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10.1245/s10434-006-9294-3
Annals of Surgical Oncology 14:1200-1211 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Bile Duct Cyst as Precursor to Biliary Tract Cancer

Kjetil Søreide, MD1,2 and Jon Arne Søreide, MD, PhD, FACS1,3

1 Department of General and Gastroenterologic Surgery, Stavanger University Hospital, Stavanger, Norway
2 Department of Pathology, Stavanger University Hospital, 4068, Stavanger, Norway
3 Department of Surgical Sciences, University of Bergen, Bergen, Norway

Correspondence: Address correspondence and reprint requests to: Kjetil Søreide, MD; E-mail: ksoreide{at}mac.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
Background: Bile duct cysts (BDC) are rare, of uncertain origin, and occur most often in young females of Asian descent. Increasingly, BDCs are reported in the Western population, often with coexistent biliary tract cancer.

Methods: The PubMed and Medline literature databases were searched for pertinent publications regarding the clinical association and molecular biological development of can-cerogenesis in BDC. Reports from the last two decades were emphasized.

Results: Cancer is found in 10–30% of adults with BDC. The cancer-risk is low in childhood (<1% in the first decade), and shows a clear increase with age. Cholangiocarcinoma is the most common malignancy in BDC, and represents a 20- to 30-fold risk compared to the general population. The mean age of malignancy in BDC is 32 years (about two decades earlier than in the general population). Type I and type IV cysts show a higher cancer incidence, even after cyst excision. Pathological findings strongly suggest a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of pancreatico-biliary maljunction (PBM). Reflux of pancreatic enzymes, amylase, bile stasis, and an increased intraductal concentration of bile acids contribute to proliferative activity of bile acids in BDC. While microsatellite instability, k-ras mutations, expression of COX-2 and bcl-2, and increased telomerase activity seem to occur early; involvement of cyclin D1, ß-catenin, DPC-4/Smad4 and p53 appear later in car-cinogenesis.

Conclusion: Increased molecular knowledge substantiates the clinically related cancer-risk in BDC. Surgery remains the golden standard for treatment, relieves patients from associated complications, and interrupts the cancerous potential in BDC.

Key Words: Bile duct cyst • Biliary tract • Neoplasia • Cancer • Pathophysiology • Molecular biology • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
Bile duct cysts (BDC) are rare and of unknown origin,1 with a predominating occurrence in females of the Asian population. BDC may represent a precursor for biliary tract cancer development, especially in adults.2–4 While more than 60% of patients with bile duct cysts are diagnosed during the first decade of life, about 20% go undiagnosed into adulthood.5–7 When left undetected, BDC seems to pose an increased risk through, as of yet poorly understood molecular mechanisms, with neoplastic changes of the biliary epithelium. Although more than six decades have passed since the first report of neoplastic change within a bile duct cyst,8 knowledge is still scarce concerning the cancerogenetic process. In this review, we address the current knowledge of the multistep, multifactorial pathway that causes BDC to be a precursor for biliary tract cancer.


   METHODS
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 ABSTRACT
 INTRODUCTION
 METHODS
INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
We reviewed the Medline database for articles concerning malignancy in bile duct cyst. The search terms "bile duct cyst" and "choledochal cyst" were matched with "neoplasia", "cancer", "malignancy", "carcinogenesis" and related terms. The bibliography of all retrieved papers was searched to further retrieve papers of interest. Papers from the English literature were included. Case reports, when not presenting unique features to the understanding of carcinogen-esis, were not included. Emphasis was put on the last two decades, and on major case-series published up to August 30th 2006.


   INCIDENCE AND CLASSIFICATION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
BDC are typically described as a disease of childhood, and are encountered three times more often in females than males.4,9 The prevalence is highest in Asian countries9,10 and, for unknown reasons, with a special predilection in Japan.9 The incidence varies from 1:1000 in Japan, to 1:13,500 in the United States and 1:15,000 in Australia.11 In more recent years, BDC are increasingly being reported from Western countries, with adults (age >16 years) representing up to 74% of all patients reported, possibly due to improved non-invasive hepatobiliary imaging.2,10–19 While cancer in BDC is rare in children, the risk increases over time,20 with a cancer-incidence in the third, fourth, and fifth decade of life of about 5–10%, 20–30%, and up to 40–60%, respectively.21

Bile duct cysts are classified according to site, extent, and shape of the cystic anomaly (Fig. 1Go). Alonso-Lej et al.22 proposed a classification for extrahepatic bile duct cysts in 1959, which was later modified by Todani.7 Todani incorporated the int-rahepatic dilatations as described by Caroli23 (known by the eponym Caroli’s disease) into a comprehensive classification system as shown in Fig. 1Go. Most types of cancer have been described to develop in BDC, but cholangiocarcinoma (adenocarcinoma) is the most frequently encountered neoplasm and may develop in all kinds of cysts. Type I and type IV cysts show a higher cancer-incidence, even after cyst excision.24,25


Figure 1
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  		FIG. 1. Todani classification of bile duct cysts. The distribution of cyst types is similar in adults and children, with the exception of type IV cysts which are seen more frequently in adults.15,18,38 An extensive literature review on the prevalence of cysts according to type shows that type I cysts are most frequently encountered (79%), followed by type IV (13%), type III (4%), type II (2.6%), and least frequently type V cysts (Caroli’s disease) which is found in less than 1% of all reported patients. The figure is derived from Søreide et al.2 Copyright British Journal of Surgery Society Ltd. Reproduced with permission. Permission is granted by John Wiley & Sons Ltd on behalf of the BJSS Ltd.

 

   AETIOLOGY
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
Currently, no clearly defined aetiology of BDC exists. However, based on clinical and experimental data, several pathophysiologic observations have been offered.1,2,4,26

The most favoured hypothesis about the formation of BDC is the "long common channel" (LCC) theory, as first described by Babbitt.27 A pancreatico-biliary malunion (PBM), also referred to as an anomalous pancreatobiliary ductal junction, with an LCC (i.e., >15 mm) (Fig. 2Go) is thought to allow pancreatic juice to reflux into the biliary system, possibly resulting in increased intraductal pressure and inflammation, which, in combination, may lead to ductal dilatation.28–32 This theory has, in part, been confirmed in experimental studies.33 Contradictory to these reports is the fact that PBM is detected variably in 60–96% of patients,26,34 thus suggesting that PBM alone cannot be responsible for the cystic dilatation. In Japan, there has allegedly been no reports of bile duct cysts without an associated PBM.3 The various types and patho-physiological roles of PBM is beyond the scope of this review and has recently been entertained elsewhere.3,35,36 Even though several theories exist,2,26,37 the most likely contributors to bile duct dilatation seem to include either anatomic or functional obstruction (or both in tandem) possibly in conjunction with increased intraductal pressure. Type IVA cysts are seen more frequently in adults,15,18,38 which may suggest that, although of congenital origin, the lesions may progress with time or may develop later in life.


Figure 2
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  		FIG. 2. Pancreatobiliary anatomy with variations. a Normal anatomy of pancreatic duct (PD) and biliary duct (BD) junction. b Pancre-aticobiliary maljunction (PBM) with a long common channel (LCC). c Bile duct cyst with normal junction of ducts. d Bile duct cyst associated with PBM and LCC.

 

   DIAGNOSIS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
Clinical Presentation
The "classic triad" of jaundice, pain, and an abdominal mass (Table 1Go) is seen in about 85% of children, but far less common in adults (in about 25%).16 Abdominal pain, with or without jaundice, or symptoms suggestive of pancreatic or biliary origin, may prompt hepatobiliary imaging, which usually leads to the suspicion or diagnosis of cystic disease of the biliary tree. When present, jaundice or cholangitis may reflect an underlying neoplastic process in the BDC.


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  		TABLE 1. Presentation, symptoms, and complications in bile duct cysts
 
Since the initial report by Irwin8, a total of 24 BDC-associated cancers was presented in 197739, which had only increased to 106 cases 20 years later.40 Current selected series11–19,21,25,41–53 reporting of cancer in adults with BDC are given in Table 2Go. Neoplasia in BDC may be synchronous (detected and present at the time of cyst diagnosis) or metachronous (detected or developed in the course of time after primary detection or treatment). In the past, one third of cancers were metachronous in presentation/occurrence. This figure may decrease in the future as more BDC are detected earlier, and undergo proper, primary cyst resection, instead of cyst-drainage.


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  		TABLE 2. Selected case-series of bile duct cysts in adults with associated cancer development reported over the past two decades
 
Biochemical Markers
Although abnormal levels of the widely used biochemical liver tests and hyperamylasemia are commonly encountered, no specific laboratory parameters are diagnostic or specific for BDC.10,12,14,16,47 Abnormal laboratory values may in fact reflect frequently associated complications, such as pancreatitis or cholangitis, rather than the BDC per se. More recent developments in the understanding of biliary tract carcinogenesis have suggested several potential serum and bile markers for the diagnosis of cholangiocarcinoma.54,55 Among these are the tumor antigens carbohydrate antigen 19–9 (CA19-9) and carcinoembryonic-antigen (CEA), several cytokines (e.g., interleukin-6), metabolic products (e.g., lactate), proteases such as trypsino-gen-2, regulatory peptides (i.e., pancreatic polypep-tide), and (epi-)genetic lesions (i.e., K-ras and p53 mutations, p16INK4a or p14ARF promoter hyperme-thylation). However, currently, they serve at best, as an adjunctive tool in diagnosis. More specific markers for cholangiocarcinoma detection are still needed and would be of value in high-risk groups, such as patients with BDC.

Imaging of the Biliary Tract
BDC are often first suspected or diagnosed by he-patobiliary imaging studies initiated for evaluation of upper abdominal complaints, such as acute pancreatitis or cholangitis.2,18,28,56 A bile duct cyst may be visualized by any of the modalities available,37 such as ultrasonography, computed tomography, magnetic resonance cholangiopancreaticography (MRCP), or by direct (invasive) ductal imaging using endoscopic retrograde cholangio-pancreaticography (ERCP). For most clinical purposes, the current, golden standard’ for visualising a bile duct cyst is probably MRCP (Fig. 3Go).57–59 Biliary tract cysts can be visualized on MRCP with a comparable sensitivity but without the risks of ERCP-related complications. Most recently, the development of multidetector computed tomography (MDCT) has proven useful and more accurate in imaging the pancreaticobiliary system,60 and with the more widespread availability of MDCT, its role and possible improvements in imaging of bile duct disease will be clarified.37,58–61


Figure 3
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  		FIG. 3. MRI diagnosis of bile duct cyst. In (a) is depicted frontal image of type I cyst, and in (b) the corresponding transverse image of the same patient. Note stone located in cyst (arrow). GB denotes gallbladder; BDC denotes bile duct cyst. The figure is derived from søreide Copyright Brit-ish Journal of Surgery Society Ltd. Reproduced with permission. Permission is granted by John Wiley & Sons Ltd on behalf of the BJSS Ltd.

 

   COMPLICATIONS ASSOCIATED WITH BILE DUCT CYSTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
NEOPLASIA IN BILE DUCT...
 SURGICAL ONCOLOGICAL MANAGEMENT
 COMPLEX SCENARIOS
 OUTCOME AND PROGNOSIS
 REFERENCES
 
A variety of hepato-biliary complications may precipitate or complicate the course of disease, and have been addressed elsewhere.2,18,26 Formation of stones (cystolithiasis, hepaticolithiasis), and related inflammation and infections (calculus cholecystitis, cholangitis, intrahepatic abscess), secondary changes (hepatic cirrhosis with portal hypertension), mechanical obstruction of pancreatic duct and development of cholangiocarcinoma are associated problems and significantly more often seen in adults with BDC.6,11–14,16,18,19,42,46,62,63 In fact, between 60 and 80% of adults with choledochal cysts experience one or more of the above mentioned complications.6,14 The most dreaded complication of BDC, however, is that of cancer arising in the cyst epithelium, most often as a cholangiocarcino-ma (adenocarcinoma).


   NEOPLASIA IN BILE DUCT CYSTS
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 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
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 NEOPLASIA IN BILE DUCT...
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 COMPLEX SCENARIOS
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Risk of Malignancy
It is well established that 10–30% of adults with bile duct cysts develop cholangiocarcinoma (Table 2Go).3,12,14,16,20,25,47,49 The cancer may arise either in the cyst wall itself,7 or in remnant tissue or undilated parts of the extra- or intrahepatic bile duct.24 The risk of cancer is low in childhood (<1% in the first decade), but shows a clear increase with age (>10% in the third decade),64 and may be as high as 40–50% in those older than 50 years.21 Cholangiocarcinoma is the most common malignancy in patients with biliary duct cysts, and represents a 20- to 30-fold risk in patients with BDC, compared to the general population. However, the incidence of bile duct cancer has been reported to be more than 120 times greater than that of the general population, and the risk remains high even after surgical treatment.21,24 In addition, the incidence increases with age (0.7% in the first decade to more than 14% after 20 years of age),20 and the mean age of malignancy in BDC is 32 years (about two decades earlier than in the general population). Cancer has been reported to develop even in children,7,32,65 which puts emphasis on the importance of early diagnosis and treatment.

Pancreato-Biliary Maljunction and Biliary Malignancy
The presence of an pancreatico-biliary maljunction (PBM; Fig. 2Go) imposes an increased risk of malignant change in both the gallbladder and bile duct.3,25,28,34,35,66 Reflux of pancreatic enzymes, amylase, bile stasis, and an increased intraductal concentration of bile acids, contribute to the proliferative activity of bile acids on the epithelium lining the cystic bile duct wall (Fig. 4Go).32,67,68


Figure 4
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  		FIG. 4. Pancreaticobiliary anomaly with reflux.

 
The cause of regurgitation of pancreatic juice into the biliary system might be due to a high pressure difference between the sphincter of Oddi and the duodenum, in addition to the lack of sphincter function at the abnormal junction of the pancreati-cobiliary ductal system.32,64 Pathological findings strongly suggest that there is a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of the biliary tract in PBM.35,55,68–74 The resulting sequence of pancreatobiliary reflux, inflammation, dysplasia with biliary stasis due to poor drainage of a stagnant pool of bile may ultimately lead to increased mutagenicity of the bile acids.30,32,67,68,74–78 The molecular events contributing to carcinogenesis remains poorly understood, however knowledge is evolving (Fig. 5Go).


Figure 5
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  		FIG. 5. Stepwise model illustrating sequential molecular and cellular changes in bile duct cyst epithelium.

 
Molecular Events in Carcinogenesis
Recently, substantial progress has been achieved in the understanding of the cellular and molecular mechanisms playing a role in biliary carcinogene-sis including oncogenes and tumor suppressor genes.79–81 Premalignant alterations in the epithelial wall of the cyst increase with age,82 which is in accordance with the age-related cancer incidence.20 Molecular biological analysis has revealed high incidence of cellular proliferation activating factors such as Tissue Growth Factor (TGF)-{alpha}, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF) from the hyperplasia stage.69,83 A high incidence of k-ras gene mutation can be found in hyperplasia,69 and k-ras mutations occur frequently in cases with a long common channel.84

The predominant occurrence of BDC in females could lead to the notion of a hormonal influence on pathogenesis. In fact, increased estrogen receptor expression has been found in patients with PBM, and most frequently in patients with neoplasic changes in the biliary epithelium.85 Furthermore, microsatellite instability, a well recognized molecular pathway in colorectal carcinogenesis,86 seems to play an important role in the development of biliary tract cancer, especially in association with PBM.73 Microsatellite instability could be observed in 60% of all cases with dysplasia.69

In cancerous lesions, a high rate of overexpression of cyclin D1, ß-catenin, p53, as well as p53 gene mutation has been recognized. In addition, bcl-2 expression and activation of telomerase are probably early events causing carcinogenesis of the PBM gall-bladder mucosa.78 They might be the important factors causing carcinogenesis associated with chronic inflammation. Apparently, k-ras mutations develop at an early stage in hyperplasia and metaplasia, whereas Deleted in Pancreas Cancer (DPC-4, or Smad4) mutations occur at a later stage, when ade-nocarcinoma is evident.69,87 Both dilated and non-dilated non-cancerous parts of the bile duct in patients with an PBM contain k-ras and p53 mutations, which proves for the highly malignant potential in the biliary epithelium.72,74 A PBM is a risk-factor for gallbladder neoplasia in itself, and a cholecystec-tomy should thus always be included in the surgical management of patients with or without a dilated bile duct.24,34,66,68,69,78,88–92

The progressive development of mutations is in accordance with the known stepwise malignant epithelial changes shown for cholangiocarcinoma in general,76,84,93 and suggests that a multistep process contributes to the carcinogenesis, similar to that of other gastrointestinal cancers.81,86,94,95 In addition, after preventive operation with resection of the extrahepatic bile duct is performed, cancer development in the remnant biliary tract or pancreatic duct is rare, although reported.21,96,97 Whether the carcino-genesis is a result of the accumulation of genetic alteration from shortly after birth, or a result of regurgitation of gastrointestinal juice due to hepati-coenterostomy, remains unknown. Since a high frequency of COX-2 is positive in PBM, COX-2 inhibitors such as NSAIDs may play an important role in preventing carcinogenesis.

Although epigenetic changes has not been investigated in the neoplastic epithelium of BDC, recent studies indicate that tumor suppressor genes can be epigenetically silenced through promoter hyperme-thylation. However, Yang et al.55 recently studied the methylation profiles of 12 candidate tumor suppressor genes (APC, E-cadherin/CDH1, MGMT, RASSF1A, GSTP, RAR-ß, p14ARF, p15INK4b, p16INK4a, p73, hMLH1 and DAPK) in 72 cases of cholangiocarcinoma, including equal number cases of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. They included a total of ten cases of benign biliary epithelia, which were included as controls. The methylation status of tumor suppressor genes was analyzed using methylation-specific PCR. Of note, 85% of all cholangiocarcinomas had methylation of at least one tumor suppressor gene.55 The frequency of tumor suppressor gene methylation in cholangiocarcinoma ranged from about 50–65% (i.e., RASSF1A, p15INK4b, p16INK4a, and APC) to 25–45% (E-cadherin/CDH1, p14(ARF), p73, MGMT, and hMHL1), to <15% for GSTP, RAR-ß and DAPK. Although single tumor suppressor gene methylation can be seen in benign biliary epithelium, methylation of multiple tumor suppressor genes is only seen in cholangiocarcinoma. About 70% (50/72) of the cholangiocarcinomas had three or more tumor suppressor genes methylated and 52% (38/72) of cases had four or more tumor suppressor genes methylated. Concerted methylation of multiple tumor suppressor genes was closely associated with methylation of RASSF1A, p16 and/or hMHL1. Methylation of RASSF1A was found significantly more common in extrahepatic cholangiocarcinoma than intrahepatic cholangiocarcinoma, while GSTP was more frequently seen in intrahepatic compared to extrahepatic cholangiocarcinoma. This indicates that methylation of promoter CpG-islands of tumor suppressor genes is a common epigenetic event in cholangiocarcinoma. Based on distinct methylation profiles, intrahepatic cholangiocarcinoma and extrahepatic cholangiocar-cinoma appear to be two closely related, but biologically unique, neoplastic processes. Taking advantage of the unique concurrent methylation profile of multiple genes in cholangiocarcinoma may facilitate the distinction of cholangiocarcinoma from benign biliary epithelium in clinical settings in the future. Further investigation into the carcinogenesis related to BDC and cancer-development may illuminate the role of epigenetic mechanisms in pathogenesis. However, it seems likely to assume an important role for aberrant methylation also in BDC-associated cholangiocarcinoma, given the substantial number of changes found by Yang et al.55


   SURGICAL ONCOLOGICAL MANAGEMENT
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 ABSTRACT
 INTRODUCTION
 METHODS
 INCIDENCE AND CLASSIFICATION
 AETIOLOGY
 DIAGNOSIS
 COMPLICATIONS ASSOCIATED WITH...
 NEOPLASIA IN BILE DUCT...
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 OUTCOME AND PROGNOSIS
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The imperative goal for surgical oncological management is the preventive, total excision of the extrahepatic biliary tree at risk (Fig. 6Go). Subsequent risk of malignant change in both the bile duct cysts and the gallbladder have led to the rejection of the various drainage procedures, which were frequently performed prior to the 1980s. Consensus has now been reached on complete cyst excision with chole-cystectomy92 and Roux-en-Y hepaticojejunostomy reconstruction as the golden standard of management.4,11,12,14,16,18,26,46,47,98,99 Elective cyst excision can be performed with low morbidity and near zero mortality in experienced hands, and should be done to reduce the risk of future cancer.12,100


Figure 6
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  		FIG. 6. Resected bile duct cyst with gallbladder. Resected BDC with cholecystectomy. The opened cyst contained a pigment stone (black arrow). The patient had pre-operative bouts of pancreatitis which led to the diagnosis of the cyst (type I). GB denotes gallbladder; BDC denotes bile duct cyst.

 
Factors to consider before surgical treatment of patients with biliary cystic disease have been suggested by Lippsett & Pitt (Table 3Go).99 Resection of the cyst together with the gallbladder (Fig. 6Go), and reconstruction using a standard Roux-en-Y loop for an end-to-side-hepaticojejunostomy is the mainstay of the operative approach. Detailed description of operative techniques and controversies in management strategies are provided elsewhere.2,4,18,46,99,101 Preferably, upon resection of the BDC, a frozen section should be performed to rule out the presence of cancer. A cholecystectomy is recommended due to the high risk for gallbladder malignancy, particularly associated with a PBM.66,92 In order to prevent the development of biliary tract (and gallbladder) carcinogenesis in patients with PBM, a recent study suggests that the cystic-dilated choledochus should be excised in childhood before its development to a precancerous stage. In spindle-like and nondilation types, cholecystectomy is absolutely necessary in early adulthood before the age of 40.66


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  		TABLE 3. Pre-operative considerations in patients with bile duct cysts
 
Some patients will be diagnosed with a coexistent bile duct cancer upon the detection of a BDC. A "curative resection" should be attempted if the patient is an operative candidate and the neoplasm is resectable.102 In this context, only about 10% of the patients may be resectable at the time of diagnosis. Palliative measures, such as endoscopic or percutaneous biliary drainage to relieve jaundice, should be considered in patients with unresectable disease.79,81,95 In the latter case, the prognosis is grim, with no long-term survivors.

Only anecdotal reports exist to the use of adjuvant chemo- or radio-therapy,103 and, in general, cholan-giocarcinoma responds poorly to chemo- or radio-therapy.104 Whether adjuvant therapy helps reduce the recurrence rate after resection remains controversial, and effects on survival in the palliative setting is limited. Newer radiation therapy techniques, including intraluminal transcatheter brachytherapy, intraoperative radiation therapy, intensity-modulated radiation therapy, and three- and four-dimensional treatment planning, permit radiation dose escalation without significant increases in normal tissue toxicity, thereby increasing the effective radiation dose.104 Results of studies employing hepatic transplantation with radiation therapy are encouraging.105 Hopefully, new techniques, such as photodynamic therapy (PDT) may help improve these numbers. PTD is a relatively new local, minimally invasive procedure that can be used to treat cholangiocarcinoma.106 Although these new approaches hold promise, the prognosis in patients with biliary cancers remains poor, and the integration of novel therapeutic strategies is strongly required to improve survival. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangio-carcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome.107 Molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are important pathways that may serve as potential molecular therapeutic targets for cholangiocarcinoma in the future.


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Particular considerations are required for patients with Caroli’s disease, of which 10–25% may present with an intrahepatic cholangicarcinoma.108–110 Surgical options range from partial hepatectomy to liver transplantation.108,110–115 In diffuse forms of Caroli’s disease biliary drainage techniques have often proved ineffective in preventing recurring bouts of cholan-gitis. While partial liver resection may be feasible, such as in monolobar disease, sometimes the associated congenital hepatic fibrosis may preclude this option. In a setting precluding partial resection, liver transplantation may represent the only effective and durable form of treatment.26,108,110,112,116

BDC diagnosed in the pregnant patient is a challenging scenario,117–121 especially with the synchronous presence of cancer.120 This combined and complex clinical challenge is extremely rare, and thus a management strategy has to be based on individual planning. But a few notes on strategy can be found in the literature. For one, pregnant patients with BDC require careful management, especially to avoid cyst rupture; cesarean section may be preferable to normal vaginal delivery in most cases. Second, although the preferred management of a BDC is excision and Roux-en-Y reconstruction, this may have to be deferred until after delivery, depending on gestation age, because of the risk of fetal mortality and maternal morbidity that is associated with this procedure. Last, an individual approach must be applied with continuous evaluation of both mother and child.119,120


   OUTCOME AND PROGNOSIS
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Long-term survival in patients who have developed malignancy is rare, and the prognosis equals that of patients in the general population with cholangio-carcinoma.79–81 Although all patients with biliary cysts require lifelong follow up, patients with type I and IV cysts, those with an PBM24,28,34 and those with cyst parts that have not been fully removed, such as intrahepatic dilatation of type IV cysts,24 should be subject to a more intense long-term surveillance.

Excision of a BDC greatly reduces, but does not eliminate, the risk of developing malignant change within the biliary tree. In fact, the incidence of post excision malignancy has been estimated at 0.7% in a comprehensive review.21 A more "radical" excision of the intrapancreatic portion of the choledochal cyst has been advocated.122 Development of malignancy has been reported to occur both in proximal and distal parts of the bile duct years after cyst excision.96,97,123,124 Thus, long-term follow-up seems to be warranted; however, no guidelines exist. We believe that an individualized plan should be developed for the particular patient, taking into account overall morbidity, age, and quality of life when designing mode and frequency of follow-up. Imperative is the pre-emptive surgical resection soon after diagnosis to interrupt the potential for malignant change in the biliary tree.

Overall, excision of bile duct cysts is regarded a safe procedure. Based on the current known risk for malignant change in cystic disease of the biliary tract, complete excision of these lesions is recommended as early as possible, preferably before puberty, in order to decrease the risk of developing cancer.

Received for publication July 11, 2006. Accepted for publication September 25, 2006.


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 OUTCOME AND PROGNOSIS
 REFERENCES
 

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