New Insights: c-kit Mutation in Dogs Strongly Predicts Mast Cell Tumor Recurrence

Clinical Value of Various Histological Factors in Cutaneous and Subcutaneous Mast Cell Tumors in 197 Dogs

Katherine Boyd, Melanie Dobromylskyj, Imogen Schofield, Dan O’Neill, Celia Figueroa, Owen Davies

Background

Canine mast cell tumors (MCTs) account for up to 20% of all skin and subcutaneous tumors in dogs, displaying highly variable biological behavior. Histological grading systems such as Patnaik and Kiupel are commonly used, but they fail to fully predict outcomes, especially for intermediate-grade tumors. Other proposed prognostic markers—such as mitotic count, Ki67, argyrophilic nucleolar organizer regions (AgNOR), and c-kit mutations—have been studied, but their independence and relative predictive value remain unclear. This study aimed to evaluate the prognostic significance and independence of several histological and molecular factors for MCT-specific survival (MSS) and recurrence in a large cohort of dogs treated in primary care.

Methods

This retrospective cohort study analyzed 197 dogs (199 MCTs) identified from a UK commercial laboratory database between January 2017 and August 2020. Each case underwent a standardized histological prognostic panel assessing Patnaik and Kiupel grade, mitotic count, Ki67, AgNOR, KiAg, c-kit mutation (exons 8 and 11), and KIT staining pattern. Clinical and outcome data were collected via the VetCompass database. Multivariable Cox proportional hazards regression was used to identify independent predictors of MCT-specific survival and recurrence, incorporating age and adjunctive therapy as covariates. Receiver operating characteristic (ROC) analyses determined optimal cut-offs for prognostic indices.

Results

Among all tumors, mitotic count > 5 was the only independent predictor of poorer MCT-specific survival (HR 10.2, p < 0.001). In low-grade (Patnaik I/II or Kiupel low-grade) MCTs, c-kit exon 11 mutation predicted decreased survival (HR 20.8, p = 0.015). For recurrence, independent predictors included c-kit exon 11 mutation (HR 10.0, p < 0.001), older age, and histological tumor-free margin < 2 mm. In low-grade tumors, both c-kit exon 11 mutation (HR 23.2, p = 0.007) and AgNOR ≥ 2.25/cell (HR 13.7, p = 0.016) were associated with higher recurrence risk. Ki67, while correlated with other indices, did not independently predict survival or recurrence. The 4-year MCT-specific survival was 86% overall.

Limitations

This retrospective study relied on existing pathology reports from multiple pathologists without centralized review, introducing variability. Incomplete follow-up data and limited staging reduced the accuracy of outcome classification, likely underestimating MCT-related deaths. Some factors—such as tumor size, duration, and growth rate—were unavailable. The relatively small number of tumor-related deaths and subcutaneous cases limited statistical power for subgroup analysis.

Conclusions

The study highlights the greater prognostic value of c-kit exon 11 mutations and AgNOR over Ki67 in predicting outcomes in canine MCTs. Mitotic count remains a strong and independent indicator of poor survival, while close surgical margins (<2 mm) increase recurrence risk. These findings support using c-kit mutation testing alongside mitotic index and margin evaluation to refine prognostication and clinical management in dogs with cutaneous and subcutaneous MCTs.

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