256 outcome [39]. Tumor-inﬁltrating neutrophils are used to predict outcome in patients with adenocarcinoma of the bronchioloalveolar carcinoma subtype [40] and gastric carcinoma [41]. In a recent report, it was concluded that the type, density, and location of immune cells within the tu- mor samples are a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer [42]. In conclusion, we conﬁrm our earlier pilot study ﬁndings and conﬁrm that stromal MCs correlate with a good prognosis in a large cohort of 4,444 invasive breast cancer patients with long-term follow-up. It highlights the critical role that the host stromal reaction, in particular the inﬂammatory cell inﬁltrate, plays in modulating cancer progression. MCs can be used as markers for risk stratiﬁ- cation in invasive breast cancers. Acknowledgements This work was supported in part by the Canadian Institutes of Health Research Strategic Training Program (Grant STP-53912), Translation Acceleration Grant from the Cana- dian Breast Cancer Research Alliance and the National Institute of Health Strategic Partnering to Evaluate Cancer Signatures program. The Genetic Pathology Evaluation Center is supported by an unre- stricted educational grant from sanoﬁ-aventis, Canada. D. Huntsman and T. Nielsen are Michael Smith Health Foundation for Research Scholars. References 1. Baek JY, Tefferi A, Pardanani A, Li CY (2002) Immunohisto- chemical studies of c-kit, transforming growth factor-beta, and basic ﬁbroblast growth factor in mast cell disease. Leuk Res 26:83–90 2. Shijubo N, Kojima H, Nagata M, Ohchi T, Suzuki A, Abe S, Sato N (2003) Tumor angiogenesis of non-small cell lung cancer. Microsc Res Tech 60:186-198 3. Ibaraki T, Muramatsu M, Takai S, Jin D, Maruyama H, Orino T, Katsumata T, Miyazaki M (2005) The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non- small cell lung cancer. Eur J Cardiothorac Surg 28:617–621 4. Tataroglu C, Kargi A, Ozkal S, Esrefoglu N, Akkoclu A (2004) Association of macrophages, mast cells and eosinophil leuko- cytes with angiogenesis and tumor stage in non-small cell lung carcinomas (NSCLC). Lung Cancer 43:47–54 5. Kankkunen JP, Harvima IT, Naukkarinen A (1997) Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. Int J Cancer 72:385–388 6. Lachter J, Stein M, Lichtig C, Eidelman S, Munichor M (1995) Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum 38:290–293 7. Yamamoto T, Katayama I, Nishioka K (1997) Expression of stem cell factor in basal cell carcinoma. Br J Dermatol 137:709–713 8. Imada A, Shijubo N, Kojima H, Abe S (2000) Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarci- noma. Eur Respir 15:1087–1093 9. Theoharides CT, Conti P (2004) Mast cells: the JEKYLL and HYDE of tumor growth. Trends Immunol 25:235–241 10. Ribatti D, Vacca A, Nico B, Crivellato E, Roncali L, Dammacco F (2001) The role of mast cells in tumour angiogenesis. Br J Haematol 115:514–521 123 Breast Cancer Res Treat (2008) 107:249–257 11. Dabiri S, Huntsman D, Makretsov N, Cheang M, Gilks B, Bajdik C, Gelmon K, Chia S, Hayes M (2004) The presence of stromal mast cells identiﬁes a subset of invasive breast cancers with a favourable prognosis. Mod Pathol 17:690–695 12. Aaltomaa S, Lipponen P, Papinaho S, Kosma VM (1993) Mast cells in breast cancer. Anticancer Res 13:785–788 13. Chan JK, Loizzi V, Magistris A, Hunter MI, Rutgers J, DiSaia PJ, Berman ML (2005) Mast cell density, angiogenesis, blood clot- ting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 99:20–25 14. Tomita M, Matsuzaki Y, Onitsuka T (1999) Correlation between mast cells, survival rates in patients with pulmonary adenocar- cinoma. Lung Cancer 26:103–108 15. Tan SY, Fan Y, Luo HS, Shen ZX, Guo Y, Zhao LJ (2005) Prognostic signiﬁcance of cell inﬁltrations of immunosurveil- lance in colorectal cancer. World J Gastroenterol 11:1210–1214 16. Burtin C, Ponvert C, Fray A, Scheinmann P, Lespinats G, Lori- don B, Canu P, Paupe J (1985) Inverse correlation between tumor incidence and tissue histamine levels in W/WV, WV/+, and +/+ mice. J Natl Cancer Inst 74:671–674 17. Olivotto IA, Bajdik CD, Ravdin PM, Speers CH, Coldman AJ, Norris BD, Davis GJ, Chia SK, Gelmon KA (2005) Population- based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 23:2716–2725 18. Cheang MC, Treaba DO, Speers CH, Olivotto IA, Bajdik CD, Chia SK, Goldstein LC, Gelmon KA, Huntsman D, Gilks CB, Nielsen TO, Gown AM (2006) Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal anti- body 1D5 in predicting survival. J Clin Oncol 24:5637–5644 19. Liu CL, Prapong W, Natkunam Y, Alizadeh A, Montgomery K, Gilks CB, van de Rijn M (2002) Software tools for high- throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol 161:1557–1565 20. Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio- informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259 21. Bhowmick AN, Moses LH (2005) Tumor-stroma interactions. Curr Opin Genet Dev 15:97–101 22. West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP, Montgomery K, Zhu S, Patel R, Hernandez-Boussard T, Goldblum JR, Brown PO, van de Vijver M, van de Rijn M (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3:e187 23. Ghiara P, Boraschi D, Villa L, Scapigliati G, Taddei C, Tagliabue (1985) In vitro generated mast cells express natural cytotoxicity against tumour cells. Immunology 55:317–324 24. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23:8959–8967 25. Henderson WR, Chi EY, Jong EC, Klebanoff SJ (1981) Mast cell-mediated tumor-cell cytotoxicity. Role of the peroxidase system. J Exp Med 153:520–533 26. He S, Walls AF (1998) Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inﬂammatory cells in vivo. Br J Pharmacol 125:1491–1500 27. Vliagoftis H, Boucher WS, Mak LL, Theoharides CT (1992) Inhibition of mast cell secretion by oxidation products of natural polyamines. Biochem Pharmacol 43:2237–2245 28. Farram E, Nelson DS (1980) Mouse mast cells as anti-tumor effector cells. Cell Immunol 55:294–301 29. Latti S, Leskinen M, Shiota N, Wang Y, Kovanen PT, Lind- stedt KA (2003) Mast cell-mediated apoptosis of endothelial cells in vitro: a paracrine mechanism involving TNF-alpha-