Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and third most common gastrointestinal tract malignancy [
Given the low rates of GBC in North American, most existing knowledge regarding GBC is derived primarily from studies conducting in South America and Asia. This study examines a large cohort of gallbladder carcinoma patients in the United States (US) in an effort to define the demographics, clinical, and pathologic features impacting clinical outcomes in American GBC patients.
Data for the current study was extracted from the Surveillance, Epidemiology, and End Result (SEER) database provided by the National Cancer Institute between 1973 and 2013. SEER Stat software version 8.0.4 was utilized to extract data from 18 SEER registries (Alaska Native Tumor Registry, Arizona Indians, Cherokee Nation, Connecticut, Detroit, Georgia Center for Cancer Statistics, Greater Bay Area Cancer Registry, Greater California, Hawaii, Iowa, Kentucky, Los Angeles, Louisiana, New Jersey, New Mexico, Seattle-Puget Sound, and Utah).
22,343 patients with GBC were identified using the SEER International Classification of Disease for Oncology (ICD-O-3) codes C23.9 [
A total of 22,343 cases of GBC were reported in the SEER database from 1973 to 2013. The number of GBC cases increased from approximately 200 cases per year in the 1970s to >1,000 cases per year after 2010, with a significant spike in 2000 (Table
Annual cases of gallbladder carcinoma from the Surveillance, Epidemiology, and End Result (SEER) database (1973–2013).
Year | New cases |
---|---|
1973 | 246 |
1974 | 289 |
1975 | 304 |
1976 | 261 |
1977 | 294 |
1978 | 299 |
1979 | 306 |
1980 | 331 |
1981 | 332 |
1982 | 289 |
1983 | 294 |
1984 | 325 |
1985 | 296 |
1986 | 287 |
1987 | 294 |
1988 | 285 |
1989 | 304 |
1990 | 294 |
1991 | 292 |
1992 | 447 |
1993 | 419 |
1994 | 407 |
1995 | 449 |
1996 | 397 |
1997 | 414 |
1998 | 422 |
1999 | 426 |
2000 | 820 |
2001 | 886 |
2002 | 837 |
2003 | 924 |
2004 | 874 |
2005 | 937 |
2006 | 935 |
2007 | 975 |
2008 | 907 |
2009 | 1,002 |
2010 | 1,009 |
2011 | 1,042 |
2012 | 1,089 |
2013 | 1,103 |
Demographics and clinical profile of 22,343 patients with gallbladder carcinoma from the Surveillance, Epidemiology, and End Result (SEER) database (1973–2013).
Variables | Frequency (%) |
---|---|
|
22,343 |
|
71.17 ± 12.534 |
|
|
Male | 6,549 (29.3%) |
Female | 15,794 (70.7%) |
|
|
Alaska | 46 (0.2%) |
East | 6,684 (29.9%) |
Northern Plains | 4,230 (18.9%) |
Pacific Coast | 9,605 (43.0%) |
Southwest | 1,778 (8.0%) |
|
|
Caucasian | 14,280 (64.0%) |
African American | 2,056 (9.2%) |
Hispanic | 3,740 (16.8%) |
Asian/Pacific Islander | 1,861 (8.3%) |
American Indian/Alaska Native | 375 (1.7%) |
|
|
Well differentiated | 2,252 (15.3%) |
Moderately differentiated | 5,619 (38.2%) |
Poorly differentiated | 6,238 (42.5%) |
Undifferentiated | 592 (4.0%) |
|
|
Yes | 15,791 (88.2%) |
No | 2,105 (11.8%) |
|
|
No treatment | 6,811 (31.8%) |
Surgery only | 11,769 (55.0%) |
Radiation only | 545 (2.6%) |
Both surgery and radiation | 2,269 (10.6%) |
|
2.715 ± 0.061 |
| |
No treatment | 0.618 ± 0.049 |
Surgery only | 3.685 ± 0.093 |
Radiation only | 0.815 ± 0.075 |
Both surgery and radiation | 4.029 ± 0.184 |
|
|
Well differentiated | 5.926 ± 0.266 |
Moderately differentiated | 3.720 ± 0.151 |
Poorly differentiated | 1.664 ± 0.073 |
Undifferentiated | 1.293 ± 0.167 |
|
19,439 (87.0%) |
|
16,856 (75.4%) |
|
|
3-month | 66% |
6-month | 50% |
9-month | 41% |
1-year | 34% |
2-year | 22% |
3-year | 17% |
4-year | 14% |
5-year | 13% |
Annual cases of gallbladder carcinoma from the Surveillance, Epidemiology, and End Result (SEER) database (1973–2013).
Most cases of GBC presented as poorly differentiated tumors (42.5%), followed by moderately differentiated (38.2%), well differentiated (15.3%), and undifferentiated (4.0%) tumors. Most patients presented with lymph node involvement (88.2%).
Surgical resection alone was the most common treatment modality (55.0%). Surgical resection and adjuvant radiation were utilized by 10.6%, while radiation alone was used in 2.6% of patients. 31.8% of patients received neither surgery nor radiation. The number of GBC treated with surgery increased in the 1980s, with a concomitant decrease in patients receiving no treatment (Figure
Trends in the treatment modalities utilized for gallbladder carcinoma from the Surveillance, Epidemiology, and End Result (SEER) database (1973–2013).
Overall survival was 2.72 ± 0.06 years. Surgical resection was associated with significantly improved survival (3.69 ± 0.09 years) compared to patients receiving no treatment (0.62 ± 0.05 years) or radiation alone (0.82 ± 0.08 years) (Table
Survival outcomes of 22,343 patients with gallbladder carcinoma from the Surveillance, Epidemiology, and End Result (SEER) database (1973–2013).
Overall | Surgery alone | Radiation alone | Both surgery and radiation | Neither | |
---|---|---|---|---|---|
|
2.715 ± 0.061 | 3.685 ± 0.093 | 0.815 ± 0.075 | 4.029 ± 0.184 | 0.618 ± 0.049 |
|
|||||
|
|||||
3-month | 66% | 75% | 76% | 96% | 42% |
6-month | 50% | 61% | 50% | 84% | 23% |
9-month | 41% | 51% | 32% | 72% | 14% |
1-year | 34% | 44% | 29% | 60% | 10% |
2-year | 22% | 31% | 21% | 35% | 5% |
3-year | 17% | 24% | 6% | 26% | 3% |
4-year | 14% | 21% | 3% | 21% | 2% |
5-year | 13% | 18% | 2% | 18% | 2% |
SE = standard error.
Kaplan Meier curves illustrating actuarial survival for patients with gallbladder carcinoma from the Surveillance, Epidemiology, and End Results database (1973–2013).
When stratified by tumor grade, well differentiated tumors had the longest survival (5.93 ± 0.27 years), followed by moderately differentiated (3.72 ± 0.15 years), poorly differentiated (1.66 ± 0.07 years), and undifferentiated (1.29 ± 0.17 years) tumors.
Overall mortality was 87.0% and cancer-specific mortality was 75.4%. Cumulative survival remained low, and 1-, 2-, and 5-year survival were 34%, 22%, and 13%, respectively.
Multivariate analysis identified moderately differentiated (OR 1.43; 95% CI, 1.27–1.61), poorly differentiated (OR 3.10; 95% CI, 2.72–3.54), and undifferentiated (OR 3.10; 95% CI, 2.26–4.25) tumors as independently associated with increased mortality,
GBC is an aggressive malignancy associated with multiple etiologies and high mortality [
The large variation in incidence worldwide is due to a combination of exposure to environmental risk factors and heritable genetic traits [
Female gender increases the risk of GBC by twofold to sixfold [
The most significant risk factor for GBC is gallstones (relative risk (RR) = 3.0–23.8) and is present in the majority (69–85%) of patients [
The prognosis of GBC is extremely poor, most often due to its late diagnosis. Patients with GBC in this study often had advanced stage and grade by the time of diagnosis. The majority of patients presented with either poorly (42.5%) or moderately (38.2%) differentiated disease, and over 85% of patients had lymph node involvement.
The extensive progression of disease can be explained at least in part due to the difficulty in diagnosis [
GBC most commonly arises due to the dysplasia-carcinoma sequence but can occasionally occur due to polyps and adenoma-carcinoma progression [
The near silent and chronic progression of GBC results in many diagnoses (70%) detected incidentally [
The tragic consequence of incidental discovery and late diagnosis is a one-year survival of 34%, a cumulative five-year survival of 13%, and a mean overall survival of only 2.7 years. Previous studies have specifically recognized extended disease and the number of positive lymph nodes as important predictors of worsening outcomes [
Surgical resection is the standard of care for GBC patients [
The use of radiation as a treatment modality alone has inferior survival rates compared to surgical resection and is typically used in combination with chemotherapy when surgery is not feasible [
Future improvements in therapy are focused on individual processes of carcinogenesis [
There are several limitations to this study which need to be considered. The SEER database does not accurately code all clinical factors which may affect patient survival. Secondly, information on chemotherapy received was not provided in detail, limiting this study’s ability to evaluate the effect of adjuvant or neoadjuvant therapy. There may also be an element of selection bias, since SEER registries are more likely to sample from urban than from rural areas. Despite these limitations, the SEER database has data obtained a representative sample of the US population and therefore these findings can be generalized to the overall population.
GBC is an uncommon malignancy that presents most often among females in their 8th decade of life, with advanced stage of disease and lymph node involvement. The incidence of GBC has doubled in the last decade concurrent with increases in cholecystectomy rates attributable in part to improved histopathological detection, as well as laparoscopic advances and enhanced endoscopic techniques. Surgical resection confers significant survival benefit in GBC patients. The role of radiation therapy remains controversial, and adjuvant radiation therapy in addition to surgical resection has been shown to confer a small survival advantage. Despite treatment, overall and cancer-specific survival remains low. Given its rarity, all GBC patients should be enrolled in clinical trials or registries to optimize treatment and clinical outcomes for these patients.
The authors declare that they have no conflicts of interest.