tumor markers in abdominal cancers

1. TUMOUR
MARKERS
TAWFIQ MOHAMMAD ALNAWAFLEH
MD, MRCS.

2. OUTLINE
DEFENITION
TYPES OF TUMOUR MARKERS
Ideal TUMOUR MARKER
USES OF TUMOUR MARKERS
TUMOUR MARKERS IN ABDOMINAL SURGERY

3. DEFENITION
• Substance that can be detected in higher than normal
amount in serum , urine, or tissue of patient with certain
types of cancer .
• Tumor marker are produced either by the cancer cells
themselves or by the body in a response to the cancer.

4. • No tumor marker is pathognomonic
• Most used as a surveillance tool to monitor for
recurrence of the neoplasm
• Most are not stoichiometric : amount produced is not in
direct proportion to the tumor bulk, although there may
be some evidence that CEA and PSA are .

5. IDEAL TUMOR
MARKERS
• Be specific to the tumor
• Level should change in response to tumor size
• An abnormal level should be obtained in the presence of
micrometastases
• The level should not have large fluctuations that are
independent of changes in tumor size
• Levels in healthy individuals are at much lower
concentrations than those found in cancer patients
• Predict recurrences before they are clinically detectable
• Test should be cost effective

8. USES OF TUMOUR
MARKERS
Screening populations at risk
Not all tumor markers are good screening tools
Diagnosis
Use results from markers, imaging, risk factors, and symptoms
Prognosis
Concentration of the marker determines prognosis
Detection of recurrence
Once tumor is removed, elevations of marker can indicate regrowth
Monitoring response to treatment
Decreased levels of tumor marker indicate therapy is working
Increased levels of tumor marker may indicate need for a change to
therapy
Clinical staging of cancer
Estimating tumor volume

9. Carcinoembryonic
antigen (CEA)
• Glycoprotein
• Found in embryonic endodermal epithelium
• Serum levels disappear almost completely after birth, but
small amounts may be present in the colon.
• Elevated in primary colorectal cancer as well as with breast,
thyroid, lung, ovarian, prostate, liver, pancreatic cancer.
• Elevated in benign conditions including diverticulitis,
cholecystitis, Pancreatitis, Inflammatory bowel disease,
peptic ulcer disease, bronchitis, liver abscess, and alcoholic
cirrhosis, especially in smokers and in elderly persons

10. • Use of CEA level as a screening test for colorectal
cancer is not recommended
• Useful if obtained preoperatively and postoperatively in
patient with CR Ca
• Preoperative elevation indicator of poor prognosis
• The 2007 ASCO clinical practice guidelines state that the
data are insufficient to support the use of CEA to
determine whether to give a patient adjuvant therapy ,
that data stronger for the use of CEA for monitoring for
postoperative recurrence
• CEA measurement is the most cost-effective approach
for detecting metastasis.

11. • In cases in which the patient would be a candidate for
resection of recurrent colorectal cancer or systemic therapy,
the 2006 ASCO guidelines recommend the postoperative CEA
testing be performed every 3 moths in patient with stage two
or three disease for at least 3 years
• CEA is the marker of choice for monitoring metastatic CR Ca
during systemic therapy.
• CEA can be used in conjunction with diagnostic imaging and
history and physical exam for monitoring patient during active
therapy
• In the absence of measurable disease, an increase in CEA
level may be taken to indicate treatment failure.

12. • Individual laboratory assays vary slightly, but the typical
upper limit of normal for CEA in non-smokers is 3.8
micrograms per liter (mcg/L). For smokers, the upper
limit of normal is 5.5 mcg/L

13. Alpha-Fetoprotien
• glycoprotein that is normally produced during gestation by the fetal liver and
yolk sac.
• Levels decrease soon after birth in healthy adults.
• serum concentration of which is often elevated in patients with HCC. Serum
levels of AFP do not correlate well with other clinical features of HCC such as
size, stage, or prognosis.
• Elevated serum AFP occurs in pregnancy , with tumors of gonadal origin (both
germ cell(ovary or testicle) and non-germ cell) and in a variety of other
malignancies, of which gastric cancer is the most common.
• Elevated serum AFP may also be seen in patients with chronic liver disease
without HCC such as acute or chronic viral hepatitis . AFP may be slightly higher
in patients with cirrhosis due to hepatitis C .
• Benign conditions that can cause elevations of AFP : cirrhosis, hepatic necrosis,
acute hepatitis, chronic active hepatitis, ataxia telangiectasia, wiskott-aldrich
syndrome, neural tube defect, and pregnancy.

14. • The sensitivity of an elevated AFP level for detecting HCC is
60% .
• AFP is considered to be sensitive and specific enough To be
used for screening for HCC in high risk population .
• Current recommendations are to screen healthy hepatitis B
virus carriers with annual or semiannual measurement of AFP
and to screen carriers with cirrhosis of any etiology with twice-
yearly measurement of AFP level and liver ultrasonography.
• AFP efficacy in early diagnosis of HCC is limited
• Larger proportion of patients diagnosed with HCC are now
AFP seronegative due to imaging technology improvement
•

15. • It is generally accepted that serum levels greater than 500 mcg/L
(normal in most laboratories is between 10 and 20 mcg/L) in a high-risk
patient is diagnostic of HCC.However, HCC is often diagnosed at a
lower AFP level in patients undergoing screening.
• Not all tumors secrete AFP, and serum concentrations are normal in up
to 40 percent of small HCCs.
• Furthermore, an elevated AFP may be more likely in patients with HCC
due to viral hepatitis compared with alcoholic liver disease.
• Elevated levels were associated with the presence of stage III or IV
fibrosis, an elevated international normalized ratio, and an elevated
serum aspartate aminotransferase level.
• AFP levels are normal in the majority of patients with fibrolamellar
carcinoma, a variant of HCC.
• Patients with cirrhosis and persistently elevated AFP values have an
increased risk of developing HCC compared with those who have
fluctuating or normal levels.
• Despite the issues inherent in using AFP for the diagnosis of HCC, it
has emerged as an important prognostic marker, especially in patients
undergoing resection and those being considered for liver
transplantation. Patients with AFP levels >1000 mcg/L have an
extremely high risk of recurrent disease following transplantation,
irrespective of the tumor size

16. CA 19-9
• Cancer antigen 19-9 , sialylated Lewis (a) antigen
• Tumor related antigen
• Glycoprotein
• CA 19-9 levels are not a useful tumor marker.
• CA 19-9 requires the presence of the Lewis blood group antigen (a glycosyl
transferase) to be expressed. Among individuals with a Lewis-negative
phenotype (an estimated 5 to 10 percent of the population), CA 19-9 levels are
not a useful tumor marker
• One study found that serum concentrations above 37 U/mL represented the
most accurate cutoff value for discriminating pancreatic cancer from benign
pancreatic disease, but the sensitivity and specificity for pancreatic cancer at
this level were only 77 and 87 percent, respectively
• The data are insufficient to recommend use CA19-9 for screening, diagnosis,
surveillance, or monitoring of therapy for colon Ca
• 2006 ASCO guidelines there are insufficient data to recommend use of CA 19-9
for screening, diagnosis, or determination of operability of pancreatic cancer

17. • Patient with locally advanced or metastatic cancer
receiving active therapy, CA19-9 can be measured at the
start of therapy and every 1-3 months while therapy is
given, elevation in serial CA19-9 levels may indicate
progressive disease and should be confirmed by
additional studies.
• Although several marker candidates have emerged from
preclinical studies (and one, macrophage inhibitory
cytokine-1, appears particularly promising ), none has
replaced CA 19-9 to date

19. C- KIT
• proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117,
is a receptor tyrosine kinase protein that in humans is
encoded by the KIT gene.
• Antibodies to CD117 are widely used in
immunohistochemistry to help distinguish particular types of
tumor in histological tissue sections. It is used primarily in the
diagnosis of GISTs, which are positive for CD117, but
negative for markers such as desmin and S-100, which are
positive in smooth muscle and neural tumors, which have a
similar appearance. In GISTs, CD117 staining is typically
cytoplasmic, with stronger accentuation along the cell
membranes. CD117 antibodies can also be used in the
diagnosis of mast cell tumors and in distinguishing
seminomas from embryonal carcinomas

20. • around 95 percent of GISTs arising in adults
overexpress KIT. Approximately 80 percent of GISTs
have KIT gene mutations that lead to constitutive
activation of the KIT receptor.

21. PSA
• Androgen-regulated serine protease produced by the
prostate epithelium.
• PSA is normally present in low concentrations in the
blood of all adult males.
• PSA levels may be elevated in the blood of men with
benign prostatic hyperplasia, as well as in men with
prostate cancer
• PSA levels have been shown to be useful in evaluating
the effectiveness of prostate cancer treatment and
monitoring for recurrence after therapy.

23. • In monitoring for recurrence, a trend of increasing levels is
considered more significant than a single absolute elevated
value.
• Although PSA has widely used for prostate Ca screening, the
utility of PSA screening remains controversial.
• In 2010 American cancer society updated its guidelines for the
early detection of prostate Ca to state that men who have at
least a 10 years life expectancy should have an opportunity to
make an informed decision with there health care provider
about whether to be screened for prostate Ca with DRE and
serum PSA, after receiving information about the benefits,
risks, and uncertainties associated with prostate Ca
screening, this recommendation was reinforced in their 2013
guideline.

24. • Studies have estimated that PSA elevations can precede
clinical disease by 5 to 10 years or even longer .
• PSA has a half-life of 2.2 days, and levels elevated by
different benign conditions will have variable recovery
times(DRE, Ejaculation,)
• The five-alpha reductase inhibitors finasteride and
dutasteride lower PSA levels.
• The traditional cutoff for an abnormal PSA level in the
major screening studies has been 4.0 ng/mL .

25. Screening for prostate
cancer
• When a decision is made to screen, screening be performed with
prostate specific antigen (PSA) tests at intervals ranging from every
two to four years. We suggest not performing digital rectal examination
as part of screening.
• When a decision is made to screen, screening stop after age 69 or
earlier when comorbidities limit life expectancy to less than 10 years,
or the patient decides against further screening. Stopping screening at
age 65 may be appropriate if the PSA level is less than 1.0 ng/mL.
• Men with an abnormal DRE (if performed) or PSA level above 7 ng/mL
should be referred, without further testing, to an interventional
specialist who can evaluate them for a transrectal ultrasound-guided
prostate biopsy.
• men with a PSA level between 4 ng/mL and 7 ng/mL undergo repeat
testing several weeks later . Prior to repeat PSA testing, men should
abstain from ejaculation and bike riding for at least 48 hours. Men with
symptomatic prostatitis should be treated with antibiotics before
retesting. Men with a repeat PSA level above 4 ng/mL should be
referred for transrectal ultrasound-guided prostate biopsy.

26. • Numerous strategies have been proposed to improve the
diagnostic performance of PSA when levels are less than 10.0
ng/mL. These strategies include measuring PSA velocity
(change in PSA over time), PSA density (PSA per unit volume
of prostate), free PSA, complexed PSA, and using age- and
race-specific reference ranges.
• There is no consensus on using any of the PSA modifications,
and none of them has been shown in clinical trials to reduce
the number of unnecessary biopsies or improve clinical
outcomes. The total PSA cutoff of 4.0 ng/mL has been the
most accepted standard because it balances the tradeoff
between missing important cancers at a curable stage and
avoiding both detection of clinically insignificant disease and
subjecting men to unnecessary prostate biopsies.

27. VMA
• Pheochromocytoma are diagnosed by testing 24-hour
urine samples for catecholamines and their metabolites
as well as by determinig plasma metanephrine levels.
• The 24-hour urinary vanillylmandelic acid (VMA)
excretion has poor diagnostic sensitivity and specificity
compared with fractionated 24-hour urinary
metanephrines.
• False-positive VMA tests may result from ingestion of
caffeine, raw fruits, or medications (alpha-methyldopa).

28. • Urinary metanephrines are 98% sensitive and also about
98% specific for pheochromocytomas, whereas VMA
measurement are slightly less sensitive and specific.

29. P53
• Tumor suppressor gene.
• Because of its central role in preventing the propagation of
cells with DNA damage, p53 has been referred to as the
“guardian of the genome”.
• The p53 gene on chromosome 17p is the most commonly
mutated gene in human cancer. In about 50 to 70 percent of
CRCs, p53 inactivation occurs by a mutation of one allele
followed by loss of the remaining wild type gene.
• The identification of p53 mutations in an individual CRC is of
potential clinical significance, prognostically and
therapeutically. In many but not all studies, patients whose
tumors harbor p53 mutations have worse outcomes and
shorter survival than those without such mutations.

30. • Given the association of p53 pathway inactivation with CRC, it
is unclear why patients with the Li Fraumeni syndrome (a
condition caused by a germline mutation in p53 in which
patients frequently develop carcinomas, sarcomas, and
leukemias) are not at particularly increased risk of developing
CRCs.
• Li-Fraumeni syndrome : is an inherited autosomal dominant
disorder that is manifested by a wide range of malignancies
that appear at an unusually early age . Li-Fraumeni syndrome
is also known as the Sarcoma, Breast, Leukemia, and Adrenal
Gland (SBLA) cancer syndrome. This cancer predisposition
syndrome is inherited as an autosomal dominant disorder and
is associated with abnormalities in the tumor protein p53 gene
(TP53).

31. CA 125
• A protein that is higher than normal in approximately 80 percent of
women with ovarian cancer. It can be measured with a blood test.
CA 125 is commonly used to monitor women with ovarian cancer.
• The normal values for CA 125 may vary slightly among individual
laboratories. In most laboratories, the normal value is less than 35 U
/ml.
• The most common use of the test is the monitoring of people with a
known cancer that elevates CA 125 level, such as cancer of the
ovary. In the patient who is known to have a malignancy, such as
ovarian cancer, the CA 125 level can be monitored periodically. A
decreasing level generally indicates that therapy, including
chemotherapy, has been effective, while an increasing level
indicates tumor recurrence. Because of normal test variation, small
changes are usually not considered significant. A doubling or halving
of the previous value would be important.

32. • In the patient who is being evaluated for a pelvic mass, a CA
125 level greater than 65 is associated with malignancy in
approximately 90% of cases. However, without a
demonstrable mass, the association is much weaker.
• A number of benign conditions can cause elevations of the CA
125 level, including pregnancy, endometriosis, uterine
fibroids(benign tumors), pancreatitis, normal menstruation,
pelvic inflammatory disease, and liver disease. Benign tumors
or cysts of the ovaries can also cause an abnormal test result.
• Increases can also be seen in cancers other than ovarian
cancer, including malignancies of the uterine tubes,
endometrium, lung, breast, pancreas, and gastrointestinal
tract.

33. • So if you have a higher than normal CA 125 level, you could have
ovarian cancer or a more common and less serious condition. Pelvic
ultrasound may be helpful to know if you have ovarian cancer, although
the only way to know for sure if you have ovarian cancer is to have
surgery. As a result, CA 125 is not recommended as a stand-alone
screening test for ovarian cancer.
• Combined CA 125 and pelvic ultrasound — Several studies have
looked at using CA 125 and pelvic ultrasound together to detect ovarian
cancer. However, the results of these studies have been somewhat
disappointing:
1) Many women had unnecessary surgery because of false positive
test results (the CA 125 or pelvic ultrasound was abnormal but no
cancer was found).
2) Some studies of CA 125 and pelvic ultrasound have found more
cancers at an early, more treatable stage, while others have not. No
published studies have shown that these tests reduce the risk of dying
of ovarian cancer.

34. Cancer antigen CA 27-29
• The MUC-1 gene product in the serum may be
quantitated by using radioimmunoassay with a
monoclonal antibody against the CA 27-29
• Ca 27-29 levels can be elevated in breast as well as in
cancers of the colon, stomach, kidney, lung, ovary,
pancreas, uterus, and liver
• First trimester pregnancy ,endometriosis, benign breast
disease, kidney disease, and liver disease also may be
associated with elevated CA 27-29 levels.

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