Cytokeratin-19 fragment (CYFRA 21-1)

CYFRA 21-1 Overview

CYFRA 21-1 is a laboratory test that measures the concentration of a soluble fragment of cytokeratin 19 in the blood (serum or plasma). Cytokeratins are structural proteins (intermediate filaments) that form part of the cytoskeleton within epithelial cells. There are over 20 different types of cytokeratins, expressed in various epithelial tissues.

Cytokeratin 19 (CK19) is primarily found in simple or pseudostratified epithelia, such as those lining the airways (bronchi) and certain ducts. When epithelial cells, particularly cancer cells, undergo rapid turnover, damage, or necrosis, fragments of these cytokeratins can be released into the bloodstream. The CYFRA 21-1 test specifically detects a fragment of CK19.

Elevated levels of CYFRA 21-1 in the blood can be associated with certain types of cancer, particularly those originating from epithelial tissues expressing CK19, making it useful as a tumor marker.

Biology of CYFRA 21-1

Cytokeratins, like CK19, are generally insoluble proteins forming the structural framework within cells. However, during processes like cell death (apoptosis or necrosis) or increased cell turnover (often seen in tumors), these proteins can be cleaved by enzymes (like caspases). This process releases soluble fragments into the circulation.

The CYFRA 21-1 assay typically uses two different monoclonal antibodies that recognize specific epitopes on the cytokeratin 19 fragment, allowing for its quantitative measurement in blood samples. The measured fragment has a molecular weight of approximately 30 kDa.

Clinical Indications for CYFRA 21-1 Testing

The primary clinical indications for ordering a CYFRA 21-1 test include:

1. Lung Cancer:
   • Primarily used in Non-Small Cell Lung Cancer (NSCLC), especially the squamous cell carcinoma subtype, where it tends to be most frequently elevated.
   • Can aid in prognosis (higher levels often correlate with more advanced stage and poorer outcome).
   • Used for monitoring response to therapy (a decrease suggests treatment effectiveness).
   • Can help in detecting recurrence after treatment (a rising level may indicate relapse).
2. Bladder Cancer:
   • Used particularly in monitoring muscle-invasive bladder carcinoma.
   • Levels may correlate with tumor stage and prognosis.
   • Can be useful for monitoring treatment response and detecting recurrence.
3. Other Cancers (Less Common): Elevated levels may also be seen less frequently in other epithelial malignancies, including squamous cell carcinomas of the head and neck, esophagus, or cervix, but its role is less established compared to lung and bladder cancer.

CYFRA 21-1 is not recommended for general cancer screening due to insufficient sensitivity and specificity.

Interpretation of CYFRA 21-1 Levels

Interpretation must be done in the context of the patient's clinical situation, imaging, and other diagnostic findings.

• Normal Range: The upper limit of the normal range for CYFRA 21-1 is typically around 2.3 - 3.3 ng/mL, but this can vary depending on the specific laboratory assay used. Always refer to the laboratory's reference range.
• Elevated Levels in Cancer:
  • Significantly elevated levels are most suggestive of the cancers listed above, particularly NSCLC (especially squamous cell type) and muscle-invasive bladder cancer.
  • The degree of elevation often correlates with tumor burden, stage, and prognosis. Very high levels are usually associated with advanced or metastatic disease.
  • Serial measurements are more informative than a single value. A significant decrease after therapy indicates response, while a rise often suggests progression or recurrence.

Factors Affecting CYFRA 21-1 Levels

Elevated CYFRA 21-1 levels are not entirely specific to cancer. Mild to moderate elevations can occur in various benign conditions, potentially causing false-positive results:

• Benign Lung Diseases: Such as pneumonia, tuberculosis, COPD, pulmonary fibrosis.
• Benign Liver Diseases: Such as hepatitis or cirrhosis (usually slight increases, often up to ~10 ng/mL).
• Renal Failure / Impaired Kidney Function: Decreased clearance can lead to elevated levels (often up to ~10 ng/mL).
• Other Inflammatory Conditions: Conditions causing epithelial damage or inflammation.

Limitations and Considerations

• Specificity: Not specific to cancer; benign conditions can cause elevations.
• Sensitivity: Not all relevant cancers will cause elevated levels, especially in early stages. A normal level does not exclude cancer.
• Monitoring Role: Primarily valuable for monitoring diagnosed patients, tracking changes over time relative to a baseline level.
• Sample Contamination: Cytokeratins are present in epithelial cells, including those in saliva. Contamination of the blood sample collection tube or the sample itself with saliva can lead to falsely elevated results. Careful sample collection technique is important.
• Assay Variability: Results may vary slightly between different laboratory methods. Serial monitoring should ideally be done using the same laboratory and method.

The CYFRA 21-1 Blood Test Procedure

• Sample Type: Blood serum or plasma.
• Preparation: No specific patient preparation (like fasting) is generally required.
• Collection: Standard venipuncture to draw a blood sample from a vein in the arm. Care should be taken to avoid saliva contamination during handling.
• Analysis: Performed in a clinical laboratory using specific immunoassays (e.g., ELISA, chemiluminescence).

References

1. Molina, R., Agusti, C., Filella, X., Jo, J., Joseph, J., Gimenez, N., & Ballesta, A. M. (2003). Study of a new tumor marker, CYFRA 21-1, in malignant and nonmalignant diseases. *Tumour Biology*, 24(1), 1–6. https://doi.org/10.1159/000070489
2. National Cancer Institute (NCI). (n.d.). Tumor Markers. NCI Dictionary of Cancer Terms. Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tumor-marker
3. Holdenrieder, S., & Stieber, P. (2009). Tumor markers in peripheral blood. In *Tumor Markers: From Prognosis to Therapy Decision*. Wiley-VCH Verlag GmbH & Co. KGaA. (Chapter discussing CYFRA 21-1)
4. Kulpa, J., Wójcik, E., Reinfuss, M., & Kołodziejski, L. (2002). Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. *Clinical Chemistry*, 48(11), 1931–1937.
5. Wu, J. T. (Ed.). (2005). *Tumor Markers: Physiology, Pathobiology, Technology, and Clinical Applications*. AACC Press. (Provides overview of various tumor markers including CYFRA 21-1).