Comparative aspects of mast cell neoplasia in animals and the role of KIT in prognosis and treatment

Abstract

Mast cell neoplasia clinical presentation and biological behaviour vary considerably across mammalian species, ranging from a solitary benign mass to an aggressive systemic malignancy. Mutations in the KIT Proto‐Oncogene Receptor Tyrosine Kinase (KIT) gene are common molecular abnormalities involved in mast cell tumorigenesis. KIT mutations often occur in dog, cat and human neoplastic mast cells and result in altered Kit protein structure and function. In dogs, certain KIT mutations are associated with more malignant and lethal disease. In contrast, KIT mutations in feline and human mast cell neoplasms are not correlated with prognosis, but are of value in diagnosis and treatment planning in humans. KIT genetic abnormalities have not been well investigated in other species, although aberrant cytoplasmic Kit protein staining detected in neoplasms of the ferret, horse and cow resembles aberrant Kit staining patterns detected in neoplastic mast cells of dogs, cats and humans. Mutations within KIT are classified as either regulatory‐type or enzymatic pocket‐type mutations according to their location within the KIT Proto‐Oncogene. Mutations within the enzymatic pocket domain confer tumour resistance to tyrosine kinase inhibitors (TKIs). Hence, knowledge of tumour KIT mutation status adds valuable information for optimizing patient treatment strategies. The use of TKIs in combination with conventional chemotherapeutics has opened a new treatment avenue for patients unresponsive to existing drugs. This review highlights the similarities and differences of mast cell neoplasia in mammals with a special focus on the involvement of KIT in the canine and feline forms in comparison to human mast cell neoplasia.

RNAScope in situ Hybridization as a Novel Technique for the Assessment of c-KIT mRNA Expression in Canine Mast Cell Tumor

“…It has been extensively described that the immunohistochemical localization of KIT protein in neoplastic canine mast cells may have three different patterns: perimembranous labeling (pattern I), focal or stippled cytoplasmic labeling along with loss of perimembranous labeling (pattern II), and diffuse cytoplasmic labeling (pattern III) ( 1 , 15 , 17 , 18 ). Pattern I has been associated with a low aggressive biological behavior, whereas both patterns II and III have been associated with a decreased overall survival time and an increased incidence of local recurrence ( 16 , 18 , 19 ). As for now, there is no truly reliable biological marker that can predict canine MCT behavior ( 17 ), so it is of utmost importance to investigate novel biomarkers and assays that can be sensitive, specific, and predictive at the same time.…”

Clinical characteristics of mastocytoma in dogs

“…Відповідно до сучасного трактування у гуманній медицині (Akin et al, 2010;Alvarez-Twose et al, 2016;Okhotnikova et al, 2018) САМ, обумовлений вивільненням медіаторів з активованих мастоцитів, об'єднує гетерогенну групу захворювань, які характеризуються клінічними ознаками ураження шкіри, слизових оболонок шлунково-кишкового тракту і дихальних шляхів, органів серцево-судинної та нервової систем, у тому числі й системними реакціями, зокрема, алергією та анафілаксією. Як свідчить аналіз літературних повідомлень (Willmann et al, 2018;Tamlin et al, 2020) перебіг захворювань, за безпосередньої участі активованих ОК, у людини та в тварин має певні відмінності. За даними медичної літератури (Frieri & Quershi, 2013;Valent et al, 2015;Gülen et al, 2016;Pardanani, 2016;Frolova et al, 2018;Leguit et al, 2020) на мастоцитоз частіше хворіють діти у яких хвороба перебігає у шкірній формі (зазвичай, як пігментна кропив'янка, рідше солітарна мастоцитома) і при досягненні пубертатного віку хвороба, як правило, регресує.…”

KIT mutations in mast cell tumours from cheetahs (Acinonyx jubatus) and domestic cats (Felis catus)

“…Mast cell neoplasia affects a variety of species including humans, cats, dogs, birds, reptiles and amphibians 1,2 . The clinical manifestation and biological malignancy of mast cell neoplasia vary considerably not only across species but also within species.…”

“…In cats and dogs, mast cell tumours (MCTs) are clinically erratic, ranging from benign nodules to malignant and metastatic disease 4,5 . Despite these differences in biological behaviour, mutations of the KIT proto‐oncogene receptor tyrosine kinase ( KIT ) within the neoplastic mast cell DNA are common in these species 1 …”

“…Kit protein structure and activity is disrupted by mutation within the KIT gene. KIT gain‐of‐function mutations cause constitutive Kit protein activation in the absence of ligand binding and are implicated in the biology of mast cell malignancies in humans, cats and dogs 1,3,7,8 . In canine MCTs, KIT mutations are detected in 8%‐29% of cases and are correlated with more malignant disease 8‐11 .…”