CC2 (01.LAB) - Tumor Markers PDF

CLINICAL CHEMISTRY 2 01 [LAB] | Tumor Markers PRELIMS A.Y. 2022-2023 TWO MAJOR PROCESS IN CELL GROWTH abnormally regulated or unbalanced cell...

CLINICAL CHEMISTRY 2 01 [LAB] | Tumor Markers PRELIMS A.Y. 2022-2023 TWO MAJOR PROCESS IN CELL GROWTH abnormally regulated or unbalanced cell division 1. Proliferation - Increase in number by cell division - Rapid and successive Types of Tumors - Important in replacing cells BENIGN MALIGNANT 2. Differentiation - Changes in characteristics NOT cancer; typically Cancerous that can cause - One cell type to another grow at a slow rate serious health problems - Becomes specialized cells Usually harmless and May be life-threatening do not spread to other and may often cause - For repair and replacement parts of the body death - Ex: zygote, embryonic stem cell Their growth can If tumor is small, may be interfere with the ability removed, but sometimes of healthy tissues to they grow back Definition of Terms grow and thrive They can spread TUMORIGENESIS - emergence of tumor cells May grow large (metastasize) to other when the growth and development of a enough to apply parts of the body and pressure to vital body destroy them normal cell loses control organs, resulting in TUMOR - a mass of tissue where new cells are serious illness or death being formed even if the body does not need When too large, they them, and old cells do not die when they may require surgical removal for cosmetic should purposes or to NEOPLASIA - a form of pathologic hyperplasia preserve surrounding in which normal cells undergo hyperplasia in tissues. less controlled/unregulated conditions and After removing, they usually do not grow serve no purpose back CANCER - disease of an abnormal growth Rarely life-threatening CELLULAR ADAPTATION Atrophy Decrease in size of cells of organs that have already reached full maturation May be caused by ischemia (deficient supply of O2), disuse, pressure, exhaustion or hormone deficiency Hyperplasia Involves the multiplication of cells capable of dividing in an organ or tissue, which may consequently have increase in volume Serves a useful purpose and is controlled by stimuli Hypertrophy Increase of size of cells that do not divide (cardiac muscle cells, skeletal muscle cells and nerve cells) Metaplasia Cells change from one cell type to METASTASIS another cell type Occurs when cancer cells break off the original tumor causing it to travel to its TUMOR adjacent organs The name for a swelling or lesion formed by an A highly selective multistep processes abnormal growth of cells involving numerous tumor cell-host cell and An abnormal new mass of tissue that serves cell-matrix interactions no purpose An abnormal growth resulting from a cell that “The larger, more aggressive, or rapidly lost its normal growth control restraints and growing the primary neoplasm, the greater started multiplying uncontrollably the likelihood that the tumor cells will Caused by body tissues that grow to form an metastasize.” abnormal mass that is initiated by BLESSY MAE D. Page | 1  CC2 LAB | MLS 308 DIFFERENT FORMS OF CANCER DNA replicates (copies) Solid tumors (breast, prostate and lungs) Organelles double in number, to prepare for - Stationary and can usually be palpated if division they are significantly large and accessible Includes: Diffuse tumors (leukemia and Hodgkin’s a. G1 (first growth) - interval between the disease) conclusion of mitosis and the start of - Especially the leukemias (the cancer of the DNA replication leukocytes) which are not restricted to any b. S (synthesis → copy DNA) - interval one location. during which the nuclear genome is replicated Definition of Terms c. G2 (second growth) - interval between completion of nuclear DNA replication Carcinoma Malignant tumors derived from epithelial cells and the onset of mitosis Group that represents the most common cancers Mitosis (M Phase) Breast, prostate, lung, colon cancer Prophase - condensation of chromatin Sarcoma Malignant tumors derived from Metaphase - chromosomes align in middle connective tissue or mesenchymal Anaphase - pulling and formation of cleavage cells furrow Lymphoma Malignancies derived from Telophase - cell doubles and hematopoietic (blood forming) cells Leukemia G0 Germ Cell Tumors derived from totipotent cells Cell cycle arrest Tumor (single cell that gives rise to another Form of the resting state, or quiescence, in organism) which cells reside until they receive Most often found in the testicle and appropriate signals ovary Treatment Surgical removal Radiotherapy Chemotherapy Hormonal therapy Immunotherapy Some malignant cancers cannot be cured completely. Often, a tumor that fits this description can still be treated, however, APOPTOSIS extending the life of the patient. Programmed cell death A natural self-destruct system present in all SIGNAL TRANSDUCTION PATHWAY cells An orderly and specific transmission of The natural process the body employs for the growth-regulatory messages from outside replacement of cells and the deletion of the cell to the machinery controlling damaged cells inherent in the normal replication inside the cell nucleus functioning of multicellular organisms Controls cell cycle and apoptosis Control mechanism for tissue remodeling during growth and development Provides a way for the body to eliminate cells CELL CYCLE that have been produced in excess, that have One of the most important determining factors developed improperly, or that have sustained controlling cell proliferation genetic damage Involves the passage of a cell through a complete round of replication 4 phases = G1, S, G2, M phase MARKERS FOR APOPTOSIS p53 protein - prevents cells with damaged DNA from dividing or, when damage is too Interphase great, promotes cell death Not part of mitosis but included in cell cycle Bcl 2 (B-cell lymphoma 2) - a family of protein Cell is in a resting phase, performing cell that either promotes or inhibits apoptosis and functions control apoptosis via governing mitochondrial BLESSY MAE D. Page | 2  CC2 LAB | MLS 308 outer membrane permeabilization (MOMP), 3. Immunoglobulin superfamily (mainly: which is a key step in the intrinsic pathway of IgD, IgM) – large protein that are apoptosis involved in the recognition, binding, or Fas/Fas ligand (FasL/CD95L/CD178) - belongs adhesion process to the tumor necrosis factor (TNF) family in which the ligation of Fas with FasL results in the SIGNS AND SYMPTOMS OF CANCER: CAUTION activation of a caspase cascade that initiates apoptosis Change in bowel or bladder habits. - Necrosis: cell death linked to inflammation; A sore that will not heal. inflammation induced Unusual discharge or bleeding. - Apoptosis: non-inflammation induced Thickening or lump in the breast, testicles or elsewhere. Indigestion or difficulty swallowing. ANGIOGENESIS Obvious change in a wart or mole. Fundamental process by which new blood Nagging cough or hoarseness. vessels are formed; formation of blood vessels RISK FACTORS Provide a gateway for tumor cells to enter the Growing older - higher risk for people over 65 circulation and to metastasize to distant sites Poor diet, lack of physical activity, or being Critical, not only for the growth of solid tumors, overweight but also for the shedding of cells from the Ionizing radiation primary tumor and the development of Certain chemicals and other substances metastasis at distant sites Some viruses and bacteria THREE TYPES: Family history of cancer – could not be 1. Healthy angiogenesis → due to exercise avoided 2. Therapeutic angiogenesis → seen in Alcohol patients with ischemia Tobacco 3. Unhealthy angiogenesis → abnormal Sunlight branching of blood vessels Cancers are curable if detected EARLY and treated PROPERLY. Studies have shown that early detection of cancer can lead to superior long-term survival. Thus, there is an urgent need to search for cancer biomarkers with high sensitivity and specificity to allow for early cancer detection, effective treatment, and decreased mortality. ADHESION MOLECULES Specific class of transmembrane glycoprotein involved wherever cells are moving and interacting - Wound healing, inflammation, cancer metastasis Regulate the migration of leukocytes to sites of inflammation or into lymphatic tissue The appearance has impacted the behavior of the tumor cell THREE CLASSES: 1. Selectins - involved in white blood cells, platelet and endothelium interaction within the circulation TUMOR MARKERS 2. Integrins – involved in the interaction of Substances produced by tumor cells or by cells with extracellular matrix (enzymes, other cells of the body in response to cancer or collagen, proteins) certain benign (noncancerous) conditions BLESSY MAE D. Page | 3  CC2 LAB | MLS 308 Can be found in the blood, in the urine, in the - Detection of recurrence following tumor tissue, or in other tissues surgical removal of tumor Different tumor markers are found in Prognosis different types of cancer, and levels of the - Reflect the aggressiveness of the tumor same tumor marker can be altered in more - Help predict the outcome of the patient than one type of cancer Early Detection Tumor marker levels are not altered in all Target Therapy people with cancer, especially if the cancer is early stage RISK MARKERS Some tumor marker levels can also be altered Some people have a greater chance of in patients with noncancerous conditions developing certain types of cancer because of a change, known as a mutation or alteration, Sensitivity vs. Specificity in specific genes. The clinical value of any given tumor marker The presence of such a change is sometimes will depend on its specificity and sensitivity, called a risk marker as well as its intended clinical use. Tests for risk markers can help the doctor to For example, PSA can be used in the screening estimate a person’s chance of developing a of prostate cancer, resulting in early detection certain cancer and treatment. Risk markers can indicate that cancer is more Serum HER2/neu is used as a marker of likely to occur, whereas tumor markers can prognosis and monitoring therapy for breast indicate the presence of cancer cancer. The difference in their usefulness is due to their LAB DIAGNOSIS difference in tissue specificity and cancer Biopsy sensitivity: PSA is organ-specific but not X-rays cancer specific, whereas HER2/neu is cancer- Computed tomography (CT) scans specific but not tissue-specific and is found to Magnetic resonance imaging (MRI) be increased in breast cancers, as well as lung Positron emission tomography (PET) scans and other epithelial cell tumors. Lab assays (Tumor markers) - The blood levels of serum tumor markers are determined by: a. Tumor proliferation b. Tumor volume c. Proteolytic activities in the tumor cell d. Release from necrotic tumor cells TYPES OF TUMOR MARKERS I. Enzymes, Serum Proteins, and Hormones Enzymes can be used as tumor markers but are not specific for cancers. Levels often reflected tumor progression and paralleled the clinical status of the patient High proliferation rate of tumor cells Clinically useful for monitoring the success of therapy Malignant tumors: exhibit high rate of glycolytic activity in the presence of oxygen *Dedifferentiation - backward; from adult to ENZYME ASSOCIATED MALIGNANT DISEASE primitive cell; hallmark of aggressive malignancy Prostatic ACP Prostate CA, late stage CLINICAL UTILITIES OF TUMOR MARKERS Lysozyme Colon CA; monocytic and Screening myelomonocytic leukemia - AFP = primary hepatoma - PSA = prostate CA LDH Acute leukemia; malignant - BRCA1 & BRCA2 = breast and ovarian CA lymphoma; germ cell tumors; metastatic colon, breast and - APC (adenomatous polyposis coli) lung cancers Monitoring Treatment - Effective of antitumor drugs BLESSY MAE D. Page | 4  CC2 LAB | MLS 308 5’- nucleotide Lung cancer; liver metastases MONOCLONAL KIT ASSOCIATED MAJOR phosphodiesterase MALIGNANT DISEASE Sialyltransferase Nonspecific but is common in CA 125 Ovarian CA breast and colorectal Hybri-BREScan (CA 549) or Breast CA Fucosyltransferafe Multiple malignant tumors CA 15-3; CA 27-29 Metastatic breast CA Thymidine kinase Hodgkin’s lymphoma; certain Hybri-CMark (CA 195) or Pancreatic CA leukemias; small cell CA of the CA 19-9 lung CA 72-4 Gastric CA Terminal Lymphoblastic cancer deoxynucleotidyl Free PSA Differentiate between transferase BPH and prostatic CA CK-BB Adenocarcinoma of prostate, lung & stomach; not specific IV. Nonspecific Tumor Markers Lipid-associated sialic acid in the plasma Type 2 macro CK Metastatic liver cancer & various (LASA-P) (oligomeric CAs mitochondrial CK) Inexpensive Simple to measure Type 1 macro CK Various neoplastic diseases Useful in monitoring therapy (complex bet CK-BB Detect recurrence for patients with known & IgG) diagnosis Mitochondrial Various CAs; prognosticator for Commonly used in leukemia and Hodgkin’s, CK-IgA complex patients with advanced tumors breast, colon Galactosyltransferase II Ovarian, liver, and esophageal V. Cell-specific Tumor Markers cancers 1. Squamous cell antigen (SCCA) Placental ALP (PALP) Advanced colorectal CA; not - Marker for squamous cell CA specific 2. Chromogranin A (CgA) - Marker of neuroendocrine cell CA Placental-like ALP Germ cell tumors (seminomas) & 3. Neuron-specific enolase (NSE) (Regan) ovarian CAs; not specific - Marker of neuroendocrine cell CA Liver ALP Liver metastases; seminomas; ovarian CAs RECOMMENDATIONS FOR TEST ORDERING Bone ALP Osteosarcoma; bone metastases Ordering Serial Tests Most tumor markers are nonspecific LD-1 Testicular germ cell tumors Difficult to differentiate between malignant (seminomas, yolk sac tumor) diseases and benign diseases based solely on elevated results of a single test LD-4 & LD-5 Most cancers at advanced stage Using the Same Kit II. Carcinoembryonic Proteins Inconsistent lab results due to different The expression of some proteins, slated to be commercial kits. turned off during the normal developmental processes, may be reactivated by tumor cells. Half-Life of the Tumor Marker CEA (carcinoembryonic antigen), AFP The pre-existing tumor marker needs (alpha-fetoprotein) sufficient time to clear from circulation before Present in nanogram or picogram in blood obtaining a blood specimen. Specificity and sensitivity = not 100% Determine the proper interlude after surgery Higher than that of enzymes, serum proteins, & and before testing hormones Know the half-life Correlates well with tumor activity Potential for predicting prognosis Hook Effect Observed in sandwich-type solid phase III. Monoclonal Defined Tumor Markers immunoassay Use monoclonal antibodies Tends to give a falsely low value when the Greater degree of specificity and sensitivity serum concentration of the tumor marker rises above a certain level BLESSY MAE D. Page | 5  CC2 LAB | MLS 308 - Remedy: DILUTION 3 CA 15-3 Represents distinct epitopes No hook effect in immunoassays based on a on a high-molecular weight competitive binding format (300-450 kD) mucin glycoprotein expressed by various adenocarcinomas METHODS (associated with breast CA) Immunoassay - the most commonly used Observed in 70-80% of method to measure tumor markers patients with metastatic breast cancer High Performance Liquid Chromatography Elevated level = chronic (HPLC) - catecholamines and metabolites hepatitis, liver cirrhosis, Immunohistochemistry and Immunofluorescence sarcoidosis, tuberculosis, SLE - receptors for estrogen and progesterone; for - Sarcoidosis: chronic; unknown cause tissue specimens characterized by Enzyme assay formation of nodules (skin, lungs, bones, lymph nodes) FREQUENTLY ORDERED TUMOR MARKERS Currently used to monitor the 1 A1-fetoprotein Major fetal serum protein and clinical course of patients with (AFP) the major carcinoembryonic BREAST CANCER proteins More sensitive and specific Newborns initially have high marker for monitoring the serum AFP values that decline clinical course of patients with to adult levels at an age of metastatic breast cancer 7-10 months. than CEA Upper normal level = 15 ng/mL More sensitive marker for Elevated AFP: metastasized breast cancer - During pregnancy than CEA - Many benign liver diseases (hepatitis, liver 4 CA 19-9 The molecule carrying the CA cirrhosis) 19-9 epitope appears as a Successfully used in mucin in the sera of patients screening, staging, prognosis but as a ganglioside in tumor and treatment, monitoring of cells hepatoma/HEPATOCELLULAR Related to Lewis blood group CARCINOMA (HCC) substances Also used as a tumor marker Serum Ag from cancer patient for TESTICULAR CANCER. belonging to Le(a-b+) or - Seminomatous tumors: Le(a+b- ) directly from malignant Not organ specific germ cells Various adenocarcinomas: - Nonseminomatous tumors: pancreatic, lung, colorectal, differentiate into embryonal and gastric CAs carcinoma, teratoma, choriocarcinoma, and yolk Highest sensitivity: PANCREATIC sac tumors and GASTRIC CANCER ➔ Teratoma: Useful for monitoring the heterogenous mixture success of therapy of different cells; Detect recurrence in those derived from different cancer patients cell or germ layers Upper normal limit = 37 U/mL ➔ Choriocarcinoma: trophoblastic cells; forming in uterus after 5 Carcinoembryonic Glycoprotein with a molecular fertilization; small Antigen (CEA) weight of 200 kD number develops in First of the carcinoembryonic testes and ovary proteins discovered by Gold & Freedman 2 CA 125 First defined by a murine The most widely used tumor monoclonal antibody OC 125 marker for raised against a serous GASTROINTESTINAL TUMOR ovarian CA cell line today; nonspecific marker for Glycoprotein antigen in which COLORECTAL CANCER a carbohydrate moiety is also Before surgical resection, part of the antigenic baseline CEA values are determinant typically obtained to confirm Useful for detecting ovarian successful removal of the tumors at an early stage and tumor burden. for monitoring treatments It is recommended that CEA without surgical restaging levels are serially monitored Upper normal limit = 35 U/mL every 2-3 months to detect Elevated level = >80% recurrence and determine non-mucinous epithelial therapy efficacy. ovarian CA Elevated levels: liver damage, heavy smokers, patient BLESSY MAE D. Page | 6  CC2 LAB | MLS 308 following radiation treatment pregnancy test; formed and chemotherapy at the beginning of Upper normal range = 2.5-5 pregnancy ng/mL - Germ cell tumors of High levels are associated ovary and testis with malignancy - 60-70% patients with seminomas 6 β2-Microglobulin Low molecular weight protein (β2-M) = 11,800 D 10 Chromogranin A Major soluble protein on the The constant light chain of chromaffin granule HLA expressed on the surface (catecholamine-storage of most nucleated cells vesicle) Seen in surfaces of Released from the adrenal lymphocytes and monocytes medulla together with Nonspecific tumor marker catecholamines Stable in serum but degrades Useful index of sympathoadrenal rapidly in the urine at pH