Elevation of tumour marker CA-125 in serum & body fluids: interpret with caution

Commentary
Elevation of tumour marker CA-125 in serum & body
fluids: interpret with caution
Indian J Med Res 125, January 2007, pp 10-12
The cancer antigen (CA) -125 is a high molecular
mass glycoprotein produced both by ovarian cancer
cells as also by normal cells of tissues derived from
coelomic epithelium. Serum CA-125 levels are used
as a marker of tumour activity in patients known to
have ovarian carcinoma1 and commercial tests for
serum CA-125 have been available since 1983. In
women with histologically proven ovarian
carcinoma, levels of serum CA-125 are elevated
>35 U/ml in more than 80 per cent of cases. Levels
are also measured after debulking surgery and during
chemotherapy.
Response to chemotherapy is quite usefully
assessed in ovarian carcinoma patients who have a
high persisting level of serum CA-125 after surgery.
It provides the oncologist with a marker of disease
activity that should drop progressively with each
successive dose of treatment. Ease of access to the
glycoprotein marker in the blood is crucial to its
practical use in the clinic. Relapse after completion
of treatment for ovarian carcinoma may also be
monitored using serum CA-125 levels, especially in
those patients who had a high tumour marker level
prior to their initial treatment. A relatively small
proportion, nearly 20 per cent, of ovarian carcinoma
patients will not produce elevated serum CA-125
levels and is termed “marker negative”. Repeated
measurement of this marker will not usually provide
useful information and can be omitted.
However, elevation of CA-125 levels may occur
in malignant conditions other than ovarian cancer,
in benign diseases and in 1-2 per cent of normal
healthy individuals. Some of the malignant
conditions associated with elevated tumour marker
include lung, bladder, gastric, hepatic and pancreatic
cancers, leukaemia, non-Hodgkin’s lymphoma and
mediastinal teratoma. This tumour marker is also
elevated in pleural effusion associated with Meigs’
syndrome secondary to ovarian fibroma and pseudo-
Meigs’ syndrome related to other benign pelvic
tumours2.
Benign conditions associated with elevated CA-
125 levels are diverse and include cardiac failure,
pleuropulmonary diseases, chronic liver disease,
connective tissue disease, peritoneal dialysis and
recent surgery. In a Spanish study of 380 randomly
selected patients attending a general hospital clinic,
16 per cent had CA-125 levels greater than 35 U/
ml3. The most frequent diagnoses in women were
pulmonary diseases and heart failure, and the most
frequent diagnosis in men was hepatic cirrhosis.
These benign conditions generally represent injury
or proliferation of mesothelial cells leading to serosal
effusions (pleural effusion or ascites). Given the
similar embryonic developmental origins of
peritoneal and pleural lining cells, it is hardly
surprising that irritation or inflammation of either
tissue results in an elevated secretion of CA-125 into
the fluid.
Serum CA-125 levels are generally found to be
higher in malignant conditions compared to benign
conditions. Any cut-off value should be interpreted
with caution. Levels exceeding 1000 U/ml have
been described in benign conditions associated with
10
massive pleural effusion and ascites4. Kalantri et
al5 in this issue have studied CA-125 levels in
pleural effusion and ascitic fluid. In this study, all
patients with ascites and 70 per cent with pleural
effusion had elevation of tumour marker in body
fluid when the aetiology was tuberculous or
pyogenic. Levels of tumour marker were
significantly higher in ascitic fluid compared with
pleural effusion leading to suggestion that
peritoneal epithelium had a greater capacity to
secrete CA-125 than pleural epithelium. Their
findings are in contrast with another recent study
from India where elevated CA-125 in peritoneal
fluid was found in only one out of 36 patients with
TB peritonitis6. Measurement of ascitic fluid levels
of tumour markers like CA-125 has never been a
routine part of ovarian cancer management in the
clinic, for various reasons. Likewise, CA-125 levels
in pleural fluid are not routinely measured for
ovarian or other cancers. Simultaneous
measurement of CA-125 in serum and body fluids
and/or simultaneous assay of CA-125 with a panel
of other tumour markers may improve diagnostic
accuracy in malignant and non-malignant diseases.
Elevation of CA-125 in serum, and less
commonly in other body fluids, will continue to
challenge the diagnostic acumen of physicians. The
challenges are likely to be greater for physicians
managing patients of South Asian ethnicity. The first
scenario can be of a female patient with large pleural
effusion, negative tuberculin skin test, negative TB
smears, negative cytology and markedly elevated
CA-125 level. While in a 20 yr old the diagnosis of
malignant effusion may be difficult to accept but in
a 70 yr old such a diagnosis can be easily proposed
by the physician and a terminal prognosis accepted
by the family. Systemic symptoms of anorexia,
weight loss and cachexia are common to TB, cancer
and other systemic diseases. In tuberculous pleural
effusion smear examinations for acid fast bacilli are
rarely positive. TB culture takes several weeks to
report and the yield of positive culture result is low.
In such a case needle pleural biopsy would be the
investigation of choice as it is minimally invasive
and is likely to be positive showing chronic
granulomatous inflammation in majority of patients
with TB effusion.
Differentiation between abdominal TB and
malignancy may be even more difficult. Abdominal
distension, abdominal pain, abdominal mass and
weight loss are common symptoms. Abdominal TB
is associated with omental thickening, mesenteric
lymphadenopathy, pelvis or tubo-ovarian mass,
ascites and elevation of CA-125 levels in serum and
ascitic fluid. Ascitic fluid examination reveals an
exudate with lymphocyte predominance. Yield of TB
smear and culture remains very low. Tuberculin skin
test has limited usefulness in high prevalence area
and a negative skin test may be seen in many patients
with histologically confirmed abdominal TB7. While
detection of Mycobacterium by polymerase chain
reaction has high sensitivity but availability, cost and
quality control are important limiting factors in
developing countries. Peritoneal biopsy (e.g.,
laparoscopic) would clinch the diagnosis in such
cases. Response to anti-TB therapy is apparent within
few weeks, with symptoms improving first but
resolution of inflammatory masses may take several
months.
Chronic liver disease, secondary to viral or toxic
cause, is another common medical condition that is
prevalent in South Asian developing countries. In
advanced disease stages, rapidly declining general
health is associated with abdominal distension and
pleural effusion. Pleural effusion is a transudate that
is often large (hepatic hydrothorax). This may be
recurrent mimicking malignancy and may become a
source of considerable discomfort. Very high levels
of CA-125 may suggest an underlying ovarian cancer
but raised tumour marker may also occur with
hepatocellular carcinoma or simply due to presence
of large amount of ascites and pleural effusion4.
Decisions based on elevated tumour marker may lead
to inappropriate management and suboptimal
symptom palliation.
HUSSAIN & CAMILLERI: CA-125 IN SERUM & BODY FLUIDS 11
From an oncologist’s point of view, it would
seem that there will be limited general application
of a test on ascitic or pleural fluid that does not
reliably distinguish between different malignant
tumours or indeed between benign and malignant
causes. The lack of specificity of this glycoprotein
makes its measurement unhelpful as a screening tool.
Serum CA-125 should, therefore, not be used as a
screening tool for picking up asymptomatic cases of
ovarian cancer. The American College of Physicians
(ACP), The European Group on Tumour Markers
(EGTM), The European Society of Medical
Oncology (ESMO), The National Institute for Health
(NIH) and The National Academy for Clinical
Biochemistry all agree on this point. Research is
ongoing on algorithms that calculate risk of ovarian
cancer based on serial CA-125 values and referral of
patients at highest risk for transvaginal sonography.
Use of the algorithm is currently being evaluated in
a trial with 200,000 women in the UK that will test
critically the ability of a two-stage screening strategy
to improve survival in ovarian cancer8.
A general physician may remember that some
common medical conditions can be associated with
elevated tumour marker in serum and in body fluids.
Cardiac failure and chronic liver disease can be
picked up by a careful bedside clinical examination.
Tuberculosis may be less easy to confirm and indeed
facilities for further confirmatory tests, in many under
resourced areas, may either be not readily available
or beyond the financial means. A therapeutic trial of
anti-TB medications for 4-6 wk would be justified if
doubt persists about the final diagnosis.
Finally from a researcher’s perspective, CA-125
is an ovarian tumour marker and the challenge is to
detect early stage ovarian cancer that can be cured
with currently available therapy. CA-125 is also a
marker of mesothelial proliferation and there is still
much to learn about the mechanisms of CA-125
production at various sites in the body and its
utilization in medical conditions other than ovarian
carcinoma.
Syed Fayyaz Hussain* & Philip Camilleri+
Kettering General Hospital &
University of Leicester, UK &
+Radiotherapy & Oncology Department
Northampton General Hospital, UK
*For correspondence:
e-mail: Syed.Hussain@kgh.nhs.uk
References
1. Bast RC Jr, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB.
CA125: the past and the future. Int J Biol Markers 1998;
13 : 179-87.
2. Timmerman D, Moerman P, Vergote I. Meig’s syndrome
with elevated serum CA 125 levels: two case reports and
review of the literature. Gynecol Oncol 1995; 59 : 405-8.
3. Miralles C, Orea M, Espana P, Provencio M, Sanchez A,
Cantos B, et al. Cancer antigen 125 associated with multiple
benign and malignant pathologies. Ann Surg Oncol 2003;
10 : 150-4.
4. Hussain SF, Grayez J, Grigorian A, Green JT. A female
with massive pleural effusion and marked elevation of CA-
125. Postgrad Med J 2004; 80 : 300-1.
5. Kalantari Y, Naik G, Joshi SP, Jain A, Phatak S, Chavan
R, et al. Raised CA-125 in non-malignant pleural and
ascetic fluid samples. Indian J Med Res 2007; 125 : 25-30.
6. Bandyopadhyay R, Bandyopadhyay SK, Ghosal J, Kumar
U, Dutta A. Study of biochemical parameters of ascitic fluid
in exudative ascites with special reference to tuberculous
peritonitis. J Indian Med Assoc 2006; 104: 174 : 176-7,
185.
7. Muneef MA, Memish Z, Mahmoud SA, Sadoon SA,
Bannatyne R, Khan Y. Tuberculosis in the belly: a review
of forty-six cases involving the gastrointestinal tract and
peritoneum. Scand J Gastroenterol 2001; 36 : 528-32.
8. Bast RC Jr, Badgwell D, Lu Z, Marquez R, Rosen D,
Liu J, et al. New tumor markers: CA125 and beyond.
Int J Gynecol Cancer 2005; 15 (Suppl 3) : 274-81.
12 INDIAN J MED RES, JANUARY 2007