Role of Cancer

Antigen-125 in
Tuberculosis
Jennifer , MCP Wongkar
Introduction

Tuberculosis (TB) Major Global Health Problem

• In 2014, estimated 9.6 million new TB cases.

• TB deaths  1.5 million cases

Diagnosis :
Bacteriological + clinical examination
Pulmonary TB :
& Radiological (X-Ray)

Symptoms & clinical examination,

Extra-pulmonary TB : bacteriological & histopathologic
sample taken from affected organ
Introduction
• Result of sputum AFB (-)
Suspected cases Sputum
of Pulmonary tb Exam • No specimen available,
ex. dry cough

Other methods to Dx

• Molecular biology  high cost, sophisticated equipment

& human resources  difficult to apply as a routine exa
mination, especially in developing countries.

• Biochemical parameters  Markers of cellular activity,

acute phase reactants, enzymes  found can help Dx TB

• Tumor markers  Cancer Antigen 125 (CA-125) can be

used as one of supporting the diagnosis of TB
 Cancer Antigen-125 (CA-125)
• CA-125  identified by Bast et al. in 1981, through OC125
monoclonal antibody developed from mice injected ovarian
cancer cells.

• Serum CA-125 levels detect ↑↑ at nearly 80% of patients

with ovarian cancer  Various subsequent studies, CA-125
as diagnosis & monitoring th/ in ovarium cancer

• CA-125 is a glycoprotein measuring >200 KD, detected

using a murine monoclonal antibody OC 125.

• CA-125, expressed in various tissues derived from :

• Mesothelialpleural,pericardial,peritoneal,endometrial
cells, genital tract cells & amniotic membrane.
• Not from mesothelial tracheal-bronchial epithelium,
amniotic tissue & cervical mucous membrane.
CA-125
low quantities CA-125 in serum
Healthy men & women
, generally < 35 U/ml

upper limit of normal

level CA-125
CA-125 ↑
Normal • women during menstruation, pregnancy & post
conditions menopause

Benign • heart failure, pleural & lung disease, chronic liver

diseases disease, peritoneal dialysis.

• Ovarium, endometrium, cervix, lung, breast, liver, stomach,

Malignancy pancreas, leukemia, non-Hodgkins lymphoma, mediastinal
teratoma & colorectal malignancy
CA-125
Physiological
& Secrete ↑↑ CA-125
Pathological Cells CA-125 blood / body
factors liquids

• Levels of serum CA-125 

>> in malignancy : benign conditions

• CA-125 levels > 1000 U/ml associated with malignancy,

• But, studies reported, CA-125 >1000 U/ml on a massive

pleural effusion & ascites due to TB & pyogenic.
• Cut off point ??

• Levels of CA-125 can’t be used to determine the cause 

malignancy or not malignancy
CA-125
• effective diagnostic tool
Tumor marker • not invasive
• method for tumor screening

Interestingly, CA-125 also found to be ↑

in patients with TB.

• 1980s  reported ↑ of CA-125 in patient with ascites 

initially suspected of ovarian malignancies, & ultimately di
agnosed with TB peritoneal

• 1995  reported ↑ CA-125 in patients with pulmonary TB.

•
• 1996, Indonesia - Medan  Zain LH reported 8 peritoneal
TB cases with ↑ of CA-125.
CA-125 & Tuberculosis
Elevated CA-125 Pulmonary TB &
in TB Extrapulmonary TB
pleural, peritoneal, pelvic, miliary,
& intra-abdominal

Hypothesis
1. Activation of the inflammatory cascade by M.TB 
abnormal proliferation on mesothelial cells, causing
an ↑ in CA-125.
2. Surface antigen of mycobaterium have same cell
epitope membrane of the tumor marker CA-125.

Immunohistochemistry
Granulomas of TB  associated w/ inflammation & proliferati
on of mesothelium  ↑ production & secretion of CA-125 
showed CA-125 formed a fine line around the granuloma
CA-125 & Tuberculosis
After the discovery of CA-125 in TB, many other studies
reported that tumor marker CA-125, CA-199, & carcino
embryonic antigen (CEA)  found to be higher in
patients with TB than in the normal population.

These results provide a clue, that tumor marker may

have clinical value for the diagnosis of TB.

• Jingjing et al. in China  CA-125 ↑ significantly &

positively correlated in patients with pulmonary TB,
compared to other tumor marker CA-199 and CEA.
• Value CA-125 cutoff point was 10.30 U/ml, with a
sensitivity of 0.956 & specificity of 0.850.
CA-125 & Tuberculosis
↑ cases of extrapulmonary TB
• TB pleural  20% of extrapulmonary TB in US
• Diagnosis  analysis, cytology & adenosine deaminase
(ADA) of pleural fluid. IFN-γ, also can help the Dx

Study by Aoki et al. in Japan, comparing IFN-γ, ADA, &

CA-125 as a diagnostic parameter in TB pleurisy

85.7% of the total sample  ↑ pleural fluid ADA &

serum CA-125, when combined measurement can be
useful as a Dx of TB pleurisy.

Cut-off point of serum CA-125 >35 U/ml obtained

100% sensitivity, 75% specifity.
CA-125 & Tuberculosis
Peritoneal TB
Peritoneal TBoften also found in
present w/ascites, Complicate
ovarian
abd pain, abd/adnexa the Dx
malignancies
mass & ↑ CA-125

Often diagnosis of TB, made after laparotomy performed in p

atients with initial suspicion of ovarian malignancies
Oge et al, reported 20 women with initially suspected ovarian
malignancies  final Dx of TB pelvis & periotenal, made after:
laparotomy (11 patients), laparoscopy (2 pts) & biopsy (7 pts)

Zain LH in Medan, reported 8 cases of peritoneal TB with ↑

CA-125 with average concentration of 370.7 U / ml.
Zain concluded  ↑ CA-125 with the ascites fluid exudates
cell count >350/m3, lymphocyte predominant
 Considered peritoneal TB as diagnosis.
CA-125 & Tuberculosis
In addition to the measurement of serum CA-125,
there are also studies measuring the
levels of CA-125 in pleural fluid.

• Shokouhi et al. studies  CA-125 levels in the pleural

fluid of patients w/pleural effusion.

• The mean levels caused by tuberculosis was 159.1±214

;malignancies is 2149.2 ±4513.6statistically significant.
•
• Cut off values from ROC curves, is 221.5 - 253.5.

• CA-125 value >> the range  likely lead to malignanc

y, and << is TB.
CA-125 & Tuberculosis
CA-125 is usefull to diagnosis in pulmonary TB &
extrapulmonary TB

Kanagarajan et al.  50 samples Pts. with suspected TB,

examination CA-125 & TB Dx confirmed by culture mTB
This study concluded : ↑CA-125 is useful to diagnosis pul
monary & extrapulmonary TB with sensitivity, specificity,
& high negative predictive value

In lymphadenitis TB  levels of CA-125 found normal, maybe

because the lymphadenitis TB, doesn’t involve the
mesothelial tissue containing epithelial so there’s no elevated
levels of CA-125.
CA-125 & Tuberculosis
Cut off point of CA-125 in TB  show variations.

Study by Huang et al.  research in patients w/ pulmonary

TB & TB serositis (pleurisy, pericarditis, peritonitis).

Higher level of CA-125 in TB serositis : Pulmonary TB

234.82 ± 279.25 48.26 ± 53.30

P<0.001

Subgroup analysis showed a mean CA-125 highest in

peritoneal TB  820.67 ± 419.22 U / ml.
CA-125 & Tubeculosis Activity

Fortun et al Yilmaz et al Mohammad et al

Country Spain Turki Mesir
Subject TB : other pulm TB : inactive TB TB : Pneumonia :
onary diseases : control control
Samples 89 96 80
Median / M 46 : 24 38,4 ± 30,5 65.58 ± 69.77
ean (IU/ml)
Cut off 32,5 U/ml 31 U/ml 21,05 U/ml
Sensitivity 68,6 % 97,5% 82,5%
Specivity 77,8 % 100% 72,5%
+ predictive 66,7% - 77,3%
value
- predictive 79 % - 83,3%
value
CA-125 & Tubeculosis Activity

Yilmaz et al.
Ca125 is beneficial in determination of
TB activity & in diferentiation between active & i
nactive pulmonary TB

Kanagarajan et al.
CA-125 Levels appear to be associated with :
- number of bacillary  highest in miliary TB &
pulmonary TB with cavities.
CA-125 & Tubeculosis Activity

Kim et al. in Korea,

100 patients with active pulmonary TB,

Stratified by levels of CA-125normal : increased CA-125

Univariate analysis, showed significantly associated with

elevated levels of CA-125 :
• Female gender (p <0.001)
• Sputum  + (p <0.030)
• Thorax X-ray  extensive pulmonary lesions (p=0.004)

Cavities / bronchiectasis on X-ray 

↑ but not significant
CA-125 & Monitoring Therapy Response in
Tuberculosis

Monitoring response Chest X-Ray, Sputum

therapy of AFB & Culture of
Pulmonary TB mycobacterium

Not effective
 Monitoring therapeutic response in extrapulmonal TB

Fast & precise to Dx of TB,

• Quantiferon-TB
but results not associated
• T-Spot TB
with disease severity or
response to therapy

CA-125  considered to be used to monitoring therapy

in TB, especially in extrapulmonary TB involving serous
 CA-125 is expressed on epithelial cells
CA-125 & Monitoring Therapy
Response in Tuberculosis
Huang et al
Study the levels of CA-125 as monitor therapeutic
response in TB with & without serositis
64 patients with TB
 40 pulmonary TB
 24 extrapulmonal TB (involvement serositis), :
13 pleural TB, 8 pecardisis TB & 3 peritoneal TB

Given anti-TB drugs therapy

CA-125 measured at initiating therapy, 2nd & 6th
months, & every 6 months up to 2 years

Cutt off  35 U/ml  Sensitivity to diagnose TB disease

activity in serositis group was 100%, which is higher than the
group of pulmonary TB at 45%
CA-125 & Monitoring Therapy
Response in Tuberculosis
Huang et al
CA-125 levels fall gradually after therapy is given anti-TB drugs
in both groups (Figure 1).
In the TB serositis group, CA-125 ↓ with ↓ ↓ fluid in the pleural
effusion/pericardial/peritoneum.
CA-125 & Monitoring Therapy Response in
Tuberculosis
In 1 patient with pleural TB,  24th month  CA-125 ↑
 after examination, right pleural effusion (+)

Increased serum CA-125 is also associated with the

presence of TB recurrence (Figure 2)
CA-125 & Monitoring Therapy Response in
Tuberculosis

Yilmaz et al Study  Serum CA-125 levels decreased

significantly after treatment (p <0.0001).

After Tx  CA -125 decreased

Pulmonary TB, newly DX
CA-125 before treatment :
109.7 ± 86.9 U / ml
Monitoring
• 2nd mo : 38.4 ± 30.5 U / ml
• 4th mo : 16.4 ± 13.2 U / ml
• 6rh mo : 11.0 ± 7.7 U / ml
• 3rd year : 10.5 ± 7.3 U / ml
(p <0.0001)  Statistically significant

Cut off point : 31 U/ml  Sensitivity of 97.5% & Specificity of 100%

CA-125 & Monitoring Therapy
Response in Tuberculosis
Based on these results,

CA-125
 Parameter that needs to be taken into account in
determining the activity of the disease

CA-125 is suitable for use as a marker monitoring

therapy than use for screening or diagnosis

because CA-125
can also be elevated in
both benign conditions or cancer
Summary
• Elevated levels of CA-125 is found in both pulmonary TB and
extrapulmonary TB involving serous tissues

• Elevated CA-125 in TB might be useful to detect the activity

of TB, especially in special cases

• Elevated CA-125 was found significantly higher in patients wi

th active pulmonary tuberculosis compared with inactive pul
monary TB.

• Decreased levels of CA-125 after therapy anti-TB drugs, can

be used as an indicator of therapeutic response.

• Measurement of serum levels of CA-125 in combination with

clinical response, radiological & sputum smear examination o
ffering good therapy response monitoring for patients receivi
ng anti-TB drugs.