Download to read offline
Tumour markers of all carcinoma surgery.pptx
- 1. What is atumor marker? • Indicators of cellular, biochemical, molecular, or genetic alterations by which neoplasia can be recognised • Surrogate measures of cancer biology, providing insight of its behaviour • Mostly useful when cancer is clinically not detectable • to determine the presence of a tumor based on measurement in the blood or secretions and that can be detected in various body fluids and on the surface of cancer cells.
- 2. Ideal tumour marker •highly sensitive • highly specific • 100% accuracy in differentiating between healthy individuals and tumor patients. • able to differentiate between neoplastic and non-neoplastic disease and show positive correlation with tumor volume and extent.
- 3. • predict earlyrecurrence and have prognostic value. • preceding the neoplastic process, so that it should be useful for screening early cancer. • easily assayable and be able to indicate all changes in cancer patients receiving treatment.
- 4. Classification of Tumourmarkers
- 5. TUMOUR MARKER 1. WHOLECELLS 2. PROTEINS a. ONCOFETAL MARKERS b. CARBOHYDRATE ANTIGENS c. HORMONES d. ENZYMES AFP CA 15-3 ACTH ALP CEA CA 19-9 B HCG NSE CA 125 Calcitonin PAP Insulin LDH Serotonin Catecholamines Gastrin 3. RNA BASED MARKERS TUMOUR RNA 4. DNA BASED MARKERS TUMOUR DNA EPIGENETIC CHANGES
- 6. Potential uses • Screening •Diagnosis & Confirmation • Staging • Prognosis • Monitoring • Followup
- 7. • In orderto use a tumor marker for screening in the presence of cancer in asymptomatic individuals in general population, the marker should be produced by tumor cells and not be present in healthy people. • However, most tumor markers are present in normal, benign and cancer tissues and are not specific enough to be used for screening cancer.
- 8. Oncofetal antigens 1. A-fetoprotein(AFP): • HCC, Non seminomatous testicular cancers • Single chain polypeptide, 700kDa • High levels in fetus, fall after birth, increased during pregnancy • Testing- immunoassay kits • Upper limit of normal in healthy, non pregnant <10 ng/mL • Sensitivity for HCC 54% • Intrahepatic cholagiocarcinomas, colorectal mets, liver disease with no HCC
- 9. • Screening- inaddition to USG • In high risk population cutoff- 100ng/mL • USG + AFP for HCC- 97% Sensitivity (78% USG alone), 63% sensitivity • AFP alone- 31% • Prognosis- reflects tumour size • Levels >400: larger tumours • Correlates stage and prognosis • Correlated AFP response to therapy- recurrence free and overall survival
- 10. • Monitoring- declineafter resection/ablation/chemo • Ideal should be <10 ng/mL • Avoids prolonged use of ineffective chemo
- 11. 2. Carcinoembryonic antigen(CEA)- colorectal, gastrointestinal, lung and breast carcinoma. • Fetal life, in low conc in healthy adults • Glycoprotein, 200 kDa • A component of glycocalyx (luminal side of cell membrane of epithelial intestinal cells • Secreted in circulation, mucous secretions of GIT and biliary tree • Inv in Cell adhesion, inhibition of apoptosis caused by loss of ECM anchorage
- 12. • Testing- Immunoassaykits • Normal <2, Borderline 2.5 to 5.0 ng/mL, Elevated >5 ng/mL • Borderline- benign (IBD, pancreatitis, cirrhosis, COPD), smoking • Screening- low sensitivity in early disease, not useful • Prognosis- Elevated levels– burden of tumour– coincides with stage – prognostic value • Preoperative serum CEA is an independent predictor of survival
- 13. • Monitoring- inrecurrent disease • Post treatment levels >5ng/mL in colorectal cancer recurrence (sensitivity- 71%; specificity- 88%) • Sensitivity- 68%; specificity – 97% (when cutoff 10 ng/mL) • Monitoring response to chemotherapy in patients with metastatic colorectal cancer • patients with advanced cancer whose CEA levels fall during chemotherapy survive significantly longer than those patients whose CEA levels do not change or increase.
- 14. Carbohydrate antigens 1. CA19-9- Pancreatic ductal adenocarcinoma. • Monitoring response to therapy, not as diagnostic marker • Mucin type GP, on surface of pancreatic cancer cells • Initially detected by monoclonal antibodies against color cancer cell lines in mouse model. • CA 19-9 epitope present in biliary tree • Increased in biliary conditions (acute and chronic)
- 15. • Testing- immunoassay,upper limit- 37 u/mL • Limited as diagnostic marker because of : -Negative lewise Ag blood group indl (10%) -Benign biliary diseases: false positives -also increased other cancers- stomach (5%), colon (15%), HCC (7%), lunf (13%)
- 16. • Screening- at>37 U/mL, 79% Sensitivity & 82-90% Specificity (for pancreatic ductal adenocarcinoma) • PPV for ca pancreas in screening- 0.9% • Not useful • More accuracy when patient symptomatic, cutoff >100 u/mL----- specificity nearly 98%
- 17. • Prognosis- shownto correlate with tumour burden. • For eg. Higher CA 19-9 levels Higher tumour stage • Of patients who undergo curative resection, those whose CA 19-9 levels returned to normal survive longer than those whose levels do not. • Monitoring- serial monitoring required • In recurrence- CA 19-9 rises before clinical/ radiological evidence. • Failure to fall post chemo poor tumor response
- 18. • CA 125-ovarian and endometrial carcinomas, fallopian tube, cervix, pancreas, colon, lung, liver • Benign conditions- endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease, cirrhosis, and ascites • Aka MUC16 • Carbohydrate epitope on a glycoprotein carcinoma antigen • Present in fetus, derivative of coelomic epithelium, incl peritoneum, pleura, pericardium and amnion • In healthy indl, detected by IHC in epithelium of fallopian tubes, endometrium, endocervix. Not normally expressed by ovarian epithelium
- 19. • Testing- measuredby immunoassay, upper limit at 35 u/mL • Elevated levels in 50% early stage patients, 80% late stages of ovarian • Ovarian mass- sensitivity 83-90%, sp 87-97% • Screening- not useful (poor specificity) • Prognosis- elevated levels during diagnosis worst prognosis as those with normal levels • with increasing stage, greater percentages of patients have elevated CA 125 levels: 50% of stage I patients, 70% of stage II patients, 90% of stage III patients, and 98% of stage IV patients.
- 20. • Monitoring- Partialor complete response to therapy is associated with a decrease in the CA 125 level in more than 95% of patients. • Increase level- correlated with burden • Precede clinical/radiological occurrence
- 21.
- 22. Enzymes • Alkaline Phosphatase(ALP)- primary or secondary liver cancer, metastatic cancer with bone or liver involvement. • Normal range upto 300 IU/L • Prostatic acid phosphatase (PAP)- prostate cancer, Increased PAP activity may be seen in osteogenic sarcoma, multiple myeloma and bone metastasis of other cancers and in some benign conditions such as osteoporosis and hyperparathyroidism. • Range- upto 4.0
- 23. Lactate dehydrogenase (LDH) •LDH is involved in tumor initiation and metabolism. Cancer cells rely on increased glycolysis resulting in increased lactate production in addition to aerobic respiration in the mitochondria, even under oxygen- sufficient conditions • Elevated levels found in Dysgerminoma
- 24.
- 25. Immunoglobulins • Detected byProtein Electrophoresis • Globulins are monoclonal aka M Proteins, they stick together and form monoclonal “spike ‘’ or M spike on test. • Elevated in Blood and urine - Multiple Myeloma - Waldenstrom Macroglobinemia Levels are important as older people show low levels of spike without malignancy. Use: Screening and follow up (reponse to treatment)
- 26. Thyroglobulin • Tissue specificglycoprotein produced by thyroid follicular cells • Normal value : < 60mcg/L • Elevated in Thyroid cancer, also in breast and Lung cancer
- 27. Beta 2 Microglobulin •Normal Values: <2.5mcg/ml • Elevated Multiple myeloma, Chronic Lymphocytic leukemia and some Lymphomas Non Neoplastic: viral hepatitis, Non Cancerous kidney disease. • Determine prognosis – higher values have poor prognosis
- 28. Bladder Tumor Antigen •BTA – present in urine of many patients with bladder cancer • Sensitivity: 50-60% • Specificity: 92% • Used along with Nuclear Matrix Protein 22 to tests Recurrence • Not widely used .
- 29.
- 30. Chromogranin A • NormalValue: <76ng/dl in men , <51 ng/ml in women • Sensitivity : 92%, Specificity : 96% • Most sensitive tumor marker for Carcinoid (33%) with localised disease and 66% in those with Metastatic cancer • Elevated in : Neuroendocrine tumors - Carcinoid tumor - Neuroblastoma - Small cell lung cancer - Pancreatic islet cell tumors - Prostate cancers
- 31. CALCITONIN • Controls serumcalcium levels in blood and is secreted by parafollicular C cells. • Normal Value: 5-12 pg/ml • T1/2 : 12 min • Elevated : Malignant: Medullary thyroid carcinoma and Lung cancer Benign :Thyroid Nodules Uses: - Screening in high risk groups (MEN 2), diagnosis, response to therapy and recurrence. -To diagnose C-cell hyperplasia and medullary thyroid cancer(>100pg/ml)
- 32. Human Chorionic Gonadotropin(hcG) • Glycoprotein synthesized by synctio trophoblastic cells of normal placenta. • Alpha – identical with FSH,LH,TSH; Beta – specific for HCG • Normal Value: <20 IU/L for males and non pregnant females. • Half life in serum Approx. 5 days. • Elevated : Gestational trophoblastic disease and Molar Pregnancy (>100,000IU/L) Choriocarcinoma Germ cell tumors Testicular Cancers (60%)
- 33. Benign conditions whichmay have elevated levels- • Hepatitis, cirrhosis, biliary tract obstruction, alcoholic liver disease ataxia telangiectasia and hereditary tyrosinaemia. Physiological conditions with elevated levels- • Pregnancy and the first year of life. • Infants have extremely high levels which fall to adult values between 6 months and 1 year of age. • A slower than normal rate of fall may indicate the presence of a tumour.
- 34. Diagnostic: • For trophoblasticdisease. • Serum HcG levels do not usually differentiate trophoblastic tumours Vs normal pregnancy. • Very high levels outside the range for twin pregnancies may lead to suspicion of a trophoblastic tumour. • For diagnosing trophoblastic tumours, HcG assays are usually used in combination with ultrasound. • Sample for assay- Serum or urine. • Reference range- Serum: 0 - 5 IU/L.
- 35. Clinical applications: • Incombination with hCG, for monitoring patients with NSGCT (mandatory). • Independent prognostic marker for NSGCT (e.g. of the testis). • Diagnostic aid for hepatocellular carcinoma and hepatoblastoma. • Screening for hepatocellular carcinoma in high risk populations (e.g.in patients with cirrhosis due to hepatitis B or C). • Surveillance is recommended using 6-monthly AFP measurement and abdominal ultrasound, with AFP> 20 g/L and rising prompting further investigation.
- 36. • AFP >10,000ng/mL or beta-hCG >50,000 mIU/mL at initial diagnosis portray a poor prognosis, with a 5-year survival rate of 50%. • Patients with AFP and beta-hCG levels that do not decline as expected after treatment have a significantly worse prognosis, and changes in therapy should be considered.
- 37. Inhibin • Peptide hormoneproduced by ovarian granulosa cells. • inhibits secretion of FSH by acting on anterior pituitary gland. • Reaches peak of 772 ‡ 38 U/L in the follicular phase of the menstrual cycle and usually becomes nondetectable after menopause. • Elevated in: -Ovarian tumors (mostly mucinous cystadenoca and Granulosa cell tumor) - postmenopausal woman, premenstrual women with infertility / amenorrhea. • Serum levels reflect the tumor burden. • Used for tumor surveillance after treatment to assess for residual or recurrent disease.
- 38. Estradiol • One ofthe first markers identified in the serum of patients with granulosa cell tumors. • Not a sensitive marker for granulosa cell tumors. • ~30% of tumors do not produce estradiol, because they lack theca cells. • However, monitoring serum estradiol postoperatively may be useful for detecting recurrence of an estradiol-secreting tumor.
- 39. Receptor markers Estrogen &Progesterone Receptors • Breast cancer tissues are commonly tested by IHC • 7/10 breast cancer tests positive for atleast one of these marker • Termed ER/PR Positive ( >10Fmol is positive) • Predictor of prognosis ( better prognosis) and hormonal therapy(Tamoxifen and Aromatase inhibitors) • >60% of ER and <10% of ER – tumor respond
- 40. Epidermal Growth factorreceptor • Tyrosine kinase family of receptors • EGF signaling pathways 4 known receptors –EGFR,erb B2,erbB3,erb B4 • EGFR Activation: cell proliferation, DNA repair, invasion, angiogenesis and metastases • Increased Expression: Colorectal , Braest , Lung(NSCLC), Head &Neck and Pancreatic Cancers. • Increased expression: disease progression , poor outcome and survival rate. • Targeted therapy: Geftinib, Erlotinib,Cetuximab against these receptors.
- 41. HER -2/neu (C-erbB2) •Over expression seen in some Breast cancer, also in some Gastric cancers • 1 in 3 women with breast cancer test positive for HER-2/neu • Predictor of prognosis • Marker Positive pts respond well – Anthracycline based chemotherapy > CMF • More likely to repond to immunotherapy – Herceptin (Trastuzumab) against this receptor
- 42. Acute Phase reactants Inflammatorymarkers C Reactive Proteins ,Ferritin ESR, Viscosity Metabolites VMA , HIAA Viral Antigens Cytogenetic products Ultra Structural Components Polyoma, SV 40 Philadelphia Chromosome Desmin, Vimnetin
- 45. TESTING METHODS Serology Flow Cytometry EnzymeAssays Immunological Immuno histochemistry Radio immune assay ELISA Cytogenetic Analysis FISH (Fluorescent in situ Hybridisation) Spectral Karyotyping Comparative Genomic Hybridization Genetic Analysis Sequencing (Automated ) Reverse Transcription Gel Electrophoresis DNA micro array analysis Proteomics Surface – enhanced laser Desorption/ Ionization
- 46. CLINICAL USE OFTUMOR MARKERS MALIGNANCY TUMOR MARKER DETECTION METHOD ADRENAL CARCINOMA Breast Carcinoid Colorectal Stomach Pancreas Choriocarcinoma Germ cell tumors HEPATOMA Steroids , catecholamines CA 15.3,CA 27.29, ER,PR,HER -2NEU 5 HIAA CEA, CA 19.9 Beta HCG AFP, Beta HCG, LDH,PLAP (seminoma) AFP SEROLOGY SEROLOGY, TISSUE IHC Urine SEROLOGY, TISSUE IHC SEROLOGY, TISSUE IHC SEROLOGY, TISSUE IHC SEROLOGY, SEROLOGY, TISSUE IHC
- 47. MALIGNANCY TUMOR MARKERDETECTION METHOD LYMPHOMA MELANOMA MYELOMA OVARIAN PROSTATE SARCOMA THYROID LDH, CYTOGENETIC ALTERATIONS TYROSINASE IMMUNOGLOBULIN CA125 PSA CYTOGENETIC ALTERATIONS THYROGLOBULIN CALCITONIN (MEDULLARY) SEROLOGY GENETIC ANALYSIS SEROLOGY SEROLOGY SEROLOGY/ TISSUE IHC SEROLOGY/TISSUE IHC GENETIC ANALYSIS SEROLOGY
- 48. Drawbacks • Cancer Heterogenecity •Lack of specificity and sensitivity • Normal individual also have small amounts • Higher levels only with large tumor volume. • Some cancer never have higher levels
- 49.