Identification of prognostic factors in canine mammary malignant tumours: a multivariable survival study

Abstract

Background: Although several histopathological and clinical features of canine mammary gland tumours have been widely studied from a prognostic standpoint, considerable variations in tumour individual biologic behaviour difficult the definition of accurate prognostic factors. It has been suggested that the malignant behaviour of tumours is the end result of several alterations in cellular physiology that culminate in tumour growth and spread. Accordingly, the aim of this study was to determine, using a multivariable model, the independent prognostic value of several immunohistochemically detected tumour-associated molecules, such as MMP-9 and uPA in stromal cells and Ki-67, TIMP-2 and VEGF in cancer cells.

Results: Eighty-five female dogs affected by spontaneous malignant mammary neoplasias were followed up for a 2-year post-operative period. In univariate analysis, tumour characteristics such as size, mode of growth, regional lymph node metastases, tumour cell MIB-1 LI and MMP-9 and uPA expressions in tumour-adjacent fibroblasts, were associated with both survival and disease-free intervals. Histological type and grade were related with overall survival while VEGF and TIMP-2 were not significantly associated with none of the outcome parameters. In multivariable analysis, only a MIB-1 labelling index higher than 40% and a stromal expression of MMP-9 higher than 50% retained significant relationships with poor overall and disease-free survival.

Conclusions: The results of this study indicate that MMP-9 and Ki-67 are independent prognostic markers of canine malignant mammary tumours. Furthermore, the high stromal expressions of uPA and MMP-9 in aggressive tumours suggest that these molecules are potential therapeutic targets in the post-operative treatment of canine mammary cancer.

Figure 1

Kaplan-Meier disease free survival curves comparing immunohistochemical clinico-pathological factors in 85 dogs with MMTs. Female dogs with tumours larger than 3 cm, invasive growth, MIB-1 labelling index higher than 40%, and high uPA and MMP-9 immunoexpressions in stromal cells had significantly shorter disease-free intervals.

Figure 2

Kaplan-Meier overall survival curves comparing clinical and histopathological parameters in 85 dogs with MMTs. Dogs with tumours smaller than 3 cm, with expansive growth, well to moderately differentiated and classified as complex carcinomas had significantly longer survival times.

Figure 3

Kaplan-Meier overall survival curves comparing several immuno-histochemical factors in 85 dogs with MMTs. MIB-1 labelling index higher than 40%, and increased MMP-9 and uPA immunoexpressions predicted poorer survival times.