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Annals of Surgical Oncology 10:150-154 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Cancer Antigen 125 Associated With Multiple Benign and Malignant Pathologies

C. Miralles, MD, PhD, M. Orea, MD, P. España, MD, PhD, M. Provencio, MD, PhD, A. Sánchez, MD, B. Cantos, MD, R. Cubedo, MD, E. Carcereny, MD, F. Bonilla, MD, PhD and T. Gea, MD, PhD

From the Servicio de Oncología Médica (CM, PE, MP, AS, BC, RC, EC, FB) and Servicio de Bioquímica (MO, TG), Clínica Puerta de Hierro, Hospital Universitario, Madrid, Spain.

Correspondence: Address correspondence and reprint requests to: Pilar España, MD, PhD, Servicio de Oncología Médica, Hospital Universitario Clínica Puerta de Hierro, San Martín de Porres 4, 28035, Madrid, Spain; Fax: 34-91-3730535; E-mail: mpespanas{at}seom.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Cancer antigen (CA) 125 tumor-associated antigen is a high molecular glycoprotein used for follow-up of epithelial ovarian cancer. The test is often requested as a differential diagnosis in patients with pleural or peritoneal fluid. This study analyzes the prevalence of CA-125 increases in a population of patients attending a general hospital and discusses the possible clinical implications of increased levels.

Methods: On 4 different days, 380 CA-125 assays were performed in randomly selected patients attending our hospital. Serum CA-125 was measured with a commercial enzyme immunoassay, and clinical records were reviewed for assessment of clinical parameters.

Results: Sixty-one patients (16%) had increased CA-125. The pathologies of these patients were heart failure in 9 (14.7%), lung disease 11 (18%), hepatic cirrhosis in 7 (11.4%), malignant tumors in 9 (14.7%), intra-abdominal nonhepatic disease in 6 (10%), previous surgery in 17 (27.8%), and miscellaneous in 2 (3%). Effusions were seen in 34 patients (55.7%).

Conclusions: Our data confirm the variety of benign and malignant pathologies coursing with increased CA-125. Cardiovascular and chronic liver disease were the most frequent diagnoses in patients with increased CA-125; this supports the opinion that CA-125 lacks utility as a marker for malignancy. CA-125 could have a role in the follow-up of cardiovascular, hepatic, and tumoral diseases with serosal involvement.

Key Words: CA-125 • Serum markers • Mesothelial cells • Ovarian cancer • Serosal involvement


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The cancer antigen (CA) 125 tumor-associated antigen is a high molecular glycoprotein produced by normal cells of different tissues derived from the celomic epithelium. Increased levels have been found in several pathologic situations, and this has demonstrated clinical utility for monitoring the course of epithelial ovarian cancer. Even though clinical utility other than the follow-up of ovarian carcinoma has not been accepted, many physicians still request the test in various clinical situations, especially as a potential marker of occult ovarian carcinoma when serosal structures are involved. When the level is high, multiple analyses and x-rays are required to confirm or refute the supposed occult malignancy. All these tests have important psychological and economic consequences for patients. The use of the CA-125 serum assay as a single diagnostic tool is restricted by the fact that the antigen CA-125 is produced by normal epithelia and not only by the ovarian cancer cell. We performed this study to evaluate the prevalence of CA-125 increases in a wide-ranging patient population attending a general hospital and to assess the possible meaning of that increased level.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
A total of 380 CA-125 assays were performed on 4 different days in randomly selected patients attending our general hospital clinics. The first day, 93 assays were performed; on the second day, 97; on the third day, 93; and on the fourth, 94; all were the first serum samples received in the biochemical laboratory from both inpatients and outpatients. Serum CA-125 was measured with an enzyme immunoassay (AxSYM CA-125, Abbott Diagnostics, Abbott Park, IL). A value >35 U/mL was considered increased. Patients with increased serum CA-125 levels were evaluated, and their clinical records were reviewed. The clinical parameters evaluated were age; sex; clinical diagnosis; presence of pleural, pericardial, or peritoneal effusion; and a history of previous surgery at an interval of <4 weeks. Patients were divided into seven groups according to clinical diagnosis: (1) heart failure, (2) lung disease, (3) hepatic cirrhosis, (4) malignant tumors, (5) intra-abdominal (nonhepatic), (6) history of recent previous surgery, and (7) miscellaneous.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
A total of 61 (16%) patients had a value of CA-125 >35 U/mL (13 patients the first day, 14 the second day, and 17 the third and fourth days); 15 were women and 46 were men, with a median age of 65 years (range, 17–93 years). The most frequent diagnoses in women were lung disease and heart failure (5 patients in each group), and the most frequent diagnosis in men was hepatic cirrhosis (10 patients; Table 1).


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  		TABLE 1. Clinical characteristics of the series
 
The pathologies with increased markers were previous surgery, 17 patients (27.8%); lung disease, 11 patients (18%); heart failure, 9 patients (14.7%); cancer, 9 patients (14.7%); liver cirrhosis, 7 patients (11.4%); intra-abdominal nonhepatic disease, 6 patients (10%); and miscellaneous, 2 patients (3%). The median value of CA-125 was 100 U/mL (range, 37–897 U/mL); the malignant tumor group had the highest mean value (345 U/mL), and the highest level (897 U/mL) was seen in a patient with hepatic carcinoma. Some CA-125 values >100 U/mL were found in all groups (Table 2).


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  		TABLE 2. Serum levels of CA-125 in different clinical situations (N = 61)
 
Effusions were found in 34 patients (55.7%). Seventeen patients (50%) had pleural effusion, and seven of these patients had heart failure. Twelve patients (35.3%) were found to have ascites, four of them because of liver cirrhosis. Pericardium effusion was found in three patients (8.8%). The pathologies with the highest rates of effusion were previous surgery (8 cases), heart failure (8 cases), malignant tumors (7 cases), and liver cirrhosis (5 cases); 2 of the 11 patients with lung disease also had pleural effusions.

Seventeen patients (27.8%) had had previous surgery: abdominal surgery in eight patients, heart and lung surgery in six patients, and CNS surgery in three patients.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The usefulness of serological markers as a part of diagnosis, follow-up, and screening in cancer is a topic with relevant clinical and social implications. Few serological markers have been approved for diagnosis and follow-up of patients with cancer, and none has demonstrated efficacy as a tool for cancer screening. CA-125 is a sensitive, but not specific, tumor marker that is especially used in the diagnosis and follow-up of ovarian cancer. According to Petignat et al.,1 only 349 (33%) of the 1057 CA-125 assays performed in a regional hospital in Switzerland during a 16-month period were correctly requested because of follow-up monitoring of ovarian carcinoma.

More than 2000 articles on serological CA-125 were published before 1998, and they demonstrated that increased levels of this marker are found in multiple benign and malignant conditions.2–4 The aim of this study was to analyze the prevalence of increased serum CA-125 in a group of patients with different pathologies attending our hospital and to analyze whether there were any common clinical features to explain the marker increment.

Benign pathologies were the most frequent causes of increased serum CA-125 in our study. They accounted for 85% of all the increased cases; the other 15% were malignant tumors, and only one of them corresponded to an ovarian carcinoma. The CA-125 antigen is expressed in amnion and its derivatives of fetal celomic epithelia and in many adult tissues, such as the epithelium of fallopian tubes, endometrium, endocervix, pleura, peritoneum, and pericardium.5

Zeimet et al.6,7 have investigated the release of CA-125 in established ovarian cancer cell lines and in human peritoneal mesothelial cells, both grown as monolayers. Constitutive CA-125 shedding was found to be approximately five times higher in human peritoneal mesothelial cells as compared with ovarian cancer cells.

Heart failure,8 benign pleuropulmonary diseases,9 peritoneal tuberculosis,10–13 liver cirrhosis,14,15 and pancreatic16,17 and gynecological processes18–22 are associated with increased levels of CA-125. The probable etiology of this marker increment is a diffuse insult to the mesothelial cells. When mesothelial cells of the pleura, peritoneum, pericardium, tunica vaginalis testis, or fallopian tube are abnormally stimulated, they can increase their normal production of CA-125, and its serum level increases. Peritoneal tuberculosis is one of the clinical situations in which use of this marker can be very confusing, especially in those cases presenting with mesenteric thickening or ovarian masses.10–13 Other conditions mainly associated with surgical or traumatic rupture of the peritoneum, such as dialysis23–25 or abdominal surgical procedures,26 have been associated with high serum CA-125 levels.

In our study, the relationship of the marker to surgical procedures is evident. Seventeen of the 61 patients had undergone surgery <4 weeks before the CA-125 determination. The surgery was thoracic or abdominal in most patients—14 (82%) of 17—but, curiously, 3 patients had had brain surgery for nonmalignant conditions. A prospective study by Epiney et al.27 compared the levels of CA-125 in patients having recent abdominal surgery with a group in which the surgery was extra-abdominal. The proportion of patients with increased serum CA-125 was significantly higher in the abdominal surgery group.

Lung, liver, biliary tract, stomach, colorectal, and pancreatic malignant tumors are all associated with an increase of serum CA-125 concentrations. This marker is also increased in patients with non-Hodgkin’s lymphoma, and increased levels correlate with mediastinal and/or abdominal involvement or serosal effusions.28 Different tumor types were seen in our series, all of them with widely disseminated disease.

The origin of the marker in the four cases with CNS pathology is not clear, and this condition is not mentioned in medical literature except in patients having malignant tumors with brain metastases29–31 or as part of a paraneoplastic syndrome. We interpret this finding as secondary to a surgical or inflammatory insult of the meningothelial cells. Meningothelial cells are embryonally related to the serosal mesothelial cells.

Markers are often used in support of an elusive clinical diagnosis, and the results are not infrequently the matter of clinical discussions leading to new diagnostic tests. The emotional, social, and economic consequences of improperly used markers are evident and obviously negative.

Clinical evidence supports the fact that CA-125 is nonspecifically increased in any process that injures or irritates the mesothelial cells, such as peritoneal dialysis, surgery, infectious diseases, malignant invasion, or even high venous pressure secondary to cardiac insufficiency. Clinical use of CA-125 as a marker should be limited to following up diseases such as ovarian carcinoma and, possibly, to monitoring cardiac insufficiency or treating peritoneal tuberculosis.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Increased CA-125 is not specific for ovarian malignancy. Increased CA-125 serum levels occur in a diversity of physiological nonmalignant and malignant conditions. The common factor in all of them is serosal involvement. Cardiovascular and chronic liver diseases are the most frequent pathologies seen in the pool of patients with CA-125 increases. Our data confirm the wide spectrum of pathologies coursing with increased CA-125 and its relation to processes affecting organs derived from the celomic epithelium. Because of this relationship and the possible parallel between marker levels and the amplitude of the serosal involvement, a possible role should be considered for this glycoprotein as a marker of clinical evolution and response to treatment of these processes.


   Acknowledgments
 
The acknowledgment is available online at www.annalssurgicaloncology.org.


   Footnotes
 
Increased cancer antigen (CA) 125 is not specific for ovarian malignancy. Clinical evidence supports the fact that CA-125 is nonspecifically increased in any process that injuries the mesothelial cells derived from fetal celomic epithelia.

Received for publication May 10, 2002. Accepted for publication September 17, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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  13. Mas MR, Comert B, Saglamkaya U, et al. CA-125: a new marker for diagnosis and follow-up of patients with tuberculous peritonitis. Dig Liver Dis 2000; 32: 595–7.[CrossRef][Medline]
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  16. Ahmed AS, Long M, Donaldson D. Lessons to be learned: a case study approach—ascites and elevated serum CA-125 due to a pancreatic carcinoma. A diagnostic dilemma. J R Soc Health 2000; 120: 47–51.[Medline]
  17. Sperti C, Pasquali C, Perasole A, et al. Macrocystic serous cystadenoma of the pancreas: clinicopathologic features in seven cases. Int J Pancreatol 2000; 28: 1–7.[Medline]
  18. Kammerer-Doak DN, Magrina JF, Nemiro JS, et al. Benign gynecological conditions associated with a CA-125 level >1,000 U/ml. A case report. J Reprod Med 1996; 41: 179–82.[Medline]
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  22. Tavmergen E, Sendag F, Goker EN, et al. Value of serum CA-125 concentrations as predictors of pregnancy in assisted reproduction cycles. Hum Reprod 2001; 16: 1129–34.[Abstract/Free Full Text]
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