This study describes the demographic, presentation, management and survival of patients diagnosed with gallbladder cancer in the Australian Capital Territory (ACT). Gallbladder cancer is a rare malignancy in the Australian population and carries a poor prognosis. When considering the mid-period population of the ACT, the incidence rate is calculated at 0.75 per 100.000 people. The median age of diagnosis was 70.4 years, with 74% of the patients being female. These findings are consistent with the incidence and age at diagnosis reported in western countries such as the USA and Canada. In fact, the incidence rate in these geographical areas is reported to be less than 2 per 100.000 [18], while the median age of gallbladder cancer diagnosis in Australia, is reportedly between 67 and 73 years old [5].
Gallbladder cancer affects women disproportionately, as noted by previous studies [19, 20]. It is not well described why female patients have a higher rate of gallbladder cancer, but it is possibly due to risk factors such as gallstones, early menarche, late menopause, early first childbirth and likely estrogen and progesterone receptors participating in the pathogenesis of GBC [20]. In our cohort, we found that 74% of patients were female, a number consistent with previous reports[19, 20].
Most of our cohort was found to have local spread or metastatic disease at presentation, with 68% of patients presenting with stage III or IV. 31% of the cohort was found with distant metastasis at presentation, consistent with stage IVB. This high proportion is expected as gallbladder cancer is mainly asymptomatic until late stages, where local invasion or distant metastatic disease can cause symptoms [21]. On the contrary early gallbladder cancer is often found incidentally after cholecystectomy or imaging performed for different indications, with better outcomes for these patients [13].
In the Australian Capital Territory, an estimated 659 laparoscopic cholecystectomies were completed in 2014–2015 per 100 000 people, the lowest number of all the Australian states and territories. Although the incidence of incidental finding of gallbladder cancer after cholecystectomy is only found to be approximately 0.7% − 0.8% in western countries [13, 22], it is expected that with a growing number of elective and emergency cholecystectomies, the number of late-stage presentation of gallbladder cancer would decrease. In Australia the total number of cholecystectomies has increased from 46 332 in 2000–2001 to 60470 in 2020–2021. This is a 30.5% increase for this procedure according to the Australian Institute of Health and Welfare [23]. This hypothesis is supported by the link between cholecystectomy and gallbladder cancer which has been suggested before, when a decrease in the rate of this procedure was thought to be responsible for the rise in the incidence of gallbladder cancer in the ‘80s and ‘90s in South America [24, 25]. Future research is needed to assess if the rising numbers of cholecystectomies will result in a lower rate of late-stage presentations for gallbladder cancer.
We found an overall survival rate for all patients of 20% at 5 years, consistent with a high mortality malignancy. This is similar to recent reports of overall survival in western reports [26, 27]. We found statistically significant differences in survival between stages, with 63% of patients with stage 1 disease alive at 5 years, while no patient with stage 4 disease survived at 5 years. These results reflect and align with validation of the recently updated staging system, which has found similar differences in survival according to stages [15]. The AJCC 8th edition has recently been updated from the previous 7th edition, which has now divided stage II into IIA and IIB (Image 1). The main update reflects evidence that, a malignancy located on the hepatic side (IIB) has a worse prognosis than one located on the serosal side (IIA), possibly due to a higher neural invasion and lymph node involvement [15]. This difference was not noted in the validation study. Our cohort was too small to attempt to find a difference in survival between stage IIA and IIB, which requires a higher number of subjects, a limitation of this study.
Preoperative inflammation of the gallbladder and a high neutrophil-lymphocyte ratio are considered negative prognostic factors in gallbladder cancer [28, 29]. These findings contribute to the idea that patients presenting with acute cholecystitis who undergo cholecystectomy and are found to have gallbladder cancer intraoperatively or on histopathology, have a worse prognosis than those found incidentally. The explanation for this is not described but it is suggested it could be due to a higher likelihood of angiolymphatic or perineural invasion [29].
In our current cohort 31% of patients underwent cholecystectomy for acute cholecystitis and were incidentally found to have gallbladder cancer on routine histopathological examination. We showed no statistically significant difference in survival between for those presenting with acute cholecystitis. However, the numbers were small.
Intraoperative spillage during laparoscopic cholecystectomy is thought to confer a poorer prognosis for gallbladder cancer, secondary to possible spillage of malignant cells within the peritoneal cavity and seeding of the peritoneum leading to peritoneal carcinomatosis. Multiple reports have shown that patients who develop this intraoperative complication have a worse outcome, although the numbers available are often low [30, 31]. In our cohort, intraoperative spillage occurred in 38% of those undergoing surgical resection. These patients had no statistically significant survival difference compared to those without this complication.
We acknowledge several limitations of this paper. The study population is small, a statistically limiting factor. Given the low incidence of this malignancy, it is not possible to achieve a higher number of study subjects. The study does not report on the histological subtype of gallbladder cancer, an important prognostic factor. The incidence rate was calculated based on the population of the ACT. An estimation of the population with the catchment area is likely to be inexact given a wide draining area and give a false incidence rate. Laboratory findings were not included in the data collection and could not be included in the analysis of results
Patients with gallbladder cancer presenting with acute cholecystitis is not an uncommon presentation in a Western population with high incidence of cholelithiasis and low incidence of gallbladder cancer. There seems to be no significant difference in outcomes however, the results need to be interpreted with caution due to the small numbers.