NEW INSIGHTS INTO PATHOGENESIS AND PROGNOSIS OF CANINE SARCOMAS

The majority of canine soft tissue and visceral sarcoma prognostic studies have been influenced by a “one size fits all” approach which lead researchers to merge different subtypes of sarcomas in the same study population. The consequent heterogeneity of cases hampered the interpretation of the results per each tumor category and impeded the comparison of the results among different studies and their application in veterinary clinical oncology. The majority of these studies have also been characterized by non-standardized and non-rigorous methods. Given these premises, the aims of this thesis were to identify valuable prognostic factors specific for different canine sarcoma subtypes, following rigorous and repeatable methods, leading to a better definition of patient outcome, as well as provide novel insights into canine sarcoma pathogenesis, providing a basis for improved clinical management and possibly targeted therapy. The introduction provides an overview of classification and prognostic factors in cutaneous and subcutaneous soft tissue sarcomas (STSs), as well as visceral sarcomas, with a special focus on canine perivascular wall tumors (cPWTs) and splenic stromal sarcomas (SSSs). The introduction is followed by the description of four distinct investigations. The first study analysed the impact of clinical and histopathological variables on local recurrence (LR) and overall survival time (OST) in a large series of retrospectively collected surgically excised cPWTs finding that histological grade, tumor necrosis, mitotic count, status of surgical margins, tumor ulceration, and location on distal extremities had an impact on LR and that ulceration, grade III, necrosis >50% and higher mitotic count were correlated with shorter OST. The study results suggested that all these prognostic factors need to be considered to predict cPWTs prognosis more accurately. The second study aimed at evaluating the immunohistochemical expression of survivin and β-catenin in a series of retrospectively collected surgically excised cPWT samples to investigate their possible involvement in the tumorigenesis and progression of these tumors. Additionally, the study attempted to recognize the prognostic impact of survivin, β-catenin, and Ki-67, together with histopathological and clinical variables, on LR and OST. cPWTs variably expressed survivin and β-catenin at both nuclear and cytoplasmic level, and increased nuclear survivin was associated to a reduced OST. Inclusion of survivin immunohistochemical expression analysis when diagnosing cPWTs may allow to better define patient prognosis and to eventually plan adjuvant treatments in selected dogs. Additionally, survivin and β-catenin may be potential therapeutic targets for more aggressive phenotypes of these tumors. Finally, the study confirmed the prognostic role of mitotic count and tumor size in cPWTs. The third study focused on canine STSs surgical margin assessment investigating the impact of clean but close margins (CbCMs) on LR. The study reported that the cumulative incidence of LR at three years differed significantly between infiltrated margins, CbCMs, and tumor-free margins. Canine STSs excised with infiltrated margins had the greatest risk of LR, and the rate of LR with CbCMs was greater than LR rate of tumor-free margins. Both when CbCMs were grouped with infiltrated margins and when CbCMs were grouped with tumor-free margins, a significant difference between groups persisted. Thus, the conclusion was that CbCMs should be considered as a separate prognostic category for canine STSs. The fourth study assessed the impact of pathological and clinical variables on the occurrence of metastasis in 32 cases of canine SSSs, which were classified into different subtypes on the basis of histomorphological and immunohistochemical features. The research has demonstrated a potential prognostic role of the grading system usually applied to canine cutaneous and subcutaneous STSs, and a statistically significant prognostic role of mitotic count in predicting SSS metastatic spread. Furthermore, the study results suggested that differentiating between different SSS subtypes may not have prognostic value. Finally, age and sex of dogs, and administration of adjuvant chemotherapy seemed not to impact the risk of development of metastases, although further studies are needed. This thesis shed light on some aspects of the pathology and prognostication of canine sarcomas. The author hopes that the reported results will be relevant to veterinary pathologists and surgical oncologists who are involved in canine sarcomas diagnosis and treatment. Furthermore, the author expects that the studies included in this thesis may provide novel insights for future research in this field.