Introduction
CA- 125 is a high molecular weight transmembrane glycoprotein. It was first detected in ovarian cancer cells, but several studies showed that it is normally expressed on different cell surfaces present in various organs (lung, prostate, pleura, pericardium, and peritoneum). (1-4) With rich oligosaccharide chains, the physiological role of CA-125 is considered to protect the epithelial luminal surfaces from physical stress through hydration or lubrication process thus protecting them from mechanical stress. (1)

Clinically, it has been used as a marker of ovarian cancer, in monitoring, risk stratification and prognostication. CA 125 levels also rise in other malignancies such as lung cancer, mediastinal teratoma and non-Hodgkin lymphoma. (5, 6) Although CA 125 is a well-known marker of ovarian cancer, its serum levels are also upregulated in multiple nonmalignant pathological states but also in physiologic conditions: pregnancy, menstruation, liver cirrhosis, pelvic inflammatory disease, peritoneal trauma, ascites, lung cancer and congestion due to heart failure. (7,8)

Understanding the alternative causes of raised CA 125 is essential for appropriate clinical decision-making. Elevated CA 125 in the absence of malignancy can lead to unnecessary anxiety, invasive procedures, and delays in identifying the actual underlying condition. Therefore, this case is reported to aware healthcare professional’s that they should interpret CA 125 results within the broader context of the patient's clinical presentation, imaging findings, and other relevant laboratory parameters to avoid diagnostic pitfalls.

Case Report

A 62-year-old woman with a history of hypertension and coronary artery disease presented with progressive dyspnea and pleuritic chest pain for two weeks. She had no abdominal symptoms or weight loss. An incidental CA 125 test showed a markedly elevated level of 680 U/mL (normal <35 U/mL), while other tumor markers including CEA and AFP were within normal limits. Pelvic ultrasound confirmed normal ovarian and uterine structures. CT imaging of the chest and abdomen revealed a large pericardial effusion without abdominal masses, lymphadenopathy, or pelvic abnormalities. Echocardiography demonstrated cardiac tamponade physiology. Pericardiocentesis drained exudative fluid with a protein concentration of 4.2 g/dL. Cytological examination showed no malignant cells, and a diagnosis of idiopathic pericarditis was established. Following pericardiocentesis and NSAID therapy, her CA 125 decreased to 85 U/mL within two weeks and normalized to 22 U/mL after complete resolution of the effusion.

Discussion

CA 125 is produced by mesothelial cells lining the serous cavities, including the pericardium, pleura, and peritoneum. Elevated levels can therefore be seen in non-malignant conditions such as serosal inflammation and heart failure. In this patient, pericardial inflammation likely led to mesothelial activation and increased CA 125 release.

Stressed mesothelial cells produce CA 125 in response to both fluid overload and inflammation. For example, in heart failure, elevated venous pressure results in fluid congestion within mesothelial-lined spaces, triggering the release of inflammatory markers such as IL-6, IL-10, and TNF. (9) Mesothelial cells can be stimulated by inflammation, mechanical stress, or fluid accumulation to produce CA 125, and studies have shown that inflammatory cytokines such as IL-1 are potent inducers of CA 125 production. (10)

In pericardial effusion, congestion often causes fluid buildup not only in the pericardium but also in the pleural and abdominal cavities, worsening inflammation in a vicious cycle. High venous pressure in these areas, rich in mesothelial cells, further promotes CA 125 release. (11)

Additionally, bacterial translocation or endotoxin production, especially in right heart failure with bowel congestion, can enhance CA 125 production even more. (11)

In large ovarian tumors with pleural effusion, as seen in Meigs syndrome, CA 125 levels are typically high. Here, the tumor induces fluid accumulation in the peritoneal cavity, and mechanical irritation from the fluid stimulates mesothelial cells to produce CA 125. Similarly, in our case, pericardial fluid accumulation and inflammation likely irritated the mesothelial cells lining the pericardium, resulting in elevated CA 125 levels. This rise reflects mesothelial activation rather than direct tumor secretion.

This case highlights the importance of interpreting CA 125 results in the context of clinical findings and imaging studies, and of considering benign causes before pursuing oncological referrals to avoid unnecessary investigations and patient anxiety.

Conclusion

Clinicians should interpret elevated CA-125 with caution, especially in patients with serosal effusions, to avoid unnecessary oncologic referrals and patient anxiety

Authors Contribution: All authors are independent experts and equally contributed to the expert

article published.

Funding: None declared

Conflict of Interest: None declared

1. Huang F, Chen J, Liu Y, Zhang K, Wang J, Huang H. New mechanism of elevated CA125 in heart failure: the mechanical stress and inflammatory stimuli initiate CA125 synthesis. Medical hypotheses. 2012 Sep 1;79(3):381-3.

2. Scholler N, Urban N. CA125 in ovarian cancer. Biomarkers in medicine. 2007 Dec 1; 1(4):513-23.

3. Lloyd KO, Yin BW. Synthesis and secretion of the ovarian cancer antigen CA 125 by the human cancer cell line NIH: OVCAR-3. Tumor biology. 2000 Dec 15; 22(2):77-82.

4. Lei Y, Zang R, Lu Z, Zhang G, Huang J, Liu C et al. ERO1L promotes IL6/sIL6R signaling and regulates MUC16 expression to promote CA125 secretion and the metastasis of lung cancer cells. Cell Death & Disease. 2020 Oct 14; 11(10):853.

5. Bottoni P, Scatena R. The role of CA 125 as tumor marker: biochemical and clinical aspects. Advances in cancer biomarkers: from biochemistry to clinic for a critical revision. 2015 Jan 1:229-44.

6. Miralles C, Orea M, Espana P, Provencio M, Sánchez A, Cantos B et al. Cancer antigen 125 associated with multiple benign and malignant pathologies. Annals of Surgical Oncology. 2003 Mar;10(2):150-4.

7. Núñez J, Minana G, Núñez E, Chorro FJ, Bodí V, Sanchis J. Clinical utility of antigen carbohydrate 125 in heart failure. Heart failure reviews. 2014 Sep;19(5):575-84.

8. Llàcer P, Bayés-Genís A, Núñez J. Carbohydrate antigen 125 in heart failure. A New era in the monitoring and control of treatment. Medicina Clínica (English Edition). 2019 Apr 5;152(7):266-73.

9. Kosar F, Aksoy Y, Ozguntekin G, Ozerol I, Varol E. Relationship between cytokines and tumour markers in patients with chronic heart failure. European journal of heart failure. 2006 May;8(3):270-4.

10. Turgut O, Tandogan I, Yilmaz MB, Gul I, Gurlek A. CA125 levels among patients with advanced heart failure: an emerging independent predictor for survival. International journal of cardiology. 2010 Nov 5;145(1):71.

11. Krack A, Sharma R, Figulla HR, Anker SD. The importance of the gastrointestinal system in the pathogenesis of heart failure. European heart journal. 2005 Nov 1;26(22):2368-74.