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Prognostic Factors in Periampullary Adenocarcinoma. a Retrospective Study Over an 11 Year Period. Elebro, Jacob

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Prognostic Factors in Periampullary Adenocarcinoma. a Retrospective Study Over an 11 Year Period. Elebro, Jacob Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period. Elebro, Jacob 2016 Document Version: Publisher's PDF, also known as Version of record Link to publication Citation for published version (APA): Elebro, J. (2016). Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period. Lund University: Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Pr EL JACOB inted by Media- E BRO Tr yc k, L und University 2016 Prognostic factors in periampullary adenocarcinoma Nordic Ecolabel 341903 Prognostic factors in periampullary adenocarcinoma A retrospective study over an 11 year period JACOB ELEBRO DEPARTMENT OF CLINICAL SCIENCes | LUND UNIVERSITY 2016 Lorem ipsum dolor year period retrospectiveA an study11 over Erum simus repera vel mo berio quam ium nam sum re nihil mos aut faciis eum audios etur? 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Lund University, Faculty of Medicine 192740 Doctoral Dissertation Series 2016:48 ISBN 978-91-7619-274-0 ISSN 1652-8220 789176 48 9 Prognostic factors in periampullary adenocarcinoma 1 2 Prognostic factors in periampullary adenocarcinoma A retrospective study over an 11 year period Jacob Elebro DOCTORAL DISSERTATION by due permission of the Faculty of Medicine, Lund University, Sweden, to be defended at the Lecture Hall of the Radiotherapy Building, 3rd floor, Department of Oncology, Skåne University Hospital, Lund Friday May 13, 2016 at 09.15 am. Faculty opponent Professor Ivar Prydz Gladhaug Head of Department, Institute of Clinical Medicine University of Oslo, Norway 3 Organization Document name LUND UNIVERSITY Doctoral dissertation Department of Clinical Sciences Date of issue Division of Oncology and Pathology 13th of May 2016 Skåne University Hospital, Lund, Sweden Author Jacob Elebro Sponsoring organization Title and subtitle Prognostic factors in periampullary adenocarcinoma. A retrospective study over an 11 year period Abstract Periampullary adenocarcinoma, including pancreatic cancer, has a poor prognosis that has not improved in the last decades. Therefore, in order to find more effective treatment regimens, it is necessary to gain more insight into the biology and clinical behaviour of these tumours. This thesis entails a thorough histopathological characterization of retrospectively collected tumours from a consecutive cohort of patients with resected periampullary adenocarcinoma, followed by tissue microarray-based immunohistochemical studies of eight candidate protein biomarkers. Tumours were classified as being of pancreatobiliary type (PB-type) or intestinal type (I-type), using histological criteria, and all biomarker analyses were performed in strata according to morphological type. In Paper I, histopathological studies showed that a standardized and meticulous protocol for assessment of the surgical specimens, as well as blind revisions of slides, had impact on the decision on tumour origin, the number of involved lymph nodes and involved margins. The biomarker studies in Paper II revealed that expression of the global gene regulator special AT-rich sequence- binding protein 1 (SATB1) was an independent factor of poor prognosis in PB-type tumours. SATB1 expression, however, also indicated a better response to adjuvant chemotherapy, in particular in I-type tumours. A closely related protein, SATB2, was found to be expressed in a few tumours only, making it difficult to draw any firm conclusions on its prognostic value. In Paper III, biomarker studies on proteins related to gemcitabine metabolism revealed that a high ratio between cytoplasmic and nuclear expression of human protein R (HuR) indicated resistance to chemotherapy in PB-type tumours. In I-type tumours, high expression of human equilibrative nucleoside transporter 1 (hENT1) was a favourable prognostic factor and high expression of deoxycytidine kinase (dCK) indicated sensitivity to chemotherapy. In Paper IV, biomarker studies on the human epidermal growth factor receptors 1-3 (HER1-3) revealed a potential negative predictive effect of high EGFR (HER1) expression in relation to adjuvant chemotherapy in PB-type tumours. Six percent of I-type tumours had high expression of HER2, and gene amplification was confirmed in assessable cases. In I-type tumours, high expression of HER3 was a favourable prognostic factor, but not independent of other prognostic factors. Several of the potentially treatment predictive associations described in this thesis are novel, and may be of clinical interest if the results can be repeated in other cohorts and if the mechanistic basis is understood. The results presented here must be however be interpreted with caution, since the cohort is retrospective and many tests have been made. Key words: Periampullary adenocarcinoma, pancreas, bile duct, ampulla, duodenum, immunohistochemistry, tissue microarray, prognosis Classification system and/or index terms (if any) Supplementary bibliographical information Language: English ISSN and key title: 1652-8220 ISBN 978-91-7619-274-0 Recipient’s notes Number of pages:83 Price Security classification I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation. Signature Date 4 Prognostic factors in periampullary adenocarcinoma A retrospective study over an 11 year period Jacob Elebro 5 The research presented in this thesis was supported by: The Swedish Research Council, the Swedish Cancer Society, the Gunnar Nilsson Cancer Foundation, the Mrs Berta Kamprad Foundation, the Swedish Government Grant for Clinical Research, Lund University Faculty of Medicine and University Hospital Research Grants. Cover photo by Jacob Elebro Copyright: Jacob Elebro, 2016 Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:48 ISBN 978-91-7619-274-0 ISSN 1652-8220 Printed in Sweden by Media-Tryck, Lund University Lund 2016 En del av Förpacknings- och Tidningsinsamlingen (FTI) 6 “It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” Arthur Conan Doyle, Sherlock Holmes “If facts conflict with a theory, either the theory must be changed or the facts.” Benedict Spinoza “If the facts don't fit the theory, change the facts.” Albert Einstein 7 Contents Original papers 11 Abbreviations 13 Introduction 15 Periampullary adenocarcinoma 15 Epidemiology 15 Aetiology 16 Life style and environmental factors 16 Germline mutations 17 Prognosis 19 Early detection 20 Radiology 21 Treatment 21 Surgery 21 Chemotherapy 22 Targeted therapy 24 Radiotherapy 24 Personalized therapy 25 Mutations, deletions and amplifications 27 KRAS 27 P53 28 CDKN2A 28 DPC4 29 Less frequent genetic events 29 Histopathology of periampullary adenocarcinoma 31 Tumour origin in periampullary adenocarcinoma 31 Pancreatobiliary and intestinal morphological subtypes 35 Tumour stage (T-stage) 35 Lymph node involvement (N-stage) 36 Tumour size 37 Differentiation grade 37 Invasion of lymphatic vessels 37 Invasion of microscopic blood vessels 37 8 Perineural growth 37 Invasion of peripancreatic fat 38 Margins 38 Investigative prognostic and predictive biomarkers 39 SATB1 39 SATB2 39 hENT1 40 dCK 41 HuR 42 EGFR, HER2 and HER3 42 The present investigation 45 Aims 45 Specific aims 45 Material and Methods 47 Summary of Results and Discussion 49 Paper I 49 Paper II 50 Paper III 51 Paper IV 53 Limitations to the study (paper I-IV) 54 Conclusions and Future Perspectives 57 Populärvetenskaplig sammanfattning 59 Acknowledgements 63 References 65 9 10 Original papers The thesis is based on studies reported in the following papers, and are referred to in the text by their respective Roman numerals: I. Elebro J, Jirström K. Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma. Diagnostic Pathology 9:80 (2014) II. Elebro J, Heby M, Gaber A, Nodin B, Jonsson
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