Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma

Margareta Heby, Jakob Elebro, Björn Nodin, Karin Jirström, Jakob Eberhard, Margareta Heby, Jakob Elebro, Björn Nodin, Karin Jirström, Jakob Eberhard

Abstract

Background: Adenocarcinoma of the periampullary region is associated with poor prognosis and new prognostic and treatment predictive biomarkers are needed for improved treatment. Membranous expression of podocalyxin-like 1(PODXL), which is a cell-adhesion glycoprotein and stem cell marker, has been found to correlate with an aggressive tumour phenotype and adverse outcome in several cancer types. The aim of the present study was to examine the clinicopathological correlates, prognostic and predictive significance of tumour-specific PODXL expression in a retrospective cohort of pancreatic and periampullary carcinoma, morphologically divided into intestinal type (I-type) and pancreatobiliary type (PB-type) tumours.

Methods: Immunohistochemical expression of PODXL was analysed in tissue microarrays with primary tumours and a subset of paired lymph node metastases from 175 patients operated with pancreaticoduodenectomy for periampullary adenocarcinoma. Chi square test was applied to analyse the relationship between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox regression models were applied to estimate differences in 5-year overall survival (OS) and recurrence-free survival (RFS) in strata according to membranous and non-membranous PODXL expression.

Results: Membranous PODXL expression was significantly higher in primary PB-type (49.5 %) as compared with I-type (17.5 %) tumours. In PB-type tumours, PODXL expression was significantly associated with female sex (p = 0.005), location to the pancreas (p = 0.005), and poor differentiation grade (p = 0.044). Membranous PODXL expression was significantly associated with a reduced RFS (HR = 2.44, 95 % CI 1.10-5.44) and OS (HR = 2.32, 95 % CI 1.05-5.12) in I-type tumours and with a reduced RFS (HR = 1.63, 95 % CI 1.07-2.49) but not OS in PB-type tumours. PODXL remained a significant independent prognostic factor only in I-type tumours (HR = 5.12, 95 % CI 1.43-18.31 for RFS and HR = 7.31, 95 % CI 2.12-25.16 for OS). Patients with I-type tumours displaying membranous PODXL expression had a significant beneficial effect of adjuvant chemotherapy regarding 5-year OS.

Conclusion: Membranous expression of PODXL is significantly higher in PB-type than in I-type periampullary adenocarcinomas and an independent factor of poor prognosis in the latter. The results further indicate a beneficial effect of adjuvant chemotherapy on I-type tumours with membranous PODXL expression, suggesting the potential utility of PODXL as a biomarker for improved treatment stratification of these patients.

Keywords: Biomarkers; Immunohistochemistry; Pancreatic cancer; Periampullary adenocarcinoma; Podocalyxin-like 1; Prognosis; Response prediction.

Figures

Fig. 1
Fig. 1
Sample immunohistochemical images. Immunohistochemical images of PODXL- negative non-malignant pancreatic tissue from two cases (top row), primary intestinal-type (I-type) tumours (left column), primary pancreatobiliary-type (PB-type) tumours (mid-column) and metastases (right column) with different PODXL staining scores (0–4). Asterisks indicate paired samples; i.e. from the same case/resection specimen. Score 0 = negative staining, score 1 = weak cytoplasmic positivity in any proportion of cells, score 2: moderate-strong cytoplasmic positivity in any proportion of cells, score 3: distinct membranous positivity in < = 50 % of cells and score 4 = distinct membranous positivity in >50 % of cells. All images with 10X original magnification
Fig. 2
Fig. 2
PODXL expression in primary tumours and metastases
Fig. 3
Fig. 3
Survival according to membranous versus non-membranous PODXL expression. Kaplan-Meier estimates of recurrence free and 5-year overall survival in patients with intestinal and pancreatobiliary type tumours, respectively. NM= non-membranous, M= membranous PODXL expression
Fig. 4
Fig. 4
Survival according to PODXL expression and adjuvant chemotherapy. Kaplan-Meier estimates of 5-year overall survival in combined strata of membranous (M)/ non-membranous (NM) PODXL expression and adjuvant (A) /no adjuvant (NA) chemotherapy in patients with intestinal type tumours and intestinal type + ampullary pancreatobiliary type tumours, respectively. NM= non-membranous, M= membranous PODXL expression

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Source: PubMed

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