Laboratory Medicine Practice Guidelines Use of Tumor Markers in Liver, Bladder, Cervical, and Gastric Cancers Edited by Catharine M. Sturgeon and Eleftherios Diamandis The National Academy of Clinical Biochemistry Presents LABORATORY MEDICINE PRACTICE GUIDELINES USE OF TUMOR MARKERS IN LIVER, BLADDER, CERVICAL, AND GASTRIC CANCERS EDITED BY Catharine M. Sturgeon Eleftherios P. Diamandis Catharine M. Sturgeon H. Barton Grossman Department of Clinical Biochemistry, Royal Infirmary of Department of Urology, The University of Texas M. D. Edinburgh, Edinburgh, UK Anderson Cancer Center, Houston, TX Michael J. Duffy Peter Hayes Department of Pathology and Laboratory Medicine, St Scottish Liver Transplant Unit, Department of Medicine, Vincent’s University Hospital and UCD School of Medicine Royal Infirmary of Edinburgh, Edinburgh, United Kingdom and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ralf-Thorsten Hoffmann Ireland Department of Clinical Radiology, LMU-Klinikum- Grosshadern, University of Munich, Germany Barry R. Hoffman Department of Pathology and Laboratory Medicine, Seth P. Lerner Mount Sinai Hospital, and Department of Laboratory Department of Urology, Baylor College of Medicine, Medicine and Pathobiology, University of Toronto, Houston, TX Ontario, Canada Florian Lohe Department of Surgery, LMU-Klinikum-Grosshadern, Rolf Lamerz University of Munich, Germany Department of Medicine, Klinikum of the University Munich, Grosshadern, Germany Johanna Louhimo Department of Clinical Chemistry, Helsinki University Herbert A. Fritsche Central Hospital, Finland Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX Ihor Sawczuk Department of Urology, Hackensack University Medical Katja Gaarenstroom Center, Hackensack, NJ Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands Kazuhisa Taketa Johannes M.G. Bonfrer Clinical Trial Center, Brain Attack Center, Oota Memorial Department of Clinical Chemistry, Netherlands Cancer Hospital, Fukuyama, Japan Institute, Amsterdam, the Netherlands Eleftherios P. Diamandis Thorsten Ecke Department of Pathology and Laboratory Medicine, Mount Department of Urology, Helios Hospital, Bad Saarow, Sinai Hospital, and Department of Laboratory Medicine and Germany Pathobiology, University of Toronto, Ontario, Canada Copyright © 2010 by the American Association for Clinical Chemistry, Inc. All rights reserved. Single copies for personal use may be printed from authorized Internet sources such as the NACB’s home page (http://www.aacc.org/members/nacb/LMPG/Pages/default.aspx), provided it is printed in its entirety, including this notice. Printing of selected portions of the document is also permitted for personal use, provided the user also prints and attaches the title page and cover pages to the selected reprint or otherwise clearly identifies the reprint as having been produced by the NACB. Otherwise, this document may not be reproduced in whole or in part, stored in a retrieval system, translated into another language, or transmitted in any form without express written permission of the National Academy of Clinical Biochemistry. Such permission may be requested from NACB, 1850 K Street, Suite 625, Washington, DC, 20006-2213. Permission will ordinarily be granted, provided the NACB logo and the following notice appear prominently at the front of the document: Reproduced (translated) with permission of the National Academy of Clinical Biochemistry, Washington, DC. This document (PID 5780) was approved by the National Academy of Clinical Biochemistry Board of Directors in July 2008. The NACB is the Academy of the American Association for Clinical Chemistry. Table of Contents 1. Introduction 1 2. Tumor Markers in Liver Cancer 3 3. Tumor Markers in Bladder Cancer 17 4. Tumor Markers in Cervical Cancer 25 5. Tumor Markers in Gastric Cancer 31 References 35 Acknowledgment 53 Appendix 55 Chapter 1 Introduction We present here to clinical chemists, clinicians, and other prac- document. As might be expected, many of the NACB recom- titioners of laboratory and clinical medicine the latest update mendations are similar to those made by other groups, as is of the National Academy of Clinical Biochemistry (NACB) made clear from the tabular comparisons presented for each Laboratory Medicine Practice Guidelines for the use of tumor malignancy (2). markers in liver, bladder, cervical, and gastric cancers. These To prepare these guidelines, the literature relevant to the use guidelines are intended to encourage more appropriate use of tumor markers was reviewed. Particular attention was given of tumor marker tests by primary care physicians, hospital to reviews, including the few relevant systematic reviews, and physicians, and surgeons, specialist oncologists, and other to guidelines issued by expert panels. If possible, the consen- health professionals. sus recommendations of the NACB panels reported here were Clinical practice guidelines are systematically developed based on available evidence (ie, were evidence based). NACB statements intended to assist practitioners and patients in recommendations relating to general quality requirements for making decisions about appropriate health care for specific tumor marker measurements, including tabulation of important clinical circumstances (1). An explanation of the methods causes of false-positive tumor marker results that must also be used when developing these guidelines has previously been taken into account (eg, heterophilic antibody interference, high- published (2) and has been included as an Appendix to this dose hooking) have previously been published (3). 1 Chapter 2 Tumor Markers in Liver Cancer BACKGROUND because it is already generally accepted that where surveil- lance has been systematically implemented, it is beneficial for Hepatocellular carcinoma (HCC) is the fifth most common selected cirrhotic patients (29). In developed countries, about cancer in men and the eighth most common cancer in women 30%-40% of patients with HCC are now diagnosed sufficiently worldwide (4,5). It is also the third most common cause of early for curative treatments. cancer-related death (6), with 500,000 new cases diagnosed Because many patients with early disease are asymptom- annually. The age-adjusted worldwide incidence varies by geo- atic (30,31), HCC is frequently diagnosed late, by which time it graphic area, increasing from 5.5/100,000 of the population in is often untreatable (32). Suspicion of disease may first arise in the US and Europe to 14.9/100,000 in Asia and Africa (7). The patients with liver cirrhosis who develop ascites, encephalopa- higher incidence observed in Europe during the past decade thy, or jaundice (33). Some patients initially present with upper probably reflects the increasing number of cases of hepatitis C abdominal pain, weight loss, early satiety, or a palpable mass in infection (8,9) and liver cirrhosis (10), both strong predisposing the upper abdomen (31). Other symptoms include obstructive factors for HCC (11). jaundice, diarrhea, bone pain, dyspnea, intraperitoneal bleed- In most parts of Asia and Africa, hepatitis B virus infection ing, paraneoplastic syndromes [eg, hypoglycemia (34), eryth- is most relevant (12), with ingestion of aflatoxin B1 from con- rocytosis (35), hypercalcemia (36,37)], severe watery diarrhea taminated food an additional contributory factor (13). In the West (37), or cutaneous features (eg, dermatomyositis; 38). and Japan, hepatitis C virus infection is the main risk factor (7,14- Diagnostic imaging modalities include ultrasound, com- 17), although patients with alcoholic cirrhosis or hemochroma- puted tomography (CT), and MRI (6,39). Ultrasound is widely tosis are also at increased risk (18). In these parts of the world, available, noninvasive, and commonly used in patients with older patients are more likely than young patients to develop HCC to assess hepatic blood supply and vascular invasion by HCC (15,16). In contrast, in developing countries HCC more fre- the tumor, as well as intraoperatively to detect small tumor nod- quently affects younger individuals who have chronic hepatitis ules. Although CT of the liver is sometimes used to investigate B (19), with carriers having twice the relative risk of develop- abnormalities identified on ultrasound, it is rarely used for pri- ing the disease. Cirrhotic patients have a higher risk than noncir- mary screening. American Association for the Study of Liver rhotic patients, with annual HCC incidences of 2%-6.6% (20) and Diseases (AASLD) guidelines specifically state that there are 0.4% (21), respectively. Worldwide, 380 million individuals are no data to support surveillance with CT scanning (40). MRI infected with hepatitis B and 170 million with hepatitis C (22). provides high-resolution images of the liver. Protective vaccination is possible for hepatitis B but not hepatitis Specimens for histopathology are usually obtained by C. New therapeutic antiviral strategies (eg, pegylated α-interferon biopsy under ultrasound or CT guidance. Risks of biopsy combined with ribavirin or other drugs such as lamivudine) are include tumor spread along the needle track (1%-2.7% over- available for treatment of hepatitis B and C (23-25). all) (41,42). The histological appearance of HCC ranges from The rationale behind screening for HCC by regular liver well-differentiated to poorly differentiated lesions of large ultrasound and tumor