicates that there is no prognostic relevance to the grade of canine osteosarcoma, putting into doubt the necessity of grading these tumors unless there are further prognostic, prospective studies that better illustrate the utility of these grading schemes.⁴

• Mammary cancer. This is quite common in our canine patients, less so in felines. While there is a strong relationship between the development of mammary cancer and the spay status, plenty of our spayed female dogs and cats still get mammary cancer.

Canine mammary cancer is an incredibly diverse array of histologic features, owing, in part, to the epithelial and myoepithelial components of the mammary gland. A widely utilized canine mammary cancer grading scheme utilizes tubule formation, mitotic count, and nuclear pleomorphism to arrive at grade I, II, or III tumors.⁵ This grading scheme is predictive of patient outcome post-surgical excision with grade III tumors exhibiting lower survival times, higher metastatic rates, and higher recurrence.

Feline mammary tumors are not as diverse histologically as their canine counterparts, and the vast majority are carcinomas. Two separate grading schemes are currently used in the cat. One is similar to the dog, where tubule formation, mitotic count, and nuclear pleomorphism scores are utilized to generate a three-tiered grade.¹ As in dogs, this grading scheme is predictive of patient survival, with increased recurrence and patient demise associated with the grade II and III mammary carcinomas.

A more recent feline mammary grading scheme that uses lymphovascular invasion, nuclear features, and mitotic count has also been shown to be predictive of patient outcome; however, due to the relatively novelty of this grading scheme, more study is needed.⁶

While other grading schemes exist in veterinary medicine, including canine urothelial carcinomas, feline pulmonary carcinomas, and canine soft tissue sarcomas, the aforementioned cancer types serve to illustrate where we stand with grading schemes and where many of the challenges lie.

Many of the grading criteria we use are adopted from human grading schemes. Some tumor grading criteria are wrongly applied across species (i.e. canine soft tissue sarcomas grading schemes used in cats, where there is no accepted grading scheme). Almost all the grading schemes we rely on in veterinary medicine are poorly, if ever, validated in the literature.

I am often asked, “How do we know if the grades are even relevant for our patients?” The reality is we do not know. Combine interobserver variation, challenges of accurately identifying mitotic figures (thereby leading to erroneous mitotic counts), and the vagueness of some grading scheme features, it is a wonder that we grade any tumors at all.

Building better grading schemes

Knowing the challenges, how can we work together to build better and more robust grading schemes that are validated and reproducible? It will require clinicians and pathologists to work together, gathering the necessary follow-up information on patients to determine if a specific grading scheme is relevant. If not, then a new one can be developed and validated.

In recent years, a groundswell of interest in canine grading schemes, standardization, and prognostic studies has begun to emerge and is detailed by the Veterinary Cancer Guidelines and Protocol group. Developing new grading schemes takes time and initiative. Progress is slow, but it behooves all of us to work together for the common good of improving the outcomes of our patients.

As human medicine has started to embrace precision medicine, more of our clients will demand the same, and if we continue to rely on outdated or poorly validated grading schemes, we cannot even begin to ethically consider how to interpret advanced genomic data in the context of patient care and outcome.

Andrew D. Miller, DVM, Dipl. ACVP, is an associate professor at Cornell University College of Veterinary Medicine. Dr. Miller is the current director of the Anatomic Pathology Laboratory at the Cornell University Animal Health Diagnostic Center. His research focuses on diagnostic and comparative oncologic pathology and neuropathology. Miller is a member of the Evidence-Based Veterinary Medical Association (EBVMA), with different members writing this column. While all articles are reviewed for content, the opinions and conclusions of the author(s) do not necessarily reflect the views of the EBVMA or Veterinary Practice News. For information about the association or to join, visit https://www.ebvma.org.

References

1. Avallone G, et al. Review of Histological Grading Systems in Veterinary Medicine. Vet Pathol. 2021; 58(5):809-828. https://pubmed.ncbi.nlm.nih.gov/33769136/
2. Patnaik AK, et al. Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol. 1984;21(5):469–474. https://pubmed.ncbi.nlm.nih.gov/6435301/
3. Kiupel M, et al. Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Vet Pathol. 2011;48(1):147–155. https://pubmed.ncbi.nlm.nih.gov/21062911/
4. Schott CR, et al. Histologic grade does not predict outcome in dogs with appendicular osteosarcoma receiving the standard of care. Vet Pathol. 2018;55(2):202–211. https://pubmed.ncbi.nlm.nih.gov/29284372/
5. Peña L, et al. Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up. Vet Pathol. 2013;50(1):94–105. https://pubmed.ncbi.nlm.nih.gov/22688585/
6. Mills SW, et al. Prognostic value of histologic grading for feline mammary carcinoma. Vet Pathol. 2015;52(2):238–249. https://pubmed.ncbi.nlm.nih.gov/25060990/