Serum Tumor Markers

Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as “cellular tumor markers.” These lab tests are easy to obtain and useful for follow-up in a patient with known malignancy. In general, they are not appropriate for screening in individuals of average risk, except for prostate-specific antigen (PSA), which is commonly used but controversial. Tumor markers have an important role in the diagnosis, prognosis, and monitoring of patients with cancer. However, they are not as specific or sensitive as tissue biopsy and are not used solely for cancer diagnosis. Panels of tumor markers have been increasingly adopted in recent years.

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Overview

Definition

  • Serum tumor markers, usually just referred to as “tumor markers,” are proteins or carbohydrates that increase due to cancer.
  • Cellular tumor markers are also used to detect the presence of malignant cells with distinctive genetic changes.
  • Both can usually be measured in circulating cells of different body fluids and in tissues. 

Uses and limitations

Uses:

Baseline level should be established at the time of initial presentation.

  • Evaluating tumor response to therapy (e.g., chemotherapy, radiotherapy, or surgery)
  • Monitoring for tumor recurrence (e.g., carcinoembryonic antigen (CEA) with colon cancer)
  • Determining stage, prognosis, and treatment plan for certain malignancies (e.g., hCG pretreatment level included in the International Federation of Gynecology and Obstetrics (FIGO) staging system for choriocarcinoma)
  • Screening for cancer (e.g., prostate-specific antigen (PSA) testing for prostate cancer)

Limitations:

  • False positives: elevated tumor marker but no cancer
  • False negatives: Tumor marker is not elevated despite the presence of cancer.

Classification

  • Cellular tumor markers
    • Indicate expression of oncogenes
    • Example: carbohydrate antigen 125 (CA-125) in ovarian cancer
  • Humoral tumor markers
    • Detected in bodily fluids such as blood or urine in concentrations higher than physiological values
    • Produced by tumorous cells at a higher level than normal 
    • Example: Prolactinoma causes an elevation in the normal secretion of prolactin.

Clinical Significance

Levels of tumor markers can be useful in monitoring response to treatment for many cancers but have drawbacks and false positives.

Common tumor markers

  • CEA
    • Obtained preoperatively and postoperatively in patients with colon cancer
    • Used in treatment planning and assessment of prognosis
    • Not used for screening:
      • Low diagnostic ability
      • Significant overlap with benign disease
    • False positives with:
      • Benign GI conditions such as gastritis, peptic ulcer, diverticulitis, liver disease
      • Also can be elevated in smokers and patients with chronic obstructive pulmonary disease (COPD)
  • Carbohydrate antigen 19-9 (CA19-9) 
    • A tetrasaccharide found in numerous malignancies
      • Most strongly associated with pancreatic cancer
      • Also associated with colorectal cancer and other forms of GI cancer
    • Used in posttreatment monitoring for recurrence in patients with pancreatic cancer
    • False positives are common in patients with:
      • Pancreatitis
      • Cirrhosis
  • CA-125 
    • A protein; also known as mucin 16
    • Function in cancer: participates in cell-to-cell interactions necessary for metastasis
    • Used in patients with ovarian cancer to follow response to chemotherapy
    • Not commonly used for screening; can be elevated in patients with
      • Endometrial cancer
      • Lung cancer
      • Breast cancer
      • Pregnancy
  • CA 15-3
    • Used in monitoring treatment response in patients with metastatic breast cancer
    • Has drawbacks; can see a transient increase in 20% of patients successfully treated with systemic therapy
    • False positives can also be seen in patients with:
      • Vitamin B12 deficiency and megaloblastic anemia
      • Thalassemia or sickle cell disease
      • Benign ovarian cysts
  • PSA
    • A glycoprotein normally secreted by the prostate gland that functions to dissolve cervical mucus and allow for sperm motility
    • Elevated with prostate cancer 
      • Used for prostate cancer risk stratification
      • Posttreatment monitoring
      • Screening for prostate cancer (controversial)
    • False positives can be seen with:
      • Prostatitis
      • Benign prostatic hyperplasia
  • Thyroglobulin
    • A glycoprotein secreted by follicular thyroid gland cells
    • Normally serves as a substrate for the production of thyroid hormones
    • Used as a tumor marker postoperatively for monitoring of recurrence of papillary or follicular thyroid cancer
  • Chromogranin A (CgA) 
    • A glycoprotein secreted by neuroendocrine cells
    • Used in patients with both functional and nonfunctional pancreatic neuroendocrine tumors (PanNETs) and GI carcinoid tumors
    • Less sensitive in colorectal and lung NETs
    • False positive results can be seen with:
      • Proton-pump inhibitors (e.g., omeprazole)
      • Some foods
      • Chronic atrophic gastritis
      • Chronic kidney disease
      • Inflammatory bowel disease
      • Cirrhosis

Multiple tumor marker testing

  • Tumor marker elevation in isolation may represent a false positive or false negative.
  • Multiple tumor markers allow for better sensitivity and specificity.
  • Tumor marker panels and the development of parallel testing procedures are sometimes used in combination:
    • Breast cancer panel: CEA, CA 15-3, and CA 27.29
    • Pancreas cancer panel: CEA, CA 19-9, and CA 72-4
    • Liver cancer panel: CEA and alpha-fetoprotein (AFP)
  • Multiple markers for cancer of unknown primary site: CEA, CA19-9, CA 15-3, and CA 125 are not generally useful in diagnosis or management.

Comprehensive List of Tumor Markers

Table: Comprehensive list of tumor markers
AbbreviationTumor marker nameAssociated malignancy
AFPAlpha-fetoproteinHepatocellular cancer, metastatic disease in the liver, germ cell tumor
CA 15-3Cancer antigen 15-3Breast cancer
CA 19-9Carbohydrate antigen 19-9Pancreatic cancer (also elevated in colorectal cancer, esophageal cancer, and hepatocellular cancer)
CEACarcinoembryonic antigenColorectal cancer, pancreatic, gastric, and lung cancer
CA-125Cancer antigen 125Ovarian cancer
CgAChromogranin ANeuroendocrine tumors in the pancreas; GI carcinoid tumors
CT, CGRP-alphaHuman calcitoninMedullary thyroid cancer
hCGHuman chorionic gonadotropinTesticular cancer, germ cell tumor
PSAProstate-specific antigenProstate cancer
TAG72Tumor-associated glycoprotein 72Gastric cancer
TgThyroglobulinFollicular or papillary thyroid cancer

References

  1. Nagpal, M., et al.(2016). Tumor markers: A diagnostic tool. National Journal of Maxillofacial Surgery, 7(1), 17-20. Doi: 10.4103/0975-5950.196135
  2. Holdenrieder, S., et al. (2016). Clinically meaningful use of blood tumor markers in oncology. BioMed Research International. https://doi.org/10.1155/2016/9795269
  3. Strosberg, J.R. & Del Rivero, J.D. (2021). Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors. UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/overview-of-tumor-biomarkers-in-gastroenteropancreatic-neuroendocrine-tumors
  4. Hainsworth, J.D. & Greco, A. (2019). Overview of the classification and management of cancers of unknown primary site. UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/overview-of-the-classification-and-management-of-cancers-of-unknown-primary-site
  5. Macrae, F. A., Parikh, A. R., Ricciardi, R. (2021). Clinical presentation, diagnosis, and staging of colorectal cancer. UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-staging-of-colorectal-cancer
  6. Mayer, I.A. (2021). Systemic treatment for metastatic breast cancer: General principles. UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/systemic-treatment-for-metastatic-breast-cancer-general-principles

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