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pT1b gallbladder adenocarcinoma. A more typical example composed of a handful of glands invading into the muscle bundles. Some of the invasive glands show paradoxical acidophilia that creates a contrast with the surface in-situ carcinoma (high-grade dysplasia) component and allows their recognition as invasion, not invagination. In this case, muscularis is more compact and thicker and invasion is confined to the upper segment of the muscularis
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There are highly conflicting data on relative frequency (2–32%), prognosis, and management of pT1b-gallbladder carcinoma (GBC), with 5-year survival ranging from > 90% in East/Chile where cholecystectomy is regarded as curative, versus < 50% in the West, with radical operations post-cholecystectomy being recommended by guidelines. A total of 473 in...
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... A recent multicenter study demonstrated the pathological mis-staging of pT2 as pT1 in the range of 29%. [19] Among the recently proposed guidelines for the daily management of pT1b GBC, the most relevant are as follows: First, the entire gallbladder should be subjected to microscopic examination to exclude pT2 carcinoma. Second, the pathological sampling status should be documented, and if not completely sampled, the number of submitted blocks. ...
... Fifth, it is advisable to sample the cystic duct margin in all cholecystectomy specimens during the initial examination. [19] Most pathological reports lack standardization, and essential information is often unavailable. A uniform pathological report, including the macroscopic and microscopic features of GBC, is required worldwide to optimize the prediction of prognosis and patient care. ...
Gallbladder cancer (GBC) is a rare malignancy worldwide, with 140,000 new patients each year and more than 100,000 deaths annually. The review aims to address the controversial aspects of managing GBC. Regional differences of the study worldwide remain pending, and comparative mutational profiles will provide more information on the pathogenesis of GBC. However, certain pathologic aspects are discussed, such as the staging of early GBC, outcome differences between T2 pathologically staged patients, and the necessity of a uniform pathologic report. The surgical management of GBC is still under debate. The extent of liver resection, type of lymphadenectomy, and selection of patients for extended resection are aspects of the disease that require revision. Laparoscopic and robotic approaches were initially slow to develop. However, with time, they have demonstrated their value in the surgical management of GBC. The OMEGA survey, performed to analyze the management practice of surgical treatment of GBC worldwide, demonstrated differences from the recommended guidelines. The OMEGA study, the largest cohort study, examined the outcomes of surgical intervention in 3676 patients from 133 centers. Regarding future directions, the value of collaborative efforts between centers and regions must be emphasized to better understand the different aspects of the disease and globally improve therapeutic strategies for GBC.
... Variation in survival data for early stage tumours may also be related to substantial subjectivity and geographic differences in the pathological classification of non-invasive vs minimally invasive (T1) carcinomas, and international collaborations are underway to establish standardized descriptive criteria to better characterize the behaviour of early GBC. 20 There is more consistency between the literature and current guidelines for T2 tumours, suggesting a potential benefit for liver resection, but any associated survival benefit is only shown on univariable analysis and lost on multivariable analysis in our study and others. 11,12,21 This may partly be explained by confounding effects of positive margins, nodal status or comorbidities on univariable analysis. ...
Background Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).
... Other management options include chemotherapy and radiotherapy, immunotherapy, and targeted therapy by monoclonal antibody biological agents [41][42][43][44][45]. The current rapidly evolving, multimodal therapeutic approach [46] and Medicaid expansion [47] have improved the results, opening new perspectives even in inoperable cases involving palliative treatment [4,13,[48][49][50]. ...
... A study conducted in Australia including 104 patients with GB carcinoma and a median follow-up of 60 mo found a median overall survival of 35 mo in those with intended curative resection and 4 mo in inoperable cases with palliative treatment [36]. For a T1b follow-up of 69.9 mo, the disease-free survival was 92% [50]. For advanced stage III-IV GB carcinoma patients, the overall survival was as follows: 1-year at 47.6%; 2-year at 29.1%; and 3-year at 19.9% [157]. ...
Gallbladder (GB) carcinoma, although relatively rare, is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis. It is closely associated with cholelithiasis and long-standing large (> 3 cm) gallstones in up to 90% of cases. The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes, GB wall calcification (porcelain) or mainly mucosal microcalcifications, and GB polyps ≥ 1 cm in size. Diagnosis is made by ultrasound, computed tomography (CT), and, more precisely, magnetic resonance imaging (MRI). Preoperative staging is of great importance in decision-making regarding therapeutic management. Preoperative staging is based on MRI findings, the leading technique for liver metastasis imaging, enhanced three-phase CT angiography, or magnetic resonance angiography for major vessel assessment. It is also necessary to use positron emission tomography (PET)-CT or 18F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake. Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6% of cases. Multimodality treatment is needed, including surgical resection, targeted therapy by biological agents according to molecular testing gene mapping, chemotherapy, radiation therapy, and immunotherapy. It is of great importance to understand the updated guidelines and current treatment options. The extent of surgical intervention depends on the disease stage, ranging from simple cholecystectomy (T1a) to extended resections and including extended cholecystectomy (T1b), with wide lymph node resection in every case or IV-V segmentectomy (T2), hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y, and adjacent organ resection if necessary (T3). Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery, but much attention must be paid to avoiding injuries. In addition to surgery, novel targeted treatment along with immunotherapy and recent improvements in radiotherapy and chemotherapy (neoadjuvant-adjuvant capecitabine, cisplatin, gemcitabine) have yielded promising results even in inoperable cases calling for palliation (T4). Thus, individualized treatment must be applied.
... Variation in survival data for early stage tumours may also be related to substantial subjectivity and geographic differences in the pathological classification of non-invasive vs minimally invasive (T1) carcinomas, and international collaborations are underway to establish standardized descriptive criteria to better characterize the behaviour of early GBC. 20 There is more consistency between the literature and current guidelines for T2 tumours, suggesting a potential benefit for liver resection, but any associated survival benefit is only shown on univariable analysis and lost on multivariable analysis in our study and others. 11,12,21 This may partly be explained by confounding effects of positive margins, nodal status or comorbidities on univariable analysis. ...
Background Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).
... Variation in survival data for early stage tumours may also be related to substantial subjectivity and geographic differences in the pathological classification of non-invasive vs minimally invasive (T1) carcinomas, and international collaborations are underway to establish standardized descriptive criteria to better characterize the behaviour of early GBC. 20 There is more consistency between the literature and current guidelines for T2 tumours, suggesting a potential benefit for liver resection, but any associated survival benefit is only shown on univariable analysis and lost on multivariable analysis in our study and others. 11,12,21 This may partly be explained by confounding effects of positive margins, nodal status or comorbidities on univariable analysis. ...
Background
Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).
Methods
The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity.
Findings
On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62–3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55–5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02–1.37], p = 0.031) but not OS (HR 1.05 [0.91–1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used.
Interpretation
In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit.
... Variation in survival data for early stage tumours may also be related to substantial subjectivity and geographic differences in the pathological classification of non-invasive vs minimally invasive (T1) carcinomas, and international collaborations are underway to establish standardized descriptive criteria to better characterize the behaviour of early GBC. 20 There is more consistency between the literature and current guidelines for T2 tumours, suggesting a potential benefit for liver resection, but any associated survival benefit is only shown on univariable analysis and lost on multivariable analysis in our study and others. 11,12,21 This may partly be explained by confounding effects of positive margins, nodal status or comorbidities on univariable analysis. ...
Background:
Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).
Methods:
The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity.
Findings:
On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used.
Interpretation:
In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit.
Funding:
Cambridge Hepatopancreatobiliary Department Research Fund.
Gallbladder cancer (GBC) is a rare malignancy worldwide, with 140,000 new patients each year and more than 100,000 deaths annually. The review aims to address the controversial aspects of managing GBC. Regional differences of the study worldwide remain pending, and comparative mutational profiles will provide more information on the pathogenesis of GBC. However, certain pathologic aspects are discussed, such as the staging of early GBC, outcome differences between T2 pathologically staged patients, and the necessity of a uniform pathologic report. The surgical management of GBC is still under debate. The extent of liver resection, type of lymphadenectomy, and selection of patients for extended resection are aspects of the disease that require revision. Laparoscopic and robotic approaches were initially slow to develop. However, with time, they have demonstrated their value in the surgical management of GBC. The OMEGA survey, performed to analyze the management practice of surgical treatment of GBC worldwide, demonstrated differences from the recommended guidelines. The OMEGA study, the largest cohort study, examined the outcomes of surgical intervention in 3676 patients from 133 centers. Regarding future directions, the value of collaborative efforts between centers and regions must be emphasized to better understand the different aspects of the disease and globally improve therapeutic strategies for GBC.
