Gastrointestinal Tumour Markers

Gastrointestinal Gastrointestinal tumor markerstumor markers

Nagarjun RaoNagarjun RaoMD, FRCPath, Diplomate of American Board of MD, FRCPath, Diplomate of American Board of PathologyPathology

Ratnadeep GangulyRatnadeep Ganguly MD MD

Apollo Gleneagles HospitalsApollo Gleneagles HospitalsKolkataKolkata

IntroductionIntroduction

Tumor markers - Measurable molecules that Tumor markers - Measurable molecules that are associated with a malignancy. are associated with a malignancy.

Tumor-derived - produced by tumor cells ORTumor-derived - produced by tumor cells OR Tumor-associated – produced by the body in Tumor-associated – produced by the body in

response to tumor. response to tumor. May be in circulation or tissue bound.May be in circulation or tissue bound. Although there are a multitude of tumor Although there are a multitude of tumor

markers, very few of them have found their markers, very few of them have found their way into clinical practice because of their way into clinical practice because of their lack of specificity. However, some of these lack of specificity. However, some of these non-specific markers have found a place in non-specific markers have found a place in monitoring cancer treatment rather than in monitoring cancer treatment rather than in diagnosis.diagnosis.

Introduction (contd.)Introduction (contd.)

Clinical uses –Clinical uses –– DiagnosisDiagnosis– StagingStaging– To indicate prognosisTo indicate prognosis– To monitor treatment To monitor treatment – In follow-up to monitor for cancer In follow-up to monitor for cancer

recurrence.recurrence.

DiagnosisDiagnosis

Some tumor markers are associated with Some tumor markers are associated with many types of cancer; others, with as few as many types of cancer; others, with as few as one – Not specificone – Not specific

Some tumor markers are always elevated in Some tumor markers are always elevated in specific cancers; most are less predictable.specific cancers; most are less predictable.

Most are found in low levels in healthy Most are found in low levels in healthy persons,persons,

Can be associated with non-neoplastic Can be associated with non-neoplastic diseases as well. diseases as well.

No tumor marker test is free of false No tumor marker test is free of false negatives or false positives.negatives or false positives.

Staging and prognosisStaging and prognosis

Quantitative assays can be useful Quantitative assays can be useful for staging - higher levels can for staging - higher levels can indicate more advanced cancer indicate more advanced cancer and a worse prognosis in some and a worse prognosis in some cases. cases.

This info can be used in choosing This info can be used in choosing treatment modalitiestreatment modalities

Treatment monitoringTreatment monitoring

The most common use of tumor markers.The most common use of tumor markers. Levels drop with response to Rx. Levels drop with response to Rx. Stable or increasing levels often indicate Stable or increasing levels often indicate

lack of response. lack of response. The choice of tumor marker to use for The choice of tumor marker to use for

monitoring is important.monitoring is important.– Use only a marker elevated before treatment.Use only a marker elevated before treatment.– Timing of the tests – Enough time must be Timing of the tests – Enough time must be

given for initial marker to be completely given for initial marker to be completely cleared from the blood. False elevations may cleared from the blood. False elevations may be seen with tests done too soon.be seen with tests done too soon.

RecurrenceRecurrence

Periodic testing can detect a Periodic testing can detect a recurrence earlier than an recurrence earlier than an ultrasound, x ray, or physical ultrasound, x ray, or physical examination.examination.

MethodologyMethodology

Immunoassay – Immunoassay – – Antigen (tumor Antigen (tumor

marker) + Antibody marker) + Antibody → → If that tumor marker If that tumor marker is present, these very is present, these very specific antibodies specific antibodies bind to the markers. bind to the markers.

– Some type of label, Some type of label, often a radioactive often a radioactive substance, is then substance, is then used to measure the used to measure the amount of bound amount of bound marker and antibody marker and antibody →→ The quantity of The quantity of tumor marker is tumor marker is calculated. calculated.

Colorectal cancerColorectal cancer

Diagnosis and screeningDiagnosis and screening CEA – A glycoprotein which is the most useful CEA – A glycoprotein which is the most useful

and widely investigated marker for colorectal and widely investigated marker for colorectal cancer.cancer.

Both the proportion of patients with elevated Both the proportion of patients with elevated levels and the extent of elevation are levels and the extent of elevation are primarily dependent on disease stage. primarily dependent on disease stage.

>2.5 ng/ml - 28% Duke’s A>2.5 ng/ml - 28% Duke’s A 45% Duke’s B45% Duke’s B 75% Duke’s C75% Duke’s C 84% Duke’s D 84% Duke’s D


> 5 ng/ml – Proportion of patients with increased levels – > 5 ng/ml – Proportion of patients with increased levels – 3% Duke’s A 3% Duke’s A

25% Duke’s B25% Duke’s B 45% Duke’s C45% Duke’s C 65% Duke’s D65% Duke’s D Lack of sensitivity for early disease - CEA is of little value in Lack of sensitivity for early disease - CEA is of little value in

the detection of Dukes’ A or B colorectal cancer. the detection of Dukes’ A or B colorectal cancer. Lack of specificity - Only approximately 90% using a cut-off Lack of specificity - Only approximately 90% using a cut-off

point of 2.5 ng/ml . Benign diseases and other advanced point of 2.5 ng/ml . Benign diseases and other advanced types of adenocarcinoma can cause types of adenocarcinoma can cause ↑ CEA.↑ CEA.

CEA cannot be used as a screening test in asymptomatic CEA cannot be used as a screening test in asymptomatic populationspopulations

Cannot be used as a diagnostic markerCannot be used as a diagnostic marker In a patient with symptoms with a grossly elevated value - In a patient with symptoms with a grossly elevated value -

Highly suggestive of colorectal ca. Highly suggestive of colorectal ca.


PrognosisPrognosis High levels correspond with more High levels correspond with more

advanced stagesadvanced stages Duke’s B – High levels of CEA may help Duke’s B – High levels of CEA may help

identifying a sub-group who have a identifying a sub-group who have a higher risk of aggressive disease who higher risk of aggressive disease who may require adjuvant treatmentmay require adjuvant treatment

Preliminary data suggest that both Preliminary data suggest that both serum and tissue levels of CA 19-9 serum and tissue levels of CA 19-9 may also be prognostic in colorectal may also be prognostic in colorectal cancer.cancer.


MonitoringMonitoring Marker of choice for monitoring patients with Marker of choice for monitoring patients with

colorectal cancer – since 1980scolorectal cancer – since 1980s Early studies showed that serial CEA levels could Early studies showed that serial CEA levels could

detect recurrent disease many months (usually 4-10 detect recurrent disease many months (usually 4-10 months) in advance of clinical evidence of disease months) in advance of clinical evidence of disease

Most sensitive for hepatic or retroperitoneal disease; Most sensitive for hepatic or retroperitoneal disease; Relatively insensitive for either local, peritoneal or Relatively insensitive for either local, peritoneal or pulmonary involvement.pulmonary involvement.

Some investigators - A slowly rising CEA usually Some investigators - A slowly rising CEA usually indicates a locoregional recurrence while rapidly indicates a locoregional recurrence while rapidly increasing levels usually suggest hepatic metastasis. increasing levels usually suggest hepatic metastasis.


Monitoring (contd.)Monitoring (contd.) Pietra N et al. Dis colon rectum, 1998Pietra N et al. Dis colon rectum, 1998 Single institution prospective randomized trial to Single institution prospective randomized trial to

appraise the value of CEA in detecting local appraise the value of CEA in detecting local recurrence.recurrence.

207 patients; 207 patients; ↑↑ CEA - most frequent indication of local CEA - most frequent indication of local recurrence in patients without clinical symptoms. recurrence in patients without clinical symptoms.

CEA measurement was more cost-effective than other CEA measurement was more cost-effective than other procedures including CT for the diagnosis of local procedures including CT for the diagnosis of local recurrence. recurrence.

Intensive follow-up with CEA might be more beneficial Intensive follow-up with CEA might be more beneficial for patients with rectal cancer than for those with for patients with rectal cancer than for those with colonic cancer, as local recurrence was more frequent colonic cancer, as local recurrence was more frequent after rectal cancer resection.after rectal cancer resection.

Optimal interval for serial CEA screening – 2-3 monthsOptimal interval for serial CEA screening – 2-3 months


Other markers –Other markers –– CA19-9, CA242 and cytokeratins CA19-9, CA242 and cytokeratins

((e.g., e.g., TPA and TPS) have also been TPA and TPS) have also been evaluated for this malignancy . May evaluated for this malignancy . May complement CEA; further work complement CEA; further work required to see which marker is required to see which marker is most complementary to CEA. most complementary to CEA.

Pancreatic cancerPancreatic cancer

DiagnosisDiagnosis CA 19-9 – Most widely usedCA 19-9 – Most widely used Mean specificity – 90%, sensitivity – 81%, using a cut-Mean specificity – 90%, sensitivity – 81%, using a cut-

off point of 37 IU/mloff point of 37 IU/ml May be raised in other conditions – other advanced May be raised in other conditions – other advanced

cancers, non-neoplastic conditions including cancers, non-neoplastic conditions including pancreatitis, cholangitis and hepatocellular jaundicepancreatitis, cholangitis and hepatocellular jaundice

In presence of jaundice – specificity becomes lesserIn presence of jaundice – specificity becomes lesser Of limited value in diagnosing pancreatic cancer, esp. Of limited value in diagnosing pancreatic cancer, esp.

early cases – can complement radiologic procedures, early cases – can complement radiologic procedures, especially in non-jaundiced pts.; only 55% of patients especially in non-jaundiced pts.; only 55% of patients with tumors <3 cm in size have with tumors <3 cm in size have ↑ CA 19-9.↑ CA 19-9.

Pancreatic cancerPancreatic cancer

Prognosis and monitoringPrognosis and monitoring CA 19-9 has the potential but is as yet CA 19-9 has the potential but is as yet

unproven for routine use for these purposesunproven for routine use for these purposes Other markers such as CA50, CA242, CA195, Other markers such as CA50, CA242, CA195,

DU-PAN 2, and CAM 17.1/WGA have also DU-PAN 2, and CAM 17.1/WGA have also been described for pancreatic cancer. been described for pancreatic cancer.

Investigated less widely than CA19-9 but Investigated less widely than CA19-9 but appear to provide similar data. appear to provide similar data.

CA19-9 therefore remains the "gold standard CA19-9 therefore remains the "gold standard marker" against which future markers for marker" against which future markers for pancreatic cancer will be evaluated.pancreatic cancer will be evaluated.

Gastric cancerGastric cancer

The most widely described markers for The most widely described markers for gastric cancer are CEA, CA19-9 and CA72-4.gastric cancer are CEA, CA19-9 and CA72-4.

Of these CA72-4 appears to be the most Of these CA72-4 appears to be the most sensitive and specific, followed by CA19-9 sensitive and specific, followed by CA19-9 and CEA.and CEA.

None of these markers is useful in either None of these markers is useful in either screening or diagnosing early gastric screening or diagnosing early gastric cancer. cancer.

Their role in the follow-up of patients with Their role in the follow-up of patients with diagnosed disease remains to be diagnosed disease remains to be evaluated. evaluated.

Esophageal cancerEsophageal cancer

Biochemical markers have been little Biochemical markers have been little investigated in esophageal cancer.investigated in esophageal cancer.

Preliminary data - best available Preliminary data - best available markers for the squamous cell ca. are markers for the squamous cell ca. are SCC and cytokeratins [SCC and cytokeratins [e.ge.g., CYFRA 21-1, ., CYFRA 21-1, TPA, TPS] ; CA19-9 - adenocarcinoma.TPA, TPS] ; CA19-9 - adenocarcinoma.

Presently, these markers are of little Presently, these markers are of little value in either the diagnosis or value in either the diagnosis or management of oesophageal cancer.management of oesophageal cancer.

Hepatocellular Hepatocellular carcinomacarcinoma ScreeningScreening αα-fetoprotein – marker of choice-fetoprotein – marker of choice Value of AFP in screening has not been Value of AFP in screening has not been

assessed in a prospective randomized assessed in a prospective randomized trial.trial.

For endemic areas with high prevalence. For endemic areas with high prevalence. NIH consensus conference (1986): NIH consensus conference (1986):

HBsAg +, with CAH or cirrhosis to be HBsAg +, with CAH or cirrhosis to be screened every 3 months and every 4-6 screened every 3 months and every 4-6 months on USG. months on USG.

Hepatocellular Hepatocellular carcinomacarcinoma DiagnosisDiagnosis Differential diagnosis between HCC Differential diagnosis between HCC

and hepatitis &/or cirrhosis and hepatitis &/or cirrhosis Measurement of fucosylated fraction of Measurement of fucosylated fraction of

AFP (AFP L3, P4 and P5) versus AFP (AFP L3, P4 and P5) versus “normal” AFP – more in HCC.“normal” AFP – more in HCC.

In benign conditions – AFP elevations In benign conditions – AFP elevations are transient, in malignancy concs. are transient, in malignancy concs. remain high or may increase – AFP remain high or may increase – AFP assays at 2-3 weeks’ interval may assays at 2-3 weeks’ interval may eliminate false-raised values eliminate false-raised values

ConclusionsConclusions

Screening:Screening:– Lack of sensitivity for early disease and Lack of sensitivity for early disease and

lack of specificity for malignancylack of specificity for malignancy– The above coupled with low prevalence The above coupled with low prevalence

of GIT cancers in general pop. prevent of GIT cancers in general pop. prevent the use of these markers in screening the use of these markers in screening asymptomatic general pops. Exception asymptomatic general pops. Exception : AFP screening in high risk areas. : AFP screening in high risk areas.


DiagnosisDiagnosis– Limited due to lack of sensitivity of Limited due to lack of sensitivity of

these markersthese markers Follow-up of patients with Follow-up of patients with

diagnosed cancersdiagnosed cancers– To detect asymptomatic recurrences To detect asymptomatic recurrences

that can be operated upon for curethat can be operated upon for cure– Cheaper than conventional Cheaper than conventional

radiological proceduresradiological procedures


Caveats while using CEA in Caveats while using CEA in surveillance of pts. with diagnosed surveillance of pts. with diagnosed colorectal cancer :colorectal cancer :– ↑ ↑ usually in advanced diseaseusually in advanced disease– Not all patients with recurrent disease Not all patients with recurrent disease

will have ↑ levelswill have ↑ levels– High levels may occur in other High levels may occur in other

conditionsconditions– Some cytotoxic therapies can cause Some cytotoxic therapies can cause

transient rise of levelstransient rise of levels


Esophageal and gastric cancer – Esophageal and gastric cancer – Markers contribute very little to Markers contribute very little to diagnosis or follow-updiagnosis or follow-up

Future approaches: Assays for Future approaches: Assays for mutated c-oncogenes and mutated c-oncogenes and suppressor genessuppressor genes

Gastrointestinal Tumour Markers

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