Introduction
Pancreatic cancer is the fourth leading cause of
cancer-related mortality in USA (1) and is a highly lethal disease,
characterized by difficulty of diagnosis, distant metastasis and
aggressive local invasion at an early stage (2). The 5-year survival rate of pancreatic
cancer was reported to be <5.5% (3–5) and
almost all the patients succumbed to their disease within 2 years
(6). Therefore, in order to
improve prognosis, the key determinant is accurate diagnosis at an
early stage. The detection of serum tumor markers was shown to be
an effective and non-invasive diagnostic tool, with >5 serum
tumor markers for the diagnosis of pancreatic cancer. It was
recently suggested that CA125 and CA72-4 (7,8) were
potentially of clinical value for the diagnosis of pancreatic
cancer, although they were commonly considered as biomarkers for
the diagnosis of ovarian and gastric cancer, respectively. However,
in practice, there was inadequate availability of information
regarding the use of CA125 and CA72-4 for the diagnosis of
pancreatic cancer and it was hypothesized that the combined
detection of these markers may increase their diagnostic
sensibility or specificity. Receiver operating characteristic (ROC)
curves (9,10) have been widely used as a standard
approach for calculating the sensitivity and specificity of medical
diagnostic tests. In this study, we aimed to investigate the
diagnostic sensitivity and specificity of single and combined
marker detection by ROC and evaluate the correlations between serum
markers and clinically relevant parameters.
Materials and methods
Study population
Between January, 2012 and June, 2013, data were
collected on 75 patients (31 females and 44 males) with pancreatic
cancer, with a median age of 57 years (range, 25–80 years) and 70
patients with benign pancreatic diseases (27 women and 43 men),
with a median age of 47 years (range, 26–73 years) in the PLA
General Hospital, Beijing, China. All diagnoses were confirmed by
at least one of the following: intraoperative biopsy examination,
pathological examination, or radiological detection. According to
the fifth edition of the TNM classification (11), there were 13 stage I, 8 stage II
and 54 stage III–IV patients. The location of the tumor was divided
into head and body/tail. The tumor size was divided into ≤5 or
>5 cm in diameter. Serum samples were collected prior to
operation or chemotherapy and the patients provided informed
consent for the analysis of CA125, CA19-9 and CA72-4. This study
was approved by the Medical Ethics Committee of the PLA General
Hospital (Beijing, China).
Evaluation of tumor markers
The serum CA19-9, CA125 and CA72-4 levels were
measured using the electrochemiluminescence immunoassay on the
Roche cobas 6000 analyzer (Roche Diagnostics, Mennheim, Germany).
The recommended cut-off values for diagnostic purposes were 37 U/l
for CA19-9, 33 U/l for CA125 and 10 U/l for CA72-4.
Statistical analysis
The Mann-Whitney U test (SPSS 17.0 statistical
software package for Windows; SPSS Inc., Chicago, IL, USA) was
applied to determine the differences in marker levels, followed by
a logistic regression analysis to identify the related serum
markers in the diagnosis of pancreatic cancer and yield a logistic
equation and an ROC curve. The MedCalc statistical software package
(MedCalc Software, Mariakerke, Belgium) was to assess the
difference between different areas under the curve (AUC) and to
evaluate the diagnostic sensitivity and specificity at the optimal
cut-off. The data was described by Q1–3. P<0.05 was
considered to indicate a statistically significant difference.
Results
Serum concentrations of CA19-9, CA125 and
CA72-4 in different groups
The concentrations of CA19-9, CA125 and CA72-4 in
patients with pancreatic carcinoma were significantly higher
(P<0.05) compared with those in patients with benign pancreatic
diseases (Table I).
 | Table ISerum concentrations of CA19-9, CA125
and CA72-4 in different patient groups [median
(Q1–3)]. |
Table I
Serum concentrations of CA19-9, CA125
and CA72-4 in different patient groups [median
(Q1–3)].
| Groups | CA125 (ng/ml) | CA19-9 (ng/ml) | CA72-4 (ng/ml) |
|---|
| Pancreatic
carcinoma | 34.1 (12.3,
164.8)a | 414.6 (60.6,
3132.0)a | 2.8 (1.7,
15.3)a |
| Benign pancreatic
diseases | 17.9 (10.7,
87.4) | 14.3 (7.8, 57.0) | 1.2 (1.0, 1.9) |
Value of serum CA19-9, CA125 and CA72-4
single and combined detection in the diagnosis of pancreatic
cancer
Logistic regression analysis was performed to
identify related serum markers; subsequently, CA19-9 (P<0.05)
and CA72-4 (P<0.05) were selected into the logistic regression
equation (y=1.496−0.004xCA19-9 −
0.207xCA72-4, P<0.001). In terms of AUC, the combined
detection of CA19-9 and CA72-4 was significantly higher (P<0.05)
compared to that of other markers. The maximum corresponding
sensitivity and specificity was yielded at the optimal cut-off
point and the sensitivity of CA19-9 was the highest among marker
detection, whereas the specificity of the combined detection of
CA19-9 and CA72-4) was higher compared to others (Table II and Fig. 1).
| Table IIPerformance characteristics of serum
biomarkers for distinguishing pancreatic cancer from benign
pancreatic diseases. |
Table II
Performance characteristics of serum
biomarkers for distinguishing pancreatic cancer from benign
pancreatic diseases.
| Markers | ROC area (%) | 95% CI | Sensitivity (%) | Specificity (%) |
|---|
| CA19-9 | 83.8a | (76.8–89.4) | 73.3 | 85.7 |
| CA125 | 60.2a | (51.7–68.2) | 30.7 | 88.6 |
| CA72-4 | 78.7a | (71.2–85.1) | 71.4 | 87.1 |
| CA19-9 + CA72-4 | 89.5 | (83.3–94.0) | 70.6 | 92.8 |
Association between serum markers and
clinically related parameters of pancreatic cancer
The concentrations of CA125 and CA19-9 in patients
with pancreatic adenocarcinoma were found to be significantly
higher (P<0.05) compared with those with pancreatic
neuroendocrine carcinoma. By contrast, as regards the levels of
CA72-4, there was no significant difference (P>0.05) between
pancreatic adenocarcinoma and pancreatic neuroendocrine carcinoma.
In terms of tumor location, the concentrations of CA125, CA19-9 and
CA72-4 were not significantly different (P>0.05) between head
and body/tail. The levels of CA125, CA19-9 and CA72-4 in stage
III–IV patients were found to be higher compared with those in
stage II patients, although the difference was not significant
(Table III).
| Table IIIAssociation between serum markers and
clinically related parameters of pancreatic cancer [median
(Q1–3)]. |
Table III
Association between serum markers and
clinically related parameters of pancreatic cancer [median
(Q1–3)].
| | CA125 | CA19-9 | CA72-4 |
|---|
| |
|
|
|
|---|
| Parameters | No. | Value (ng/ml) | P-value | Value (ng/ml) | P-value | Value (ng/ml) | P-value |
|---|
| Histological
type |
| Adenocarcinoma | 62 | 46.4
(14.4–186.3) | | 649.3
(132.9–3783.0) | | 3.4 (1.7–16.4) | |
| Neuroendocrine
carcinoma | 13 | 15.0 (9.7–58.4) | <0.05 | 18.2 (7.7–107.7) | <0.05 | 2.2 (1.8–4.5) | 0.291 |
| Location |
| Head | 42 | 33.6
(12.3–169.3) | | 412.4
(100.8–2237.5) | | 2.7 (1.5–15.8) | |
| Body/tail | 33 | 38.0
(12.3–162.0) | 0.835 | 415.6
(36.4–3665.5) | 0.658 | 3.4 (1.8–12.7) | 0.806 |
| TNM stage |
| I | 13 | 11.7 (10.0–85.9) | | 53.3
(13.4–1107.3) | | 2.1 (1.1–3.6) | |
| II | 8 | 38.5
(11.3–183.1) | | 226.1
(78.7–3623.7) | | 3.4 (2.1–15.3) | |
| III–IV | 54 | 53.5
(17.2–532.3) | 0.064 | 492.6
(81.4–4653.7) | 0.386 | 8.1 (1.8–122.8) | 0.082 |
| Size (cm) |
| ≤5 | 18 | 14.5 (10.0–57.0) | | 151.1
(27.2–935.6) | | 2.4 (1.6–6.42) | |
| >5 | 26 | 20.9
(13.2–141.6) | 0.346 | 348.8
(47.0–1594.5) | 0.28 | 2.8 (1.4–18.0) | 0.702 |
Discussion
As previously described, serological markers that
were in essence antigens and bioactive materials from tumor
tissues, minimally produced by normal cells (12), were commonly used for the diagnosis
of pancreatic carcinoma, particularly CA19-9, an intracellular
adhesion molecule with a molecular weight of >500000, that was
widely applied in the identification of pancreatic cancer. In a
previous study by Goonetilleke and Siriwardena (13), a systematic review of the MEDLINE
database revealed that the median sensitivity of CA19-9 for
diagnosing pancreatic cancer was 79, whereas the median specificity
was 82%. Additionally, in a previous trial by Ni et al
(14), the sensitivity of CA19-9
for the diagnosis of pancreatic cancer was ~80, whereas the
specificity was merely 43%. Moreover, in a study by Ma et al
(12), it was demonstrated that
the sensitivity and specificity of CA19-9 for the diagnosis of
pancreatic cancer were 79.49 and 95.31%, respectively.
Our study demonstrated that the concentration of
CA19-9 in patients with pancreatic adenocarcinoma was significantly
higher compared to that in pancreatic neuroendocrine carcinoma
patients. Although the concentrations of CA19-9, CA125 and CA72-4
in stage III–IV were higher compared to those in stage II patients,
the differences were not significant.
In 2001, CA125 (mucin 16) was identified by
molecular cloning (15) as a cell
surface glycoprotein that could be involved in promoting ovarian
cancer cell growth. It was originally considered as a specific
biological marker for ovarian cancer; however, with an increasing
number of studies, it was demonstrated that it could also play an
important role in diagnosing different types of cancer, including
gastric, colorectal and pancreatic carcinoma. Furthermore, CA125
was found to be an independent predictor of poor outcome in
pancreatic ductal adenocarcinoma and was strongly associated with
patient survival rate (16). It
was suggested that the concentrations of CA19-9 and CA125 were
correlated with tumor size, clinical stage and tumor
differentiation (17). However, in
our study, the levels of serum CA125, CA19-9 and CA72-4 were not
strongly affected by tumor size and although the specificity of the
combined detection (CA19-9 + CA72-4) was increased to 92.8%, its
sensitivity was inferior to that of CA19-9.
In conclusion, our findings suggested the
specificity of the combined detection of CA19-9 and CA72-4) was
increased to 92.8%, suggesting it may be a valuable strategy for
pancreatic cancer screening at an early stage. In terms of
sensitivity, the CA19-9 was found to be a reliable biomarker for
the diagnosis of pancreatic cancer. Furthermore, the concentrations
of CA125 and CA19-9 were found to be significantly different
between pancreatic adenocarcinoma and neuroendocrine carcinoma.
Acknowledgements
This study was supported by grant no. 2011AA02A111
from the National High Technology Research and Development Program
of China (863 Program).
Abbreviations:
|
ROC
|
receiver operating characteristic
|
|
AUC
|
area under the ROC curve
|
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