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Gastrointestinal Tumour Markers


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This is a presentation at Apollo Hospital Kolkata, where Dr nagarjun Rao was my mentor and guide

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Gastrointestinal Tumour Markers

  1. 1. Gastrointestinal tumor markers Nagarjun Rao MD, FRCPath, Diplomate of American Board of Pathology Ratnadeep Ganguly MD Apollo Gleneagles Hospitals Kolkata
  2. 2. Introduction <ul><li>Tumor markers - Measurable molecules that are associated with a malignancy. </li></ul><ul><li>Tumor-derived - produced by tumor cells OR </li></ul><ul><li>Tumor-associated – produced by the body in response to tumor. </li></ul><ul><li>May be in circulation or tissue bound. </li></ul><ul><li>Although there are a multitude of tumor markers, very few of them have found their way into clinical practice because of their lack of specificity. However, some of these non-specific markers have found a place in monitoring cancer treatment rather than in diagnosis. </li></ul>
  3. 3. Introduction (contd.) <ul><li>Clinical uses – </li></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Staging </li></ul></ul><ul><ul><li>To indicate prognosis </li></ul></ul><ul><ul><li>To monitor treatment </li></ul></ul><ul><ul><li>In follow-up to monitor for cancer recurrence. </li></ul></ul>
  4. 4. Diagnosis <ul><li>Some tumor markers are associated with many types of cancer; others, with as few as one – Not specific </li></ul><ul><li>Some tumor markers are always elevated in specific cancers; most are less predictable. </li></ul><ul><li>Most are found in low levels in healthy persons, </li></ul><ul><li>Can be associated with non-neoplastic diseases as well. </li></ul><ul><li>No tumor marker test is free of false negatives or false positives. </li></ul>
  5. 5. Staging and prognosis <ul><li>Quantitative assays can be useful for staging - higher levels can indicate more advanced cancer and a worse prognosis in some cases. </li></ul><ul><li>This info can be used in choosing treatment modalities </li></ul>
  6. 6. Treatment monitoring <ul><li>The most common use of tumor markers. </li></ul><ul><li>Levels drop with response to Rx. </li></ul><ul><li>Stable or increasing levels often indicate lack of response. </li></ul><ul><li>The choice of tumor marker to use for monitoring is important. </li></ul><ul><ul><li>Use only a marker elevated before treatment. </li></ul></ul><ul><ul><li>Timing of the tests – Enough time must be given for initial marker to be completely cleared from the blood. False elevations may be seen with tests done too soon. </li></ul></ul>
  7. 7. Recurrence <ul><li>Periodic testing can detect a recurrence earlier than an ultrasound, x ray, or physical examination. </li></ul>
  8. 8. Methodology <ul><li>Immunoassay – </li></ul><ul><ul><li>Antigen (tumor marker) + Antibody -> If that tumor marker is present, these very specific antibodies bind to the markers. </li></ul></ul><ul><ul><li>Some type of label, often a radioactive substance, is then used to measure the amount of bound marker and antibody -> The quantity of tumor marker is calculated. </li></ul></ul>
  9. 9. Colorectal cancer <ul><li>Diagnosis and screening </li></ul><ul><li>CEA – A glycoprotein which is the most useful and widely investigated marker for colorectal cancer. </li></ul><ul><li>Both the proportion of patients with elevated levels and the extent of elevation are primarily dependent on disease stage. </li></ul><ul><li>>2.5 ng/ml - 28% Duke’s A </li></ul><ul><li> 45% Duke’s B </li></ul><ul><li> 75% Duke’s C </li></ul><ul><li> 84% Duke’s D </li></ul>
  10. 10. Colorectal cancer <ul><li>> 5 ng/ml – Proportion of patients with increased levels – 3% Duke’s A </li></ul><ul><ul><li>25% Duke’s B </li></ul></ul><ul><li> 45% Duke’s C </li></ul><ul><li>65% Duke’s D </li></ul><ul><li>Lack of sensitivity for early disease - CEA is of little value in the detection of Dukes’ A or B colorectal cancer. </li></ul><ul><li>Lack of specificity - Only approximately 90% using a cut-off point of 2.5 ng/ml . Benign diseases and other advanced types of adenocarcinoma can cause ↑ CEA. </li></ul><ul><li>CEA cannot be used as a screening test in asymptomatic populations </li></ul><ul><li>Cannot be used as a diagnostic marker </li></ul><ul><li>In a patient with symptoms with a grossly elevated value - Highly suggestive of colorectal ca. </li></ul>
  11. 12. Colorectal cancer <ul><li>Prognosis </li></ul><ul><li>High levels correspond with more advanced stages </li></ul><ul><li>Duke’s B – High levels of CEA may help identifying a sub-group who have a higher risk of aggressive disease who may require adjuvant treatment </li></ul><ul><li>Preliminary data suggest that both serum and tissue levels of CA 19-9 may also be prognostic in colorectal cancer. </li></ul>
  12. 13. Colorectal cancer <ul><li>Monitoring </li></ul><ul><li>Marker of choice for monitoring patients with colorectal cancer – since 1980s </li></ul><ul><li>Early studies showed that serial CEA levels could detect recurrent disease many months (usually 4-10 months) in advance of clinical evidence of disease </li></ul><ul><li>Most sensitive for hepatic or retroperitoneal disease; Relatively insensitive for either local, peritoneal or pulmonary involvement. </li></ul><ul><li>Some investigators - A slowly rising CEA usually indicates a locoregional recurrence while rapidly increasing levels usually suggest hepatic metastasis. </li></ul>
  13. 14. Colorectal cancer <ul><li>Monitoring (contd.) </li></ul><ul><li>Pietra N et al. Dis colon rectum, 1998 </li></ul><ul><li>Single institution prospective randomized trial to appraise the value of CEA in detecting local recurrence. </li></ul><ul><li>207 patients; ↑ CEA - most frequent indication of local recurrence in patients without clinical symptoms. </li></ul><ul><li>CEA measurement was more cost-effective than other procedures including CT for the diagnosis of local recurrence. </li></ul><ul><li>Intensive follow-up with CEA might be more beneficial for patients with rectal cancer than for those with colonic cancer, as local recurrence was more frequent after rectal cancer resection. </li></ul><ul><li>Optimal interval for serial CEA screening – 2-3 months </li></ul>
  14. 15. Colorectal cancer <ul><li>Other markers – </li></ul><ul><ul><li>CA19-9, CA242 and cytokeratins ( e.g., TPA and TPS) have also been evaluated for this malignancy . May complement CEA; further work required to see which marker is most complementary to CEA. </li></ul></ul>
  15. 16. Pancreatic cancer <ul><li>Diagnosis </li></ul><ul><li>CA 19-9 – Most widely used </li></ul><ul><li>Mean specificity – 90%, sensitivity – 81%, using a cut-off point of 37 IU/ml </li></ul><ul><li>May be raised in other conditions – other advanced cancers, non-neoplastic conditions including pancreatitis, cholangitis and hepatocellular jaundice </li></ul><ul><li>In presence of jaundice – specificity becomes lesser </li></ul><ul><li>Of limited value in diagnosing pancreatic cancer, esp. early cases – can complement radiologic procedures, especially in non-jaundiced pts.; only 55% of patients with tumors <3 cm in size have ↑ CA 19-9. </li></ul>
  16. 17. Pancreatic cancer <ul><li>Prognosis and monitoring </li></ul><ul><li>CA 19-9 has the potential but is as yet unproven for routine use for these purposes </li></ul><ul><li>Other markers such as CA50, CA242, CA195, DU-PAN 2, and CAM 17.1/WGA have also been described for pancreatic cancer. </li></ul><ul><li>Investigated less widely than CA19-9 but appear to provide similar data. </li></ul><ul><li>CA19-9 therefore remains the &quot;gold standard marker&quot; against which future markers for pancreatic cancer will be evaluated. </li></ul>
  17. 18. Gastric cancer <ul><li>The most widely described markers for gastric cancer are CEA, CA19-9 and CA72-4. </li></ul><ul><li>Of these CA72-4 appears to be the most sensitive and specific, followed by CA19-9 and CEA. </li></ul><ul><li>None of these markers is useful in either screening or diagnosing early gastric cancer. </li></ul><ul><li>Their role in the follow-up of patients with diagnosed disease remains to be evaluated. </li></ul>
  18. 19. Esophageal cancer <ul><li>Biochemical markers have been little investigated in esophageal cancer. </li></ul><ul><li>Preliminary data - best available markers for the squamous cell ca. are SCC and cytokeratins [ e.g ., CYFRA 21-1, TPA, TPS] ; CA19-9 - adenocarcinoma. </li></ul><ul><li>Presently, these markers are of little value in either the diagnosis or management of oesophageal cancer. </li></ul>
  19. 20. Hepatocellular carcinoma <ul><li>Screening </li></ul><ul><li>α -fetoprotein – marker of choice </li></ul><ul><li>Value of AFP in screening has not been assessed in a prospective randomized trial. </li></ul><ul><li>For endemic areas with high prevalence. </li></ul><ul><li>NIH consensus conference (1986): HBsAg +, with CAH or cirrhosis to be screened every 3 months and every 4-6 months on USG. </li></ul>
  20. 21. Hepatocellular carcinoma <ul><li>Diagnosis </li></ul><ul><li>Differential diagnosis between HCC and hepatitis &/or cirrhosis </li></ul><ul><li>Measurement of fucosylated fraction of AFP (AFP L3, P4 and P5) versus “normal” AFP – more in HCC. </li></ul><ul><li>In benign conditions – AFP elevations are transient, in malignancy concs. remain high or may increase – AFP assays at 2-3 weeks’ interval may eliminate false-raised values </li></ul>
  21. 22. Conclusions <ul><li>Screening: </li></ul><ul><ul><li>Lack of sensitivity for early disease and lack of specificity for malignancy </li></ul></ul><ul><ul><li>The above coupled with low prevalence of GIT cancers in general pop. prevent the use of these markers in screening asymptomatic general pops. Exception : AFP screening in high risk areas. </li></ul></ul>
  22. 23. Conclusions <ul><li>Diagnosis </li></ul><ul><ul><li>Limited due to lack of sensitivity of these markers </li></ul></ul><ul><li>Follow-up of patients with diagnosed cancers </li></ul><ul><ul><li>To detect asymptomatic recurrences that can be operated upon for cure </li></ul></ul><ul><ul><li>Cheaper than conventional radiological procedures </li></ul></ul>
  23. 24. Conclusions <ul><li>Caveats while using CEA in surveillance of pts. with diagnosed colorectal cancer : </li></ul><ul><ul><li>↑ usually in advanced disease </li></ul></ul><ul><ul><li>Not all patients with recurrent disease will have ↑ levels </li></ul></ul><ul><ul><li>High levels may occur in other conditions </li></ul></ul><ul><ul><li>Some cytotoxic therapies can cause transient rise of levels </li></ul></ul>
  24. 25. Conclusions <ul><li>Esophageal and gastric cancer – Markers contribute very little to diagnosis or follow-up </li></ul><ul><li>Future approaches: Assays for mutated c-oncogenes and suppressor genes </li></ul>