Cancer of Unknown Primary PDF
Preview Cancer of Unknown Primary
Cancer of Unknown Primary Alwin Krämer Harald Löffl er Editors 123 Cancer of Unknown Primary Alwin Krämer (cid:129) Harald Löffl er Editors Cancer of Unknown Primary Editors Alwin Krämer Harald Löffl er Clinical Cooperation Unit Molecular Clinical Cooperation Unit Molecular Hematology/Oncology Hematology/Oncology German Cancer Research Center (DKFZ) German Cancer Research Center (DKFZ) and University of Heidelberg and University of Heidelberg Heidelberg Heidelberg Germany Germany ISBN 978-3-319-22580-7 ISBN 978-3-319-22581-4 (eBook) DOI 10.1007/978-3-319-22581-4 Library of Congress Control Number: 2015952541 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2016 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. T he publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www. springer.com) Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Harald Löffl er and Alwin Krämer 2 Epidemiology, Risk Factors, and Survival in CUP: Pointers to Disease Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Kari Hemminki 3 Biologic Features of CUP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Harald Löffl er and Alwin Krämer 4 Prognostic Factors and Their Role in the Management of CUP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Harald Löffl er and Alwin Krämer 5 Diagnostic Work-up of CUP: An Approach to Current Recommendations and Underlying Evidence . . . . . . . . . . . 67 Alwin Krämer and Harald Löffl er 6 The Radiologist’s Approach to CUP . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Philipp M. Kazmierczak , Axel Rominger , and Clemens C. Cyran 7 Cancer of Unknown Primary: The Pathologist’s Approach . . . . . . . . . 91 Albrecht Stenzinger and Wilko Weichert 8 Treatment of Disseminated CUP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Gerdt Hübner 9 Concepts of Radiotherapy in Cancer of Unknown Primary . . . . . . . . 125 David Krug and Florian Sterzing 10 Favorable Subsets Among Cancers of Unknown Primary . . . . . . . . . 151 Kanwal Raghav and Gauri R. Varadhachary v vi Contents 11 Novel Diagnostic and Therapeutic Strategies in the Management of Patients with Cancers of Unknown Primary Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 F. Anthony Greco and John D. Hainsworth 12 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Alwin Krämer and Harald Löffl er Chapter 1 Introduction Harald Löffl er and Alwin Krämer 1.1 Defi ning Cancer of Unknown Primary Cancer of unknown primary (CUP) usually refers to histologically proven cancer where no primary lesion has been detected although the initial diagnostic work-up has been completed. The label “CUP” should not be used when a metastatic lesion has been found but an appropriate search for a primary origin has not yet been done. This is already the fi rst problem with the defi nition of CUP, since it is not exactly defi ned what the minimum requirements with respect to an appropriate staging are. Indeed, CUP nowadays accounts for 2–3 % of all cancer-related deaths in Germany [1 ], while older publications state the proportion of CUP to be 5–10 % of all cancers [ 2 ], with this likely being the result of improved diagnostic possibilities to identify the primary. Malignant lesions of non-epithelial origin such as lymphomas and sarcomas must not be categorized as CUP, meaning that CUP usually refers to an epithelial origin. On the other hand, undifferentiated tumors with unknown primary and no signs of any differentiation – neither epithelial nor non-epithelial – are compatible with the defi nition of CUP, simply because there is no other meaningful category. This delineation is also somewhat problematic, since the assignment of epithelial versus non-epithelial origin depends on the diagnostic methodology used: It can safely be assumed that the “undifferentiated tumor” category has lost ground over the past, say, 30 years due to the improved repertoire of immunohistochemistry, and site-of-origin assignment by gene expression profi ling and related techniques may bring this category on the verge of extinction. Thirdly, the defi nition of “no primary” is far from being always clear. There are CUP cases with multiple, more or less equally advanced metastases, but others H. Löffl er (*) (cid:129) A. Krämer Clinical Cooperation Unit Molecular Hematology/Oncology , German Cancer Research Center (DKFZ) and University of Heidelberg , Heidelberg , Germany e-mail: h.loeffl [email protected]; [email protected] © Springer International Publishing Switzerland 2016 1 A. Krämer, H. Löffl er (eds.), Cancer of Unknown Primary, DOI 10.1007/978-3-319-22581-4_1 2 H. Löffl er and A. Krämer show a leading lesion or a solitary one, and here the question may arise whether the leading or solitary lesion is in fact the primary. Arguments against the notion of the leading lesion being the primary (which, of course, should be default) may include the presence of more than one possible assignment, e.g., an adenocarcinoma within the liver which could be intrahepatic cholangiocarcinoma as well as a metastasis from an unknown primary [3 ], or a histology clearly arguing against the clinically suspected origin, e.g., if a CT scan suggests nodal-positive lung cancer but histol- ogy suggests intestinal adenocarcinoma in the absence of an intestinal lesion. In such cases, primary lesions showing atypical or rare histologic features should be always considered. For example, when a solitary skin lesion with a histology sug- gestive of adenocarcinoma but no systemic involvement is found, primary adnexal carcinoma of the skin must be considered [4 ]. Finally, it has to be mentioned that some authors have extended the defi nition of CUP also to cases where metastases without a primary were diagnosed solely based on clinical fi ndings without histological confi rmation [ 5 , 6 ]. We do not think that this approach is useful, since even if we are quite sure from a clinical perspec- tive that lesions are malignant, they could still be lymphoma or sarcoma. Hence, cases without histological confi rmation should rather be called “suspected malignoma, not otherwise specifi ed,” and of course, a histological confi rmation is nowadays nearly always recommended – the only exception being cases where the general condition or comorbidities clearly preclude any cancer-specifi c intervention. I n summary, there is some inconsistency regarding the defi nition of CUP both in clinical practice and in the literature. Within this book, we would like to adhere to the defi nition of histologically proven cancer with no primary despite completed staging, excluding non-epithelial malignancies. 1.2 Some Thoughts About History and Present T hough not being historians, we think we are on the safe side stating that CUP has been known for longer than cytostatic drug therapy to treat it: A database search with the combination “cancer” and “unknown primary” retrieved a paper from 1946 as earliest search result [7 ]. The earliest registry data on CUP we are aware of cover the period 1921–1981; in this series, less than 20 % of patients received cytostatic drugs or hormones [5 ]. In 1993, Hainsworth and Greco, the authors of Chap. 1 1 of this book, stated [8 ]: “The majority of patients with cancer of an unknown primary site do not benefi t from other than supportive treatment. A minority, however, do benefi t from palliative treatment, and a few are candidates for curative treatment.” This minority was defi ned by the presence of a clear working hypothesis warranting site-specifi c therapy [8 ]. Although this view is unfortunately not completely outdated yet, it has shifted quite signifi cantly since then because of two reasons: Firstly, drug therapy for the 1 Introduction 3 abovementioned majority of CUP patients has been improved as combinations con- taining platinum derivatives and third-generation cytostatics have been successfully established due to promising results in phase II trials. Moreover, the advent of molecularly targeted drugs, although not widely established in CUP yet, offers a clear perspective for further improvements of which the majority of CUP patients may benefi t. Secondly, our possibilities toward fi nding a working hypothesis have clearly improved due to immunohistochemistry, which was introduced in the 1980s and has been further advanced since then, and gene expression profi ling, which has been made available in recent years. T oday, we face the problem of how to handle these new possibilities since there is still a shortage of evidence-based data. In this book, we will repeatedly be con- fronted with the contrast between currently established standards and novel possi- bilities. We think that there is no defi nitive answer to the question how much evidence is needed in order to integrate these novel possibilities into standard of care. Regarding this, we hope that our book will be helpful in ongoing discussions by offering a balanced view on current evidence. 1.3 Our Approach Toward CUP W hen a patient is labeled as having CUP, it should be avoided to perform endless diagnostic studies which may be triggered by the reluctance to accept the fact that we cannot fi nd the primary. Likewise, we should stop believing that, when we have fi nally come to the conclusion that we really cannot fi nd the primary, there is more or less nothing we can do for the patient anymore. Instead, we should keep in mind that at present, the median overall survival of CUP patients lies in the range of 1 year. Therefore, taking a rapid decision about how to help our patient best might be preferable over spending several months of this remaining lifetime performing diag- nostics. On the other hand, we must keep in mind that there are subgroups of CUP with a clearly better prognosis. Hence, diagnostics should focus on identifying these subgroups while avoiding procedures from which no therapeutic consequences are expected. This book is intended to give some advice on how to handle these complex chal- lenges in the management of CUP patients. First of all, we would like to equip the reader with in-depth knowledge about both current evidence and novel approaches in the diagnostics and therapy of CUP. Based on this, we advocate a structured approach toward the management of CUP patients. We will start with some funda- mentals about epidemiology, biology, and prognostic factors, and then look at our diagnostic repertoire and its rational use in detail. Next, the reader will fi nd details about current therapeutic strategies for both the “standard case” and important sub- groups to be treated differently. Finally, we will turn to emerging novel diagnostic and therapeutic strategies, which are subject to current research activities and will lead us to possible future directions.
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