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Serology Tumor Marker E. Henny Herningtyas Clinical Pathology Department, FM-UGM Tumor Marker Definition • Tumor marker: any substance present in or produced by tumor itself or produced by host in response to a tumor that can be used to differentiate tumor from normal tissue, which can be detected in cell, tissue or body fluids, qualitatively or quantitatively by chemical, immunological or molecular biological method to identify the presence of cancer Classification of Tumor Marker & its association with malignancy Type of Tumor Marker Major disease Minor disease Enzyme: Alkaline phosphatase Bone, Liver, Placenta Creatine kinase Prostate, Lung (SSC) Lactate dehydrogenase Liver, lymphoma, leukemia Neuron Specific Enolase Lung (SSC), Neuroblastoma Prostatic Acid Phosphatase (PAP) Prostate Cancer Prostatic Specific Antigen (PSA) Protatic Cancer Leukemia, Sarcoma, Lymphoma Breast, colon, ovary, stomach Breast, colon, stomach. Lung Pheochromocytoma, Carcinoid, Osteogenic sarcoma, multiple myeloma, bone metastasis BPH Classification of Tumor Marker & its association with malignancy Type of Tumor Marker Major disease Minor disease Hormones: ACTH Lung (Small cell carcinoma) Calcitonin HCG Medullary carcinoma thyroid Choriocarcinoma Pancreatic, breast, gastric, colon Carcinoid, breast, lung Testicular tumor, trophoblastic tumor Oncofetal antigen: Alpha-fetoprotein CEA Primary hepatocellular Ca Colorectal Ca Tissue polypeptide antigen Sq cell ca antigen Breast, colon, ovary Cervical, lung skin Teratoma of ovary & testis Gastrointestinal, pancreatic, lung, breast ChorioCa (TPA+), hepatocellular (TPA -) Gastrointestinal, ovaries, urogenital Classification of Tumor Marker & its association with malignancy Type of Tumor Marker Major disease Minor disease Carbohydrate antigen: CA 15-3 Breast Pancreatic, lung, ovary, colorectal Metastatic ovarian, prostate, lung Ovarian, cervical, endometrial CA 549 CA 27.29 Mucin-like Carcinoma Associated Antigen (MCA) CA 125 Breast Breast (recurrent) Breast Ovaries, endometrial Pancreatic Du PAN 2 Blood group antigen: CA 19-9 CA 50 CA 72-4 CA 242 Colorectal, pancreatic Pancreatic, colorectal Gastrointestinal,ovary Pancreatic, colorectal Pancreatic, lung, breast, gastrointestinal Biliary, hepatocellular, gastrointestinal Gastrointestinal, hepatic Gastrointestinal, hepatic Breast, colon Gastric carcinoma Different types of serum tumor marker Serologic Tumor Biomarker • Tumor biomarker in body fluid is categorized as: – tumor-associated protein ex: oncofetal protein – oncoproteins – proteomics profile Tumor-associated protein • Oncofetal protein • Protein that are expressed in fetal tissue during development but are not normally found in adult tissue • Protein that seem to be expressed in many cancers but have also been found to be present in other non-neoplastic conditions • Consist of: – alpha-fetoprotein (AFP) – Carcioembryonic antigen (CEA) – Epithelial antigen: CA 19-9, CA 125, and CA 15-3 Oncoproteins • Protein that are involved with the regulation of cell cycle and become overexpressed or mutated almost exclusively in neoplastic conditions; • Examples – Her2/Neu, – cMyc – Grb-2 Cancer Proteomic • A patterns of protein expression in serum that appear to be unique to specific types of cancer • Biomarker for early tumor detection • Not yet available in clinical setting Functional Classification of Abdominal Tumor Markers 1. Oncofetal antigen: AFP, CEA 2. Protein epithelial: CA 19-9, CA 125, and CA 15-3 proteins; 3. Polypeptide hormone: β-hCG, placental isoform Alkaline phosphatase 4. Hormon-like protein: parathyroid hormone-like protein Monoclonal-Ab-Defined Tumor Markers Tumor Marker •Major Malignant Disease CA125 •Ovarian carcinoma CA19-9 •Pancreatic carcinoma CA15-3 •Breast carcinoma CA72-4 •Gastric carcinoma HER2/neu •Breast carcinoma Abdominal Malignancy • Based on organ origin: – colon cancer – gastric cancer – hepatoma/hepatocarcinoma (HCC) – pankreas cancer Serological Tumor Marker Associated with Individual Abdominal Malignant Disease Malignant Disease Major Marker Other marker Colorectal cancer CEA CA 19-5, CA 19-9, CA 72-4, NSE Gastric carcinoma CA 72-4 CA 19-9, CA 50, CEA, ferritin, CK-BB, hCG, LASA-P, pepsinogen II Hepatocellular carcinoma AFP CEA, ferritin, rGT, ALP, TPA, γglutamyltransferase Pancreatic carcinoma CA 19-9 CA 19-5, CA 50, CA 72-4, CEA, CK-BB, ADH, ALP Vipoma (pancreas) VIP CA 19-5, CA 50, CA 72-4, CEA, CK-BB, ADH, ALP CANCER SCREENING RECOMMENDATIONS Recommendations from the American Cancer Society for cancer screening programs in average risk, asymptomatic people: Colorectal cancer (men or women, 50 yo & more): • Faecal occult blood tes & flexible sigmoidoscopy (annual at age 50, then every year faecal occult blood and every 5 year for flexible sigmoidoscopy) • Double contrast barium: at age 50 yo, then every 5-10 year • Colonoscopy: at age 50 yo, then every 10 years. Faecal occult blood (1) • Indication: – Suspected occult gastrointestinal haemorrhage (including potential screening test for colorectal carcinoma) • Procedure • The most common method is a simple and inexpensive qualitative chemical test using guaiacimpregnated paper. • Haem (in faecal blood) has pseudoperoxidase activity and catalyses the release of a free oxygen radical from hydrogen peroxide (in the developing solution), • resulting in the oxidation of phenolic chromogens (in guaiac) to quinones, and the production of a blue colour. • Faecal samples are collected from several (e.g. three, consecutive) bowel actions, or following rectal examination. Faecal Occult Blood (2) • Precautions • Avoid sample collection during menstruation, active haemorrhoids, anal fissures, etc. • Results • In trials of faecal occult blood screening for colorectal carcinoma, the sensitivity of tests for detecting cancer presenting within 2 years was 37–79%, and the specificity was as low as 87%. • False positives – Diet containing animal haemoglobin or vegetable peroxidase (tests may recommend exclusion of red meat and certain uncooked fruits and vegetables for 3 days before and during collection period). – Aspirin and NSAIDs; use of rectal drugs (Note: iron therapy should nott affect guaiac-based tests). Faecal Occult Blood (3) False negatives: • GI lesions, including carcinoma, may bleed intermittently or not at all. Insensitive for blood loss from upper GI tract, unless considerable (haem is metabolised in the small bowel). • High dose vitamin C intake (reducing agent). Other methods of detecting faecal occult blood: • Qualitative immunochemical tests that are specific for human haemoglobin: – minimizing dietary false +ves, – but nevertheless have a significant false +ve rate as they tend to react to physiological’ quantities of faecal blood. – more expensive and more complicated. • Quantitative tests include 51Cr-labelled red cells and radioassay of faecal samples. The upper limit of normal is ~2mg Hb/g faeces. Carcinoembryonic antigen (CEA) • A glycoprotein with a molecular weight of approximately 200kDa, discovered by Gold and Freedman in 1965. • Tumor marker for gastrointestinal cancer today, but most CEA assays have replaced polyclonal with monoclonal anti-CEA antibodies. • CEA is high in : – ~60% of colorectal carcinoma, especially in advanced disease (80–100% if metastasised to liver), – bronchial carcinoma, – breast carcinoma – a variety of non-malignant conditions including inflammatory bowel disease, liver disease, pancreatitis, and in so heavy smokers Carcinoembryonic antigen (CEA) • CEA levels can be elevated in breast, lung, and liver cancers, among others. • Could be used to follow patients during therapy and to detect recurrence after successful surgery, metastases and poor prognosis prior to resection of colon cancer • Increased CEA can be found in: – Liver damage – radiation treatment and chemotherapy. • Form part of the AJCC staging system • CEA can be used as a marker for monitoring colorectal cancer ( Bast, 2001 ). CA 72-4 • A mucin-like human adenocarcinoma-associated antigen, TAG-72, which is a high-molecular-weight (> 106Da) mucin-like complex molecule. • Can be detected in both fetal epithelia and sera from patients with various carcinomas, • Considered to be a carcinoembryonic protein. • Currently, CA 72-4 is considered to be useful marker for the management of patients with gastric and colorectal carcinoma. • Proposed as a specific marker for tumor occurrence of resectable gastric cancer ( Marrelli, 2001 ) and a prognostic marker for survival ( Gaspar, 2001 ). • CA 72-4 has been reported to be an independent prognostic marker for survival in colorectal cancer ( Louhimo, 2002 ) in multivariate analysis together with β-hCG and CEA. ALPHA-FETOPROTEIN (AFP) • Major carcinoembryonic proteins. • Normal value (<16 ng/mL (SI: <16 mL) , at third trimester of pregnancy maximum 550 ng/mL (SI: 550 mL) • Increased: Hepatoma (hepatocellular carcinoma), testicular tumor (embryonal carcinoma, malignant teratoma), neural tube defects (in mother’s serum [spina bifida, anencephaly, myelomeningocele]), fetal death, multiple gestations, ataxia–telangiectasia, some cases of benign hepatic diseases (alcoholic cirrhosis, hepatitis, necrosis), in pregnancy • Decreased: Trisomy 21 (Down syndrome) in maternal serum • The most useful serum marker for the diagnosis and management of hepatocellular carcinoma (HCC) and germ cell tumors Alpha-Fetoprotein (AFP) • Transiently elevated: during pregnancy and in many benign liver diseases. • Used as successfull screening for hepatocellular carcinoma in China • Tests for both AFP and hCG are helpful in reducing clinical staging errors in patients with some testicular tumors and aid in the differential diagnosis of various germ cell tumors. • Because an increase of fucosylation of AFP (hence the lentil lectin reactivity of serum AFP) has been found in primary hepatocellular carcinoma, the determination of lentil lectin reactivity of serum AFP was found helpful not only in order to differentiate between primary hepatocellular carcinoma and benign liver diseases but also to provide an early signal indicating that hepatocellular carcinoma may begin to develop in patients with liver disease. • Combined screening with AFP and ultrasonography results in increased sensitivity from 75% to near 100% in detecting hCC of patients with hepatitis B and C • AFP is currently offered for prenatal screening for neural tube defects and, in conjunction with free β-hCG and unconjugated estriol, for Down syndrome Carbohydrate antigen (CA) 19-9 • Normal value: <37 U/ml (SI:<37 kU/L) • Primary used to determine resectability of pancreatic cancers (ie, >1000U/mL 95% unresectable) • Increased: GI cancers such as pancreas, stomach, liver, colorectal, hepatobiliary, some cases of lung and prostate, pancreatitis • CA19-9 may be useful in monitoring effects of treatment in pancreatic carcinoma, and possibly colorectal and gastric carcinomas. Prostate Specific Antigen • Protein that produced by cell of prostate gland and its level can be detected in plasma of the man. • Normal level:<4 ng/mL • Elevated concentration: – Benign: prostatitis, BPH – Malignancy: prostate cancer Recommendations for Ordering Tumor Marker Test (1) • Never Rely on the Result of a Single Test • When Ordering Serial Testing, be Certain to Order Every Test from the Same Laboratory Using the Same Assay Kit. • Be Certain that the Tumor Marker Selected for Monitoring Recurrence was Elevated in the Patient Prior to Surgery. • Consider the Half-Life of the Tumor Marker when Interpreting the Test Result. Recommendations for Ordering Tumor Marker Test (2) • Consider How the Tumor Marker is Removed from or Metabolized in the Blood Circulation • Consider Ordering Multiple Markers to Improve Both the Sensitivity and the Specificity for Diagnosis. Key Message • Recommended screening for colorectal cancer is faecal occult blood • Serological tumor marker is useful for diagnosis, monitoring and recurrence detection in abdominal malignancy, not screening Thank you for the attention