Cellular Proliferation in Canine Cutaneous Mast Cell Tumors: Associations withc-KITand Its Role in Prognostication

Abstract

Abstract. Canine cutaneous mast cell tumor (MCT) is a common neoplastic disease in dogs. Due to the prevalence of canine MCTs and the variable biologic behavior of this disease, accurate prognostication and a thorough understanding of MCT biology are critical for the treatment of this disease. The goals of this study were to evaluate and compare the utility of the proliferation markers Ki67, proliferating cell nuclear antigen (PCNA), and argyrophilic nucleolar organizing region (AgNOR) as independent prognostic markers for canine MCTs and to evaluate the use of these markers in combination, as each marker assesses different aspects of cellular proliferation. An additional goal of this study was to evaluate the associations between cellular proliferation and c-KIT mutations and between cellular proliferation and aberrant KIT protein localization in canine MCTs. Fifty-six MCTs treated with surgical excision alone were included in this study. Each MCT was evaluated for Ki67 expression, PCNA expression, and KIT protein localization using immunohistochemistry; for AgNOR counts using histochemical staining; and for the presence of internal tandem duplication c-KIT mutations using polymerase chain reaction amplification. In this study, increased Ki67 and AgNOR counts were both associated with significantly decreased survival. On the basis of these results, we recommend that the evaluation of cellular proliferation, including evaluations of both Ki67 expression and AgNORs, should be routinely used in the prognostication of canine MCTs. Additionally, the results of this study show that MCTs with aberrant KIT protein localization or internal tandem duplication c-KIT mutations are associated with increased cellular proliferation, further suggesting a role for c-KIT in the progression of canine MCTs.

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

“…In dogs, approximately 9–30% of mast cell tumors (MCTs) show c‐kit mutations, including internal tandem duplications (ITDs) in the juxtamembrane domain, resulting in constitutive activation of KIT in the absence of ligand binding,1, 2 and activating point mutations in c‐kit extracellular domains (eg, exons 8 and 9) 3. In general, ITDs are associated with an increased risk of metastasis and local recurrence, higher tumor proliferation index, and aberrant KIT localization 2, 4, 5, 6…”

Comparative analysis of markers of cell proliferation in canine mast cell tumours according to current classifications

“…The expression of Ki-67 increases from G 1 phase, and reaches its peak level during the M phase (Scholzen and Gerdes 2000). Since many previous studies showed that Ki-67 is an accurate prognostic marker for MCT (Abadie et al 1999, Scase et al 2006, Webster et al 2007, Dos Santos Costa Poggiani et al 2012, we used its expression as a reference value for other analyzed proteins and histopathological grading systems. We showed that the expression of Ki-67 increased proportionally to the MCT grade.…”

E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors

“…It is unclear whether multiple MCTs represent metastatic spread or new neoplasms (Kiupel et al, 2005;Mullins et al, 2006;Murphy et al, 2006;Preziosi et al, 2007). The molecular events and etiology of MCT development and progression are not well elucidated but are thought to be multifactorial (Kiupel et al, 2004;Turin et al, 2006;Scase et al, 2006;Webster et al, 2007;Thamm and Vail, 2007). The clinical and histological characteristics of cutaneous canine MCTs provide useful prognostic information.…”

“…Clinical and molecular studies of MCTs have focused on precisely identifying the molecular alterations for each grade and defining the biochemical and biological impact on cancer cell proliferation and differentiation (Bostock et al, 1989;Simoes et al, 1994;Abadie et al, 1999;Leibman et al, 2000;Lana et al, 2000;Bergmann, 2003;Scase et al, 2006;Wu et al, 2004;Webster et al, 2007;Strefezzi et al, 2009). The expression profiles of a variety of biological markers, such as Ki67, c-Kit, Ag-NOR, chymase and tryptase, have been investigated as potential prognostic markers (e.g.…”

“…The expression profiles of a variety of biological markers, such as Ki67, c-Kit, Ag-NOR, chymase and tryptase, have been investigated as potential prognostic markers (e.g. progression, metastasis and life expectancy) (Bostock et al, 1989;Simoes et al, 1994;Abadie et al, 1999;Bergmann, 2003;Scase et al, 2006;Wu et al, 2004;Webster et al, 2007).…”