Section 3 Choledochal Cyst

### **Chapter 3**

## Choledochal Cyst: Clinical Features, Diagnosis and Treatment Perspectives

*Magaly Torres, Mitzi Becerra, Beatriz Calderón, Iván Salinas, María Ruiz and Jorge Ventura*

### **Abstract**

Choledochal cyst is a congenital or acquired anomaly affecting the biliary tree in which exists a dilatation of the bile duct, not only the choledochus is affected but also the intrahepatic and extrahepatic ducts might be affected. The clinical presentation is not specific, even the classic triad with abdominal pain, mass, and jaundice is not common as suspected, found only in 10% of cases. Clinicians must rely on imaging studies for diagnosis and classification. The treatment is cyst excision with hepaticoenterostomy in most of the cases, but in some others, a liver transplant would be necessary. These patients require lifelong follow-up due to its rate of recurrence compared with general population.

**Keywords:** choledochal cyst, biliary cyst, biliary tree, biliary tract disease, jaundice, roux-en-Y, hepaticoenterostomy, hepaticojejunostomy, hepaticoduodenostomy

### **1. Introduction**

Choledochal cyst (CC) is an entity where there is a dilatation at any level of the bile duct, more common in the choledochus, hence its name. Although in almost all the literature, it is referred to as a "choledochal cyst," the most appropriate way to


*Adapted from Witcombe JB, Cremin BJ. The width of the common bile duct in childhood. Pediatr Radiol. 1978;7:147–149.*

### **Table 1.**

*Mean common bile duct diameter and range according to patient age.*

refer to this pathology would be dilation of the bile duct, since it does not necessarily present as a cyst, and it is not necessary to appear in the choledochus either.

Therefore, to refer to a dilated duct, it is necessary to know the normal diameter of the common bile duct (choledochus). A study by Pina and colleagues reports an average of 5–6 mm in diameter of the common bile duct in adult patients; however the diameter varies according to age and measurement method (**Table 1**) [1, 2]. Another study where measurements were made on 173 children aged between 1 day and 13 years reported an average diameter of the common bile duct of 1.27 mm (± 3.3 mm) and < 1.2 mm in newborn and children up to 3 months [3]. Consequently, any measurement greater than reported can be considered abnormal.

### **2. Classification of choledochal cyst**

Diverse classifications have been proposed to categorize the CC. Currently, Todani's classification has been the most extensively accepted (**Figure 1**). It was

#### **Figure 1.**

*Types of choledochal cysts according to Todani's classification. Type I (a = choledochal cyst in a narrow sense; b = segmental choledochal dilatation; c = diffuse or cylindrical dilatation.). Type II supraduodenal diverticulum. Type III (a = choledochocele; b = diverticular choledochocele). Type IV multiple dilatations [a = involving the intrahepatic biliary tract; b = sparing the intrahepatic biliary tract. Type V (or Caroli's disease): Corresponds to multiple intrahepatic dilatations.*

### *Choledochal Cyst: Clinical Features, Diagnosis and Treatment Perspectives DOI: http://dx.doi.org/10.5772/intechopen.106451*

described in 1977, based on evidence of the existence of various anatomical forms of biliary cystic dilatation that occur not only in the choledochus, but also in any part of the bile duct between the liver and the duodenum, previously the classifications for this entity include only choledochus dilations [4].

According to Todani's classification, CCs are classified into five types:


Furthermore, there exists a special variant of CC named "forme fruste," where the patients present with typical symptoms of CCs and are associated with abnormal pancreaticobiliary duct junction but little or no dilation of biliary ducts. It could be considered as an incomplete or atypical pathology [6].

### **3. Epidemiology and incidence**

There is an outstanding regional tendency, which affects predominantly Asian population with an incidence of 1 in 1000 live births, and two-thirds of the reported cases occur in Japan, compared with an incidence of 1 in 100,000–150,000 live births in the Western population [7, 8].

CCs type I and IV are more common and have a female-to-male ratio of 4:1 or 3:1. The cause for the Asian and female predominance remains under study, recent research studies settle that congenic bile duct dilatation has genetic basis, not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one gene for the disease to develop. That is consistent with the low frequency and sporadic presentation of CC [9–11].

### **4. Etiology and pathophysiology**

The etiology of a choledochal cyst remains unknown at present time, leading to the postulation of multiple theories. "Long common channel" theory by Babbit has been the most accepted explanation for the origin of the choledochal cyst. This theory states that the pancreaticobiliary junction is located outside the duodenal wall [12, 13].

In normal conditions, the common bile duct and the pancreatic duct enter into the duodenal muscle layer (sphincter of Oddi) and join in the submucosal layer just

### **Figure 2.**

*Pancreaticobiliary maljunction classification. Komi classification and Japanese study group on Pancreaticobiliary Maljunction (JSPBM).*

before opening into the duodenal lumen. This junction helps to regulate the output of digestive enzymes into the intestinal lumen but in a pancreaticobiliary maljunction (PBM), there is a dysfunction of the sphincter because the duct is external of the duodenal muscle layer, forming an extended common channel, 1–2 cm proximal to the sphincter of Oddi [14].

The maljunction of both ducts occurs during the fifth week of gestation. In normal embryological development, the pancreatic ventral bud fuses side by side with the dorsal bud, and in the sixth week, 180-degree rotation (clockwise) of ventral and choledochal, bud of the pancreas occurs around the duodenum to reach their finale positions [15]. PBM appears to be associated to the malrotation of the ventral bud, as the proximal portion of the hepatic diverticulum extends and the ventral primordium has been displaced away from the duodenum by elongation of the proximal part of the diverticulum.

Histological and immunohistochemical studies have demonstrated that the union of these two buds might occur in an oblique position, producing the formation of a long common channel [14, 16].

PBM was classified by Komi in 1992 into three types, based on the fusion pattern (**Figure 2**):


In 2015, the Committee on Diagnostic Criteria of the Japanese Study Group on Pancreaticobiliary Maljunction (JSGPM) proposed a classification into four types [18]:


In addition to PBM and a higher pressure of the pancreatic duct, the developed long channel allows reflux of pancreatic juice into the common bile duct. However, it has been found that not all abnormal pancreaticobiliary junctions present dilatation of the bile duct, which could explain only a part of its pathophysiology.

Pancreatic proenzymes also play an important role in the origin of the choledochal cyst, inasmuch as they come into contact with the bile and activate before reaching the duodenum, they generate a state of inflammation, obstruction, increased pressure in the choledochus, and consequently, greater dilation [19]. Furthermore, trypsinogen, when activated into trypsin, modifies a protein called lithostatin in its insoluble form, aggregating and forming protein plugs. These plugs are compacted in the common channel or in the narrow distal part of the cyst, causing pancreatitis or increasing the pressure of the bile duct so much that it sometimes generates biliary perforation.

Pancreaticobiliary reflux and activation of proenzymes generate intermittent symptoms such as abdominal pain, vomiting, jaundice, and increased aminotransferases in children. This fact is confirmed by a retrospective study of 80 patients where biliary amylase measurements were performed, finding a relationship between the presence of biliary amylase and clinical manifestations, with the presence of jaundice as the most common symptom in those with amylase <200 U/L, and with the presence of abdominal pain in those with amylase >200 U/L [20].

It has been observed in adulthood that pancreaticobiliary reflux presents as dilatation of the bile duct and malignancy. This is secondary to the fact that biliary stasis, which was previously mixed with the refluxing pancreatic enzymes, creates damage to the biliary epithelium. Chronic inflammation activates the point mutation of KRAS, overexpresses COX2, and inactivates TP53, generating greater cell proliferation and consequently epithelial hyperplasia, which appears benign in childhood, but in adulthood presents as dysplasia and subsequent carcinogenesis. The site of malignant occurrence is generally within the cyst, but it can be anywhere within the biliary tree [21].

On the other hand, Babbitt's theory is confronted by authors who state that PBM is present in only 50–80% of cases and that in choledochal cyst diagnosed prenatally, there wasn't the presence of reflux, and suggest that neonatal pancreatic acini are not able to produce enough pancreatic enzymes [22]. For unknown reason, despite the presence of PBM, bile duct dilatation may not occur and frequently does not generate symptoms. Therefore, in these patients, PBM tends to be diagnosed at a later stage [23].

This previous theory applies to choledochal cyst types I and IV. Regarding type II (true CBD diverticulum) and type III (choledochocele), it is suspected that the cause is related to biliary duplications cysts for type II and biliary or duodenal duplications cysts for type III [24].

Type V CC and fibrocystic liver disease are related with both being a spectrum of the same congenital disease; ductal dysgenesis affects the biliary tree at multiple levels from the small intrahepatic bile ducts (congenital hepatic fibrosis) to the larger bile ducts (Caroli disease). The etiology type V CC is accepted to be a halt in the remodeling of the ductal plates, and it is associated with biliary atresia [25].

Alternatively, suboptimal number of ganglion cells has been demonstrated in the narrow portion in the distal common bile duct of patients with choledochal cyst when compared with controls. This might lead to the dilation of the proximal segment of the common bile duct, describing a pathogenesis similar to achalasia and Hirschsprung's disease [26].

### **5. Prenatal diagnosis**

The bile duct cyst is scarcely detected in the prenatal stage, the cases reported in the literature range between 20 and 30sdg, being the earliest case described in the 16th week of gestation [27, 28]. The multi-slice high-resolution ultrasound visualizes several planes simultaneously, including sagittal, coronal, transverse, and oblique views being the main tool in the prenatal approach allowing an early diagnosis [27–29].

Among the suggestive findings is the presence of an anechoic cystic image in the right upper quadrant without central vascularity to the application of the Doppler and which is in relation to the contiguity with the gallbladder, in addition to allowing to evaluate the position of the cyst, the state of the proximal ducts, vascular anatomy, and the hepatic echotexture [27, 29].

The advantage of prenatal diagnosis is that it allows the multidisciplinary team adequate neonatal support and prompt surgical planning. During pregnancy, the behavior should be expectant with follow-up ultrasounds, prioritizing childbirth. After birth, the diagnosis can be confirmed with magnetic resonance cholangiopancreatography. There are no international publications so far about perinatal management [30, 31].

Differential diagnosis should include retroperitoneal cysts (hydronephrosis, polycystic kidney, cystic neuroblastoma, or adrenal hematoma) and intraperitoneal cysts (ovarian cysts, epiploic and mesenteric cysts, intestinal duplication, intestinal atresia, biliary atresia, pancreatic and hepatic cysts) [31, 32].

In a series of 13 patients with biliary disease and abnormal prenatal examinations, the correct diagnosis was made prenatally only in 15% of cases. The difficulty in differential diagnosis in the newborn lies between the bile duct cyst and cystic biliary atresia. Given the difficulty that exists of differential between these two entities by prenatal ultrasound, a child with presumed bile duct cyst should undergo an early examination to rule out biliary atresia. So far there are no unequivocal differential parameters that are accepted [30–32].

### **6. Clinical features**

Clinical presentation patterns differ according to the age group at onset of symptoms and the type of cyst. The classic triad of abdominal pain, abdominal mass in

### *Choledochal Cyst: Clinical Features, Diagnosis and Treatment Perspectives DOI: http://dx.doi.org/10.5772/intechopen.106451*

the right upper quadrant, and jaundice, although predominant in children, is only reported in 5–10% [33, 34].

Abdominal pain is the most frequent symptom (61–94%) with a slight predominance in older children and adults, which has an intermittent course with a variable time interval from days to years [35, 36]. Abdominal mass and jaundice are usually a manifestation of newborns and infants. Cholangitis, pancreatitis, and liver function test abnormalities are common and are thought to be secondary to a PBM or choledocholithiasis [36–38].

The infantile presentation is characterized by obstructive cholestatic syndrome. Jaundice follows an intermittent pattern since the obstruction of the biliary tree is incomplete; unlike cystic biliary atresia, the main differential diagnosis in this age group.

The presentation of acute abdomen secondary to biliary peritonitis due to rupture of the cyst is rare, predominantly in infants (1–2%). Older children and adults with choledochal cyst present biliary or pancreatic symptoms, mainly associated with abdominal pain. The clinic in this age range is given by entities secondary to chronic biliary stasis, manifesting as complications: cholelithiasis (49%), cholangitis (32%), acute pancreatitis (10%), hepatolithiasis (7%), biliary carcinoma (3%), portal hypertension (2%), and chronic pancreatitis (2%) [39–43]. Fifteen percent of patients with CC may be asymptomatic [36].

On the one hand, some specialized centers in Asia reported direct comparison studies about the clinicopathological differences between children and adults with choledochal cyst. Pediatric patients were more likely to have abdominal mass (52.4% vs. 21.2%) and jaundice (33.3 vs. 0%) compared with adults. Children are more frequently associated with PBM (85.7% vs. 59.6%) and sudden severe stenosis of the terminal common bile duct (76.2% vs. 42.3%). Adults were more likely to have abdominal pain (98% vs. 76.2%), frequently stone disease, and they are more associated with neoplasms (21.2% vs. 21.0%). Malignancy rates are widely reported to be 14–18% [44–46].

On the other hand, a multi-institutional analysis from eight centers in North America and Europe reported clinical characteristics among children and adults, with mean age at diagnosis of 5 years and 45 years, respectively. Adults had more abdominal pain than children (71.8% vs. 40.7%), and children had more jaundice compared with adults (31.9% vs. 11.6%) [36].

Regarding the symptoms according to the type of cyst, jaundice is observed mainly in type I (56%) and IV cysts. Hepatomegaly, palpable mass and episodes of biliary pancreatitis are more prevalent in type I. Exclusively intrahepatic cysts (type V) present mainly with cholangitis and gallstones [47].

### **7. Diagnosis**

There is no specific marker for choledochal cyst in blood tests, what commonly occur are variations in serum concentrations of amylase, bilirubin, and hepatobiliary enzymes when the patient becomes symptomatic; however, in asymptomatic patients, it can occur or not some variation in blood tests.

Ultrasonography (US) is the initial study when pathology of the bile duct is suspected, the advantage of this study is that it is noninvasive, and in expert hands, it can give a very approximate diagnosis. The main finding in US is dilation of the biliary tract, although it is also useful for evaluating the position of the cyst, the proximal ducts, vascularity, whether there are stones in the bile duct and the characteristics of the liver parenchyma.

A technectium-99 HIDA scan may provide more information if a choledochal cyst is suspected by US, being helpful to distinguish a cyst for biliary atresia.

The abdominal computed tomography (CT) scan can show the bile duct along with intrahepatic and intrapancreatic ducts; it is especially useful to rule out tumors at this level with the disadvantage of exposing the patient to radiation and the difficulty to observe the common channel and the biliopancreatic junction clearly. Therefore, CT cholangiography is more sensitive to assess the biliary tree, it identifies the presence of stones and diagnose the choledochal cyst; with a sensitivity above 90%, but with the risk of generating hepatotoxicity or nephrotoxicity due to the contrast medium [48].

For these reasons, the most recommended study is magnetic resonance cholangiopancreatography (MRCP), which has a sensitivity of 90–100% for diagnosis, with the advantage of not being invasive and not exposing radiation (**Figure 3**). Some centers even have the possibility of generating 3D images for better visualization. This study allows evaluation of the anatomy of the intrahepatic and extrahepatic bile ducts, the pancreaticobiliary junction, as well as the measurement of the length of the common channel, which is generally >15 mm [49–51].

Endoscopic retrograde cholangiopancreatography (ERCP) is also a diagnostic option; however, it is not the most common to perform due to its invasive method, although it is very useful, especially in those patients whose clinical and imaging studies are inconclusive. With this study, the path of the common channel, the common bile duct, and the position of the cyst can be assessed. However, ERCP relies on

### **Figure 3.**

*Coronal T2 MRCP shows a cystic dilation of the common bile duct (arrow) with preserved intrahepatic bile ducts. The gallbladder (asterisk) and the duodenum (arrowhead) are visualized as well.*

### *Choledochal Cyst: Clinical Features, Diagnosis and Treatment Perspectives DOI: http://dx.doi.org/10.5772/intechopen.106451*

experienced personnel to perform the procedure, with a 10% rate of complications such as pancreatitis, infection, or bleeding. [52].

Intraoperative cholangiography (IOCG), like ERCP, is not indicated as a routine diagnostic method, it is only suggested in exceptional cases where previous studies have not been conclusive.

### **8. Management**

Medical treatment limits to the administration of antimicrobial therapy in case of cholangitis or supportive therapy in pancreatitis, trying to stabilize the patient prior to operative approach. If rupture of the cyst manifests, a drainage must be placed, pointing out the weirdness of these presentation [53].

Historically, drainage or cystenterostomy was the surgical management, but the high risk of malignant transformation and the recurrence of the symptoms demands aggressive surgical management as the overriding treatment [53, 54].

The prenatal diagnosis of congenital biliary dilatation (CBD) has helped to follow these patients after birth, establishing the ideal time to treat them, if the conditions of the patient allow it, the surgical procedure is recommended at the age of 6 months old. About half of the patients with prenatally diagnosis of CBD are asymptomatic; but if obstructive jaundice, cholangitis, pancreatitis, liver dysfunction, vomiting due to compression of the gastric outlet, or even rupture of the cyst development may be a mandatory earlier surgical exploration, even in the neonatal period [54].

Surgical treatment depends on the CC type. Type I, which is the most common, requires complete cyst excision followed by restoration of the biliary-enteric continuity.

A transverse or oblique incision is the traditional way to reach the hepatic hilum, but the laparoscopic approach (LA) has been increasingly adopted since 1995 when the first successful laparoscopic cyst excision with hepaticojejunostomy (HJ) was performed. A systematic review and update meta-analysis where 1767 patients were enrolled (853 laparoscopic group, 914 open group) reported that the operative time was longer in laparoscopic group, but also less intraoperative bleeding and less intraoperative blood transfusion as well as less time to initial feeding. Length of hospital stay was longer in open group. Short- and long-term postoperative complications were similar in both groups, but the total postoperative morbidity was lower in the laparoscopic group [55].

Minimal invasive robotic-assisted (RA) cyst excision and Roux-en-Y HJ were first reported by Woo in 2006 in a Type I cyst; since then, this practice has gained supporters. In a systematic review and meta-analysis, six studies with 484 patients (307 LA and 177 RA) were analyzed, the results and total complications showed no significant difference between the two groups. [56, 57]. Examination of the data regarding robotic CC excision is needed to determine the utility of this approach in children [53].

The CC transection should be at level of the common hepatic duct to assure a wide anastomosis, a complete excision of the distal portion into the duodenum just above of the pancreatic duct to avoid damage. It is not mandatory to perform IOCG, unless there are no images prior surgery through MRCP; although it is reported that in infants the biliopancreatic junction is very small and can easily go unnoticed during the CC excision. Therefore, if any doubts exist about the situation of the pancreaticobiliary junction, it is recommended to perform IOCG for reducing the risk of injury to the main pancreatic duct.

Some authors practice intraoperative antegrade cholangiography to evaluate also the common channel in all cases because endoscopic retrograde cholangiopancreatography

#### **Figure 4.**

*Intraoperative cystoscopy of the distal portion of the cyst with plug proteins. Level 1 likelihood of leaving residual cyst. Level 2 adequate to perform the transection. Level 3 likelihood of injuring the pancreatic duct.*

is difficult to perform in early infancy due to the skill required and the potential for complications.

During the transection of the cyst, an adequate view of the hepatic ducts near the dilation is essential to discard stenosis or hypoplasia, which is related to bad prognosis. If protein plugs are present, wash them out by irrigating with saline solution or remove them with a blunt instrument or a pediatric cystoscope (**Figure 4**) [21, 58].

The biliary reconstruction can be performed through either Roux-en-Y HJ or hepaticoduodenostomy (HD). A systematic review and meta-analysis reported 715 patients, of which 403 (56.3%) were performed a HJ and 312 (43.6%) a HD. Operative time, operative bleeding and length of stay favoring HD, similar rates of complications, including cholangitis. Some disadvantages of the HD are the bile reflux with an estimated incidence of ~5% and require more research and long-term studies [59]. The latest findings in patients followed up by Takada endoscopically demonstrate mild to moderate gastric erosion, but in his study, the development of metaplasia in the stomach [60] is unknown.

A wide Kocher maneuver and a further distal anastomosis in the duodenum have been described to decrease the bile reflux [61]. HD has the advantage to follow through with endoscopic revisions if a late complication is presented, like stenosis of the anastomosis or intrahepatic lithiasis. It is worth to mention that the HD is easier to perform laparoscopically in contrast to the technically challenging HJ. To prevent stenosis of the anastomosis, it is recommended to avoid excessive dissection when dissecting the anterior wall and completely excise ulcerative lesions from the inner wall of the cyst.

A prospective randomized controlled trial describes that a shorter loop Roux-en-Y HJ reconstruction for choledochal cyst is equally effective individualizing the length of the loop based on the distance between the hepatic hilum and the umbilicus,

compared with the traditional 40 cm length loop; with no episodes of cholangitis in either group in the following 6 months [62].

### **8.1 Management for the other choledochal cysts**

Type II is a diverticulum of the bile duct, it is the most infrequent presentation of a CC. Surgical removal through laparoscopic approach with excellent results in the reports, but it is known that long-term follow-up and more clinical reports are needed [63].

Type III is a cystic dilatation of the distal common bile duct within the ampulla of Vater protruding into the duodenum, also called choledochocele. The treatment depends on the type of choledochocele, needing endoscopic transduodenal drainage of the lesion in pure choledochocele and with sphincterotomy and complete excision in diverticular choledochocele. Multiple endoscopic technics have been referred such as balloon dilation after incision of the cyst or stent placement, unroofing by partial snare excision of the cyst wall, or complete resection with a polypectomy snare [64, 65].

Type IVa or IVb CC involves dilatation of both intrahepatic and extrahepatic biliary trees. The standard procedure remains to be a complete excision of the dilated common bile duct and a hepaticoenterostomy. Depending on imaging studies, a hepatic segmentectomy or lobectomy might be needed in case of obstruction or to eradicate the segment with the most dilated intrahepatic cysts.

Major late complications such as pancreatic duct stones, intrahepatic calculi, stenosis might need other interventions such as pylorus-preserving pancreatoduodenectomy or duodenum-preserving pancreatic head resection. And sometimes a liver transplant is the only way to preserve a high quality of life [66].

Type V CC benefits from liver transplantation, a related living donor should be considered in time before the onset of life-threatening complications [66, 67].

### **9. Outcome and complications**

The advancement of surgical treatment to include cyst excision has resulted in minimal morbidity and mortality and reduced the number of late complications, compared with past operative treatment of cystenterostomy. The most common short-term outcome in hepaticoenterostomy is anastomotic leakage and as a late complication continues to be anastomotic stricture (2.5–17%) and cholangitis (23–40%) [68–71].

Perioperative morbidity is higher in adults than children (35.1% vs. 16.3%), requiring more surgical procedures following resection of the common bile duct cyst. However, adults were more likely to have wound, hepatobiliary, or gastrointestinal complications: seromas (3.1%), wound infections (9.7%), and perihepatic abscesses (7.7%). Instead, children had more anastomotic leaks (3%) and gastrointestinal tract perforations (3%) [36].

Early diagnosis and cyst excision result in low complication rates in most experienced centers. The technique of Roux-en-Y HJ is favored by most, although comparable results can be achieved by HD. Anyway, either procedure can be performed laparoscopically as well [68, 69]. In most reports comparing laparoscopic cyst excision with open cyst excision in children, operative time was found to be longer and overall costs higher when laparoscopy was used, but there was significantly less blood loss, and the duration of hospitalization was shorter. There were no significant differences in the incidence of bile leakage or wound infection rates. Although

technically challenging and time-consuming, laparoscopic excision imparts less surgical stress on patients than open excision, and parents are generally more satisfied with the smaller scars.

Despite late complications being reduced with current surgical management, studies suggest that long-term follow-up is indicated due to the potential for problems such as anastomotic stricture, cholangitis, intrahepatic stone formation, and malignancy [69, 72]. Malignant degeneration occurs more often in type I and IV cysts and rarely in type II and III. This is particularly important in incompletely resected cystic hepatic ducts or recurrent cysts [46, 73].

Biliary cancer is reported in 5–10% of patients, increasing the incidence greater than 50% in patients over 50 years. The risk of malignancy is greatly reduced after cyst excision but is still elevated as compared with the general population, with an incidence ranging between 2.5 and 28% in adults. Nevertheless, it is reduced between 0.7 and 5.4% after complete surgical excision, with a 95.5% 5-year survival (adults 94.6%; children, 97.2%) [36, 74]. Therefore, lifelong follow-up with ultrasound, liver profile, and CA19–9 levels are recommended annually. Some authors perform biochemical follow with aspartate transaminase and alkaline phosphatase, every 4 months for 2 years; then every 6 months for 5 years [46].

A technectium-99 HIDA scan at 6 and 18 months after surgery can reveal mild episodes of cholangitis in asymptomatic patients or in those with occasional symptoms (less than two episodes per year), requiring only conservative therapy. If cholangitis is recurrent, a reoperation is advocated. In addition, technectium-99 HIDA scan can suggest the presence of anastomotic stricture with delayed flow greater than 60 minutes. However, percutaneous transhepatic cholangiography has still been considered to achieve definitive diagnosis [75].

Anastomotic stricture could occur as a consequence of small, tensive anastomosis, inflammation, or infection. Among the most used options are endoscopic retrograde cholangiopancreatography, percutaneous transhepatic biliary drainage, balloon dilation, and stenting with good results. Some authors pointed out that balloon dilation should be the first step as successful rate was 81%, whereas reoperation was considered as the final choice in all circumstances [69, 76].

Intrahepatic stone formation in the intraoperative setting has been evaluated and reported in the literature and seen in patients who showed no stone formation in the preoperative course. Stone formation has been reported to occur anywhere from 3 to 22 years postoperatively. However, if the duct is patent and there is no stenosis of the hepaticojejunostomy, stones are likely to pass spontaneously [77]. Intrahepatic stones usually present in cases of stenosis that initially cause bile stasis and lead to stone formation.

Todani and colleagues reported a 25-year review with the identification of biliary complications primarily associated with either anastomotic stricture or primary ductal stricture and recommended a wide hepatic hilum anastomosis to prevent biliary complications [78].

### **10. Conclusions**

Choledochal cyst is a biliary anomaly that is often diagnosed at early age due to the imaging studies that are currently used. A careful and meticulous search can help establish early treatment, before serious sequelae arise.

### *Choledochal Cyst: Clinical Features, Diagnosis and Treatment Perspectives DOI: http://dx.doi.org/10.5772/intechopen.106451*

Although the management of CC is established with acceptable results, a high rate of complications related to surgical procedures is still reported, so it is necessary to acquire an extensive knowledge of the different variants and provide greater technical skills that are acquired with practice to have better results and minimize the number of complications. In the same way, follow-up is necessary to detect the presence of malignancy in time and offer timely treatment.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Magaly Torres\*, Mitzi Becerra, Beatriz Calderón, Iván Salinas, María Ruiz and Jorge Ventura Pediatric Surgery Department, Hospital de Pediatría CMNO IMSS, Guadalajara, México

\*Address all correspondence to: magtorresa@gmail.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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### **Chapter 4**

## Characteristics, Diagnosis and Treatment of Choledochal Cysts

*Umut Tüysüz*

### **Abstract**

Choledochal cysts are congenital dilatations of the intra- and extrahepatic biliary tract that cause various pancreatic and hepatobiliary disorders. Pancreaticobiliary maljunction (PBM) results in choledochal cysts. PBM is a congenital pancreatic and bile duct juncture anomaly. It is widely accepted that the clinical presence of PBM is an etiological factor in the pathogenesis of biliary carcinogenesis in patients with choledochal cysts. For definitive diagnosis, ultrasonography sometimes shows the relationship with the biliary tract. If USG findings cannot rule out other causes, ideally MRI should be performed together with MRCP. CT may be the initial test for undiagnosed common bile duct malformations. In rare cases where conventional imaging results are uncertain, nuclear hepatobiliary iminodiacetic acid (HIDA) scanning enables the evaluation of radiological trace of involvement and accumulation in cystic structures associated with the biliary system. Todani added five anomalies and organized the most commonly used classification system. There are five subtypes. A type I cyst, A choledochal diverticulum (Todani type II), Choledochoceles (Todani type III), type IV cyst, Caroli disease (Todani type V). Surgical treatment should be based on the extent of biliary involvement based on the widely used Todani classification and anatomical findings and the presence or absence of PBM. The standard treatment in most CCs is the resection of the bile duct up to the lobar bifurcation. Residual postoperative intrapancreatic choledochal cyst may also lead to secondary carcinogenesis and associated morbidity. The localization of the pancreatic cyst is inside the head of the pancreas, close to the neck and to the left of the bile duct. Surgical treatment options include laparoscopic treatment. Its main advantages include excellent visualization and low blood loss.

**Keywords:** choledochal cysts, pancreaticobiliary maljunction, choledochal diverticulum, choledochoceles, caroli disease, cholangiocarcinoma

### **1. Introduction**

Choledochal cysts are congenital dilatations of the intra- and extrahepatic biliary tract that cause various pancreatic and hepatobiliary disorders, collectively known as congenital cystic dilatation of the common bile duct [1]. Its total incidence is about 1/100,000–1/150,000 in the Western population and 1/1000 in the Asian population [2]. The male-to-female ratio was reported to be approximately 1:3 or 1:4 [3]. Since

they do not contain an epithelial structure, they are not real cysts. They are choledochal malformations that can be detected by imaging and cover various morphological anomalies of the biliary ductal system [4–6]. The exact cause of choledochal malformations is unclear. However, a number of theories were proposed about their pathogenesis, ranging from complete congenital anomaly to sequelae of multiorgan disease process [2]. Choledochal malformations are prone to complications such as cholestasis, pancreatitis, cholangitis, and cholelithiasis. Moreover, some of them, especially those associated with chronic inflammation, have a 50% higher probability of malignant transformation [2]. Choledochal malformations are mostly observed in the pediatric population. An estimated 25% of them are detected in the first year of life and after, while 35–55% by the age of 10 [2]. Up to 20% of them occur in adulthood and have a worse prognosis than in childhood [7, 8].

The similar incidence rates of choledochal cysts in the Western and Eastern cohorts are probably associated with similar etiology. Babbitt's theory is the most commonly proposed one. According to this theory, pancreaticobiliary maljunction (PBM) results in choledochal cysts. PBM is a congenital pancreatic and bile duct juncture anomaly caused by the union of the common duct and pancreatic and bile ducts outside the wall of the duodenum [9]. It is widely accepted that the clinical presence of PBM is an etiological factor in the pathogenesis of biliary carcinogenesis in patients with choledochal cysts. Here, the pancreatic duct and the bile duct are united at a position 1–2 cm proximal to the sphincter of Oddi [10–14]. The presence of pancreaticobiliary ductus junction anomaly allows reflux of pancreatic secretions into the biliary tree. This is the accepted theory for etiopathogenesis of cysts [15, 16]. The clinical presence of PBM is widely considered to be etiological in biliary carcinogenesis in patients with choledochal cysts [17–20]. PBM induces the reflux of pancreatic enzymes into the bile duct, which is thought to be involved in the formation of the bile duct cysts and the development of cancer within the biliary cyst [21]. Biliary cysts (BDC) have a 100–1000 times lower incidence rates in Western series [22–24]. Most of the studies with Western series reported BDC in adults, which had less association with PBM compared with Eastern series [25]. The common duct theory posits that the PBM above the sphincter of Oddi complex causes reflux of pancreatic and digestive enzymes into the bile duct. As a result, wall weakness and subsequent dilatation occur. Moreover, high levels of phospholipase A2 and trypsinogen in the bile of choledochal cyst patients were suggested to exacerbate inflammation and epithelial deterioration in the bile duct [26].

There is no consensus for the diagnosis of PBM, at least in Western countries. Diagnosis includes MRCP, ERCP, and functional criteria (measurement of intrabiliary amylase level). The diagnosis of PBM is based on two strict criteria: (1) The presence of conclusive evidence for the intraduodenal junction between the choledochal and the main pancreatic duct, and (2) the presence of an abnormal common duct longer than 10 mm. PBM is found in only 50–80% of choledochal cyst cases [27].

In a multicenter study conducted in France, 72.2% of patients with BDC were found to have PBM. While 66.8% of the patients were adults, 33.2% were children (<15 years old). The most common symptoms were abdominal pain (64.3%), jaundice (24.7%), cholangitis (24%), and pancreatitis (23.6%). At the same time, the most common types were C-P type I (57.2%), P-C type II (34.5%), and type III (complex type) (8.3%). The mean common duct length was 15.8–6.8 mm while children had shorter common ducts (5.3–13.8 mm). The common duct was longer than 6 mm in 97.6% of the patients and longer than 10 mm in 90.5%. Considering the abnormal common duct longer than 8 mm based on the diagnosis, the sensitivity and specificity

### *Characteristics, Diagnosis and Treatment of Choledochal Cysts DOI: http://dx.doi.org/10.5772/intechopen.109023*

rates were 97.6% and 80%, respectively, while the positive and negative predictive values were 99.2% and 57.1%, respectively. In the same study, the coexistence of the common duct longer than 8 mm and amylase values above 8000 UI/L were associated with positive predictive and specificity rates of more than 90%. In terms of the association between PBM and Todani BDC types, there was a coexistence rate of 78.4% for type I and IVb, 16.6% for type II, 33.3% for type III, and 19% for type IVa. Although the relationship between type IV and type I BDC and PBM was not significant, the incidence of biliary cancer in type I and type IV patients with PBM was 83.3 and 25%, respectively. The relationship between PBM and BDC is similar in Asia and the West cohorts as 72% [22, 23]. Likewise, coexistence of PBM is more frequent in type IV and type I (69 and 78%, respectively), which is less in type II and III (16.6 and 33.3%, respectively) [9, 22–25]. However, there was no association between type V (Caroli disease) and PBM [28]. PBM type P-C subtype is more commonly found with BDC-type Ic (fusiform) while PBM-type C-P subtype is more common with BDCtype Ia. Therefore, in patients with slightly large choledochal (approximately 20 mm), the evidence of the presence of P-C-type PBM represents a key indication for the diagnosis of Todani BDC type Ic diagnosis. Then, complete resection is planned [29, 30]. Anatomical studies showed that 80–85% of adults have a short common duct, whose mean length was reported to be 4.6 mm ± 2.2 mm. In the last study, the mean common duct length was found to be 13.8 ± 5 in patients with suspected PBM. This also confirmed Kawisawa's notion of considering common duct length as the main morphological diagnostic tool for PBM [24]. However, there is no consensus for the cutoff value for the abnormally long common duct. This length is variable during infancy. More than 90% of adults and infants had a common duct length equal to or greater than 10 mm. Taking a cutoff value of 8 mm for the abnormal common duct length may indicate high precision for the diagnosis of PBM. Apart from morphological tools, functional methods using intrabiliary amylase measurement are easy to perform. In one study, intrabiliary mean amylase values were significantly higher in patients with PBM compared with those without PBM (> 50,000 versus <2000, respectively). A literature survey also showed that intrabiliary amylase value of >10,000 UI/L is an important functional tool to confirm the diagnosis of PBM [31]. Intrabiliary amylase concentration can be measured by the following methods: (1) by intraoperative sampling from the gallbladder during cholecystectomy prior to cholangiography or any other manipulation; (2) preoperatively through transhepatic fineneedle aspiration from the gallbladder; and (3) less frequently through bile aspiration during ERCP [32]. In the case of intrabiliary amylase level > 8000 UI/L and common duct length of >8 mm, a definitive diagnosis of PBM can be made with a sensitivity of 87% and a positive predictive value of 90%. However, if the intrabiliary amylase level is normal, the diagnosis of PBM cannot be completely ruled out. When the intrabiliary amylase level is normal and the common duct length is <8 mm, negative predictive value is close to 90%. Therefore, this could be an appropriate method to rule out PBM and then BDC diagnosis. Likewise, the level of amylase in the gallbladder is slightly higher than in the biliary tract, which may support the stagnation theory in carcinogenesis. These theories blamed pancreatic fluid reflux and its attack to biliary tract as the main culprit of cancer degeneration in especially dilated segments against the cholangiocarcinoma degeneration in the distal part of the biliary tree even when these observations were not directly related to Caroli disease, with or without PBM. In the presence of PBM, especially the Todani type I BDC, the incidence of biliary cancer seems to increase. Cholangiocarcinoma cancer degeneration develops 10 years earlier than those without PBM [33]. There is a high risk of cancer degeneration in patients who

underwent cyst enterostomy due to BDC [34, 35]. The global cancer incidence of 8.3% in patients with PBM also including children observed in a Western cohort study was similar to what was reported in Eastern series, albeit at a slightly higher rate [22, 23].

Each entity has different imaging findings, diagnostic features, and surgical management. When it is not detected incidentally in prenatal imaging, it is frequently found in the right upper quadrant ultrasound examination performed for the symptoms and signs of pain, palpable mass, or cholestasis in childhood and young adults [2, 36]. Bile duct larger than 10 mm without obstruction in childhood is always associated with choledochal malformation [37]. For definitive diagnosis, ultrasonography sometimes shows the relationship with the biliary tract. If USG findings cannot rule out other causes, ideally MRI should be performed together with MRCP [36]. The T2-weighted technique routinely used in MRCP allows for a quality depiction of the hepatobiliary system [9]. MRI-MRCP with or without contrast enhancement is a method of choice in preoperative planning. Contrast application indicates malignant change and the choice of alternative approach [38]. CT may be the initial test for undiagnosed common bile duct malformations that are detected later in life or incidentally. The frequency of incidentally detected choledochal cysts in adults has increased from 10–36% due to the availability and convenience of CT [7]. The sensitivity of CT cholangiopancreatography in showing the common pancreatobiliary and pancreatic duct is 64% [39]. Due to concomitant sedation requirements, ERCP and percutaneous cholangiography carry independent risks and should be reserved for situations that are difficult, complicated, or contraindicated for MRI [40]. Diagnostic confirmation is more difficult in individuals with a cholecystectomy history. MRCP has been used more than ERCP or intraoperative cholangiography in the last 10 years for the diagnosis of PBM. MRCP is the most useful method for detecting PBM as it shows the junction of the common pancreatic duct and the common bile duct outside the duodenal wall even in patients with a clearly normal common duct. In the most recent series, the detection rate of PBM by MRCP is 82–100% [41]. Therefore, in patients with or without BDC, MRCP has been indeed used more frequently as the first-choice method than the endoscopic ultrasound or ERCP for focusing on the pancreatic head region [42]. In rare cases where conventional imaging results are uncertain, nuclear hepatobiliary iminodiacetic acid (HIDA) scanning enables the evaluation of radiological trace of involvement and accumulation in cystic structures associated with the biliary system. This is especially important in distinguishing of true choledochal malformation from imitations such as pancreatic pseudocyst and duodenal duplication cyst [43]. Combining preoperative and intraoperative imaging methods during surgical intervention planning reduces the need for preoperative and postoperative ERCP or percutaneous transhepatic cholangiography. Indeed, the addition of intraoperative cholangiopancreatography to preoperative MRCP, especially in pediatric patients, effectively determines intrahepatic biliary structures. This, in turn, may change surgical planning and diagnostic classification by reducing invasive preoperative imaging methods [44]. Ultrasound, MRI-MRCP with or without contrast enhancement, and CT are considered in evaluating complications and examining malignant transformation.

### **2. Clinical presentation and diagnosis**

In adults, symptoms are usually nonspecific, vague abdominal pain being the most common [15]. When specific symptoms arise, they are typically of acute biliary tract

### *Characteristics, Diagnosis and Treatment of Choledochal Cysts DOI: http://dx.doi.org/10.5772/intechopen.109023*

and pancreatic origin [45]. In some patients, the classic symptom triad of abdominal pain, palpable abdominal mass, and jaundice occurs in only 25% of adults, while 85% of children have at least two features of the classic triad. Unexpected presentations such as gastric outlet obstruction, cyst perforation, giant cystolithiasis, giant cyst, and mixed type were reported [46]. Although the frequency of emerging symptoms is similar in Western and Eastern populations, associated biliary conditions such as cholecystitis, cholangitis, and choledocholithiasis are more common at presentation in the Eastern population [20, 22]. Recently, ultrasound has been found to have high sensitivity in the examination of biliary tract diseases [47]. Prenatal diagnosis was also defined in some cases at the 15th week of gestation [48]. In the evaluation of intrapancreatic residual choledochal cyst, it is important that the soft tissue neoplasm is found within the cyst wall, and the wall has a uniform and smooth structure, which should be indicated in the imaging [49]. Peripancreatic lymph nodes are classified as abnormal growth in residual choledochal cysts to prevent carcinogenesis misdiagnosis [50]. In this context, spiral CT-type B has higher resolution than ultrasound and MRCP. All three diagnostic methods can be used together. Serum CA19-9 and carcinoembryonic antigen are listed in the routine preoperative examination of choledochal cyst and are used as important reference indices for the prediction of bile duct carcinogenesis [51]. Caroli syndrome may present with right upper quadrant pain or signs of portal hypertension. It is usually a childhood or young adult disease.

### **3. Classification of common bile duct malformations**

It is important to categorize malformations for the purpose of appropriate management and risk classification. First in 1959, Alonso-Lej proposed a classification scheme that included four anomalies of the biliary tree. Later, in 1977, Todani added five anomalies and organized the most commonly used classification system [33, 52]. In the Todani classification, a type I cyst features fusiform or spherical dilatation in the entire extrahepatic bile duct. It is the most common type in both the Western and Eastern populations. It is observed in 65–84% of the Eastern cohort and 67–73% in the Western cohort. It is divided into three within itself: type Ia: diffuse cystic dilatation, type Ib: focal saccular cystic dilatation, and type Ic: diffuse fusiform dilatation.

Type Ib cystic dilatation typically results from the more distal common choledochal segment. Type II cyst, which involves the lateral wall of the common bile duct, is also called an extra-hepatic supraduodenal biliary diverticulum. Type III cyst choledochal is a cystic dilatation of the duodenal intramural segment of the common bile duct. It can also have a mass effect while protruding into the lumen of the duodenum. Todani identified type IV cyst also as multiple extrahepatic biliary cysts. It could be either isolated in extrahepatic bile duct (type IVb) or combined with multiple large intrahepatic biliary cysts (type IVa). Type V cyst, on the other hand, is known as Caroli disease. It is characterized by multiple large and small intrahepatic biliary dilatations. Coexistence of Caroli disease and congenital hepatic fibrosis is called Caroli syndrome. In 2004, Visser proposed a revised classification to facilitate the diagnosis and management of choledochal bile duct malformations [53]. Here, the spectrum of Todani type I and type IV anomalies was classified under the name of congenital choledochal cyst. Type II koledokal divertikül and type III koledokosel. Likewise, depending on the way it manifests, Caroli disease or syndrome was called type V. In the Visser's classification, congenital choledochal cysts (Todani types I and IV) consist of focal or diffuse extrahepatic bile duct dilatation with varying degrees of intrahepatic involvement. It is the most common type of malformation with incidence rates of approximately 1/100,000–1/150,000. Common duct syndrome is the most commonly considered cause. Other proposed causes include increased intraluminal pressure due to narrow biliary stricture (stenosis), abnormal recanalization during organogenesis, reovirus infection, and insufficient ganglion cells in narrow bile duct part resulting in dilatation [8, 38].

### **4. Choledochal diverticulum**

A choledochal diverticulum (Todani type II) is described as outpouching in the extrahepatic supraduodenal common bile duct. It is rare, has an incidence rate of less than 1/1,000,000 and accounts for approximately 2% of Todani-type malformations [2, 6]. It is a true diverticulum lined with biliary epithelium [2]. Histologically, it is similar to gallbladder duplication. It is associated with the common bile duct with a thin stalk. Increased intraluminal pressure as a result of sphincter of Oddi dysfunction was suggested as the cause.

### **5. Choledocele**

It was first described by Courcy Wheeler in 1940 [54]. Choledochoceles (Todani type III) are poorly understood entities of the choledochal malformations. It is different from other choledochal cysts (CCs). True choledochoceles are the dilated segment of the common bile duct that prolapses or herniates into the small intestine [2, 55]. Their origin has long been the subject of debate. One hypothesis is that these cysts may be caused by an anomaly acquired by the ampulla of Vater's rudimentary lower embryonic bud or by dysfunction or obstruction of the sphincter of Oddi [56]. Although multiple etiological factors are considered, the most commonly blamed factor is inflammation after stone (calculus) passage or damage to the wall. It could be lined with biliary epithelium or ectopic mucosa of the intestine, or it may lie completely bare. It is very rare with an incidence rate of less than 1/1,000,000. It accounts for 1–4% of choledochal malformations [6]. Its differential diagnosis from submucosal duodenal lesions or periampullary duodenal duplication cysts is difficult. The diagnosis is typically made by cholangiography or endoscopic ultrasonography [57].

### **6. Caroli disease and syndrome**

It was first defined by French gastroenterologists in 1958 as congenital multiple intrahepatic cystic dilatation pattern. Caroli disease (Todani type V) is a rare autosomal recessive disorder. It is the second most common type of malformation. It is observed at a ratio of 6–30% in the West and 18–19% in the East. It is the most common type of choledochal malformation with an incidence rate of approximately 1/500,000 in Western countries [2, 6]. Caroli disease is characterized by *in utero* malformation product of the ductal plate and congenital intrahepatic ectasia of the bile duct. When Caroli disease is observed together with congenital hepatic fibrosis, it is called Caroli syndrome [2, 6]. The intrahepatic biliary tract originates from monolayer cells around the portal branches, called the ductal plate [55]. These cell layers are structured to produce small ducts in the periphery and large bile ducts in the hilum.

### *Characteristics, Diagnosis and Treatment of Choledochal Cysts DOI: http://dx.doi.org/10.5772/intechopen.109023*

Ductal plate malformation at the level of the great bile duct results in Caroli disease [2, 58]. Imaging studies show varying size of intrahepatic saccular cystic structures associated with the biliary system. On MRI and CT, it appears as ectatic bile ducts around enlarged portal branches. It is called the central dot sign, which is thought to be highly indicative for the diagnosis of Caroli disease [2]. Complications of Caroli disease include intraductal stone formation due to bile stasis and recurrent cholangitis [2, 6]. Besides causing intrahepatic cysts by blocking the large bile ducts, Caroli syndrome also affects peripheral bile ducts as a result of congenital hepatic fibrosis [2, 59]. Associated conditions include congenital choledochal cysts, cholangiocarcinoma (7–10% incidence), autosomal recessive polycystic kidney disease, and renal cystic diseases involving medullary sponge kidney [2]. Here, the association of renal and hepatic diseases is the common genetic locus (PKHD1 gene on 6p21 chromosomal region) [58].

### **7. Complications**

Complications of common bile duct malformations range from cholestasis with stone formation to recurrent cholangitis, pancreatitis, biliary and hepatic fibrosis, and malignant transformation (cholangiocarcinoma). Cholestasis is the result of external compression of a large extrahepatic cystic malformation causing a regional mass effect or inadequate prolonged biliary drainage by the malformed biliary tract [60]. Stone formation can occur anywhere along the affected biliary system. Recurrent cholangitis and cholecystitis are probably multifactorial. The reasons blamed for this are static lithogenic bile salts as well as chronic inflammation, reflux of pancreatic enzymes, and intestinal bacterial reflux [2]. Regardless of the underlying cause, recurrent cholangitis attacks lead to fibrosis in the cyst wall, ductal sclerosis, and an increased risk of malignant degeneration [6]. Hepatic fibrosis may develop when chronic inflammation affects the intrahepatic biliary system as in congenital choledochal cysts (Todani type IVa) and Caroli disease (Todani type V). Malignant transformation is the best known and feared complication of choledochal malformations. The thesis that chronic inflammation in the malformation-affected biliary system results in cellular dysplasia is assumed to be correct. Chronic inflammation destroys protective mucin-producing epithelial cells. This effect is also enhanced by carcinogen products such as bile salts metabolized by *Escherichia coli*.

The risk of developing malignancy is between 6% and 30% in patients with choledochal cysts. This risk is low in childhood (<1%) but increases by 30–40% at the age of more than 50 years [45, 61]. The malignancy of choledochal cysts originates from both the gallbladder and the choledochal. In a large-scale Japanese study with patients who had choledochal cysts and developed cancer, 62.3% had gallbladder cancer, 32.1% bile duct cancer, and 4.7% had both, which was consistent with other reports [15, 62]. Gallbladder cancer is found in 5% of choledochal cyst patients with PBM [63]. An evaluation of the adult cohort revealed that this is usually observed in the sixth or seventh decade of life [64]. With the cumulative effect of biliary stasis and chronic inflammation itself, the risk of malignancy increases with age [2, 7]. Cholangiocarcinoma develops in a small subgroup of patients (0.7–3%), especially in type I and IV, after surgical resection [18, 22, 65, 66]. This shows that the risk of malignancy does not completely regress after resection in this group of patients. The etiology of this residual malignancy is unclear. Many studies performed in the East and West do not have follow-up periods long enough to determine persistent risk

because it takes more than three decades to occur [67, 68]. However, currently, there is a 6% risk of malignancy after complete cyst resection, while there is a 33% risk of malignancy after incomplete cyst resection [69]. The most common type of cancer is adenocarcinoma, followed by anaplastic carcinoma, undifferentiated carcinoma, and squamous cell carcinoma [70]. About 70% of malignancies originate from the cystic wall. Cholangiocarcinoma in adults and rhabdomyocarcinoma or adenocarcinoma in children are frequently observed. Twenty-four percent of them originate from the gallbladder. The remaining 6% are hepatocellular carcinoma and pancreatic carcinoma [7, 70, 71]. Intrahepatic cysts have a low malignant potential depending on the extent of the involved area and the extent of inflammation and hepatic parenchymal atrophy [20, 72, 73]. Among the different types of choledochal malformations, extrahepatic choledochal cysts (Todani types I and IV) have the highest risk of developing cancer. They are followed by intrahepatic choledochal cysts (Todani type IVa), Caroli disease (Todani type V), choledochal diverticulum (Todani type II), and choledochocele (Todani type III). A surveillance strategy is proposed for patients treated primarily for cyst types I and IV and unresected type V using annual liver function tests, Ca 19–9 measurement and biannual ultrasound assessment for 20years post cyst resection, with biannual liver function testing, Ca 19–9 measurement and 3-yearly ultrasound assessment thereafter [74]. it has been opined that long- term follow-up strategies might not be associated with a better prognosis. One report suggested that follow-up with regular clinic reviews alone does not affect the resectability of cholangiocarcinoma [75].

### **8. Surgical treatment**

Surgical treatment should be based on the extent of biliary involvement based on the widely used Todani classification and anatomical findings and the presence or absence of PBM [76]. The treatment goal for choledochal malformations is to eliminate the risk of malignancy and to treat complications. Surgical treatment depends on the localization and size of the cyst rather than the morphological features [53, 55, 72]. The standard treatment in most CCs is the resection of the bile duct up to the lobar bifurcation, specifically toward the pancreatic parenchyma close to the pancreatic duct junction. Biliary tract continuity is provided by roux-en-Y hepaticojejunostomy (HJ), hepaticoduodenostomy (HD), or jejunal interposition [64, 77, 78]. Hepaticoduodenostomy presents an effective approach to biliary reconstruction following surgical interventions for choledochal cysts. It presents a faster alternative to hepa ticojejunostomy in both operative times and length of stay, with similar rates of complications, including the feared cholangitis [79]. Proximal cyst excision is a non-precisely programmable procedure that needs attention to preserve the portal vein and hepatic artery. Although extrahepatic congenital choledochal cysts usually require complete excision of the entire extrahepatic biliary tree using cholecystectomy and hepaticojejunostomy, more conservative surgical options can be used if there is limited involvement in the distal bile duct, and the interventional approach is based on a 3-cm-size threshold [5, 60]. When the cyst extends into the pancreas, its management is critical and sometimes challenging. During recurrent cholangitis attacks, adhesions in the tissues surrounding the portal vein and pancreas could develop. For these reasons, complete excision may not be possible due to peritoneal infection, bleeding, and the risk of postoperative pancreatic leak [80–82]. The residual intrapancreatic portion of the choledochal cyst hosts multiple pathological changes such as pancreatitis, secondary calculus in the bile duct, and even

### *Characteristics, Diagnosis and Treatment of Choledochal Cysts DOI: http://dx.doi.org/10.5772/intechopen.109023*

carcinogenesis [83, 84]. Acute pancreatitis is often secondary to the intrapancreatic portion of the postoperative residual choledochal cyst [85]. Residual postoperative intrapancreatic choledochal cyst may also lead to secondary carcinogenesis and associated morbidity. Some previous reports showed that stone formation not only stimulates cancer, but also some carcinogenic factors may exist in the residual intrapancreatic part of the choledochal cyst [86]. These findings indicated the necessity of surgical excision of asymptomatic residual choledochal cysts. Intrapancreatic choledochal cysts carry a 0.7–6.0% risk of malignant transformation [5]. There has been no consensus so far on whether excision of the intrapancreatic common bile duct cyst is necessary if there are no clinical symptoms. At the same time, the optimal timing of surgery is unclear. The proximal and distal endpoint of the biliary malformation including involvement of the ampulla of Vater expanding into the pancreatic head should be determined preoperatively [72]. Generally, the localization of the pancreatic cyst is inside the head of the pancreas, close to the neck and to the left of the bile duct [87]. Investigation and differentiation of a residual intrapancreatic choledochal cyst should be started from the back and right side of the pancreatic head. Then, it is gradually deepened into the left field. During this procedure, the direction of the bile duct is confirmed at intervals by fine needle aspiration and finger control [88]. The separation should be close to the bile duct wall. When the lumen terminates abruptly near the end of the bile duct, attention should be paid to the junction of the pancreatic and bile ducts. The diagnosis of a residual intrapancreatic cyst is relatively easy with type-B ultrasonography, CT, and magnetic resonance cholangiopancreatography (MRCP) [89]. Preoperative MRCP examination is crucial to prevent pancreatic duct injury during surgery. It clearly shows the specific anatomy of the pancreatobiliary junction [90]. Different cholangiopancreatography angles of duct reveal the angle of the cholangio-pancreatic duct junction, the rough flow direction to the main pancreatic duct, and the length of the stenosed portion of the lower portion of the bile duct [91].

Because of the high risk of malignancy arising from inadequate resection of the mucosa, any residual area should be excised and always followed up regularly. It is difficult to distinguish pathological changes in choledochal cysts from the inflammatory bile duct. The extent of the excision is mainly based on radiological and intraoperative findings. Surgical treatment is ideally adopted for type I CC. In Todani type IV with intrahepatic and extrahepatic cysts, extrahepatic cysts should be definitively excised. If intrahepatic cysts are limited, biliary-enteric reconstruction is performed along with partial hepatectomy. Especially in patients with bilobar involvement and with diffuse intrahepatic dilatation associated with complications such as stones, cholangitis, and biliary cirrhosis, liver transplantation should be considered [92, 93]. In the distal management of choledochal cysts, if there is no relationship between the choledochal cyst and the pancreatic duct in the preoperative imaging, the distal cyst is excised at a distance of about 5 mm at the junction with the pancreatic duct of the visible bile duct, and the stump is sutured [94]. If the choledochal cyst extends to the junction of the pancreatic duct, the same procedure is adopted. Sometimes, the insufficiency of the ampulla of Vater is observed along with a cylindrical cyst. The distal end of the choledochal cyst opens directly into the duodenum with the insufficient ampulla, and the pancreatic duct appears to be attached to the cyst. In this case, the cylindrical cyst and papilla are excised, and duodenum mucosa and pancreatic duct are subjected to ductoplasty as a modified procedure of local excision of early noninvasive adenocarcinoma and benign lesions in the papilla. Secondary infections may require antibiotics, drainage, and sometimes surgery. Partial hepatectomy and liver transplantation are disputable. However, it is successful in the presence of diffuse intrahepatic ductal dilatation, stenosis, and multiple intraluminal stones [72]. If resection is not performed, long-term follow-up of intrahepatic biliary cysts is required [20, 72]. Despite their low malignant potential, choledochal diverticula (Todani type II) are prophylactically excised to prevent the sequelae of compression effect on adjacent structures [55]. Usually, these cysts are ligated at the neck and excised without the need for reconstruction of bile duct [12]. However, sometimes extrahepatic bile duct excision may be required. In this case, sometimes patients with tight adhesion of the diverticulum to the extra- or intrahepatic biliary tract due to inflammation may be encountered. Releasing the diverticulum from the bile duct could be technically challenging [95]. The isolated segment is removed, and primary repair is performed via T-tube with a low recurrence rate without the need for cholecystectomy [60, 96]. Choledochoceles, which are very similar to choledochal diverticulum, have a low malignant potential of approximately 2.5% throughout life [5]. If they cause biliary or intestinal obstruction, they are excised [6, 55, 56]. Due to the low risk of malignancy, unroofing (endoscopic or transduodenal sphincteroplasty) or transduodenal excision (in large cysts) is the optimal treatment. Endoscopic monitoring should be considered for younger patients treated with sphincterotomy. The prognosis of Caroli disease or syndrome depends on the extent of involvement, but is generally poor. Localized disease is treated with prophylactic hepatic lobectomy. Recurrent and life-threatening cholangitis, liver failure, cirrhosis, portal hypertension, or malignant disease requires orthotopic liver transplantation [97, 98]. Surgical treatment options include laparoscopic treatment. Its main advantages include excellent visualization and low blood loss [99]. In addition, it has better postoperative recovery, less surgical trauma and postoperative pain, less abdominal wall trauma, less cavity drainage time, reduced postoperative paralytic ileus time, and shorter hospital stay. The overall complication and mortality rates are also lower compared with the series involving treatment with open surgery [100, 101]. Recent report supports HD as an effective alternative to the conventional Roux-en-Y HJ reconstruction in laparoscopic excision of choledochal cyst in children [102]. Exposure of the anastomotic site and IHBD is very difficult to achieve by conventional endoscopy. DBE provides a direct view of these sites and enables diagnostic assessment and minimally invasive therapy to be performed simultaneously. It will replace more invasive treatments such as percutaneous transhepatic intervention and surgical procedures [103].

### **Author details**

Umut Tüysüz Department of Liver Transplantation Surgery, Hamidiye Etfal Education and Research Hospital, Istanbul, Turkey

\*Address all correspondence to: umutuysuz@gmail.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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Section 4

## Gallbladder Cancer

### **Chapter 5**

## Gallbladder Cancer: Diagnosis and Surgical Management

*Asmita Chopra and Alessandro Paniccia*

### **Abstract**

Gallbladder cancer (GBCa) is a biliary tract malignancy that is common in South America and Southeast Asia, where patients often present with abdominal pain and jaundice. However, most cases of GBCa in the United States are diagnosed incidentally following cholecystectomy. The pre-operative diagnosis and evaluation involves imaging with ultrasound, CT, MRI, and PET. In patients with incidental GBCa, the histopathology directs further management. The surgical management of GBCa ranges from a simple cholecystectomy to liver resection with lymphadenectomy. Bile duct and vascular resections are reserved to obtain negative margins. To date, multiple controversies remain in the management of GBCa. The determination of type of surgery is based predominantly on T stage. The need for liver resection for tumor on the peritonealized surface continues to be debated. The added value of neoadjuvant and peri-operative therapy is being actively investigated. Systemic therapy has greatly evolved encompassing the use of capecitabine, gemcitabine-cisplatin, with recent addition of taxanes, HER2 inhibitors, and immunotherapy using PD-L1 inhibitors including Durvalumab. This chapter describes current diagnosis and treatment practices for GBCa especially determinants of surgical management and the benefits of peri-operative systemic therapy highlighting the recent advances and shortcomings.

**Keywords:** gallbladder cancer, radical cholecystectomy, incidental cancer, neoadjuvant, PD-L1 inhibitors

### **1. Introduction**

Gallbladder cancer (GBCa) is the most common form of biliary tract cancer and is associated with a particularly insidious course coupled with an aggressive biological behavior. While GBCa constitutes 40% of diagnosed biliary tract malignancies, the incidence has been reported to be as high as 80–95% in autopsy studies [1, 2]. Gallbladder cancer has the worst prognosis of all bile duct malignancies with a 5-year relative survival of 19% [1]. While rare in the developed world, including the United States, incidence of GBCa is high in South America and Southeast Asia, and is highest in women of North India [3]. The most important risk factor of GBCa is chronic cholelithiasis, with more than 85% cases of gallbladder cancer being associated with gallstones. Conversely, less than 3% of patients with gallstones, eventually develop gallbladder cancer. As such, there is no role for prophylactic cholecystectomy in patients with asymptomatic gallstone disease in the absence of high risk features

such as associated polyps measuring more than 10 mm, and gallbladder wall thickening [4]. Females are two times more likely to develop GBCa compared to their male counterparts [5]. Additional risk factors of gallbladder cancer include: chronic inflammation, porcelain gallbladder, infections including bacterial (most commonly Salmonella and Helicobacter) and parasitic (Clonorchis and Opisthorchis), primary sclerosing cholangitis, smoking, obesity, gallbladder polyps, and family history of gallbladder cancer [4]. Additionally genetic mutations associated with other gastrointestinal malignancies—including TP53 mutation (47.1–59%), ERBB2/3 amplification (9.8–19%), CDKN2A/B loss (5.9–19%), ARID1A mutation (13%), KRAS mutation (4–13%), PIK3CA mutation (5.9–12.5%), NRAS mutation (6.3%) and BRAF mutation (1–5.9%)—have also been reported in GBCa [6]. In this chapter, we discuss the diagnosis of GBCa in patients with clinical symptoms as well as asymptomatic patients who are incidentally diagnosed on imaging or following pathological evaluation of a cholecystectomy specimen. We also discuss the various determinants of surgical and medical management of patients with GBCa, as well as the recent advances in treatment strategies.

### **2. Diagnosis of gallbladder cancer**

### **2.1 Clinical presentation**

Patients with gallbladder cancer may present with constitutive symptoms of weight loss and anorexia, and in advanced cases with abdominal pain, abdominal mass and jaundice. These symptoms are more commonly reported in areas with high incidence of gallbladder cancer, including South America and North India. In developed countries, including the United States, most cases of gallbladder cancer are found incidentally after cholecystectomy. While incidental gallbladder cancer is seen in less than 2% of the routine cholecystectomies done for benign disease, it accounts for more than 50% of all gallbladder cancer diagnosis [7, 8]. The current indications for cholecystectomy in asymptomatic patients have partly been dictated by the presence of risk factors predictive of malignancy. These include patient age more than 60 years with GB polyp less than 10 mm, history of primary sclerosing cholangitis and presence of GB polyp, Asian race, GB wall thickening more than 4 mm, and polyp more than 10 mm [9, 10].

### **2.2 Imaging**

Imaging plays an important role in diagnosing a gallbladder cancer. Ultrasound is the first imaging modality used for gallbladder pathologies. It comes with the advantage of lack of ionizing-radiation exposure, cost-effectiveness, and realtime imaging of the gallbladder (e.g., assessment of intraluminal mass mobility). Ultrasound findings of gallbladder wall thickening, mass, or polyp (measuring more than 10 mm in size) are most suggestive of malignancy [11, 12]. The presence of gallstones and the absence of pericholecystic fluid as seen with acute cholecystitis—in the presence of asymmetric gallbladder thickening—is associated with an increased risk of GBCa [11]. However, routine transabdominal ultrasound is hindered by the observer bias as well as by the negative impact of body habitus and bowel interposition. In recent years, advancement in ultrasound using contrastenhanced ultrasound imaging (CEUS) and high-resolution ultrasound (HRUS),

have greatly enhanced the ability of ultrasound to differentiate between benign and malignant diseases [13, 14]. Endoscopic ultrasound (EUS) is increasingly utilized to improve diagnosis of gallbladder neoplasms. EUS may have a theoretical advantage over traditional transabdominal ultrasound, as it utilizes higher frequency waves and benefits from reduced intervening tissue between the probe and the target of interest [14, 15]. However, direct comparison of endoscopic ultrasound (EUS) and high-resolution transabdominal ultrasound has shown similar rates of diagnosis of gallbladder cancer and neoplastic polyps, with no added benefits obtained by EUS [16, 17]. With these findings, the non-invasive aspect of HRUS makes it preferable over an EUS.

Cross sectional gallbladder imaging may be performed with computed tomography (CT) or magnetic resonance imaging (MRI). Common CT imaging findings for GBCa include GB wall thickening, evidence of an isolated hypodense intraluminal mass, GB wall calcification, and porcelain GB. CT imaging is also especially helpful in identifying infiltration of surrounding organs, LN involvement, peritoneal nodules, and distant metastasis [18, 19]. MRI of the abdomen can also be used to diagnose GBCa, which is seen as an irregular, hypointense lesion on T1-weighted images and hyperintense lesion on T2-weighted images. GBCa often demonstrates early enhancement during MRI performed with gadolinium contrast [20, 21].

GBCa is an FDG-avid malignancy, and thus can be diagnosed with a PET (positron emission tomography) scan [22]. Nonetheless, the low negative predictive value of this test limits its utility [23]. However, the application of FDG PET in the evaluation of residual disease after diagnosis of incidental gallbladder cancer is increasing. While CT scan is the primary imaging to evaluate residual disease, PET has been shown to detect residual disease and LN metastasis in patients with otherwise normal CT scans, in about 25% of the patients [24, 25].

Diagnostic laparoscopy plays a paramount role in confirming pre-operative imaging findings with high applicability in identifying peritoneal disease and/or disseminated solid organ disease. Diagnostic laparoscopy has been shown to identify occult disseminated disease in more than 25% patients of GBCa, who are otherwise found to have localized disease on imaging studies [26]. However, this rate is much lower in patients with incidental GBCa, with benefits noted only in patients with T3/ T4 tumors, positive resection margin and poor differentiation on final histopathology evaluation [27].

### **2.3 Biopsy**

Biopsy of suspicious gallbladder masses is not recommended, due to fear of tumor dissemination and bile peritonitis. While previous studies have noted transhepatic route to be safer in terms of GB perforation and peritonitis, the concern for tumor seeding remains. Current NCCN guidelines recommend against biopsy and recommend resection of suspicious masses [28]. Biopsy is however required for patients with unresectable disease to establish diagnosis prior to starting treatment. This has been done percutaneously, laparoscopically or via EUS, however, a core biopsy is preferred for diagnosis [28–30]. Bile cytology obtained through ERCP has also been used to identify GBCa in patients with suspicious lesions. However, recent studies investigating the potential role of liquid biopsy of the bile to identify tumor DNA reported higher predictive value than bile cytology in identifying GBCa [31]. None of these methods are currently indicated in patients who have a potentially resectable tumor and are good surgical candidates.

### **2.4 Tumor markers**

Various tumor markers have been evaluated for gallbladder cancer, and currently, the most used tumor marker in clinical practice is CA19-9. The other tumor markers include CA242, CEA and CA125 [32]. While none of these markers are diagnostic, or specific to GBCa, their levels alone or in combination have been shown to have prognostic implications and may be used to monitor response to therapy [32, 33].

In addition to the tumor markers, various other hematological markers have been shown to have diagnostic and prognostic importance in GBCa. Inflammatory markers have been shown to have prognostic significance with neutrophil-lymphocyte ratio, and platelet-lymphocyte ratio negatively impacting survival and monocyte-lymphocyte ratio predicting response to chemotherapy [34–36]. Recent studies also note the prognostic potential of red cell distribution width and calreticulin in predicting tumor burden [37, 38].

Additionally liquid biopsies identifying circulating free DNA (cf-DNA) and micro-RNA (miRNA) have been shown to have both diagnostic as well as prognostic potential [39, 40]. Identification of certain miRNA mutations may also guide therapeutic interventions [41].

### **3. Incidental gallbladder cancer and determinants of surgical resection**

Incidental GB cancer identified on pathology after routine cholecystectomy, accounts for more than half of the cases of GBCa [7, 8]. Evaluation and management of patients with incidental GBCa is vastly different from patients diagnosed pre-operatively. Since incidental GBCa are identified on pathological evaluation of grossly benign gallbladders, they are identified at an earlier stage and often with no surrounding invasion. As such, patients with incidental GBCa have increased rates of complete resection and better survival than patients who are diagnosed with GBCa pre-operatively [42]. **Table 1** depicts the most recent tumor staging by the AJCC 8th edition classification.

Pathological evaluation of the operative specimen, importantly the depth of invasion (T-stage), involvement of cystic duct margin and in some cases involvement of hepatic or peritoneal surface of the gallbladder, ultimately dictates further management. Re-resection is warranted in most patients to excise residual disease or to obtain adequate margins [8]. Approximately 75% of patients with incidental GBCa—for whom re-resection is performed—demonstrate residual disease which is an independent predictor of poor prognosis. A noteworthy exception—where re-resection is not recommended- is represented by patients with T1a tumors confined to the mucosa where a simple cholecystectomy is considered an oncologically adequate resection. In addition, resection is not recommended for T4 tumors which are unresectable due to loco-regional invasion and for patients with distant metastatic disease [44, 45]. Re-resection is warranted once the cancer invades through the muscular layer. It is typically described as hepatectomy of segment 4b and 5 with lymphadenectomy of at least six lymph nodes and is associated with improved disease-free survival and overall survival in patients with T1b, T2 and T3 tumors [46, 47]. T2 tumors, where cancer invades the peri-muscular connective tissue without invading the serosa, have been a great area of interest. In this group of patients, the location of the tumor, specifically hepatic surface versus peritoneal surface, has been shown to significantly impact recurrence rates and overall survival [48]. This led to the modification of the

*Gallbladder Cancer: Diagnosis and Surgical Management DOI: http://dx.doi.org/10.5772/intechopen.109208*


### **Table 1.**

*TNM staging of gallbladder cancer (AJCC 8th edition) [43].*

AJCC staging in the 8th edition to subclassify T2 tumors into T2a where the tumor is located on the peritoneal side and T2b where the tumor is located on the hepatic side [43]. Data suggest that T2b tumors have worse prognosis compared to T2a tumors; in addition, some authors reported improved outcomes when T2b tumors are diagnosed pre-operatively (prior to formal oncological resection) compared to patients who undergo re-resection [48, 49]. Recent studies suggest that hepatic resection only impacts survival in patients with T2b tumors but not T2a [50]. However, the later findings need to be further validated, and the current practice continues to include hepatic resection in all T2 tumors.

Lymph node positivity is an important negative prognostic factor in GBCa. While lymph node (LN) involvement is an important prognostic factor of gallbladder cancer, routine cholecystectomy specimens do not include formal lymphadenectomy [51]. Routine cholecystectomy occasionally includes excision of the cystic node. The positivity of the cystic node has not been shown to be predictive of loco-regional disease, nor is predictive of survival in patients with GBCa [52]. Lymphadenectomy of the pericholedochal, the peri-portal lymph nodes up to the superior-posterior pancreatoduodenal lymph nodes is recommended for complete oncological resection [29]. The presence of positive lymph nodes around the aorta, celiac axis or the SMA constitutes a very poor prognostic factor, with 0% survival noted at 5 years [53]. CBD resection does not improve the quality of the lymph node dissection nor the lymph node yield [54]. In addition, various studies have led to the determination of what constitutes an adequate lymphadenectomy for staging purpose and the current recommendation is

for a minimum harvest of six lymph nodes [43]. Bile duct resection is not routinely recommended for gallbladder cancer unless a positive cystic duct margin is noted on final pathology [45].

Residual disease is another important predictor of prognosis in patients with GBCa. Found in more than half of the patients with incidental GBCa, it represents an independent poor prognostic factor, with survival rates similar to patients with metastatic disease [55]. However, recent studies from Japan suggest that the location of residual disease may impact prognosis, with disease in the extrahepatic bile duct or distant sites having worse prognosis compared to disease in the gallbladder bed [56]. While some residual disease may be identified on imaging, specifically PET CT, there are now attempts to develop scoring systems that utilize tumor stage and grade to predict residual disease in patients with GBCa [57].

Lymphovascular invasion and perineural invasion noted in the pathological specimen are also poor prognostic factors [58, 59]. Despite their impact on survival the presence of residual disease, lymphovascular invasion and perineural invasion have no impact on the decision-making for re-resection versus systemic therapy in patients with GBCa. Current attempts on developing additional scoring systems inclusive of these factors remain modest at best [60].

Timing to definitive surgery is a very important determinant of prognosis. Most studies suggest the best outcomes are noted in patients who undergo re-resection between 4 and 8 weeks after the initial cholecystectomy [61].

Intra-operative diagnosis of gallbladder cancer—when resectable—may be ideal, as it would allow the surgeon to perform radical resection during the primary surgery. However multiple concerns remain regarding this approach. Frozen section analysis of suspicious gallbladder lesions remains inconsistent with false positive and false negative results seen in up to 25% of the patients [62]. Additionally, the identification of tumor at the cystic duct margin, which would mandate the need for further biliary duct resection, may be inaccurate in many cases [63]. Thus, current practice for patients undergoing routine cholecystectomy with concerning intra-operative findings remains final histopathology based treatment planning.

### **4. Systemic therapy in gallbladder cancer**

Gallbladder cancer is an aggressive malignancy with early recurrence and metastasis even after complete surgical resection. There is an unmet need for effective systemic therapy and reliable biomarkers specifically for GBCa. Due to the rarity of this disease, most studies investigating systemic therapeutic options often encompass all biliary tract malignancies—including intra and extrahepatic cholangiocarcinoma—which have distinct genetic features and clinical behaviors thus confounding data interpretation and applicability.

### **4.1 Neoadjuvant therapy**

While surgical resection is the mainstay of treatment of GBCa, the high rate of early recurrence after complete resection supports the undeniable need for more effective patient selection strategies for surgical resection and systemic perioperative therapy. Peri-operative therapy and multimodality treatments have been shown to improve outcomes in patients with extrahepatic biliary tract cancers including GBCa [64]. While neoadjuvant therapy has been advantageous in patients with locally

advanced disease, there is mounting interest in the use of chemotherapy even in patients with resectable disease [65, 66]. However, data to support this approach are limited, and mostly obtained from studies encompassing all biliary tract cancers, with limited dedicated studies focusing solely on GBCa.

Neoadjuvant chemotherapy for GBCa has evolved significantly over the last two decades. Currently the first line neoadjuvant therapy consists of Gemcitabine-Cisplatin (Gem-Cis) based chemotherapy, which has been shown to improve overall survival and progression free survival compared to both gemcitabine and 5-Flurouracil (5-FU) based chemotherapy [67, 68]. Recently, higher response rates up to 40–50%—were reported with the use of combination chemotherapy by combining "gemcitabine- nab-paclitaxel- cisplatin" [69]. Additional studies conducted on patients who have disease refractory to Gem-Cis have shown improved progression free survival with the administration of FOLFOX or FOLFIRI, justifying the use of these regimens as second line therapy in GBCa [70, 71] (**Table 2**).

There is currently no clear evidence supporting the use of neoadjuvant chemoradiation in patients with GBCa [72]. However, a phase III randomized trial— POLCAGB—is currently underway comparing the survival outcomes of neoadjuvant chemotherapy versus chemoradiotherapy in patients with GBCa [73].

Immunotherapy has been shown to improve response to chemotherapy and impact survival in patients with GBCa in patients with locally advanced—unresectable or metastatic disease. PD-L1 is a known target for immunotherapy that is present in about a quarter of pathological specimens of biliary tract cancer [74, 75]. Studies have shown improved response rates to neoadjuvant therapy when PD-L1 inhibitor, Durvalumab is combined with Gem-Cis [76]. The TOPAZ-1 trial confirmed the safety and efficacy of Durvalumab plus Gem-Cis, demonstrating improved overall survival versus placebo plus chemotherapy (estimated 24-month was 24.9% vs. 10.4%). Moreover, it showed improvements in prespecified secondary end points including objective response rate up to 26.7% vs. 18.7% (OR 1.6; 95% CI, 1.11–2.31). It is important to note that the


*ABC: advanced biliary cancer; RCT: randomized control trial; Gem-Cis: gemcitabine- cisplatin; LA: locally advanced; FOLFIRINOX: 5-flurouracil- irinotecan-oxaliplatin; FOLFOX: 5-flurouracil-oxaliplatin; FOLFIRI: 5-flurouracilirinotecan; 5FU: 5-flurouracil; OS: overall survival; and PFS: progression free survival.*

### **Table 2.**

*Trials evaluating chemotherapy use in gallbladder cancer.*

TOPAZ-1 trial was designed to address a locally advanced-unresectable or metastatic population of biliary tract cancer—among which approximately 25% represented GBca—with previously untreated disease but included patients who developed recurrent disease more than 6 months after surgery with curative intent and more than 6 months after the completion of adjuvant therapy [77].

### **4.2 Adjuvant therapy**

Due to the low incidence of GBCa, most of the data on the impact of adjuvant therapy on survival of patients with GBCa are derived from studies done on patients with any biliary tract cancer. While initial randomized control trials with gemcitabine-based adjuvant therapy failed to show a survival benefit in biliary tract cancers, examination of adjuvant capecitabine (BILCAP trial), suggested positive trends towards survival when adjusted for nodal positivity and tumor grade [78–80]. These studies also prompted dedicated examination of patients with GBCa. Retrospective analysis of large cohorts, including two studies that utilized National Cancer Database and a subsequent meta-analysis of more than 20,000 patients have shown an association between adjuvant chemotherapy and prolonged survival in patients with GBCa, especially in the presence of node positive disease [81–84].

There is also an increased interest in the use of adjuvant chemoradiotherapy in gallbladder cancer. Recent studies including propensity matched analysis of patients receiving adjuvant chemoradiotherapy versus chemotherapy have noted improved survival and reduced local recurrence associated with the use of adjuvant chemoradiation. These findings are especially noted in patients with tumor stage T2 or lymph node positive disease [85, 86]. In addition, a secondary analysis of the phase II intergroup trial, SWOG S0809—that evaluated adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine—demonstrated improved OS in patients with extrahepatic cholangiocarcinoma and GBCa compared to historical controls. Furthermore, the data suggested that adjuvant chemoradiation positively impacted local control in patients with node positive disease [87].

### **4.3 Peri-operative chemotherapy**

There is now a great interest in the use of peri-operative therapy in patients with incidental GBCa (i.e., prior to formal oncological resection in patients who are diagnosed with incidental GBCa after a cholecystectomy). It may be hypothesized that timing of systemic therapy prior to formal resection would allow downstaging of the residual disease, allowing complete resection of the tumor. While no definitive data exist to suggest the superiority of either regimen (i.e., peri-operative versus adjuvant) there are currently two randomized control trials underway to ascertain the merits of the two approaches. Both the OPT-IN trial and the ACO-GAIN trial are examining the difference in oncological outcomes of patients treated with peri-operative gemcitabine- cisplatin therapy compared to those who undergo radical resection without any intervening systemic therapy [88, 89].

### **5. Surgical resection of GBCa**

All GBCa with T-stage including T1b to T3 warrant a radical cholecystectomy after having ascertained the absence of distal lymphadenopathy (i.e., periaortic, celiac, and *Gallbladder Cancer: Diagnosis and Surgical Management DOI: http://dx.doi.org/10.5772/intechopen.109208*

retropancreatic) and metastatic disease. Similar to the operative principles used in patients undergoing re-resection, patients diagnosed pre-operatively and those found to have GBCa on intra-operative frozen section should undergo cholecystectomy with hepatic resection of segment 4b and 5, along with lymphadenectomy with bile duct resection reserved only for obtaining negative margins [45]. Additional aspects of the surgery may include bile duct resection, vascular resection and extended hepatectomy, all of which are performed with the single goal of obtaining negative resection margins. There is currently no role of port site resection in patients who were diagnosed following a previous laparoscopic cholecystectomy, as this practice does not impact disease-free or overall survival [90].

Traditionally, the concern for port site seeding, chimney effect and concern for peritoneal dissemination, led to radical cholecystectomy being done as an exclusively open procedure [91–93]. However, studies comparing minimally invasive and open radical cholecystectomies have noted no oncological differences between laparoscopic and open surgery, with improved intra-operative and peri-operative outcomes in patients undergoing laparoscopic resection [94, 95]. Thus this procedure is now performed both laparoscopically and robotically. While most of the data on robotic oncological safety is derived from studies on laparoscopic radical cholecystectomy, there is an increasing trend of utilization of the robotic platform for this surgical procedure [96, 97].

### **6. Conclusion**

Gallbladder cancer, although rare, is an aggressive malignancy and the most common biliary tract cancer. With the increased cholecystectomy rate, most patients in the western world are diagnosed incidentally. Pathological evaluation of the gallbladder not only establishes diagnosis, but also guides further treatment planning, based on the accurate knowledge of the T-stage and of the cystic duct margin. The early systemic recurrence and poor overall survival—even after complete resection—warrant the use of multimodality treatment with chemotherapy and immunotherapy. Systemic therapy is currently the first line treatment in patients unable to undergo surgical resection, moreover, it is increasingly being advocated in the neoadjuvant and perioperative period to improve resection rates and possibly disease-free survival.

### **Conflict of interest**

The authors declare no conflict of interest.

*Biliary Tract – Review and Recent Progress*

### **Author details**

Asmita Chopra1 and Alessandro Paniccia2 \*

1 Department of Surgery, University of Toledo, Toledo, OH, USA

2 Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

\*Address all correspondence to: panicciaa2@upmc.edu

© 2022 The Author(s). Licensee IntechOpen. 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.

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