Patrick Micke1, Carina Strell1, Johanna Mattsson1, Alfonso Martín-Bernabé2, Hans Brunnström3, Jutta Huvila4, Malin Sund5, Fredrik Wärnberg6, Fredrik Ponten1, Bengt Glimelius1, Ina Hrynchyk7, Siarhei Mauchanski8, Salome Khelashvili8, Gemma Garcia-Vicién9, David G Molleví9, Per-Henrik Edqvist1, Aine O Reilly2, Sara Corvigno10, Hanna Dahlstrand10, Johan Botling1, Ulrika Segersten11, Agnieszka Krzyzanowska12, Anders Bjartell12, Jacob Elebro13, Margareta Heby13, Sebastian Lundgren13, Charlotta Hedner13, David Borg13, Jenny Brändstedt13, Hanna Sartor14, Per-Uno Malmström11, Martin Johansson15, Björn Nodin13, Max Backman1, Cecilia Lindskog1, Karin Jirström16, Artur Mezheyeuski17. 1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 85, Sweden. 2. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. 3. Department of Clinical Sciences Lund, Division of Pathology, Lund University, Lund, Sweden; Department of Genetics and Pathology, Division of Laboratory Medicine, Region Skåne, Lund, Sweden. 4. Department of Pathology, University of British Columbia, Vancouver, Canada; Department of Pathology, University of Turku, Turku, Finland. 5. Department of Surgical and perioperative sciences/Surgery, Umeå University, Umeå, Sweden. 6. Department of Surgery at Institute of Clinical Sciences, Sahlgrenska University Hospital Göteborg, Göteborg, Sweden. 7. City Clinical Pathologoanatomic Bureau, Minsk, Belarus. 8. N.N. Alexandrov National Cancer Centre of Belarus, 223040 Minsk, Belarus. 9. ProCURE, Program Against Cancer therapeutic Resistance, Catalan Institute of Oncology, Molecular Mechanisms and Experimental Therapy in Oncology Program (ONCOBELL), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. 10. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 85, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. 11. Department of Surgical Sciences, Uppsala University, Uppsala 751 85, Sweden. 12. Department of Translational Medicine, Division of Urological Cancers, Lund University, Lund, Sweden. 13. Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, SE-221 00 Lund, Sweden. 14. Diagnostic Radiology, Department of Translational Medicine, Lund University, Skåne University Hospital, Lund, Sweden. 15. Department of Laboratory Medicine at Institute of Biomedicine, Sahlgrenska Universitety Hospital Göteborg, Göteborg, Sweden. 16. Department of Genetics and Pathology, Division of Laboratory Medicine, Region Skåne, Lund, Sweden; Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, SE-221 00 Lund, Sweden. 17. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 85, Sweden. Electronic address: artur.mezheyeuski@igp.uu.se.
Abstract
BACKGROUND: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed. METHODS: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns. FINDINGS: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR(95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59(1.49-8.62)) associations of the tumour stroma fraction with survival. INTERPRETATION: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance. FUNDING: The Swedish Cancer Society, The Lions Cancer Foundation Uppsala, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P.O.Zetterling Foundation, and The Sjöberg Foundation, Sweden.
BACKGROUND: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed. METHODS: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns. FINDINGS: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR(95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59(1.49-8.62)) associations of the tumour stroma fraction with survival. INTERPRETATION: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance. FUNDING: The Swedish Cancer Society, The LionsCancer Foundation Uppsala, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P.O.Zetterling Foundation, and The Sjöberg Foundation, Sweden.
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