Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors

doi:10.21203/rs.3.rs-2532001/v1

Purpose: Risk factors of Gallbladder Cancer (GBC) are not well-defined resulting in greater than 60% of GBCs being diagnosed incidentally following cholecystectomy performed for presumed benign indications. As most localized GBC require more extensive oncologic surgery beyond cholecystectomy, this study aims to examine factors associated with incidentally found GBC to improve preoperative and intraoperative diagnosis.

Methods: The American College of Surgeons National Surgical Quality Improvement Program Database from 2007-2017 was used to identify cholecystectomies performed with and without a final diagnosis of GBC. Univariate and multivariable logistic regression were used to compare demographic, intraoperative, and postoperative characteristics among those with and without a diagnosis of GBC.

Results: The incidence of GBC was observed to be 0.11% (441/403,443). Preoperative factors associated with risk of GBC included age >60 (OR 6.51, p<.001), female sex (OR 1.75, p<.001), history of weight loss (2.58, p<.001), and elevated preoperative alkaline phosphatase level (OR 1.67, p=.001). Open approach was associated with 7 times increased risk of GBC compared to laparoscopic approach (OR 7.33, p<.001). In addition to preoperative factors and surgical approach, longer mean operative times (127 minutes vs 70.7 minutes, p<.001) were significantly associated with increased risk of GBC compared to benign final pathology.

Conclusion: This study demonstrates that those with incidentally discovered GBC at cholecystectomy are unique from those undergoing cholecystectomy for benign indications. By identifying predictors of GBC, surgeons can choose high risk individuals for pre-operative oncologic evaluation and consider better tools for identifying GBC such as intraoperative frozen pathology.

Gallbladder Cancer

Cholecystectomy

National Surgical Quality Improvement Program

Worldwide, gallbladder cancer (GBC) is the fifth most common type of gastrointestinal malignancy [1]. In the United States, GBC has an incidence of approximately 1.2 in 100,000 [2] and is associated with a poor 5-year overall survival ranging from 16–19% [2,3]. The high mortality of GBC is largely attributed to late diagnosis and advanced disease at presentation in symptomatic patients. Patients with early-stage GBC are typically asymptomatic or have non-specific symptoms at presentation [4,5] which leads to frequent incidental diagnosis via histopathology following a simple cholecystectomy performed for presumed benign gallbladder disease.

Approximately 50–70% of GBCs are diagnosed incidentally after cholecystectomy performed for presumed benign indications [6–9]. Of these incidentally diagnosed cases, 60 to 80% are noted at early enough pathologic stages [8,10] to benefit from resection to a negative margin [5] and regional lymph node staging. Current National Comprehensive Cancer Network guidelines recommend simple cholecystectomy for patients with T1a (tumor confined the mucosa) disease only and any patients with T1b (tumor confined to the muscularis) or more advanced resectable disease to undergo segment IVb and V hepatic resection along with portal lymphadenectomy [11]. The failure to diagnose patients with GBC preoperatively or intraoperatively results in a majority of patients with resectable GBC required to undergo reoperation and misses the opportunity for preoperative evaluation by a hepatobiliary specialist, clinical staging, appropriate surgical planning, and potentially even neoadjuvant chemotherapy treatment [12].

The primary aim in this study is to use a large national database to identify preoperative and intraoperative factors associated with cases of incidentally diagnosed GBC to identify characteristics that can aid in earlier clinical suspicion and diagnosis of GBC. In doing so, we also quantify the contemporary incidence of GBC found after cholecystectomy and characterize surgical outcomes for patients with incidental GBC diagnosis in comparison to those with benign biliary pathology.

Data Source:

The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Participant User Files (PUF) were utilized to identify all patients undergoing cholecystectomy from 2007–2017. NSQIP is a national program that is validated as a measure of quality improvement in the United States. NSQIP collects data from 700 individual hospitals and captures more than 1 million cases annually [13]. Current Procedural Terminology (CPT) codes 47562, 47563, 47564, 47600, 47605, 47610, 47612, 47620 were utilized to capture all patients undergoing laparoscopic or open cholecystectomy. All patients who underwent any type of concurrent liver procedure and/or lymphadenectomy were excluded. Additionally, all patients with a preoperative diagnosis of disseminated cancer were also excluded from analysis. This study was deemed to be exempt for institutional review board approval by the Human Subject Protection Office at the Penn State College of Medicine.

Primary Outcomes of Interests:

The primary outcome of interest was a final pathological diagnosis of GBC. Patients with GBC were identified by International Classification of Disease (ICD) code (ICD-9: 156.0 and ICD-10: C23). NSQIP records one primary diagnosis based upon final pathologic data available after surgery. Preoperative diagnoses are not available.

Statistical Analysis:

All baseline demographics were compared between those who were found to have a diagnosis of GBC and those who did not. Categorical variables were expressed as percentages and continuous variables were expressed as medians with interquartile ranges (IQR). Categorical variables (gender, race, inpatient vs outpatient procedure status, transfer status, body mass index (BMI), history of substantial weight loss (> 10% of BMI within 6 months), smoking status, functional status prior to surgery, American Society of Anesthesiologist (ASA) classification, preoperative diagnosis of diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), hypertension, chronic steroid use, and ascites) were compared using chi-square test for categorical variables and Kruskal-Wallis for continuous variables. Additionally, preoperative laboratory values (creatinine, albumin, alkaline phosphatase, white blood cell count (WBC), hematocrit, platelet count, international normalized ratio (INR), total bilirubin, aspartate aminotransferase (AST), sodium, and blood urea nitrogen values were compared between groups using Kruskal-Wallis test. Operative details including surgical approach as either open (CPT: 47600, 47605, 47610, 47612, 47620) vs laparoscopic (CPT: 47562, 47563, 47564)), cases status (nonemergent vs emergent), and total operative time were also compared between groups. Multivariable logistic regression model was used to evaluate the likelihood of having a final pathologic diagnosis of GBC. Lastly, surgical outcomes including length of stay (LOS), surgical site infection (SSI), pneumonia, deep vein thrombosis, pulmonary embolism, respiratory failure, renal insufficiency, urinary tract infection, cerebral vascular accident, cardiac arrest, myocardial infarction, transfusion requirements, postoperative sepsis, required return to the operating room, and 30-day mortality were compared between those with a diagnosis of GBC and those without. All statistical tests were 2-sided with a p-value < 0.05 considered statistically significant. Analysis was performed using SAS version 9.4 (SAS Institute Inc).

This study included 403,443 patients undergoing cholecystectomy with 0.11% (441/403,443) found to have GBC on final pathology. Table 1 presents demographic comparison of those undergoing cholecystectomy found to have GBC compared to those who did not have a final diagnosis of GBC. The median age of those with GBC was significantly older than those without (72 vs 50, p < .001). Non-Caucasian patients made up a larger percentage of those with GBC compared to those without GBC (African American (15.2% vs 9.3%), Hispanic (3.6% vs 3.3%), Native American (6.3% vs 4.6%), and Asian (0.5% vs 0.1%)). Conversely, Caucasian patients made up a lower percentage of those with GBC compared to those who did not have GBC (59.2% vs 72.1%, p < .001). A higher percentage of patients with GBC reported substantial weight loss (> 10% of body weight in 6 months) prior to their operation compared to those without GBC (5.2% vs 0.9%, p < .001). Additionally, a higher percentage of patients with GBC were found to have a normal BMI (18.5–24.9) (29.9%) compared to those without GBC (16.5%), while a lower percentage of patient with GBC had an obese BMI (> 30) (29.8%) compared to those without GBC (44.7%) (p < .001). There was no difference between the two groups in terms of gender distribution, CHF, and rate of preoperative diagnosis of sepsis (p > 0.05). Patients with GBC had higher rates of systemic disease preoperatively compared to those without GBC with came to ASA classification with 62.5% of patients with GBC having an ASA classification of 3 or higher compared to only 31.6% of those without gallbladder cancer.

Table 1

Demographic and preoperative conditions of entire cohort stratified by postoperative finding of gallbladder adenocarcinoma versus benign pathology.
	Incidentally Found Gallbladder Cancer (N = 441)	No Gallbladder Cancer (N = 403,002)	p value
Age			< 0.001
Mean (SD)	69.9 (12.96)	49.9 (17.54)
Median	72.0	50.0
Interquartile range	62.0, 80.0	35.0, 63.0
Gender			0.460
Female	299 (67.8%)	279778 (69.4%)
Male	142 (32.2%)	123224 (30.6%)
Race			<0.001
Caucasian	261 (59.2%)	290525 (72.1%)
African American	67 (15.2%)	37609 (9.3%)
Hispanic	16 (3.6%)	13473 (3.3%)
Native American	28 (6.3%)	18349 (4.6%)
Asian	2 (0.5%)	506 (0.1%)
Unknown	67 (15.2%)	42540 (10.6%)
Inpatient/outpatient Procedure			< 0.001
Inpatient	325 (73.7%)	170935 (42.4%)
Outpatient	116 (26.3%)	232067 (57.6%)
Transfer Status			< 0.001
Admitted from Home	404 (91.6%)	384011 (95.3%)
Transfer from Acute Care Hospital	28 (6.3%)	14757 (3.7%)
Transfer from Chronic Care Facility	8 (1.8%)	2140 (0.5%)
Other	1 (0.2%)	2094 (0.5%)
Body Mass Index			< 0.001
Underweight (< 18.49)	13 (2.9%)	11366 (2.8%)
Normal Weight (18.5–24.9)	132 (29.9%)	66366 (16.5%)
Overweight (25-29.9)	119 (27%)	108761 (27%)
Obese (> 30)	127 (28.8%)	180294 (44.7%)
Unknown	50 (11.3%)	36215 (9%)
Diabetes			< 0.001
No	341 (77.3%)	351845 (87.3%)
Yes	100 (22.7%)	51157 (12.7%)
Current smoker within one year			0.001
No	388 (88%)	329586 (81.8%)
Yes	53 (12%)	73416 (18.2%)
Functional Status Prior to Surgery			0.007
Independent	88 (20%)	63278 (15.7%)
Partially or Totally Dependent	4 (0.9%)	1453 (0.4%)
Unknown	349 (79.1%)	338271 (83.9%)
History of severe COPD			0.016
No	420 (95.2%)	391487 (97.1%)
Yes	21 (4.8%)	11515 (2.9%)
Congestive heart failure (CHF)			0.394
No	437 (99.1%)	400606 (99.4%)
Yes	4 (0.9%)	2396 (0.6%)
Hypertension requiring medication			< 0.001
No	172 (39%)	260779 (64.7%)
Yes	269 (61%)	142223 (35.3%)
Steroid use for chronic condition			0.016
No	425 (96.4%)	394871 (98%)
Yes	16 (3.6%)	8131 (2%)
> 10% loss body weight in last 6 months			< 0.001
No	418 (94.8%)	399414 (99.1%)
Yes	23 (5.2%)	3588 (0.9%)
Ascites			0.007
No	437 (99.1%)	401962 (99.7%)
Yes	4 (0.9%)	1040 (0.3%)
Currently on dialysis (pre-op)			0.868
No	438 (99.3%)	400511 (99.4%)
Yes	3 (0.7%)	2491 (0.6%)
Sepsis			0.707
No preoperative Sepsis	407 (92.3%)	369948 (91.8%)
Preoperative Sepsis	34 (7.7%)	33054 (8.2%)
ASA classification			< 0.001
1-No Disturb	9 (2%)	46034 (11.4%)
2-Mild Disturb	156 (35.4%)	229527 (57%)
3-Severe Disturb	241 (54.6%)	116888 (29%)
4-Life Threat	35 (7.9%)	10444 (2.6%)
5-Moribund	0 (0%)	109 (0%)

Differences were also identified in preoperative lab values when comparing patient with GBC compared those without a final diagnosis of GBC (Table 2). Patients with GBC had lower median preoperative albumin levels (3.6 vs 3.9), WBC (7.4 vs 7.8), and hematocrit levels (37.7 vs 39.3) (p < .001). Median serum alkaline phosphatase was significantly higher in patients with GBC (103.0 IU/L) compared to patients without GBC (82.0 IU/L, p < .001). There was no difference between groups when comparing preoperative platelet count (p = 0.532).

Table 2

Preoperative laboratory values of entire cohort stratified by postoperative finding of gallbladder adenocarcinoma vs benign pathology.
		Incidentally Found Gallbladder Cancer		No Gallbladder Cancer		p value
Serum Creatinine (mg/dl)						< 0.001
N		422		354210
Mean (SD)		1.0 (0.72)		0.9 (0.63)
Median		0.8		0.8
Interquartile range		0.7, 1.1		0.7, 1.0
Serum Albumin (g/dl)						< 0.001
N		357		307421
Mean (SD)		3.6 (0.77)		3.8 (0.63)
Median		3.6		3.9
Interquartile range		3.1, 4.1		3.4, 4.2
Serum Alkaline Phosphatase (IU/L)						< 0.001
N		380		337363
Mean (SD)		157.0 (146.72)		100.8 (70.83)
Median		103.0		82.0
Interquartile range		76.0, 171.0		64.0, 110.0
Serum White Blood Cell (cells × 1000/µl)						< 0.001
N		423		357612
Mean (SD)		8.1 (3.54)		8.6 (3.77)
Median		7.4		7.8
Interquartile range		5.7, 9.2		6.1, 10.2
Serum Hematocrit (%)						< 0.001
N		429		361425
Mean (SD)		37.2 (5.43)		39.1 (4.75)
Median		37.7		39.3
Interquartile range		33.8, 40.8		36.3, 42.1
Serum Platelet Count (cells × 1000/µl)						0.532
N		423		357024
Mean (SD)		261.3 (105.76)		249.8 (77.08)
Median		241.0		243.0
Interquartile range		190.0, 309.0		199.0, 292.0
International Normalized Ratio (INR)						0.012
N		282		139869
Mean (SD)		1.1 (0.32)		1.1 (0.28)
Median		1.1		1.0
Interquartile range		1.0, 1.2		1.0, 1.1
Serum Total Bilirubin (mg/dl)					0.002
N	380		337219
Mean (SD)	1.2 (1.76)		0.9 (1.00)
Median	0.6		0.6
Interquartile range	0.4, 1.1		0.4, 0.9
Serum AST (IU/L)					0.001
N		373		331538
Mean (SD)		50.2 (71.21)		48.2 (79.38)
Median		26.0		24.0
Interquartile range		20.0, 47.0		18.0, 40.0
Serum Sodium (mEq/L)						0.001
N		423		353021
Mean (SD)		138.4 (3.63)		139.1 (2.91)
Median		139.0		139.0
Interquartile range		137.0, 141.0		137.0, 141.0
Blood Urea Nitrogen (mg/dl)						<0.001
N		404		345765
Mean (SD)		15.9 (9.43)		13.3 (7.73)
Median		14.0		12.0
Interquartile range		10.0, 19.0		9.0, 16.0

A majority (93.1%) of cholecystectomies included in this study were performed laparoscopically (375,487/403,443). While 46% of cholecystectomies that resulted in a GBC diagnosis were performed via an open approach, only 6.9% of cholecystectomies performed for benign pathology were performed via an open approach (p < .001). A lower percentage of cholecystectomies performed for GBC were performed as emergent cases (6.6%) compared to cholecystectomies performed in those without GBC (11.1%, p = 0.002). Cholecystectomies performed for GBC were found to have a significantly longer median operative time (106.0 minutes, IQR 71.0-160.0) when compared to cholecystectomies performed for benign pathology (60.0 minutes, IQR 42.0–86.0) (Table 3).

Table 3

Operative Detail of entire cohort stratified by of entire cohort stratified by postoperative finding of gallbladder adenocarcinoma vs benign pathology.
		OR	Lower 95%	Upper 95%	p-value
Age	< 60	Reference
	> 60	6.506	5.115	8.276	< .001
Sex	Male	Reference
	Female	1.751	1.424	2.154	< .001
Race	Caucasian	Reference
	Unknown	1.877	1.427	2.470	0.6273
	African American	2.197	1.673	2.887	0.1557
	Asian	2.043	0.499	8.372	0.7813
	Hispanic	1.998	1.201	3.325	0.5564
	Native American	1.588	1.072	2.354	0.6784
Approach	Laparoscopic	Reference
	Open	7.330	6.000	8.955	< .001
BMI	Normal Weight	Reference
	Obese	0.489	0.381	0.628	< .001
	Overweight	0.641	0.499	0.824	0.6122
	Underweight	0.553	0.312	0.981	0.3831
	Unknown	0.805	0.578	1.120	0.1808
History of Weight Loss	No	Reference
	Yes	2.578	1.669	3.983	< .001
Alk Phos Level	Within Normal Range < 140	Reference
	Elevated > 140	1.671	1.340	2.084	< .001
	Unknown	1.277	0.966	1.690	0.9320

Multivariable logistic regression modeling the likelihood of final pathologic examination revealing a diagnosis of a GBC is presented in Table 4. Patients older than 60 years old were found to be 6.5 times more likely than patients younger than 60 years old to be diagnosed with GBC (OR 6.5, p < .001). Compared to male patients, female patients were more likely to have a diagnosis of GBC (OR 1.8, p < .001). Patients with a history of substantial weight loss were 2.58 times more likely to have a final diagnosis of GBC compared to those without weight less and those with obese BMI were less likely to be diagnosed with GBC (OR 0.49, < .001) compared to those with normal BMI. Patients with preoperative elevated alkaline phosphatase levels (> 140 IU/L) were significantly more likely to have a final pathologic diagnosis of GBC compared to those with non-elevated preoperative alkaline phosphatase levels (OR 1.7, p < .001). Patients that underwent an open cholecystectomy were significantly more likely than those undergoing a laparoscopic cholecystectomy to be diagnosed with GBC (OR 7.3, p < .001). Compared to Caucasian race, African American, Asian, Hispanic, and Native American race was not associated with a finding of GBC on final pathology (p > 0.05).

In addition to preoperative and intraoperative characteristics, differences were identified among those with GBC and those without GBC in terms of postoperative outcomes and complications. While median LOS was 1.0 day (IQR 0–3.0) for patients without GBC, median LOS for patients diagnosed with GBC was 4.0 days (IQR 1.0–7.0) (p < .001). Rates of superficial surgical site infections, organ space infections, postoperative pneumonia, unplanned intubation, pulmonary embolism, renal insufficiency, urinary tract infections, strokes (with neurologic deficits), cardiac arrests, myocardial infarction, transfusion requirements, deep vein thromboses, postoperative sepsis, and 30-day mortality were all higher in patients with GBC compared to those without GBC (Table 5, p < 0.05).

Table 5

Postoperative outcomes of entire cohort stratified by of entire cohort stratified by postoperative finding of gallbladder adenocarcinoma vs benign pathology
	Incidentally Found Gallbladder Cancer (N = 441)	No Gallbladder Cancer (N = 403,002)	p value
Length of Total Hospital Stay (days)			< 0.001
Median	4.0	1.0
Interquartile range	1.0, 7.0	0.0, 3.0
Superficial Surgical Site infection			0.002
No Complication	431 (97.7%)	399486 (99.1%)
Superficial Incisional SSI	10 (2.3%)	3516 (0.9%)
Deep Surgical Site Infection			0.486
Deep Incisional SSI	1 (0.2%)	461 (0.1%)
No Complication	440 (99.8%)	402541 (99.9%)
Organ Space Surgical Site Infection			< 0.001
No Complication	423 (95.9%)	400184 (99.3%)
Organ/Space SSI	18 (4.1%)	2818 (0.7%)
Wound Disruption			0.504
No Complication	441 (100%)	402594 (99.9%)
Wound Disruption	0 (0%)	408 (0.1%)
Pneumonia			< 0.001
No Complication	432 (98%)	400509 (99.4%)
Pneumonia	9 (2%)	2493 (0.6%)
Unplanned Intubation			0.002
No Complication	435 (98.6%)	401376 (99.6%)
Unplanned Intubation	6 (1.4%)	1626 (0.4%)
Pulmonary Embolism			< 0.001
No Complication	436 (98.9%)	402506 (99.9%)
Pulmonary Embolism	5 (1.1%)	496 (0.1%)
Occurrences Ventilator Use > 48 Hours			0.251
No Complication	438 (99.3%)	401572 (99.6%)
On Ventilator greater than 48 Hours	3 (0.7%)	1430 (0.4%)
Progressive Renal Insufficiency			< 0.001
No Complication	434 (98.4%)	402447 (99.9%)
Progressive Renal Insufficiency	7 (1.6%)	555 (0.1%)
Acute Renal Fail			0.053
Acute Renal Failure	2 (0.5%)	507 (0.1%)
No Complication	439 (99.5%)	402495 (99.9%)
Urinary Tract Infection			< 0.001
No Complication	430 (97.5%)	400228 (99.3%)
Urinary Tract Infection	11 (2.5%)	2774 (0.7%)
Stroke with Neurological Deficit			0.001
No Complication	439 (99.5%)	402749 (99.9%)
Stroke/CVA	2 (0.5%)	253 (0.1%)
Cardiac Arrest			0.001
Cardiac Arrest	3 (0.7%)	494 (0.1%)
No Complication	438 (99.3%)	402508 (99.9%)
Myocardial Infarction			< 0.001
Myocardial Infarction	4 (0.9%)	565 (0.1%)
No Complication	437 (99.1%)	402437 (99.9%)
Transfusion Requirement			< 0.001
No Transfusions Required	414 (93.9%)	399588 (99.2%)
Transfusion Required	27 (6.1%)	3414 (0.8%)
Deep Vein Thrombosis			< 0.001
No Deep Vein Thrombosis	436 (98.9%)	402240 (99.8%)
Deep Vein Thrombosis	5 (1.1%)	762 (0.2%)
Sepsis			< 0.001
No Complication	416 (94.3%)	399049 (99%)
Sepsis	25 (5.7%)	3953 (1%)
Return to OR			< 0.001
No	421 (95.5%)	398415 (98.9%)
Yes	20 (4.5%)	4587 (1.1%)
Mortality			< 0.001
No Mortality within 30 days	424 (96.1%)	401650 (99.7%)
Mortality within 30 days	17 (3.9%)	1352 (0.3%)

As one of the largest studies to date, our study defines the incidence of a diagnosis of GBC after cholecystectomy performed for presumed benign indications to be 0.11%. In addition, our study was able to identify both preoperative and intraoperative characteristics that can be used as signals to raise a surgeon’s suspicion of the possibility of GBC prior to surgical intervention: age > 60, female sex, history of preoperative weight loss, preoperatively elevated alkaline phosphatase level, and use of open surgical approach.

The frequency of incidentally diagnosed GBC after cholecystectomy has been documented to range from 0.19–0.89% [14–17]. While the incidence of GBC after cholecystectomy was previously presumed to be close to 1% [18], recent studies have demonstrated the true incidence has likely decreased over time [15]. This can likely be explained by the widespread adoption of laparoscopy leading to a higher volume of cholecystectomies performed. By increasing the number of cholecystectomies performed for benign indications, especially in young patients, the population at risk for developing GBC continues to decrease. The low incidence demonstrated in this study (0.11%) is likely reflective of this established temporal trend as well as the fact that all patients with suspected/known GBC (all patients undergoing concurrent liver and lymphadenectomy procedures) were excluded from this study making the frequency expressed in this study truly incidentally discovered GBC.

In addition to establishing the incidence of unsuspected GBC after cholecystectomy, this study identified preoperative and intraoperative characteristics that were significantly associated with a final diagnosis of GBC. These characteristics can be used as signals to raise the suspicion of a possible GBC prior to simple cholecystectomy. Results of this study are consistent with previous studies identifying older age [15,16,19] and female sex [15,16] as risk factors for incidental GBC diagnosis after cholecystectomy. In addition to demographic characteristics, it is important to note that this study also identified preoperative symptoms (history of weight loss) as well as preoperative laboratory values (elevated alkaline phosphatase) as associated with a final diagnosis of GBC. Another important observation from this study is the association of an open surgical approach and incidental diagnosis of GBC. While laparoscopic cholecystectomy is routinely performed for a majority of benign gallbladder pathology [20,21], with open cholecystectomy reserved for special circumstances [21] or converted cases when laparoscopic procedures cannot be completed or performed safely [22]. The decision to perform open cholecystectomy as opposed to laparoscopic cholecystectomy or requirement to convert from laparoscopic to open cholecystectomy should be recognized as an indication to consider the possibility of a GBC as opposed to benign pathology.

Identification of patients at high risk for GBC prior to simple cholecystectomy is essential and can substantially alter the clinical course and outcomes for patients with GBC. Patients with suspected GBC can substantially benefit from referral to a surgical oncologist prior to simple cholecystectomy. Referral allows for hepatobiliary specialist to evaluate patients with additional preoperative imaging, tumor markers, and importantly, perform clinical staging. Previous research has identified that patients with GBC evaluated by a specialist are more likely to undergo definitive resection compared to patients who are not referred [23]. Additionally, while high quality data is lacking, current guidelines recommend consideration of neoadjuvant chemotherapy for locally advanced GBC [11,12], which can only occur if high risk patients are recognized and evaluated prior to simple cholecystectomy.

If GBC is not suspected preoperatively, but a procedure requires an open surgical approach or has a longer than average operative time, consideration the possibility of GBC can be made intraoperatively. While diagnosis intraoperatively does miss the opportunity for preoperative work up and clinical staging, it is still preferable to incidental diagnosis on final pathology. Intraoperative diagnosis of GBC can be made via frozen pathology with high specificity [24]. Intraoperative diagnosis of GBC allows the opportunity to perform a more appropriate surgery for patients with GBC. Diagnosis of GBC intraoperatively on frozen pathology can be used as an indication to convert from laparoscopic to open technique [12,25] especially in difficult cases, as bile spillage and tumor violation have been found to be associated with worse overall survival in patients with GBC [26]. Additionally, based upon surgeon experience, consideration of an extended (radical) cholecystectomy with segmental hepatectomy and lymphadenectomy could be undertaken to avoid need for reoperation.

While this study identifies important preoperative and intraoperative characteristics to aid in the diagnosis of GBC, it should be considered in light of some inherent limitations. While using a national database allows for inclusion of a large population from a diverse geographic area, there is risk for selection bias based upon which patients are included in this database. Additionally, this study is limited by available variables recorded in NSQIP and does not include details of presenting symptoms (jaundice, acute cholecystitis), preoperative imaging findings, and pathologic staging. Also, data on surgical decision making of approach (open vs laparoscopic) and reason for conversion is not available in NSQIP. Lastly, it is important to note that this study includes all subtypes of GBC, not just adenocarcinoma, given the lack of granularity of available ICD codes used to identify GBC.

This study demonstrates that those with incidentally discovered GBC at cholecystectomy are unique from those undergoing cholecystectomy for benign indications. By identifying predictors of a final diagnosis of GBC, high risk individuals can be identified pre-operatively and undergo further oncologic evaluation prior to surgical resection. Additionally, by identifying intraoperative risk factors, we can selectively employ intraoperative frozen pathology and plan appropriate surgical treatment with extended cholecystectomy and lymph node dissection when indicated.

Conflict of Interest: None declared for all manuscript authors.

Presented at Digestive Disease Week 2021, quick-shot oral presentation, virtual, May 21^st-23rd

Author Contributions:

Substantial contributions to the conception or design of the work: Olecki, Mayhew, Perez-Holguin, Wong, Stahl, Peng, Dixon, Gusani

Drafting the work or revising it critically for important intellectual content: Olecki, Mayhew, Perez-Holguin, Wong, Stahl, Peng, Dixon, Gusani

Final approval of the version to be published: Olecki, Mayhew, Perez-Holguin, Wong, Stahl, Peng, Dixon, Gusani

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Olecki, Mayhew, Perez-Holguin, Wong, Stahl, Peng, Dixon, Gusani

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
Howlader N, Noone A, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975–2018. Bethesda, Maryland: National Cancer Institute; 2021.
Aloia TA, Járufe N, Javle M, Maithel SK, Roa JC, Adsay V, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015;17(8):681 − 90.
Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.
Steinert R, Nestler G, Sagynaliev E, Müller J, Lippert H, Reymond MA. Laparoscopic cholecystectomy and gallbladder cancer. J Surg Oncol. 2006;93(8):682-9.
Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol. 2008;98(7):485-9.
Fuks D, Regimbeau JM, Le Treut YP, Bachellier P, Raventos A, Pruvot FR, et al. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg. 2011;35(8):1887-97.
Shih SP, Schulick RD, Cameron JL, Lillemoe KD, Pitt HA, Choti MA, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. 2007;245(6):893–901.
Varshney S, Butturini G, Buttirini G, Gupta R. Incidental carcinoma of the gallbladder. Eur J Surg Oncol. 2002;28(1):4–10.
Creasy JM, Goldman DA, Gonen M, Dudeja V, O'Reilly EM, Abou-Alfa GK, et al. Evolution of surgical management of gallbladder carcinoma and impact on outcome: results from two decades at a single-institution. HPB (Oxford). 2019;21(11):1541-51.
National Comprehensive Cancer Network. Hepatobiliary Cancer (Version 2.2021). 2021.
Gamboa AC, Maithel SK. The Landmark Series: Gallbladder Cancer. Ann Surg Oncol. 2020;27(8):2846-58.
Raval MV, Pawlik TM. Practical Guide to Surgical Data Sets: National Surgical Quality Improvement Program (NSQIP) and Pediatric NSQIP. JAMA Surg. 2018;153(8):764-5.
Søreide K, Guest RV, Harrison EM, Kendall TJ, Garden OJ, Wigmore SJ. Systematic review of management of incidental gallbladder cancer after cholecystectomy. Br J Surg. 2019;106(1):32–45.
Pitt SC, Jin LX, Hall BL, Strasberg SM, Pitt HA. Incidental gallbladder cancer at cholecystectomy: when should the surgeon be suspicious? Ann Surg. 2014;260(1):128 − 33.
Muszynska C, Lundgren L, Lindell G, Andersson R, Nilsson J, Sandström P, et al. Predictors of incidental gallbladder cancer in patients undergoing cholecystectomy for benign gallbladder disease: Results from a population-based gallstone surgery registry. Surgery. 2017;162(2):256 − 63.
Konstantinidis IT, Deshpande V, Genevay M, Berger D, Fernandez-del Castillo C, Tanabe KK, et al. Trends in presentation and survival for gallbladder cancer during a period of more than 4 decades: a single-institution experience. Arch Surg. 2009;144(5):441-7; discussion 7.
Kwon AH, Imamura A, Kitade H, Kamiyama Y. Unsuspected gallbladder cancer diagnosed during or after laparoscopic cholecystectomy. J Surg Oncol. 2008;97(3):241-5.
Koshenkov VP, Koru-Sengul T, Franceschi D, Dipasco PJ, Rodgers SE. Predictors of incidental gallbladder cancer in patients undergoing cholecystectomy for benign gallbladder disease. J Surg Oncol. 2013;107(2):118 − 23.
Lo CM, Liu CL, Lai EC, Fan ST, Wong J. Early versus delayed laparoscopic cholecystectomy for treatment of acute cholecystitis. Ann Surg. 1996;223(1):37–42.
Visser BC, Parks RW, Garden OJ. Open cholecystectomy in the laparoendoscopic era. Am J Surg. 2008;195(1):108 − 14.
Hu ASY, Menon R, Gunnarsson R, de Costa A. Risk factors for conversion of laparoscopic cholecystectomy to open surgery - A systematic literature review of 30 studies. Am J Surg. 2017;214(5):920 − 30.
Perlmutter BC, Naples R, Hitawala A, McMichael J, Chadalavada P, Padbidri V, et al. Factors that Minimize Curative Resection for Gallbladder Adenocarcinoma: an Analysis of Clinical Decision-Making and Survival. J Gastrointest Surg. 2021.
Aoki T, Tsuchida A, Kasuya K, Inoue K, Saito H, Koyanagi Y. Is frozen section effective for diagnosis of unsuspected gallbladder cancer during laparoscopic cholecystectomy? Surg Endosc. 2002;16(1):197–200.
Cavallaro A, Piccolo G, Di Vita M, Zanghì A, Cardì F, Di Mattia P, et al. Managing the incidentally detected gallbladder cancer: algorithms and controversies. Int J Surg. 2014;12 Suppl 2:S108-S19.
Wullstein C, Woeste G, Barkhausen S, Gross E, Hopt UT. Do complications related to laparoscopic cholecystectomy influence the prognosis of gallbladder cancer? Surg Endosc. 2002;16(5):828 − 32.

No competing interests reported.

Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors

Status:

Journal Publication

Version 1

Abstract

Introduction

Materials And Methods

Statistical Analysis:

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1