A case report of feline mast cell tumour with intertumoral heterogeneity: Identification of secondary mutations c.998G>C and c.2383G>C in KIT after resistance to toceranib

Abstract

A 12-year-old male domestic cat with multiple subcutaneous mast cell tumours (MCTs) presented with a 2-week history of pruritus and raw/bleeding skin from self-trauma at Kagoshima University Veterinary Teaching Hospital. Polymerase chain reaction (PCR) and histopathological analyses revealed intertumoral heterogeneity among tumour locations based on the mutation status of KIT. In addition, the expression pattern of KIT was characterized. After failed treatment with vinblastine (2.0-2.2 mg/m², intravenous administration, two doses in total) or nimustine (25 mg/m², intravenous administration, two doses in total), toceranib (2.2-2.6 mg/kg, orally administered, every other day) was administered to treat recurrent MCTs harbouring the KIT exon eight internal tandem duplication mutation, achieving a complete response. However, toceranib resistance developed 2 months after treatment initiation. Subsequent PCR analysis was conducted to identify the mutational status of KIT in each MCT and to detect the presence of secondary mutations associated with the acquisition of toceranib resistance. Secondary KIT mutations (c.998G>C and c.2383G>C), which were not initially detected in tumour cells at diagnosis, were identified after the development of resistance to toceranib. This indicates that the tumour cells in feline MCTs in the same case have diverse characteristics. Our findings encourage further investigation into the development of therapeutic strategies for feline MCTs, particularly focusing on the heterogeneous nature of KIT/KIT and overcoming acquired resistance to toceranib.

Keywords: KIT mutation; acquired resistance; cat; heterogeneity; mast cell tumour; resistance to toceranib.

FIGURE 1

Clinical appearance of this case. Multiple subcutaneous masses on the right side of the neck (a) and femur (b). Bleeding is observed in the largest masses of both lesions: red arrowhead (a) and black arrowhead (b).

FIGURE 2

Identification of intertumoral heterogeneity in mast cell tumour (MCT). (A) Internal tandem duplication (ITD) of 13 nucleotides (underlined, wild type; double underlined, and mutant) and insertion of two nucleotides (broken line) were identified in genomic deoxyribonucleic acids extracted from MCTs. ITD were detected in MCTs located in the right neck (a), right femur (b), and trunk (c), but not in the spleen (d) or left cheek (e). (B) Immunohistochemistry for KIT expression and mutation status. Membranous (pattern I; upper panel) and focal/stippled cytoplasmic (pattern II; lower panel) expression patterns were observed in splenic and trunk MCTs, respectively. (C) Tumour location, KIT expression pattern, and ITD mutation status in exon 8. Bar, 20 mm.