D2-40/podoplanin expression in cancer stroma by immunohistochemical staining is associated with poor prognosis in bladder cancer patients after radical cystectomy

Abstract

ObjectivesWe assessed whether D2-40/podoplanin (PDPN) could be used to identify bladder cancer patients with a higher probability of benefiting from cisplatin-based combination chemotherapy. Patients and methodsWe investigated PDPN expression by immunohistochemical analysis of cystectomy specimens from 96 bladder cancer patients who had undergone radical cystectomy without neoadjuvant or adjuvant cisplatin-based combination chemotherapy until recurrence. We classified the cases into 2 groups according to the achievement of 2-year recurrence-free survival (RFS) and evaluated whether PDPN expression was associated with patient prognosis. We also classified the 96 cases into 3 groups according to the possible need for perioperative chemotherapy based on the response to chemotherapy after recurrence as “unnecessary” (achieving 2-year RFS), “responder” (recurring within 2 years and responding to chemotherapy after recurrence), and “non-responder” (not responding chemotherapy following recurrence) and compared PDPN expression between these groups. ResultsAmong 13 cases diagnosed with clinically <T2 disease, all 13 cases achieved 2-year RFS. Only 6 (8.7%) and 9 cases (13.0%) were classified as “responders” and “non-responders,” respectively, out of 69 cases with clinical T2 or higher disease who received cisplatin-based chemotherapy after recurrence. We identified PDPN expression in cancer stroma cells were morphologically fibroblasts, but not in cancer cells. Cases with <1% PDPN staining positivity ratios showed significantly better prognosis compared to that in cases with ≧1% (log-rank tests). Moreover, the positive predictive value and specificity of a <1% PDPN positive staining ratio were 89.5% and 86.7%, respectively, for “unnecessary” perioperative chemotherapy in the 69 cases. ConclusionOur results confirmed that cisplatin-based perioperative chemotherapy is unnecessary in many cases requiring radical cystectomy. To our knowledge, this is the first report of PDPN expression in bladder cancer stroma cells that are morphologically fibroblasts. Although PDPN expression might be associated with poor prognosis after surgery, we did not find that it helped to predict chemotherapy response. Whether PDPN expression by fibroblasts in high-risk bladder cancer cases is a marker for prognosis after radical cystectomy and response to perioperative cisplatin-based chemotherapy to avoid unnecessary chemotherapy warrants further investigation.