The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma

// Lai Mun Wang 1, * , Michael A. Silva 2, * , Zenobia D’Costa 3, * , Robin Bockelmann 3, * , Zahir Soonawalla 2 , Stanley Liu 4 , Eric O’Neill 3 , Somnath Mukherjee 3 , W. Gillies McKenna 3 , Ruth Muschel 3 , Emmanouil Fokas 3 1 Department of Pathology, Oxford University Hospital NHS Trust, University of Oxford, Oxford, UK 2 Department of Surgery, Oxford University Hospital NHS Trust, Oxford, UK 3 Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, Oxford, UK 4 Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada * These authors contributed equally to this work Correspondence to: Emmanouil Fokas, e-mail: emmanouil.fokas@oncology.ox.ac.uk Keywords: desmoplasia, stroma density, αSMA, pancreatic cancer, prognosis Received: September 21, 2015      Accepted: December 01, 2015      Published: December 26, 2015 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. We examined the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. FFPE-tissue from the pancreatectomy of 145 patients was immunohistochemically stained for haematoxylin-eosin and Masson’s trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). After a mean follow-up of 20 months (range, 2–69 months), the median OS was 21 months and the 3-year OS was 35.7%. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS ( p = 0.001), PFS ( p = 0.007), LPFS ( p = 0.001) and DMFS ( p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1–2) but not late (pT3–4) stage tumors. Additionally, late pT-stage (pT3–4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion and administration of adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Altogether, stroma density constitutes an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the dynamic complexity of desmoplasia and indicate that highly-dense stroma is correlated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC patients after adjuvant chemotherapy is warranted and will be performed in a prospective study.