Introduction

Carcinoembryonic antigen (CEA) is a nonspecific serum biomarker that is elevated in many malignancies, including colorectal cancer, medullary thyroid cancer, breast cancer, and mucinous ovarian cancer. CEA was first detected in colon cancer cells by Freedman and Gold and was eventually found in various other epithelial cells in the stomach, tongue, esophagus, cervix, and prostate.[1] This glycoprotein has a molecular weight of 200 kDa and is normally derived from fetal embryonic endodermal epithelium, controlled by fetal oncogenes.

CEA usually disappears from serum after birth. However, small quantities of CEA may remain in colon tissue. CEA and related genes (29 are present, with 18 normally expressed) constitute the CEA family in human beings and are clustered in chromosome 19q13.2.[2] Serum CEA elevation is not a definitive marker of any particular cancer site of origin since this finding is associated with various types of malignant and nonmalignant medical conditions (see Table. Malignant and Nonmalignant Conditions Associated with Carcinoembryonic Antigen Elevation).[3] Therefore, obtaining CEA levels in isolation is not recommended for routine cancer screening or diagnosis. CEA is currently being studied as a target for various cancer-directed therapies.[4][5]

Table

Table. Malignant and Nonmalignant Conditions Associated with Carcinoembryonic Antigen Elevation.

Pathophysiology

CEA belongs to the immunoglobulin family called "CEA-related cell adhesion molecules" (CEACAMs). CEA is closely associated with various endothelial cell functions, including adhesion, proliferation, and migration of cells both in vivo and in vitro.[6] This molecule is present on the endoluminal side of the cell membrane of normal cells. CEA is thought to inhibit apoptosis and, hence, is involved in tumor pathogenesis. Although CEA is predominantly associated with gastrointestinal tumors, the literature indicates a strong correlation with breast, lung, ovarian, cervical (mucinous adenocarcinoma), and thyroid cancers.

Specimen Requirements and Procedure

The clinical laboratory should provide readily available information to healthcare practitioners requesting tumor markers. This information encourages the selection of the appropriate tests, discourages inappropriate requests, and ensures that specimen timing and other preanalytical requirements are met. The laboratory is also responsible for guaranteeing that the results are analytically accurate and that detailed, informative reports are provided to the clinician who made the request.

CEA measurement is usually conducted on a blood sample collected by a phlebotomist or other qualified healthcare personnel. A small (3-5 mL) quantity of blood is placed in a vial and sent to the laboratory to measure the CEA level. The possible complications of such a procedure include needle site pain or stinging, bruising, bleeding, and infections, though the risk is minimal. Blood collection typically takes less than 5 minutes and does not need specific requirements, such as fasting. Occasionally, a CEA test is performed on bodily fluids, including pleural, peritoneal, and, rarely, cerebrospinal fluid.[7]

Tumor biomarkers are generally stable, but serum or plasma should be separated from the clot as soon as possible and stored at 4 °C or -30 °C and below if tests are to be performed within a short period. The temperature should be set to -70 °C or below if longer storage is required.[8]

Testing Procedures

Many commercially available products utilize different technologies, such as sandwiched enzyme-linked immunosorbent assay, immunonephelometry, chemiluminometric immunoassay, and immunomagnetic reduction. CEA levels can fluctuate based on the type of testing procedure utilized. Therefore, discordant serial CEA levels must be carefully correlated with differences in testing procedures. Using monoclonal antibodies directed against the 6 reactive isotopes of CEA in specific assays could result in erroneous findings among patients previously treated with monoclonal antibodies.[9]

The most widely utilized method for measuring CEA levels is the automated 2-step monoclonal enzyme immunoassay (EIA).[10] In this technique, a trapping antibody is attached to a microparticle. A solid support captures this microparticle and any bound CEA molecules during the washing steps. Compared to traditional colorimetric detection, fluorescence enhances sensitivity, especially when dealing with low CEA concentrations. By automating the process, key factors such as incubation time, temperature, and washing are standardized, leading to improved analytical performance. This method is commonly referred to as "microparticle enzyme immunoassay" (MEIA).[11]

Beyond fluorescence, chemiluminescence has emerged as another effective detection method for CEA assays. In this approach, a phosphate ester of adamantyl dioxetane acts as a substrate. When this substrate encounters alkaline phosphatase bound to the CEA-antibody complex, it breaks down into an unstable intermediate. This intermediate subsequently emits light, the intensity of which is measured by a luminometer. The sustained light production allows for multiple readings, potentially increasing the assay's precision.[12][13]

Another variant of CEA measurement is the direct immunometric assay. Unlike the traditional EIA, this method utilizes a magnetic particle to which the trapping antibody is bound, enabling the physical separation of CEA-bound complexes from unbound materials with a magnetic field. Additionally, the 2nd antibody in this assay is polyclonal and labeled with acridinium, eliminating the need for an enzymatic reaction and simplifying the assay process.[14][15]

Interfering Factors

Measurements of tumor biomarkers may be affected by the same interferences that impact all immunoassays, but certain factors are especially important to consider.[16][17] Since tumor biomarker concentrations can vary significantly, protocols that detect high-dose "hooking" effects must be implemented. These protocols help reduce the likelihood of inaccurately reporting low results, particularly in patients tested for these markers for the first time. The risk of "hooking" may be minimized by utilizing solid-phase antibodies with a higher binding capacity, employing sequential assays incorporating a washing step, and testing specimens at 2 different dilutions.[18][19]

Specimen carryover may occur when highly concentrated samples are tested, making it essential to check for this issue periodically. This phenomenon, known as sample-to-sample carryover, can lead to erroneous test results, particularly in immunoassays where a highly concentrated analyte from a sample may contaminate subsequent samples.[20][21] To mitigate this risk, laboratories should implement protocols that monitor and minimize carryover effects, ensuring accurate and reliable test outcomes.[22]

Some patient sera may contain anti-immunoglobulin (Ig) antibodies, primarily IgG, that can interact with the antibodies used in immunoassay reagents. Additionally, high levels of human anti-mouse antibodies (HAMAs) may be found in the serum of cancer patients who have undergone treatment with mouse monoclonal antibodies for imaging or therapeutic reasons. These interferences can lead to inaccurately high or low results.[23] Detecting such interference requires a strong clinical awareness, which is enhanced by having relevant clinical information available.

Several approaches may be taken to investigate potential interference, including testing the specimen at various dilutions, reassessing after treatment with a commercially available blocking agent, adding nonimmune mouse serum to the reaction mixture and retesting, and using a different method, preferably one with a distinct methodology. Caution is advised when interpreting the results.[24][25]

CEA is predominantly metabolized in the liver. Consequently, hepatic and biliary dysfunction are associated with elevated CEA levels, causing false positives. High first-pass hepatic metabolism results in significantly elevated levels corresponding to CEA-producing tumors or metastases outside the portal venous drainage territory. Tumor differentiation influences CEA levels, with well-differentiated cancers typically showing higher levels.[26][27] Smoking is a benign condition commonly affecting CEA levels. Evidence demonstrates that smoking increases CEA levels.[28][29]

Results, Reporting, and Critical Findings

Reference intervals for tumor biomarkers should be derived from an appropriate healthy population and ideally specific to the assay used. These intervals are most relevant for cancer patients before treatment, as the patient’s individual “baseline” levels become the key reference for monitoring tumor biomarkers over time. Once a stable baseline is established posttreatment, a sustained increase in biomarker levels, even within the reference range, may indicate potential relapse and should be investigated further.[30][31]

The degree of clinically significant change in tumor biomarker levels should be clearly defined, taking into account both analytical and biological variability and the time interval between tests. For most tumor biomarkers, a confirmed increase or decrease of 25% is typically regarded as a clinically significant change.[32]

Ranges

In healthy, nonsmoking adults, CEA is considered within normal limits at a level less than or equal to 3.0 µg/L. Adults who smoke may have elevated CEA, raising normal maximum limits to 5 µg/L. Pretreatment serum CEA levels greater than 5 µg/L but less than 10 µg/L suggest localized disease, a low likelihood of recurrence, and a favorable prognosis. A serum level above 10 µg/L indicates a higher probability of recurrence and poorer prognosis.

Serum titers over 20 µg/L are usually associated with metastatic disease in breast and colon cancers. However, given the variability in CEA expression or secretion, values below 2.5 µg/L do not necessarily rule out primary, recurrent, or metastatic cancers. For colorectal cancers, a CEA threshold of 2.5 µg/L carries a sensitivity of 82% and a specificity of 80%, while a threshold of 10 µg/L has a sensitivity of 68% and a specificity of 97%.[33]

Advantages

Serum-based CEA testing is a cost-effective surveillance method for various cancers and is part of national and international surveillance guidelines. Along with imaging studies, this test is an equally important tool to assess ongoing response to palliative treatments in metastatic cancers. Serum-based CEA testing is easy and widely available, even in a community setting.[34][35]

Drawbacks

Due to low sensitivity and specificity, serum CEA testing is unsuitable as a screening test for malignancies. While used to detect cancer recurrence following primary surgical and adjuvant treatments, a single measurement is insufficient due to its low sensitivity and high false-positive rate, making serial measurements essential. Raising the CEA cutoff to greater than 10 µg/L and combining it with other modalities, such as computed tomography (CT) imaging of the chest, abdomen, and pelvis at 12-month intervals, is recommended rather than using serum CEA as a standalone test for monitoring colorectal cancer recurrence.[36]

Individuals exposed to certain animal antigens may develop antibodies to CEA that may affect CEA levels, producing unreliable results. People who smoke are highly likely to have false-positive results, making the test unreliable in this population. CEA testing is not recommended for follow-up monitoring after primary treatment of colon cancer in patients who actively smoke.[37]

Clinical Significance

Carcinoembryonic Antigen Measurement in Colorectal Cancer Diagnosis and Posttreatment Surveillance

CEA is a reliable prognostic biomarker for colorectal cancer recurrence in patients who have undergone surgical resection and adjuvant chemotherapy.[38] A CEA level exceeding 5 µg/L at the time of initial colorectal cancer diagnosis signifies a poor prognosis.[39] However, normalization of elevated CEA levels after surgery does not indicate a poor prognosis. Routine presurgical CEA assessment is generally not recommended, but postoperative monitoring is more effective for detecting recurrence within the 1st year after surgery and for prognostication.

Monitoring CEA levels after primary treatment of colorectal cancer was found to be effective in detecting recurrences treatable with curative intent in the Follow-up After Colorectal Surgery (FACS) trial.[40] National guidelines in North America and Europe also recommend measuring CEA during postoperative follow-up in colorectal cancer.[41][42] Serial CEA monitoring is advised before starting treatment and then every 3 months during active treatment and surveillance to assess response to resection and systemic therapy (chemotherapy/radiotherapy) in colorectal cancer.[43]

In colorectal cancer, serum CEA normalizes 6 weeks after tumor resection. Persistently elevated CEA levels may indicate the presence of residual tumor tissue due to incomplete resection or recurrence. Restaging malignancy should be considered if CEA is persistently above baseline, potentially suggesting cancer progression. CEA levels should not be checked too early, ie, 4 to 6 weeks before starting a new therapy, as some chemotherapeutic agents may elevate CEA falsely.[44][45]

CEA elevation precedes clinical recurrence, allowing for early suspicion or detection of this complication. The American Society of Clinical Oncology guidelines (2006 and 2013 updates) recommend that for patients with stage II or III colorectal cancer who are candidates for surgery or chemotherapy, CEA levels should be measured every 3 months for at least 2 years postoperatively or posttreatment, along with annual CT imaging, and then every 6 months for a total of 5 years.[46]

The sensitivity and specificity of serial CEA measurement in detecting recurrent colorectal cancer are approximately 80% and 70%, respectively. CEA monitoring has the advantage of providing a lead time of about 5 months compared to other diagnostic methods for detecting recurrence. Early detection and timely resection increase the chance of surgical cure when treating recurrent tumors.

Postresection Detection of Liver Metastasis or Oligometastases

CEA is the most sensitive indicator of surgically resectable colorectal liver metastasis.[47] Evidence shows that patients with colon cancer and liver metastasis who have preoperative CEA levels of 30 µg/L or lower are more likely to have resectable metastatic lesions and, hence, prolonged survival.[48] Combining CEA monitoring and CT imaging improves the detection of metastasis at a surgically curable stage compared to either method alone.

Carcinoembryonic Antigen Measurement in Medullary Thyroid Carcinoma

The revised guidelines from the American Thyroid Association for managing medullary thyroid carcinoma indicate that CEA is not a specific biomarker for this type of cancer. However, measuring CEA levels remains valuable for assessing disease progression and monitoring after thyroidectomy. According to Chen et al and guidelines from the North American Society for Neuroendocrine Tumors (NANETS), preoperative CEA levels greater than 30 µg/L suggest extrathyroidal spread of the disease, with levels above 100 µg/L indicative of more invasive pathology, including lymph node involvement and distant metastasis.[49]

Surgical treatment should be planned with total thyroidectomy, central cervical lymph node dissection, and unilateral lateral cervical lymph node dissection when CEA levels exceed 30 µg/L. Pretargeted radioimmunotherapy, which involves radiolabeled monoclonal antibodies against CEA, is a promising treatment modality for medullary thyroid carcinoma. Patients with persistent CEA levels after colon cancer surgery and a negative diagnostic workup for metastatic disease should direct their diagnostic evaluation toward medullary thyroid carcinoma, including calcitonin measurement and neck ultrasound.[50]

Carcinoembryonic Antigen Measurement in Ascitic Fluid

CEA levels are proven to be of some value in cases where ascitic fluid cytology is inconclusive. Serum levels greater than 5 µg/L are suggestive of carcinoma. Higher values are common in cancers with peritoneal involvement, with a sensitivity of 51% and specificity of 97% for carcinomatosis (p <0.01).[51]

Carcinoembryonic Antigen Measurement in Pleural Fluid

An elevated CEA level in a patient with pleural effusion and negative cytology precludes the need for more invasive modalities, such as VATS-guided biopsy, to rule out a malignant etiology. In contrast, lower CEA levels may require a close follow-up.[52]

Carcinoembryonic Antigen Measurement in Non-Small-Cell Lung Cancer

Around 30% of patients with stage I non-small-cell lung cancer have positive N2 to N3 nodes at the time of diagnosis due to limited preoperative imaging sensitivity. Preoperative CEA levels help identify patients with advanced disease that may be missed on imaging. Higher CEA levels correlate with advanced stage, nodal metastasis, and poor survival. CEA measurement potentially identifies the patient population who may benefit from invasive mediastinal lymph node staging by mediastinoscopy or endoscopic ultrasound, as well as neoadjuvant chemotherapy or chemoradiotherapy rather than upfront surgery.[53][54]

Carcinoembryonic Antigen Measurement in Breast Cancer

Currently, the routine use of CEA in screening for breast cancer is not recommended by the American Society of Clinical Oncology due to limited sensitivity and specificity. However, besides the biomarkers CA 15-3 and CA 27.29, CEA and diagnostic imaging may be used to monitor patients with metastatic disease receiving active therapy.[55]

Quality Control and Lab Safety

A robust quality management system is essential for any laboratory.[56] Effective internal quality control procedures must ensure that automated tumor marker methods achieve within-run variability of less than 5% and between-run variability of less than 10%. While newer technologies may deliver superior precision, manual or research-based assays may exhibit higher variability.[57] If an assay run fails to meet predefined acceptance criteria, immediate corrective actions are necessary to prevent the reporting of inaccurate results. These acceptance criteria should be established in advance, following logical frameworks such as the Westgard rules.[58] Given the need for long-term monitoring in cancer care, assay stability over extended periods must be ensured.

Quality control materials must be sourced independently from the method's manufacturer, as controls provided in kits may present an overly positive assessment of performance.[59] Including at least 1 authentic serum matrix control from an external source, alongside the manufacturer's quality control materials, is essential. All tumor markers must incorporate negative and low positive controls that reflect concentrations pertinent to significant decision-making points. A broad concentration range should be covered, and ideally, a highly concentrated control should occasionally be included to check dilution accuracy, whether manual or onboard.

Proficiency testing specimens should preferably be created from genuine patient sera. The process may involve diluting high-concentration patient sera into a normal serum base pool for tumor markers. Proficiency testing specimens must be commutable with patient specimens to facilitate valid comparisons between methods.[60] Specimens prepared by spiking purified analyte into serum base pools are likely to provide an overly optimistic impression of between-method performance.[61] Specimens should assess performance over the working range and include an assessment of linearity on dilution, baseline security, and stability of results.[62][63]

Every clinical laboratory must establish and implement a thorough safety program. A designated safety officer or safety committee chair should be responsible for overseeing the development and maintenance of the safety program. However, accountability ultimately lies with the laboratory leadership.[64] In smaller facilities, 1 person may handle safety across departments, but the Occupational Safety and Health Administration mandates appointing a chemical hygiene officer to guide the chemical hygiene plan.[65]

Key components of the laboratory safety program include educating and motivating all employees about safety matters. New employees should receive a copy of the general laboratory safety manual during their orientation. The laboratory's continuing education program should incorporate periodic safety talks.[66]

Another crucial element of the laboratory safety program is ensuring compliance with established safety standards. Measures should include proper chemical labeling, appropriate fire extinguisher placement, functioning ventilation hoods, correct grounding of electrical equipment, and ergonomic practices to prevent musculoskeletal disorders, such as using suitable pipetting devices and laboratory furniture. Effective procedures for handling and disposing of biohazardous materials, including patient specimens, must also be covered.[67]

Enhancing Healthcare Team Outcomes

In cancer treatment where CEA is utilized as a tumor marker, the contribution of each healthcare team member is vital for fostering patient-centered care, enhancing outcomes, and ensuring safety. Physicians lead by diagnosing, creating treatment plans, upholding ethical standards, and collaborating with specialists. Advanced practitioners evaluate patients, modify care plans as necessary, and provide education to empower informed decision-making. Nurses play a crucial role in offering essential support to patients, coordinating additional services, and ensuring effective communication within the team to promote safety. Pharmacists oversee medication management, educate patients regarding their use, and strive to maximize treatment efficacy.

Successful interprofessional communication and coordinated care are achieved through structured meetings and shared health records, which are essential for harmonizing treatment approaches, minimizing errors, and cultivating a unified strategy. By integrating their specialized knowledge, ethical dedication, and effective communication skills, the healthcare team significantly improves both patient outcomes and overall team performance.

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Disclosure: Vijaya Kankanala declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Zubair declares no relevant financial relationships with ineligible companies.

Disclosure: Shiva Kumar Mukkamalla declares no relevant financial relationships with ineligible companies.