Tumor Markers


By the end of this session the reader should be able to:

  • Describe the use of the following serum tumor markers: alpha-fetoprotein, cancer antigen 19-9, carbohydrate antigen 125, carcinoembryonic antigen, estrogen and progesterone receptors, human chronic gonadotropin, prostatic acid phosphatase, prostate-specific antigen, squamous cell carcinoma antigen, terminal deoxynucleotidyl transferase, and bladder tumor associated antigen
  • Discuss the proper use of tumor markers
  • Describe the difference in sensitivity and specificity of prostate specific antigen versus prostatic acid phosphatase
  • Discuss the effect of changing cut-off points on the specificity of cancer antigen 19-9
  • Discuss the effect of combination of carcinoembryonic antigen and cancer antigen 19-9 in the detection of recurrence of gastric cancer
  • Describe the implications of binding of prostate specific antigen with respect to the probability of prostate cancer


Adenoma - benign epithelial tumor

Benign - not malignant, not recurrent, favorable for recovery

Cancer - a relative autonomous growth of tissue

Malignant - tending to become progressively worse, having properties of invasion and metastasis

Metastasis - transfer of disease from one organ to another not directly connected to it

Sarcoma - connective tissue tumor, most are malignant

Tumor - new growth of tissue which is uncontrolled


Cancer is the second most common cause of death in the United States. Many strategies are employed for early diagnosis and monitoring of therapy. Tumor markers’ primary use is limited to detecting recurrence and monitoring therapy, but are sometimes used as screening tests. It is important that clinicians understand how sensitivity, specificity and prevalence impact the use of tumor markers.


Tumor Marker

Definition: a substance produced by a tumor or by a host in response to the tumor’s presence; such substances can be measured in blood, fluid secretions, or tissues by chemical, immunochemical, and molecular biology methods or by cytochemical staining

Classifications: markers include enzymes and isoenzymes, specific proteins, hormones, oncofetal antigens, carbohydrate epitopes, receptors, metabolites, and genetic changes

Use of Tumor Markers

  1. For screening populations and high-risk groups
  2. As an aid in diagnosis (limited value; lack of specificity and sensitivity)
  3. In staging or confirmation of histopathology
  4. In therapy to monitor drug response
  5. To check for recurrence (main use)

Their use is mainly in carcinoma, less so in sarcoma.

Examples of Tumor Markers

AFP (alpha-fetoprotein)
A tumor-associated protein. Increased in non-seminomatous testicular cancer; useful for monitoring its clinical management. Also increased in primary hepatocellular cancer and germ-cell tumors of yolk-sac origin.
CA 19-9 (Cancer Antigen 19-9)
A tumor-associated glycoprotein. Increased in 80% of patients with pancreatic adenocarcinoma but rarely in patients with benign pancreatic disease. Useful in monitoring post-operative patients for disease recurrence.
CA 125 (Carbohydrate Antigen 125)
Tumor-associated glycoprotein. Increased in most patients with epithelial ovarian cancer. Should be used as an aid in the detection of residual ovarian cancer in patients who have undergone first-line therapy and should be considered for diagnostic second-look procedures. FDA approved for this purpose only.
Carcinoembryonic Antigen (CEA)
A glycoprotein. Increased in a variety of malignancies, predominantly colorectal cancer, but also CA of pancreas, breast, cervix, uterus, ovary, bladder, and lung. Useful for monitoring patients for disease recurrence. Persistently elevated levels or increasing levels may reflect the presence of residual or disseminated malignancy and indicate poor prognosis.
Estrogen and Progesterone Receptors (ER and PR)
Cytosol from breast tumor tissue
Useful for both identifying hormone-dependent tumors and as prognostic markers. Identifies those patients who will respond to hormone therapy and those who will need more aggressive treatment. If ER and PR are both positive, there should be a better response to hormone therapy. ER-positive tumors have been associated with longer disease-free interval for the patient and possibly longer survival.
Human Chorionic Gonadotropin (hCG)
Serum or urine
A glycoprotein hormone consisting of an α- and β-chain. Increased in pregnancy with peak between 8th and 12th week of gestation. Increased in trophoblastic cancers such as choriocarcinoma and hydatidiform mole. AFP is normal in these forms of cancer. hCG (and free β) and AFP are increased in non-seminomatous germ-cell tumors of the testes and are essential for monitoring clinical management.
Prostatic Acid Phosphatase (PAP)
Elevated in prostatic cancer. Useful for monitoring treatment of patients with confirmed prostatic cancer. Elevated levels following treatment may indicate residual or recurrent disease. Test has relatively low sensitivity.
Prostate-Specific Antigen (PSA)
A glycoprotein and serine protease. Increased in prostatic cancer but also in benign prostatic hypertrophy (BPH). Useful in monitoring treatment of patients with prostate cancer. Increasing the cut-off point to 10 μg/L reduces positive results from BPH to <2-3%. PSA exists in the free form and bound to proteins like α1-antichymotrypsin. Measurement of the ratio of free to total PSA may have advantages in the differential diagnosis of BPH, especially in the diagnostic “grey level” of 4-25 μg/L of total PSA. The proportion of free non-complexed PSA to total PSA is significantly lower in patients with untreated prostate cancer than in patients with BPH. 13-psa.jpg
Her2/neu Her2/neu is human epidermal growth factor receptor. Her2/neu is used to predict response of breast tumors in chemotherapy. Herceptin (trastuzumab) is a humanized monoclonal antibody that binds to Her2/neu and inhibits activation of the receptor, consequently breast tissue that is positive for Her2/neu are candidates for Herceptin therapy. Currently the test is best performed on breast tissue biopsy specimens.
Squamous Cell Carcinoma (SCC) Antigen Fraction
A glycoprotein and subfraction of a tumor-associated antigen (TAA). Increased levels are associated with tumor progression or recurrence in cervical and uterine squamous cell cancer. Useful for monitoring clinical management.
Terminal Deoxynucleotidyl Transferase (TDT)
Peripheral blood or bone marrow
Elevated in lymphoblastic leukemia and undifferentiated leukemia and in chronic myelogenous leukemia in blast crisis. Considered to be a biochemical marker for certain immature lymphocytes. Levels may increase and decrease as certain leukemia patients remit and relapse. May be helpful in the classification of leukemia and in selection and monitoring of therapy. Not FDA approved.
Bladder Tumor Associated antigen (BTA) stat Test
The BTA test is a single step immunochromatographic assay for bladder associated antigen in voided urine. The associated antigen is a human complement factor H related protein (hCFHrp) The clinical specificity of the test is 95.9% and clinical sensitivity 40-59%. The test is superior to the voided urinary cytology in the detection of recurrent bladder cancer. It will reduce, but not eliminate, the use of cystoscopy.
SOURCE: American Medical Association Family Medical Guide, 4th ed., Hoboken, NJ: Jon Wiley & Sons, 2004.

Sensitivity and Specificity of PAP vs. PSA in Prostatic Cancer

PAP Positivity PSA Positivity
BPH 3% 63%
Stage A 0% 52%
Stage B 8% 78%
Stage C 60% 100%
Stage D 90% 100%

Exact figures may differ somewhat between studies, but in principle, there is agreement. PAP is less sensitive than PSA, but it is more specific.

Reference: Rock, R.C. et al. Evaluation of a monoclonal immunoradiometric assay for prostate-specific antigen. Clin. Chem., 33: 2257- 2261, 1987

Effect of Cut-off Point on Specificity of CA 19-9

Cut-off: 37 U/mL Cut-off: 60 U/mL
Pancreatitis 20.3% (14/69) 8.9% (6/69)
Hepatitis 16.3% (7/43) 9.3% (4/43)
Cirrhosis 30.5% (18/59) 6.8% (4/59)
Misc. benign conditions 12.5% (16/124) 7.3% (9/124)
Pancreatic cancer 75.9% (63/83) 73.2% (60/82)

Reference: Shaw, N.Y., Hutton, J.M., et al. Evaluation of CA 19-9 Levels as a Marker for Pancreatic Cancer. Clin. Chem. 33: 1034, 1987 (Abstract)

Effect of Test Selection and Test Combination on Sensitivity of Tumor Markers

Test Disease Post-op Sensitivity for Recurrence of Cancer
CEA Colorectal Cancer 90%
CEA Gastric Cancer 59%
CEA Pancreatic Cancer 31%
CA 19-9 Colorectal Cancer 58%
CA 19-9 Gastric Cancer 79%
CA 19-9 Pancreatic Cancer 100%

Conclusion: CEA is the preferred test for patients with colorectal cancer and CA 19-9 is the preferred test for patients with pancreatic cancer. The combination of CA 19-9 with CEA increases the sensitivity for detection of recurrence of gastric cancer to 94%.

Reference: Staab, HJ. et al. The Clinical Validity of Circulating Tumor-associated Antigens CEA and CA 19-9 in Primary Diagnosis and Follow-up of Patients with Gastrointestinal Malignancies. Klin. Wochenschr. 63, 106, 1985.


Case 1

A 30-year-old woman was admitted with a 9-month history of amenorrhea and an admission serum β-hCG value of 3,800 IU/L. X-ray studies revealed a lesion in the left lung, and a CT scan demonstrated small lesions in the frontal and left parietal lobes of the brain. Biopsies confirmed the presence of choriocarcinoma. The patient received radiation and chemotherapy treatment, and serum β-hCG values returned to normal.

Three months later, a modest increase in the serum β-hCG signaled a possible recurrence of a tumor. All visualization studies were negative. The physician sent a separate serum specimen to an outside laboratory, which performed whole molecule (intact) hCG studies. The result was negative. Five months later, X-ray studies revealed a tumor in the right lung. The tumor was removed and chemotherapy repeated. The patient has been in remission since then.

The whole (intact) molecule hCG assay is less sensitive and less specific as a tumor marker than the β-hCG assay since the alpha subunit is identical for luteinizing hormone, thyroid-stimulating hormone, follicle-stimulating hormone, and human chorionic gonadotropin (hCG).

Case 2

(J. Urol. 170(4):1305, 2003)

A 59-year-old man underwent radical prostatectomy for prostate adenocarcinoma. Serum PSA at diagnosis was 8.5 ng/ml (Hybritech assay). Pathological examination of the removed tissue showed evidence of extracapsular extension, positive margins and bilateral seminal vesicle involvement. Following surgery the patient received adjuvant radiation therapy to the prostate bed. Postoperatively, PSA was undetectable (Hybritech assay).

Ten months following surgery, PSA measured 37 ng/ml on the AxSYm assay (normal range <4 ng/ml). Repeat AxSYm assay PSA measurement 2 weeks later was 31.3 ng/ml. Evaluation, including bone scan and abdominal computerized tomography, was negative for metastatic disease. Therapy was initiated with 10.8 mg goserelin depot injection and 50 mg bicalutamide daily. Three weeks after initiation of hormonal therapy PSA measured 0.02 ng/ml by Hybritech but 6 weeks later measured 28.2 ng/ml by AxSYm. Because of this discrepancy, repeat PSA’s were measured within 3 days of each other using the different assays, and results varied significantly with the PSA measuring less than 0.01 ng/ml on the Hybritech assay but 23.6 ng/ml on the AxSYm assay.

  1. Where the tumor marker assays used appropriately in this case?
  2. Describe the mechanism of action of goserelin and bicalutamide.
  3. What other lab test might have been useful prior to prescribing goserelin and bicalutamide?
  4. Give a possible reason for the discrepancy in the PSA results.

Case 3

A 69 year old male saw his physician with complaints of lower back pain. The patient was otherwise in good health. There were no urinary symptoms. Examination of the prostate gland revealed a firm nodule. Other routine laboratory tests, including serum calcium, were normal. The PSA was 78 µg/L (normal: <4.0).

  1. What are causes of lower back pain?
  2. What is the likely diagnosis?
  3. What procedures can be performed to confirm the diagnosis?

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