GBC is a lethal malignancy which is a relatively common condition in our setting, with a high mortality due to the delayed presentation and aggressive tumor biology [1, 2]. It portrays significant differences in presentation, prognosis among various age groups and sex [3]. It is common among females and elder population [2, 5] which correlates with our study result, 63% patients were above 60years age and 70% were females. The reason for Female predominance may be attributable to high incidence of gall stones and their hormonal profile [5] but it is yet to delineate the exact role of female hormones in GBC pathogenesis with more extensive studies. It is also more prevalent in elderly population, and this may be correlated to the increased prevalence of gallstones and infection of the biliary tract in elders [2, 5].
In the initial stages, the symptoms are often nonspecific, making it challenging to distinguish from other prevalent clinical conditions such as chronic cholecystitis and biliary colic. This intricacy can impede the preoperative assessment of suspicious lesions, resulting in delayed diagnosis and timely treatment [7]. The most common presenting symptom in GBC patients is abdominal pain. Other symptoms that are usually indicative of advanced tumor stage are including jaundice and constitutional symptoms like Anorexia and weight loss [6, 7]. In our study, abdominal pain was the most common presenting symptom, reported by 78% of patients followed by constitutional symptoms (LOA, LOW) from 38% patients and jaundice by 21% patients. Even patients with neck tumor had abdominal pain as most common presenting symptom with high frequency/early onset of jaundice. Our study provides supportive evidence for considering operative evaluation in patients with jaundice. In a nutshell, while jaundice may complicate the management of gallbladder carcinoma, it does not automatically render a patient ineligible for surgery [5, 9].
Previous studies generally suggest that the presence and severity of comorbidities can negatively impact the survival of patients with gallbladder cancer. Comorbidities can affect treatment options, treatment tolerance, and overall health status, which in turn can influence prognosis [8].Surprisingly; our findings did not reveal any statistically significant differences between the two groups in terms of Overall survival (OS) and Disease free survival (DFS). However, it is noteworthy that within our study cohort, a subgroup of five patients who had comorbidities did experience mortality attributed to complications arising from these concurrent medical conditions. This suggests a nuanced scenario where, despite the absence of a statistically significant disparity in survival rates between patients with and without comorbidities, the impact of these additional health concerns manifested in certain cases through complications leading to fatal outcomes. This underscores the complex interplay between comorbidities, their associated complications, and the final outcomes in gallbladder cancer patients.
While the precise connection between gallstone disease and gallbladder carcinoma remains incompletely elucidated, there exists evidence indicating that prolonged gallstone disease may heighten the susceptibility to developing gallbladder cancer. The presence of gallstones and biliary duct stones is postulated to incite persistent inflammation, potentially culminating in dysplasia [9]. The risk amplifies with the size of the stones, with those exceeding 3 cm in diameter exhibiting a 9.2–10.1-fold higher likelihood compared to stones under 1 cm [10]. This augmented risk is likely ascribed to intensified local epithelial irritation. Moreover, the incidence of gallbladder cancer aligns with the prevalence of gallstone disease, which disproportionately affects specific populations [11, 12]. However, it's notable that only a minor fraction (1–3%) of individuals with cholelithiasis progress to gallbladder cancer, suggesting the involvement of additional risk factors [11]. Among those diagnosed with gallbladder cancer, a significant majority (70–90%) have a history of cholelithiasis [9]. In our investigation, a history of gallstones was present in 67% of the patients. This observation aligns with the findings in the existing literature.
FDG-PET scanning combined with CT (PET/CT) integrates both metabolic and anatomical localization of suspicious lesions. Studies have demonstrated its ability to detect primary gallbladder cancers at a rate of 95.9%, lymph node involvement at 85.7%, and metastatic disease at 95.9% [13]. In fact, nearly a quarter of gallbladder cancer patients who underwent preoperative PET scanning experienced alterations in their surgical management [14]. However, the utility of PET/CT in biliary malignancies remains a topic of debate. No studies have yet demonstrated whether patients who undergo PET/CT exhibit improved survival when compared to a comparison group with similar staging on CECT. Our study indicated that patients with comparable stages on contrast-enhanced CT (CECT) and PET/CT did not exhibit differences in terms of OS and DFS benefits. This indicates that PET/CT may also have constraints when it comes to detecting smaller, unnoticed metastases. This statement requires further studies to clarify/rectify.
As of the present date, no randomized controlled trial (RCT) has been conducted to directly compare the outcomes of liver wedge excision with segment IVb/V excision. Currently, a research group in Korea is actively recruiting patients for a study that aims to compare liver wedge excision with segment 4b/5 bisegmentectomy in terms of recurrence rates and survival rates [15]. This underscores the notion that using wedge excision can yield equally favorable oncological results. Furthermore, the perioperative outcomes observed in our study align well with findings in the published literature [16, 17]. The two groups exhibited similar rates of complications, margin positivity, and survival benefits. However, the anatomical resection group demonstrated a lower incidence of colon/duodenum resection, which did not impact the outcome between these two groups.
Complications in gallbladder surgery are a crucial consideration. In our series, the assessment of post-operative morbidity, specifically classified according to the Clavien Dindo score as grade III and above, revealed a rate of 14.8%. Among these cases, 2.2% of patients necessitated intervention due to bile leakage. It's worth highlighting that this observed rate of post-operative morbidity is notably lower when compared to a distinct study carried out at the esteemed Memorial Sloan-Kettering Cancer Center (MSKCC). In that study, the documented rate of post-operative morbidity was reported as 19%. The MSKCC investigation delved into a range of factors, encompassing major hepatectomy and segment 4b/5 bisegmentectomy in the context of gallbladder cancer [18]. While perioperative complications might result in delays in commencing chemotherapy, our study found that such delays did not impact OS and DFS. This underscores the significance of promptly diagnosing and managing complications, highlighting their pivotal role in achieving improved outcomes.
The prognosis of the gallbladder cancer which was diagnosed preoperatively or diagnosed incidentally after simple cholecystectomy was not different if curative surgery was achieved [5]. Similar to the literature, the survival was not different between incidentally or preoperatively diagnosed patients in our study. On the other hand, the question of whether incidental gallbladder cancer patients experience a more favorable prognosis compared to non-incidental tumors of the same stage remains uncertain. However, a number of studies suggest that early incidental GBC is associated with a more positive prognosis [19, 20]. Conversely, when curative surgery was achieved, the prognosis of gallbladder cancer diagnosed either preoperatively or incidentally after simple cholecystectomy showed no significant difference [21]. In line with this existing literature, our study found no disparity in survival between patients diagnosed incidentally or preoperatively. But its prognosis was very poor in incidental group when it comes to younger age group. The important thing which play role is timing of surgery in IGBC patients.
Histopathological examination revealed several factors significantly associated with the survival of patients. These factors include histological variants, degree of differentiation, presence of perineural invasion (PNI) and lymphovascular invasion (LVI), margin status, T stage, and lymph node positivity. Prior research also supports the significant impact of these factors on patient survival [22, 24–27]. Among these factors, the histological subtype of gallbladder cancer emerges as a pivotal prognostic determinant. Specifically, papillary carcinoma emerges as harboring the most favorable prognosis, whereas squamous and adenosquamous carcinomas tend to exhibit heightened aggression, thereby translating to poorer prognoses. Although quite rare, small cell carcinoma tends to metastasize early, often resulting in death shortly after diagnosis [9, 27]. The degree of differentiation also holds importance in predicting survival. Our study demonstrated a statistically significant survival advantage among patients with papillary adenocarcinoma and those with well-differentiated tumours, as indicated by bivariate Cox regression analysis. Furthermore, our analysis indicated an interrelationship between these two factors, often associated with an early disease stage (None in stage IV). Conversely, poorly differentiated tumours tended to present at more advanced stages (Stage III / IV). Thus particular histological subtype of gallbladder cancer and the extent of differentiation collectively wield crucial roles in sculpting patient prognosis.
The presence of PNI and LVI holds notable significance, indicating a less favourable outcome [23]. These factors, PNI and LVI, act as independent prognostic indicators for disease-free survival and emerge as independent predictors of early recurrence as well [26, 27], aligning closely with the findings of our study. Within our study cohort, 24 patients displayed positive PNI, and among them, a striking 83% were classified under stage pT3/4. Turning to LVI, 32 patients exhibited LVI positivity, with a noteworthy 81% falling into stage pT3/4. Both the log-rank test and hazard ratio analysis underscored the statistically significant survival disadvantage posed by these two factors, mirroring the findings of earlier studies [23, 26, and 27]. Study also reflects that patients with PNI and LVI tend to exhibit more advanced disease stages and experience substantially poorer prognosis.
Existing literature highlights significant survival disparities between node-negative and node-positive diseases, with 5-year survival rates ranging from 58% -77% for the former, in contrast to 0% − 45% for the latter [9]. Regional lymph node involvement is observed in 19–62% of T2 tumours and 75–85% of T3/T4 tumours, while N2 lymph node involvement is noted in 18–36% of T2 tumours and 42–71% of T3/T4 tumours [22, 27]. Our study's findings align closely with these previous reports, as the rate of lymph node positivity increased with higher pT stages: 0% in T1, 17% in T2, 54% in T3, and 100% in T4. The extent of nodal involvement holds significance as a prognostic factor. While both node location and count exhibited significance in univariate analysis a study, only the count of positive nodes retained significance in multivariate analysis [24]. It has been suggested that involvement of peripancreatic nodes indicates a worse prognosis. Notably, for patients presenting with advanced disease, the median survival dwindles to 2–4 months [9]. Our study, too, displayed estimated 1- and 3-year DFS rates were 73% and 47%, respectively. The median OS was 58, 46, 22 and 11 months in Stage I, II, III, and IV respectively, indicating poor survival and early recurrence in GBC, particularly among those with positive lymph node status. For cases featuring positive nodes, conducting regional lymph node dissection may enhance patient survival, contingent upon achieving a feasible R0 resection [25]. Throughout all stages of GBC, an R0 resection emerges as an independent, positive prognostic factor [23, 27]. Our findings also underscore a worsened prognosis (OS and DFS) among patients with positive lymph nodes, higher T stages, and margin positivity (p < 0.05)
A recent systemic review which analyzed six published retrospective study results on neoadjuvant chemotherapy (NACT) showed that 30.47% had disease progression out of 420 study population [28]. Although 67.38% of patients (283 of 420) showed good response to NACT, just 51.66% (217 of 420 cases) were operated, out of which only 171 cases were deemed to be feasible for surgical resection and had curative resection. Out of the cases that underwent curative surgery, 91.81% had R0 resection (157 out of 171 patients). The overall survival rate was found to be 18.5–50.1 months for patients in whom curative surgery was done and 5.0–10.8 months for no surgery patients. In our study the response rate was 21% among the patients who had completed NACT course (Gem-Cis 3 cycles). The median Overall survival in NACT group was 8months and progression free survival was 4months. The Median survival in patients who underwent curative resection was 15months. Our study population showed slightly discouraging results towards NACT treatment modality. No sufficient data exist to advocate the regular use of neoadjuvant chemotherapy in advanced GBC, as data showed that only 1/3 of patients benefited and had a R0 resection. Further research should be the randomized controlled trials to further quantify the benefit of neoadjuvant chemotherapy in advanced GBC [28].
A multi-institutional analysis study in USA showed 15.8% patients developed a local recurrence only, while 65.8% and 18.4% developed either a distant or a local plus distant recurrence, respectively [29]. Of note, the most common site of recurrence was the liver (34.4%) followed by the peritoneum (15.6%). The median time to recurrence and median recurrence-free survival among all patients were 9.5 months and 11.2 months respectively. Median time to recurrence was comparable among patients who developed a local, distant or local and distant recurrence [29]. In our study we found similar recurrence pattern. Only 5 patients had isolated local recurrence, 21 patients had local and systemic recurrence and rest 20 had only systemic recurrence. Among systemic recurrence; 31% patients had in liver (13/41), 26% had peritoneal deposits and rest 26% had at multiple sites. The median disease free survival in our study was 17months and most recurrence occurred in initial 24months and usually in node positive GBC patients.
Limitation
A notable bias in our study arises from its retrospective nature, which constrains comprehensive data collection and analysis. Despite this limitation, we hold the belief that this review can still offer valuable insights into the management of patients with GBC and potentially enhance prognostic capabilities.