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Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained., Patients and Methods: We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2 years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive., Results: Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767)., Conclusion: TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC., Design: A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches., Conclusions: The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Canine mammary tumours (CMTs) are the most common tumours of entire female dogs and represent a promising model for human breast cancer. Little is known about the presence and prognostic value of lymphangiogenesis in CMTs. The aims of the present study were to analyze selected characteristics of lymphatic vessels in CMTs, to evaluate their prognostic significance and to compare these results with studies of human breast cancer. Fifty-six benign CMTs, 55 malignant CMTs and 13 control samples of normal canine mammary gland tissue were studied. Serial immunohistochemical labelling with the lymphatic marker prox-1 and the proliferation marker Ki67 was performed. In intratumoural (IT) and peritumoural (PT) regions, the lymphatic vessel density (LVD), mean lymphatic vessel perimeter (LVP) and relative area occupied by lymphatic vessels (LVA) were analyzed. Lymphatic endothelial cell proliferation (LECP) and tumour cell proliferation (TCP) were also measured. Lymphatic vessels were identified in IT and PT regions and lymphangiogenesis was present in both regions. The IT lymphatic vessels were smaller, less numerous and occupied a smaller relative area compared with those of the PT region. Although no differences in lymphatic vessel parameters were observed between benign and malignant tumours, control tissue differed significantly from neoplastic tissue. None of the lymphatic vessel parameters showed a prognostic value, except for LECP in PT regions of benign tumours. The findings were in accordance with results of investigations into human breast cancer, which supports the use of dogs with spontaneously occurring CMTs as an animal model in comparative oncology trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Angiogenesis in canine mammary tumours (CMTs) has been described previously; however, only the intratumoural (IT) region has been studied and information on peritumoural (PT) angiogenesis is lacking. In this study, the blood vessel density (BVD), blood vessel perimeter (BVP) and blood vessel area (BVA) in IT and PT regions of 56 benign CMTs, 55 malignant CMTs and 13 samples of normal mammary gland tissue were analyzed. In addition, the blood endothelial cell proliferation (BECP) as an indicator of ongoing angiogenesis was investigated. The prognostic value of each parameter was also examined. Blood vessels and proliferating blood endothelial cells were present in IT and PT regions of both benign and malignant tumours. The vessels in the PT region had a significantly higher area and perimeter compared with those in the IT region. Malignant tumours showed significantly more vessels with a smaller total BVA and a higher BECP compared with benign tumours and control tissue. In the PT regions there was a significantly higher BVD, BVA and BVP compared with the vessels in control tissue. Only the IT and PT BVD and PT BECP in benign tumours allowed prediction of survival. The morphology of blood vessels in CMTs shows similarities with those in human breast cancer, which strengthens the case for the use of dogs with CMTs in comparative oncology trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Canine mammary tumours (CMTs) are the most common neoplasms in intact female dogs. Bitches with spontaneously arising CMTs represent a promising animal model for human breast cancer research. The aim of the present study was to develop an immunohistochemical protocol for the identification of blood and lymphatic vessels in CMTs. Antibodies specific for human lymphatic vessels (prox-1, lyve-1, podoplanin and D2-40) and blood vessels (von Willebrand factor [vWf], CD31 and CD34) were utilized. Serial sections of 18 samples (eight samples of normal canine mammary tissue, five benign and five malignant CMTs) were examined. Antibodies specific for podoplanin, D2-40 and CD34 showed no immunoreactivity with canine tissue. Prox-1 and CD31 were determined to be the most suitable markers for lymphatic and blood vessels, respectively., (Copyright © 2012 Elsevier Ltd. All rights reserved.)