Prognostic and predictive significance of KIT protein expression and <i>c‐kit</i> gene mutation in canine cutaneous mast cell tumours: A consensus of the Oncology‐Pathology Working Group

Thamm, Douglas H.; Avery, Anne C.; Berlato, Davide; Bulman-Fleming, Julie; Clifford, Craig; Hershey, Alexander; Intile, Joanne L.; Jones, Pamela D; Kamstock, Debra A.; Liptak, Julius M.; Pavuk, Alana; Peauroi, John R.; Powell, Roger; Rissetto, Kerry; Valli, V. E.; Webster, Joshua D.

doi:10.1111/vco.12518

Cited by 26 publications

(38 citation statements)

References 29 publications

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“…14 Abnormal expression patterns of the KIT protein and mutations in the c-kit proto-oncogene have been linked to poor patient outcome in ccMCTs. 29 As a transmembranous protein, KIT has a perimembranous location in nonneoplastic mast cells and less aggressive ccMCTs. Aberrant localization in the cytoplasm is associated with an unfavorable prognosis.…”

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confidence: 99%

Internal Tandem Duplication of Exon 8 of c-kit Is Associated With Longer Total Survival in Canine Cutaneous Mast Cell Tumors

Brocks¹,

Bertram

Bartel

et al. 2020

Vet Pathol

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Canine cutaneous mast cell tumors (ccMCTs) have a highly variable biological behavior and accurate prognostication is essential for therapeutic intervention. Internal tandem duplications (ITD) of exon 11 are the most commonly detected c-kit mutation in ccMCTs and are associated with poor prognosis and increased cellular proliferation. The prognostic value of detecting mutations in other exons of c-kit has not been systematically examined. In this study, we analyzed the prognostic value of ITD mutations of exon 8 in c-kit of ccMCTs in comparison to ccMCTs with ITD mutations of exon 11 and ccMCTs without mutations of exon 8 or 11. The mutational status, histological grade, KIT expression pattern, Ki67 index, AgNOR (argyrophilic nucleolar organizing region) score, and Ag67 score were determined in 221 ccMCTs, and outcome was available for 101 dogs. ITD mutations of exon 8 were found in 73/221 (33%), of exon 11 in 100/221 (45%), and none of these mutations in 50/221 (22%) of ccMCTs. None of the dogs with mutations of exon 8 died due to suspected ccMCT-related cause, but 23% dogs with ccMCTs with mutations of exon 11 died due to suspected ccMCT-related cause. Prognostic parameters in ccMCTs with exon 11 mutations were commonly associated with a high proliferative activity and poor prognosis, while prognostic markers in ccMCTs with mutations of exon 8 had lower values similar to those observed in ccMCTs without mutations in exons 8 or 11 of c-kit. This study indicates that screening for ITD mutations in exon 8 in ccMCTs may be helpful to identify less aggressive ccMCTs and may be recommended as a supplementary prognostic test.

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confidence: 99%

Internal Tandem Duplication of Exon 8 of c-kit Is Associated With Longer Total Survival in Canine Cutaneous Mast Cell Tumors

Brocks¹,

Bertram

Bartel

et al. 2020

Vet Pathol

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“…It is important to consider that c-kit mutations and abnormal expression of c-kit are related to increase in vitro cell proliferation of MCTs [ 27 ]. c-kit is a reliable immunohistochemical marker, and a positive relationship is expected between the presence of c-kit mutations and a higher grade of canine MCT [ 8 , 9 ]. The findings of the present study show that the expression of p53 was similar to that of c-kit, indicating that p53 expression can also be used to estimate the prognosis of canine MCTs.…”

Section: Discussionmentioning

confidence: 99%

Histological classification and expression of markers of canine mast cell tumors

et al. 2020

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Background and Aim: Mast cell tumors (MCTs) are malignant neoplasms that are common in dogs. Their biological behavior is variable and unpredictable. The aim of the present study was to analyze the histological classification and expression of markers of canine MCTs. Materials and Methods: Thirty samples of canine MCTs were graded according to the histological classification methods of Patnaik and those of Kiupel. The expression of phosphoprotein 53 (p53) and c-kit proteins was quantified by immunohistochemistry using image processing software, ImageJ - a public domain computer program, developed at the National Institutes of Health. Results: It was possible to determine the grade of 100% of the samples. According to Patnaik's classification, 20.00% of the samples were Grade 1, 43.30% were Grade 2, and 36.70% were Grade 3. According to Kiupel's classification, 56.67% of the samples were of high intensity and 43.33% were of low intensity. Grade 1 tumors had the highest expression of p53 and c-kit, and Grade 2 had the lowest expression. The results showed that it is necessary to perform both histological grading methods. The classification into high and low intensity may provide more consistent results than the three-level grading system. However, a smaller number of categories, although it facilitates the classification, may not be sufficient for the prognosis. Conclusion: Quantitative evaluation of p-53 and c-kit expression is a useful tool to increase the accuracy of the analysis and to aid in choosing the treatment method for canine MCTs. Histological grading should be combined with other diagnostic methods.

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“…No single prognostic factor has perfect predictive value 34 . In human acute myeloid leukaemia, FLT3 ‐ITD mutations are common, 35,36 and are associated with an unfavourable prognosis 37,38 .…”

Section: Discussionmentioning

confidence: 99%

In situ c‐KIT mRNA quantification of canine cutaneous mast cell tumours and its relationship to prognostic factors

Seung

Cho

Kim

et al. 2020

Vet Comparative Oncology

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Cutaneous mast cell tumours (MCTs) are the most frequent malignant skin tumours in dogs. Mutations in the c‐KIT proto‐oncogene are correlated with the pathogenesis and aggressiveness of MCTs. To date, studies have focused on c‐KIT mutations and KIT protein localization, with a general lack of mRNA‐level analyses. In this study, c‐KIT mRNA expression was investigated in canine MCTs by RNA in situ hybridization (RNA‐ISH). Furthermore, we evaluated associations between c‐KIT mRNA expression and the histological grade, KIT immunohistochemical staining pattern and other clinicopathological parameters. c‐KIT mRNA expression was observed in all MCT samples, appearing as clusters of dots in the cytoplasm of neoplastic cells. A significant correlation was detected between c‐KIT mRNA expression (quantified according to the H‐score and the percentage of positive cells) and the histological grade (determined using two‐and three‐tier grading systems; P < .05). We also found a significant positive correlation (all P < .05) between c‐KIT mRNA expression and the proliferation indices (mitotic index, Ki‐67, and Ag67). However, no significant associations with c‐KIT expression from RNA‐ISH were found with respect to different KIT staining patterns. Overall, these results demonstrate that c‐KIT mRNA expression might be an additional tool for measuring the c‐KIT status in canine cutaneous MCTs and could serve as a potential prognostic factor. Further studies should evaluate the prognostic significance of c‐KIT mRNA expression in a large and uniform cohort of canine MCTs.

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Prognostic and predictive significance of KIT protein expression and c‐kit gene mutation in canine cutaneous mast cell tumours: A consensus of the Oncology‐Pathology Working Group

Cited by 26 publications

References 29 publications

Internal Tandem Duplication of Exon 8 of c-kit Is Associated With Longer Total Survival in Canine Cutaneous Mast Cell Tumors

Internal Tandem Duplication of Exon 8 of c-kit Is Associated With Longer Total Survival in Canine Cutaneous Mast Cell Tumors

Histological classification and expression of markers of canine mast cell tumors

In situ c‐KIT mRNA quantification of canine cutaneous mast cell tumours and its relationship to prognostic factors

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