Tumor Markers (PART 2) MIDTERMS W6

FREQUENTLY ORDERED TUMOR MARKERS

• Alpha Fetoprotein

• CA 125

• CA 15-3

• PSA

• CA 19-9

• Carcinoembryonic antigen (CEA)

• Chromogranin A

• Estrogen Receptor

• Human Chorionic Gonadtropin

• Homovanilic Acid & Vanilyl Mandelic Acid

• Squamous Cell Carcinoma Antigen (SCCA)

• Neuron Specific Enolase

• B2- microglobulin (B2M)

NOTE

CA 19-9- 9 is like the shaped of pancreas

CA 125- OVARY, 5 letters

CA 15-3- BREAST- 3 is like top view of breast

AFP- liver- tagalog is ATAY

ALPHA FETOPROTEIN

• Synthesized by the fetal liver

• This reexpression during malignancy classifies AFP as a carcinoembryonic protein.

• 70 kD glycoprotein related to albumin

• Infants initially have high serum AFP values that decline to adult levels at an age of 7-10 months.

• Involved in regulating oncotic pressure in the fetus.

AFP IS OFTEN ELEVATED IN

Patients with HCC and germ cell tumors.

AFP UPPER NORMAL LIMIT

15 ng/ mL

AFP CLINICAL APPLICATIONS AND INTERPRETATION

• Used for the diagnosis, staging, prognosis, and treatment monitoring of HCC.

• It is not completely specific

• Experts recommend that AFP be used in patients at high risk of developing HCC (Pt. with Hepa B / Hepa C virus induced liver cirrhosis).

AFP SENSITIVITY

40-65%

AFP SPECIFICITY

80%- 95%

THE OTHER MAJOR USE FOR AFP AS TUMOR MARKER IS FOR CLASSIFICATION AND MONIROTING THERAPY FOR TESTICULAR CANCER

• Seminomatous

• Nonseminomatous

SEMINOMATOUS

Is a tumor that formed directly from malignant germ cells

NONSEMINOMATOUS

• Tumors involve differentiation into embryonal carcinoma, teratoma, choriocarcinoma, & yolk sac tumors.

• Derived from other sources and spread quickly

NONSEMINOMATOUS GERM CELL TUMOR

• Yolk sac tumor (endodermalsinus tumor)

• Choriocarcinoma

• Embryonal carcinoma

• Teratoma

YOLK SAC TUMOR (ENDODERMAL SINUS TUMOR)

AFP- INCREASED

HCG- NO

CHORIOCARCINOMA

AFP- NO

HCG- INCREASED

EMBRYONAL CARCINOMA

AFP- INCREASED

HCG- TRACE AMOUNT

TERATOMA

AFP- NO

HCG- NO

SEMINOMA

AFP- NOT ELEVATED IN PURE TUMORS

HCG- TRACE AMOUNTS

NEURAL TUBE DEFECT

Concentration of AFP increases

EX:

• Spina bifida- the bones of the spine do not close around the spinal cord

• Down syndrome- concentration of AFP is decreases

SERUM AFP

Is also useful for tumor staging of nonseminomatous testicular cancer.

STAGES OF NONSEMINOMATOUS TESTICULAR CANCER

STAGE 1- Concentration increases by 10- 20%

STAGE 2- Concentration increases by 50-80%

STAGE 3- Concentration increases by 90-100%

METHODOLOGY FOR AFP

• Automated immunoassay

• Measure in ___ in serum & amniotic fluid

CA 125

• Is a murine monoclonal antibody raised against a serous ovarian carcinoma cell line.

• It is expressed in the ovary, in other tissues of mullerian duct origin, and in human ovarian carcinoma cells.

• Is the only clinically accepted serologic marker of ovarian cancer

CA 125 FALSELY ELEVATED IN

• Endometriosis, first trimester of pregnancy, during menstruation

• Not completely specific

ENDOMETRIOSIS

Abnormal thickening of the endometrium of the uterus

CA125 LEVELS CORRELATE WITH

Ovarian Cancer

• Stage I

• Stage II

• Stage III and IV

STAGES OF OVARIAN CANCER

STAGE I- Increases 50%

STAGE II- Increases up to 90%

STAGE III & STAGE IV- Increases by more than 90%

METHODOLOGY FOR CA 125

Detected by immunoassay that use OC 125 and M11 antibodies.

CA 125 UPPER NORMAL LIMITS

35 U/ mL

CA 15-3

• HMW mucin glycoprotein expressed by various adenocarcinoma especially those associated with the breast

• Sensitive and specific for metastatic breast cancer than CEA (Carcinoembryonic antigen)

CA 15-3 INDICATOR

Breast cancer

CA 15-3 UPPER NORMAL LIMIT

25 U/ mL

CA 15-3 ELEVATED IN

• Chronic hepatitis

• Liver cirrhosis

• Sarcoidosis

• TB

• SLE

Not completely specific marker

OTHER MARKERS FOR METASTATIC BREAST CANCER

CA 27-29

PSA (PROSTATIC SPECIFIC ANTIGEN)

• Glycoprotein produced only in the epithelial cells of the acini and ducts of the prostatic ducts in the prostate.

• It is a serine protease of the kallikrein gene family and functionally regulates seminal fluid viscosity & instrumental in dissolving the cervical mucus cap, allowing sperm to enter.

TWO FORMS OF PSA IN THE BLOOD

• Free- not bound to any substances

• Complexed- bound with a1-antichymotrypsin or a2-macroglobulin

PSA FALSELY INCREASED IN

• Prostate infection, irritation, benign prostatic hyperplasia,

• Recent ejaculation and DRE

NOT COMPLETELY SPECIFIC

PSA METHODOLOGY

Measured by IA, which detects both free PSA and PSA complexed with a1-antichymotrypsin but not a2-macroglobulin

HOOK EFFECTS (ANTIGEN EXCESS) AND HAMAS (HUMAN ANTI- ANIMAL ANTIBODIES)

Known interferences that have been reported for PSA- FALSELY NEGATIVE REPORT

PSA STANDARD TOTAL CUTOFF

<4 ng/mL

CA 19-9

• HMW mucin

• Related to Lewis blood group substance

• Le(a-b+) or Le (a+b-)

CA 19-9 INDICATOR

Not specific, elevated in various adenocarcinoma like in PANCREATIC, lung, colorectal, gastric CA

CA 19- 9 UPPER LIMIT

37 U/ mL

CARCINOEMBRYONIC ANTIGEN (CEA)

• Large heterogenous glycoprotein that is part of the immunoglobulin super family and is involved in apoptosis, immunity, and cell adhesion.

• Is the most widely used tumor marker for COLORECTAL CANCER and is also frequently elevated in lung, breast, and gastrointestinal tumors.

• It can be used to aid in the diagnosis, prognosis, and therapy monitoring for COLORECTAL CANCER

CEA HALF LIFE

2- 8 days

CEA FALSE POSITIVE IN

Radiation treatment, chemotherapy, liver damage, & heavy smoking

CEA UPPER NORMAL LIMIT

2.5- 5 ng/ mL

DEFINITIVE FOR COLORECTAL CANCER

>10 ng/ml

CEA METHODOLOGY

• Use of monoclonal anti-CEA antibodies

• It is essential that the same assay be used for serial monitoring.

• CEA levels be serially monitored every 2-3 months to detect recurrence and determine therapy efficacy.

CHROMOGRANIN A

• Major soluble protein of the chromaffin granules- a catecholamine storage vesicle

• Released from adrenal medulla with catecholamines

CHROMOGRANIN A INDICATOR

Phaeochromocytoma (dark colored cell tumor)

CHROMOGRANIN A ELEVATED IN

• Peptide producing tumor

• Pancreatic tumor

• Carcinoid tumor

• Small cell lung cancer

ESTROGEN RECEPTOR

• Localized in the nuclei of mammary & uterine tissue

• Used to identify those patients most likely to benefit from endocrine therapy

• Patient whom primary tumor are ER/PgR- rich also experience longer disease-free interval after mastectomy.

HUMAN CHORIONIC GONADTROPIN (HCG)

• 45 kD glycoprotein consisting of alpha & beta subunits.

• Is a dimeric hormone normally secreted by trophoblasts in the placenta to maintain the corpusluteum during pregnancy.

HCG IS UNIQUE SINCE IT DEGRADED INTO MULTIPLE FRAGMENTS NAMELY

• Nicked HCG

• Intact molecules

• Free beta subunit

• Hyperglycosylated form

HCG IS HIGHLY ELEVATED IN

• Trophoblastic tumor

• Choriocarcinoma

• Germ cell tumor(ovary or testes),

BETA HCG IS ELEVATED IN

Malignancies

FREE BETA HCG IS ELEVATED IN

Nonseminomatous testicular cancer

HCG IS ELEVATED AND INDICATOR OF

• Trophoblastic tumor

• Choriocarcinoma

• Germ cell tumor (ovary & testis)

• Gestational Trophoblastic disease (GTD)

GTD INCLUDES THE FF

• Hydatiform mole

• Persistent/ invasive gestational trophoblastic neoplasia

• Choriocarcinoma

• Placental site trophoblastic tumors.

HORMONES DETECTED USING PREGNANCY KIT

hCG

HCG METHODOLOGY

• Typical assays use monoclonal capture and tracer antibodies targeted toward epitopes in the beta subunit & intact hCG.

• The TOTAL BETA HCG assays are the most useful because they detect both intact hormone and free b-hCG.

IN TESTICULAR CANCER

The free B-hCG subunit is elevated in 60% - 70% of patients with nonseminomas.

HCG CAN BE USED IN COMBINATION WITH

AFP & biopsies to diagnose subtypes of testicular cancer.

HOMOVANILIC ACID AND VANILYL MANDELIC ACID

• Acidic metabolites of catecholamines

• Excreted in larger than normal amount in patient with tumor originating from neural crest

• INDICATORS FOR pheochromocytoma and neuroblastoma

SQUAMOUS CELL CARCINOMA ANTIGEN (SCCA) INDICATIVE OF

Squamous cell carcinoma of the neck, head, lung, esophagus, anal canal, renal failure, and advance cervical CA

LIPID ASSOCIATED SIALIC ACID IN PLASMA (LASA-P)

Nonspecific to any type of tumor used in conjunction with other tumor marker.

LASA- P INDICATION OF

Hematologic malignancies like Leukemia, lymphoma, hodgkin’s lymphoma, melanoma

NEURON SPECIFIC ENOLASE (NSE)

• Gamma subunit of an enolase isoenzyme in the glycolytic pathway

• ENDOCRINE TUMOR

NSE ELEVATED IN

• Tumors originating from the neuroendocrine cell system including insulinomas and glucagonomas

NSE HIGHEST LEVEL

Oat cell, small cell, and lung carcinoma

NSE IN CHILDREN

Indicator of neuroblastoma

B2- MICROGLOBULIN (B2M)

• Low molecular weight protein

• Part of constant L-chain of human histocompatibility locus antigen that is expressed on the surface of most nucleated cell

• Secreted by all nucleated cells, can be used as a spec. marker of high cell turnover that is often observed in tumors.

B2M ELEVATED ON SOLID TUMORS

• Lymphoproliferative disease

• Inflammatory disorders (RA, SLE, Sjogren’s, Chron’s disease)

B2M ASSAY

Stable in serum

B2M IN URINE

<6.0 ph it degrades rapidly

B2M NORMAL VALUE

0.9- 2.5 mg/L