Tumor markers are substances produced by tumors or the body's response to tumors that can help detect and monitor cancer. Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma and germ cell tumors. It is useful for diagnosis, staging, prognosis, and monitoring treatment response in HCC and germ cell tumors. Carcinoembryonic antigen (CEA) is elevated in various cancers including colorectal cancer. CEA levels correlate with tumor stage and burden and can help monitor treatment response and detect recurrence, though it lacks sensitivity and specificity for screening and diagnosis.

1. Tumor Markers in GI Surgery
Sushil Gyawali
MS Resident

2. Tumor Marker
Definition:
A tumor marker is a substance present in or produced by a tumor or by the tumor’s
host in response to the tumor’s presence that can be used to differentiate a tumor
from normal tissue or to determine the presence of a tumor based on
measurement in the blood or secretions.
( Ind jour Med Ped Oncology 2009)
★ They are surrogate measures of the biology of the cancer.
★ Provide insight into the clinical behavior of the tumor.

3. Cancer Biology
●
Cancer Biomarkers, by Hala Fawzy Mohamed Kamel et al, 2016 feb

4. Tumor Marker is a biomarker
● It is a ‘measurable biological indicator’
● Cellular, biochemical, molecular, or genetic
alterations
● Found in bodily fluids (blood urine, stool) or
tissues
● Correlates with a normal or pathogenic
physiological state
L.J. Sokoll, A.J. Rai, D.W. Chan, Tumor markers, Tietz Textbook of Clinical Chemistry, fifth ed., W.B. Saunders Company, Philadelphia, PA, 2012
Biochemical indicators of the presence of a tumor

5. History
Bence Jones
Protein
First tumor marker in
identified by Bence-
Jones in multiple
myeloma
1846
Amylase
• Sir Michael Foster who
reported the increase
levels of serum amylase
in patients with cancer
pancreas.
• He suggested urinary
amylase as a biomarker for
cancer pancreas.
1867
Alpha Feto
Protein
AFP
.
1956
Immunoassay
technique
1960
CEA
CEA was isolated from
human colon cancer
and was the first
“tumor antigen”
discovered
1965
Monoclonal
antibody
technique
monoclonal Abs tech was
developed which facilitates
the discovery of new tumor
markers including CA125,
CA15.3, CA19.9
1975
Indian J Med Paediatr Oncol. 2009 Jan-March

6. Cancer Detection

7. Importance
● to correlate with
tumor burden
● to distinguish benign
vs malignant disease;
● it may be prognostic,
● and it may guide
choice of therapy
and predict response
to therapy.

8. Clinical application
Tumor
marker
application
screening
Diagnosis
Tumor
staging
Localizing
tumor
(primary)
Monitoring
response
Recurrence
detection
(surveillance)
Patient stratification
Risk assessment
Prognosis

10. Ideal Tumor Marker
M.J. Duffy, Tumor markers in clinical practice: a review focusing on common solid cancers, Med. Princ. Pract.(2013)
Organ/tissue specific
Reproducible, rapid
and in expensive
Correlate with tumor
burden
Short half life:
serial
monitoring
Differentiate
neoplastic vs
non neoplastic
High
sensitivity &
specificity
Easy assayable:
noninasive
Detectable before
disease
Long lead time
Predict
early
recurrence
and
Prognostic

11. Drawbacks
Cancer heterogeneity
Lack of Specificity/Sensitivity
Not useful for screening or diagnosis
Benign diseases - FP
Smokers have raised CEA
Normal persons also have small amounts
Higher levels only with large tumor volume

12. Changes in tumor markers during disease course
1st line
therapy
2nd line
therapy

13. Serological/ Circulating tumor markers Tissue/Histochemical markers
found in blood, urine, stool, other bodily fluids
estimate prognosis
● assess the response to treatment
● monitor whether a cancer has become
resistant to treatment or recurrent
● reflects the stage (extent) of the disease
● prognosis :combined with the results of other
tests, such as biopsies or imaging
found in the actual tumors themselves, biopsy.
used to:
● diagnose, stage, and/or classify cancer
● estimate prognosis
● select an appropriate treatment (eg,
treatment with a targeted therapy)
● ER/PR(breast cancer),
● EGFR gene mutation analysis (NSCLC),
determine treatment and estimate
prognosis;

14. Classification
Mishra A , Verma M. Cancer biomarkers: are we ready for the prime time? Cancers 2010;2:190–208.

15. Common classification

16. Biomarkers may be prognostic or predictive.
● More recently, patterns of gene expression
and changes to DNA :potential use as tumor
markers.
● These types of markers are measured
specifically in tumor tissues.
● Most of the traditionally used markers are
probably not involved in tumorigenesis, but are
likely to be by-products of malignant
transformation.

17. Some Tumor Markers
Class Examples
Enzymes, isoenzymes PSA, PAP,LDH, ALP, CK and NSE
Hormones hCG, calcitonin, ACTH, gastrin, and VIP
Proteins/peptides β2-Microglobulin, NMP22, GFAP, S-100, Ferritin,thyroglobulin
Oncofetal antigens AFP and CEA
Carbohydrates CA 125, CA 15-3, and CA 27.29
Blood group antigens CA 19-9 and CA 72-4
Receptors ER, PR, EGFR
Oncogene Ras, myc, BCR-ABL
Tumor Suppressor Genes P53, Rb, BRCA1, BRCA2, and HER-2/neu
Tumor
associated Ag

18. RNA BASED MARKERS:
circulating and tissue
derived
DNA BASED MARKERS:
Gene mutation,
circulating tumor,
epigenetic changes

19. Methods for detection: analysis
● ENZYME ASSAY
● IMMUNOASSAY
● IHC
● RECEPTOR ASSAY
● Flow cytometry
● MASS SPECTROMETRY
INTERFACED WITH LIQUID OR
GAS CHROMATOGRAPHS
● MICROARRAYS
● Molecular methods: PCR, In
situ hybridization, cDNA
microarrays, fluorescent in
situ hybridization
On cell:
Immunocytochemistry,
Flow cytometry
On tissue :
Immunohistochemistry
In body fluids; Blood,
urine, CSF, Amniotic
fluid:
RIA, EIA
Tumor marker Detection/analysis

20. α-Fetoprotein (AFP)
● An oncofetal antigen,with single-chain
polypeptide
● Glycoprotein (mass : 700 kDa )
● Produced in early fetal life by the yolk sac/liver
● Elevated in HCC, hepatoblastoma, and NSGCT of
the ovary and testis
● Maternal AFP :detection of neural tube defects.

21. AFP
● AFP is measured with immunoassay kits.
● Half-life：4~6 days
● healthy, non pregnant adult <10 ng/mL
Age Level
12~15th wk POG 30~40 ng/ml
At birth 30 ng/ml
>1 year (adult) <10 ng
Levels fall to low levels after birth to
normal adult value by 18 months

22. Clinical significance
● Used for diagnosis, staging,
prognosis, & treatment
monitoring of primary HCC and
germ cell tumors
● Used for classification tumor
staging & monitoring therapy for
nonseminatous testicular cancer .
Benign Malignant
Benign liver disease (eg,
viral hepatitis, cirrhosis),
HCC (70%)
GI tract tumors Nonseminomatous
testicular tumors (50-
70%)
Liver disease and no
underlying HCC
Intrahepatic
cholangiocarcinoma
Some colorectal
cancer metastases,

23. AFP Levels
● Benign liver disease can have 200 ng/mL
● But >1000 ng/mL suggest the presence of cancer
● A significant rise in serum AFP in a patient with cirrhosis should raise concerns that
HCC may have developed.
● The AFP cutoff of 20 ng/mL has a sensitivity of 60% and a specificity of 90%.

24. Gonzalez, S. A., & Keeffe, E. B. (2011). Diagnosis of HCC: Role of Tumor Markers and Liver Biopsy. Clinics in Liver Disease

25. AFP types
● Three isoforms: AFP-L1, AFPL2, and AFP-L3.
● AFP-L3 reactivity – a/w liver cancer
● AFP-L3%, AFP-L3 as a percentage of AFP: cutoff of 10% (FUJIFILM Wako
Diagnostics).
● Indicated: in patients with CLD to assess the risk of developing HCC and
● is prognostic HCC carcinoma

26. AFP in HCC
● Serum levels > 500 μg/L (upper limit in a high-risk patient) is diagnostic of
HCC.
● However, HCC is often diagnosed at a lower AFP level in patients undergoing
screening.
● Can be normal in up to 40 % with small HCCs/ majority of fibrolamellar
variant of HCC.
● Serum levels do not correlate well with size, stage, or prognosis of HCC.

27. AFP association with Liver transplant
● Despite the issues inherent in using AFP for the diagnosis of HCC, it has
emerged as an important prognostic marker, especially in patients
being considered for liver transplantation.
● Patients with AFP levels 1,000 μg/L have an extremely high risk of
recurrent disease following the transplant, irrespective of the tumor
size.

28. AFP: Screening
● poor screening tool (sensitivity 31%)
● For screening purposes in high-risk populations, AFP is used in addition to
ultrasound imaging.
● A cutoff of 100 ng/mL is typically used
● In a recent metaanalysis of HCC screening for cirrhotic patients: ultrasound
and AFP had a sensitivity of 97% picking up HCC (78% ultrasound alone),
although sensitivity for early stage disease for combined ultrasound for AFP
screening is predictably lower (sensitivity 63%).
Tzartzeva K et al, Surveillance Imaging and Alpha Fetoprotein for Early Detection of HCC in Patients With Cirrhosis: A Meta-analysis.
Gastroenterology. 2018 May.

29. AFP: Prognosis
● AFP correlates with stage and prognosis.
1. AFP concentration reflects tumor size, with levels above 400 ng/mL
associated with larger tumors (HCC)
2. AFP doubling time, associated with poorer prognosis.
.

30. AFP: Monitoring
● Declines after resection or ablation or effective chemotherapy
● Failure to return to normal by 1 month: residual tumor
● Elevation of AFP after remission suggests tumor recurrence
● Monitoring of AFP therefore avoids prolonged use of ineffective chemotherapy.
● AFP is part of the standard surveillance regimen for HCC patients on the transplant
list.
Effect of pre- and post-treatment α-fetoprotein levels and tumor size on survival of patients with hepatocellular carcinoma treated by
resection, transarterial chemoembolization or radiofrequency ablation: a retrospective study Adriana Toro et al. 2016 BMC surgery

31. Recommendation
● The American Association for the Study of
Liver Diseases recommends surveillance
(targeted repeated screening in at risk patients)
every 6 months for individuals with cirrhosis using
liver ultrasound with or without AFP
measurements
● Overall survival is improved with the combined
modality.

32. Des-γ-carboxy prothrombin (DCP)
● DCP is an abnormal form of the coagulation factor prothrombin.
● In the liver, in the cases of dietary deficiency, vitamin K absence or antagonism, warfarin, DCP is produced.
● In HCC, gene expression of the enzyme is defective, resulting in DCP.
● DCP is most commonly used clinically in countries with a high prevalence of HCC, such as Japan, for early
detection, monitoring, and recurrence.
● DCP, and AFP and AFP-L3% are independent markers,
● DCP correlates with tumor size, although it is less sensitive for detecting small tumors.
● In a case control study of patients with HCC carcinoma or cirrhosis, clinical sensitivity for cancer detection in early stage disease increased
to 78% compared with 53% for AFP alone and 61% for DCP alone.
● In a multicenter prospective study in 441 subjects with liver disease, the relative risk of developing HCC carcinoma was 4.8 with a DCP cutoff
of 7.5 μg/L.
Sokoll, L. J. Tumor markers. Contemporary Practice in Clinical Chemistry, (2020).

33. CARCINOEMBRYONIC ANTIGEN (CEA)
● An oncofetal protein (1965)
● Low concentrations in healthy adults.
● cell surface anchored glycoprotein (mass 200 kDa)
● component of the glycocalyx, located on the luminal side of the cell membrane of normal
epithelial intestinal cells.,
● CEA functions as an cell-cell adhesion molecule and may be involved in tumor invasion and
metastasis
● Is able to inhibit apoptosis induced by loss of anchorage to the ECM.

34. CEA
● CEA is a glycosylphosphatidylinositol cell surface anchored glycoprotein:as functional colon
carcinoma L-selectin and E-selectin ligands, which may be critical to the metastatic dissemination
of colon carcinoma cells
● Secreted into the circulation and is also found in the mucous secretions of the stomach, small
intestine, and biliary tree.
● Metabolized in the liver, hence liver damage impairs CEA clearance •
● CEA has a specificity for colorectal cancer of 90%, but a sensitivity of only 40% to 75%.

35. CEA: Serum Level
Levels:
Borderline levels : benign disorders
such as IBD, pancreatitis, cirrhosis, COPD
<2.5 ng/ml Normal
2.5-5 borderline
>5 ng/ml Elevated
In smokers: <5ug/ml upper limit
WHY INCREASE??
Benign Malignant
• cirrhosis,
• emphysema
• rectal polyps
• ulcerative colitis
• benign breast
disease
• DM
• Pancreatitis
• CRF, HD
• Diverticulitis
• IBS
• Pneumonia
• Hypothyroidism
• any acute or chronic
inflammatory state.
primary cancers
• CRC (60-80%)
• breast,
• pancreatic,
• liver,
• lung,
• gastric,
• Ovarian/uterine
• Metastatic liver
disease
False positive CEA : due to the presence of heterophilic antibodies in the specimen

36. CEA: Screening /Diagnosis
● Lacks both sensitivity and specificity
● Most types of cancer do not produce a high level of CEA
● Elevated CEA levels : only 5%-40% of patients with localized disease
● It is not reliable for diagnosing cancer or as a screening test for early
detection of cancer.

37. CEA: PROGNOSIS
● In CRC, Elevated CEA levels reflect the burden of tumor and correlate with
the stage of disease.
● CEA levels 5.0 ng/mL or greater are associated with an adverse impact on
survival that is independent of tumor stage
● With increased values : risk of recurrence and development of
metastatic disease.

38. Preoperative CEA values :prognostic significance
● Preoperative CEA before potentially curative resections :
1. If do not normalize following surgical resection, by 6 weeks or within 6 weeks of
starting treatment.
persistent/residual disease /Treatment failure
2. Has prognostic significance.
Independent predictor of survival (higher preoperative level
poorer survival/prognosis)

39. CEA: Monitoring
● CEA levels : recommended at baseline and at 2-3 months for 3 years following surgery and
then every 6 months until 5 years
A CEA level > 5 ng/mL in any patient who has undergone treatment for colorectal
adenocarcinoma should be considered tumor recurrence unless proven otherwise.
● CUT OFF for recurrence - 5-ng/mL sensitivity of 71% and specificity of 88%
- 10 ng/mL sensitivity for of 68% and specificity of 97%.
● A recent Cochrane review therefore recommends using a 10-mg/mL cutoff during
monitoring

40. CEA concentration for monitoring disease course in CRC ff

41. CEA: In Metastatic CRC
● Also monitoring response to chemotherapy in patients with metastatic
colorectal cancer.
● An elevated CEA level is an independent factor associated with poor
survival and progression on 5-fluorouracil–based chemotherapy in patients
with metastatic colorectal cancer.
● In advanced cancer whose CEA levels fall during chemotherapy survive
significantly longer than those whose do not change or increase.

42. CEA: serial measurement
● Serial measurement of CEA can detect disease recurrence even among patients with an
initially normal CEA level, although the sensitivity is lower (between 27 and 50%).
● Thus, a postoperative CEA elevation indicates recurrence with high probability, but a normal
postoperative CEA level (even if it was initially elevated) is not useful for excluding a disease
recurrence.
● 30-40% of all cases of CRC recurrences are not associated with measurable elevations in
serum CEA.
● The benefit of CEA monitoring is limited to a small number of patients with recurrent CRC and
is not cost-effective.

43. CEA: SERIAL TESTING
● Frequency of Testing
● The optimal timing is unclear.
● Although one study suggests better disease-free survival
in patients who have a CEA level checked every 1 or 2
months compared to less frequent intervals, these results
have not been confirmed by others, and no study has
shown a survival benefit for any CEA testing frequency.
● Adjuvant therapy with a 5-fluorouracil-based regimen
may falsely elevate the serum CEA level, possibly
because of treatment-related changes in liver function.
● Thus, waiting until adjuvant treatment is completed to
initiate CEA surveillance is advisable
ASCO guidelines suggest
Postop CEA testing every 3 months for at
least 3 years after initial therapy in patients
with stage II or III disease, if the patient is a
potential candidate for surgery or systemic
therapy
NCCN guideline :
Postop CEA testing every 3–6 months for 2
years and then every 6 months for a total of
5 years . These guidelines suggest that
serial testing be limited to patients who
have T2 or higher stage and who would be
considered potential candidates for
resection of isolated metastases.

44. CEA and CA19.9
● CEA is not increased in 15%-40% of patients with colorectal cancer
● CA 19-9 is also increased in approximately 35% to 40% of patients with advanced colorectal
cancer.
● In contrast to CEA, CA 19-9 is significantly decreased in patients who smoke.
● There is no significant transient increase of CA 19-9 in patients with colorectal cancer using
chemotherapy and patients with high preoperative levels of CA 19-9 might have a poorer
survival.
● A drawback of using CA 19-9 is that patients with poorly controlled diabetes mellitus, even
without any malignancy, have a significant greater level of CA 19-9 than healthy people.
● Therefore, an increase of CA 19-9 in patients with colorectal cancer and diabetes might not be
an indication of advanced disease activity
: CA 19-9 As a Marker in Addition to CEA to Monitor Colorectal Cancer Jolanda Stiksma et al 2014

45. CA 19-9 As a Marker in Addition to CEA to Monitor Colorectal
Cancerl
JolandaStiksma
https://doi.org/10.1016/j.clcc.2014.09.004
● Evaluation of response to chemotherapy, according to the RECIST criteria,
should be based on structural imaging such as CT /MRI
● CEA is most sensitive for hepatic and retroperitoneal metastases, but least
sensitive for local recurrence and peritoneal or pulmonary disease.
● Current guidelines recommend surveillance for CRC using a combination of
periodic clinical visits, CEA levels, CT, and colonoscopy.
● Conventional imaging techniques including CT and MRI are classically used for
routine surveillance and decision-making in CRC, but emerging techniques such
as PET may be additionally employed.

46. Carbohydrate Antigen 19-9 ( CA 19.9)
● CA 19-9 is a mono-sialoganglioside, exists as a glycolipid attached to a
sialylated Lewis A blood group antigen.
● In serum, CA 19-9 occurs as a circulating carbohydrate-rich glycoprotein
associated primarily with mucin
● CA 19-9 is considered to be a tumor-associated, rather than tumor-
specific antigen

47. CA 19.9
● First identified by Koprowski and coworkers in 1979
● Detected by monoclonal antibodies raised against colon cancer cell lines
in a mouse spleen model.
● Half-life of approximately 14 h.
● The CA 19-9 epitope is normally present within the biliary tree.
● Produced by pancreatic and biliary ductal cells,
● Secreted by gastric, colonic, endometrial, and salivary epithelia.
In pancreatic cancer, CA19-9 serves as a predictive biomarker

48. CA19.9
● Biliary tract disease, both acute and chronic, can elevate serum CA 19-9
levels.
● It is a mucin, does not increase during pregnancy
● Serum level: < 37 U/mL (immunoassay)

49. Lacks sensitivity/specificity
1. Non secretors: negative Lewis a blood
group antigen (10% of population)
cannot synthesize CA 19-9. CA-19-9 is
not expressed even in those with large
tumors.
2. Elevated in benign biliary tract disease
3. Elevated in other cancers.
● DUPAN2, MIC1 done is such cases
Ca 19.9 elevation
Ca Pancreas 71-93%
Ca colon 20-40%
Ca Stomach 21-42%
HCC 7-9%
Ca Lung 13-15%
sensitivity 90%
specificity 70%

50. CA19.9 : False positive
CA19-9 is present in fetal tissues
and normal gastrointestinal
epithelial cells .
CA19-9 is not tumor type-specific :
malignancies, originating from the
colorectum, gastric system, lung,
breast, and liver , pancreatic NET.
Benign conditions of CA 19.9 elevation
Bile duct
obstruction and
inflammation
Colon
diverticulitis
Interstitial
Pulmonary
disease
Gastric ulcer Pancreatitis
(acute/chronic)
Pulmonary
fibrosis
Collagen vascular
disease
Black tea/
heavy tea
consumption
Uncontrolled
DM
Hypothyroidism Endometriosis
Roles of CA19-9 in pancreatic cancer: Biomarker, predictor and promoter GuopeiLuo

51. CA 19.9: Cut-off value
● in diagnosing PDAC in symptomatic patients.
● If higher cutoffs are used, the specificity rises so that, at levels greater
than 1000 U/ml, the marker's specificity approaches 100%.
Tessler DA, et al. Predictors of cancer in patients with suspected pancreatic malignancy without a tissue
diagnosis. Am J Surg 2006;191(2):191e7.
Sensitivity : 79-80%
Specificity : 82-90%
Tessler et al.2006 demonstrated : CA 19-9 cutoff > than 37 U/mL had a specificity of
nearly 100% for detecting pancreatic cancer in patients with a pancreatic mass,
significant weight loss >20 pounds, and bilirubin level 3 mg/dL.
FN: Lewis Ag neg
FP: obstructive jaundice( 10-60%)
Other conditions

52. DU-PAN-2/ S-PAN-1
● Duke Pancreatic Monoclonal Antigen Type 2 ,is the precursor of CA19-9.
DU-PAN-2 CA19-9
● Thus, DU-PAN-2 may have the potential to compensate for the diagnostic
limitation of CA19-9 in Lewis-negative patients
Singh S et al. The clinical utility and limitations of serum carbohydrate antigen (CA 19-9) as a diagnostic tool for pancreatic cancer and cholangiocarcinoma. Dig Dis Sci 2011
Mediated by Lewis Ag
CA 50: CA 19-9 and CA 50 complement each other in pancreatic and other carcinomas, used
simultaneously, improves sensitivity.
DUPAN <150 U/ml
Sn Sp
SPAN 1 81-92 % 76-85%
DUPAN 2 48 to 72% 85 to 94%,

53. CA 19.9 : RESECTABILITY
● For determining resectability of locally advanced or metastatic disease
● Important: CA 19-9 is best used in conjunction with clinical evaluation and
imaging when determining resectability.
Schliemann MG, Ho HS, Bold RJ. Utility of tumor markers in determining resectability of pancreatic
cancer. Arch Surg 2003
Preop level
>150 U/ml PPV 88%
<150 U/ml NPV 64%

54. CA 19.9 : Malignant vs Benign condition
● Kim and colleagues devised a simple algorithm
Kim HJ et al. A new strategy for the application of CA 19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver
operating characteristic curve. Am J Gastroenterol 1999.
 Suspected biliary tract Ca:
2 groups
Cholangitis/Cholestasis
Present Not present
Cut off : 37 U/ml
recommended
assessed once acute process has resolved
alternative cutoff value of 300 U/mL may be
applied.

55. CA19.9 : Biliary drainage
● If CA 19-9 levels rapidly decrease following biliary drainage
 indicate a benign biliary condition rather than a malignant process
● Variations in CA 19-9 levels have been observed to occur anywhere from
48 h to several weeks.
● After stone extraction, CA 19-9 levels started to decrease and reached
normal values 1-28 days later.
Mann DV, Edwards R, Ho S, Lau WY, Glazer G. Elevated tumour marker CA 19- 9: clinical interpretation
and influence of obstructive jaundice. Eur J Surg Oncol 2000
Dogan ÜB, Gümürdülü Y, G olge N, Kara B. Relationship of CA 19-9 with choledocholithiasis and cholangitis.
Turk J Gastroenterol 2011

56. CA19.9 : UDCA Use
● Unknown mechanism, it is postulated that biliary sludge causes transient
increases in pressure within the bile ducts and consequently, temporary
production and elevation of CA 19-9 by cholangiocytes.
● UDCA decreases the pressure within the biliary ductal system, results
decreased CA 19-9 levels.
In a single study by Cheong et al. on patients GB sludge and elevated CA 19-9,
 6/11 (54.5%) of patients displayed normalization of CA 19-9 levels after receiving UDCA treatment
compared to 1/4 (25%) of patients who did not receive treatment with UDCA.
 Median duration of UDCA therapy needed for normalization of CA 19-9 levels was 4.5 months.
Cheong JH et al. Endoscopic ultrasonography in patients with elevated carbohydrate antigen 19-9 of obscure origin. World J Gastrointest Endosc
2013;5(5):251e4.

57. CA19.9 : Screening
● Asymptomatic cases: PPV for pancreatic cancer : 0.9%. (very low)
Not useful as a screening tool.
● In symptomatic patients, increasing levels of CA 19-9 make the diagnosis of
pancreatic cancer more accurate. (cutoff level of 100 U/mL , the specificity
98%.)

58. CA 19.9 : Prognosis
● Correlates with tumor burden.
higher CA 19-9 levels higher tumor stage.
● After curative resection, those whose CA 19-9 levels returned to normal
survive longer than those whose levels do not.
1. Pre-operative < 37 U/mL) have a prolonged median survival (32-36 months) compared to
(>37 U/mL) (12-15 months).
2. A CA 19-9 serum level of <100 U/mL implies likely resectable disease whereas levels
>100 U/mL suggest unresectablity or metastatic disease
Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of
pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol. 2012.

59. CA 19.9 : MONITORING
● Serial measurement monitor response to therapy.
● After curative resection, a rise in CA 19-9 level has been shown to precede
clinical or imaging evidence of recurrence.
● In patients with unresectable or metastatic disease, failure of CA 19-9
levels to fall with chemotherapy reflects poor tumor response.
● However, in both settings, the lack of alternative effective therapies limits
the utility of serial monitoring of CA 19-9

60. CA 19.9 : PROGNOSIS
● The degree of elevation of CA-19-9 (both at initial presentation and in the
postoperative setting) is associated with long-term prognosis.
● Furthermore, in patients who appear to have potentially resectable
disease, the magnitude of the CA-19-9 level can also be useful in predicting
the presence of radiographically occult metastatic disease

61. ● CA 19-9 may serve as a prognostic marker in the perioperative
evaluation of patients with pancreatic cancer.
● Specifically, high postoperative CA 19-9 levels have been associated
with poor survival.
● Serial CA 19-9 levels may be combined with imaging in evaluating
efficacy in patients undergoing treatment of advanced pancreatic cancer.
Multicenter, 2010 march

62. CA 19.9 : predictor
Predictor
1） Evaluating the efficacy of neoadjuvant therapy
2） Assessing resectability
3） Postoperative CA19-9 for evaluating prognosis
4） Predicting response to adjuvant chemotherapy
5） Evaluating the efficacy of systemic chemotherapy
6） Normal baseline CA19-9 for evaluating long-term survival
Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter Guopei Luo et al , April 2021 , Reviews on
Cancer

63. Colorectal Cancer: Survelliance (CEA/CA19.9)
● National Academy of Clinical Biochemistry (NACB) recommends : 50 years or
older should undergo screening for colorectal cancer.
● Multiple screening procedures exist : Fecal occult blood test (FOBT) is the most
widely used CB in stool
● CEA estimation is recommended at the beginning of therapy then every 1–3
months all through the therapeutic regimen, it is also the marker of choice for
metastatic cases of CRC.
● CA19-9 has been used as prognostic marker, in surveillance of CRC after
surgical resection and as monitoring marker for therapeutic intervention in
advanced cases.
Cancer Biomarkers, By Hala Fawzy Mohamed Kamel et al, 2016

64. CA Gallbladder
● CA 19-9, CEA and CA 125 can predict resectability in GBC and
● Raised levels of CA 19-9 and CA 125 can predict poor prognosis in patients
with elevated levels.
Role of CA 19-9, CEA, and CA 125 as the predictors of resectability and survival in the patients of Carcinoma Gall Bladder
Saumya,et al Jour of Carcinogenesis, 2020
AIIMS , India
71 pts
January 2018 and Sep 2019
both serum CA 19-9 and serum CA 125 may act
as a good adjunct for diagnosis of cases of
carcinoma gallbladder along with imaging studies

65. Ca GB
● Raised CA19.9 and CEA predict metastatic disease in patients with GBC
without jaundice with a high specificity (prognostic)
● CA19-9 was better than CEA in prediction of tumor burden & recurrence.

66. Ca GB
 539 patients with Ca GB
 Seoul National University Hospital, Korea
 The relationship between tumor marker levels and overall survival (OS) was analyzed
● CA 19-9 had a stronger association with prognosis than CEA,
● 65 IU/mL for CA 19-9 may be suggestive in evaluating the prognosis of
GBC

67. Carbohydrate antigen 125 (CA 125/ MUC16)
● is a carbohydrate epitope on a glycoprotein carcinoma antigen.
● It is present in the fetus and in derivatives of the coelomic epithelium,
including peritoneum, pleura, pericardium, and amnion.
● In healthy adults, CA 125 has been detected by IHC in the epithelium of the
fallopian tubes, endometrium, and endocervix.
● However, ovarian epithelium does not normally express any CA 125.

68. LDH
● LDH catalyzes lactate to pyruvate
● LDH3 is involved in tumor initiation and metabolism.
● LDH 100~250 IU/L
● high-grade lymphomas: blood levels correlate closely
with disease activity and response to therapy
● LDH is a marker of metastases especially in liver and
is independent prognostic factor ,increased LDH had
reduced survival (metastatic melanoma)
● Expression of LDH 5 and VEGF in tumors and the
stroma has been found to be a strong prognostic
factor for diffuse or mixed-type gastric cancers.
● Measuring LDH levels can be helpful
in monitoring treatment for cancer.
● Noncancerous conditions that can
raise LDH levels include
● heart failure,
● hypothyroidism,
● anemia,
● pre-eclampsia,
● meningitis,
● encephalitis,
● acute pancreatitis,
● HIV and
● lung or liver disease

69. ALKALINE PHOSPHATASE NEURON SPECIFIC ENOLASE(NES)
● source: Liver ,bone, placenta
1. Primary or secondary liver cancer
2. Metastatic cancer with bone or liver
3. Bronchogenic Ca (SCC)
● PALP–trophoblast-sera of pregnant women
● PALP- ovarian, lung,trophoblastic GI
cancers, seminoma, Hodgkins disease
Found in tumors originating from the neuroendocrine
cell system.
Neuronal tissue, neuroendocrine tissue , APUD tissue
● SCLC,
● Neuroblastoma,
● pheochromocytoma
● Carcinoid,
● medullary carcinoma of thyroid
High levels- poor prognosis

70. Chromogranin
● Chromogranin A,B
Secretogranin 2,3,4&5
● Found in neuroendocrine cells
● Its wide distribution & co-secretion make
it an excellent histochemical &plasma
marker of NET
● eg: carcinoid tumors neuroblastoma,
pheochromocytoma
● IMMUNO ASSAY
Carcinoid tumours can be monitored
by
● urine levels of
5-hydroxyindoleacetic acid (5HIAA),
● and polypeptides such as gastrin or
glucagon are useful in the
management of rare
gastrointestinal tumours.

71. GENETIC MARKERS
1. Oncogenes- Activation of proto
oncogenes-
2. Suppressor genes- Loss of gene-
deletion or monosomy
3. IMMUNOHISTOCHEMISTRY
Oncogenes Tumor suppressor genes
Ras Leukemia,
lymphoma
Rb gene RB
C-myc Leukemia,
lymphoma,
SCLC
P53 Colorectal,
breast, lung
Her-2/neu Breat,
Ovarian , GI
APC Colon
RET Papillary
thyroid Ca
BRCA1,2 Breast ,
Ovarian
BCR ABL CML DCC Colon

72. P53
● tumor suppressor gene
● negative regulator of cell growth
● most frequently mutated genes in human cancers
● p53 mutations occur in 0 to 77% of stomach
cancers
● enhances the self-renewal ability of gastric epithelial
cells and results in an increase in undifferentiated cells in
the gastric epithelia
● Can be measured in either tissue, fibroblast, white
cell, or serum.
Busuttil RA.et al; Role of p53 in the progression of gastric cancer. Oncotarget. 2014 Dec

73. Genomics Proteomics
1. The study of patterns of DNA changes (or
mutations) is called genomics.
2. Study of entire set of genes in a genome
3. By looking for DNA changes in blood,
stool, or urine, scientists may be able to
find cancers very early.
4. Looking at the patterns of changes is
likely to prove more useful than looking
for single DNA changes.
1. This technology looks at the patterns of
all the proteins in the blood instead of
looking at individual protein levels.
2. study of all the proteins expressed by
the genome.
3. Allows to look at thousands of proteins
at one time
4. This information could then be used to
develop a blood test that might look only
at these important proteins. Then, blood
or a tissue sample could be checked for
the protein pattern as a way to find
cancer.

74. When ordering a tumor marker
Never rely on the result of a single test
Multiple markers to improve the sensitivity and specificity for diagnosis
Order the nonspecific markers for cost-saving and for their high sensitivity.
Consider the half-life of the tumor marker when interpreting the test result
Consider how the tumor marker is removed or metabolized from the blood circulation
When ordering serial testing, order every test from the same laboratory using the same assay kit
– BASELINE tumor marker preoperatively is important for follow-up.
Sharma S. Tumor markers in clinical practice: General principles and guidelines. Indian J Med Paediatr Oncol. 2009

75. Hook effect
● The Prozone effect (antigen excess )
● Observed when a very high amount of an analyte(Ag)
is present in the sample but the observed value is
falsely lowered.
● More commonly in sandwich assays.
● The mechanism of this significant negative interference is the capability of a high level of
an analyte (antigen) to reduce the concentrations of “sandwich” (antibody 1: antigen :
antibody 2) complexes that are responsible for generating the signal by forming mostly
single antibody:antigen complexes.
● β-hCG, prolactin, calcitonin, aldosterone, cancer markers (CA 125, PSA), etc.

76. Take home message
● Good history
● Physical examination.
● Use confirmatory investigations:
Histopathology, ultrasonography,
CECT.
● Considering half life while
interpreting the result
● Do serial testing
● Use a battery of markers(>1
marker/tumor)
● Panel testing is better than testing
a single marker
Tumor marker Organ Use
Carcinoembryonic
antigen (CEA)
Colorectal/hepatic Monitoring therapy
Prognosis
Detecting
recurrence
Screening for
hepatic metastases
CA 19-9 Pancreatic Monitoring therapy
Alfa-fetoprotein HCC Diagnosis
Detecting
recurrence
Monitoring therapy
No ideal tumor marker is known so far

77. Test combinations that will give more exact results
Pancreas/Stomach CEA, CA 19-9, CA 72-4 :
Liver: CEA, AFP
Oesophagus: CEA, Cyfra 21-1
Colorectal: M2-PK; CEA, CA 19-9, CA 125
Testicle: AFP, BHCG
Lung: CEA, CA 19-9, CA 125, NSE, Cyfra 21-1

79. THANK YOU
For Your Patience