**Gallbladder Cancer: Surgical Management**

**Gallbladder Cancer: Surgical Management**

#### Adrian Bartoș, Andrei Herdean and Dana Monica Bartoș Dana Monica Bartoș Additional information is available at the end of the chapter

Adrian Bartoș, Andrei Herdean and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67561

#### **Abstract**

[28] Ma MZ, Kong X, Weng MZ, Zhang M, Qin YY, Gong W, Zhang WJ, Quan ZW. Long noncoding RNA-LET is a positive prognostic factor and exhibits tumor-suppressive activity

[29] Liu B, Shen ED, Liao MM, Hu YB, Wu K, Yang P, Zhou L, Chen WD. Expression and mechanisms of long non-coding RNA genes MEG3 and ANRIL in gallbladder cancer.

[30] Ma F, Wang SH, Cai Q, Zhang MD, Yang Y, Ding J. Overexpression of LncRNA AFAP1-AS1 predicts poor prognosis and promotes cells proliferation and invasion in gallbladder cancer. Biomed Pharmacother. 2016;**84**:1249–1255. DOI: 10.1016/j.biopha.2016.10.064. [31] Wang SH, Wu XC, Zhang MD, Weng MZ, Zhou D, Quan ZW. Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting

[32] Wang SH, Wu XC, Zhang MD, Weng MZ, Zhou D, Quan ZW. Upregulation of H19 indicates a poor prognosis in gallbladder carcinoma and promotes epithelial-mesenchymal

[33] Lv W, Wang L, Lu J, Mu J, Liu Y, Dong P. Long noncoding RNA KIAA0125 potentiates cell migration and invasion in gallbladder cancer. Biomed Res Int. 2015;**2015**:108458.

[34] Wang L, Zhang Y, Lv W, Lu J, Mu J, Liu Y, Dong P. Long non-coding RNA Linc-ITGB1 knockdown inhibits cell migration and invasion in GBC-SD/M and GBC-SD gallbladder cancer cell lines. Chem Biol Drug Des. 2015;**86**:1064–1071. DOI: 10.1111/cbdd.12573. [35] Wu XS, Wang XA, Wu WG, Hu YP, Li ML, Ding Q, Weng H, Shu YJ, Liu TY, Jiang L, Cao Y, Bao RF, Mu JS, Tan ZJ, Tao F, Liu YB. MALAT1 promotes the proliferation and metastasis of gallbladder cancer cells by activating the ERK/MAPK pathway. Cancer

in gallbladder cancer. Mol Carcinog. 2015;**54**:1397–1406. DOI: 10.1002/mc.22215.

Tumour Biol. 2016;**37**:9875–9886. DOI: 10.1007/s13277-016-4863-y.

AKT2. Tumour Biol. 2016;**37**:9721–9730. DOI: 10.1007/s13277-016-4852-1.

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Biol Ther. 2014;**15**:806–814. DOI: 10.4161/cbt.28584.

DOI: 10.1155/2015/108458.

60 Updates in Gallbladder Diseases

Gallbladder cancer represents one of the rare and highly fatal neoplastic diseases, early diagnosis and treatment being the key for an acceptable outcome. The best survival results are obtained for patients with T1-T2 stage, a radical cholecystectomy being sufficient in most of these cases. For advanced tumors, major liver resections could be necessary to obtain optimal oncological results. Although a high percentage of the patients are diagnosed with unresectable disease, the continuous progresses made in the field of surgical therapy and oncological treatment could finally improve the outcome of this neoplastic pathology.

10.5772/67561

**Keywords:** gallbladder cancer, surgical treatment, hepatic resection, radical colecistectomy, hepatic limphadenectomy

## **1. Introduction**

Biliary tract cancers are a group of neoplastic diseases that arise from the biliary epithelium. According to their localization, they are divided into: intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma and gallbladder cancer. Gallbladder cancer represents one of the rare and highly fatal neoplastic diseases; early diagnosis and treatment are the key [1].

## **2. Epidemiology: risk factors**

Gallbladder cancer is the fifth most common type of digestive cancer and the most frequent biliary tract cancer. The maximum incidence of this disease is reported in Chile, Bolivia and

other South-American countries [2]. Urban population presents a higher risk of developing gallbladder cancer [1]. The prognosis is a very poor one, with a 5-year overall survival rate of less than 10% [2]. During the last decade, the mortality rate has improved in developed countries, while in developing countries it is still at a high level [1]. Chronic inflammation of the gallbladder mucosa and all its predisposing factors increase the incidence of the disease. The most common risk factors for developing gallbladder cancer are: gallbladder lithiasis, old age, female sex, tobacco and alcohol abuse, multiple pregnancies, low physical activity, obesity and infectious diseases. The most common pathogens implicated in the development of gallbladder cancer are *Salmonella typhi*, *Salmonella paratyphi* and Helicobacter [1]. Gallstones, especially large ones, frequently associated with Mirizzi syndrome, represent the most common predisposing factor for gallbladder cancer [1]. Gallbladder polyps, the porcelain gallbladder and anatomical abnormalities of the ampulla of Vater, which causes bile reflux, are also predisposing factors. Diet is another important risk factor in the development of gallbladder cancer; increased intake of fried foods or those that cause constipation (less than one bowel movement in 6 days) increases the risk. On the other hand, in women, the intake of boiled beans, or in men, the intake of fish, lowers the incidence of gallbladder cancer. The involvement of environmental factors such as heavy metals (high levels of nickel, cadmium, manganese, copper, chromium and lead, as well as low levels of selenium or zinc) is not yet fully understood, requiring prospective studies conducted on large groups of patients [1]. Also, mutations of K-ras or p53 genes are still being studied; identifying a link between these mutations and the development of gallbladder cancer is still difficult [1].

A separate entity is represented by incidental gallbladder cancer discovered at histopathological examination of specimens resulted from cholecystectomy performed for gallbladder lithiasis [3]. These cases represent 47% of all cases of gallbladder cancer [4].

#### **3. Pathology**

Gallbladder cancer develops similar to other digestive cancers: the progression can be observed from dysplasia to infiltrative carcinoma at the level of gallbladder mucosa. The preneoplastic nature of gallbladder polyps is controversial, however there is some data showing the progression to adenocarcinoma. About 3–6% of the patients present with gallbladder polyps at the ultrasound examination [5]. Most of them are cholesterol polyps without any risk of becoming malignant. The risk of polyps for becoming malignant has been associated with old age, dimensions over 1 cm and the presence of a single polyp [5].

Gallbladder cancer presents most often as monocentric; multifocal forms are extremely rare. The most common localization is at the fundus of the gallbladder (60%), followed by the body (30%) and the infundibulum (10%) [5].

These tumors are considered highly aggressive since infiltrative forms are rapidly involving hepatic parenchyma, mostly segments IVb and V. Also, tumor extension can occur towards the cystic duct and its confluence with the common hepatic duct, in which case the presentation could be similar to a Klatskin tumor [6]. Malignant tumors of the gallbladder can invade the branches of the hepatic artery or portal vein, which leads to the atrophy of the ipsilateral lobe and compensatory hypertrophy of the contralateral lobe.

The most common histological type of gallbladder malignant tumor is adenocarcinoma. The papillary form of adenocarcinoma has the best prognosis because this type of tumor tends to be noninvasive or minimally invasive [5]. However, we must not forget the other histological types, such as squamous cell or adenosquamous carcinoma, mucinous carcinoma, signet ring cell carcinoma and not least lymphomas and neuroendocrine tumors. Rare forms are represented by melanomas or secondary tumors localized at the level of the gallbladder.

Gallbladder cancer most commonly spreads directly into the surrounding organs. Step by step spreading is further enabled by thin gallbladder wall, which is formed by only one muscular layer and by the fact that the connective tissue of the gallbladder is continuous with the interlobular connective tissue of the liver [7]. This highly aggressive malignant tumor also spreads through satellite lymphatic vessels of the cystic duct to the hilar lymph nodes and further to the gastroduodenal lymph nodes, retropancreatic lymph nodes, celiac trunk lymph nodes and finally to the interaortocaval lymph nodes. Advanced cases of the disease determine enlarged lymph nodes at the level of the hepatic hilum, which erode and invade the portal vein wall, causing thrombosis and all the consequences of portal hypertension. Spreading to the peritoneum, which determines the occurrence of paraneoplastic ascites, as well as pulmonary and hepatic metastases, determine the infaust evolution of terminal cases.

## **4. Diagnosis**

other South-American countries [2]. Urban population presents a higher risk of developing gallbladder cancer [1]. The prognosis is a very poor one, with a 5-year overall survival rate of less than 10% [2]. During the last decade, the mortality rate has improved in developed countries, while in developing countries it is still at a high level [1]. Chronic inflammation of the gallbladder mucosa and all its predisposing factors increase the incidence of the disease. The most common risk factors for developing gallbladder cancer are: gallbladder lithiasis, old age, female sex, tobacco and alcohol abuse, multiple pregnancies, low physical activity, obesity and infectious diseases. The most common pathogens implicated in the development of gallbladder cancer are *Salmonella typhi*, *Salmonella paratyphi* and Helicobacter [1]. Gallstones, especially large ones, frequently associated with Mirizzi syndrome, represent the most common predisposing factor for gallbladder cancer [1]. Gallbladder polyps, the porcelain gallbladder and anatomical abnormalities of the ampulla of Vater, which causes bile reflux, are also predisposing factors. Diet is another important risk factor in the development of gallbladder cancer; increased intake of fried foods or those that cause constipation (less than one bowel movement in 6 days) increases the risk. On the other hand, in women, the intake of boiled beans, or in men, the intake of fish, lowers the incidence of gallbladder cancer. The involvement of environmental factors such as heavy metals (high levels of nickel, cadmium, manganese, copper, chromium and lead, as well as low levels of selenium or zinc) is not yet fully understood, requiring prospective studies conducted on large groups of patients [1]. Also, mutations of K-ras or p53 genes are still being studied; identifying a link between these

mutations and the development of gallbladder cancer is still difficult [1].

lithiasis [3]. These cases represent 47% of all cases of gallbladder cancer [4].

old age, dimensions over 1 cm and the presence of a single polyp [5].

(30%) and the infundibulum (10%) [5].

**3. Pathology**

62 Updates in Gallbladder Diseases

A separate entity is represented by incidental gallbladder cancer discovered at histopathological examination of specimens resulted from cholecystectomy performed for gallbladder

Gallbladder cancer develops similar to other digestive cancers: the progression can be observed from dysplasia to infiltrative carcinoma at the level of gallbladder mucosa. The preneoplastic nature of gallbladder polyps is controversial, however there is some data showing the progression to adenocarcinoma. About 3–6% of the patients present with gallbladder polyps at the ultrasound examination [5]. Most of them are cholesterol polyps without any risk of becoming malignant. The risk of polyps for becoming malignant has been associated with

Gallbladder cancer presents most often as monocentric; multifocal forms are extremely rare. The most common localization is at the fundus of the gallbladder (60%), followed by the body

These tumors are considered highly aggressive since infiltrative forms are rapidly involving hepatic parenchyma, mostly segments IVb and V. Also, tumor extension can occur towards the cystic duct and its confluence with the common hepatic duct, in which case the presentation could be similar to a Klatskin tumor [6]. Malignant tumors of the gallbladder can invade Gallbladder cancer can be diagnosed either preoperative or intraoperative during surgical treatment for another disease or after the histopathological examination of the specimen resulted from cholecystectomy for gallbladder lithiasis. The clinical signs of gallbladder cancer are not specific, which is why more than half of the cases cannot be diagnosed preoperatively. The lack of efficient screening methods for this disease also leads to the impossibility of an early diagnosis. The systematic examination of the specimens resulting from cholecystectomy improved the early diagnosis rate of this extremely aggressive neoplastic disease.

Even though clinical signs and symptoms are not specific, knowing and following them in patients suspected of having this disease is particularly important for proper management. Symptoms associated with gallbladder lithiasis or choledochal lithiasis are commonly found in the clinical presentation of gallbladder cancer. So, in symptomatic patients, abdominal pain with the character of biliary colic is a common sign, especially in cases when the cancer is diagnosed incidentally, during the treatment for an acute or chronic cholecystitis.

Jaundice and angiocholitis are also frequently seen in the clinical presentation of the gallbladder cancer [6]. In addition to jaundice, we can observe other paraneoplastic signs and symptoms like asthenia, fatigue and marked weight loss.

The physical examination of the patients reveals discomfort in the right hypochondrium, where it can also be found as a hard mass, which is poorly delimited and fixed due to tumor invasion of surrounding organs. If gallbladder cancer is suspected, some laboratory tests and imaging examinations must be performed in order to establish a correct diagnosis.

Required laboratory tests are the usual ones and they determine mainly an extrahepatic cholestasis syndrome. Prolonged biliary stasis can also determine high levels of serum transaminases and other parameters that show liver failure. Most of the times, the laboratory findings do not establish an accurate diagnosis unless they reveal an advanced stage of disease. Biological signs of advanced disease are: anemia, low levels of serum albumin, high levels of leukocytes and extremely high alkaline phosphatase and conjugated bilirubin levels [5]. Relevant tumor markers are CEA and CA 19-9. A high level of CEA has a specificity of 90% for malignant tumors of the gallbladder, but has a low sensitivity (50%) [5] when it is used for screening because it is also elevated by benign tumors. The tumors markers have a low utility for gallbladder cancer's diagnosis but they are extremely important for the follow-up of these patients.

Imaging exams are crucial for diagnosing and staging of this disease and they usually reveal asymmetric thickness of the gallbladder wall. Since polyps or malignant tumors of the gallbladder could have similar imaging characteristics to the normal gallbladder wall, an accurate diagnosis is difficult to establish. The situation can be further complicated by a certain degree of inflammation of the gallbladder wall caused by lithiasis.

The ability of ultrasound examination to reveal this disease has been appreciably improved by employing ecoendoscopic techniques, which in some cases is even more accurate than computed tomography (CT) or magnetic resonance imaging (MRI) [6]. CT imaging with intravenously administered contrast may reveal a tumor at the level of the gallbladder, which invades hepatic parenchyma and other adjacent organs. Despite this, an accurate staging using CT is hard to achieve due to the weak sensitivity for identifying possible lymph node metastases [6]. MRI has better sensitivity for both identifying possible lymph node metastases and for revealing any invasion at the level of the adjacent hepatic parenchyma. This is best evidenced by MRI T2 sections [8].

## **5. Staging**

Staging is a key moment in the management of patients presenting with malignant gallbladder tumors. The American Joint Committee on Cancer (AJCC) proposes the tumor-lymh nodes-metastasis (TNM) staging as follows (**Table 1**).

Complete staging is obtained by a combination of imaging: ultrasound, CT, MRI, positron emission tomography (FDG-PET) and diagnostic laparoscopy. Diagnostic laparoscopy is superior in identifying possible peritoneal spread, as well as other absolute contraindications for radical surgery. Its employment has lead to a decreased rate of blind laparotomies [9].

Diagnostic laparoscopy combined with intraoperative ultrasound techniques, with or without contrast, has better sensitivity in identifying liver metastases and allows for a more precise evaluation of tumor adjacent blood vessels involvement. The invasion of adjacent organs (liver, stomach, duodenum, pancreas, colon, greater omentum and abdominal wall) can also been revealed through laparoscopy. In case of a suspected distant metastasis, the FDG-PET examination is recommended [6].


**Table 1.** TNM staging (after AJCC 7th edition).

invasion of surrounding organs. If gallbladder cancer is suspected, some laboratory tests and

Required laboratory tests are the usual ones and they determine mainly an extrahepatic cholestasis syndrome. Prolonged biliary stasis can also determine high levels of serum transaminases and other parameters that show liver failure. Most of the times, the laboratory findings do not establish an accurate diagnosis unless they reveal an advanced stage of disease. Biological signs of advanced disease are: anemia, low levels of serum albumin, high levels of leukocytes and extremely high alkaline phosphatase and conjugated bilirubin levels [5]. Relevant tumor markers are CEA and CA 19-9. A high level of CEA has a specificity of 90% for malignant tumors of the gallbladder, but has a low sensitivity (50%) [5] when it is used for screening because it is also elevated by benign tumors. The tumors markers have a low utility for gallbladder cancer's diagnosis but they are extremely important for the follow-up of these patients. Imaging exams are crucial for diagnosing and staging of this disease and they usually reveal asymmetric thickness of the gallbladder wall. Since polyps or malignant tumors of the gallbladder could have similar imaging characteristics to the normal gallbladder wall, an accurate diagnosis is difficult to establish. The situation can be further complicated by a certain degree

The ability of ultrasound examination to reveal this disease has been appreciably improved by employing ecoendoscopic techniques, which in some cases is even more accurate than computed tomography (CT) or magnetic resonance imaging (MRI) [6]. CT imaging with intravenously administered contrast may reveal a tumor at the level of the gallbladder, which invades hepatic parenchyma and other adjacent organs. Despite this, an accurate staging using CT is hard to achieve due to the weak sensitivity for identifying possible lymph node metastases [6]. MRI has better sensitivity for both identifying possible lymph node metastases and for revealing any invasion at the level of the adjacent hepatic parenchyma. This is best

Staging is a key moment in the management of patients presenting with malignant gallbladder tumors. The American Joint Committee on Cancer (AJCC) proposes the tumor-lymh

Complete staging is obtained by a combination of imaging: ultrasound, CT, MRI, positron emission tomography (FDG-PET) and diagnostic laparoscopy. Diagnostic laparoscopy is superior in identifying possible peritoneal spread, as well as other absolute contraindications for radical surgery. Its employment has lead to a decreased rate of blind laparotomies [9].

Diagnostic laparoscopy combined with intraoperative ultrasound techniques, with or without contrast, has better sensitivity in identifying liver metastases and allows for a more precise evaluation of tumor adjacent blood vessels involvement. The invasion of adjacent organs (liver, stomach, duodenum, pancreas, colon, greater omentum and abdominal wall) can also

imaging examinations must be performed in order to establish a correct diagnosis.

of inflammation of the gallbladder wall caused by lithiasis.

nodes-metastasis (TNM) staging as follows (**Table 1**).

evidenced by MRI T2 sections [8].

**5. Staging**

64 Updates in Gallbladder Diseases

The preoperative histopathological diagnosis is not considered necessary in case of clinical or imagistic suspicion of gallbladder cancer, because during biopsy, peritoneal or biopsy tract spreading may occur. In addition, the rate of false negative results of biopsies is significant [5]. As such, a negative biopsy must not be taken into consideration.

## **6. Surgical treatment of gallbladder cancer**

The treatment of gallbladder cancer is a multimodal one and implicates a multidisciplinary team. Needless to say, the treatment methods must be adapted both to the patient's status and the stage of the disease [3]. Surgical treatment remains the only curative alternative, but its results have been improved by the emergence of new oncologic treatments. Surgical treatment is done according to the stage of the disease and is divided in two categories: curative and palliative. It is necessary to identify the absolute contraindications for radical surgery. These are: liver metastases, peritoneal carcinomatosis, involvement of N2 lymph nodes (lymph nodes of the celiac trunk, peripancreatic lymph nodes, periduodenal lymph nodes and superior mesenteric lymph nodes) and the invasion to the lesser omentum or of greater blood vessels [9]. If at least one of the contraindications above is identified, surgery can be considered just for palliation. The invasion of adjacent organs (colon, duodenum and liver) does not represent an absolute contraindication to radical surgery; en bloc resection of the tumor and invaded organs could be performed [3].

#### **6.1. Radical treatment: indications and prognosis**

#### *6.1.1. T1 tumors*

Usually, incidentally diagnosed cancers on specimens resulting from cholecystectomy are T1a tumors. These lesions are limited to the lamina propria and the performed cholecystectomy is considered to be sufficient if obtained resection margins are negative. In cases with T1b tumors, due to the 50% 1-year survival rate [3], a follow-up on the initial intervention with a resection of IVb and V segments of the liver (**Figure 1**) and limphadenectomy along the portal pedicle is necessary.

#### *6.1.2. T2 tumors*

For this type of tumors, simple cholecystectomy is not sufficient. Hepatic resection and locoregional lymphadenectomy is necessary. Major hepatic resections (right hepatectomy or extended right hepatectomy) may be necessary if the invasion of the right branch of the portal vein occurs. Simple cholecystectomy performed in T2 tumors offers a 5-year survival rate of 40%, compared to an 80% 5-year survival rate for en bloc resections of the tumor [3]. Given its close anatomical relation with the gallbladder, the right branch of the portal pedicle is most susceptible to tumoral invasion. In some cases, in order to obtain negative resection margins, it is necessary to perform a bile duct resection and a biliodigestive anatomosis. Thus, an extemporaneous examination of the cystic stump is vital for certifying oncologic

**Figure 1.** Resection of segment IVb-V, "in block" with the tumoral gallbladder. Dissection of the glissonian pedicles (intraoperative aspect, from the personal archive of the authors).

radicality. It is important that bile duct resection to be performed in attentively selected cases where the benefit outweighs the complication rate of the necessary biliodigestive anastomosis [1]. Lymphadenectomy is demonstrated to improve the prognosis if N1 lymph nodes are involved, whereas in patients presenting N2 lymph nodes involvement, lymphadenectomy will not bring certain benefits [3]. Thus, N2 lymph nodes involvement represents a negative factor in patient outcome.

#### *6.1.3. T3 tumors*

The preoperative histopathological diagnosis is not considered necessary in case of clinical or imagistic suspicion of gallbladder cancer, because during biopsy, peritoneal or biopsy tract spreading may occur. In addition, the rate of false negative results of biopsies is significant [5].

The treatment of gallbladder cancer is a multimodal one and implicates a multidisciplinary team. Needless to say, the treatment methods must be adapted both to the patient's status and the stage of the disease [3]. Surgical treatment remains the only curative alternative, but its results have been improved by the emergence of new oncologic treatments. Surgical treatment is done according to the stage of the disease and is divided in two categories: curative and palliative. It is necessary to identify the absolute contraindications for radical surgery. These are: liver metastases, peritoneal carcinomatosis, involvement of N2 lymph nodes (lymph nodes of the celiac trunk, peripancreatic lymph nodes, periduodenal lymph nodes and superior mesenteric lymph nodes) and the invasion to the lesser omentum or of greater blood vessels [9]. If at least one of the contraindications above is identified, surgery can be considered just for palliation. The invasion of adjacent organs (colon, duodenum and liver) does not represent an absolute contraindication to radical surgery; en bloc resection of the tumor and invaded

Usually, incidentally diagnosed cancers on specimens resulting from cholecystectomy are T1a tumors. These lesions are limited to the lamina propria and the performed cholecystectomy is considered to be sufficient if obtained resection margins are negative. In cases with T1b tumors, due to the 50% 1-year survival rate [3], a follow-up on the initial intervention with a resection of IVb and V segments of the liver (**Figure 1**) and limphadenectomy along

For this type of tumors, simple cholecystectomy is not sufficient. Hepatic resection and locoregional lymphadenectomy is necessary. Major hepatic resections (right hepatectomy or extended right hepatectomy) may be necessary if the invasion of the right branch of the portal vein occurs. Simple cholecystectomy performed in T2 tumors offers a 5-year survival rate of 40%, compared to an 80% 5-year survival rate for en bloc resections of the tumor [3]. Given its close anatomical relation with the gallbladder, the right branch of the portal pedicle is most susceptible to tumoral invasion. In some cases, in order to obtain negative resection margins, it is necessary to perform a bile duct resection and a biliodigestive anatomosis. Thus, an extemporaneous examination of the cystic stump is vital for certifying oncologic

As such, a negative biopsy must not be taken into consideration.

**6. Surgical treatment of gallbladder cancer**

organs could be performed [3].

66 Updates in Gallbladder Diseases

the portal pedicle is necessary.

*6.1.1. T1 tumors*

*6.1.2. T2 tumors*

**6.1. Radical treatment: indications and prognosis**

As in the case of T2 tumors, for T3 tumors, simple cholecystectomy is not considered sufficient from an oncological point of view. Hepatic resection and loco-regional lymphadenectomy are necessary. If adjacent organs are involved, en bloc resection is necessary due to the difficulty in distinguishing, from a macroscopic point of view, between inflamed tissue and tumor invasion. A 5-year survival rate between 30 and 50% is obtained in case of R0 resections [3].

#### *6.1.4. T4 tumors*

T4 classified tumors are in most cases unresectable without any oncologic radicality pretention. In this stage, the palliative surgical approach combined with chemoradiotherapy is the only therapeutic alternative [3].

#### **6.2. Surgical technique**

#### *6.2.1. Open and laparoscopic cholecystectomy*

Simple cholecystectomy is the surgical intervention whereby the gallbladder and a portion of the cystic duct are removed. This can be performed either open or by laparoscopy. Regardless of the approach, three types of cholecystectomy can be distinguished: retrograde, anterograde or bipolar. In cases presenting with T1a gallbladder tumors, simple cholecystectomy is sufficient for obtaining a radical resection. Most guidelines state that in surgical oncology, the preferred approach is the open one, but due to a substantial improvement in laparoscopic techniques, the latter have gained popularity in recent years.

Cholecystectomy is usually performed with the patient placed in a supine position with the arms abducted, the main surgeon being situated on the patient's right side. The laparotomy is usually done through a right subcostal incision. For the laparoscopic approach, multiple variants of trocar placement have been described; it is the surgeon's decision to choose the preferred method. After entering the peritoneal cavity, the first surgical step is to evaluate the local situation and to perform adhesion's dissection, for a better view of the region of interest. At the same time, the peritoneal cavity is inspected for evidence of possible associated pathologies such as peritoneal carcinomatosis or paraneoplastic ascites and to evaluate the subhepatic region.

The cholecystectomy can be performed either retrograde (with the primary dissection of the gallbladder pedicle at the level of Calot triangle) or anterograde (with primary dissection of the gallbladder from its hepatic fossa). The anterograde cholecystectomy may be useful in cases where the primary dissection of Calot triangle is difficult due to adhesions or anatomic modifications.

The most important moment in performing the cholecystectomy is the dissection of Calot triangle, where the elements of the gallbladder pedicle are located. The isolation, ligation and resection of the cystic duct and artery are performed at this level. At this point in the procedure, the prelevation of a sample from the cystic duct stump is necessary for performing the histopathological assessment of the resection margin. The next step of the procedure is the dissection of the gallbladder from its hepatic fossa using the electrocautery. Following that, the gallbladder extraction is performed through the subxiphoidian incision, with or without the enlargement of the aponeurosis. Given the high risk of spreading malignant cells into the abdominal wall, the gallbladder is extracted using an endobag.

There is at least a theoretical risk of trocar port or peritoneal tumoral recurrence. The risk of peritoneal tumor spreading is increased by the leakage of bile or calculi from the gallbladder during its dissection. For this reason, the dissection of the gallbladder from its hepatic fossa needs to be performed with increased attention in order to minimize the risk of creating breaches into the gallbladder wall. Port-site excision is to be considered in case when the diagnosis is made incidentally based on the histopathological assessment of the cholecystectomy specimen. The practice of excising port-sites is not routinely imposed as it does not modify the survival rate of these patients [10].

#### *6.2.2. Radical cholecystectomy*

**6.2. Surgical technique**

68 Updates in Gallbladder Diseases

subhepatic region.

modifications.

*6.2.1. Open and laparoscopic cholecystectomy*

techniques, the latter have gained popularity in recent years.

abdominal wall, the gallbladder is extracted using an endobag.

survival rate of these patients [10].

Simple cholecystectomy is the surgical intervention whereby the gallbladder and a portion of the cystic duct are removed. This can be performed either open or by laparoscopy. Regardless of the approach, three types of cholecystectomy can be distinguished: retrograde, anterograde or bipolar. In cases presenting with T1a gallbladder tumors, simple cholecystectomy is sufficient for obtaining a radical resection. Most guidelines state that in surgical oncology, the preferred approach is the open one, but due to a substantial improvement in laparoscopic

Cholecystectomy is usually performed with the patient placed in a supine position with the arms abducted, the main surgeon being situated on the patient's right side. The laparotomy is usually done through a right subcostal incision. For the laparoscopic approach, multiple variants of trocar placement have been described; it is the surgeon's decision to choose the preferred method. After entering the peritoneal cavity, the first surgical step is to evaluate the local situation and to perform adhesion's dissection, for a better view of the region of interest. At the same time, the peritoneal cavity is inspected for evidence of possible associated pathologies such as peritoneal carcinomatosis or paraneoplastic ascites and to evaluate the

The cholecystectomy can be performed either retrograde (with the primary dissection of the gallbladder pedicle at the level of Calot triangle) or anterograde (with primary dissection of the gallbladder from its hepatic fossa). The anterograde cholecystectomy may be useful in cases where the primary dissection of Calot triangle is difficult due to adhesions or anatomic

The most important moment in performing the cholecystectomy is the dissection of Calot triangle, where the elements of the gallbladder pedicle are located. The isolation, ligation and resection of the cystic duct and artery are performed at this level. At this point in the procedure, the prelevation of a sample from the cystic duct stump is necessary for performing the histopathological assessment of the resection margin. The next step of the procedure is the dissection of the gallbladder from its hepatic fossa using the electrocautery. Following that, the gallbladder extraction is performed through the subxiphoidian incision, with or without the enlargement of the aponeurosis. Given the high risk of spreading malignant cells into the

There is at least a theoretical risk of trocar port or peritoneal tumoral recurrence. The risk of peritoneal tumor spreading is increased by the leakage of bile or calculi from the gallbladder during its dissection. For this reason, the dissection of the gallbladder from its hepatic fossa needs to be performed with increased attention in order to minimize the risk of creating breaches into the gallbladder wall. Port-site excision is to be considered in case when the diagnosis is made incidentally based on the histopathological assessment of the cholecystectomy specimen. The practice of excising port-sites is not routinely imposed as it does not modify the In cases with gallbladder tumors staged over T1a, the required surgical approach is radical cholecystectomy, combined, in selected cases, with liver resections. Radical cholecystectomy is defined as the removal of the gallbladder and the hepatic parenchyma corresponding to its fossa, with a resection margin of minimum 2 cm [11]. After exposing the subhepatic region, the liver parenchyma corresponding to gallbladder fossa is marked using the electrocautery. The blood loss from transected liver parenchyma can be minimized by using recent generation surgical instruments, as well as intra-anesthetic lowering the central venous pressure. The Calot triangle dissection is performed in the same manner as for simple cholecystectomy. The specimen obtained is sent for extemporaneous histopathological assessment of the resection margins. If the margins are negative, a portal pedicle lymphadenectomy is performed. If the resection margins are positive, the resection must be completed by either resecting more liver parenchyma or by the resection of the bile duct with performing a bilio-digestive anastomosis. If it is necessary to resect more liver parenchyma, an anatomical resection of segments IVb and V is considered to be appropriate [5].

#### *6.2.3. Resection of segments IVb and V*

After entering the abdominal cavity through a right subcostal incision, the liver and the subhepatic region are assessed. After splitting the hepatic parenchyma to the right side of the falciform ligament, the inflow vessels to segments IVa and IVb are identified and only the vessels to segment IVb are ligated and divided, preserving segment IVa. After this, the transection of the liver parenchyma is performed and the middle hepatic vein is identified and divided in the middle of the liver. As the transection continues, the pedicle of segment V is identified, ligated and divided. A lot of attention should be given not to damage the right and left hilar structures during transection. After the specimen is removed, the hemostasis control is performed and the abdominal cavity is drained. The abdominal wall is closed in anatomical layers [5, 12].

#### *6.2.4. Extended liver resections*

Extended liver resections are necessary especially if the tumor is localized at the level of body or infundibulum of the gallbladder. Most frequently, it is necessary to perform an extended right hepatectomy, due to the close anatomic relation between the gallbladder and the right portal pedicle. In numerous cases, it is difficult to distinguish between inflamed tissue and tumoral invasion at the level of the right portal pedicle and it is necessary to perform the right hepatectomy to ensure a curative surgical attempt.

The right hepatectomy is defined as the removal of segments V, VI, VII and VIII of the liver. The extended right hepatectomy imply additional resection of segment IV. After entering the peritoneal cavity through a right subcostal incision (Kocher incision), the first surgical step is to mobilize the liver by cutting the falciform, right triangular and coronary ligament. After the liver is mobilized, a visual and manual assessment of the liver is mandatory. By incising the hepato-duodenal ligament, the portal pedicle is visualized. It is crucial not to injure the left portal pedicle during dissection. By dissecting towards Calot triangle, the cystic artery and duct are isolated, ligated and divided. After the dissection at the level of the portal pedicle is made, the right branch of the hepatic artery and the right portal branch are isolated, ligated and divided to obtain a control on the blood inflow. The right hepatic duct may be ligated and sectioned by the time when liver transection is performed. Next step to be performed is the exposure of the right hepatic vein. By turning the liver to the left, a good assessment of the hepatic veins can be made, at the caval confluence. There might be some collateral veins that drain directly into the inferior vena cava and they must be carefully identified, ligated and divided. After the right hepatic vein is isolated, ligated and divided, the next step is the liver transection. This surgical step can be performed in multiple ways, with or without the use of recent generation surgical instruments. A fast way to perform liver transection is by using a Kelly clamp to crush the liver tissue and identify, ligate and divide the vasculo-biliary structures. After the transection is made, the diffuse blood loss from the liver tissue can be controlled with surgical devices such as plasma scalpel. For adjunctive hemostasis, a fibrin sealant patch may be used. After removing the right liver, an assessment of the whole surgical field is mandatory to identify any source of bleeding or bile leakage. Finally, drainage of the abdominal cavity is recommended. The abdominal wall is closed in anatomical layers [13].

#### *6.2.5. Bile duct resection*

Extrahepatic bile duct resection is necessary either if a tumoral invasion of the common bile duct is present or if at the extemporaneous histological assessment, malignant cells are revealed at the level of the cystic duct stump. Once negative margins are obtained, the continuity of the biliary tract is restored through a Roux-en-Y hepaticojejunostomy [11].

#### *6.2.6. Lymphadenectomy*

The status of the lymph nodes represents an important prognosis factor for all patients undergoing surgery for gallbladder cancer. Lymphadenectomy is mandatory in all cases of tumors staged T1b and above, even if there are no macroscopic signs of lymphatic spread. The prognosis in significantly improved in patients for which the lymphadenectomy is performed; the 5-year survival rate increases to 57%, compared to only 12% in cases where the lymphadenectomy was not performed [14]. The D1 lymphadenectomy is defined by the removal of lymph nodes situated at the level of the hepatic pedicle and the hepatico-duodenal ligament (cystic artery, hepatic artery, portal vein and common bile duct) (**Figure 2**). The extended lymphadenectomy (D2) consists of extending the lymphadenectomy to the N2 classified lymph nodes: periaortic, celiac artery, superior mesenteric artery and inferior vena cava nodes. This type of lymphadenectomy should be performed in cases where this is possible without performing large scale surgical procedures, which increase the risk of postoperative complications. The only certain benefit of performing the D2 lymphadenectomy is obtaining a more accurate staging; the patient survival rate is not significantly influenced [14, 15].

**Figure 2.** Lymphadenectomy along the portal pedicle. PHA, proper hepatic artery, RHA, right hepatic artery, LHA, left hepatic artery, CBD, common bile duct, PV, portal vein (intraoperative aspect, from the personal archive of the authors).

#### **6.3. Palliative treatment**

incising the hepato-duodenal ligament, the portal pedicle is visualized. It is crucial not to injure the left portal pedicle during dissection. By dissecting towards Calot triangle, the cystic artery and duct are isolated, ligated and divided. After the dissection at the level of the portal pedicle is made, the right branch of the hepatic artery and the right portal branch are isolated, ligated and divided to obtain a control on the blood inflow. The right hepatic duct may be ligated and sectioned by the time when liver transection is performed. Next step to be performed is the exposure of the right hepatic vein. By turning the liver to the left, a good assessment of the hepatic veins can be made, at the caval confluence. There might be some collateral veins that drain directly into the inferior vena cava and they must be carefully identified, ligated and divided. After the right hepatic vein is isolated, ligated and divided, the next step is the liver transection. This surgical step can be performed in multiple ways, with or without the use of recent generation surgical instruments. A fast way to perform liver transection is by using a Kelly clamp to crush the liver tissue and identify, ligate and divide the vasculo-biliary structures. After the transection is made, the diffuse blood loss from the liver tissue can be controlled with surgical devices such as plasma scalpel. For adjunctive hemostasis, a fibrin sealant patch may be used. After removing the right liver, an assessment of the whole surgical field is mandatory to identify any source of bleeding or bile leakage. Finally, drainage of the abdominal cavity is recommended. The abdominal wall is closed in

Extrahepatic bile duct resection is necessary either if a tumoral invasion of the common bile duct is present or if at the extemporaneous histological assessment, malignant cells are revealed at the level of the cystic duct stump. Once negative margins are obtained, the conti-

The status of the lymph nodes represents an important prognosis factor for all patients undergoing surgery for gallbladder cancer. Lymphadenectomy is mandatory in all cases of tumors staged T1b and above, even if there are no macroscopic signs of lymphatic spread. The prognosis in significantly improved in patients for which the lymphadenectomy is performed; the 5-year survival rate increases to 57%, compared to only 12% in cases where the lymphadenectomy was not performed [14]. The D1 lymphadenectomy is defined by the removal of lymph nodes situated at the level of the hepatic pedicle and the hepatico-duodenal ligament (cystic artery, hepatic artery, portal vein and common bile duct) (**Figure 2**). The extended lymphadenectomy (D2) consists of extending the lymphadenectomy to the N2 classified lymph nodes: periaortic, celiac artery, superior mesenteric artery and inferior vena cava nodes. This type of lymphadenectomy should be performed in cases where this is possible without performing large scale surgical procedures, which increase the risk of postoperative complications. The only certain benefit of performing the D2 lymphadenectomy is obtaining a more accurate staging; the patient survival rate is not significantly

nuity of the biliary tract is restored through a Roux-en-Y hepaticojejunostomy [11].

anatomical layers [13].

70 Updates in Gallbladder Diseases

*6.2.5. Bile duct resection*

*6.2.6. Lymphadenectomy*

influenced [14, 15].

When unresectable gallbladder cancer is certain, it is important to aid the patient by applying a palliative treatment that is meant to improve the quality of life. Patients in an advanced stage of the disease are often presenting with jaundice, pruritus, pain in the upper right abdominal quadrant or bowel obstruction [12]. The optimal palliative procedure is one that provides the remission of symptoms with a minimum of risk (**Table 2**) [12]. The palliation can be performed either endoscopically or surgically, the approach depending on the biological status of the patient and the prognosis of the disease. Surgical jaundice palliation presents a higher rate of complications compared to the endoscopic approach [16].

#### *6.3.1. Bilio-digestive anastomosis*

Performing a bilio-digestive anastomosis is necessary for unresectable locally advanced tumors, which cause jaundice. In most cases, a locally advanced tumor invades the confluence of the hepatic ducts, so a Roux-en-Y hepaticojejunostomy is not viable [12]. In these situations, endoscopic drainage by transtumoral stenting or ultrasound/CT-guided external transparietohepatic biliary drainage can be the only alternative.

#### *6.3.2. Digestive bypass*

Digestive bypasses represent a method of palliation used for patients presenting with bowel obstruction caused by tumoral invasion of the duodenum or colon. If the duodenum is


**Table 2.** Palliative options for unresectable gallbladder cancer.

involved, an Omega or Roux-en-Y gastroenteroanastomosis should be performed. If the colon is involved (a rare occurrence), an internal bypass is the most frequently used method.

## **7. Oncological treatment**

Oncological treatment supports the surgical act and is meant to improve the outcome of gallbladder cancer patients. The prognosis of this pathology is extremely poor, with a high rate of recurrence, even in patients undergoing radical surgical treatment. Thus, efficient oncological treatment is necessary in order to improve the rate of survival. There are few randomized trials conducted on patients with resectable tumors, so the efficacy of adjuvant oncological therapy cannot be well assessed. At the same time, oncological treatments can be used for palliative purposes in patients presenting unresectable tumors. The following paragraphs summarize the different types of oncological treatment.

#### **7.1. Adjuvant treatment**

Due to a high rate of recurrence, adjuvant treatment comes in the form of radiotherapy, possibly combined with chemotherapy [17]. A meta-analysis of 20 studies (6712 patients) evaluating the impact of chemotherapy, radiotherapy and their combination performed for adjuvant purposes, indicates an insignificant benefit in unselected cases. However, in cases of subgroups of patients defined as presenting an increased risk of recurrence (positive resection margins or an advanced degree of lymph node involvent), adjuvant therapy provides a positive influence on prognosis [17].

A consensus regarding the optimal adjuvant therapy has not been reached; there are multiple methods of applying this type of treatment. Due to the high risk of distant metastasis occurrence, a possible avenue of treatment can be starting with 6 months of chemotherapy, which can lead to avoiding unnecessary radiotherapy for patients that develop distant metastases (cases that would not benefit from radiotherapy anyway) [18]. In the case of patients who have positive resection margins, combined treatment (chemotherapy and radiotherapy) is recommended. An option is to perform intraoperative radiotherapy. This is meant to improve the prognosis but there is little evidence indicating a real benefit of this treatment [19]. One advantage of intraoperative radiotherapy is the possibility of targeted administration of a high dosage of radiation directly on the tumor, while protecting the adjacent, highly radiosensitive, tissues [18].

#### **7.2. Palliative oncological treatment**

In cases of unresectable tumors (see Section 6) palliative chemoradiotherapy can be performed. In the past, the used chemotherapic treatment was 5-FU, Methotrexate, Mitomicin C and Doxorubicin, with a response rate of 10–20% [5]. More recently, the use of gemcitabine and oxaliplatin has improved the response rate up to 50%. On the other hand, radiotherapy has a palliative effect for locally advanced tumors (stages T3 and above) and is usually well tolerated and insures the remission of symptoms [5]. Radiotherapy is most commonly used in combination with chemotherapy.

#### **8. Outcomes**

involved, an Omega or Roux-en-Y gastroenteroanastomosis should be performed. If the colon is involved (a rare occurrence), an internal bypass is the most frequently used method.

Digestive bypass (invasion of the colon)

• Percutaneous • Ecoendoscopic • Laparoscopic

Bowel obstruction Gastroenteroanastomosis (invasion of the duodenum)

Oncological treatment supports the surgical act and is meant to improve the outcome of gallbladder cancer patients. The prognosis of this pathology is extremely poor, with a high rate of recurrence, even in patients undergoing radical surgical treatment. Thus, efficient oncological treatment is necessary in order to improve the rate of survival. There are few randomized trials conducted on patients with resectable tumors, so the efficacy of adjuvant oncological therapy cannot be well assessed. At the same time, oncological treatments can be used for palliative purposes in patients presenting unresectable tumors. The following paragraphs sum-

Due to a high rate of recurrence, adjuvant treatment comes in the form of radiotherapy, possibly combined with chemotherapy [17]. A meta-analysis of 20 studies (6712 patients) evaluating the impact of chemotherapy, radiotherapy and their combination performed for adjuvant purposes, indicates an insignificant benefit in unselected cases. However, in cases of subgroups of patients defined as presenting an increased risk of recurrence (positive resection margins or an advanced degree of lymph node involvent), adjuvant therapy provides a posi-

A consensus regarding the optimal adjuvant therapy has not been reached; there are multiple methods of applying this type of treatment. Due to the high risk of distant metastasis occurrence, a possible avenue of treatment can be starting with 6 months of chemotherapy, which can lead to avoiding unnecessary radiotherapy for patients that develop distant metastases (cases that would not benefit from radiotherapy anyway) [18]. In the case of patients who have positive

**7. Oncological treatment**

**7.1. Adjuvant treatment**

tive influence on prognosis [17].

marize the different types of oncological treatment.

**Symptom Palliative method**

72 Updates in Gallbladder Diseases

**Table 2.** Palliative options for unresectable gallbladder cancer.

Jaundice Endoscopic placement of a stent Pruritus Surgical bilio-digestive anastomosis

Pain Celiac trunk alcoolization

#### **8.1. Perioperative morbidity and mortality for radical interventions**

The perioperative risk depends on the stage of the disease and the biological status of the patient. It is important to balance the risk of surgery to the risk of the untreated disease. Surgery should be performed with curable intent just when the patient is capable to support it. If the biological status of the patient does not support a radical approach it should be ameliorated preoperatively.

Gallbladder cancer surgery is accompanied by a lot of possible complications, some of them very difficult to manage. Most feared complications are: postoperative bleeding, bile leak and perihepatic abscess.

The perioperative mortality rate is significantly higher in patients with extended hepatic resections compared with those who underwent limited resections (resection of segments IVb and V), radical cholecystectomy or simple cholecystectomy [20]. An improvement in the outcome of patients underwent extended liver resection has been obtained by the progresses made in the field of surgical techniques, anesthetic and intensive care management.

Long-term outcome is extremely poor due to the high aggressive nature of this type of cancer. Only patients staged T1 have better long-term outcome, but unfortunately only approximately 10% of symptomatic patients reveals to be T1 and up to 20% from the incidentally diagnosed patients have T1 tumors.

#### **8.2. Survival rate after radical treatment**

The survival rate of patients undergoing surgery for gallbladder cancer depends of the disease's stage.

For T1a tumors, limited to the lamina propria, radical resection is obtained by simple cholecystectomy in many cases. The 5-year overall survival rate of these patients is reported to range between 97 and 99% [21].

For T1b and T2 patients, the oncologic radicality is easy to obtain by performing a liver resection including segments IVb and V, combined with lymphadenectomy at the level of the lesser omentum. The 5-year survival rate in these cases, if the appropriate surgical approach is performed, ranges between 59 and 90% [21].

For T3 and T4 tumors, it becomes challenging to balance the surgical risk of an extensive resection with the possible benefit. It is known that if a more extensive liver resection is performed, a higher rate of complications may occur. However, by recent improving of the surgical techniques, the rate of complications after major liver surgery has been improved and more extensive resections can be made with a diminished morbidity and mortality rate. The 5-year survival rate is reported to be 25% after major resections.

#### **8.3. Survival rate for palliative treatment**

Patients presenting unresectable gallbladder tumors benefit from palliative treatment to increase their quality of life. The overall survival rate is not significantly improved by palliative treatment, but there may be some benefits of chemoradiotherapy (as we discussed in Section 7.2).

#### **8.4. Survival rate without treatment**

Advanced gallbladder cancer has a very poor survival rate without any treatment even if the patient has a good performance status. The overall survival is 4.4 months for unresectable and untreated gallbladder cancers [20]. The presence of metastases at the moment of the diagnosis appeared to decrease the survival rate.

## **9. Future perspective**

#### **9.1. Intraoperative ultrasonography**

Because preoperative imagistic staging of gallbladder cancer is difficult, the intraoperative ultrasound techniques are more and more used to obtain an accurate staging before choosing an appropriate surgical approach. The staging laparoscopy can be combined with the ultrasonographic assessment of the tumor to improve the accuracy of the diagnosis. As it is shown by a recent meta-analysis, the sensitivity of staging laparoscopy is improved when it is associated with intraoperative ultrasonography from 55.9 to 65.7% [22]. Laparoscopic ultrasonography is used for identification of liver lesions and for showing the precise location of the tumor and its relations with surrounding blood vessels. However, the intraoperative ultrasound assessment of hepatic hilum is very difficult and requires an experienced surgeon with high knowledge of liver imaging. The sensitivity of intraoperative ultrasound has been improved by the use of micro-bubble agents [23].

#### **9.2. Navigation surgery**

For T1a tumors, limited to the lamina propria, radical resection is obtained by simple cholecystectomy in many cases. The 5-year overall survival rate of these patients is reported to

For T1b and T2 patients, the oncologic radicality is easy to obtain by performing a liver resection including segments IVb and V, combined with lymphadenectomy at the level of the lesser omentum. The 5-year survival rate in these cases, if the appropriate surgical approach

For T3 and T4 tumors, it becomes challenging to balance the surgical risk of an extensive resection with the possible benefit. It is known that if a more extensive liver resection is performed, a higher rate of complications may occur. However, by recent improving of the surgical techniques, the rate of complications after major liver surgery has been improved and more extensive resections can be made with a diminished morbidity and mortality rate. The

Patients presenting unresectable gallbladder tumors benefit from palliative treatment to increase their quality of life. The overall survival rate is not significantly improved by palliative treatment, but there may be some benefits of chemoradiotherapy (as we discussed in Section 7.2).

Advanced gallbladder cancer has a very poor survival rate without any treatment even if the patient has a good performance status. The overall survival is 4.4 months for unresectable and untreated gallbladder cancers [20]. The presence of metastases at the moment of the diagnosis

Because preoperative imagistic staging of gallbladder cancer is difficult, the intraoperative ultrasound techniques are more and more used to obtain an accurate staging before choosing an appropriate surgical approach. The staging laparoscopy can be combined with the ultrasonographic assessment of the tumor to improve the accuracy of the diagnosis. As it is shown by a recent meta-analysis, the sensitivity of staging laparoscopy is improved when it is associated with intraoperative ultrasonography from 55.9 to 65.7% [22]. Laparoscopic ultrasonography is used for identification of liver lesions and for showing the precise location of the tumor and its relations with surrounding blood vessels. However, the intraoperative ultrasound assessment of hepatic hilum is very difficult and requires an experienced surgeon with high knowledge of liver imaging. The sensitivity of intraoperative ultrasound has been

range between 97 and 99% [21].

74 Updates in Gallbladder Diseases

is performed, ranges between 59 and 90% [21].

**8.3. Survival rate for palliative treatment**

**8.4. Survival rate without treatment**

appeared to decrease the survival rate.

**9.1. Intraoperative ultrasonography**

improved by the use of micro-bubble agents [23].

**9. Future perspective**

5-year survival rate is reported to be 25% after major resections.

This new concept is being used in other surgical specialties, but in visceral surgery its usage is just at the beginning. Intraoperative navigation is a new technique that, with the use preoperative tomographic images, provides a virtual imaging of the anatomical region of interest so both the patient safety and the accuracy of the surgical procedure are improved [24].

#### **9.3. Intraoperative fluorescence**

Indocyanine is a fluorescent agent that has been used to evaluate the liver function. More recently, indocyanine is used for assessing the involvement of lymph nodes during breast and digestive surgery. In surgery of the liver, indocyanine has also been used for detecting the exact location of the tumors, the liver segmentation and biliary leakage. The role of this method is not completely understood. A disadvantage of the method is represented by the fact that only superficial tumors can be detected, due to limited depth of detected tissue [23]. There are few studies that assess the role of intraoperative fluorescence with indocyanine and further studies should be conducted to have a better view on this innovative technique.

## **10. Key points**


#### **Acknowledgements**

Adrian Bartoș is the coordinator of this chapter.

## **Author details**

Adrian Bartoș<sup>1</sup> \*, Andrei Herdean1 and Dana Monica Bartoș1,2

\*Address all correspondence to: bartos.adi@gmail.com


## **References**


[10] Fuks D, Regimbeau J, Pessaux P, Bachellier P, Raventos A, Mantion G et al. Is portsite resection necessary in the surgical management of gallbladder cancer? Journal of Visceral Surgery. 2013;150(4):277–284.

**Author details**

76 Updates in Gallbladder Diseases

\*, Andrei Herdean1

\*Address all correspondence to: bartos.adi@gmail.com

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of North America. 2010;39(2):331–342.

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5th ed. Philadelphia: Elsevier Saunders; 2012; 204–231.

and Dana Monica Bartoș1,2

2 Anatomy Department, "Iuliu Hatieganu" University of Medicine, Cluj-Napoca, Romania

[1] Gani F, Buettner S, Margonis G, Ethun C, Poultsides G, Tran T et al. Assessing the impact of common bile duct resection in the surgical management of gallbladder cancer. Journal

[2] Aloia T, Járufe N, Javle M, Maithel S, Roa J, Adsay V et al. Gallbladder cancer: expert

[3] Jayaraman S, Jarnagin W. Management of gallbladder cancer. Gastroenterology Clinics

[4] Desser TS, Hann LE. Ultrasound of the liver, biliary tract, and pancreas. In: Jarnagin W, Belghiti J, Blumgart L (Eds). Blumgart's surgery of the liver, biliary tract, and pancreas.

[5] Kingham TP, D'Angelica MI. Cancer of the gallbladder. In: Jarnagin W, Belghiti J, Blumgart L (Eds). Blumgart's surgery of the liver, biliary tract, and pancreas. 5th ed.

[6] Weber S, Yamane B, Fong Y. Biliary neoplasms. In: Greenfield L, Mulholland M (Eds). Greenfield's surgery. 1st ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams

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[9] Gallbladder cancer: epidemiology, risk factors, clinical features, and diagnosis [Internet]. Uptodate.com. 2016. [cited 28 December 2016]. Available from: http://www.uptodate. com/contents/gallbladder-cancer-epidemiology-risk-factors-clinical-features-and-

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1 Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania

Adrian Bartoș<sup>1</sup>

**References**


## **Chapter 6**

**Provisional chapter**

## **Incidental Gallbladder Cancer**

Faisal Al-alem, Rafif E. Mattar,

**Incidental Gallbladder Cancer**

Faisal Al-alem, Rafif E. Mattar, Ahmad Madkhali, Abdulsalam Alsharabi, Faisal Alsaif and Mazen Hassanain Ahmad Madkhali, Abdulsalam Alsharabi, Faisal Alsaif and Mazen Hassanain Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67654

#### **Abstract**

[22] Tian Y, Liu L, Yeolkar N, Shen F, Li J, He Z. Diagnostic role of staging laparoscopy in a subset of biliary cancers: a meta-analysis. ANZ Journal of Surgery. 2016; 87:22–27. [23] Abo T, Nanashima A, Tobinaga S, Hidaka S, Taura N, Takagi K et al. Usefulness of intraoperative diagnosis of hepatic tumors located at the liver surface and hepatic segmental visualization using indocyanine green-photodynamic eye imaging. European Journal of

[24] Okamoto T, Onda S, Matsumoto M, Gocho T, Futagawa Y, Fujioka S et al. Utility of augmented reality system in hepatobiliary surgery. Journal of Hepato-Biliary-Pancreatic

Surgical Oncology (EJSO). 2015;41(2):257–264.

Sciences. 2012;20(2):249–253.

78 Updates in Gallbladder Diseases

Gallbladder cancer (GBC) is a rare but fatal disease with an incidence of less than 5000 new cases per year in the United States. Less than 20% of GBC cases are diagnosed preoperatively. The remaining cases are diagnosed either after laparoscopic cholecystectomy or intraoperatively. GBC is discovered incidentally during histopathology following 0.25–3.0% of laparoscopic cholecystectomies; however, this constitutes 74–92% of all GBC. The most pivotal and important step is accurate patient staging. Staging dictates disease management and treatment options and predicts survival. Because of the fatality of GBC and its poor prognosis, attempts of curative surgery are limited to localized resectable disease.

**Keywords:** gallbladder, cancer, incidental, adenocarcinoma

#### **1. Introduction**

Laparoscopic cholecystectomy is the most common elective operation performed worldwide. It is the standard of care for all symptomatic gallstone diseases. Gallbladder cancer (GBC) is a rare but fatal disease with an incidence of less than 5000 new cases per year in the United States. The anatomy of the gallbladder, specifically the absence of a serosal layer between it and the liver, permits the relative early invasion of GBC into the liver [1]. GBC also tends to spread both to lymph nodes and hematogenously to the peritoneal surfaces [2]. Moreover, because of its nonspecific presentation and constellation of symptoms and signs, many of which it shares with benign diseases such as biliary colic or chronic cholecystitis, GBC tends to go undiagnosed until relatively later stages [2]. Less than 20% of GBC cases are diagnosed preoperatively. The remaining cases are diagnosed either after laparoscopic cholecystectomy

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

or intraoperatively. These cases are categorized as "incidental GBC," and their management is more complex and challenging.

## **2. Incidence and prevalence**

GBC is discovered incidentally during histopathology following 0.25–3.0% of laparoscopic cholecystectomies [3–6]; however, this constitutes 74–92% of all GBC diagnoses [7, 8]. Although rare, GBC is the most common malignant disease of the biliary tract [9]. Its incidence varies greatly by geographical location, ethnicity, and socioeconomic status. This variation is likely due to differences in both environmental and genetic factors.


GBC in such patients is of the papillary subtype [11], which is less invasive, with low metastatic potential; however, a prophylactic cholecystectomy should be considered in such patients.

The survival of these patients is largely affected by disease stage and surgical management. The 7th American Joint Committee on Cancer (AJCC) [25] reported that the five-year survival rate for patients with stage 0 (Tis) GBC is estimated to be 85%, and that it drops to 50% for patients with stage I (T1) GBC. The five-year survival rate for patients with stage II GBC is 25%, improving to 35% after extended cholecystectomy, and for patients with stage III GBC, it is 10%. In contrast, the survival rate of patients with stage IV GBC is extremely low, estimated to be less than 4%.

## **3. Time of identification and resection**

or intraoperatively. These cases are categorized as "incidental GBC," and their management

GBC is discovered incidentally during histopathology following 0.25–3.0% of laparoscopic cholecystectomies [3–6]; however, this constitutes 74–92% of all GBC diagnoses [7, 8]. Although rare, GBC is the most common malignant disease of the biliary tract [9]. Its incidence varies greatly by geographical location, ethnicity, and socioeconomic status. This varia-

• *Ethnicity*: Unlike the vast majority of malignancies, GBC commonly occurs in South America, in countries such as Chile, Bolivia, and Ecuador, and in Asia, in parts of India, Pakistan, Japan, and Korea [10, 11]. Mapuche Indians in Chile exhibit the highest rate of GBC worldwide, with rates of 12.3/100,000 and 27.3/100,000 for males and females, respectively [12]. Asia is also a high-risk continent for GBC, with the highest incidence found in Indian women followed by Pakistani women [11]. GBC also occurs frequently in eastern and central Europe; however, its

incidence is low in western and Mediterranean Europe, and in the United States [1].

• *Age and sex*: The incidence of GBC increases with age, especially in people older than 65 years

• *Gallstone disease*: Gallstones represent the most important risk factor for GBC development [14]. However, the likelihood that an individual with gallbladder stones will develop cancer is as low as 0.5% [15]. The properties of the gallstones themselves play a role in the development of GBC, as different types of stones induce different patterns of mucosal irritation and chronic inflammation [16]. Stones larger than 3 cm confer 10 times higher risk of developing cancer than do smaller stones [17]. The higher prevalence of cholesterol stones in populations with high prevalence of GBC, such as American Indians, suggests that stone

• *Obesity*: Higher body mass index is associated with higher risk of development of gallstones [18]. However, data linking obesity to GBC are conflicting. A recent meta-analysis of 14 prospective cohort and 15 case control studies revealed that excess body weight is

• *Infection*: Infections with certain bacteria such as *Salmonella* and *Helicobacter* spp. have been linked to biliary malignancies [20, 21]. Chronic bacterial cholangitis also confers a strong

• *Other risk factors*: Chronic inflammatory conditions, such as primary sclerosing cholangitis, have been linked to malignant transformation. Environmental exposure to factors such as radon in mine workers [22] and tobacco [23] has also been implicated as a risk factor for GBC. Anatomical risk factors include an anomalous pancreaticobiliary duct junction, which is found in approximately 10% of patients with GBC [24]. Histologically,

tion is likely due to differences in both environmental and genetic factors.

[13]. In addition, GBC incidence in women is six times that in men [3].

content may also be a contributing factor to cancer development [18].

indeed a risk factor for GBC development [19].

risk for biliary cancer.

is more complex and challenging.

80 Updates in Gallbladder Diseases

**2. Incidence and prevalence**

GBC can be detected during a cholecystectomy procedure if a suspicious mass is found, or after surgery. Most these cases are diagnosed following a laparoscopic cholecystectomy for associated symptomatic gallbladder stones. This alone is a risk factor for reexploration to detect the presence of potential residual disease, which greatly alters the course of disease management. For gallbladder masses found during cholecystectomy, a specialized hepatobiliary surgeon must be consulted for proper management. If no specialized surgeon is available, cholecystectomy should be aborted, and the patient should be referred to a specialized center [26]. That being said, most cases of GBC are found postoperatively on pathological examinations. These cases require further staging workup and possible reresection depending on the disease stage. The timing of resection was not studied until recently. A multicenter retrospective cohort study that included 207 patients specifically examined the timing of reresection surgery and its effect on the patients' overall survival outcomes [27]. Patients who underwent reexploration and resection were divided into three groups on the basis of the time interval from the initial cholecystectomy to reoperation: group A (less than 4 weeks), group B (4–8 weeks), and group C (more than 8 weeks). Their findings revealed that patients who were reoperated within 4–8 weeks (group B) had the longest median overall survival (40 months) compared to that in groups A and C (17.2 and 22.4, respectively), despite having similar characteristics and tumor staging as these groups.

## **4. Staging of incidental GBC**

The principles of oncological surgery remain constant in incidental GBC. The most pivotal and important step is accurate patient staging. Thus, a staging workup needs to be performed for each patient. GBC stage directly affects disease management and prognosis. TNM staging, which is recommended by AJCC guidelines [25], is the most commonly used staging system (**Table 1**). Staging dictates disease management and treatment options, and predicts survival.


**Table 1.** TNM staging for gall bladder cancer.

• **Imaging**: Transabdominal ultrasound (US) is commonly the first imaging modality used for evaluating most gallbladder diseases; however, its resolution is insufficient for GBC staging. Endoscopic US (EUS) is a method that provides high-resolution images, and consequently, accurate staging [28]. Unfortunately, EUS is an invasive procedure that carries the risk of bleeding and bowel perforation, in addition to being uncomfortable for the patient. Highresolution US (HRUS) combines the convenience of transabdominal US with the high resolution and accuracy of EUS for GBC staging [29].

The initial imaging modality for evaluating surgical resectability and providing appropriate disease staging is generally a high-resolution contrast-enhanced sectional image with a computerized tomography (CT) scan of the chest, abdomen, and pelvis. It detects the extent of the tumor, distant metastasis, and gross lymph node involvement [30]. Although HRUS provides higher accuracy than CT does when predicting the depth of local tumor invasion [31], HRUS cannot replace the standard role of CT mainly because GBC resectability is determined not just by the tumor itself, but also by its extension into adjacent organs, vascular invasion, degree of bile duct obstruction, and the existence of metastasis [32]. CT has the added advantage of enabling evaluation of these entities, which makes it the most accurate modality for determining GBC resectability [33].

Local extension of disease can be evaluated further by magnetic resonance imaging (MRI), which provides detailed evaluation of the liver parenchyma and common hepatic duct/ common bile duct, especially in patients with concomitant liver steatosis or cirrhosis. Lymph node status can also be difficult to establish preoperatively; however, abdominal CT and MRI increase the detection rate by up to 24% [34]. In terms of detecting metastatic lymph nodes in general, diffuse weighted MRI is more beneficial than multislice CT [35]. MR cholangiopancreatography using heavily T2-weighted sequences also enables the differentiation of the dilated bile duct from the adjacent tissues by producing bright signals from the fluid within the ducts [36].

In addition to these methods, 18-fluorodeoxyglucose positron emission (FDG-PET) is a technique that utilizes the hypermetabolic condition of malignant masses. It is combined with CT to produce a whole body metabolic map of glucose uptake. A previous study reported that (FDG-PET)-CT has a sensitivity of 56% for detecting omental, peritoneal, or lymphatic spread of GBC [2]. A general drawback of FDG-PET is the possibility of a falsepositive result due to detection of inflammatory areas instead of a tumor, because they both have high glucose uptakes.

• **Diagnostic laparoscopy**: The use of diagnostic laparoscopy is mainly justified by the large percentage of cases that are found to have residual nonresectable disease, in the form of peritoneal disease, occult metastasis (not evident on imaging), or local invasion to the vascular structures, which render tumors unresectable. Although the relationship between the T stage of GBC and the benefit of diagnostic laparoscopy is not yet established in cholangiocarcinomas [37], most researchers suggest the use of diagnostic laparoscopy in patients with T2/3 lesions scheduled for reresection [38, 39], in order to save them the burden of a full laparotomy. A recent meta-analysis found the accuracy of diagnostic laparoscopy to be 63.9% [40]. The sensitivity of diagnostic laparoscopy in GBC was 0.642 (95% CI: 0.579–0.7). The use of intraoperative ultrasound increased the overall performance and contributed to a minor increase in the overall sensitivity. Diagnostic laparoscopy prevented unnecessary laparotomy in 27.6% of these cases, with a mortality rate of 0.09% and morbidity of 0.37%. These data indicate that staging laparoscopy prior to laparotomy, which can be performed within the same setting, is the recommended procedure for all GBC cases [41].

• **Imaging**: Transabdominal ultrasound (US) is commonly the first imaging modality used for evaluating most gallbladder diseases; however, its resolution is insufficient for GBC staging. Endoscopic US (EUS) is a method that provides high-resolution images, and consequently, accurate staging [28]. Unfortunately, EUS is an invasive procedure that carries the risk of

Any T Any N M1

**Primary tumor (T)**

82 Updates in Gallbladder Diseases

**Regional lymph nodes (N)**

**Distant metastasis (M)**

*Source:* From Ref. [68].

**Table 1.** TNM staging for gall bladder cancer.

TX Primary tumor cannot be assessed T0 No evidence of primary tumor

T1a Tumor invades lamina propria T1b Tumor invades muscular layer

T1 Tumor invades lamina propria or muscular layer

organs or structures

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis

portal vein

lymph nodes

**Stage T N M** 0 Tis N0 M0 I T1 N0 M0 II T2 N0 M0 IIIA T3 N0 M0 IIIB T1-3 N1 M0 IVA T4 N0-1 M0 IVB Any T N2 M0

M0 No distant metastasis M1 Distant metastasis

T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver

pancreas, omentum, or extrahepatic bile ducts

T4 Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic

N1 Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or

N2 Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery

and/or one other adjacent organ or structure, such as the stomach, duodenum, colon,

Tis Carcinoma in situ

## **5. Contraindications for curative surgery**

Because of the fatality of GBC and its poor prognosis, attempts of curative surgery are limited to localized resectable disease. Absolute contraindications to surgery include the presence of distant metastasis, liver metastasis, peritoneal disease, malignant ascites, and evidence of extensive nodal disease (para-aortic lymph nodes). Major vessel involvement, which is an indicator of stage IV disease, is another contraindication for curative surgery [42].

In contrast, T3 disease with direct involvement of the duodenum, colon, or liver does not preclude resectability if R0 en-bloc resection can be achieved safely [41]. It is not considered a contraindication even though it is an indicator of aggressive disease and carries the increased possibility of lymph node involvement, which results in poor survival outcomes.

Palliative options, if appropriate, might be the only justification for intervention in unresectable cases. For example, a cholecystectomy can be performed for an acutely inflamed gallbladder, or left cholodochojejunostomy for drainage in case of failure of endoscopic stenting.

## **6. Surgical management**

Surgery is the mainstay of GBC treatment and the only curative option [43]. Surgical options are dependent on the pathological staging and may involve one or more of the adjacent organs (**Figure 1**).

#### **For stage 0-I (T1, N0, and M0):**

	- Simple cholecystectomy might be the only treatment needed in early GBC (i.e., Tis, T1a), as the risk of lymph node dissemination is low. However, great care should be exercised during the handling and mobilization of the gallbladder in order to prevent bile spillage. This is important because the bile in the gallbladder of a patient with GBC is highly contaminated with malignant cells, which increases the risk of dissemination of the cancer cells to the local areas and peritoneal cavity [44]. This concern makes open cholecystectomy the standard of care if the surgeon cannot guarantee an adequate resection with no spillage during laparoscopy [41].
	- The cystic duct resection margin is the main deterrent for further surgical intervention in T1a GBC. Tumor cell involvement of the cystic duct margin justifies reoperation and resection of the extrahepatic bile duct [43, 45]. Hepatic duct involvement suggests poor biology and is frequently associated with lymph node involvement [46]. If the margin is negative for cancer cells, cholecystectomy is sufficient and no further procedure is needed because further resection does not provide any survival benefits to these patients [47, 48].

**Figure 1.** Schematic representation of the hilar structures including the lymph nodes groups targeted during extended cholecystectomy.

• Extended cholecystectomy and lymphadenectomy

**5. Contraindications for curative surgery**

84 Updates in Gallbladder Diseases

stenting.

**6. Surgical management**

**For stage 0-I (T1, N0, and M0):**

spillage during laparoscopy [41].

to these patients [47, 48].

• Simple cholecystectomy

organs (**Figure 1**).

Because of the fatality of GBC and its poor prognosis, attempts of curative surgery are limited to localized resectable disease. Absolute contraindications to surgery include the presence of distant metastasis, liver metastasis, peritoneal disease, malignant ascites, and evidence of extensive nodal disease (para-aortic lymph nodes). Major vessel involvement, which is an

In contrast, T3 disease with direct involvement of the duodenum, colon, or liver does not preclude resectability if R0 en-bloc resection can be achieved safely [41]. It is not considered a contraindication even though it is an indicator of aggressive disease and carries the increased

Palliative options, if appropriate, might be the only justification for intervention in unresectable cases. For example, a cholecystectomy can be performed for an acutely inflamed gallbladder, or left cholodochojejunostomy for drainage in case of failure of endoscopic

Surgery is the mainstay of GBC treatment and the only curative option [43]. Surgical options are dependent on the pathological staging and may involve one or more of the adjacent

– Simple cholecystectomy might be the only treatment needed in early GBC (i.e., Tis, T1a), as the risk of lymph node dissemination is low. However, great care should be exercised during the handling and mobilization of the gallbladder in order to prevent bile spillage. This is important because the bile in the gallbladder of a patient with GBC is highly contaminated with malignant cells, which increases the risk of dissemination of the cancer cells to the local areas and peritoneal cavity [44]. This concern makes open cholecystectomy the standard of care if the surgeon cannot guarantee an adequate resection with no

– The cystic duct resection margin is the main deterrent for further surgical intervention in T1a GBC. Tumor cell involvement of the cystic duct margin justifies reoperation and resection of the extrahepatic bile duct [43, 45]. Hepatic duct involvement suggests poor biology and is frequently associated with lymph node involvement [46]. If the margin is negative for cancer cells, cholecystectomy is sufficient and no further procedure is needed because further resection does not provide any survival benefits

indicator of stage IV disease, is another contraindication for curative surgery [42].

possibility of lymph node involvement, which results in poor survival outcomes.

– The treatment strategy for incidental T1b GBC was controversial until recently. Extended cholecystectomy and lymphadenectomy improve cancer-specific survival and are recommended over cholecystectomy alone [41, 49] mainly because of the high risk of lymph node metastasis (11.5%) in GBC T1b. The recurrence rate after simple cholecystectomy is higher than that after extended cholecystectomy (12.5 vs. 2%, respectively) [41, 50]. However, this survival benefit has been debated in the literature, and simple cholecystectomy is considered sufficient for GBC T1b, especially in eastern countries [51]. Bile duct resection is indicated in cases with a positive cystic duct margin, since recurrence occurs in 50% of these cases. However, there is no evidence to support routine bile duct resection in cases with a negative cystic duct margin.

#### **For stage II (T2, N0, and M0), stage III (T3, N0-1, and M0):**

	- If no contraindication for curative surgery exists, extended cholecystectomy and lymphadenectomy are indicated in all cases where the GBC lesions invade the subserosal or deeper layers (T1b, T2, and T3). This recommendation is based on the high rate of vascular and perineural invasion and lymph node metastasis in these stages. An appropriate treatment would be extended cholecystectomy as follows:
		- (a) Bile duct resection

Although there is no evidence to support routine resection, it is indicated when invasion of the cystic duct margin is evident grossly or on a frozen section. Another indication is hepatoduodenal ligament invasion (GB neck tumor) as part of en bloc oncologic resection [43, 45, 51]. In these cases, complete removal of the bile duct is necessary, with further reconstruction using a Roux-en-Y hepaticojejunostomy technique.


mesenteric artery, and then into the para aortic area [60]. Skip lesions have also been reported, where the tumor invades celiac lymph nodes directly without hepatoduodenal lymph node involvement [61]. Regional lymph nodes of the gallbladder are defined as the nodes in the hepatoduodenal ligament, the nodes along the common hepatic artery, and the nodes cranial to the duodenal papilla on the posterior surface of the head of the pancreas [62]. Therefore, lymphadenectomy of GBC should include at least regional lymph nodes of the gallbladder [26, 41]. According to AJCC guidelines, a minimum of three lymph nodes are required for accurate nodal status evaluation, although recent studies have shown that a minimum of six lymph nodes are needed for accurate nodal evaluation [63, 64]. It is debatable whether extended lymphadenectomy (including celiac/superior mesenteric artery lymph node) as a part of routine lymph node dissection in GBC confers a survival benefit. However, studies suggest that extended lymphadenectomy ensures the removal of an adequate number of lymph nodes (more than six) and the removal of skipped lymph nodes for proper nodal staging. Therefore, extended lymphadenectomy is routinely practiced in high-volume centers [54, 61].

• Port site resections:

lymph node metastasis (11.5%) in GBC T1b. The recurrence rate after simple cholecystectomy is higher than that after extended cholecystectomy (12.5 vs. 2%, respectively) [41, 50]. However, this survival benefit has been debated in the literature, and simple cholecystectomy is considered sufficient for GBC T1b, especially in eastern countries [51]. Bile duct resection is indicated in cases with a positive cystic duct margin, since recurrence occurs in 50% of these cases. However, there is no evidence to support routine bile duct

– If no contraindication for curative surgery exists, extended cholecystectomy and lymphadenectomy are indicated in all cases where the GBC lesions invade the subserosal or deeper layers (T1b, T2, and T3). This recommendation is based on the high rate of vascular and perineural invasion and lymph node metastasis in these stages. An appropriate

Although there is no evidence to support routine resection, it is indicated when invasion of the cystic duct margin is evident grossly or on a frozen section. Another indication is hepatoduodenal ligament invasion (GB neck tumor) as part of en bloc oncologic resection [43, 45, 51]. In these cases, complete removal of the bile duct is necessary, with further reconstruction using a Roux-en-Y hepaticoje-

(b) Extended cholecystectomy includes resection of the gallbladder bed and hepatectomy to achieve an R0 oncologic resection; a 2–3-cm margin is commonly used. Liver resection for GBC treatment ranges from partial hepatectomies (nonanatomical or anatomical resection of segments 4a and 5) to major extended hepatectomies. Anatomical resection of segments 4a and 5 is considered a good oncologic option for GBC because the cystic vein was found to drain into segment 4a (37–90%) and segment 5 (52–90%) [52, 53]. A more aggressive approach consisting of routine right extended hepatectomy that includes the caudate lobe has been proposed. However, major resection does not improve survival over nonanatomical liver resection and only increases the risk of postoperative complications [54, 55]. Furthermore, major hepatectomies are associated with higher morbidity rates than partial hepatectomies are, with no added survival benefit [56–58]. Therefore, achieving R0 with limited liver resection and fewer complications is the recommended procedure for GBC [26, 41].

(c) Major hepatectomies are indicated in select cases, which are encountered less frequently in incidental GBC treatment. These are cases in which an R0 resection cannot be achieved with partial hepatectomy or if the tumor is invading the main

Lymphatic drainage of GB follows a route starting from around the cystic duct via the portal vein/hepatic artery, into the retropancreatic and celiac/superior

resection in cases with a negative cystic duct margin.

treatment would be extended cholecystectomy as follows:

**For stage II (T2, N0, and M0), stage III (T3, N0-1, and M0):**

• Extended cholecystectomy and lymphadenectomy

(a) Bile duct resection

86 Updates in Gallbladder Diseases

junostomy technique.

blood supply of the liver lobe [59].

(d) Lymphadenectomy (**Figure 1**):

– Port site resection has been proposed for lowering the chances of cancer recurrence at the site of a previous cholecystectomy. However, the use of this procedure is not supported by the evidence found in the scientific literature [41]. Port site resection does not seem to improve survival and carries a 15% risk of incisional hernia. Patients with documented port site metastasis after resection develop peritoneal disease soon after [57, 65]. Therefore, routine port site resection is not recommended [41].

#### **For stage IV and unresectable disease:**

– Patients with locally advanced GBC and unresectable disease are considered beyond the scope of curative treatment. Patients with preoperatively determined locally advanced disease (T3-4, N2) should be enrolled in clinical trials assessing neoadjuvant treatment. If these patients undergo resection, they should be enrolled in clinical trials assessing adjuvant treatment [41]. The main treatment is palliative, with the aim of ameliorating the patient's symptoms. Biliary obstruction, pain, cachexia, and infections are the usual targets for such palliative treatment. A single- or double-agent chemotherapy regimen can be added according to patient tolerance and performance status in order to provide palliation and prolong survival [26, 41].

## **7. Importance of postoperative pathological evaluation following laparoscopic cholecystectomy**

The classical postsurgical approach is to review every tissue histopathologically in order to document any concerns regarding the diagnosis and to exclude any oncological etiology. The microscopic examination of at least three sections is recommended, especially in high incidence areas [41]. The increase in cost and pathologists' workload due to evaluation of specimens from the most commonly performed surgery worldwide remains debatable. Yet, this practice might result in diagnosis of GBC in 0.25–3.0% of all samples evaluated [3–6]. Some studies recommend selective histological examination of the gallbladder on the basis of red flags in the perioperative period, on radiological imaging, and on macroscopic examination of the gallbladder. Thickening of the gallbladder wall and mucosal ulceration are the most common signs associated with malignancy [66, 67]. However, the evidence to support such a practice is still lacking.

## **8. Conclusion**

GBC is a rare but fatal disease. Most cases are discovered incidentally while treating a benign disease, indicating the importance of histopathological exam after all cholecystectomies. Therapy can be multimodal yet surgical intervention is the mainstay of GBC treatment. The most pivotal and important step is accurate preoperative staging. Staging dictates disease management and treatment options and can predict survival. Due to the rarity of the disease patients should be recruited to ongoing multicentral clinical trials.

## **Author details**

Faisal Al-alem¹, Rafif E. Mattar¹, Ahmad Madkhali¹, Abdulsalam Alsharabi¹, Faisal Alsaif¹ and Mazen Hassanain¹,²\*


## **References**


from the most commonly performed surgery worldwide remains debatable. Yet, this practice might result in diagnosis of GBC in 0.25–3.0% of all samples evaluated [3–6]. Some studies recommend selective histological examination of the gallbladder on the basis of red flags in the perioperative period, on radiological imaging, and on macroscopic examination of the gallbladder. Thickening of the gallbladder wall and mucosal ulceration are the most common signs associated with malignancy [66, 67]. However, the evidence to support such a practice

GBC is a rare but fatal disease. Most cases are discovered incidentally while treating a benign disease, indicating the importance of histopathological exam after all cholecystectomies. Therapy can be multimodal yet surgical intervention is the mainstay of GBC treatment. The most pivotal and important step is accurate preoperative staging. Staging dictates disease management and treatment options and can predict survival. Due to the rarity of the disease

Faisal Al-alem¹, Rafif E. Mattar¹, Ahmad Madkhali¹, Abdulsalam Alsharabi¹, Faisal Alsaif¹

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1 Department of Surgery, King Saud University, Riyadh, Saudi Arabia

2 Department of Oncology, McGill University Health Center, Montreal, Canada

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**Endoscopic Ultrasound and the Gallbladder**

**Provisional chapter**
