Background: Pancreatic cancer is a highly lethal malignancy with a 5‑year survival rate of less than 5%. This extremely poor prognosis is attributable to the difficulty of diagnosis, aggressive local tumor invasion, distant metastasis, and little response to chemotherapy or radiotherapy. Therefore, the primary method of improving the prognosis is accurate early diagnosis. CA19-9 is a well-known tumor marker that shows a high sensitivity for diagnosis of pancreatic cancer. A serum CA19-9 level of 37 units/ml has been used as the cut-off value for diagnosis of pancreatic cancer. It has been reported that diabetes is associated with an increased risk of pancreatic cancer (Eur J Cancer. 13:1928, 2011). In addition, the serum CA19-9 level is elevated in patients with poorly controlled diabetes (Jpn J Med. 25:278, 1986), while CA19-9 is normalized after improvement of glycemic control (J Diabetes Investig. 6:694, 2014). Thus, some patients with diabetes show a serum CA19-9 level exceeding 37 units/ml despite not having pancreatic cancer. 

Aims: This study was performed to evaluate the sensitivity, specificity, and cut-off value of serum CA19-9 for early detection of pancreatic cancer in patients with diabetes.

Methods: This was a case-control study of 236 subjects hospitalized at St. Marianna University School of Medicine from April 2007 to March 2017. The case group was selected from diabetic patients with pancreatic cancer diagnosed by gastroenterologists. The criteria for diabetes were 1) use of antidiabetic agents for previously diagnosed diabetes or 2) patients not on treatment for diabetes with HbA1c ≥ 6.5%, fasting blood glucose (FBG) ≥ 126 mg/dl, or postprandial plasma glucose (PPG) ≥ 200 mg/dl.
For each case, one control was selected from among persons who underwent examination at the diabetes center of St. Marianna University Hospital during the same period. Patients were excluded if they had other malignancies or diseases that could increase the CA19-9 level, such as interstitial pneumonia. The case group (n=118) was matched with the control group (n=118) for age, sex, and risk factors for pancreatic cancer (BMI, HbA1c, smoking, and drinking alcohol). Receiver operating characteristic (ROC) curves were plotted to determine the serum CA19-9 level predicting pancreatic cancer. The sensitivity and specificity of CA19-9 were calculated for the threshold value.

Results: The 118 patients in the case group were 76 men and 42 women aged from 58 to 88 years (average age: 71.1±8.9 years). The controls were also 118 patients with diabetes, including 77 men and 41 women aged from 47 to 89 years (average age: 70.3±8.6 years). There were no significant differences of age, sex, BMI, smoking, drinking, and HbA1c between the case and control groups. There was a weak positive correlation between HbA1c and the serum concentration of CA19-9 in the control group without pancreatic cancer (r= 0.186, P=0.55). The median plasma CA19-9 level was 15 U/ml in the patients without pancreatic cancer versus 370 U/ml in the patients with pancreatic cancer (p<0.001). According to ROC analysis, the cut-off value of plasma CA19-9 showing the maximum sensitivity and specificity for separating patients with or without pancreatic cancer was 75 U/ml. Using this cut-off value, the sensitivity and specificity of CA19-9 for pancreatic cancer was 69.5% and 98.2%, respectively. In addition, the positive and negative predictive value was 97.6% and 76.3%, respectively, while the area under the ROC curve (AUC) was 0.875 [95%CI: 0.826- 0.924]. This cut-off value showed higher diagnostic accuracy than the conventional standard value of 37 U/ml (83.9% vs. 82.2%, respectively).

Conclusions: We propose that the cut-off value of serum CA19-9 should be set at 75 U/ml when screening patients with diabetes for pancreatic cancer. A positive result could encourage clinicians to perform more expensive (but more accurate) investigations to detect pancreatic cancer, such as contrast CT, pancreatic endoscopic ultrasound (EUS), or magnetic resonance cholangiopancreatography (MRCP), rather than less expensive (but less accurate) investigations such as abdominal ultrasonography.

Proposed cut-off value of CA19-9 for detecting pancreatic cancer in patients with diabetes: A case-control study