CA 19–9 and CE A are unreliable markers for cholangiocarcinoma in patients with primary sclerosing cholangitis

Abstract: Aims/Background: Diagnosis of early cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis with available radiological methods is very difficult. This type of tumor is the second most common cause of mortality after liver failure in these patients. The recognition of CC is important for the selection of patients for, and the results of, liver transplantation (Ltx). In this study our aim was to investigate the value of measuring cancer markers (CA 19–9 and CEA) in patients with PSC for early diagnosis of CC. Methods: 72 PSC patients who were followed at our institution for a long period were included in the study; 9 with CC and 63 without CC. Furthermore, nine patients with CC but without concomitant PSC were included, as well as 24 patients with various cholestatic liver diseases. Serum levels of CA 19–9 and CEA were measured, in 39 PSC patients without CC, on multiple occasions. Moreover, bile was collected during a diagnostic ERCP from 20 patients for measurements of CA 19–9 and CEA. Results: In those PSC patients without CC during the follow-up and with more than one year of follow-up, 15 patients had increased values of CA 19–9 (>37 ng/ml) on some of the occasions. Four of them demonstrated large fluctuations (more than 100 ng/ml difference at different occasions) in serum levels of Ca 19–9. A significant correlation between high CA 19–9 values and serum alkaline phosphatase levels was observed in these patients. The sensitivity of CA 19–9 in detecting CC in PSC patients was only 63%. The sensitivity of CEA and the combination of CA 19–9 and CEA (marker product; King's College formula) were still lower (33%) although the specificity was relatively high (85%). Bile levels of the tumor markers did not demonstrate any clinically useful differences between the different patient groups. Conclusions: Tumor markers as a diagnostic tool in diagnosing CC in patients with PSC are unfortunately not as valuable as previously reported. The serum levels of CA 19–9 can rise temporarily in association with a “biochemical relapse” of PSC (increased values of serum alkaline phosphatase). The marker product of CA 19–9 and CEA has a low sensitivity but a relatively high specificity for the detection of CC in PSC patients.     

The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis

OBJECTIVES: The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum tumor marker for cholangiocarcinoma would be a useful additional diagnostic test. Previous studies have demonstrated that elevated serum concentrations of CA 19-9, a tumor-associated antigen, have good sensitivity and specificity for cholangiocarcinoma in patients with primary sclerosing cholangitis. However, the value of this tumor marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is unclear. Thus, the aims of this study were to determine the usefulness of a serum CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma. METHODS: We prospectively measured serum CA 19-9 concentrations in patients with cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an immunoradiometric assay (CIS Bio International) without knowledge of the clinical diagnosis. RESULTS: The sensitivity of a CA 19-9 value >100 U/ml in diagnosing cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and the benign bile duct stricture groups, the true negative rates were 76% and 92%, respectively. Patients with unresectable cholangiocarcinoma had significantly greater mean CA 19-9 concentrations compared to patients with resectable cholangiocarcinoma. CONCLUSIONS: These data suggest that the serum CA 19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma.     

Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis

BACKGROUND: Primary sclerosing cholangitis is a progressive cholestatic liver disease associated with cholangiocarcinoma. Brush cytology and serum tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9 [CA19-9]) have been used to diagnose cholangiocarcinoma, but there are few data comparing their effectiveness. METHODS: The effectiveness of brush cytology, carcinoembryonic antigen, and CA19-9 for the diagnosis of cholangiocarcinoma was retrospectively studied by review of patients with primary sclerosing cholangitis. Receiver operator curves were used to identify cutoff points for carcinoembryonic antigen and CA19-9. RESULTS: Of 692 patients with primary sclerosing cholangitis screened, adequate follow-up was obtained in 333, 44 (13%) of whom had a diagnosis of cholangiocarcinoma. Three hundred eighteen brush cytology specimens were obtained in 151 patients; serum carcinoembryonic antigen and CA19-9 levels were obtained in 144 and 55 patients, respectively. The overall sensitivity and specificity of brush cytology were, respectively, 46.4% (95% CI [27.5, 64.5]) and 100% (95% CI [97.2, 100]). A carcinoembryonic antigen >5.2 ng/mL had a sensitivity of 68.0% (95% CI [47.5, 83.9]) and specificity of 81.5% (95% CI [73.9, 87.7]). A CA19-9 >180 U/mL had a sensitivity of 66.7% (95% CI [34.9, 87.7]) and specificity of 97.7% (95% CI [88.2, 99.9]). In the subset of patients in which all 3 tests were obtained, (n = 45, cholangiocarcinoma = 8) the combination of an abnormal carcinoembryonic antigen or CA19-9 had the highest sensitivity: 100% (95% CI [65.1, 100.0]) with a specificity of 78.4% (95% CI [63.1, 89.7]). The combination of a positive brush cytology or an abnormal CA19-9 had a sensitivity and specificity of, respectively, 87.5% (95% CI [50.0, 99.4]) and 97.3% (95% CI [86.2, 99.9]). CONCLUSIONS: Screening patients with primary sclerosing cholangitis for cholangiocarcinoma with CA19-9 and carcinoembryonic antigen is reasonable, but the ideal intervals at which to obtain these tests and the cost-effectiveness require further study.     

Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.

Patients with primary sclerosing cholangitis are at an increased risk of developing cholangiocarcinoma, which is difficult to diagnose because the biliary tree is already distorted. Eleven patients with primary sclerosing cholangitis who underwent orthotopic liver transplantation at this hospital were evaluated. Four patients had coincidental histologically proved cholangiocarcinoma. Patients with cholangiocarcinoma in contrast to patients without tumour presented with rapid onset of persistent jaundice, pruritus, and weight loss associated with an appreciable rise in bilirubin (8x v 2x) and alkaline phosphatase (3.5x v 1.2x) over one year. Cholangiography and computed tomography showed appreciably dilated intrahepatic bile ducts (3/4 v 0/7). The diagnosis of cholangiocarcinoma could only be established before operation in one patient by fine needle aspiration cytology. Tumour was recognised at operation in one other. Histological examination of hepatectomy specimens showed that patients with cholangiocarcinoma had less advanced histological features of primary sclerosing cholangitis. Multiple areas of carcinoembryonic antigen positive epithelial atypia and carcinoma in situ were found in all patients with cholangiocarcinoma. Cholangiocarcinoma recurred in two patients at 14 and 39 months after transplantation. Superimposed cholangiocarcinoma can be predicted in most patients with cholangitis before transplantation, although a definitive diagnosis is difficult to make. Their prognosis after successful transplantation is guarded.     

Impact of dominant stenoses on the serum level of the tumor marker CA19-9 in patients with primary sclerosing cholangitis

BACKGROUND/AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk of developing hepatobiliary tumors. The tumor marker CA19-9 was claimed to indicate the occurrence of bile duct carcinoma. This study aimed to assess whether increased serum levels of CA19-9 in PSC patients with dominant stenoses indicate bile duct carcinoma. METHODS: The study cohort comprised 106 patients treated over a median time of 5.0 years (range 0.5 - 13 years). All patients were treated with ursodeoxycholic acid (UDCA) and whenever they developed dominant stenoses by endoscopic dilatation of these stenoses. In endoscopically treated patients, CA19-9 levels were measured before and 3, 6, 12 and 24 months after endoscopic dilatation. RESULTS: Of the 106 patients, 22 carcinoma-free patients and 3 patients with bile duct carcinoma had elevated CA 19 - 9 levels. In 14 out of 25 patients with elevated CA19-9 levels, dominant stenoses were diagnosed and treated by endoscopic dilatation. In 71.4 % of the endoscopically treated patients, CA19-9 levels decreased following the endoscopic intervention. CONCLUSIONS: In PSC patients, increased serum levels of CA19-9 are rarely due to the development of bile duct carcinoma. In patients with dominant stenoses, the relief of biliary obstruction by endoscopic dilatation may lead to a decrease of the serum levels of CA19-9.     

Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis

Introduction: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the hepatobiliary system characterized by chronic inflammation, progressive fibrosis, stricture formation and destruction of extrahepatic and intrahepatic bile ducts.

Areas covered: The increased incidence of cholangiocarcinoma (CCA) in PSC has been well documented and can be explained by the continuous inflammation in the biliary tree leading to an enhanced dysplasia–carcinoma sequence. Although PSC patients may progress to liver cirrhosis; CCA most commonly occurs between the ages of 30 and 45 years when cirrhosis has not yet developed. Therefore, CCA in patients with PSC occurs earlier than in patients without PSC.

Expert commentary: Despite improvement in diagnostic methods and devices, the dilemma of diagnosing CCA in patients with PSC has not been solved yet and needs further investigation.     

Markedly elevated serum CA 19-9 levels in association with a benign biliary stricture due to primary sclerosing cholangitis

We report on the case of a 55-year-old man with long-standing ulcerative colitis who developed jaundice. This led to a diagnosis of primary sclerosing cholangitis being made, with a dominant stricture in the common bile duct. Serum CA 19-9 was initially markedly raised at 26,321 U/mL but fell promptly into the normal range after stenting of the stricture. Long-term follow up of this patient has failed to show evidence of cholangiocarcinoma. We conclude that serum CA 19-9 levels need to be assessed in the clinical context of biliary obstruction and should ideally be measured after relief of that obstruction, as it may be falsely elevated due to benign biliary strictures.     

Utility of serum CA19-9 in diagnosis of cholangiocarcinoma： In comparison with CEA

AIM:The diagnosis of cholangiocarcinoma is often difficult,making management approaches problematic. A reliable serum marker for cholangiocarcinoma would be a useful diagnostic test. The aims of our study were to evaluate the usefulness of a serum CA19-9 determination in the diagnosis of cholangiocarcinoma.METHODS: We prospectively measured serum CA19-9 and CEA concentrations in patients with cholangiocarcinoma (n=35), benign biliary diseases (n=92), and healthy individuals (n=15). Serum CA19-9 and CEA concentrations were measured by an immunoradiometric assay without knowledge of the clinical diagnosis.RESULTS:The sensitivity of a CA19-9 value>37KU·L^-1 and a CEA value >22μg·L^-1 in diagnosing cholangiocarcinoma were 77.14% and 68.57%, respectively. When compared with the benign biliary diseases group,the true negative rates of serum CA19-9 and CEA were 84.78% and 81.52%,respectively. The false positive rates of serum CA19-9 and CEA were 15.22% and 18.48%, whereas the accuracy of serum CA19-9 and CEA were 82.68% and 77.95%,respectively. Serum CA19-9 and CEA concentrations were significantly elevated (P<0.001 and P<0.05) in patients with cholangiocarcinoma (290.31±5.34KU·L^-1 and 36.46±18.03μg·L^-1) compared with patients with benign biliary diseases (13.38±2.59KU·L^-1 and 13.84±3.85μg·L^-1) and healthy individuals (12.78±3.69KU·L^-1 and 11.48±3.37μg·L^-1). In 15 patients undergoing curative resection of cholangiocarcinoma,the mean serum CA19-9 concentration was decreased from a preoperative level of 286.41±4.36KU·L^-1 to a postoperative level of 62.01±17.43KU·L^-1 (P<0.001), and the mean serum CEA concentration from 39.41±24.35μg·L^-1 to 28.69±11.03μg·L6-1(P<0.05). In patients with cholangiocarcinoma,however, no correlation was found between serum CEA and CA19-9 concentrations (r=-0.036).CONCLUSION:These data suggest that the serum CA19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma. Serum CA19-9 is an effective tumor marker in diagnosing cholangiocarcinoma,deciding whether the tumor has been radically resected and monitoring effect of treatment.     

联合CA19-9、CA125和CEA检测在AFP阴性的ICC鉴别诊断中的应用价值

目的探讨血清癌抗原19-9（CA19-9）、癌抗原125（CA125）和癌胚抗原（CEA）联合检测在甲胎蛋白（AFP）阴性的肝内胆管细胞癌（ICC）患者诊断中的价值。方法2014年6月~2016年6月我院收治的ICC患者60例,根据AFP检测结果,将其分为AFP阴性组和AFP阳性组,每组分别为30例。采用微阵列酶联免疫分析法（Array-ELISA）检测血清CA19-9、CA125和CEA,采用受试者工作特征曲线（ROC）下面积（AUC）分别对各标记物及联合检测诊断的灵敏度、特异度和正确率进行评估。结果30例AFP阴性组血清CA19-9、CA125和CEA水平分别为138.8（85.7~185.1）U/ml、109.6（48.4~201.8）U/ml、11.2（17.5~21.9）ng/ml,均显著高于AFP阳性组的【（38.0（16.9~75.5）U/ml、18.1（9.3~48.1）U/ml、5.5（3.1~8.5）ng/ml）,P<0.01】;两组血清肿瘤标志物诊断ICC的ROC曲线下面积均呈现出CA19-9>CA125>CEA的趋势,在AFP阴性组,各单项诊断的ROC曲线下面积分别为0.85、0.83和0.81,显著高于AFP阳性组的【（0.55、0.45和0.42）,P<0.05】;在单项诊断ICC时,血清CA19-9、CA125和CEA的最佳临床诊断截断点分别为124.89 U/ml、96.04 U/ml和11.97 ng/ml;血清CA19-9、CA125和CEA诊断ICC的灵敏度、特异度和正确率分别为（73.33%、76.67%和71.67%）、（66.67%、70.00%和68.33%）和（60.00%、70.00%和65.00%）,以CA19-9检测诊断的效能最高;两组联合检测诊断的ROC曲线下面积均高于单项指标检测的ROC曲线下面积,且都表现为（CA19-9/CA125/CEA）>（CA19-9/CA125）>（CA19-9/CEA）>（CA125/CEA）,在AFP阴性组,各联合检测诊断的ROC曲线下面积分别为0.94、0.88、0.86和0.85 ,显著高于在AFP阳性组的【（0.74、0.62、0.58和0.52）,P<0.05】;（CA19-9/CA125/CEA）、（CA19-9/CA125）、（CA19-9/CEA）和（CA125/CEA）四种联合检测诊断的灵敏度、特异度和正确率均提高,分别为（90.00%、90.00%和90.00%）、（83.33%、83.33%和81.67%）、（76.67%、83.33%和80.00%）和（70.00%、76.67%和73.33%）,以CA19-9/CA125/CEA联合检测诊断效能最高。结论我们认为,血清CA19-9、CA125和CEA联合检测可提高对AFP阴性ICC患者诊断的正确率,需要临床扩大验证。     

Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis

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Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.     

肿瘤标志物CEA、CA19-9在人结直肠癌检测中价值

目的探讨应用肿瘤标志物进行结直肠癌检测及预后判断的临床应用价值。方法汇总本院近3年收治的经手术治疗的结直肠癌患者191例,结合血清及组织学CEA、CA19-9的结果进行分析。结果归为DukeA期的患者仅占全部病例的12.57%。组织病理切片检查CEA、CA19-9阳性率分别为98.40%、74.24%;血清CEA、CA19-9阳性率分别为51.47%和22.39%;两项指标阳性率组织病理切片明显高于血清,P〈0.05,但其浓度与Duke分期具有正相关性。结论血清CEA、CA19-9测定对结直肠癌患者的诊断预后有临床应用价值,但对早期结直肠癌的筛查效果并不理想。     

The tumor markers CEA, TPA and CA 19-9 in gastric cancer

In gastric cancer the tumor markers CEA, TPA and CA 19-9 display relatively low sensitivity, which in relation to a specificity of 90% lies between 20% and 25%. Compared with the simple ESR method, these sensitivities are not remarkably greater. But a combination of parameters based on discriminant analysis achieves distinctly greater sensitivities.     

CEA and CA19-9 in BALF from patients with idiopathic interstitial pneumonia

Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were measured in bronchoalveolar lavage fluid (BALF) in 21 patients with idiopathic interstitial pneumonia (IIP) and 7 healthy volunteers. The concentrations of both CEA and CA19-9 in the BALF were significantly higher in patients with IIP than those in healthy subjects. Significant correlations were present between the concentration of CEA and neutrophil percentage of the total BALF cells and between the concentration of CA19-9 and neutrophil percentage of the total BALF cells in the patients with IIP. Immunohistochemical study of tissue CEA and CA19-9 in the postmortem lungs of patients with IIP showed that CEA staining was present in the epithelia of respiratory bronchioles and alveoli, and it was especially increased in the region of alveoli where type II pneumocytes proliferate. CA19-9 staining was present in the epithelia of the respiratory bronchioles but absent in the epithelia of alveoli. It seems that assay of CEA in BALF may be useful to estimate the degree of pathological change and the activity of IIP.