Background
Esophageal and gastric cancers are among the most common types of cancer worldwide in terms of incidence and mortality [
1]. Historically, the majority of esophageal cancers were squamous cell carcinomas, but in the last four decades there has been a drastic increase in the incidence of adenocarcinoma, especially in many Western countries, where it is now the most common subtype [
2]. Adenocarcinoma in the esophagogastric (EG) junction is, since the 7th edition of the AJCC/UICC TNM staging system [
3], classified as esophageal cancer. Proposed risk factors for esophageal and EG junction adenocarcinoma are gastroesophageal reflux disease, obesity and decreased prevalence of
Helicobacter pylori infection [
4,
5]. Regarding gastric adenocarcinoma, the incidence has been declining for several decades [
6], possibly due to improved sanitary conditions and decreased prevalence of
Helicobacter pylori infection [
7], but globally it is still the 3rd leading cause of cancer death.
In resectable esophageal and gastric cancer, several phase III trials [
8‐
13] have shown that the addition of neoadjuvant and/or adjuvant chemotherapy or chemoradiotherapy improves survival. However, the prognosis is still poor, especially in Western populations, with 5-year survival rates less than 40 %.
Hence, in addition to primary prevention and earlier detection, the key to improved outcome for patients with esophageal and gastric cancer is to find more effective treatments and also to personalize the treatment based on prognostic and response predictive factors.
Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, belonging to the CD34 family, that is encoded on chromosome 7q32-q33. It was first discovered in renal podocytes as an anti-adhesive protein [
14] and has later been shown to be expressed in vascular endothelium [
15] and to be involved in hematopoiesis [
16] and neural development [
17]. PODXL is expressed in a range of malignancies and overexpression has mostly been linked to poor prognosis, e.g. in glioblastoma multiforme [
18], breast cancer [
19], bladder cancer [
20], periampullary and pancreatic adenocarcinoma [
21,
22] and colorectal cancer [
23‐
25]. Laitinen et al. [
26] recently showed that in surgically treated gastric cancer, patients with PODXL negative tumors had a significantly better cancer-specific 5-year survival than patients with PODXL positive tumors.
The functional role of PODXL in tumorigenesis is largely unknown, but it has been demonstrated to promote cancer cell invasion and migration and to enhance metastatic potential [
27‐
29]. Other proposed mechanisms are evasion of natural killer cell-mediated cytotoxicity [
30] and maintaining and regulating the surface expression of glucose transporters [
31]. In osteosarcoma cell lines, PODXL has been shown to promote chemoresistance to cisplatin [
32], which is particularly interesting since platinum compounds (cisplatin and oxaliplatin) are important cytotoxic drugs in the treatment of esophageal and gastric adenocarcinoma.
To our best knowledge, there are no reports on the prognostic value of PODXL expression in esophageal adenocarcinoma.
The aim of this study was to explore the expression of PODXL in both esophageal and gastric adenocarcinoma and to assess its impact on time to recurrence (TTR) and overall survival (OS) in a consecutive series of patients from southern Sweden, treated surgically between 2006 and 2010, prior to the wide implementation of neoadjuvant treatment.
Discussion
In this study on resected esophageal and gastric adenocarcinoma we have shown that PODXL is expressed in the majority of cases and correlates with poor survival, but in the subgroup of patients with PODXL negative cancers the prognosis was excellent. This finding applies to both esophageal and gastric cancer with regard to both TTR and OS. To our best knowledge, this is the first report on the prognostic role of PODXL in esophageal adenocarcinoma. Furthermore, in gastric cancer, we have validated the recent findings from Laitinen et al. [
26] of a negative prognostic impact of PODXL expression, even though the proportion of PODXL negative gastric cancer cases were lower in our study (21.5 % compared to 42.5 %). The reasons for this discrepancy are not clear, since we used the same polyclonal antibody and the same definition for negative vs. positive PODXL expression. However, whereas Laitinen et al. only examined primary tumors, we also included lymph node metastases in our analyses. This resulted in a non-significant (
p = 0.506) decrease in PODXL negative gastric cancer cases from 26.6 to 21.5 %. Another factor could be observer-dependent, such as setting the cut-off between negative and weak cytoplasmic staining. In other reports on PODXL as a prognostic marker in colorectal [
23‐
25,
40], pancreatic and periampullary adenocarcinoma [
21,
22], using the same polyclonal antibody, the most evident prognostic cut-off was observed for membranous vs. non-membranous expression, with the former being an independent factor of poor prognosis. However, in our study and in the report from Laitinen et al., the optimal prognostic cut-off was negative vs. positive, including membranous, PODXL expression. Hence, further studies are warranted to determine optimal cut-offs for prognostication, which may well differ between different types of cancer. Of note, previous studies on colorectal [
41] and pancreatic [
22] cancer, using a monoclonal anti-PODXL antibody, demonstrated a correlation between cytoplasmic PODXL expression and poor survival.
A limitation of this study is its retrospective design. However, we have managed to access all the necessary clinical data, except for recurrence status in some cases, and the tissue specimens have been thoroughly re-examined. Due to heterogeneity within tumors there is always a risk of sampling bias with the TMA-technique. However, as we used duplicate cores from different donor blocks and, when available, also included cores from lymph node metastases when denoting the highest PODXL score for each case, the risk of overestimating the proportion of PODXL negative cancers should be reduced.
In current practice, most patients with resectable esophageal or gastric adenocarcinoma receive neoadjuvant and/or adjuvant chemotherapy or chemoradiotherapy, but only a minority (10-15 %) of the patients actually benefit from the oncological treatment [
8‐
13]. For a biomarker to be really useful in clinical decision making it should not only be prognostic but also be able to predict whether a patient will benefit from a treatment or not. Further studies on PODXL in esophageal and gastric adenocarcinoma are warranted to validate its role as a prognostic biomarker and to explore whether it also may be useful as a treatment response predictive biomarker, as suggested in previous studies on colorectal [
24] and periampullary cancer [
21].
Abbreviations
CI, confidence interval; EG, esophagogastric; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival; PODXL, podocalyxin-like protein; TMA, tissue microarray; TTR, time to recurrence