GBC is a rare malignant tumor with a low incidence and poor prognosis. uGBC is a condition presenting as cholecystitis or cholecystolithiasis before cholecystectomy however turning out to be malignant pathologically after surgery. uGBC is highly occult and difficult to detect by imaging.
Historically, doctors generally believed that uGBC had a better prognosis[18]. However, with the development of the laparoscopic technique, more patients with cholecystitis and gallstones have the opportunity to receive LC. Subsequently, the number of cases of uGBC increased, even accounting for more than 50% of GBC. At the same time, we found that many uGBC patients had already entered AJCC stage 3 or even stage 4 by the time they were diagnosed[16, 19]. As a result, an increasing number of doctors suggest that the name uGBC should not apply anymore[10].
In previous studies, clinical data used for diagnosis were studied, such as CA199, which was considered an indication of gallbladder cancer[20, 21]. However, there has been little recent research into prognostic factors. We hoped to identify independent prognostic factors among patients undergoing cholecystectomy or radical cholecystectomy for GBC. Ultimately, we found that AJCC stage and CA125 and CA199 levels were independent prognostic factors for GBC, while unexpected gallbladder cancer was not. At the same time, we determined cutoff values for serum CA125 and CA199 levels and divided patients into high expression and low expression groups. The results showed that the KM curves of patients in the high expression group and the low expression group were significantly different whether the two independent influencing factors were used alone or in combination. This indicated that CA125 and CA199 should receive greater attention in clinical diagnosis. We recommend that CA125 and CA199 be used in routine preoperative examinations to predict prognosis after data are obtained.
At the same time, in the univariate regression analysis, gallbladder polyps were found to be a protective factor, which may be related to regular reexamination after the detection of gallbladder polyps.
Unexpected gallbladder carcinoma was not an independent prognostic factor. We compared the clinical data of patients of ‘expected’ and unexpected gallbladder cancer and found a significant difference in AJCC staging. This is well understood because most accidental gallbladder cancers are not radiographically distinguishable and therefore have small lesions and shallow invasion. At the same time, the KM curves of the two groups between ‘expected’ and unexpected gallbladder cancer were analyzed, and the difference in prognosis was not statistically significant. This reminds us that, as with gallbladder cancer, which also has a poor prognosis, "unexpected" is no excuse for missing the diagnosis. In particular, if patients with AJCC stage 3 are missed in diagnosis and do not undergo a second radical operation in time, the consequences will be extremely dire. Therefore, the prognosis for uGBC does not appear to be as good as previously thought.
As for the diagnosis and treatment results of the patients, among our patients included in the study, 35.29% of patients with Tis/T1 stage could not be detected by preoperative imaging, which was close to 32.44% of the study results in other parts of the world. For patients with T2, T3, and T4 stages, preoperative CT could have detected them. Because of the lack of preoperative CT examination or failure to detect it, we believe that the behavior of only diagnosing cholecystitis or stones in them is misdiagnosis or missed diagnosis. Then our misdiagnosis/missed diagnosis rate was as high as 64.71%, which was close to 67.56% in other parts of the world. Such a high rate of misdiagnosis or missed diagnosis is clearly unacceptable. This means that a large number of patients may be hit by a second operation. Preoperative CT examination is also has great significance in finding the swollen lymph nodes suspected of metastasis, which is critical for assessing clinical N staging (cStage). A second operation will delay the patient’s recovery, and a second laparotomy will bring more trauma. When missed diagnosis occurs and the patient has already undergone surgery, intraoperative frozen pathological examination becomes the last barrier to allow the patient to avoid a second operation.
Then we analyzed the causes of missed diagnosis. The study found that of the 17 patients, only 2 received attention for preoperative CT examination, and 10 may have been missed because of the lack of CT examination. Only three avoided a second operation because of timely intraoperative frozen examination, while seven suffered a second operation because there was no intraoperative frozen pathological examination. Therefore, we blame this high rate of misdiagnosis and missed diagnosis on the absence of complete preoperative examination as well as intraoperative frozen examination. Therefore, preoperative examination should be improved for patients with cholecystitis and gallstones. During cholecystectomy, strict frozen pathological examination and postoperative pathological examination should be performed on specimens[22, 23] to reduce the number of operations and prolong the survival time of patients.
Some studies have also been conducted in other regions on whether accidental gallbladder cancer is really accidental. In a study of 19 patients in Italy[11], 10 cases could be diagnosed preoperatively. India found 37 cases could be diagnosed preoperatively in 79 studies[19]. In a study of 26 people in China[14], 11 cases could be diagnosed by preoperative CT examination. This suggests that patients with cholecystitis or stones rushed to undergo surgical treatment, and missed gallbladder cancer, is an international common disease. Perhaps more attention should be paid to accidental gallbladder cancer by stopping the use of the diagnosis of uGBC to obtain a more perfect preoperative evaluation and intraoperative pathology.
Someone argue that the definition of uGBC has become an excuse for clinicians for misdiagnosis/missed diagnosis and source of neglect. Therefore, the term uGBC should be abolished and replaced with early gallbladder cancer. In our view, whether the use of the term uGBC needs to be discontinued is under debate. Most importantly, preoperative imaging evaluation and intraoperative frozen pathological examination need to be further improved so that uGBC patients can receive adequate attention, the occurrence of misdiagnosis and missed diagnosis can be reduced, and the prognoses of patients can be improved.
Our study had some limitations. The first was the short follow-up time. We will continue to follow the patients for longer periods of time to observe the final outcomes. In addition, due to the low incidence of gallbladder cancer, the number of patients included in this study was small. Therefore, multicenter collaborative studies should be carried to generate more convincing results.