Mast cells are widely distributed immune effector cells that are classically activated during hypersensitivity reactions. Mast cells (MCs) play an important role in inflammation and immune regulation and are concentrated in tissues that form a barrier to the external environment, such as the skin, gastrointestinal tract and lung. MCs are easily recognizable by their distinct cytoplasmic granules in routinely stained cytologic preparations and histologic sections (with the exception of Diff-Quik). These granules are the source of inflammatory mediators such as histamine, and various cytokines and chemokines, including eotaxin which recruits eosinophils to sites of mast cell-mediated acute inflammation. The bioactive substances within mast cell granules and accompanying eosinophils are an important source of clinical complications in a subset of animals with mast cell tumors, including local edema and hemorrhage, gastrointestinal ulceration, and delayed wound healing following surgery.

Canine Cutaneous Mast Cell Tumors

Mast cell tumors (MCTs) are among the most common cutaneous neoplasms in dogs, accounting for up to 21% of all skin tumors.¹ The etiology of canine MCTs is poorly understood; however, well-recognized breed predispositions implicate genetic factors. MCTs have a broad spectrum of biologic behavior, and commonly used grading schemes assist pathologists and clinicians in predicting clinical outcome and guiding treatment choices.

Patnaik's grading system has been widely used by pathologists since the 1980s and divides tumors into three grades based on cellularity, cell morphology, and mitotic activity.² More recently, a two-tiered grading system has been found to improve concordance between pathologists and provide more reliable prognostic information.³ Kuipel's system divides MCTs into low-grade and high-grade tumors, based on cellular atypia and variation, and mitotic activity. Studies evaluating the two-tiered system found survival time for low-grade MCTs is greater than 2 years, whereas high-grade tumors have a survival time of < 4 months. Subsequent studies have likewise found that low-grade tumors are associated with lower mortality rates and significantly longer survival times than high-grade MCTs.⁴ In both grading schemes, mitotic index is an important prognostic indicator. Evaluations of mitotic activity in canine cutaneous MCTs demonstrated that regardless of grade, mitotic index (MI) is predictive of survival.⁵ Dogs with a MI < 5 survived significantly longer (70 months) than those with MI > 5 (2 months).

In recent years, tools for evaluating and interpreting molecular markers have become widely available. The gene c-KIT (also called CD117) encodes the proto-oncogene KIT, a growth factor receptor that is normally expressed on the surface of mast cells. Aberrant expression or localization of the protein has been found to have prognostic significance, and both immunohistochemistry and PCR-based mutation analysis are routinely utilized to predict biologic behavior and response to therapy. Increased cytoplasmic localization of KIT staining, identified by IHC, is associated with increased local recurrence and a lower survival rate.⁶ Specific c-KIT mutations may have a better response to treatment with tyrosine kinase inhibitors such as Palladia (toceranib phosphate).

Subcutaneous and Visceral Mast Cell Tumors

Current grading systems pertain mostly to cutaneous tumors that arise specifically within the dermis. In dogs, MCTs that are located within the subcutis appear to behave differently to cutaneous MCTs, with extended survival times and lower rates of recurrence and metastasis.⁷ Less is known about subcutaneous MCTs; however, mitotic index correlates with clinical outcome. Those tumors with a MI > 4 have a shorter survival time than tumors with MI < 4, which may be cured by surgery alone.

MCTs occasionally arise in extracutaneous sites such as the gastrointestinal tract. In many cases, these tumors are preceded by a cutaneous neoplasm; however, primary visceral MCTs do occur. Again, established grading systems cannot be used to predict the behavior of these tumors.

Feline Cutaneous Mast Cell Tumors

Although cutaneous MCTs are common in cats, no grading system is available for accurate prognostication of feline tumors. Most feline MCTs are well-differentiated tumors that are effectively treated by complete surgical excision alone; however, a subset of tumors behave more aggressively. The most reliable prognostic indicator currently available is MI; a high MI is associated with a worse outcome.⁸ Some studies describe various histologic subtypes, including well-differentiated mastocytic, pleomorphic mastocytic or atypical subtypes; however, these have not been found to correlate with clinical outcomes.⁹

References

1.  Welle MM, et al. Canine mast cell tumours: a review of the pathogenesis, clinical features, pathology and treatment. Vet Dermatol. 2008;19(6):321–339.

2.  Patnaik AK, et al. Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol. 1984;21:469–474.

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.

4.  Sabattini S, et al. Histologic grading of canine mast cell tumor: is 2 better than 3? Vet Pathol. 2015;52(1):70–73.

5.  Romansik EM, et al. Mitotic index is predictive for survival for canine cutaneous mast cell tumors. Vet Pathol. 2007;44(3):335–341.

6.  Kiupel M, et al. The use of KIT and tryptase expression patterns as prognostic tools for canine cutaneous mast cell tumors. Vet Pathol. 2004;41(4):371–377.

7.  Thompson JJ, et al. Canine subcutaneous mast cell tumors: cellular proliferation and KIT expression as prognostic indices. Vet Pathol. 2011;48(1):169–181.

8.  Sabattini S, Bettini G. Prognostic value of histologic and immunohistochemical features in feline cutaneous mast cell tumours. Vet Pathol. 2010;47:643–653.

9.  Melville K, Smith KC, Dobromylskyj MJ. Feline cutaneous mast cell tumours: a UK-based study comparing signalment and histological features with long-term outcomes. J Feline Med Surg. 2014;[Epub ahead of print].