Gallbladder carcinoma in Brazil: Clinicopathological profile and survival outcomes from a high-volume cancer center

Abstract

BACKGROUND

Gallbladder cancer (GBC) is the most prevalent malignant tumor of the biliary tract and remains associated with poor survival outcomes due to its aggressive biological behavior and typically late diagnosis. Regional differences in incidence and outcomes emphasize the need for country-specific data. In Brazil such information remains scarce.

AIM

To evaluate the clinicopathological characteristics, therapeutic approaches, and survival outcomes of patients with GBC treated at a high-volume cancer center in Brazil.

METHODS

This retrospective study analyzed 364 patients with histologically confirmed gallbladder adenocarcinoma treated at a high-volume Brazilian cancer center from 2010 to 2024. Clinical, pathological, and treatment-related variables were analyzed. Patients were stratified into incidental GBC (IGBC) and non-IGBC groups.

RESULTS

The cohort was predominantly female (78.8%) with a mean age of 62.1 years. Most patients (72.3%) presented with stage IV disease. IGBC accounted for 54.1% of cases and showed significantly improved survival compared with non-IGBC [median overall survival (OS): 18 months vs 7 months; P < 0.001]. Radical surgery was performed in 13.5% of patients, achieving a 5-year OS of 57.5%. Independent predictors of worse OS included poor performance status [Eastern Cooperative Oncology Group > 2; hazard ratio (HR) = 1.91], advanced T stage (T3: HR = 4.38; T4: HR = 5.24), metastasis (M1; HR = 2.76), and non-IGBC diagnosis (HR = 1.35).

CONCLUSION

GBC in Brazil commonly presents at advanced stages, restricting curative options. IGBC is more prevalent and has better outcomes. Radical surgery confers the best prognosis but remains feasible in a minority of patients.

Key Words: Gallbladder neoplasms; Biliary tract neoplasms; Adenocarcinoma; Survival; Prognostic factors; Incidental cancer; Surgical oncology; Brazil

Core Tip: This retrospective study evaluated the clinicopathological characteristics, treatment strategies, and survival outcomes of patients with gallbladder carcinoma (GBC) treated at a high-volume cancer center in Brazil. Most patients presented with advanced stage disease, limiting curative options. Incidental GBC was more frequent than non-incidental cases and associated with significantly better survival. Radical surgery although feasible in a minority provided the best long-term outcomes. These findings highlighted the importance of early detection and timely referral to specialized hepatobiliary centers to improve prognosis in GBC.

INTRODUCTION

Despite being relatively rare in global cancer statistics, gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and exhibits aggressive biological behavior[1,2]. The nonspecific nature of early symptoms often delays diagnosis until the disease has progressed to unresectable or metastatic stages, resulting in poor overall survival (OS) rates[3]. Epidemiological data demonstrate a marked geographical heterogeneity in GBC incidence. High incidence regions include parts of Latin America, particularly Chile, Bolivia, and Peru, and certain Asian countries such as India, Bangladesh, and Nepal[4,5]. According to the World Health Organization and the Global Burden of Disease Study, Chile and Bolivia continue to report the highest age-standardized death rates for gallbladder and biliary tract cancers, reaching 10.43 per 100000 inhabitants[6]. In contrast, Brazil exhibits an intermediate incidence with age-standardized death rates of 0.8 per 100000 for males and 1.3 per 100000 for females[1,7]. These regional disparities are attributed to a complex interplay of genetic predispositions, environmental exposures, dietary patterns, and healthcare access[8,9].

GBC is typically diagnosed in two distinct clinical scenarios: Incidental GBC (IGBC) through histopathological analysis following cholecystectomy for presumed benign disease; and non-IGBC via imaging studies performed to investigate abdominal symptoms. The widespread adoption of laparoscopic cholecystectomy has led to an increase in incidental diagnoses, now accounting for more than half of GBC cases globally[10,11]. IGBC is frequently detected at earlier stages, correlating with better tumor differentiation, lower rates of lymphovascular invasion, and significantly improved survival compared with non-IGBC[12-14]. The reported prevalence of IGBC after cholecystectomy ranges from 0.19% to 2.80% in international series[15,16] and from 0.34% to 2.30% in Brazilian studies[17,18].

Complete surgical resection remains the only potentially curative treatment for GBC. While simple cholecystectomy may be sufficient for in situ and T1 tumors, more advanced cases require extended resections, including hepatic wedge resection and regional lymphadenectomy, to achieve oncologic disease clearance[19-21]. Moreover, since most cholecystectomies for gallstones are performed by general surgeons in centers without hepatobiliary expertise, timely referral to specialized centers is critical. Unfortunately, many patients fail to undergo timely surgical intervention due to delayed diagnosis, poor performance status, or inadequate referral systems[20,22,23].

Given the regional variability in GBC presentation and outcomes, a better understanding of its behavior in different populations is crucial for developing effective public health strategies. In Brazil data regarding the epidemiology, management, and outcomes of GBC remain scarce. To our knowledge no previous studies have provided a comprehensive overview of GBC management in the Brazilian setting. This study therefore aimed to provide an in-depth analysis of the clinicopathological characteristics, therapeutic approaches, and survival outcomes of patients with GBC treated at a high-volume cancer center in Brazil, thereby addressing a critical knowledge gap and offering data that may inform future national healthcare strategies. These findings may also help elucidate the role of Brazil in the global epidemiology of GBC and provide a valuable reference for comparative international studies.

MATERIALS AND METHODS

Study design and setting

This was a retrospective, single-center cohort study conducted at the Instituto do Cancer, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, a high-volume tertiary referral cancer center. The study period spanned from January 2010 to February 2024. The institutional review board approved the study protocol. Given the retrospective nature of the research and the use of anonymized data, the requirement for informed consent was waived. Patients were stratified into two groups based on the mode of diagnosis: (1) IGBC when the diagnosis was established through pathological examination of gallbladder specimens following cholecystectomy for presumed benign disease; and (2) Non-IGBC when the diagnosis was established preoperatively via imaging studies based on clinical suspicion.

Patient selection

All consecutive adult patients (≥ 18 years) referred to our institution with a diagnosis or clinical suspicion of GBC were screened for eligibility. Inclusion criteria comprised histologically confirmed diagnosis of gallbladder adenocarcinoma and availability of complete clinical, pathological, and follow-up data. Patients with IGBC who had undergone radical surgery at external institutions prior to referral were excluded from this study.

Data collection and variables

Clinical and demographic data were extracted from electronic medical records, including age, sex, body mass index, and Eastern Cooperative Oncology Group (ECOG) performance status. Laboratory data included pretreatment serum levels of carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA). Staging was based on the American Joint Committee on Cancer Tumor-Node-Metastasis (TNM) Classification, 8^th Edition. Due to changes in staging criteria during the study period, stratification by T2a and T2b subcategories was not performed. Imaging studies for pretreatment staging included contrast-enhanced CT of the chest, abdomen, and pelvis as well as magnetic resonance imaging when clinically indicated. Positron emission tomography-CT was employed selectively to evaluate suspected distant metastasis.

Treatment strategies

Patients were stratified into four groups according to the initial treatment decisions guided by multidisciplinary tumor board discussions, considering tumor stage, patient comorbidities, and functional status: (1) Curative-intent surgery: Patients with resectable disease and ECOG ≤ 2 underwent radical resection, including hepatic wedge resection of segments IVb and V, and regional lymphadenectomy; (2) Observation group: Patients with IGBC who had no evidence of residual disease (RD) and were not candidates for re-resection (ECOG ≥ 3 and/or delayed referral > 6 months) and/or refused re-resection; (3) Palliative treatment: Patients with advanced or unresectable disease and/or ECOG ≥ 3 received systemic chemotherapy (gemcitabine and cisplatin-based regimens) and/or best supportive care; and (4) Exclusive follow-up: Applied to patients with T1a IGBC deemed adequately treated by simple cholecystectomy. Contraindications for curative surgery included distant metastasis (M1 disease), extensive vascular invasion, and poor performance status (ECOG ≥ 3).

Surgical procedures

Diagnostic laparoscopy or laparotomy was routinely employed to exclude peritoneal dissemination prior to definitive surgical treatment. Intraoperative frozen section analysis of the cystic duct margin was routinely performed in patients with non-IGBC. Hepatic resections followed oncologic principles, ensuring at least a 2 cm margin from the gallbladder bed. Adequate lymphadenectomy was defined as the retrieval of ≥ 6 lymph nodes along the hepatoduodenal ligament (including cystic duct, common bile duct, proper hepatic artery, and portal vein) and along the common hepatic artery.

For patients with IGBC undergoing re-resection, the same surgical principles were applied. A frozen biopsy of the cystic duct stump was performed when tumor involvement was present or could not be assessed on the previous pathological report. RD in re-resection specimens was defined as the presence of malignant cells in any component of the surgical specimen, including liver parenchyma, cystic duct, peritoneum, or lymph nodes.

Follow-up protocol

Post-treatment surveillance included clinical evaluation, imaging studies, and tumor marker assessments (CA 19-9 and CEA). Patient follow-up was performed every 4 months for the first 2 years, and every 6 months thereafter until the fifth year. Patients lost to follow-up for over 12 months were considered censored at their last recorded visit.

Statistical analysis

Continuous variables were presented as mean ± SD or median with interquartile range (IQR), depending on normality assessed by the Shapiro-Wilk test. Categorical variables were expressed as n (%). Categorical variables were compared using the χ² test or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t test or Mann-Whitney U test, depending on the distribution of data. Survival analyses were performed using the Kaplan-Meier method, and comparisons between groups were assessed with the log-rank test. Survival was calculated (in months) from the date of diagnosis to the date of death (death from any cause) or last medical appointment. The Cox proportional hazards model was employed to identify independent prognostic factors for OS. Variables with P < 0.05 in univariable analyses were included in the multivariable model. Hazard ratios and 95% confidence intervals were reported. All statistical analyses were conducted using SPSS software, version 20 (IBM Corporation, Armonk, NY, United States). Two-sided P values < 0.05 were considered statistically significant.

RESULTS

Patient cohort and baseline characteristics

Between January 2010 and February 2024, 446 patients were referred to our institution with a diagnosis or clinical suspicion of GBC. After applying patient selection criteria, 364 patients with histologically confirmed gallbladder adenocarcinoma were included in the final analysis (Figure 1). The cohort was predominantly female (78.8%) with a mean age of 62.1 years (range: 24-87 years). IGBC accounted for 54.1% of cases (n = 197) while 45.9% (n = 167) were non-IGBC. At diagnosis advanced disease (stage IV) was present in 72.3% of patients (n = 263). Patients with non-IGBC exhibited significantly higher rates of advanced T stage (T4: 56.9% vs 8.6%; P < 0.001), nodal involvement (N+: 82.0% vs 60.4%; P < 0.001), and distant metastasis (M1: 80.2% vs 62.4%; P < 0.001) compared with patients with IGBC.

Figure 1 Study flowchart with therapeutic management of patients with gallbladder carcinoma. GBC: Gallbladder carcinoma; CT: Computed tomography; IGBC: Incidental gallbladder cancer.

Baseline characteristics and comparative analyses between IGBC and non-IGBC groups are shown in Table 1. The time from diagnosis to initiation of treatment was significantly shorter in patients with non-IGBC (median: 1.7 months) compared with patients with IGBC (median: 3.2 months; P < 0.001). Patients with non-IGBC also had significantly poorer clinical performance status (ECOG) and more advanced T, N, M, and TNM stages (P < 0.001 for all comparisons). Serum CA 19-9 and CEA levels were significantly higher in patients with non-IGBC.

Table 1 Characteristics of gallbladder cancer patients according to the groups - incidental gallbladder cancer and non-incidental gallbladder cancer, n (%).

Variables	Total (n = 364)	IGBC (n = 197)	Non-IGBC (n = 167)	P value
Sex				0.627
Female	287 (78.8)	157 (79.7)	130 (77.8)
Male	77 (21.2)	40 (20.3)	37 (22.2)
Age (years), mean ± SD	62.1 ± 12.0	61.6 ± 12.2	62.8 ± 11.8	0.344
Body mass index (kg/m2), mean ± SD	25.8 ± 5.7	26.3 ± 5.8	25.3 ± 5.5	0.085
Δt diagnoses to therapeutic approach (months)				< 0.001
mean ± SD	4.0 ± 7.7	5.4 ± 10.1	2.4 ± 2.1
Median (IQR)	2.5 (1.5-4.1)	3.2 (2.0-5.1)	1.7 (1.1-2.8)
CEA, median (IQR)	4.2 (2.2-19.5)	3.4 (1.9-10.9)	5.7 (2.8-22.2)	0.047
CA 19-9, median (IQR)	499 (97-8347)	171 (60-1186)	2897 (230-20465)	< 0.001
ECOG performance status scale				< 0.001
ECOG 0/1/2	227 (63.1)	141 (71.9)	86 (52.4)
ECOG 3/4	133 (36.9)	55 (28.1)	78 (47.6)
Final approach				< 0.001
T1a (follow-up)	7 (1.9)	7 (3.6)	0 (0)
Curative surgery	49 (13.5)	32 (16.2)	17 (10.2)
Observation	29 (8.0)	29 (14.7)	0 (0)
Palliative	279 (76.6)	129 (65.5)	150 (89.8)
T				< 0.001
T1a	9 (2.5)	7 (3.6)	2 (1.2)
T1b	21 (5.8)	19 (9.6)	2 (1.2)
T2	80 (22.0)	72 (36.5)	7 (4.8)
T3	142 (39.0)	82 (41.6)	60 (35.9)
T4	112 (30.8)	17 (8.6)	95 (56.9)
N				< 0.001
N0	108 (29.7)	78 (39.6)	30 (18.0)
N+	256 (70.3)	119 (60.4)	137 (82.0)
M				< 0.001
M0	107 (29.4)	74 (37.6)	33 (19.8)
M1	257 (70.6)	123 (62.4)	134 (80.2)
TNM				< 0.001
I	22 (6.0)	19 (9.6)	3 (1.8)
II	29 (8.0)	24 (12.2)	5 (3.0)
III	30 (8.2)	21 (10.7)	9 (5.4)
IV	283 (77.7)	133 (67.5)	150 (89.8)
Mortality following diagnosis
30-day mortality	6 (1.6)	1 (0.5)	5 (3.0)	0.098
90-day mortality	48 (13.2)	13 (6.6)	35 (21.0)	< 0.001

IGBC: Incidental gallbladder cancer; IQR: Interquartile range; CEA: Carcinoembryonic antigen; CA 19-9: Carbohydrate antigen 19-9; ECOG: Eastern Cooperative Oncology Group; TNM: Tumor-node-metastasis; SD: Standard deviation.

Therapeutic management

Among the total cohort 65 patients (17.9%) were initially referred for evaluation within the curative-intent surgery group. Intraoperative identification of unresectable disease or distant metastases precluded curative resection in 16 cases. Consequently, 49 patients (13.5%) ultimately underwent curative-intent surgery, comprising 32 with IGBC and 17 with non-IGBC. Seven patients (1.9%) diagnosed with T1a IGBC were considered cured following simple cholecystectomy and were subsequently managed through surveillance alone within the exclusive follow-up group.

Twenty-nine patients with IGBC, representing 8.0% of the cohort, had no evidence of RD on staging and were managed conservatively without additional surgical intervention. These individuals were subsequently followed through surveillance alone within the observation group. Palliative treatment, comprising systemic chemotherapy with gemcitabine plus cisplatin and/or best supportive care, was initially administered to 263 patients with stage IV disease. An additional 16 patients from the surgical cohort were subsequently included in this group following laparoscopy or laparotomy that revealed unresectable disease or distant metastases.

Survival analysis

At a mean follow-up of 17.5 months (median of 32.6 month; IQR: 10-60 months for survivors), 276 deaths were recorded. Loss to follow-up was 8.0%. The median OS for the entire cohort was 11.5 months with a 5-year OS rate of 15.4%. The OS outcomes varied significantly according to TNM and T staging. The 5-year OS was 88.6% for stage I, 61% for stage II, 35.4% (median OS: 48.7 months) for stage III, and 2.3% (median OS: 7.5 months) for stage IV (Figure 2A). The estimated 5-year OS for T1a and T1b was 80% and 70.9%, respectively (median not reached for T1a/T1b). The median OS was 22.9 months for T2, 9.8 months for T3, and 6.8 months for T4 patients (P < 0.001 for all comparisons) (Figure 2B).

Figure 2 Overall survival of patients with gallbladder carcinoma. A: According to the tumor-node-metastasis stage; B: According to the T stage; C: According to the presence of lymph node metastasis; D: According to the presence of metastatic disease.

Analyzing the impact of lymph node involvement, patients without nodal involvement (N0) had a median OS of 33.0 months compared with 8.5 months in those with nodal metastases (N+). Corresponding 5-year OS rates were 39.2% for patients with N0 and 5.4% for patients with N+ with the difference reaching statistical significance (P < 0.001) (Figure 2C). The presence of metastatic disease was strongly associated with poorer survival outcomes. Patients without distant metastases (M0) had a median OS of 51.8 months compared with 7.5 months in those with metastatic disease (M1), and the 5-year OS rates were 46.3% for M0 and 3.2% for M1 (P < 0.001) (Figure 2D).

Patients with IGBC had significantly superior OS compared with non-IGBC (median OS: 18 months vs 7 months; P < 0.001). The 5-year OS rate was 23% for IGBC and only 6% for non-IGBC (Figure 3A). Regarding the therapeutic approach, patients who underwent curative-intent surgery had better survival compared with patients receiving palliative treatment (5-year OS rate: 57.5% vs 1.3%, P < 0.001) (Figure 3B). The median OS for palliative treatment cases was 7.5 months. The estimated 5-year survival for T1a tumors treated by cholecystectomy alone and those under follow-up (observation) was 75.0% and 54.1%, respectively. In the multivariable analysis (Table 2), ECOG > II, more advanced T stage, presence of distant metastasis (M1), and non-IGBC were independent factors associated with worse survival.

Figure 3 Overall survival of patients with gallbladder carcinoma. A: According to the incidental gallbladder cancer and non-incidental gallbladder cancer groups; B: According to the therapeutic approach of all patients. IGBC: Incidental gallbladder cancer.

Table 2 Univariable and multivariable analysis for overall survival - all gallbladder cancer patients.

Overall survival, variables	Univariable			Multivariable
	HR	95%CI	P value	HR	95%CI	P value
Male (vs female)	1.50	0.87-1.53	0.300	-	-	-
Age > 65 (vs < 65 years)	0.91	0.71-1.17	0.453	-	-	-
ECOG > 2 (vs 0-1)	2.78	2.18-3.56	< 0.001	1.91	1.48-2.48	< 0.000
Stage T1 (Ref)
vs T2	3.83	1.74-8.44	0.001	2.80	1.25-6.28	0.013
vs T3	8.76	4.07-18.87	< 0.001	4.38	1.94-9.89	< 0.000
vs T4	13.63	6.27-29.66	< 0.001	5.24	2.25-12.16	< 0.000
N+ (vs N0)	3.02	2.24-4.08	< 0.001	0.99	0.69-1.43	0.969
M1 (vs M0)	5.01	3.62-6.95	< 0.001	2.76	1.88-4.05	< 0.000
Non-IGBC (vs IGBC)	2.24	1.76-2.85	< 0.001	1.35	1.01-1.80	0.041

HR: Hazard ratio; CI: Confidence interval; ECOG: Eastern Cooperative Oncology Group; IGBC: Incidental gallbladder cancer.

Curative-intent surgery subgroup analysis

Clinicopathological and surgical characteristics of the 49 patients who underwent curative surgery are shown in Table 3. The mean age was 62.9 years, and 81.6% were female. The median interval between diagnosis and institutional care was 1.7 months (IQR: 0.9-3.3), and the median time between diagnosis and surgery was 2.7 months (IQR: 1.5-4.1). Intraoperative frozen section biopsy of the cystic duct was performed in 35 patients (71.4%), with one positive case requiring extrahepatic bile duct resection (1/35, 2.9%). The most common pathological stage was pT2 (40.8%). The mean number of dissected lymph nodes was 7 (± 5), and lymph node metastasis (pN+) was present in 38.8% of patients. Adequate lymphadenectomy (≥ 6 nodes) was achieved in 51.0% of cases. The majority of patients were classified as pTNM stage III (44.9%). Of the 32 IGBC cases, port site excision was performed in 11 (34.4%) patients with one case being positive (1/11, 9.1%). Furthermore, RD was found in 53.1% of patients with IGBC undergoing re-resection. There was no postoperative mortality, and the median hospital stay was 7 days.

Table 3 Clinical, surgical and pathological characteristics of gallbladder cancer patients submitted to curative intent surgery, n (%)/mean ± SD.

Variables	n = 49 (%)
Sex
Female	40 (81.6)
Male	9 (18.4)
Age (years)	62.9 ± 12.2
Body mass index (kg/m2)	26.3 ± 5.5
Type of case
Non-IGBC	32 (63.5)
IGBC	17 (34.7)
Epiplon
Negative	47 (95.9)
Positive	2 (4.1)
pT
pT1a	2 (4.1)
pT1b	8 (16.3)
pT2	20 (40.8)
pT3	18 (36.7)
pT4	1 (2.0)
pN
pN0	30 (61.2)
pN+	19 (38.8)
pM
pM0	45 (91.8)
pM1	4 (8.2)
pTNM
I	7 (14.3)
II	14 (28.6)
III	22 (44.9)
IV	6 (12.2)

IGBC: Incidental gallbladder cancer; TNM: Tumor-node-metastasis.

The 5-year OS was 57.5% for all patients who underwent curative surgery. The 5-year OS varied significantly according to pathological tumor stage (pT) as illustrated in Figure 4A. Patients with pT1a tumors had a 5-year OS rate of 100% and those with pT1b of 87.5%. Survival declined notably in more advanced stages with 61.9% for pT2 tumors and 38.1% for pT3/pT4 tumors (median OS of 43.4 months). Patients with pN0 had better outcomes although statistical significance was not achieved (5-year OS: Not reached vs 52.8 months for pN+; P = 0.134) (Figure 4B). According to the pTNM stage, the 5-year OS rates were 100% for stage I, 63.6% for stage II, 53.3% for stage III, and 43.0% for stage IV (Figure 4C). There was no significant difference in OS for IGBC and non-IGBC in patients who underwent curative-intent surgery (P = 0.475) (Figure 4D). In addition, in patients with IGBC survival was notably higher in patients without RD after re-resection (83.3% vs 41.3% for those with RD; P = 0.017).

Figure 4 Overall survival of patients with gallbladder carcinoma referred to curative intent. A: According to the pT status; B: According to the presence of regional lymph node; C: According to the tumor-node-metastasis stage; D: According to the incidental gallbladder cancer and non-incidental gallbladder cancer groups. TNM: Tumor-node-metastasis; IGBC: Incidental gallbladder cancer.

DISCUSSION

This study provided one of the most comprehensive real-world analyses of GBC in Brazil, highlighting the significant clinical challenges associated with late-stage diagnosis and limited access to curative treatment. Despite advances in diagnostic imaging and surgical techniques, GBC remains a highly lethal malignancy with most patients presenting at advanced stages where curative interventions are often no longer feasible[24,25].

Our cohort reflects these global challenges with 72.3% of patients diagnosed at stage IV, a dismal median OS of 11.5 months, and a 5-year survival probability of 15.4%, consistent with previously reported survival ranges of 5%-15%[19,26]. The predominance of female patients (78.8%) and the mean age at diagnosis of 62 years align with established epidemiological patterns[27,28]. In our cohort 54.1% of patients had incidental diagnoses, comparable to international reports in which IGBC accounts for more than half of GBC cases[13,14,29]. IGBC was associated with significantly better survival outcomes compared with non-IGBC (median OS: 18 months vs 7 months; P < 0.001). Patients with non-IGBC exhibited significantly poorer performance status (ECOG) and more advanced T, N, M, and TNM stages (P < 0.001 for all comparisons), corroborating findings from previous studies[12-14]. This underscores the importance of thorough pathological assessment of all cholecystectomy specimens, even when performed for presumed benign disease.

Radical resection remains the cornerstone of potentially curative treatment for GBC. In our cohort only 13.5% of patients underwent curative-intent surgery, a proportion consistent with international series[19,30]. These patients achieved markedly superior outcomes with a 5-year OS of 57.5%, exceeding survival rates reported in population-based analyses, including the Surveillance, Epidemiology, and End Results database (28.8%)[31] and multicenter cohorts (24.8%)[32]. These findings emphasize the pivotal role of specialized hepatobiliary centers and the necessity of multidisciplinary oncologic management. Previous surgical series have also underscored TNM stage as the principal prognostic determinant with 5-year survival declining progressively from 94.7% in stage I to 2.6% in stage IVB disease[33]. Consistently, our study demonstrated significantly worse outcomes among patients with advanced T stage (T3/T4) and higher TNM stages[20].

Comparative data from high-incidence regions provide important context for our Brazilian cohort. In Chile, the country with the world’s highest GBC incidence, population-based registries report that approximately 64% of patients present with stage IV disease with a 5-year OS around 10%, decreasing to 2% in stage IV and exceeding 80% only in stage I alongside a marked female predominance (about 80%)[34,35]. Similarly, cohorts from the Ganges belt of northern India and neighboring regions such as Pakistan and Bangladesh show a younger age at diagnosis (fifth to sixth decades), female predominance, and advanced presentation with low resection rates and median OS of 5-12 months in unresectable disease[6,36-38]. Compared with these high-incidence regions, our Brazilian cohort exhibits a similar epidemiologic profile characterized by a predominance of late-stage disease (72.3% stage IV) and limited eligibility for curative surgery (13.5%) with a higher proportion of incidental diagnoses (54%), likely reflecting the widespread adoption of laparoscopic cholecystectomy. Survival outcomes in our series parallel those reported internationally when adjusted for stage and treatment, underscoring the universal prognostic importance of tumor stage, ECOG performance status, and resectability. These findings suggest that despite regional differences in incidence and access to care the biological aggressiveness of GBC and the critical role of specialized hepatobiliary centers in improving outcomes are consistent worldwide.

Accurate staging remains essential for prognosis and treatment planning. Although guidelines recommend retrieval of at least six lymph nodes for accurate staging[20,39,40], only 51% of our surgical patients met this benchmark. This rate, however, was considerably higher than the 16.7% to 24.5% adequacy reported in previous series[41-43], and lymph node harvesting was significantly higher in academic centers[44]. Adequate lymphadenectomy not only improves staging accuracy but has also been associated with improved survival in several studies[43-46]. Ongoing efforts are needed to standardize surgical practices to ensure compliance with these quality indicators. Interestingly, while nodal status is widely recognized as a prognostic factor, our study did not demonstrate a statistically significant difference in survival between patients with pN0 and pN+ after curative surgery. This may be explained by the exclusion of patients with distant nodal metastasis (M1) from curative procedures and reinforces the importance of precise patient selection.

Re-resection improves survival in IGBC, particularly in T2 and T3 tumors, with 5-year survival rates of 41% compared with 15% among patients who did not undergo re-resection[47]. RD after re-resection in IGBC is a critical prognostic factor, associated with worse disease-specific survival and OS even after achieving R0 margins[48-52]. Our study confirmed the negative prognostic impact of RD (5-year OS: 83.3% without RD vs 41.3% with RD; P = 0.017) with all patients with RD receiving adjuvant chemotherapy.

A noteworthy observation in our study was the similar survival between patients with IGBC who underwent surgery and those managed with observation. The latter group comprised patients initially eligible for re-resection but who did not undergo surgery due to delayed referral, poor clinical status, or refusal. However, this finding is subject to significant selection bias as the prolonged interval before intervention may have resulted in the natural selection of patients without disease progression. Moreover, the absence of molecular or genomic profiling limits a deeper understanding of tumor biology, potentially explaining survival heterogeneity.

Most patients in our study eventually received chemotherapy with a gemcitabine-cisplatin regimen. However, although this regimen is widely used as first-line chemotherapy for unresectable GBC, the median OS remains poor, underscoring the limited efficacy of current systemic therapies in this malignancy[53]. Given the unsatisfactory outcomes with conventional chemotherapy, future clinical trials should investigate novel systemic treatment strategies for advanced and unresectable GBC. In parallel, public health initiatives should prioritize the development of structured referral pathways to improve early diagnosis and timely access to specialized surgical care.

Our study has inherent limitations, including its retrospective design and single-center nature. Nevertheless, it provides valuable real-world evidence on the management of GBC in Brazil, a region historically underrepresented in the global literature. The novelty of this work lies in characterizing for the first time the epidemiologic and clinical profile of Brazilian patients with GBC, thereby addressing a relevant knowledge gap and potentially fostering future multicenter collaborations and external validation efforts that may integrate molecular and genomic analyses to further elucidate prognostic heterogeneity and inform personalized management strategies.

CONCLUSION

Most patients referred to our specialized cancer center presented with advanced-stage GBC and were managed with systemic or palliative treatment. IGBC was more frequent and associated with improved outcomes, primarily due to diagnosis at earlier stages. Surgical treatment, although feasible in only a minority of patients, remains the sole potentially curative option, conferring significant survival benefits. Among IGBC patients who underwent surgery, the absence of RD correlated with superior outcomes. Notably, patients with isolated lymph node RD achieved prolonged survival with adjuvant therapy and retained a chance of cure. A subgroup of patients with IGBC without evidence of RD who were managed with observation exhibited survival rates comparable with those who underwent surgery although this finding is likely biased by delayed referral and patient selection. Our findings highlight the urgent need for structured referral pathways and national protocols for the management of IGBC in Brazil. Prompt referral to specialized hepatobiliary centers is essential to maximize opportunities for curative treatment and to improve patient outcomes.