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 Leukemia, Sarcoma,
Lymphoma
Creatine kinase Prostate, Lung (SSC) Breast, colon, ovary,
stomach
Lactate dehydrogenase Liver, lymphoma, leukemia Breast, colon, stomach.
Lung
Neuron Specific Enolase Lung (SSC), Neuroblastoma Pheochromocytoma,
Carcinoid,
Prostatic Acid Prostate Cancer Osteogenic sarcoma,
Phosphatase (PAP) multiple myeloma, bone
metastasis
Prostatic Specific Protatic Cancer BPH
Antigen (PSA)
 Classification of Tumor Marker & its
association with malignancy
Type of Tumor Marker Major disease Minor disease
Hormones:
ACTH Lung (Small cell carcinoma) Pancreatic, breast, gastric,
colon
Calcitonin Medullary carcinoma thyroid Carcinoid, breast, lung
HCG Choriocarcinoma Testicular tumor,
trophoblastic tumor
Oncofetal antigen:
Alpha-fetoprotein Primary hepatocellular Ca Teratoma of ovary & testis
CEA Colorectal Ca Gastrointestinal,
pancreatic, lung, breast
Tissue polypeptide Breast, colon, ovary ChorioCa (TPA+),
antigen hepatocellular (TPA -)
Sq cell ca antigen Cervical, lung skin 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
CA 549 Breast Metastatic ovarian, prostate,
CA 27.29 Breast (recurrent) lung
Mucin-like Carcinoma Breast -
Associated Antigen (MCA) Ovarian, cervical, endometrial
CA 125 Ovaries, endometrial
Pancreatic Pancreatic, lung, breast,
Du PAN 2 gastrointestinal
Biliary, hepatocellular,
gastrointestinal
Blood group antigen:
CA 19-9 Colorectal, pancreatic Gastrointestinal, hepatic
CA 50 Pancreatic, colorectal Gastrointestinal, hepatic
CA 72-4 Gastrointestinal,ovary Breast, colon
CA 242 Pancreatic, colorectal 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
Major
Malignant Disease Other marker
Marker

Colorectal cancer CEA CA 19-5, CA 19-9, CA 72-4, NSE

CA 19-9, CA 50, CEA, ferritin, CK-BB, hCG,

Gastric carcinoma CA 72-4
LASA-P, pepsinogen II
CEA, ferritin, rGT, ALP, TPA, γ-
Hepatocellular carcinoma AFP
glutamyltransferase
CA 19-5, CA 50, CA 72-4, CEA, CK-BB, ADH,
Pancreatic carcinoma CA 19-9
ALP
CA 19-5, CA 50, CA 72-4, CEA, CK-BB, ADH,
Vipoma (pancreas) VIP
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 guaiac-
impregnated 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