Lung cancer tumor markers in serous effusions and other body fluids
Abstract
From its onset and during its progression, lung cancer may affect various extrapulmonary structures. These include the serous membranes, the pleura and pericardium, and less frequently the central nervous system, with leptomeningeal involvement. In these cases, fluid accumulates in the serous membranes which may contain substances secreted by the tumor. Measuring the concentrations of these substances can provide useful information for elucidating the origin of the fluid accumulation, either in pleural and pericardial effusions or in cerebrospinal fluid. This paper describes the histological types of lung cancer that most frequently affect the serosa and leptomeninges. It also reviews the literature on tumor markers in different fluids and makes recommendations for their interpretation.
1Introduction
Lung cancer (LC) is the third most common cancer in the United States. According to the American Cancer Society, 236,740 new cases are expected in the general population in 2022, with an estimated mortality rate of 130,180 cases [1]. In 2020, there were more than 2.2 million new cases of LC worldwide with a forecast of 1.8 million deaths.
In Europe the data are similar to those of the US. In 2020, 2,339,617 cases of lung cancer were recorded, representing 13.5% of tumors among men (315,054 cases) and 7.9% among women (162,480 cases) [2]. Lung cancer is the leading cause of death due to cancer in men and the third highest in women [3]. It rose from fourth to third place among women in 2019, probably due to the increase in tobacco consumption in women since 1970 [4].
The severity of the prognosis of LC means that the clinical practices for the treatment of the disease need to be continuously updated. Today, due to advances in the understanding of specific molecular pathways, it is possible (and also essential) to differentiate between adenocarcinoma, squamous cell carcinoma, and other histological types of LC. Thanks to this new knowledge, targeted therapies can be designed which incorporate drugs that are effective against particular types of tumor but may be toxic in other contexts (for example, tyrosine kinase inhibitors).
The 2015 World Health Organization (WHO) classification reflects the distinction between types of LC [5].
1.1Non-small cell lung cancer
• Adenocarcinoma
Currently this is the most common histological type. Like squamous cell carcinomas, adenocarcinomas are made up of large cells [6]. The nuclei are vesicular and clear, with nucleoli; the cytoplasm is wide, with formation of vacuoles of mucus. Adenomas present great heterogeneity, and often have more than one morphological pattern within the same tumor [7].
• Squamous cell carcinoma
Histologically, these tumors are made up of large cells and abundant cytoplasm. Well-differentiated forms present keratinization of the cytoplasm and intercellular bridges. From the immunohistochemical perspective, they express high molecular weight cytokeratins and CEA [8].
• Large cell carcinoma
The morphology, architecture and immunohistochemistry of these large lung cancer cells differ from those of the other histological types (i.e., squamous, glandular or small cell lung cancer, SCLC).
1.2Neuroendocrine tumors and SCLC
These tumors express neuroendocrine markers (chromogranin, synaptophysin and CD5). Prognosis is poor, and EGFR mutations have occasionally been described.
• Adenosquamous carcinoma
• Sarcomatoid carcinoma
• Unclassifiable carcinomas and others
A frequent complication of lung cancer is pleural and/or pericardial effusion and, to a lesser extent, leptomeningeal involvement. Very often, the pleural effusion is the first sign patients notice and is the reason why they consult their doctor.
Approximately 20% of patients with lung cancer develop a pleural effusion at some point in their disease, and between 2% and 7% have pericardial effusion [9]. Although brain metastases are common, fewer than 1% have leptomeningeal involvement [10, 11].
The rates of serous effusions are not the same in all types of LC. They are more frequent in adenocarcinomas; due to their peripheral location and ability to metastasize, they more easily invade the pleura and pericardium, creating malignant effusions as the first sign of cancer. In squamous cell carcinoma, pleural effusions occur more frequently once the disease is progressing. For their part, SCLCs are particularly aggressive and present a high proportion of effusions and a high level of leptomeningeal involvement, though less than adenocarcinoma. Table 1 shows neoplasms associated with malignant pleural effusions.
Table 1
Pathologies associated with malignant pleural effusions [39]
| Malignancy | Histologic subtype | Prevalence (%) |
| Lung cancer | Adenocarcinoma (ADC) | 29–37 |
| Small Cell Lung Cancer (SCLC) | 6–9 | |
| Squamous cell carcinoma (SCC) | 2 | |
| Breast cancer | Breast adenocarcinoma | 8–40 |
| Gynecological malignancy | Ovarian adenocarcinoma | 18–20 |
| Gastrointestinal cancer | Gastric adenocarcinoma | 2 |
| Colorectal adenocarcinoma | 1 | |
| Pancreatic adenocarcinoma | 3 | |
| Kidney Cancer | Renal Cell Carcinoma | 1 |
| Hematological malignancy | Lymphoma | 3–16 |
| Skin cancer | Melanoma | 5–6 |
| Mesothelioma | Malignant mesothelioma | 1–6 |
| Sarcoma | Sarcoma | 1–3 |
2Lung cancer and effusions
An effusion is a pathological accumulation of fluid in the space between the visceral and parietal serosa (the pleural or pericardial space). In cancer patients there are two main types:
– Neoplastic or malignant effusions, in which the serosa is colonized by tumor cells; in most cases they are exudates.
– Paraneoplastic or paramalignant effusions, in which, in general, the serosa is not colonized by tumor cells. Strictly speaking, these include only effusions in cancer patients that cannot be attributed to specific processes (e.g., cardiogenic shock, cirrhosis, etc.). They can be either transudative or exudative, [9, 12]. The Table 2 shows type and etiology of serous effusions in patients with lung cancer according to Light’s criteria.
Table 2
Type and etiology of serous effusions in patients with lung cancer
| Transudates | Exudates |
| Paraneoplastic | Neoplastic or malignant |
| •Obstruction of lymph vessel | •Neoplastic invasion of serosa |
| •Pulmonary thromboembolism | •Mesothelioma |
| •Hypoalbuminemia | •Infiltration due to contiguity |
| •Superior vena cava syndrome | •Metastasis |
| •Atelectasia | Paraneoplastic |
| •Radiotherapy | •Pulmonary thromboembolism |
| •Chemotherapy (cardiotoxicity) | •Pulmonary obstruction with pneumonia |
| •Radiotherapy | |
| •Chemotherapy (toxicity in serosa) | |
| •Opportunistic infections (pericardial effusions) |
Effusions in LC may have different etiologies:
– Malignant, with infiltration of the serosa by tumor cells: direct involvement of the membrane due to infiltration by contiguity or metastasis, and secretion of cytokines such as vascular endothelial growth factor.
– Disruption of the thoracic duct: metastasis, infiltration.
– Reduced lymphatic drainage: metastasis.
– Increased hydrostatic pressure: superior vena cava syndrome.
– Reduced oncotic pressure which can occur with cachexia, massive liver metastases and the resulting hypoalbuminemia.
– Decreased pleural pressure: atelectasis or trapped lung.
– Direct damage to the serosa due to ionizing radiation or chemotherapy (alectinid).
– Heart failure caused by chemotherapy.
– Increase in pulmonary interstitial fluid: pulmonary thromboembolism, and pneumonia due to tumoral bronchial obstruction or secondary to treatment.
3Diagnosis of neoplastic effusions
It is important to correctly diagnose pleural fluids as malignant or non-malignant according to the TNM classification of the International Association for the Study of Lung Cancer (IASLC) (8th edition, 2015) [13]. The presence of malignant pleural or pericardial effusion is associated with low patient survival. Patients with stage I/III lung cancer and benign serous effusions (pleural and/or pericardial) are candidates for tumor resection, and have a better prognosis than patients with malignant effusion even with the same TNM; the latter are considered metastatic (M1a), and are non-operable [14].
Therefore, an accurate differential diagnosis in these patients is essential in order to establish prognosis and select treatment. The simplest definitive method for diagnosing a neoplastic effusion is pleural fluid cytology. Between 30% and 50% of cytologies are negative, and percutaneous pleural biopsy increases the sensitivity for detecting malignant pleural effusion by 10%. Thoracoscopy has additional diagnostic value in undiagnosed cases of exudative pleural effusion with high clinical suspicion of malignancy, but it is a highly invasive procedure. Therefore, alternative methods are necessary to be able to select patients for these tests.
4Tumor markers and effusions
4.1Pleural effusion
Tumor markers (TMs) play a key role in the differential diagnosis of serous effusions. It is difficult to establish reference limits for TMs in this context, since the measurement is only performed in cases of an accumulation of fluid due to a pathological cause; fluid is not extracted in healthy individuals.
Tumor markers are used for differential diagnosis in effusions with etiologies other than cancer, for example infectious, immunological, and chemical etiologies in which the mesothelium is compromised, and others involving physical processes such as decreased colloid osmotic pressure or increased hydrostatic pressure that do not affect the integrity of the mesothelium. Two types of TM are found in effusions [15]:
1. TMs that are not usually secreted by the mesothelium in benign conditions (e.g., CEA, CA15-3, CA72-4, CA19-9); concentrations are lower in the fluid than in serum.
2. TMs that are normally secreted by mesothelial cells in benign conditions [16] (CYFRA 21-1, CA125, and mesothelin) at concentrations higher than those described in serum in healthy individuals and with a fluid/serum ratio greater than 1 : 1.
Metastases are among the most frequent causes of malignant pleural effusion; they mainly affect the lung, breast, ovaries and the lymph system [17].
Several authors have studied TMs in serous fluids to distinguish between benign and malignant conditions, usually without taking into account the capacity of the mesothelium to produce them. The results obtained vary widely, so it is difficult to recommend a cut-off value and determine the diagnostic yield. The Barcelona consensus of 1994 proposed the following steps [18]:
• Assess marker concentration
• Rule out false positives
• Control evolution
In this situation, it is difficult to control evolution since in most cases only one measurement is available, and in the rest of the cases the time between the samples is insufficient for adequate interpretation. In addition, it should be borne in mind that there are many variables that can affect TM concentrations, such as the analytical technique used, the cut-off value chosen, the presence of benign diseases that can increase TM concentrations such as tuberculosis, empyemas, or inflammatory processes caused by other conditions [19].
For TM assessment to be useful, high specificity is necessary and the number of false positives must be reduced. This is achieved by raising the cut-off point of the TMs to ensure that benign pleural effusions do not exceed it. As Table 3 shows, the studies with the highest discriminant values are the ones with the highest specificity. To improve sensitivity, the combined use of several TMs has been proposed [20].
Table 3
Diagnostic value of tumor markers in pleural effusions
| Tumor marker | Cut-off point | Sensitivity | Specificity | Units | Author | Assay |
| CEA | 45 | 41 | 100 | ng/mL | Porcel et al. [21] | ECLIA |
| CA15-3 | 77 | 40 | 100 | kU/L | ||
| CEA | 60 | 37 | 100 | μg/L | Trapé et al. [40] | ECLIA |
| CA15-3 | 80 | 38 | 100 | kU/L | ||
| CA19.9 | 201 | 22 | 100 | kU/L | ||
| CA72.4 | 21 | 33 | 100 | kU/L | ||
| CEA | 5.88 | 52 | 95 | ng/mL | Santoribio et al. [41] | ECLIA |
| CA15-3 | 24.7 | 54 | 90 | U/mL | ||
| CA19.9 | 7.0 | 50 | 93 | U/mL | ||
| CA125 | 1433 | 33 | 95 | U/mL | ||
| CEA | 2.0 | 65 | 95 | ng/mL | Topolcan et al. [42] | TRACE |
| CA15-3 | 7.6 | 96 | 95 | kIU/L | LIA | |
| CA19.9 | 17.9 | 46 | 95 | kIU/L | IRMA | |
| CA125 | 2545 | 41 | 95 | kIU/L | ||
| CEA | 2.2 | 56 | 89 | μg/mL | Volaric et al. [43] | ECLIA |
| CA125 | 844.2 | 49 | 67 | mU/mL | ||
| CEA | 2.9 | 84 | 97 | ng/mL | Feng et al. [44] | ECLIA |
| CA19.9 | 12.89 | 60 | 92 | U/mL | ||
| Cyfra 21.1 | 43.1 | 67 | 86 | μg/mL | ||
| CEA | 6.5 | 45 | 100 | ng/mL | Gaspar el at. [24] | MPEIA |
| CA15.3 | 62.4 | 40 | 100 | kU/L | ||
| CA19.9 | 103 | 18 | 100 | kU/L | ||
| CEA | 40 | 35 | 100 | ng/mL | Villena et al. [45] | RIA |
| CA 15.3 | 53 | 40 | 100 | IU/mL | ||
| CA72.4 | 16 | 30 | 100 | IU/mL | ||
| Cyfra 21.1 | 150 | 24 | 100 | U/L | Ferrer et al. [46] | RIA |
| CEA | 40 | 35 | 100 | ng/mL | ||
| CA 125 | 1000 | 37 | 100 | ng/mL | ||
| CEA | 288 | 24 | 100 | ng/mL | Trapé et al. [47] | ECLIA |
| CA 125 | 2385 | 33 | 100 | U/mL | ||
| CA 15.3 | 82.2 | 54 | 100 | U/mL | ||
| CYFRA 21.1 | 175 | 50 | 100 | ng/mL | ||
| CA19.9 | 585.4 | 47 | 100 | kU/L | ||
| CEA | 50 | 31 | 100 | ng/mL | Porcel et al. [12] | ECLIA |
| CA 125 | 2800 | 19 | 100 | U/mL | ||
| CA 15.3 | 75 | 37 | 100 | U/mL | ||
| CYFRA 21.1 | 175 | 25 | 100 | ng/mL |
ECLIA: Electrochemiluminescence immunoassay; MPEIA: Magnetic Particle Enzyme Immunoassay; TRACE: Time resolved amplified cryptate; LIA: Lumino-immune assay; IRMA: Immuno-radiometric assay; RIA: Radioimmunoassays.
5Inflammatory processes and tumor markers: False positives
Some benign processes with high levels of inflammation or necrosis of the serosa and surrounding tissues, such as empyema and tuberculous or complicated parapneumonic effusions, can present high TM concentrations in serous fluid. The levels may reach up to 10 times the concentrations of benign effusions without inflammation.
Excluding purulent effusions, Porcel et al. (2017) obtained a slight improvement in sensitivity [41% (45 ng/mL) vs 31% (50 ng/mL) for CEA and 40% (77 IU/mL) vs 37% (75 IU/mL) for CA15-3] with cut-off points similar to or slightly lower than when these effusions are included [21].
These inflammatory effusions are easily identifiable using routine laboratory biomarkers such as adenosine deaminase (for tuberculous effusions or empyema), differential leukocyte count (for empyema or complicated parapneumonic effusions) or C-reactive protein as a marker of inflammation (for tuberculous effusions, empyema, parapneumonic effusions, and severe inflammation) [22, 23], which we can term markers of benignity. These tests allow us to identify false positives and to apply higher discriminant values in patients with positive biomarkers of benignity, thus improving the specificity.
Another cause of high values of TMs in serous fluids is the passage from serum to fluid through the membrane, either due to the presence of tumors that do not invade the mesothelium or other pathological processes such as kidney failure or liver disease that raise serum TM concentrations [22]. These possible false positives can be detected by the fluid/serum (F/S) ratio [24]. Patients with neoplastic invasion of the mesothelium will present higher concentrations in fluid than in serum, while in patients with elevated concentrations in serum the F/S ratio for markers that are usually produced by the mesothelium will be below 1 : 1.
Applying these criteria, our group has evaluated two strategies: one based on a high cut-off value (CEA = 60 μg/L, CA15-3 = 80 KU/L; CA19-9 = 201KU/L and CA72-4 21 KU/L) and the other on a low cut-off point and F/S ratio (CEA = 5 μg/mL; CA15-3 = 30 KU/L, CA19-9 = 37 KU/L and CA72-4 = 6.7 KU/L and F/S>1.2), seeking maximum specificity [16]. The sensitivity and specificity of more than 400 pleural effusion samples were assessed, obtaining a sensitivity of 64% for the high cut-off point and 77% for the low cut-off point and F/S ratio, with specificities of 100% and 98% respectively.
When classifying them according to the biomarkers of benignity (ADA, CRP and % of polynuclear cells) in the group with negative values, the low cut-off point and F/S ratio strategy showed a sensitivity of 80% and a specificity of 100%, and for the high cut-off point the sensitivity was 67% at maximum specificity. In both strategies, the positive predictive value (PPV) was above 99%. For the group with positive biomarkers of benignity, the sensitivity fell in both strategies; maximum specificity was maintained in the high cut-off point strategy, but fell below 95% for the low cut-off point and F/S ratio, with a PPV of 68.8%.
To facilitate the interpretation of TMs in serous fluids, Figure 1 describes an algorithm based on the experience with pleural effusions. The cut-off points established for specificities of 100% in different studies by the same group may be different, so the PPVs may not reach 100%. For this reason, the PPVs are shown as greater than 99%.
![Algorithm for interpretation of TMs in serous fluids [40].](https://content.iospress.com:443/media/tub/2024/46-s1/tub-46-s1-tub220024/tub-46-tub220024-g001.jpg)
6Pericardial effusion
Very few studies have assessed tumor markers in pericardial fluid [22]. Szturmowicz et al. found higher concentrations of CEA and CYFRA 21.1 in malignant pericardial effusions than in non-malignant ones, obtaining values of 80 ng/mL and 0.5 ng/mL respectively for CEA and 260 ng/mL and 22.4 ng/mL for CYFRA 21.1. In view of their results, they proposed optimal cut-off values for these TMs of 5 ng/mL for CEA and 100 ng/mL for CYFRA 21.1 [23].
In previous work the same authors studied non-specific enolase (NSE), obtaining values of 41.8 ng/mL. They argued against its evaluation in blood samples [25].
Karatolios et al. also found higher values in malignant pericardial effusions with specificities of 100% for the following TMs:
[cut off (sensitivity) CEA, 8.5 ng/mL (48%), CA 19.9, 856(15%), CA 72.4, 19.5 UI/mL (45%); SCC, 216 ng/mL (4%), NSE, 348.5 ng/mL (7%)] [26].
The European Society of Cardiology guidelines [27] recommend cut-off points of 5 ng/mL for CEA and 100 ng/mL for CYFRA 21.1.
7Cerebrospinal fluid
Approximately 20% of patients with lung cancer may have metastatic involvement of the central nervous system, although a few of them, around 10% [28], have leptomeningeal involvement, that is neoplastic meningitis (NM). Glass et al. reported that patients with brain metastases without leptomeningeal involvement did not present tumor cells in CSF [29]. The most frequent histological types in NM are SCLC and adenocarcinoma. Other tumors that can produce meningeal metastases are breast tumors, melanomas, lymphomas and leukemias [30, 31]. The diagnosis is made by CSF cytology, but the sensitivity is only 40–60% [32, 33].
Some TMs in cerebrospinal fluid have been studied as aids to diagnosis. As in the case of serous effusions, the discriminant values vary notably from study to study. In general, the CSF concentrations of non-neoplastic meningitis for most TMs (CEA, CA15-3, CA19-9, CA125 and CA72-4) are undetectable, while CSF concentrations of other markers such as NSE and S100 are low and indicate damage to the CNS [34, 35], and so false positives are possible. Table 4 displays the TMs and the discriminant values proposed by various authors.
Table 4
Diagnostic value of tumor markers in CSF with leptomeningeal involvement
| Tumor marker | CSF concentration | Sensitivity | Specificity | Units | Author assay |
| CEA | 4.522 | 81 | 100 | ng/mL | Shi et al. [37] ELISA |
| CA125 | 1.720 | 93 | 65 | U/mL | |
| CA15-3 | 1.695 | 61 | 93 | U/mL | |
| CA19.9 | 1.47 | 69 | 79 | U/mL | |
| CYFRA 21.1 | 1.51 | 79 | 90 | ng/mL | |
| NSE | 9.155 | 92 | 52 | ng/mL | |
| CEA | 0.279 | 97 | 100 | ng/mL | Zhang et al. [36] CLIA |
| CYFRA 21.1 | 1.145 | 97 | 100 | ng/mL | |
| CEA | 3.4 | 71 | 88 | ng/ml | Wang et al. [32] ECLIA |
| CYFRA 21.1 | 5.5 | 35 | 100 | ng/ml | |
| NSE | 14.6 | 57 | 67 | ng/ml | |
| CYFRA 21.1 | 1.61 | 80 | 95 | ng/mL | Hyun et al. [48] ECLIA |
ELISA: double antibody sandwich enzyme linked immunosorbent assay; CLIA: immunochemiluminescent assay; ECLIA: electrochemiluminescence immunoassay.
In addition, increases in CSF TM concentrations due to leakage and/or dysfunction of the blood-brain barrier, or contamination via the blood due to traumatic lumbar puncture, may not have been correctly assessed [36, 37]. Therefore the intrathecal synthesis of the TMs should be measured, in the same way as other macromolecules such as specific IgG in infectious diseases or light chains in multiple sclerosis [31, 36]. Zhang et al. used cut-off points of 1.145 ng/mL for CYFRA 21-1 and 0.279 ng/mL for CEA, finding higher sensitivities and specificities than using the F/S ratio. For their part, Corsini et al. determined CEA, CA125, CA15-3 and CA19-9 in CSF and serum and also the intrathecal synthesis of TMs [38]. The sensitivity of intrathecal synthesis was 94.4% for CEA, 50% for CA125, 83.3% for CA15 -3 and 66.7% for CA19-9. Patients with NM presented intrathecal synthesis of at least one of these markers, but none of the patients with non-neoplastic neurological diseases showed intrathecal synthesis of any TMs; therefore, this strategy seems more useful to be able to identify the origin of the malignant meningitis.
8Conclusions
Lung cancer patients may present serous effusions due to different etiologies, either cancer- or non-cancer-related.
In lung cancer, invasion of the pleural and pericardial serosa by tumor cells is a frequent event. This invasion is more common in adenocarcinomas and SCLC than in other histological types.
Determining whether or not the effusion is malignant is important, given the implications for therapy. An error can lead to overtreatment (surgery when the effusion is malignant and is considered benign) or undertreatment (no surgery when it is benign and considered malignant), which can lead to a worse prognosis.
In the differential diagnosis of serous effusions, the cut-off points described for each of the TMs vary widely. The diagnostic performance of TMs is good when high cut-off points are used to obtain specificities greater than 99%, and combinations of TMs are used to increase sensitivity.
The diagnostic yield can be improved by identifying possible false positives and using specific cut-off points for each group, obtaining higher sensitivity for specificities above 99%.
Leptomeningeal metastases can occur during the progression of lung cancer, with ADC and SCLC being the most frequently involved tumors.
In non-neoplastic neurological processes, the concentrations of some TMs are usually undetectable. For correct interpretation, it is important to confirm the integrity of the blood-brain barrier and bear in mind its possible contamination due to traumatic lumbar puncture. The determination of the intrathecal synthesis of the markers may be a good alternative.
Acknowledgments
We thank Michael Maudsley for his indispensable technical assistance.
Author contributions
CONCEPTION: JT and SB
DATA CURATION: SB, LG-G, CG-F and JT
ANALYSIS OF DATA: SB, LG-G. CG-F and JT
PREPARATION OF THE MANUSCRIPT:SB, JT and LG-G
REVISION FOR IMPORTANT INTELLECTUAL CONTENT: SB, LG-G, CG-F and JT
SUPERVISION: JT
Conflict of interest
Jaume Trapé, Silvia Bérgamo, Laura González-García and Carolina González-Fernández have no conflict of interest to report.
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