title: Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma.
abstract: We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Diana
authors.affiliation: Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Lai Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Zenobia
authors.initials: Z
authors.lastname: D'Costa
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Abul
authors.initials: A
authors.lastname: Azad
authors.affiliation: Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Soonawalla
authors.affiliation: Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Allen
authors.affiliation: Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
authors.forename: Stanley
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: W Gillies
authors.initials: WG
authors.lastname: McKenna
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.|Current address: Department of Radiotherapy and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D018951:Antigens, CD20 / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism*; D016019:Survival Analysis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C089226:CA9 protein, human
keywords: desmoplastic stroma; hypoxia; macrophages; prognosis; vessel density