Serum Tumor Markers

Serum tumor markers are proteins or carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). 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 Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands-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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

  • Serum tumor markers, usually just referred to as “tumor markers,” are proteins or carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of 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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix 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 Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis system for choriocarcinoma)
  • Screening for cancer (e.g., prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands-specific antigen (PSA) testing for prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. 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 Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). 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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix 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 Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis, peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease, diverticulitis, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
      • Also can be elevated in smokers and patients with chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. 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 Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. 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 Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. 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 Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer to follow response to chemotherapy
    • Not commonly used for screening; can be elevated in patients with
      • Endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
      • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
      • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • 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 Megaloblastic anemia Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies. Megaloblastic Anemia
      • Thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia or sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
      • Benign ovarian cysts Ovarian cysts Ovarian cysts are defined as collections of fluid or semiliquid material, often walled off by a membrane, located in the ovary. These cysts are broadly categorized as either functional or neoplastic. Neoplastic ovarian cysts are subcategorized as either benign or malignant. Ovarian Cysts
  • PSA
    • A glycoprotein normally secreted by the prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands gland that functions to dissolve cervical mucus and allow for sperm motility
    • Elevated with prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer 
      • Used for prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer risk stratification
      • Posttreatment monitoring
      • Screening for prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer (controversial)
    • False positives can be seen with:
      • Prostatitis Prostatitis Prostatitis is inflammation or an irritative condition of the prostate that presents as different syndromes: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain, and asymptomatic. Bacterial prostatitis is easier to identify clinically and the management (antibiotics) is better established. Prostatitis
      • Benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia
  • Thyroglobulin
    • A glycoprotein secreted by follicular thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland cells
    • Normally serves as a substrate for the production of thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones
    • Used as a tumor marker postoperatively for monitoring of recurrence of papillary or follicular thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
  • Chromogranin A (CgA) 
    • A glycoprotein secreted by neuroendocrine cells
    • Used in patients with both functional and nonfunctional pancreatic neuroendocrine tumors Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs) ( PanNETs PanNETs Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs)) and GI carcinoid tumors Carcinoid tumors Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome
    • 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 Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
      • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
      • Inflammatory bowel disease
      • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. 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 Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. 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
Abbreviation Tumor marker name Associated malignancy
AFP Alpha-fetoprotein Hepatocellular cancer, metastatic disease in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, germ cell tumor
CA 15-3 Cancer antigen 15-3 Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
CA 19-9 Carbohydrate antigen 19-9 Pancreatic cancer (also elevated in colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer, esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer, and hepatocellular cancer)
CEA Carcinoembryonic antigen Colorectal cancer, pancreatic, gastric, and lung cancer
CA-125 Cancer antigen 125 Ovarian cancer
CgA Chromogranin A Neuroendocrine tumors in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas; GI carcinoid tumors Carcinoid tumors Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome
CT, CGRP-alpha Human calcitonin Medullary thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
hCG Human chorionic gonadotropin Testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer, germ cell tumor
PSA Prostate-specific antigen Prostate cancer
TAG72 Tumor-associated glycoprotein 72 Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
Tg Thyroglobulin Follicular or papillary thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). 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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