Stromal heterogeneity in pancreatic cancer and chronic pancreatitis

Lena Haeberle; Katja Steiger; Anna Melissa Schlitter; Sami Alexander Safi; Wolfram Trudo Knoefel; Mert Erkan; Irene Esposito

doi:10.1016/j.pan.2018.05.004

Stromal heterogeneity in pancreatic cancer and chronic pancreatitis

Pancreatology. 2018 Jul;18(5):536-549. doi: 10.1016/j.pan.2018.05.004. Epub 2018 May 12.

Authors

Lena Haeberle¹, Katja Steiger², Anna Melissa Schlitter², Sami Alexander Safi³, Wolfram Trudo Knoefel³, Mert Erkan⁴, Irene Esposito⁵

Affiliations

¹ Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany.
² Institute of Pathology, Technische Universitaet Muenchen, Munich, Germany.
³ Department of Surgery, University Hospital of Duesseldorf, Duesseldorf, Germany.
⁴ Department of Surgery, Koc University Hospital, Istanbul, Turkey.
⁵ Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany. Electronic address: irene.esposito@med.uni-duesseldorf.de.

PMID: 29778400
DOI: 10.1016/j.pan.2018.05.004

Abstract

Background/objectives: An abundant stromal reaction is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). The cells mainly responsible for the stromal reaction are activated pancreatic stellate cells (PSCs). Despite their crucial role, PSCs are not well characterized. PSCs share characteristics with the better-known hepatic stellate cells (HSCs). The aim of this study was a detailed analysis of PSCs in PDAC and CP.

Methods: Whole-slide specimens of CP (n = 12) and PDAC (n = 10) were studied by histochemistry and immunohistochemistry. The stroma was evaluated using Movat's pentachrome stain. PSCs were tested by immunohistochemistry for PSC markers (α-SMA, CD34, desmin, NGFR, SPARC and tenascin C) and HSC markers (α-crystallin B, CD56, NGF, NT-3, synaptophysin and TrkC). Alpha-SMA, tenascin C, SPARC and NT-3 staining were verified on tissue micro arrays (TMAs) from a well-characterized cohort of 223 PDAC patients. PSCs isolated from human PDAC and CP tissue samples as well as HSCs were evaluated by immunofluorescence.

Results: While the stroma of CP cases was characterized by a collagen-rich fibrosis, PDAC stroma displayed higher mucin content (p = 0.0002). PSCs showed variable expression of tested markers. In PDAC samples, staining of most markers was found around tumor complexes, while CP samples showed a greater variety of localizations. Alpha-SMA staining correlated with collagen-rich fibrosis (p = 0.012), while NT-3 staining correlated with mucin-rich stroma (p = 0.008). A peritumoral staining was confirmed for α-SMA, tenascin C, SPARC and NT-3 in the PDAC TMA cohort (n = 223). In a subgroup of patients with pancreatic head tumors and UICC 2009 IIB (n = 144), α-SMA staining intensity was a prognostic factor for overall survival at uni- and multivariate analysis (p = 0.036 and p = 0.002).

Conclusions: The close similarities between PSCs and HSCs were confirmed. Heterogeneous expression patterns of the tested markers might reflect different levels of activation or differentiation, or even multiple subpopulations of PSCs. Survival analysis suggests an impact of stromal composition on survival.

Keywords: Chronic pancreatitis; Pancreatic cancer; Pancreatic stellate cells; Stromal reaction; Tumor microenvironment.