Pancreatic Head Adenocarcinomas - Histopathologic Evaluation and Prognostic Factors
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AbstractPrimary adenocarcinomas located in the pancreatic head may arise from the distal bile duct, the ampulla, the periampullary duodenum, and the pancreatic tissue itself. These tumours are distinct cancer entities whose pathobiology, staging, and clinical course have unique features. The aims of the present study were to investigate how the standardized histopathological examination protocol ensures correct classification of tumour origin of pancreatic head adenocarcinomas. Furthermore, we examined how different approaches to assessment of lymph node metastases and expression of cyclooxygenase-2 (COX-2) in the tumours can predict long-term outcome. Finally, we assessed COX-2 expression and effects of PGE2 on cells proliferation and collagen synthesis in pancreatic stellate cells in vitro. The precise anatomical site of origin is often difficult to establish during preoperative investigations or during surgery and therefore the final diagnosis is always the result of the histopathological examination. The predetermined diagnostic criteria, with special focus on the anatomical site of origin, are essential to improve the accuracy of diagnosis. Furthermore, high workload per pathologist increases the precision of the histopathologic diagnosis. The presence of lymph node metastasis is a major determinant of long-term survival in pancreatic head cancers. In patients operated with pancreatoduodenectomy, N status and LNR are superior to the number of metastatic node as prognostics indicators. The predictive value of these variables depends on the cancer origin. In ampullary and distal bile duct cancer, N status discriminates between subgroups of patients with different long-term survival whereas in pancreatic cancer, LNR is clearly more powerful in prognostic subclassification. In patients with pancreatic cancer, multivariate analysis identified LNR > 0.2 as an independent predictor of poor long-term survival. LNR could therefore be proposed as a standard, alternative measure of nodal involvement in the pancreatic cancer. Overexpression of COX-2 has been described in several tumours, however the data on the prognostic importance of COX-2 in pancreatic head adenocarcinomas are inconsistent. In our study COX-2 is overexpressed in >70% of pancreatic, ampullary and distal bile duct cancers and is associated with the histopathological type of differentiation, with the degree of differentiation, and with a favourable prognosis. In pancreatic cancer, in a multivariate model, COX-2 negative tumours and LNR > 0.2, independently predicted poor prognosis. When assessed by immunohistochemistry, COX-2 is mainly expressed in pancreatic carcinoma cells, and these cells are regarded as the main source of PGE2 in pancreatic cancer tumour tissue. COX-2 was not detected in the stroma, however COX-2 was detected in the cultured pancreatic stellate cells (PSC), and could be further induced by interleukin-1ß (IL-1ß), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-ß1 (TGFß). Treatment of PSC with PGE2 suppressed both TGFß-stimulated collagen synthesis and PDGF-stimulated DNA synthesis, suggesting that inhibition of COX-2 may inadvertently accelerate fibrosis progression in pancreatic cancer. This thesis confirms that standardised histopathological evaluation after pancreatoduodenectomy with special focus on the tumour origin, lymph node assessment, degree and type of differentiation is necessary to obtain accurate and reliable survival estimates. Furthermore, our findings of the COX-2 expression in the tumours, and the PGE2 effects on pancreatic stellate cells, revealed new aspects of biological mechanisms involved in progression of pancreatic cancer.
List of papers
|I. Pomianowska E, Grzyb K, Westgaard A, Clausen OPF, Gladhaug IP Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer Eur J Surg Oncol 2012; 38:1043-1050. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.ejso.2012.07.113|
|II. Pomianowska E, Westgaard A, Mathisen Ø, Clausen OPF, Gladhaug IP Prognostic relevance of number and ratio of metastatic lymph nodes in resected pancreatic, ampullary and distal bile duct carcinomas Ann Surg Oncol 2013; 20:233-241. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1245/s10434-012-2592-z|
|III. Pomianowska E, Schjølberg AR, Clausen OPF, Gladhaug IP COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favorable prognosis BMC Cancer 2014; 14:458. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. The published version is available at: https://doi.org/10.1186/1471-2407-14-458|
|IV. Pomianowska E, Sandnes D, Grzyb K, Schjølberg AR, Aasrum M, Tveteraas IH, Tjomsland V, Christoffersen T, Gladhaug IP Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer 2014; 14:413. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. The published version is available at: https://doi.org/10.1186/1471-2407-14-413|