What’s up with criteria of malignancy?

Once a population of cells has been deemed neoplastic, assessment for any criteria of malignancy should be performed. Criteria of malignancy are a list of features that can be used to assess whether a population is benign or malignant. In the majority of cases, multiple (at least 3) criteria of malignancy should be seen before a population is confidently deemed malignant. 

It should be noted that these features typically are only emphasized for epithelial, mesenchymal, or melanocytic populations. Aside from mast cell tumors, criteria of malignancy are not often applied to round cell tumors. The following outlines some of the criteria of malignancy used in cytologic assessment.

Anisocytosis: This describes when different cell sizes are observed. This can range from mild to marked.

Anisokaryosis: This describes when different nuclear sizes are observed. This can range from mild to marked.

Prominent/multiple/oddly shaped nucleoli: Nucleoli are visible and can be multiple or unusually shaped. Nucleoli are normally round, but can become angular, rectangular, or stellate. Note: Diff Quik stain often causes nucleoli to stand out more prominently, even in benign populations.

Multinucleation: More than one nucleus is seen in a single cell. Remember, some non-neoplastic cell types normally contain multiple nuclei including osteoclasts and multinucleated giant cells.

Atypical/increased mitotic figures: Mitotic figures can be seen normally in some tissues (e.g. lymph nodes), however, within neoplastic populations, increased numbers of mitotic figures can indicate a more aggressive population. Mitotic figures can also appear atypical morphologically (star-burst or ring patterns, etc).

Nuclear molding: When a cell contains more than one nucleus and the two nuclei are molding around each other (similar to hugging!).

Varying nuclear to cytoplasmic ratios: N:C ratio refers to the amount of cytoplasm a cell has in relation to the size of its nucleus. Significant variation in the N:C ratio between cells is considered a criteria of malignancy (i.e. some cells contain a small amount of cytoplasm and a large nucleus, while others contain a large amount of cytoplasm and a small nucleus, etc).

Cytomegaly and karyomegaly: Cytomegaly describes cells that are abnormally large. Karyomegaly describes nuclei that are abnormally large.

Keep in Mind!

It should be recognized that not all tumor types follow the basic cytologic rules for determination of benignancy vs. malignancy. For example, mammary neoplasms can appear markedly atypical cytologically and be benign (and vice versa). Neuroendocrine neoplasms such as thyroid tumors can appear cytologically benign yet be malignant. Reactive fibroblasts can appear markedly atypical yet represent a normal physiologic response to inflammation/tissue damage. There are a variety of specific tissues/tumor types that do not follow these rules and require memorization/experience by the cytologist in order to avoid misdiagnosis. 

Additionally, it is important that multiple criteria of malignancy should be observed before a confident cytologic diagnosis of malignancy is assigned.  This is because some non-neoplastic populations inherently exhibit some of these features, such as hepatocytes which normally exhibit prominent nucleoli, transitional epithelial cells which normally exhibit some anisocytosis and anisokaryosis, amongst others. These features must also be memorized by the cytologist in order to avoid over-interpretation and a premature diagnosis of malignancy.

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About the Author: Kate Baker, DVM, MS, DACVP (Clinical Pathology)

Dr. Kate Baker grew up in Nashville, Tennessee and completed her DVM at the University of Tennessee in 2012. She then went on to complete a small animal rotating internship and then a clinical pathology residency and Masters degree at the University of Illinois. Dr. Baker became board certified in 2016 and currently works as an educator, diagnostician, and consultant. Her professional passion is creating resources and experiences for veterinarians to learn and thrive in practice.