DOI: 10.1111/tog.

12704 2021;23:21–7
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Raised CA125 – what we actually know. . .

Tamara Howe MBBS MRCOG PGDipMedEd,a* Nava Sokolovsky BA MSc BM BCh,b Ahmad Sayasneh MBChB MD(Res)
c d d
MRCOG, Kazal Omar MBChB MD FRCOG, Farshad Tahmasebi MD MRCOG MSc
a
ST7 Trainee in Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology, Princess Royal University Hospital, Kings’s College
Hospital NHS Foundation Trust, Farnborough Common, Orpington BR6 8ND, UK
b
ST2 Trainee in Obstetrics and Gynaecology, Department of Gynaecological Oncology, St Thomas’ Hospital, London SE1 7EH, UK
c
Consultant Gynaecologist and Gynaecological Oncology Surgeon, Department of Gynaecological Oncology, St Thomas’ Hospital,
London SE1 7EH, UK
d
Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Princess Royal University Hospital, Kings’s College
Hospital NHS Foundation Trust, Farnborough Common, Orpington BR6 8ND, UK
*Correspondence: Tamara Howe. Email: tamara.howe@nhs.net

Accepted on 16 April 2020. Published online 2 December 2020.

Key content  To understand how CA125 is used as a diagnostic tool and to

 Carbohydrate antigen 125 (CA125) is an antigen used
in the diagnosis of epithelial nonmucinous ovarian
cancers.
 CA125 may be elevated in many benign and malignant
conditions, so elevated levels can cause confusion over
patient management.
 The multidisciplinary team is important when planning care for
patients with suspected ovarian cancer.
Learning objectives
 To know the factors leading to CA125 production and its
mechanism of action.
assess the treatment response of ovarian cancer.
 To appreciate patient care options in cases of falsely
elevated CA125.
Ethical issues
 Is the CA125 blood test being used in patients appropriately
and safely?
 In patients with elevated CA125 levels, does this lead to
unnecessary investigations and invasive treatments?
Keywords: CA125 / gynaecological causes of raised CA125 /
nongynaecological causes of raised CA125 / ovarian cancer / ovarian
cancer follow-up

Please cite this paper as: Howe T, Sokolovsky N, Sayasneh A, Omar K, Tahmasebi F. Raised CA125 – what we actually know. . . The Obstetrician & Gynaecologist
2021;23:21–7. https://doi.org/10.1111/tog.12704

assays, a normal level of CA125 is considered to be

Introduction
Ovarian cancer is the leading cause of death from any
gynaecological malignancy.1 Its insidious nature means that
over 70% of women diagnosed will present with late stage
disease (stage III or IV). For this reason, screening for ovarian
cancer has the potential to considerably affect mortality by
detecting it at an earlier stage. For many years, analysis of
carbohydrate antigen 125 (CA125) levels has been the ‘go-to’
investigation for ovarian cancer screening, despite no true
evidence of its efficacy.2
CA125 was first identified by Bast et al. in 1981.3 Bast and
his team isolated the murine monoclonal antibody OC125,
which recognises an epitope on a molecule called CA125 –
so-named because it is the 125th antibody produced against
the ovarian cancer cell line. To date, many other monoclonal
antibodies have been found to target CA125, though OC125
remains the best known.3 CA125 is also known as mucin 16
(MUC16) because it is encoded by the MUC16 gene, located
on chromosome 19 (see Figure 1).4 In most commonly used
<35 IU/ml.5
CA125 levels can increase in both physiological and
pathological conditions. Most research has focused on the
antigen’s molecular structure, with its function remaining a
source of much speculation. CA125 is expressed in tissues
derived from embryonic coelomic epithelia. These include
the endometrium, m€ ullerian epithelium, peritoneum, pleura
and pericardium.2 Within these epithelia, CA125 is
synthesised by mesothelial cells in response to assorted
stimuli, most notably mechanical stress and inflammation.6 It
has been postulated that CA125 plays a role in cell-mediated
immunity by suppressing the response to natural killer cells
and promoting attachment to mesothelial cells by binding
to mesothelin.7
Production of CA125 in response to stress
It is the clinician’s role to discern whether or not elevated
serum CA125 is associated with a benign condition or a

ª 2020 Royal College of Obstetricians and Gynaecologists 21

 Raised CA125 – what we know. . ..
Tandem repeats
≥ 60
(heavily glycosylated)
N-terminal
domain
(heavily
glycosylated)
SEA modules
Putative
cleavage site
TM
Cytoplasmic tail
COOH
Figure 1. CA125, also known as mucin 16 (MUC16), is a protein
encoded by the MUC16 gene on chromosome 19.8 TM =
transmembrane domain.
malignant process. To establish this, it is initially important to
ascertain the biological mechanisms and pathophysiological
processes that stimulate CA125 production. In turn, this
permits us to understand why the CA125 antigen is raised in
such a diverse range of conditions. Current theories suggest
that CA125 is synthesised in the mesothelial cells as a stress
response. This may either occur because of mechanical stress
caused by fluid congestion, or inflammatory stress instigated
by the release of cell mediators, such as tumour necrosis
factors and interleukins.9
CA125 and mechanical stress
Many studies have demonstrated a link between elevated
CA125 and the presence of fluid overload in serosal spaces,
regardless of fluid aetiology. Hung et al.10 looked at patients
with pulmonary oedema, with or without evidence of
associated chronic heart failure (CHF). The study showed
that CA125 levels were higher in patients with pleural
effusions, regardless of CHF status. They also found a
moderate relationship between raised CA125 and decreasing
22
albumin, which can be linked to fluid overload. Comparable
results have been shown in patients with ascites: CA125 levels
are elevated both in association with benign conditions, such
as liver cirrhosis,11 and in association with malignancies, such
as tumours of the digestive tract.12
Topalak et al.13 investigated the link between fluid and
serum CA125 levels for many different gynaecological and
nongynaecological diseases, such as hepatic disease, lung
cancer and nongynaecological peritoneal carcinomatosis.
Patients were divided into those with and without features
of peritoneal or pleural effusions. Raised CA125 levels were
identified in many different conditions, in particular in the
presence of effusions. Despite this, the highest levels are seen
in patients with ascites associated with ovarian cancer, with a
positive correlation between ascites volume and CA125 level.
This suggests that the CA125 antigen is not produced directly
by the tumour and is therefore not a tumour marker per se.
Instead, it is released by the mesothelial cells in response to
the mechanical stretch produced by the fluid. Levels of
CA125 in the ascitic fluid do correlate with the serum levels,
but are much higher than those seen in the blood. This
indicates that the antigen originates in the ascitic fluid, rather
than in the tumour itself.12 In vitro studies have
demonstrated that mechanical stretch of mesothelial cells
causes upregulation of MUC16, lending further support to
this theory.10
CA125 and inflammatory stress
Alternative evidence suggests that CA125 may also be
released in response to inflammatory stress. This may
explain why elevated levels are seen when there is no sign
of serosal effusion;13 for example, in cases of subhepatic
abscess or well-controlled CHF, when there is no evidence of
oedema. Indeed, in vitro studies have demonstrated secretion
of CA125 in response to stimulation with tumour necrosis
factors and interleukins.7
Ovarian cancer and CA125
CA125 testing and the diagnosis of ovarian cancer
Serum CA125 levels are often elevated in ovarian epithelial
cancers but less commonly seen to be in non-epithelial
cancers of the ovary.14 For this reason, in the diagnosis of
ovarian cancer, a CA125 test is often used in conjunction
with transvaginal ultrasound scanning (TVUSS). However,
there is little evidence that this approach can reduce mortality
from ovarian cancer, partly because 50% of women with
stage I disease, and those with occult cancers identified at
prophylactic surgery, have normal levels of this
tumour marker.14
For patients with symptoms of ovarian cancer, current
national guidance recommends CA125 testing as an initial
investigation.1 CA125 level is also required to calculate a risk
ª 2020 Royal College of Obstetricians and Gynaecologists

of malignancy index (RMI) for patients presenting with
ovarian cysts. A level of over 250 IU/ml should trigger
referral to a cancer centre for subsequent management.15
Although CA125 screening is used in the diagnosis of
symptomatic patients, there is currently no evidence to
suggest that screening postmenopausal women with a one-off
CA125 serum blood test will reduce patient mortality.16
CA125 testing in patient follow-up of ovarian cancer
CA125 level may also be used to assess patient response to
chemotherapy and surgical treatment.15 Serum levels are
expected to fall by half within 10 days of surgical resection.17
Postoperative levels correlate with residual tumour mass18
and have a considerable value, which is predictive for
survival.19 For patients who enter complete remission with
chemotherapy treatment, the median time for CA125
normalisation is 1.5 months, while for patients achieving
partial remission it is 4 months.20 Despite this, for 40% of
patients achieving normal CA125 concentrations,
microscopic or macroscopic disease will be found at
second-look surgery.21
The British Gynaecological Cancer Society (BGCS)
advises that CA125 measurement during follow-up is not
mandatory and has not been proven to be of survival
benefit.15 One study demonstrated a shorter interval to
deterioration in global health score or death when treatment
was initiated by an abnormal CA125, compared with those
who received no treatment until they were symptomatic.22
However, the decision for CA125 follow-up must be
individualised: since a rising CA125 level may indicate
recurrence of surgically resectable disease, some patients
may wish to know what might lie ahead, while for others, it
may trigger an image that will determine timing and value
of further treatment.23
Raised CA125 without ovarian cancer
The sensitivity and specificity of CA125 assay is known to be
poor. CA125 levels are elevated in only 75–90% of patients
with advanced disease,24 so it is not an effective screening
tool or stand-alone measurement.25 False-positive results
have been identified in both malignant and benign
conditions.26 Subsequently, it may now be used as a
surrogate biomarker for screening and diagnosis in diseases
other than ovarian cancer.27
Alternative causes of raised CA125 levels may be
physiological or pathological. Johnson et al.28 used data
from a cohort of postmenopausal women in a large cancer
screening trial in the USA to assess lifestyle factors that can
increase CA125 levels. Results demonstrated higher levels in
smokers, women with breast cancer and women using
hormone replacement therapy (HRT), although in most
women these levels were still within the normal range.28
ª 2020 Royal College of Obstetricians and Gynaecologists
Howe et al.
CA125 in pregnancy and the menstrual cycle
CA125 levels fluctuate across the menstrual cycle, with a
peak during menstruation followed by a steady decline until
the end of the cycle.29 Since this fluctuation is not seen in
women who have undergone hysterectomy with ovarian
conservation,30 it suggests that CA125 is linked to the
endometrium. In vitro studies have demonstrated that a
higher concentration of CA125 is produced in endometrial
stromal cells during the proliferative and early secretory
phases; this indicates that production of CA125 is associated
with estrogen-dominated cell growth and activity.31 It has
been postulated that the cause of this may be linked to the
tissue–blood barrier being temporarily weakened at
menstruation. Therefore, endometrial cells release CA125
into the blood, exhibiting higher serum levels. Despite this,
changes in CA125 levels remain mostly within the normal
range in most women.29,30
Serum CA125 levels are altered in pregnancy, with a rise in
the first trimester being attributed to increased production by
the decidua.32 From the start of the second trimester, a
reduction in values can be observed;32 however, some studies
have suggested levels may be further increased by pregnancy
complications, such as pre-eclampsia.33 For these reasons, a
higher cut-off value for serum CA125 levels in pregnancy
may be applicable,34 but no consensus has been reached.
When appropriate, analysing CA125 in pregnancy can help to
support or refute a diagnosis, but the test should only be
undertaken when clinically indicated and always interpreted
with care.
CA125 and endometriosis
A clear link has been identified between raised CA125 levels
and endometriosis. For patients with stage II and above
endometriosis, CA125 levels may reach into the hundreds of
units per millilitre, compared with healthy controls. Levels
have also been shown to be predictive of considerable pelvic
adhesions in such patients.35
CA125 and benign conditions
CA125 levels have been shown to be elevated in various benign
conditions, including gynaecological pathologies such as benign
ovarian cysts, tubo-ovarian abscess, endometriosis, pelvic
inflammatory disease, fibroids and ovarian hyperstimulation
syndrome.26 Many nongynaecological conditions are also
associated with markedly elevated CA125 levels, including
liver cirrhosis;13 lung diseases like interstitial lung disease and
tuberculosis;36 and heart diseases such as heart failure, atrial
fibrillation and pericardial disease.8,9 Observations also suggest
that, in patients with heart disease, CA125 may be used as a risk
stratification tool because particularly high levels have been
linked to rehospitalisation and death.8
Figure 2 summarises the physiological and pathological
causes of raised CA125 levels.
23
 Raised CA125 – what we know. . ..

Raised serum CA125

Pathological causes Physiological causes

Benign causes Malignant causes - Pregnancy

(levels fluctuate with (levels progressively - Menstruation
disease severity) rise over time) - Age

Gynaecological causes - Ovarian cancer

- Endometriosis - Endometrial cancer
- Benign ovarian tumours - Pancreatic cancer
- Acute/chronic salpingitis - Primary peritoneal cancer
- Uterine fibroids - Lung cancer
- Pelvic inflammatory disease - Breast cancer
Nongynaecological causes - Bowel cancer
- Cirrhosis ± ascites - Lymphoma
- Chronic/active hepatitis
- Acute/chronic pancreatitis
- Renal failure
- Interstitial lung disease
- Tuberculosis
- Heart failure
- Atrial fibrillation
- Pericardial disease

Figure 2. Flow chart summarising the physiological and pathological causes of raised CA125.

pelvic or abdominal pain, increased urinary urgency/

CA125 testing in everyday clinical practice
CA125 testing in primary care
In 2011, the National Institute for Health and Care
Excellence (NICE) produced guidance for primary care
professionals on the use of CA125 testing (see Box 1 for a
summary). It recommended testing all women presenting
with symptoms of ovarian cancer. These symptoms included
persistent abdominal distension, early satiety/loss of appetite,
Box 1. Summary of NICE guidance for CA125 testing in primary
care.1
CA125 testing is advised for all women with red flag symptoms raising
suspicion of ovarian cancer (especially if 50 years or older)
Symptoms include:
Bloating
Early satiety  reduction in appetite
Pelvic  abdominal pain
Increased urinary urgency or frequency
Other symptoms to consider:
Unexplained weight loss
Unexplained fatigue
Unexplained change in bowel habit
New onset symptoms of irritable bowel syndrome in women >50 years
frequency, unexplained weight loss, fatigue or changes in
bowel habit. If the patient’s CA125 level is greater than
35 IU/ml, then an abdominal and pelvic ultrasound
is indicated.1
A recent study investigated the outcome of CA125 testing
in primary care in accordance with the NICE guidance. The
authors reviewed a cohort of 4379 women whose CA125
levels had been tested, identifying 152 patients with a newly
raised serum CA125 level (>35 IU/ml). Follow-up data
demonstrated the diagnosis of 16 ovarian cancers. They
concluded that CA125 testing in primary care has a high
specificity for identifying ovarian and primary peritoneal
cancer. It was further suggested that lowering the cut-off
value for CA125 may increase its sensitivity, but would likely
reduce the specificity.37
CA125 testing in patients with ovarian cysts
The Royal College of Obstetricians and Gynaecologists
(RCOG) advises that determining a CA125 level is not
routinely needed for the diagnosis of a simple cyst in
premenopausal women. It also advocates use of the
International Ovarian Tumor Analysis (IOTA) Group M
(malignant) and B (benign) rules for ovarian cyst

24 ª 2020 Royal College of Obstetricians and Gynaecologists


classification. Within this risk stratification process, a serum
CA125 level is not required. Any patient with a single
malignant feature (‘M-rule’) identified on ultrasound
requires referral to the gynaecological oncology team. In
large studies, this classification method reportedly has a
sensitivity of 95% and specificity of 91%.38 Current guidance
for CA125 testing in postmenopausal women with ovarian
cysts is more straightforward. At present, the
recommendation for this cohort of women is that a serum
CA125 level is crucial if any cystic lesion of more than 1 cm
in diameter is identified on the ovary. This is to support risk
stratification and calculation of the RMI.39
CA125 testing outside of clinical guidelines
It is not unusual for serum CA125 testing to be performed
outside of the current guidance, or for the levels to be
elevated in the absence of ovarian cancer. This can pose a
challenge to clinicians. For such patients, a thorough history
and clinical examination must be completed to exclude all
possible physiological and pathological causes of a raised
CA125 level. Involvement of the multidisciplinary team
(MDT) will make it possible to individualise patient
management plans. Traditionally, assays for carbohydrate
antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA)
have been used in the screening criteria for gynaecological
pelvic malignancies40 and may be beneficial for patients in
whom no obvious cause of a raised CA125 level is found.
Serial monitoring of CA125 levels is advantageous in such
patients41 because it has been observed that levels appear to
rise progressively over time in patients with malignancy. On
the contrary, with benign conditions, levels exhibit a more
stable pattern and have the potential to fluctuate with disease
severity.22 Hence, observing a trend of CA125 levels over time
will likely support or discredit any further management plan.
A decision for further imaging or invasive investigations
should be made by the gynaecological oncology MDT. The
risks and benefits should be weighed up against the
possibility of a delayed cancer diagnosis. In such a scenario,
delaying treatment may mean that the patient’s disease
reaches a more advanced stage at final diagnosis.
Investigations considered by the MDT should include
computed tomography (CT) of the patient’s chest,
abdomen and pelvis, and a diagnostic laparoscopy. Such
surgery will allow the surgeon to fully visualise the abdomen
and pelvis, including the peritoneal surfaces. If necessary,
biopsies can be taken and sent for histology to aid
a diagnosis.
CA125 testing – the unintended consequences
As clinicians, our intention is to do no harm; at the
forefront of our management, we are appropriately focused
on excluding a cancer diagnosis. However, patient-centred
care is always important, and communications about and
ª 2020 Royal College of Obstetricians and Gynaecologists
Howe et al.
explanations of tumour marker testing should begin in
primary care. Inappropriate use of CA125 testing may result
in unnecessary investigations and invasive treatments, which
– in turn – can lead to considerable anxiety for
the patient.42
Studies have demonstrated that investigations for
suspected cancer may have negative effects, even for
patients who are ultimately diagnosed with a benign
condition.43,44 Anxiety, psychological distress43 and
immune-endocrine changes44 may remain for weeks or
months after a benign diagnosis. This effect of screening on
mental health and quality of life can be difficult to quantify.5
We must understand the psychological impact of cancer
screening, even in the context of a non-cancer diagnosis.
There are two overriding themes in the literature to consider.
The first is ‘over-reassurance’ for patients, which may
subsequently delay seeking help in the future. This is
understood to be influenced by patients attributing
subsequent symptoms to the benign diagnosis, fear of the
distress caused by the previous ‘false alarm’, and concerns
about wasting doctors’ time. The second theme relates to
‘under-support’ following a non-cancer diagnosis. Patients
are concerned their symptoms will not be taken seriously or
will be dismissed as unimportant.45
The future of CA125 as a tumour marker
Despite CA125 being the most widely used biomarker, it is
neither sufficiently sensitive nor specific to determine a
diagnosis on its own. There has been a suggestion that using
age-specific CA125 cut-off points may be more accurate and
reduce false-positive results, but this requires further
research.5 Many efforts have been made to improve the
diagnostic performance of markers or marker combinations
in the hope that this would improve sensitivity for early
detection. Markers that have been investigated include
human epididymis protein 4 (HE4), mesothelia, CA72-4,
inhibin, kallikreins, and osteopontin.46
Human epididymis protein 4
Of all of these markers, HE4 is one of the most promising.5
HE4 is also known as WAP-type four disulphide core 2
(WFDC2) and is expressed in ovarian cancer cells, especially
in histological subtypes of serous and endometrioid
carcinoma.47 Studies have demonstrated that, as a single
marker or combined with CA125, HE4 has the highest
sensitivity compared with other combinations examined,
especially in early stage ovarian cancer. It is also not falsely
elevated as frequently as CA125. In one particular trial, HE4
was found to have a sensitivity of 73% (versus 86% with
CA125) when used to detect ovarian cancer.48 Moreover,
recent preliminary data have demonstrated elevated HE4
levels in newly diagnosed ovarian cancer patients with
25
 Raised CA125 – what we know. . ..
normal CA125 levels. Despite these data, HE4 has not yet
been approved for use in screening.5
Risk of ovarian malignancy algorithm
The risk of ovarian malignancy algorithm (ROMA) is a test
that has been devised as a first-line marker for referring high-
risk patients to tertiary centres.49 ROMA comprises assays of
HE4 and CA125 and considers the woman’s menopausal
status. One multicentre prospective study evaluated the use
of CA125, HE4 and ROMA in epithelial cancer diagnosis.
The authors concluded that ROMA helped to differentiate
epithelial ovarian cancer from benign disease and that HE4
was more effective in detecting patients with ovarian
cancer.50 ROMA has also been found to perform equally as
well as RMI in detection of ovarian cancer.49
Risk of ovarian cancer algorithm
To further improve the sensitivity and specificity of CA125,
the risk of ovarian cancer algorithm (ROCA) was created.
This looks at a patient’s age and serial CA125 levels over time,
without respect to the absolute value. Although it has been
shown to detect early stage cancers, these levels are not robust
in reducing mortality from ovarian cancers and are costly
to implement.5
Conclusion
CA125 has long been described as the ‘gold standard’ tumour
marker in ovarian cancer diagnosis. However, it is possible to
argue that this is not the case because CA125 testing offers no
reduction in patient mortality. It also unable to detect pre-
invasive disease, so cannot be utilised within a national
screening programme.5 Nevertheless, CA125 testing has a
role in everyday clinical practice because it supports
clinicians in risk stratification for both gynaecological and
nongynaecological conditions. It is the doctor’s responsibility
to use the test appropriately, while explaining its limitations
to the patient. It is becoming clear that we, as doctors,
underestimate both the physical and psychological
consequences of performing this ‘harmless’ blood test.
What the future holds for CA125 within the diagnosis of
ovarian cancer remains to be determined; meanwhile, in
today’s healthcare arena, we should be mindful of the
implications of such a test and interpret its results
with caution.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
FT instigated, researched, wrote and edited the article. TH
researched, wrote and edited the article. AS instigated and
edited the article. NS researched and wrote the article. KO
26
wrote and edited the article. All authors read and approved
the final version of the manuscript.
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