Su SB, Qin SY, Chen W, Luo W, Jiang HX. Carbohydrate antigen 19-9 for differential diagnosis of pancreatic carcinoma and chronic pancreatitis. World J Gastroenterol 2015; 21(14): 4323-4333 [PMID: 25892884 DOI: 10.3748/wjg.v21.i14.4323]
Corresponding Author of This Article
Dr. Hai-Xing Jiang, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. Jianghaixing2001@163.com
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Carbohydrate antigen 19-9 for differential diagnosis of pancreatic carcinoma and chronic pancreatitis
Si-Biao Su, Shan-Yu Qin, Wen Chen, Wei Luo, Hai-Xing Jiang
Si-Biao Su, Shan-Yu Qin, Wei Luo, Hai-Xing Jiang, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Wen Chen, Department of Educational Administration, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
ORCID number: $[AuthorORCIDs]
Author contributions: Jiang HX designed the study, searched the databases, extracted the data, analyzed the results, and wrote the manuscript; Su SB helped design the study, search the databases, and write and revise the manuscript; Qin SY formulated the research question, and helped with database searches and analysis; Chen W and Luo W helped design the data abstraction form and served as second reviewers in extracting the data; all authors have read and approved the final manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Hai-Xing Jiang, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. Jianghaixing2001@163.com
Telephone: +86-771-5312726 Fax: +86-771-5356758
Received: September 20, 2014 Peer-review started: September 21, 2014 First decision: October 14, 2014 Revised: October 30, 2014 Accepted: January 8, 2015 Article in press: January 8, 2015 Published online: April 14, 2015
AIM: To evaluate the utility of carbohydrate antigen 19-9 (CA19-9) for differential diagnosis of pancreatic carcinoma and chronic pancreatitis.
METHODS: We searched the literature for studies reporting the sensitivity, specificity, and other accuracy measures of serum CA19-9 levels for differentiating pancreatic carcinoma and chronic pancreatitis. Pooled analysis was performed using random-effects models, and receiver operating characteristic (ROC) curves were generated. Study quality was assessed using Standards for Reporting Diagnostic Accuracy and Quality Assessment for Studies of Diagnostic Accuracy tools.
RESULTS: A total of 34 studies involving 3125 patients with pancreatic carcinoma and 2061 patients with chronic pancreatitis were included. Pooled analysis of the ability of CA19-9 level to differentiate pancreatic carcinoma and chronic pancreatitis showed the following effect estimates: sensitivity, 0.81 (95%CI: 0.80-0.83); specificity, 0.81 (95%CI: 0.79-0.82); positive likelihood ratio, 4.08 (95%CI: 3.39-4.91); negative likelihood ratio, 0.24 (95%CI: 0.21-0.28); and diagnostic odds ratio, 19.31 (95%CI: 14.40-25.90). The area under the ROC curve was 0.88. No significant publication bias was detected.
CONCLUSION: Elevated CA19-9 by itself is insufficient for differentiating pancreatic carcinoma and chronic pancreatitis, however, it increases suspicion of pancreatic carcinoma and may complement other clinical findings to improve diagnostic accuracy.
Core tip: Pancreatic carcinoma and chronic pancreatitis show similar clinical manifestations. Differential diagnosis of pancreatic carcinoma and chronic pancreatitis remains a challenge, particularly in patients with pancreatic masses that may be benign (inflammatory) or malignant. Carbohydrate antigen 19-9 (CA19-9) shows promise for differentiating the diseases. We evaluated the usefulness of CA19-9 in this systematic review.
Citation: Su SB, Qin SY, Chen W, Luo W, Jiang HX. Carbohydrate antigen 19-9 for differential diagnosis of pancreatic carcinoma and chronic pancreatitis. World J Gastroenterol 2015; 21(14): 4323-4333
Pancreatic carcinoma is the fourth leading cause of cancer deaths in the United States. Currently, the most effective treatment is surgical resection[2,3]. However, approximately 80% of tumors are unresectable at diagnosis, and these patients show a 5-year survival rate below 5%. The clinical manifestations of pancreatic carcinoma resemble those of chronic pancreatitis. In fact, chronic pancreatitis is strongly associated with pancreatic malignancy and may help to cause it. For example, individuals in parts of Southern India with idiopathic chronic pancreatitis unassociated with alcohol abuse show a high incidence of pancreatic carcinoma.
Differential diagnosis of pancreatic carcinoma and chronic pancreatitis remains a challenge, particularly in patients with pancreatic masses that may be benign (inflammatory) or malignant. This differentiation is important in order to avoid unnecessary resection in patients with inflammatory masses: 5%-10% of patients subjected to pancreatic resection are ultimately diagnosed with pancreatitis rather than pancreatic carcinoma. Differentiation is also important in order to identify correctly pancreatic masses as cancerous and avoid leaving behind malignant masses. Pancreatic carcinoma is incurable in many patients who also have chronic pancreatitis, because the cancer is multicentric or advanced.
Carbohydrate antigen 19-9 (CA19-9) is the most popular serum-based marker for diagnosis of pancreatic cancer, and it is useful for detecting disease recurrence after surgery[6,7]. However, this biomarker has limited diagnostic power. CA19-9 level can be normal in patients with localized disease, therefore, it is less effective for screening for early pancreatic cancer. High CA19-9 levels can also occur in benign diseases, including chronic pancreatitis and nonmalignant jaundice[6-8].
Diagnosis of pancreatic cancer at an early, resectable stage is especially difficult when the patient also presents with chronic pancreatitis[9,10], therefore, we wondered whether CA19-9 might be useful for differentiating the two diseases. We performed a systematic review and meta-analysis of the utility of CA19-9 as a serum tumor marker and its sensitivity and specificity for distinguishing pancreatic carcinoma and chronic pancreatitis.
MATERIALS AND METHODS
In June 2013 we searched MEDLINE (1980 to May 2013), EMBASE (1980 to May 2013), Web of Science (1990 to May 2013) and Cochrane databases. Although no language restrictions were imposed initially, for the full-text review and final analysis only English language articles were included. Additional articles were searched using the “Related articles” function in PubMed and by manually searching reference lists of identified articles and review articles. The following search terms were used: “pancreatic carcinoma” or “pancreatic cancer” and “chronic pancreatitis” and “carbohydrate antigen 19-9” and “diagnosis” or “sensitivity” or “specificity”. We contacted experts in the field to ask about studies that we may have missed in the databases. Conference abstracts and letters to the editor were excluded because of the limited data they contained.
Study inclusion criteria
A study was included when it provided both the sensitivity (true-positive rate) and specificity (true-negative rate) of using serum CA19-9 levels to diagnose pancreatic carcinoma or chronic pancreatitis in patients of any age. Studies were also included if they reported CA19-9 values in a scatter plot format that allowed patient-level data to be extracted. Studies had to involve at least 10 patients with pancreatic carcinoma or chronic pancreatitis in order to reduce selection bias due to a small number of participants. Patients had to be diagnosed with pancreatic carcinoma based on cytology and/or histology of pancreatic tissue, or diagnosed with chronic pancreatitis based on clinical information alone or in combination with histopathological resection, radiology (endoscopic retrograde cholangiopancreatography and computed tomography) and/or endoscopic ultrasonography. Two reviewers (Su SB and Jiang HX) independently determined study eligibility, and disagreements were resolved by consensus.
Data extraction and quality assessment
These same two reviewers independently confirmed the eligibility of the final set of studies and extracted the following data: first author, publication year, participant characteristics, assay methods, sensitivity and specificity data, cut-off values, and methodological quality. Serum CA19-9 values provided in scatter plots were extracted by placing scalar grids over the plots. A receiver operating characteristic (ROC) curve was calculated for each study.
To enable us to assess the methodological quality of the included studies, we extracted data on the following study design characteristics: (1) cross-sectional or case-control design; (2) consecutive or random sampling of patients; (3) blinded (single or double) or non-blinded interpretation of experimental and reference measurements; and (4) prospective or retrospective data collection. Su SB and Jiang HX independently assessed the methodological quality of studies using the Standards for Reporting Diagnostic Accuracy (STARD) guidelines (maximum score of 25) and the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) guidelines (maximum score of 14). Average inter-rater agreement on the methodological quality checklists was 0.96. If primary studies did not report information needed to assess methodological quality, we contacted the authors in an effort to obtain the data. If the authors did not respond, we changed the response for the relevant items from “not reported” to “no” on the assessment instruments.
Standard methods recommended for meta-analyses of diagnostic test evaluations were used. Analyses were performed using Meta-DiSc for Windows (XI Cochrane Colloquium; Barcelona, Spain) and Stata 12.0 (Stata Corporation, College Station, TX, United States). The following measures of test accuracy were analyzed for each study: sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR). A summary ROC (SROC) curve was generated for each study based on a single test threshold for sensitivity and specificity[13,15]. A random-effects model was adopted to calculate the average sensitivity, specificity, and other measures across studies[16,17].
To assess the effects of STARD and QUADAS scores on the diagnostic power of CA19-9, we included them as covariates in univariate, inverse variance-weighted meta-regression. We also analyzed the effects of other covariates on DOR, such as cross-sectional design, consecutive or random sampling of patients, single- or double-blinded interpretation of experimental and reference measurements, and prospective or retrospective data collection. The relative DOR (RDOR) was calculated to analyze the change in diagnostic precision in each study per unit increase in the covariate[18,19]. P < 0.05 was considered to show statistical significance.
The heterogeneity, or variability, across studies was assessed for statistical significance using the χ2 and Fisher exact tests. Publication bias can pose problems for meta-analyses of diagnostic studies, therefore, we tested for the potential presence of this bias using funnel plots and the Egger test.
Selection and summary of studies
We identified 345 citations via electronic searches, and 106 were retrieved for detailed analysis (Figure 1). Of these, 47 studies were excluded for failing to satisfy the inclusion criteria, and another 17 were excluded because they failed to provide sufficient information for meta-analysis. Five studies were duplicate publications. Two articles were meta-analyses, and one was excluded for involving fewer than 10 participants. In the end, 34 publications were included in the analysis[21-54], involving 3125 patients with pancreatic carcinoma and 2061 patients with chronic pancreatitis. The average sample size of the studies was 153 patients (range: 24-941). Table 1 summarizes the clinical characteristics of participants in each study; the numbers of true-positive, false-positive, false- negative and true-negative results; and STARD and QUADAS scores.
Table 1 Summary of carbohydrate antigen 19-9 assay methods, results, and overall methodological quality of included studies.
Of the 34 studies in the meta-analysis, 30 had STARD scores ≥ 13, and 29 had QUADAS scores ≥ 10. All studies collected data from consecutive patients using a prospective design. No study reported interpretation of CA19-9 measurements in which analysts were blinded to the corresponding reference measurements (Table 2).
Table 2 Additional characteristics of patients and methodology in the included studies.
As shown in Figure 2, a Forest plot of serum CA19-9 levels in all 34 included studies showed that the sensitivity of this biomarker to differentiate between pancreatic carcinoma and chronic pancreatitis ranged from 0.44 to 0.96 [mean: 0.81, 95%CI: 0.80-0.83; χ2 = 77.23, P < 0.001), while the specificity ranged from 0.50 to 1.0 (mean: 0.81, 95%CI: 0.79-0.82; χ2 = 111.98, P < 0.001). The PLR was 4.08 (95%CI: 3.39-4.91; χ2 = 113.62, P < 0.001), NLR was 0.24 (95%CI: 0.21-0.28; χ2 = 86.13, P < 0.001) and DOR was 19.31 (95%CI: 14.4-25.9; χ2 = 94.02, P < 0.001). These χ2 values and associated P-values indicate significant heterogeneity among studies.
Figure 2 Forest plot showing sensitivity and specificity of carbohydrate antigen 19-9 in the diagnosis of pancreatic carcinoma.
The point estimates of sensitivity and specificity from each study are shown as solid circles. Horizontal error bars indicate 95%CI. Numbers between the plots refer to references. Pooled estimates for the serum carbohydrate antigen 19-9 assay were 0.81 for sensitivity (95%CI: 0.80-0.83) and 0.81 for specificity (95%CI: 0.79-0.82).
These measures of differential diagnostic power varied with different CA19-9 assays and cut-off values used to define CA19-9 levels as elevated or normal (Table 3). Data from the 11 studies that relied on the enzyme-linked immunosorbent assay (ELISA) method, involving 1396 patients, gave a sensitivity of 0.83 and specificity of 0.79. Data from the 17 studies using the radioimmunoassay method, involving 3074 patients, gave a sensitivity of 0.82 and specificity of 0.81. Data from the three studies that relied on an enzyme immunosorbent assay (EIA) gave a sensitivity of 0.75 and specificity of 0.79. Data from the 30 studies (4879 patients) using a cut-off value of 37 U/mL gave a sensitivity of 0.82 and specificity of 0.80. Data from the three studies using a cut-off value of 100 U/mL gave corresponding values of 0.69 and 0.85. These variations in sensitivity and specificity with CA19-9 assay and cut-off values did not achieve statistical significance (P > 0.05, Table 4), suggesting that high cut-off values such as 100 U/mL may better increase the specificity for differential diagnosis of pancreatic carcinoma.
Table 3 Bivariate estimates of diagnostic precision based on different carbohydrate antigen 19-9 assay methods and cut-off values.
Table 4 Weighted meta-regression of the effects of study design, methodological quality and assay parameters on diagnostic accuracy of carbohydrate antigen 19-9.
Number of studies
Study design and quality
STARD ≥ 13
QUADAS ≥ 10
Consecutive or random design
Assay method or cut-off value
Cut-off of 37 U/mL
Cut-off of 100 U/mL
EIA: Enzyme immunoassay; ELISA: Enzyme-linked immunosorbent assay; ND: Not done; RIA: Radioimmunoassay; STARD: Standards for Reporting Diagnostic Accuracy; QUADAS: Quality Assessment for Studies of Diagnostic Accuracy.
Instead of assessing diagnostic power using the traditional ROC plot, we calculated an SROC plot to reveal the effect of varying thresholds on sensitivity and specificity within each study. In this plot, different studies appear as different data points, allowing SROC curves to provide a global summary of test performance and illustrate the trade-off between sensitivity and specificity. Figure 3 shows an SROC curve for rates of true- and false-positive results obtained with the CA19-9 assay in individual studies. From this plot we determined the Q value, which was defined as the point of intersection of the SROC curve with a diagonal line extending from the left upper corner to the right lower corner of the plot. The Q value indicates the highest identical value of sensitivity and specificity, thereby serving as an overall measure of the discriminatory power of a test. Our SROC curve was desirably positioned near the upper left corner, and the maximum joint sensitivity and specificity was 0.81. The area under the curve (AUC) was 0.88 (Figure 3A), indicating high overall accuracy. SROC plots differed based on the CA19-9 assay method and cut-off values, but all plots were positioned near the upper left corner with AUCs near 0.88 (Figure 3B-F), again indicating high overall accuracy.
Figure 3 Summary receiver operating characteristic curves for carbohydrate antigen 19-9 assays for differential diagnosis of pancreatic carcinoma and chronic pancreatitis.
Solid circles represent each study included in the meta-analysis, with circle size proportional to the number of participants in the study. SROC curves summarize the overall diagnostic accuracy for all included studies (A), studies using a cut-off of 37 U/mL carbohydrate antigen 19-9 (CA19-9) (B), studies using a cut-off of 100 U/mL CA19-9 (C), studies based on the radioimmunoassay method to assay CA19-9 (D), studies based on the ELISA method (E), and studies based on the enzyme immunoassay method (F). ELISA: Enzyme-linked immunosorbent assay; SROC: Summary receiver operating characteristic.
Multiple regression analysis and publication bias
Quality scores based on the STARD and QUADAS guidelines were generated for every study on the basis of the title and introduction, methods, results and discussion (Table 1). These scores were used in meta-regression to assess the effect of study quality on the RDOR of CA19-9 in the differential diagnosis of pancreatic carcinoma and chronic pancreatitis. Studies of higher quality (STARD score ≥ 13; QUADAS score ≥ 10) produced RDOR values similar to those of lower-quality studies. In addition, RDOR values did not differ significantly as a function of blinding, cross-sectional or case-control design, consecutive or random sampling, prospective or retrospective design, CA19-9 assay method, or cut-off values (P > 0.05). These results suggest that study design did not significantly affect diagnostic accuracy and that the risk of detection bias was low.
The Egger test showed no significant evidence of publication bias in reports about CA19-9 assays for differential diagnosis of pancreatic carcinoma (P = 0.944).
Timely and accurate diagnosis of pancreatic carcinoma is critical for patient prognosis, but it remains a challenge because the signs and symptoms of pancreatic cancer overlap considerably with those of chronic pancreatitis. Compounding this challenge is the fact that acute or chronic pancreatitis increases the risk of pancreatic carcinoma, as well as the fact that this cancer can induce secondary inflammatory processes. In this systematic review, we find evidence that although CA19-9 levels on their own are inadequate for differentiating pancreatic carcinoma and chronic pancreatitis, elevated CA19-9 may complement other clinical tests to help confirm a diagnosis of pancreatic carcinoma.
CA19-9 is a sialylated Lewis (Lea) blood-group antigen, which was first identified as a ligand bound by monoclonal antibody 1116 NS 19-9. CA19-9 levels are elevated in > 80% of patients with advanced pancreatic cancer. However, up to 40% of patients with chronic pancreatitis also have elevated CA19-9 levels, suggesting that these levels do not reliably differentiate between patients with pancreatic carcinoma and those with chronic pancreatitis. In contrast to these earlier findings, our meta-analysis shows that the mean sensitivity of a CA19-9 assay was 0.81; mean specificity, 0.81; maximum joint sensitivity and specificity, 0.81; and AUC, 0.88. These values suggest high overall accuracy. These sensitivity and specificity values are similar to the corresponding values of 0.79-0.81 and 0.82-0.90 reported in two previous meta-analyses[6,58]. Interestingly, both previous meta-analyses examined the ability of serum CA19-9 to differentiate pancreatic carcinoma from benign pancreatic diseases in general, not specifically chronic pancreatitis.
DOR is an indicator of test accuracy that combines sensitivity and specificity data into a single number. The DOR is the ratio of the odds of positive test results in the patient with disease relative to the odds of positive test results in the patient without disease. Thus, higher DOR values indicate better discriminatory test performance. The mean DOR in our study was 19.31, implying that CA19-9 levels may be useful in diagnosing pancreatic carcinoma.
Although SROC and DOR meta-analyses provide evidence that CA19-9 can help differentiate between pancreatic cancer and chronic pancreatitis, these diagnostic indicators are difficult to interpret and relate to clinical practice. Therefore, we examined the differential diagnostic power of CA19-9 using the more clinically meaningful likelihood ratio. PLRs and NLRs of > 10 or < 0.1 indicate high accuracy. The overall PLR value in our meta-analysis was 4.08, indicating that patients with pancreatic carcinoma are ~ 4-fold more likely to have elevated CA19-9 than patients with chronic pancreatitis. On the other hand, NLR in our meta-analysis was 0.24, meaning that a patient without elevated CA19-9 would still have a 24% chance of having pancreatic carcinoma, or that 24% of patients with pancreatic carcinoma would not have elevated CA19-9. This proportion is too high to rule out pancreatic cancer in patients who do not have elevated CA19-9. These findings suggest that serum CA19-9 levels are insufficient on their own to differentiate between pancreatic carcinoma and chronic pancreatitis. A better approach may be a combined diagnostic strategy drawing on clinical information as well as findings from cytology and histology of pancreatic tissue, radiology and/or endoscopic ultrasonography.
The present meta-analysis had several limitations. First, the exclusion of conference abstracts, letters to the editor, and non-English-language studies may have led to publication bias, although our bias analysis suggests that this was not a significant problem. Second, nonrandom misclassification bias may have occurred given that different studies used different approaches to diagnose chronic pancreatitis, including histology of pancreatic tissue, radiology, endoscopic ultrasonography and/or clinical information alone. Third, CA19-9 is not routinely measured when patients present with chronic pancreatitis, so the individuals in our meta-analysis may not be completely representative of this patient population. Fourth, 5%-10% of patients lacked the Lewis enzyme, fucosyltransferase, and so cannot present elevated CA19-9 even when tumor burden is high. Finally, we did not identify any large, blinded randomized controlled trials that satisfied our inclusion criteria.
In conclusion, our meta-analysis suggests that although CA19-9 showed considerable sensitivity and specificity for differentiating pancreatic carcinoma and chronic pancreatitis, the relatively high NLR means that CA19-9 levels by themselves have insufficient diagnostic accuracy. At the same time, elevated CA19-9 should increase suspicion of pancreatic carcinoma and may complement other clinical and histological findings to help confirm a diagnosis of cancer.
Pancreatic carcinoma and chronic pancreatitis show similar clinical manifestations. Carbohydrate antigen 19-9 (CA19-9) shows promise for differentiating the diseases.
Differential diagnosis of pancreatic carcinoma and chronic pancreatitis remains a challenge, particularly in patients with pancreatic masses that may be benign (inflammatory) or malignant.
Innovations and breakthroughs
This is believed to be the first systematic review and meta-analysis of the utility of CA19-9 as a serum tumor marker and its sensitivity and specificity for distinguishing pancreatic carcinoma and chronic pancreatitis.
Available evidence suggests that elevated CA19-9 by itself is insufficient for differentiating pancreatic carcinoma and chronic pancreatitis. Nevertheless, elevated CA19-9 should increase suspicion of pancreatic carcinoma and therefore may complement other clinical findings to improve the accuracy of differential diagnosis.
This study evaluated the role of CA19-9 for differentiating pancreatic carcinoma and chronic pancreatitis and concluded that CA19-9 itself is insufficient, but elevated CA19-9 should increase suspicion of pancreatic carcinoma and therefore may complement other clinical findings to improve the accuracy of differential diagnosis. This result is reasonable and valuable for clinical practice.
P- Reviewer: Chen JQ, Kim TH S- Editor: Yu J L- Editor: Wang TQ E- Editor: Liu XM
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