Sialyl Lewis A is a sugar chain detected in CA19-9, which is frequently used as a tumor marker. CA19-9 is increased in cancer, but it is also present in small amounts in noncancerous tissues and is often elevated in benign diseases. There are many epithelial cells in the biliary system that are thought to produce CA19-9. It is also present in the epithelial cells of all tubular tissues, including salivary glands, ovaries, kidneys, prostate, and the intestinal tract. Inflammatory stimulation at these sites is believed to cause CA19-9 to deviate from the intercellular space into the blood, resulting in high levels. In gastrointestinal malignant diseases, CA19-9 is useful for the diagnosis of pancreatic cancer [1]. CA19-9 has better diagnostic accuracy for pancreatic cancer than CEA, CA 125, DUPAN-2, TPA and PSTI/TATI [2]. CA19-9 has been found to be associated with high serum CA19-9 levels in benign diseases causing biliary obstruction [3]. Values greater than 10,000 U/ml in benign disease are very rare [4].

When CA19-9 is elevated with the presence of cholelithiasis or cholecystitis, ruling out malignancy is important in determining the course of treatment. In cases where diagnosis is difficult, other modalities such as endoscopic ultrasonography (EUS) may be considered for evaluation, including drainage and cytological diagnosis.

It has been reported that drainage has a positive effect on biliary tract obstruction and jaundice, resulting in a decrease in CA19-9 in all patients with benign disease [5].

In this case, there were no findings on imaging tests that clearly suggested gallbladder malignancy, and the patient underwent surgery, with improvement in CA19-9 observed in the postoperative course.

Tsen A and Giron F reported that the mechanisms of high CA19-9 in cholelithiasis and cholecystitis are as follows: ① inflammatory stimuli and elevated biliary pressure causing the bile duct epithelium to overproduce CA19-9; ② impaired outflow of the biliary ducts causing CA19-9 to escape into the interstitium and eventually into the blood; and ③ CA19-9, which then causes backflow and leakage of CA 19–9 into the systemic circulation [6, 7].

The improvement in CA19-9 with a reduction in inflammation and lifting of the origin of the obstruction suggests that the high CA19-9 was caused by overproduction of CA19-9 in the bile duct epithelium due to inflammatory stimuli and outflow obstruction, causing CA19-9 to migrate into the stroma and vascular plexus. CA19-9 immunostaining showed the gallbladder mucosal epithelial cytoplasm and inflammatory cells such as macrophages within the thickened gallbladder wall, which is consistent with the findings of chronic cholecystitis (Fig. 4).

We considered biliary drainage and conservative therapy to reduce jaundice, but the patient had typical acute cholecystitis requiring surgery due to gallstones in the gallbladder neck. The cause of the high CA19-9 level was judged to be inflammation, and surgery was performed.

The patient’s CA19-9 level returned to normal immediately after the surgery, and no malignant tumor was detected on pathological examination. The cause of the high CA19-9 was considered to be the result of deviation of CA19-9 from the epithelium due to cholelithiasis and cholecystitis. Since an improvement in CA19-9 was observed after a reduction in inflammation and release of the obstruction, both the origin of bile duct system obstruction and the presence of inflammation were considered the factors causing increased CA19-9.

Overinvasive surgery should be avoided if malignancy cannot be completely ruled out. The following treatment strategies can be considered: ① preoperative drainage, ② intraoperative rapid cytological diagnosis, and ③ observation of the progression of tumor markers over time. Bile cytology by drainage should be performed carefully when malignancy cannot be completely ruled out because of the risk of intra-abdominal seeding. If a facility has the capability to perform endoscopic drainage of the gallbladder through the transcholedochal duct, the procedure can be considered an option for preoperative examination. This is because even in the case of malignancy, endoscopic drainage will not disperse malignant cells into the abdominal cavity. Intraoperative rapid cytology is not a definitive diagnostic tool since the accuracy of the diagnosis depends on the size of the incision and the degree of inflammation.

Currently, laparoscopic cholecystectomy is the standard surgical technique for cholecystitis, but in principle, open cholecystectomy should be performed in patients with lymph node metastasis or other strong evidence of cancer [8]. In this case, there was no obvious wall thickening or tumor suspicious for cancer, the diagnosis of acute cholecystitis was made, and early surgery was performed according to the Tokyo guidelines [9].

Postoperatively, tumor markers showed rapid improvement, which may be useful in differentiating malignant tumors. In addition, if the cause of the high CA19-9 level cannot be determined, CT, including that for gynecological diseases, may be considered before additional invasive examinations; liver function, blood glucose, HbA1c, and additional thyroid function tests; or positron emission tomography (PET) scans performed in combination [10, 11].

CA19-9 levels exceeding 10,000 U/ml in acute cholecystitis are very rare, and this case description is a valuable report. By recognizing that CA19-9 can be elevated in benign disease without overlooking malignant disease, unnecessary invasive testing can be avoided, and the patient can be treated accordingly.