|Year : 2016 | Volume
| Issue : 4 | Page : 552-557
Analysis of wedge resection of gallbladder bed and lymphadenectomy on adequate oncologic clearance for gallbladder cancer
M Tewari1, S Kumar1, S Shukla2, HS Shukla1
1 Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Web Publication||21-Apr-2017|
Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
BACKGROUND: Surgery (R0 resection) is the mainstay of treatment of gallbladder cancer (GBC) as GBC is relatively resistant to currently known chemotherapy and radiotherapy regimens. AIM: to assess if wedge resection of the gallbladder bed achieves an adequate oncological clearance in GBC (namely T1 and T2) and some T3 GBC with minimal liver infiltration. PATIENTS AND METHODS: Patients with GBC who underwent radical cholecystectomy (en bloc cholecystectomy, wedge resection of the gallbladder fossa with a ≥2 cm rim of nonneoplastic liver tissue, and regional lymph node dissection) between October 2012 and June 2015 after obtaining informed consent. RESULTS: Of thirty patients, mean age of 52 years, 5 had T1b, 13 T2, and 12 T3 GBC. R0 resection was achieved in all thirty GBC patients. Hepatic invasion was found in seven patients. The depth of hepatic invasion ranged from 0 to 9 mm. Follow-up ranged from a minimum of 12 to 43 months. Nineteen (63%) patients had N0 and 11 (37%) had N1 GBC. Total lymph node (TLND) count ranged from 1 to 12/patient with a median of 3. There was no local recurrence or systemic relapse of the disease. CONCLUSION: Wedge resection of the gallbladder bed achieves an adequate oncological clearance in early GBC. TLND counts remain poor even after a thorough standard lymph node dissection for resectable GBC.
Keywords: Gallbladder cancer, segmental IVb and V liver resection, total lymph node count, wedge resection
|How to cite this article:|
Tewari M, Kumar S, Shukla S, Shukla H. Analysis of wedge resection of gallbladder bed and lymphadenectomy on adequate oncologic clearance for gallbladder cancer. Indian J Cancer 2016;53:552-7
|How to cite this URL:|
Tewari M, Kumar S, Shukla S, Shukla H. Analysis of wedge resection of gallbladder bed and lymphadenectomy on adequate oncologic clearance for gallbladder cancer. Indian J Cancer [serial online] 2016 [cited 2019 Aug 19];53:552-7. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/552/204787
| » Introduction|| |
Gallbladder cancer (GBC) is a rare though notoriously lethal malignancy with marked ethnic and geographical variations. It is a common disease in countries such as Chile (16–27/100,000), Japan (7/100,000), India, Central Europe, Poland (14/100,000), Israel (5/100,000), and Southern Pakistan (11/100,000); however, it is uncommon in the United States (1.5/100,000).,, In India, GBC is most prevalent in the Northern and Northeastern states of Uttar Pradesh, Bihar, Orissa, West Bengal, and Assam. It is twice more common in women than in men and is the most common digestive cancer in women in Northern India.
Complete surgical resection (R0) is the only modality that provides hope for long-term survival. The optimum treatment for incidental Tis and T1a GBC is simple cholecystectomy (with negative cystic duct margin) with a 5-year survival of 100% in most studies., Extended cholecystectomy is indicated in lesions T1b and above., There is considerable controversy regarding the extent of surgical resection of liver for GBC. Surgical options include a nonanatomical wedge resection of ≥2 cm of adjacent normal liver tissue of the gallbladder bed or an anatomical parenchyma-sparing segment IVb + V resection of liver.
It has been shown that lymphatic spread occurs early, before liver involvement and that nodal involvement is a poor prognostic factor. It is proposed that the following three lymph node stations are involved in order of frequency.
- Level I: Cystic and periductal lymph nodes
- Level II: Pancreaticoduodenal (superior and posterior group) and hepatic artery lymph nodes
- Level III: Superior mesenteric and celiac axis lymph nodes.
These lymph node stations dictate the extent of lymphadenectomy with curative intent. The Japanese named these as three different pathways, namely, cholecysto-retropancreatic pathway, cholecysto-celiac pathway, and cholecysto-mesenteric pathway. It has also been hypothesized that the artery accompanying pericholedochal lymph nodes was either the regressed embryonic right hepatic artery or an aberrant right hepatic artery remaining without regression possibly explaining the reason as to why lymph node metastases characteristically arise in the pericholedochal area or the posterosuperior pancreaticoduodenal region, rather than around the hepatic artery for lymph nodes and lymphatic vessels generally exist along a feeding artery.
There is yet no consensus on the minimum number of lymph nodes required to accurately stage GBC. The large volume data available from other cancers such colon cancer and gastric cancer suggest that an inadequate number of lymph nodes examined/resected may adversely affect the overall survival of the patient and also lead to under staging., Several studies have also evaluated the role of the ratio between metastatic and examined lymph nodes (lymph node ratio [LNR]), an additional prognostic factor in different gastrointestinal malignancies.,, LNR, log odds (LODDS), and N-score are the new lymph node staging/scoring systems being assessed to stratify the prognosis of patients with GBC.,
This study analyses outcome after nonanatomical wedge resection of gallbladder bed and the total lymph node (TLND) count in thirty patients with resected Stage I–III GBC in patients with GBC.
| » Patients and Methods|| |
Patients of GBC who underwent radical cholecystectomy in the Department of Surgical Oncology, Sir Sunderlal Hospital, Institute of Medical Sciences (IMS), Banaras Hindu University (BHU), Varanasi, India between October 2012 and June 2015 had their surgical specimen evaluated pathologically to know the liver margin status following wedge resection of ≥2 cm of nonneoplastic liver tissue. A detailed history and examination were recorded on a preset pro forma after obtaining informed consent.
- All operable symptomatic GBC (Stage I–III)
- Incidental (postcholecystectomy) GBC (pT1b and higher stage).
- pTis and pT1a disease for incidental carcinoma gallbladder
- All Stage IVb disease including N2 and metastatic disease
- Patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3 and 4)
- Patients who had received prior chemotherapy
- Those who did not give consent for the study.
A total of thirty patients with GBC falling within the inclusion criteria admitted and subjected to radical cholecystectomy in the Surgical Oncology Department of Sir Sunderlal Hospital, IMS, BHU from October 2013 to June 2015 were included in this study.
During the study period, all patients with GBC falling within the inclusion criteria were subjected to radical resection. An extended/radical cholecystectomy was performed consisting of an en bloc cholecystectomy, wedge resection of the gallbladder fossa with a ≥2 cm rim of nonneoplastic liver tissue, and regional lymph node dissection.
Patients were carefully staged with a preoperative contrast-enhanced computed tomography (CECT) scan of the abdomen and thorax to assess the extent of the disease. Patients with lymph nodes of size >1 cm in the peripancreatic, celiac, and aortocaval region on CECT (i.e., N2 disease) were excluded from the study. Block review of the pathological specimen was done for incidental (postcholecystectomy) GBC, to know the T-stage of the primary tumor and margin status including cystic duct margin to decide upon the need for radical re-resection in these patients.
Assessment for appropriate margin of wedge resection of apparently normal liver tissue (about 2 cm or more) was done using intraoperative ultrasonography. Wedge resection of liver was done using Kelly's-clysis technique and/or LigaSure. Titanium clips were used for taking control of vessels and ductal structures which stood out during Kelly's-clysis or with the use of LigaSure. Pringle maneuver was used during wedge resection of liver to minimize blood loss.
A combined resection of contiguous structures, namely transverse colon and omentum were done when they were found adhered or infiltrated by the tumor, with an aim to achieve a R0 resection. Extrahepatic bile duct excision was done only in selected cases with gross invasion of the common bile duct (CBD) by the tumor or densely adherent lymph nodes. CBD resection was not done on a routine basis to facilitate lymph node dissection.
Regional lymph node dissection consisted of a complete portal lymph node dissection with thorough skeletonization of the portal structures down to including the suprapyloric lymph nodes overlying the hepatic-gastroduodenal artery junction dissecting the cystic duct, pericholedochal, periportal, perihepatic, right celiac, and posterosuperior pancreaticoduodenal nodes groups. Kocherization up to the left border of IVc was done to facilitate this dissection. An attempt for en bloc dissection of lymph nodes was made for all patients.
Patients received gemcitabine + cisplatin-based chemotherapy or chemoradiation for pT2 or higher stage and/or node positive GBC.
All patients were followed up at 3 monthly intervals for first 2 years and 6 monthly thereafter.
All statistical analyses were carried out using MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2014). Chi-square test was used for categorical variables. Fisher exact (two-tailed test) probability and cross-tabulations were also used. The result was considered statistical significance when P< 0.05.
| » Results|| |
The study included thirty patients of GBC comprising both of primary (27 patients) as well as incidental (3 patients) GBC cases. The mean age of the study population was 52 years (range 30–70 years). There were 25 females (83%) and 5 males (17%). One patient had a family history of GBC in one of his first-degree relatives. Addiction was seen in six patients. Three of them were addicted to tobacco chewing, two were tobacco chewers as well as smokers, whereas one had a habit of smoking and alcohol consumption. Twenty-four others, most of them women, had no history of addiction. Three patients were pure vegetarians and rest had a mixed dietary habit.
Majority of the patients did not have any comorbidities. Three were hypertensive, one was diabetic, two were both hypertensive and diabetic, and one was hypothyroid. All thirty patients in the study group had a good performance status with an ECOG score of one. Most common symptom was pain in right upper quadrant of abdomen seen in 24 (80%) of patients followed by dyspepsia in  53% of patients. Jaundice was present in 4 (13%) patients. Gallstones were seen in association with GBC in 24 (80%) patients, GB polyps of size >1 cm size in 2 patients, and porcelain gallbladder in 1 patient.
Location of the tumor within the gallbladder and tumor histopathology type is shown in [Table 1] and [Table 2], respectively. Fourteen patients had well-differentiated (Grade 1), nine moderately differentiated (Grade 2), and the rest seven patients had poorly differentiated (Grade 3) GBC. Four out of five patients with adenosquamous carcinoma had poorly differentiated tumor while one was moderately differentiated. Neither the location of the tumor in GBC nor tumor histology nor grade had any effect on margin status or local/distant relapse of GBC in follow-up.
Of the thirty patients, 5 (17%) had pT1, 13 (43.33%) pT2, and 12 (40%) pT3 GBC on histopathological examination. Nineteen out of the thirty (63%) patients had N0 disease. N1 disease was seen in 11 (37%) patients. A total number of lymph nodes harvested were 143 for thirty study patients. TLNC ranged from 1 to 12. Median TLNC was 3. TLND count with respect to age, gender, pT, and pN stage is shown in [Table 3]. Among the 11 patients with positive lymph nodes, the location of these positive nodes and the number of positive lymph nodes is as shown in [Table 4] and [Table 5], respectively. Most common location of positive lymph node was around CBD, i.e., pericholedochal.
|Table 3: A comparison of lymph nodes retrieved with age, gender, and stage of the gallbladder cancer|
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|Table 4: Location and number of positive lymph nodes in thirty gallbladder cancer patients|
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|Table 5: Number of positive lymph nodes retrieved in thirty gallbladder cancer patients|
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Adjuvant chemotherapy was administered in 25 patients. The follow-up ranged from 12 to 43 months. There was no local recurrence reported, and only one patient developed malignant ascites as a feature of systemic relapse of the GBC at 8 months following surgery.
| » Discussion|| |
The differences in opinion regarding the extent of liver resection in GBC stems for the inherent peculiarity anatomy and location of gallbladder. The Glisson's capsule is absent in the gallbladder bed, i.e., where it lies on to the liver and this common surface provides the venous and lymphatic drainage of the gallbladder. The venous drainage of gallbladder is through 2–20 cholecystic veins which enter the liver through the gallbladder fossa (segment IVb and V) and drain directly in the middle hepatic venous radicals. The rest of the gallbladder is drained by one or two cystic veins which commonly enter the liver, either directly or after joining the veins draining the hepatic ducts, and the upper part of the bile duct. In early mucosal lesion (T1a), venous invasion is very rare. This forms the basis of en bloc hepatic resection in T1b and above GBC. There is rarely a venous communication to portal vein. Moreover, the gallbladder wall has no submucosa – the wall comprises mucosa, muscularis layer, perimuscular connective tissue, and serosa on the peritoneal surface and results in the early hepatic invasion of GBC.
As per the tumor (T), node (N), and metastases (M) staging system of the American Joint Committee for Cancer (AJCC), GBC is staged as pT1 for GBC limited to mucosa, pT1b muscularis, pT2 perimuscular connective tissue, pT3 when tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts, and pT4 when tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures. A radical/extended cholecystectomy is indicated in pT1b and above GBC.
The extent of liver resection varies from nonanatomical wedge resection to anatomical segment IVb/V resection up to extended right hepatectomy. No randomized trials exist on the subject stating a superiority of one over the other and most surgeons follow center-specific practice.
In a retrospective study of 42 patients, Wakai et al. in 2010 described that the mode of hepatic spread of GBC has three patterns: Direct invasion through the gallbladder bed, portal tract invasion, and hepatic metastatic nodules. They found that the portal tract invasion is seen only in the vicinity (within about 1 cm) of the advancing margin of direct liver invasion. Shirai et al. in 2012 reported their outcome of the 52 patients following an extended radical cholecystectomy with liver resection margin of approximately 2 cm or more for pT2 and some pT3 GBC with localized hepatic invasion. There was no local recurrence in hepatectomy margins in any patient. They suggested that while performing a wedge hepatectomy for invasive tumor, the entire cystic plate should be resected because incomplete excision of the cystic plate violates the subserosal plane of the gallbladder and thus may leave behind tumor cells in this plane. Furthermore, complete excision of the cystic plate facilitates removal of the adipose tissue within the triangle of Calot, which usually contains cystic duct node(s).
A multicenter Japanese study reported 10-year follow-up results on 293 pT2 and 192 pT3 R0 GBC cases. There were no significant differences in survival rate or recurrence rates in the form of liver metastasis were observed between the groups that underwent resection of the gallbladder bed versus the group that underwent segmentectomy 4a + 5, and the group that underwent hepatectomy in patients with of both pT2 or pT3 GBC. There was a predilection for liver metastasis to segment 4a5. Similar study of nationwide data from the Japanese Biliary Tract Cancer Registry involving 85 patients with pT2 N0 GBC (55 treated with gallbladder bed resection, and 30 with S4a + 5 hepatectomy) found no difference between the groups in 5-year survival (76.2% for gallbladder bed resection vs. 65.9% for segment 4a + 5, P = 0.53) and disease-free survival (74.4% for gallbladder bed resection vs. 63.3% for segment 4a + 5, P = 0.23). They concluded that there was no difference in the incidence of recurrence in two groups (32.7% for gallbladder bed resection vs. 26.7% for segment 4a + 5, P = 0.39), and the recurrence occurred most frequently in both lobes than S4a + 5 of the liver following gallbladder bed resection.
There are studies that are skepticle of gallbladder wedge resection for GBC. Yamaguchi et al. have shown that anatomically the distance from the neck of the gallbladder to the right hepatic duct is only 2 mm and the distance to the bifurcation of the right anterior and posterior duct is 6 mm. Based on this finding, they suggested that surgical strategy for GBC should rely not only on the depth of invasion but also on the site of gallbladder tumor, thus propagating against a nonanatomical resection for gallbladder neck cancer lesions.
Sugita et al., in 2000, demonstrated that the venous drainage of gallbladder occurs through multiple cystic veins which drain into segment IVb and V of liver. Yoshimitsu et al. in their study supported this by demonstrating cholecystic venous drainage through helical computed tomography by injecting contrast medium in the cholecystic artery. For the proponents of anatomical segment IVb and V liver resection, this anatomical knowledge forms the basis of theoretical superiority of segment IVb + V or extended liver resections over wedge liver resection as a part of extended cholecystectomy to prevent micrometastasis. The philosophy of micrometastasis to segment IVb + V could not gain support among surgeons in the light of contrasting available literature and that is when disease recurs in GBC following treatment, it involves both lobes of liver and does not have predilection for segments IVb + V.
Ogura et al., in 1998, measured the distance between the front of carcinoma invasion and the resection plane in the hepatic parenchyma. The distance ranged between 12 and 20 mm after wedge resection, 16–35 mm after resections of segments IVB + V, and 28–58 mm after extended hepatic resections. They suggested that wedge resection of the liver bed and resection of segments IVb + V are advisable for carcinoma localized to the gallbladder alone and for liver bed type with minimal hepatic invasion and an expansive tumor growth pattern. Extensive hepatic resection should be done for GBC of the invasive liver bed and hepatic-hilar type. Pawlik et al. suggested that margin status was associated with survival, not extent of anatomical or nonanatomical hepatectomy. Many studies addressed this issue and postulated that wedge resection of gallbladder bed is sufficient for addressing the liver invasion as long as R0 resection can be achieved.,,
Our study had R0 hepatic resection margins for all thirty patients who underwent wedge resection of gallbladder bed, and there was no hepatic recurrence with a modest follow-up of 43 months.
Lymph node metastasis is a marker of adverse prognosis and some even suggest it to have different cancer biology. There is still no consensus on the optimum extent of lymph node dissection in extended cholecystectomy for GBC patients. The seventh edition of the AJCC staging manual  defines regional lymph node Group 1 (N1) as comprising the cystic duct lymph node, CBD lymph node, and the lymph nodes around the hepatoduodenal ligament (i.e., the hepatic artery lymph node and portal vein lymph node). The posterior pancreaticoduodenal lymph node, celiac artery lymph node, superior mesenteric artery lymph node, para-aortic lymph node, and pericaval lymph node are classified as belonging to regional lymph node Group 2 (N2). N2 metastasis would be interpreted as remote metastasis, and such patients would be classified as tumor node metastasis IVB. The Japanese Society of Biliary Surgery (JSBS) subdivides the nodal status of GBC into four categories, according to the anatomic location of positive LNs: N0, N1, N2, or N3. We herewith follow the AJCC classification system.
In most cases, the long-term survival cannot be predicted for patients with N2 metastasis, and radical lymph node dissection is not routinely performed.,, Regional lymph node dissection is thus recommended for the cystic duct lymph node, CBD lymph node, the lymph nodes around the hepatoduodenal ligament (hepatic artery and portal vein lymph nodes), and the posterior superior pancreaticoduodenal lymph node.
As the T-stage that is the depth of mural invasion increases so does the chances of lymph node metastasis: pT1a, 0%–2.5%; pT1b, 5%–16%; pT2, 9%–30%; T3, 39%–72%; and T4, 67%–80%.,, In our experience, we have often encountered a pT2 GBC with N2 lymph node spread making an apparently “resectable” disease “unresectable” due to widespread lymphatic metastases. Meng et al. found in their study of 55 patients with advanced GBC that if only patients with local lymph node metastasis JSBS N1–N2; AJCC N1 were chosen for surgery, 40% of 30-month survival would be seen rather than the 20% seen for distant lymph node metastasis (JSBS N3; AJCC N2). In fact, for N3 disease, there were no 2-year survivors. The survival of those with JSBS N3 and AJCC N2 disease who underwent radical resection was not significantly different from those who underwent chemotherapy other palliative treatment.
The above findings and results from several other studies reiterate the fact that pT1b GBC can have residual disease in the lymph nodes underscoring the importance of re-excision and lymph node dissection in these groups of incidental GBC and also highlight the futility of radical resection in patients with AJCC N2 disease. In the present study, lymph node metastasis was found as follows: 0% in pT1, 33.3% in pT2, and 58.3% in pT3 GBC.
Controversies exist on the optimal number of lymph nodes to stage GBC accurately. Some studies claim minimum TLND count to be eight, six, and some state it a little lower, at four  or even three.
Another area under debate is on the minimum/optimal number of lymph nodes required to accurately determine the N-stage of GBC. The sixth edition of the AJCC staging system stated that more than three lymph nodes are required to accurately determine the N-stage. However, this point is missing in the manual's seventh edition. Some surgeons are of the opinion that only 3–4 lymph nodes can be collected despite N1 regional lymph node dissection. Based on this, the Korean Association of Hepatobiliary and Pancreas Surgery guidelines propose that more than three lymph nodes should be collected for histopathologic examination of resected GBC specimen. In the present study, the TLND count ranged from a minimum of 1 to a maximum of 12 lymph nodes despite exactly the same extent of lymph node dissection. While some studies suggest that only portal lymphadenectomy is sufficient for Stage II GBC, most authors agree that dissection beyond the hepatoduodenal ligament is required to obtain a good TLND count.
Obtaining six or more TLND is often difficult and a series of 122 GBC patients reported from Memorial Sloan Kettering Cancer Center revealed a median TLND count of 3 (range 0–20). However, there are a few studies that have reported exceptional TLND count with a median harvest of 19/patient. Typical nodes in the hepatoduodenal ligament are the hilar node, cystic node, pericholedochal node, retroportal node, foramen of Winslow node, superior retro pancreatoduodenal node, and posterior pancreatoduodenal node.
The TLND retrieved per patient had no association with age, gender, pT-satge, or pN-stage of the patient in our study. As none of the patients in our series developed disease relapse survival analysis could not be done. In view of low TLND counts that are usually retrieved after a standard lymphadenectomy for GBC, it appears therefore that LNR, LODDS, and N-ratio may have an important role to play in determining the prognosis of GBC patients.
| » Conclusion|| |
Wedge resection of gallbladder bed with ≥2 cm apparently normal liver margin provides an adequate oncological clearance for stage T1b, T2, and some T3 tumors with limited hepatic invasion. TLND counts remain poor even after a thorough standard lymph node dissection for resectable GBC. The minimum cutoff hence should be three or more nodes and the prognostic value of LNR, LODDS, and N-ratio in GBC should be investigated in multicenter trials.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]