Epithelial-mesenchymal transition in undifferentiated carcinoma of the pancreas with and without osteoclast-like giant cells

Mouad El Aidi,Deyali Chatterjee,Paola Piccoli,Riccardo Bernasconi,Giulia Fiadone,Paola Mattiolo,Rita T. Lawlor,Nicola Sperandio,Giuseppe Malleo,Roberto Salvia,Lodewijk A. Brosens,Laura D. Wood,Claudio Luchini,Aldo Scarpa,Claudia Parolini,Gaetano Paolino

doi:10.1007/s00428-020-02889-3

Abstract

Undifferentiated carcinoma (UC) and undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) are peculiar variants of pancreatic ductal adenocarcinoma (PDAC), characterized by hypercellularity and absence of glandular patterns. The inflammatory microenvironment is peculiar in UCOGC, since it is dominated by macrophages and osteoclast-like giant cells. However, from a molecular point of view, both UC and UCOGC are very similar to conventional PDAC, sharing alterations of the most common genetic drivers. Clinically, UC usually show a worse prognosis, whereas UCOGC may show a better prognosis if it is not associated with a PDAC component. To highlight potential biological differences between these entities, we investigated the role of the epithelial to mesenchymal transition (EMT) in UC and UCOGC. Specifically, we analyzed the immunohistochemical expression of three well-known EMT markers, namely Twist1, Snai2, and E-cadherin, in 16 cases of UCOGC and 10 cases of UC. We found that EMT is more frequently activated in UC (10/10 cases) than in UCOGC (8/16 cases; p = 0.05). Furthermore, in UCOGC, EMT was activated with a higher frequency in cases with an associated PDAC component. Snai2 was the most frequently and strongly expressed marker in both tumor types (10/10 UC, 8/16 UCOGC), and its expression was higher in UC than in UCOGC (mean immunohistochemical score: 4.8 in UC vs. 2.1 in UCOGC, p < 0.01). Our results shed new light on the biology of UC and UCOGC: EMT appeared as a more important process in UC, and Snai2 emerged as a central EMT effector in this setting.

Highlights

Pancreatic cancer is a lethal malignancy with increasing incidence [1,2,3]
With regard to the expression pattern of epithelial to mesenchymal transition (EMT) markers, for which representative images are provided in Fig. 1 (UCOGC with an associated pancreatic ductal adenocarcinoma (PDAC) component) and Fig. 2 (UCOGC without an associated PDAC component), Twist1 was pN M TNM Associated VI
We investigated the immunohistochemical expression of Twist1, Snai2, and E-Cadherin, three well-known markers associated with EMT activation

Summary

Introduction

Pancreatic cancer is a lethal malignancy with increasing incidence [1,2,3]. The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC) [2,3,4]. The spectrum of PDAC includes some morphological variants, one of which is the undifferentiated carcinoma (UC), a distinct and hypercellular tumor entity, composed of neoplastic cells without ductal/glandular architecture [3, 4]. Within this PDAC subgroup, there is an even more particular variant, which is the undifferentiated carcinoma with osteoclast-like giant cells (UCOGC). This is morphologically very similar to UC, with the addition of histiocytes and osteoclast-like giant cells intermingled with tumor cells [3, 4]. A recent study exploring the potential role of inflammatory cells in driving the distinct morphological features of UCOGC, found that the massive recruitment of CD163 positive tumorassociated macrophages and the activation of the PD-1/PDL1 axis may partly explain its characteristic aspects [9]

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Conclusion