Managing the incidentally detected gallbladder cancer: Algorithmsand controversies
Andrea Cavallaro a, *, Gaetano Piccolo a, Maria Di Vita a, Antonio Zanghì a,Francesco Cardì a, Paolo Di Mattia a, Giuseppina Barbera a, Laura Borzì c,Vincenzo Panebianco d, Isidoro Di Carlo c, Marco Cavallaro b, Alessandro Cappellani a
a General Surgery and Senology Unit, Department of Surgery, “Policlinico e Vittorio Emanuele” Hospital, University of Catania Medical School, Via S. Sofia78, 95123 Catania, Italyb Department of Radiology, Radiology Unit, Guzzardi Hospital, Via Papa Giovanni XXIII� , 97019 Vittoria, RG, Italyc Department of Surgical Sciences, Organ Transplantation and Advanced Technologies, University of Catania, Catania, Italyd Department of Surgery, General Surgery Unit, “San Vincenzo” Hospital, Taormina, ME, Italy
a r t i c l e i n f o
Article history:Received 15 July 2014Accepted 22 August 2014Available online xxx
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a b s t r a c t
Introduction: Gallbladder cancer (GBC) is the fifth most common neoplasm of the gastrointestinal tractand the most common cancer of the biliary tract. GBC is suspected preoperatively in only 30e40% ofpatients. The other 60e70% are discovered incidentally (IGBC) by the pathologist on a gallbladderspecimen following cholecystectomy for benign diseases such as polyps, gallstones, and cholecystitis.Materials and methods: Between 1995 and 2011, 30 cases of GBC, who underwent resection withcurative intent in our institutions, were retrospectively reviewed. They were analyzed for demographicdata, and type of operation, surgical morbidity and mortality, histopathological classification, and sur-vival. Incidental GBC was compared with suspected or preoperatively diagnosed GBC. Overall survival,disease-free survival (DFS) and the difference in DFS between patients previously treated with laparo-scopic cholecystectomy and those who had oncological resection as first intervention were analyzed. Theauthors also present a systematic review to evaluate the role of extended surgery in the treatment of theincidental GBC. Results: GBC was diagnosed in 30 patients, 16 women and 14 men. The M/F ratio was1:1.14 and the mean age was 69.4 years (range 45e83 years). A preoperative diagnosis was possible onlyin 14 cases; fourteen of the incidental cases were diagnosed postoperatively after the pathological ex-amination; two were suspected intraoperatively at the opening of the surgical specimen and thenconfirmed by frozen sections. The ratio between incidental and nonincidental cases was 1, 14/1, withtwelve cases discovered after laparoscopic cholecystectomy. Eighty-one per cent of the incidental caseswere discovered at an early stage (�II). The preoperative diagnosis of the 30 patients with GBC was: GBCwith liver invasion diagnosed by preoperative CT (nine cases); gallbladder abscess perforated into he-patic parenchyma and involving the transversal mesocolon and hepatic hilum (one case); porcelaingallbladder (three cases); gallbladder adenoma (four cases); and chronic cholecystolithiasis (thirteencases). Every case, except one, with a T1b or more advanced invasion underwent IVb þ V wedge liverresection and pericholedochic/hepatoduodenal lymphoadenectomy. One patient refused further surgery.Cases with Tis and T1a involvement were treated with cholecystectomy alone. Nine of the sixteen pa-tients with incidental diagnosis reached 5-year DFS (56.25%) and eight of them are recurrence free.Surprisingly, one patient reached 38 mo survival despite a port-site recurrence (the only one in ourexperience) 2 years after the original surgery requiring further resection. Cases with non incidentaldiagnosis were more locally advanced and only two patients experienced 5 years DFS (Tables 2 and 3).
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e122
List of abbreviations
GBCA, GBC, GC gallbladder cancerIGBC incidental gallbladder cancerDFS disease free survivalOS overall survivalR0 no microscopic residual diseasAJCC American Joint Committee onPLNC number of positive nodesPSE port site excision
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Conclusion: Laparoscopic cholecystectomy does not affect survival if implemented properly. Reoperationshould have two objectives: R0 resection and clearance of the lymph nodes.
Gallbladder cancer (GBC) is the fifth most common neoplasm ofthe gastrointestinal tract and the most common cancer of thebiliary tract. The prognosis is usually dismal because of theaggressive nature of GBC: 5-year survival rates range from 5 to 20%[1]. Most patients present with advanced disease, therefore are notcandidates for curative resection. For those patients that undergoresection, long-term survival is possible but the recurrence rate isconsiderable [1e5].
GBC is suspected preoperatively in only 30% of patients. Theother 70% are discovered incidentally (IGBC) by the pathologist on agallbladder specimen following cholecystectomy for benign dis-eases such as polyps, gallstones, and cholecystitis [1e4].
IGBC is discovered in 0.20e3% of all cholecystectomies. Withgreater availability of ultrasonography, cholecystectomy hasbecome the commonest surgical procedure performed worldwide.As a result of this, we expect over time an increase of the number ofpatients with incidentally discovered gallbladder cancer[ [1,6e9].
The R0 surgical resection is the mainstay of GBC therapy:additional resection, aimed to the absence of residual disease, isconsidered to offer better survival. Patients who undergo re-resection demonstrate a 5-year survival ranging from 0 to 100%with a close relation to the GBC stage. Simple cholecystectomy maybe adequate treatment only for the earlier stages: Tis and T1a[1,3e5,8,10]
Re-resection (including radical cholecystectomy with regionallymphadenectomy) is recommended for T1b and later stage carci-nomas as long as the disease appears to be R0 resectable[1,3e5,8,11].
The management of IGBC is difficult because no guidelines havebeen established. Some technical controversies (extent of hepa-tectomy, role of lymphadenectomy, bile duct resection and port-site excision) are, still today, unsolved [1e8]. Moreover some au-thors have reported worse overall prognosis when the patient wasnot adequately treated during the first operation.
We report our experience (30 cases) in the treatment of GBC,and present a systematic review to evaluate the role of extendedsurgery in the treatment of the incidental GBC.
A Medline search was performed using the keywords “Inci-dental gallbladder cancer”, “laparoscopic cholecystectomy”,“lymph nodes dissection” and “hepatic resection”.
aro, et al., Managing the inci://dx.doi.org/10.1016/j.ijsu.20
Reviewing the literature, we focused on the following keypoints, which are still considered controversial in the managementof GBC:
1 - presentation, outcome, and management of incidentallydiscovered gallbladder cancer
2 - extent of hepatic resection3 - extent of lymph node dissection, number of nodes and
lymphnode ratio4 - resection of the common bile duct5 - surgical strategy related to depth invasion6 - meaning of port-site metastases and peritoneal disease7 - laparoscopy þ re-resection vs one stage approach8 - contraindications to the surgical treatment and combined
multiorgan resections.
2. Materials and methods
2.1. Data collection
From 1995 to 2011, 30 cases of GBC who underwent resectionwith curative intent, in the Department of General Surgery e Uni-versity of Catania, were retrospectively reviewed.
Patients demographic data, surgical procedures, postoperativeoutcomes (surgical morbidity and mortality), histopathologicalclassification, and survival data were collected in a database forfurther analysis. The diagnosis of gallbladder pathology was madeby history, physical examination, and laboratory and imagingstudies [ultrasonography and computed tomography (CT)].
2.2. Disease-free survival (DFS) analysis
The patients were divided in two groups: incidental diagnosis ofgallbladder carcinoma, and known or suspected diagnosis preop-eratively. The primary endpoint of the study was DFS at differentstages of diagnosis. The secondary endpoint was the difference inDFS between patients previously treated with laparoscopic chole-cystectomy and patients who had oncological resection as their firstintervention. The results are reported in percentages and means.
3. Results
GBC was diagnosed in 30 patients, 16 women and 14 men. TheM/F ratio was 1:1.14 and the mean agewas 69.4 years (range 45e83years).
A preoperative diagnosis was possible only in 14 cases; fourteenof the incidental cases were diagnosed postoperatively after thepathological examination; two were suspected intraoperatively atthe opening of the surgical specimen and then confirmed by frozensections.
The ratio between incidental and total cases was 16/30.According to TNM staging of the 7th edition of the AJCC, our
According to TNM staging of the 7th edition of the AJCC, ninecases were Stage I (T1N0); five cases were Stage II (T2 N0); twowere Stage IIIa (T3 N0); eight with Stage IIIb (T1eT3 N1); one with
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e12 3
Stage IVA (T4 N1); three with Stage IVB (any T, N2 or M1); two withStage 0.
Eighty-one per cent of the incidental cases were discovered atan early stage (�II). The ratio between incidental and nonincidentalcases was 1,14/1, with twelve cases discovered after laparoscopiccholecystectomy. The preoperative diagnosis of the 30 patientswith GBC was: GBC with liver invasion diagnosed by preoperativeCT (nine cases); gallbladder abscess perforated into hepatic pa-renchyma and involving the transversal mesocolon and hepatichilum (one case); porcelain gallbladder (three cases); gallbladderadenoma (four cases); and chronic cholecystolithiasis (thirteencases).
Pathological characteristics of the tumors were: five well-differentiated polypoid adenocarcinoma (G1); two well-differentiated non-polypoid adenocarcinoma of the gallbladderfundus (G1); two moderately differentiated nonpolypoid and sixmoderately differentiated polypoid adenocarcinoma (G2); four G2-G3 differentiated polypoid and one G2-G3 non polypoid adeno-carcinoma; and two and eight polypoid and nonpolypoid poorlydifferentiated GBC (G3), respectively (Table 1).
Two lesions were “in situ” cancer.Every case, except one, with a T1b or more advanced invasion
underwent IVb þ V wedge liver resection and pericholedochic/hepatoduodenal lymphoadenectomy. One patient refused furthersurgery. Cases with Tis and T1a involvement were treated withcholecystectomy alone.
One incidental case was diagnosed by intraoperative frozensection and treated accordingly with one stage procedure. Onemore case, diagnosed by intraoperative frozen section, was surgi-cally treated later because of the need of a more accurate staging.
Nine of the sixteen patients with incidental diagnosis reached 5-year DFS (56.25%) and eight of them are recurrence free. Surpris-ingly, one patient reached 38 mo survival despite a port-siterecurrence (the only one in our experience) 2 years after the orig-inal surgery requiring further resection. Cases with nonincidentaldiagnosis were more locally advanced and only two patientsexperienced 5 years DFS (Tables 2 and 3).
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4. Discussion
4.1. Presentation and outcome
Given that cholecystectomy for gallstone disease is the secondor the third most frequent procedure in digestive surgery, inci-dental GBC is going to become an increasingly frequent medicalentity.
The widespread use of laparoscopic cholecystectomy has led todiscovery of this deadly disease at an earlier stage, altering themanagement and the outcome of these patients. GBC is an inci-dental finding in 0.25e3% of patients and almost half of these casesare occasionally discovered during or after laparoscopic cholecys-tectomy for benign disease, such as gallstones and their compli-cations [47% in the series of Memorial SloaneKettering CancerCentre (MSKCC), 50% in the series of Johns Hopkins] [2,4]. Theearlier discovery results in an earlier pathological stage, andconsequently, increased long-term survival [4,6e9]. Patients withincidental GBC had a significant increase in survival whencompared with those who had a preoperative diagnosis (overall 5-year survival 15% vs 33%) [2,4].
Therefore, the general surgeon should be prepared to deal withGBC suspected or diagnosed incidentally, following a well-established treatment algorithm [5e8].
It is paramount not to violate oncological principles during thefirst operation, if a two-stage approach is necessary. For this reason,the surgeon during a laparoscopic cholecystectomy should alwaysfollow these simple rules:
- perform an accurate preoperative diagnosis;- preserve the integrity of the gallbladder- use the endobag for the removal of the gallbladder- when in doubt, give up the laparoscopy to open access- carefully inspect the gallbladder once extracted- perform a histological examination impromptu;- desufflate the pneumoperitoneum with the trocars in situ
During cholecystectomy, accidental opening of the gallbladder isdescribed in 25e30% of the cases, which clearly have a worseprognosis [3,5,9,12].
4.2. Management
The prognosis strongly depends on the stage and on the possi-bility of achieving R0 oncological resection [2e4,12,13].
Patients with IGBC can be divided into two clinical groups:
1. Patients with GBC discovered during cholecystectomy forassumed benign disease.
2. Patients with GBC diagnosed histo-pathologically after chole-cystectomy for benign disease.
All gallbladders removed for stone disease should always be cut,opened and examined carefully for any suspicious lesions beforeclosing incision. If suspicious lesion is present, the gallbladdershould be sent for a timely frozen section for diagnosis andassessment of depth of invasion. If the surgeon is trained, and theteam has experience in the management of hepatobiliary disease,radical cholecystectomy should be done. If not, the abdomenshould be closed and patient should be referred to a higher centrefor radical surgery.
When incidental GBC is diagnosed afterward by the pathologist,the surgical specimen or blocks should be carefully studied foridentification of the depth of invasion (T stage), grade and locationof the tumor (liver side/free peritoneal side/infundibulum),
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
Patient G Age Incidental TNM 7th ed. Stage 7th ed. Cystic d. Res. Size Grade Lymph Vessel Perineural 5-year survival
A.P M 63 No pT2 N1 Mx IIIB R0 R0 10 (NP) G3 No No No alive, 38 moS.A F 82 No pT4 N2 M1 IVB R0 R1 45 (NP) G3 Yes Yes Yes dead, 3 moC.I F 60 No pT3 N1 Mx IIIB R1 R1 60 (P) G3 No No Yes dead, 6 moS.L F 72 No pT3 N1 Mx IIIB R0 R1 32 (NP) G3 Yes No No dead, 8 moP.G M 76 No pT4 N1 Mx IVA R0 R1 49 (NP) G3 Yes No Yes dead, 7 moG.F M 81 No pT3 N0 Mx IIIA R0 R1 44 (NP) G3 No No No dead, 9 moP.C F 77 No pT2 N0 Mx II R0 R0 20 (P) G2 No No No dead, 24 moC.M F 45 No pT1a N0 Mx I R0 R0 25 (P) G1 No No No alive, no recurrence at 7 yearsS.G M 81 No pT3 N1 Mx IIIB R0 R1 24 (P) G2 Yes No No dead, 28 moR.M F 66 No pT1b N0 Mx I R0 R0 07 (P) G2 No No No alive, no recurrence at 6 yearsS.V F 69 No pT3 N2 Mx IVB R0 R1 30 (P) G3 Yes Yes Yes dead, 7 moA.F M 64 No pT3 N0 Mx IIIA R0 R0 35 (NP) G3 Yes Yes Yes dead 23 moF.Z. F 77 No pT2 N1 Mx IIIB R0 R0 45 NP G2-G3 Yes No No alive, no recurrence at 4 yearsT.R. M 76 No pT2 N1 Mx IIIB R0 R0 28 (NP) G3 Yes Yes No dead 18 moC.C F 73 Yes pT2 N0 Mx II R0 R0 19 (NP) G3 Yes Yes No alive, recurrence at 19 moR.C M 69 Yes pT1b N0 Mx I R0 R0 15 (NP) G1 No No No alive, 38 mo (disease recurrence)C.M M 65 Yes PT1a Nx Mx I R0 R0 18 (P) G1 No No No alive, no recurrence at 7 yearsT.F F 72 Yes pT2 N0 Mx II R0 R0 10 (NP) G2 No No No alive, no recurrence at 7 yearsG.G M 55 Yes pT2 N0 M1 IVB R1 R1 30 (P) G2-G3 No Yes Yes dead, 08 moM.P F 78 Yes pT2 N1 Mx IIIB R0 R1 14 (P) G2-G3 Yes No No dead, 26 moS.G F 57 Yes pT1b N0 Mx I R0 R0 30 (P) G2-G3 No No No alive, no recurrence at 7 yearsP.A M 71 Yes pT2 N1 Mx IIIB R0 R0 20 (P) G2-G3 Yes No No dead, 23 moC.A F 67 Yes pTis Nx Mx 0 R0 R0 06 (NP) G1 No No No alive, no recurrence at 13 moS.I. F 63 Yes pT2 N0 Mx II R0 R0 14 (NP) G2 Yes No No alive, no recurrence at 5 yearsT.R M 68 Yes pT1b N0 Mx I R0 R0 15 (P) G2 No No No alive, no recurrence at 6 yearsG.B F 72 Yes pT2 N0 Mx II R0 R0 25 (P) G2 Yes No Yes alive, no recurrence at 6 yearsA.G M 83 Yes pT1b N0 Mx I R0 R0 10 (P) G1 No No No alive, no recurrence at 8 yearsC.F M 70 Yes pT1a Nx Mx I R0 R0 04 (P) G1 No No No alive, no recurrence at 7 moP.R F 61 Yes pTis Nx Mx 0 R0 R0 12 (P) G1 No No No alive, no recurrence at 7 yearsC.R M 69 Yes pT1b Nx Mx I R0 R0 05 (P) G2 No No No dead, 6 years 6 mo
69.4
Stage T N
0 Tis N0I T1 N0II T2 N0IIIA T3 N0IIIB T1e3 N1IVA T4 N0e1IVB Any T N2
Any T Any N
Reprinted with permission from AJCC: Gallbladder. In: Edge SB, Byrd DR, Compton CC et al., eds.: AJCC Cancer StagingManual. 7th ed. New York, NY: Springer, 2010, pp 211e7.
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e124
lymphatic, vascular and perineural invasion, positive cystic ductmargin, or cystic duct node involvement [2e4,9,10e13].
Contrast enhanced triphasic computed tomography (CT) scan/Magnetic resonance imaging (MRI) are essential to restage thepatients. Positron emission tomography and computed tomogra-phy (PETeCT) does not have a role in routine imaging in GBC butthey could help to detect unsuspected metastasis, regionallymphadenopathy, peritoneal metastasis, residual disease in gall-bladder bed (post cholecystectomy), metastasis in the orifices ofthe trocars [14,15].
Adopting an iterative approach, the surgeon will also be able toprovidemore detailed information to the patient and obtain a moreaccurate informed consent to the resective procedure thus avoidingthe risk of infringing the rights of self-determination of the patient(Fig. 1).
Nowadays, reoperation for incidental GBC should have twofundamental objectives: R0 resection of the liver parenchyma withthe other adjacent structures, and clearance of the locoregionallymph nodes [2e4,7,8].
4.2.1. Extent of liver resection during reoperationAlthough simple cholecystectomy appears to be an adequate
treatment for Tis/T1a tumors, for tumors with extension deeper
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than the lamina propria (�T1b), radical re-resection with regionallymphadenectomy has been advocated.
Re-resection, including liver resection, should be performed inthese patients because most (56e60%) had residual tumor at thetime of re-operation. Furthermore, the presence of residual tumorwas found to be an important predictor of survival [2e4,6e16].
Hepatic resection for GBC has two main purposes: resect thetumor that has directly invaded the liver from the gallbladder bed,and prevent micrometastases that may recur around the gall-bladder bed. Onemore purpose could be to resect en block Glisson'ssheath of the right lobe of the liver because of potential invasion ofhepatoduodenal ligament [3e16].
Generally, operative procedures for incidental GBC include:extended cholecystectomy or Glenn resection (i.e. cholecystectomyplus partial resection of liver segments 4 and 5, approximately2e3 cm from the gallbladder bed); anatomic resection of liversegment 5 and lower part of segment 4 when GC invades the liverbed to a depth of 2 cm or more; right hepatectomy when GCinvaded the right Glisson capsule [3,7,8].
Although several authors have emphasized that the extent ofthe surgery needed to treat GBC seems to depend on the depth ofthe tumor, as noted in the literature, the preference today is forparenchyma-sparing operations, such as no anatomical wedgeresection [1,3].
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
A.P M 63 No pT2 N1 Mx IIIB R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) alive, 38 moS.A F 82 No pT4 N2 M1 IVB R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) þ VBP res dead, 3 moC.I F 60 No pT3 N1 Mx IIIB R1 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 6 moS.L F 72 No pT3 N1 Mx IIIB R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 8 moP.G M 76 No pT4 N1 Mx IVA R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 7 moG.F M 81 No pT3 N0 Mx IIIA R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 9 moP.C F 77 No pT2 N0 Mx II R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 24 moC.M F 45 No pT1a N0
MxI R0 R0 cholecystectomy, no further surgery alive, no recurrence at 7
yearsS.G M 81 No pT3 N1 Mx IIIB R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 28 moR.M F 66 No pT1b N0
MxI R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) alive, no recurrence at 6
yearsS.V F 69 No pT3 N2 Mx IVB R0 R1 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead, 7 moA.F M 64 No pT3 N0 Mx IIIA R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead 23 moF.Z. F 77 No pT2 N1 Mx IIIB R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) alive, no recurrence at 4
yearsT.R. M 76 No pT2 N1 Mx IIIB R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) dead 18 moC.C F 73 Yes pT2 N0 Mx II R0 R0 wedge res. (IVb þ V) þ lymphadenectomy (I stage) alive, recurrence at 19 moR.C M 69 Yes pT1b N0
MxI R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II
stage) þ PS excalive, 38 mo (diseaserecurrence)
C.M M 65 Yes PT1a NxMx
I R0 R0 cholecystectomy alive, no recurrence at 7years
T.F F 72 Yes pT2 N0 Mx II R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (IIstage) þ PS exc
alive, no recurrence at 7years
G.G M 55 Yes pT2 N0 M1 IVB R1 R1 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (IIstage) þ VBP
dead, 08 mo
M.P F 78 Yes pT2 N1 Mx IIIB R0 R1 cholecystectomy, refused further surgery dead, 26 moS.G F 57 Yes pT1b N0
MxI R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II
stage) þ PS excalive, no recurrence at 7years
P.A M 71 Yes pT2 N1 Mx IIIB R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (IIstage) þ PS exc
dead, 23 mo
C.A F 67 Yes pTis Nx Mx 0 R0 R0 LC alive, no recurrence at13 mo
S.I. F 63 Yes pT2 N0 Mx II R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II stage) alive, no recurrence at 5years
T.R M 68 Yes pT1b N0Mx
I R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II stage) alive, no recurrence at 6years
G.B F 72 Yes pT2 N0 Mx II R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II stage) alive, no recurrence at 6years
A.G M 83 Yes pT1b N0Mx
I R0 R0 LC (I stage) e wedge res. (IVb þ V) þ lymphadenectomy (II stage) alive, no recurrence at 8years
C.F M 70 Yes pT1a NxMx
I R0 R0 LC alive, no recurrence at 7 mo
P.R F 61 Yes pTis Nx Mx 0 R0 R0 LC alive, no recurrence at 7years
C.R M 69 Yes pT1b NxMx
I R0 R0 cholecystectomy, refused further surgery dead, 6 years 6 mo
M/F 14/16
69
Stage T N M
0 Tis N0 M0I T1 N0 M0II T2 N0 M0IIIA T3 N0 M0IIIB T1e3 N1 M0IVA T4 N0e1 M0IVB Any T N2 M0
Any T Any N M1
Reprintedwith permission from AJCC: Gallbladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer StagingManual. 7th ed. New York, NY: Springer, 2010, pp 211e7.
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e12 5
Araida et al. [16] included, in a multicenter retrospective study,293 patient with pT2 gallbladder cancer and 192 with of pT3 gall-bladder cancer.
The patients were distinguished in four groups: pT2 gallbladdercancer group with cancer on the hepatic side, pT2 gallbladdercancer group with cancer on the peritoneal side, pT3 gallbladdercancer group negative for hepatic-invasion, pT3 gallbladder cancergroup positive for hepatic-invasion.
Please cite this article in press as: A. Cavallaro, et al., Managing the inciInternational Journal of Surgery (2014), http://dx.doi.org/10.1016/j.ijsu.20
The authors showed that there was no significant differences incumulative survival rate and in recurrence rates in form of livermetastasis between patients that underwent resection of the gall-bladder bed, anatomical segmentectomy 4b þ 5 and hepatectomyfor pT2 and pT3 GBC.
Despite in the pT3 gallbladder cancer group positive for hepatic-invasion, the recurrence in the cut end of the liver was mostcommon in the group that underwent resection of the gallbladder
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e126
bed (9.4%), the authors demonstrated that in all four groups livermetastasis did not particularly tend to occur to segment 4a, 5.
Similarly, other authors have reported that there was no asso-ciation between major hepatectomy and long-term survival, andthat there was an increased association between major hepaticsurgery and perioperative morbidity [1,3,4].
In order to support this, Pawlik et al. [3], in their analysis of 148patients with incidental gallbladder adenocarcinoma, have provedthat patients who had undergone major hepatic resection(anatomical segmentectomy of 4a þ 5 or right hepatectomy) had a
Fig. 2. Non-anatomical resection of hepatic parenchyma, with a distal clearance of atleast 2 cm.
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similar risk of specific death as patients who underwent hepaticwedge resection, on both unvariate and multivariate analyses.
Rather than the type of hepatic resection, the surgeon's goalshould be to resect all disease with negative histologic margins, themost important factor that determines the final outcome. In fact,R1/R2 margin status is associated with decreased long-term sur-vival [17].
In conclusion, for gallbladder cancer without hepatoduodenalligament invasion and without any locoregional liver involvement,the wedge resection of the gallbladder bed (2e3 cm) is preferableto hepatectomy [3,5,17]. With regard to GBC that has invaded thegallbladder bed, in order to obtain negative histological margins,the preferred approach is non-anatomical resection of hepatic pa-renchyma, with a distal clearance of at least 2 cm (Fig. 2) [3,5,17].
4.2.2. Extent of lymph node dissectionToday reoperation for incidental GBC should have two funda-
mental objectives: R0 resection of the liver parenchyma with theother adjacent structures, and clearance of the locoregional lymphnodes [7,8].
GBC spreads through different pathways: locoregional,lymphatic, vascular, neural, intraperitoneal or intraductal invasion.The main lymphatic pathway of the gallbladder descends along thecommon bile duct and into the periportal nodes, then to theposterosuperior of the head of the pancreas or around the hepaticand celiac artery, and finally to the paraaortic nodes near the leftrenal vein [18e20].
Although initial nodal involvement occurred primarily in thecystic duct or pericholedochal nodes, the pathways of lymph nodeinvolvement from the first site of diffusion to the hepatoduodenal
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e12 7
ligament (cystic, pericholedochal and hilar lymph nodes) tend to behighly variable [21].
In fact, GBC can spread directly to the third level of lymph nodes,along the perivascular soft tissue (celiac, superior mesenteric arteryand the para-aortic lymph nodes), according to the three pathwaysof lymphatic drainage proposed by Ito et al. [21]: cholecysto-retropancreatic pathway (main pathway), cholecysto-celiac andcholecysto-mesenteric pathways (accessory pathways). The inci-dence of occult lymphatic metastasis discovered during reopera-tion for incidental GBC can vary from 0% to 85% in relation to thedepth of organ invasion (pT).
The reported incidence of occult lymphatic metastasis by stageis as follows: for T1a 0e2.5%, for T1b 15e25%, for T2 30e50%, for T345e75%, and for T4 > 85% [3,18,22e26] (Table 4).
Similarly to other cancers, lymphadenectomy not only providesimportant staging information, but more importantly, maydecrease the risk of locoregional recurrence. In fact, after tumorresection, the level of lymph node metastasis correlates withoverall prognosis within the same pT stage category [25,26].Miyakawa et al. [27] reported 5-year survival of 60.3% for pN0 pa-tients, 30.0% for pN1, 16.8% for pN2, and 5.9% for pN3.
Differing philosophies have previously characterized Easternand Western surgical school regarding the significance of nodenumber or node location: nowadays some of these views areconverging.
Accuracy of nodal staging depends on a critical number oflymph nodes analyzed; insufficient number of nodes retrievedduring surgery or examined pathologically leads to underestima-tion of disease stage (stage migration) [25,26].
The 6th edition of the American Joint Committee on Cancer(AJCC) required at least three nodes to be examined for adequate Nstaging. No mention of a minimum lymphnode number require-ment is made in the current 7th edition.
In a cohort of 122 patients with GBCA, who underwent R0resection at Memorial Sloan Kettering Cancer Center, the overallsurvival of patients classified as N0 based on TLNC (total lymphnode count) <6 was significantly worse than that of N0 patientsbased on TLNC �6 [28]. Similar conclusions were drawn by a Jap-anese group that retrospectively analyzed 135 patients and 2245nodes (median of 14 nodes per patient): they support the practiceof retrieving at least six nodes to both improve staging and survival[29].
These observations indicate that retrieval of a larger number(�6) of lymph nodes, than previously practiced, is advisable notonly for accurately staging the nodal status, but also for improvingsurvival due to better clearance of nodal disease.
One more emerging parameter is the involved lymph node ratio(LNR) which ideally incorporates not only the entity and biology ofdisease (PLNC e positive node count) but also the quality of lym-phadenectomy and pathologic examination (TLNC).
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Lowe et al., in a study of 36 patients, found an LNR of �0.3 to beassociated with significantly impaired prognosis. However theprognostic value of the LNR overwhen compared to total number ofinvolved nodes (TLNC) remains to be shown [30].
The AJCC staging varied the node classification over the pastthree revision of the system. In the 5th edition, nodes were char-acterized as N1 and N2 with the first group of nodes beingconsidered those in the hepatoduodenal ligament up to the hepaticartery/gastroduodenal artery junction, and those behind thepancreas and up to the celiac axis as N2. In the sixth edition anyinvolved node was considered N1.
In the 7th edition, the N2 category was restored includingregional nodes in celiac, periduodenal, and peripancreatic loca-tions, and nodes along the superior mesenteric artery: patientswithin this cluster are now categorized as stage IVB [31]. The sig-nificance of node location in term of prognosis is still not clear. In aJapanese cohort of 116 patients with GBCA undergoing R0 resec-tion, Shirai Y et al. analyzed 2406 lymph nodes in terms of numberinvolved as well as anatomical location. The authors found that 5-year survival dropped from 81% for patients with N0, to 62% forthose with a single positive node, to 43% for those with 2e3 nodesand 15% for those with four or more nodes positive. Although thenumber of positive nodes (PLNC) was an independent factordetermining prognosis, according to this study the location ofnodes was not significant [29].
Jensen et al. examined 4614 patients, surgically treated between1988 and 2004, from the SEER database. According to their studyonly about 6% of patients with early stage GB cancer currentlyreceive recommended surgical therapy in the United States. Most ofthem are patients with T3 cancers. This number is substantiallylower when we consider only those patients with T1B and T2neoplasms, who undergo appropriate therapy in approximately 3%of cases reported.
According to Jensen the lymph node evaluation is a criticalcomponent of radical resection for GBCA, and patients who un-derwent ‘‘radical resection’’ that did not include lymph nodeassessment had no significant improvement in overall survivalcompared to patients undergoing simple cholecystectomy alone(23 vs. 22 months) [26].
In western countries, lymphadenectomy has been usuallyconfined to the hepatoduodenal ligament around the hilar area(cystic, pericholedochal and hilar lymph nodes).
Fig. 3. Lymphadenectomy of the hepatoduodenal ligament around the hilar area(cystic, pericholedochal, periportal and hilar lymph nodes).
dentally detected gallbladder cancer: Algorithms and controversies,14.08.367
A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e128
The extended radical lymphadenectomy include the clearanceof all nodes along the portal structures (portal vein, hepatic arteryand common bile duct), gastrohepatic ligament, retroduodenal,peripancreatic and celiac axis lymphnodes with or without bileduct resection (Fig. 3).
While it is not routinely advocated, the extended radical lym-phadenectomy should be considered with T2 or more advanceddisease. The role of para-aortic nodal clearance remains unclear[1e4,28,30].
4.2.3. Resection of the common bile ductAlthough many surgeons advocate routine resection of the
common bile duct at the time of curative resection, resection of thecommon bile duct performed at the time of the hepatic resectionand lymphadenectomy is controversial [32,33]. GC has a strongtendency to invade the hepatoduodenal ligament in the form ofperineural invasion or lymph node metastasis, therefore, en blocresection of the regional lymph nodes together with excision of theconnective tissue around the portal and hepatic artery should beperformed, whenever lymph node dissection of the hep-atoduodenal ligament is entertained [34e36]. Shimizu et al. [10]proposed routine resection of the extrahepatic bile duct to facili-tate lymphadenectomy, avoiding common bile duct ischemia, andincreasing the number of lymph nodes harvested. However, thesebenefits have not been confirmed in other studies [32,33]. Pawliket al. [3], in their analysis of 148 patients with incidental gallbladderadenocarcinoma, showed that the median number of lymph nodesharvested at the time of lymphadenectomy was the same (n ¼ 3),regardless of whether the common bile duct was or was notresected concomitantly with lymph node dissection.
Araida et al. [32], in the largest series to date (collated by 114Japanese member institutions), analyzed a total of 4243 GBC pa-tients treated between 1994 and 2003. There were 838 R0 patientswith pT2, pT3, and pT4 GBC in which there was no cancerous in-vasion of the hepatoduodenal ligament and cystic duct in the finalanalysis. In this series, the resected and non-resected bile ductgroups did not substantially differ in terms of the 5-year cumulativesurvival and local recurrence along the hepatoduodenal ligament.
Fuks et al., examining a French multicenter database, showedthat 86% of common bile duct resectionwas performedwithout anyinformation on the cystic duct. Their study showed not only anydifferences in terms of recurrence and overall survival, but theauthors found that resection of the common bile duct was the onlyrisk factor for postoperative morbidity in a univariate analysis: itonly exposes patients to the potential complications of the bil-ioenteric anastomosis.
The same conclusion was drawn in the multicenter Japanesesurvey [32].
In conclusion, bile duct resection should be performed onlywhen the patients have a positive involvement of the cystic ductmargins, discovered either on the pathological review of the initialcholecystectomy or through biopsy of the cystic duct at the time ofthe second operation [3,32,33]. In fact, microscopic involvement ofthe cystic duct margin is associated with a residual and/or
Table 5Five-year survival according to both stage of GBC and type of surgery.
Author T1a LC T1b LC T2 LC T2 extended resection
Fong et al. [36] 19% 61%Wagholikar et al. [37] 100% 41.67%Fong et al. [38] 20% 60%Foster et al. [23] 100% 50% 38% 78%Chijiiwa et al. [39] 17% 75%
LC: Laparoscopic cholecystectomy.
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additional disease in the common bile duct in over one-third of thecases [32,33].
4.2.4. Type of treatment according to depth invasionThe depth of invasion of GBC dictates the extent of surgical
resection. In cases of carcinoma in situ or tumor invading the mu-cosa (Tis and T1a), simple cholecystectomy with negative surgicalmargins can be considered as curative surgery [3,4,23,37].
The 5-year survival after simple cholecystectomy is between 99and 100% [23,37]. When the muscularis layer is involved (T1b), a20e50% localeregional recurrence can be expected after simplecholecystectomy [3,6,37] (Table 5). At the time of reoperation, it hasbeen shown that there is a 10% incidence of residual disease in theliver bed associated with a 15e25% incidence of residual metastaticlymph node involvement [22,24,26]. The 5-year survival aftersimple cholecystectomy is between 40 and 50% [6,23,36e39].Therefore, the recommended procedure is cholecystectomy asso-ciated with resection of at least 3 cm of liver parenchyma (wedgeresection), plus adequate lymphadenectomy (Glenn's resection)[37e39]. When the tumor extends beyond the serosa and invadesthe liver or an organ or an adjacent structure (T3), there is a 36%incidence of residual disease at the liver level and 45e75% inci-dence of lymph node dissemination [5,22,25,26]. The goal of sur-gical intervention is to obtain R0 resection, hence, mandatory stepsinclude extended lymphadenectomy and extended hepatic resec-tion, associatedwith resection of other organs and structures, whennecessary (Fig. 4) [35]. T3 patients are at high risk of peritonealmetastases, therefore, explorative laparoscopy should be consid-ered in order to avoid unnecessary laparotomy. The 5-year survivalafter simple cholecystectomy is 0e15%, and reaches 25e65% afterextended resection [5,23,36] (Table 5).
4.2.5. Port-site metastasis as expression of peritoneal disease?Drouard first described the development of port-site metastases
in 1991, and additional proof came in 1994 [40,41].The prevalence of tumor seeding in port-sites after laparoscopic
cholecystectomy is very variable in published series (between 0 and40%) with higher incidences associated with gallbladder perfora-tion at the time of cholecystectomy [42e44]. It has been reported atall stages of gallbladder carcinoma and at any of the trocar sites.
It generally presents after latency, ranging from a fewmonths to3e4 years: that implies that there may be subclinical port sitedisease that goes unrecognized if not resected.
The Memorial Sloan Kettering Cancer Center recently under-lined that port-site seeding was a poor prognostic factor andseemed associated with the existence of peritoneal carcinomatosisand unresectable disease. [45].
The peritoneal tropism associated with gallbladder carcinomaseems to be aggravated by the laparoscopic technique, the mostcommon approach for cholecystectomy today. Several mechanismshave been suggested to explain the increased incidence: intra-operative perforation (up to 30% of laparoscopic cholecystectomycases) [41e44], CO2 pneumoperitoneum, repeated passages of in-struments through the trocars, increased abdominal pressure, tu-moral manipulation and the relative diminution of cellularimmunity induced by pneumoperitoneum. However, inspite ofthese suggested mechanisms, routine PSE after LC for GBCA con-tinues to be an operation of unclear utility [43e49].
Some consider it a mandatory part of a definitive resection inorder to remove potential sites of tumor seeding [3,7,8], whereasothers recommend it who believe that port site disease is equiva-lent to disseminated peritoneal disease.
The MSKCC recently published a series of 113 patients withincidental GBCA who underwent definitive resection, from 1992 to2009, after laparoscopic cholecystectomy or laparoscopic converted
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A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e12 9
to open cholecystectomy. Sixty-nine patients underwent anexploratory laparotomy with the intent of definitive resection andhad their laparoscopic port sites resected, fourty-nine did not.
In the resected port site group, port site disease was found onfinal pathology in 13 patients (19%), all associated with T2 or T3primary tumors. The presence of disease at port sites firmlycorrelated with the development of peritoneal metastases.
Evaluating patients only after an R0 resection, peritonealrecurrence was similar in patients after port site resection (18 of 53,34%) and in patients who did not undergo port site resection (13 of43, 30%, P ¼ 0.8). When only R0 resected patients were comparedand adjusted for T and N stage, therewas a 31% reduction in the riskof death, but this differencewas not significant (P¼ 0.23), therewasalso a non significant 11% reduction in the risk of disease recurrencewhen ports were removed (P ¼ 0.69). PSE did not improve overallsurvival, recurrence-free survival, or disease-specific survival inthis series. The authors therefore concluded that routine PSE wasnot warranted during secondary resection of IGBC [48].
Fucks et al (2013) presented a series of 148 patients, identified ina French multicenter database, who underwent a re-operation forresection with curative intent for IGBC. Of these 148 patients, 54(36%) had PSE while 94 patients (64%) did not (NPSE).
The primary endpoint was to assess the value of PSE duringsecondary resection with regard to short-term (specific complica-tions) and long-term (specific complications, recurrence, overallsurvival) outcome. The incidence of port-site involvement in pa-tients was 2%. Eight percent of patients developed incisional herniaat the port-site after excision.
PSE did not improve the overall survival (77%, 58%, 21% at 1, 3, 5years, respectively) compared to patients with no PSE (78%, 55%,33% at 1, 3, 5 years, respectively, P ¼ 0.37). Among the patientsundergoing R0 resection, PSE did not improve survival (79%, 60%,24% vs. 82%, 63%, 35% respectively, P ¼ 0.29). In the PSE group, 35%of patients had a recurrence, comparable to the 39% of patients with
Please cite this article in press as: A. Cavallaro, et al., Managing the inciInternational Journal of Surgery (2014), http://dx.doi.org/10.1016/j.ijsu.20
recurrence in the group without PSE: overall survival and diseasefree survival were not modified by PSE [49].
According to some authors, despite there has not been a markedchange in the number of caseswith port sites resected over the years,there has been a mildly decreasing trend in the recent era: the inci-dence of port site disease may have been impacted by the increaseduse of endo-bags, and desufflation procedure with trocar in site [21].
Nowadays PSE is left to the surgeon's experience and is notperformed routinely. Likewise, the technique of PSE is difficult andnot standardized. Trocar are often inserted with an oblique direc-tion: by centering the procedure only on cutaneous scar may pre-lude to residual disease on peritoneal side. Fucks et al. suggests theuse of thin drain trocar joining the scars on the skin and peritonealside, to guide the resection.
In conclusion, considered the risk of incisional hernia, frozensection of the peritoneum surrounding the peritoneal scars couldhelp the surgeon to identify which patients could benefit from thePSE [49].
4.2.6. Re-resection vs one stage surgeryLaparoscopic cholecystectomy, if correctly performed, did not
influence the long-term prognosis of early stage tumors (T1a, T1b,T2) [7,8]. Also, radical re-resection, performed several months afterlaparoscopic cholecystectomy, has similar results to radical resec-tion in one stage, and long-term survival can be achieved in tumorswith infiltration of the liver in patients who have previously un-dergone noncurative surgery [1,7,8,23]. Survival is strictly related tothe depth of parietal invasion of the tumor, but there is no signif-icant difference between patients with incidental GBC discoveredduring or after cholecystectomy (P ¼ 0235) [7].
4.2.7. Contraindications to additional radical resectionThe only contraindication to additional surgery is the inability to
obtain radical R0 resection. In particular, the presence of peritoneal
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A. Cavallaro et al. / International Journal of Surgery xxx (2014) 1e1210
metastasis, distant metastasis, locally advanced GBC with M1 dis-ease (according to the 7th edition of AJCC staging), lymph nodeinvasion along celiac and mesenteric vessels are commonlyconsidered contraindications to radical resection [35,50e52]. Onthe other hand, the presence of peripancreatic (head only) lymphnode disease is not a contraindication to surgical excision, andradical lymphadenectomy and pancreaticoduodenectomy can becarried out together with liver resection [35,52]. Also, the depth ofliver involvement and multiorgan locoregional involvement do notrepresent a contraindication for additional radical resection [50,51].Combined pancreaticoduodenectomy, right hemicolectomy andmajor hepatectomy are effective treatment for GBC with direct in-vasion of the adjacent organs (stomach, duodenum, pancreas, colonand liver), but only if potentially curative resection (R0) is feasible.In these cases of multiorgan resection for GBC, given radical R0resection, the long-term survival will depend on bile ductinvolvement [35,50e52]. In fact, stromal invasion of the extrahe-patic bile ducts is sometimes a prelude to hepatoduodenal ligamentinvolvement, and is also associated with a higher rate of metastasesto para-aortic nodes with a high incidence of residual tumor andpoor outcome after surgery [32].
5. Conclusion
In conclusion, incidental carcinoma of the gallbladder, as ourexperience confirms, generally is diagnosed at an earlier stage andcarries a better prognosis than non-incidentally found cancer.Laparoscopic cholecystectomy does not affect survival if imple-mented with proper technique [53e56]. Simple cholecystectomymay be an adequate treatment only for earlier stage GBC: Tis andT1a. All other stages, starting from T1b should be treated with hilar,pericholedocal, periportal lymphadenectomy, lymphadenectomy ofthe hepatoduodenal ligament and resection of at least 2e3 cm ofliver parenchyma around the liver bed, provided that no residualmicroscopic cancer (R0) remains. Resection of the main bile ductscould be necessary in hilum-type cancers with positive margins ofthe cystic duct [57,58]. More extensive liver resection or perfor-mance of multiorgan resection can be pursued in order to achieveR0 resection [59e61].
Ethical approval
This is a retrospective study based only on the analyses ofrecorded data and then no Ethical Approval was necessary.
Funding
All authors have no source of funding.
Author contribution
Andrea Cavallaro: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Gaetano Piccolo: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Maria Di Vita: Participated substantially in conception, design,and execution of the study and in the analysis and interpretation ofdata; also participated substantially in the drafting and editing ofthe manuscript.
Antonio Zanghì: Participated substantially in conception,design, and execution of the study and in the analysis and
Please cite this article in press as: A. Cavallaro, et al., Managing the inciInternational Journal of Surgery (2014), http://dx.doi.org/10.1016/j.ijsu.20
interpretation of data; also participated substantially in the draftingand editing of the manuscript.
Francesco Cardì: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Paolo Di Mattia: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Giuseppina Barbera: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Laura Borzi: Participated substantially in conception, design,and execution of the study and in the analysis and interpretation ofdata; also participated substantially in the drafting and editing ofthe manuscript.
Isidoro Di Carlo: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Vincenzo Panebianco: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Marco Cavallaro: Participated substantially in conception,design, and execution of the study and in the analysis and inter-pretation of data; also participated substantially in the drafting andediting of the manuscript.
Alessandro Cappellani: Participated substantially in concep-tion, design, and execution of the study and in the analysis andinterpretation of data. also participated substantially in the draftingand editing of the manuscript.
Conflicts of interest
All authors have no conflict of interests.
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