SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory syndrome involving the biliary tract, often accompanied by inflammatory bowel disease (IBD). This syndrome is a prototype disease linking chronic inflammation to carcinogenesis. Indeed, PSC is associated with an increased risk of cholangiocarcinoma (CCA), gallbladder cancer, hepatocellular carcinoma (HCC), and colorectal cancer. Herein, we review the risk for these malignancies in PSC and discuss rational cancer surveillance strategies for these patients. Where evidence is limited, we suggest a pragmatic approach. In this regard, we recommend interval screening for CCA with noninvasive imaging modalities and serum carbohydrate antigen 19-9 determinations annually. These imaging studies also serve to screen for gallbladder cancer and HCC. Screening for colorectal cancer is more firmly established in PSC patients with IBD and includes colonoscopy at the time of PSC diagnosis and, thereafter, at 1-2-year intervals. We also highlight areas where more information is required, such as management of biliary tract dysplasia and cancer chemoprevention in PSC. (HEPATOLOGY 2011)

Epidemiology of Primary Sclerosing Cholangitis

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Primary Sclerosing Cholangitis (PSC) is defined as a chronic cholestatic syndrome of unknown etiology characterized by fibrosing inflammatory destruction of the intra- and extrahepatic bile ducts. Inflammatory bowel disease (IBD), usually colitis, occurs in approximately 80% of patients and frequently precedes clinical recognition of hepatobiliary disease. There is a spectrum of disease presentation from isolated imaging abnormalities with minimal biochemical changes to late complications of the disease, such as cirrhosis. The disease has a male predominance.1 The reported incidence of PSC varies, depending on geographic distribution. The highest incidence (1.3 per 100,000 a year) is observed in Norway.2 The incidence in the United States, Canada, and Northern Europe is 0.9-1.3 per 100,000 and is less than 0.1 per 100,000 in Southern Europe and Asia.1, 3-6 A recent report from Sweden describes a trend toward an increased incidence of PSC over the study period of 1995-2005.7 The disease is frequently progressive, and death from cirrhosis and/or need for liver transplantation is common; however, death from cancer also occurs in a large subset of PSC patients. The risk of cancer is so substantiated that many physicians desire to institute cancer surveillance routinely for these patients. Therefore, this perspective will review cancer surveillance strategies for patients with PSC.

Cancer Risk in Patients With PSC

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Understandably, a feared complication of PSC is the development of hepatobiliary and gastrointestinal neoplasia. In a large cohort study of 604 Swedish patients with PSC, 44% of deaths were caused by cancer. Hepatobiliary neoplasia was observed in 13.3% of patients. Compared to the general population, the risk for hepatobiliary malignancy, mainly cholangiocarcinoma (CCA), was 160-fold and 10-fold for colorectal carcinoma (CRC), the letter was confined to those PSC patients with IBD.8 Others reported the risk of CCA in PSC to be 1,560 times that of the general population.9 The risk of hepatocellular carcinoma (HCC) for PSC patients with cirrhosis has been estimated to be up to 2% per year.10 A single report suggests an increased risk of pancreatic cancer in PSC,8 which has not been confirmed in other studies. A major limitation of that study was the potential misclassification of distal common bile duct CCA as pancreatic cancer. Given the lack of robust evidence that pancreatic cancer is increased in this disease, a surveillance strategy for pancreatic cancer will not be discussed. We will, therefore, focus on surveillance for CCA, gallbladder cancer (GBC), HCC, and CRC in this article.

In the recent guidelines on PSC, the American Association for the Study of Liver Diseases (AASLD) discusses surveillance for CCA, GBC, and CRC in patients with PSC.11 By definition, these guidelines require strong, evidence-based studies to make recommendations. Unfortunately, given the rarity of PSC in the general population, large-scale studies are unavailable. Moreover, since the guidelines were published, new data have become available that also may alter current practice. Hence, we will review an updated, pragmatic perspective on cancer surveillance in PSC patients. When reviewing cancer surveillance, it is also logical to take into account approaches to prevent or reduce cancer development. Chemoprevention with ursodeoxycholic acid (UDCA) is probably the best studied agent in this regard. Where information is available, the use of UDCA as a chemopreventive agent also will be reviewed.

Principles of Disease Surveillance

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Surveillance is a tactic for early disease detection with a focus on an asymptomatic at-risk population. There are several guiding principles for a successful, cost-effective surveillance strategy: (1) The population at risk needs to be rigorously identified; (2) surveillance modalities should have high sensitivity and specificity to assure high diagnostic accuracy; (3) surveillance modalities must be available, accessible, and acceptable for the patients; (4) treatment approaches should be available, standardized, and evidence based; and (5) the routine process from surveillance to treatment should be cost-effective and increase survival of the surveillance population. We will discuss these principles for specific cancers arising in PSC patients. However, we note that only carefully conducted, prospective studies can ultimately address these issues. Even when a disease is prevalent, the cost-effectiveness and improved patient outcomes attributed to surveillance are difficult to prove. We witness the decades of research to establish mammography screening in breast cancer and the controversy regarding the use of prostate-specific antigen determination for early detection of prostate cancer.12-14 Much of what we discuss is based on retrospective studies, an acknowledged limitation. Nevertheless, there is a need to provide a scholarly perspective on this topic for clinical guidance.

CCA in Patients With PSC

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Epidemiology and Risk Factors for CCA in PSC.

CCA is a common malignancy complicating PSC, with a lifetime prevalence of approximately 5%-10% among patients with PSC.9, 15-17 This cancer carries a very dismal prognosis, with a 5-year survival rate of less than 10%.18 Several studies have been conducted to identify the risk factors associated with the development of CCA and, therefore, the subset of PSC patients, which would benefit most from aggressive surveillance strategies. Older age at PSC diagnosis, smoking, alcohol use, elevated bilirubin, a longer duration of associated IBD, presence of CRC or dysplasia in patients with ulcerative colitis (UC), proctocolectomy, variceal bleeding, and polymorphism of the NKG2D gene have been suggested to increase the risk of CCA in PSC patients.8, 9, 19-24 However, these studies have not been rigorously validated. The odds ratio (OR) for these risk factors is also modest. Converse to CRC risk in UC, a correlation between CCA and longer duration of PSC has not been identified, with up to 50% of patients diagnosed with CCA within 1 year from diagnosis of PSC.8, 11, 25, 26 This inverse correlation may reflect the ascertainment bias of a referral population in tertiary care centers and the difficulties in making the initial diagnosis of CCA in PSC patients. It also could be a clue that a genetically predisposed population of PSC patients develops CCA.20 In this latter scenario, such genetically predisposed patients would have CCA early in the disease analogous to early onset, genetically defined forms of breast cancer or CRC. Overall, the subsequent risk of the development of CCA is 0.5%-1.5% a year.8, 9 Thus, a high-risk subset of PSC patients at increased risk of CCA cannot be identified. The risk also is too low to justify preemptive liver transplantation with its inherent risks and need for lifelong immunosuppression. Therefore, if surveillance strategies are to be instituted, they probably should apply to all patients with PSC.

Current Surveillance Strategies for CCA and Controversies.

A rational approach for CCA screening is an interval radiologic assessment of the biliary tree, which can be magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) or ultrasound. Computerized tomography, associated with radiation and contrast exposure, is a less favorable option. MRI and MRCP are noninvasive methods for evaluating of the structural changes of the biliary tree. Definite features of CCA on imaging studies include a typical signal intensity and enhancement of a mass on MRI or a mass on ultrasound; however, in our experience, small-mass lesions identified by MRI are often not visualized by ultrasound examination. Thickening of the bile duct wall with proximal biliary dilatation is consistent with a “possible” tumor and is equally visualized by MRI or ultrasound studies. When MRCP is used alone, it is associated with a sensitivity of 78% and specificity of 76%, with overall accuracy of 76% for CCA. A combination of MRCP with MRI improves sensitivity to 89% without a change in the test accuracy. Interestingly, the performance of ultrasound, a less expensive, more readily available technique, has a sensitivity and specificity of 57% and 94%, respectively (90%) (Table 1).27 These data were obtained in patients seeking medical advice at a tertiary care medical center, and test performance in the PSC population in general is simply unclear. Nevertheless, we suggest that either MRI/MRCP or careful ultrasound examination of the liver are reasonable imaging studies for CCA surveillance.

Table 1. Summary of Diagnostic Performance of the Different Proposed Surveillance Modalities for Hepatobiliary Cancer in Patients with PSC
ModalityCCA27GBN52*HCC74
Sensitivity (%)Specificity (%)Sensitivity (%)Specificity (%)Sensitivity (%)Specificity (%)
  • *

    Data for GBN (included adenocarcinoma and lesions with low- and high-grade dysplasia) were validated in patients with PSC for gallbladder lesions ≥0.8 cm.

  • Data for HCC were validated only for 1-2-cm lesions in patients with cirrhosis resulting from different etiologies, not specifically in patients with PSC.

  • CA 19-9 ≥20 U/mL and either test being positive.

  • Abbreviations: CCA, cholangiocarcinoma; GBN, gallbladder neoplasia; HCC, hepatocellular carcinoma; CA 19-9, carbohydrate antigen 19-9; CEUS, contrast-enhanced ultrasound; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; CT, computerized tomography; ERCP, endoscopic retrograde cholangiopancreatography; ND, no data; NA, not applicable.

Ultrasound579410070ND
Ultrasound plus CA 19-99162NANA
CEUSNDNDND5391
MRI6379ND62100
MRCP7876NDNA
MRI/MRCP8975NDNA
MRI/MRCP plus CA 19-910038NANA
CT scan7580ND5399
CT scan plus CA 19-910038NANA
ERCP9166NANA
ERCP plus CA 19-910043NANA

In addition to imaging studies, an alternative or complementary approach is the use of serum biomarkers for CCA. The only currently available serum biomarker for CCA is the carbohydrate antigen 19-9 (CA 19-9) assay. The testing of CA 19-9, with a cutoff value ≥20 U/mL, enhances MRI/MRCP sensitivity to 100% at the expense of specificity (38%) and accuracy (47%) (Table 1). Choosing a cut-off value of ≥129 U/mL improves specificity, but also decreases sensitivity.27 The latter needs to be interpreted with caution, because more than one-third of patients with this cutoff do not have CCA on 30 months of follow-up.28 Patients with negative Lewis antigen, representing 7% of the general population, are also negative for CA 19-9 and will not benefit from CA 19-9 testing.29

Endoscopic retrograde cholangiopancreatography (ERCP) with random brush cytology of the biliary tree, analogous to surveillance colonoscopy, may be considered, by some, as an alternative surveillance strategy. The sensitivity of a positive ERCP (e.g., biliary stenosis with polypoid duct lesion, dominant stricture, or marked proximal bile duct dilatation), in combination with CA 19-9 above 20 U/mL, is 100%, with an accuracy of 49% (Table 1). One of the drawbacks of ERCP with conventional cytology is the lack of sensitivity of conventional cytology for the diagnosis of CCA (a sensitivity of 8% for only positive results and 46% for both positive and suspicious for malignancy results).27 Fluorescence in situ hybridization (FISH) analysis may add to the value of conventional cytology.30-33 It is utilized for the identification of aneusomy (i.e., numerical amplification of selected chromosomes or chromosomal loci), which is considered equivalent to aneuploidy (a term restricted to assays examining the whole genome). Unequivocally positive FISH results, as in the detection of polysomy, have a sensitivity of 38% for CCA detection, but a specificity and accuracy of 98% and 83%, respectively.27 This increases the diagnostic yield over conventional cytology. Overall, based on performance of test combinations, we still find it difficult to advocate for ERCP-based surveillance. The technique is also burdened by complications including pancreatitis and cholangitis, making it undesirable as a surveillance modality. Indeed, 10% of PSC patients require hospitalization after an ERCP.34 Therefore, an ERCP with brushings for conventional cytology and FISH analysis is a confirmatory test, indicated if noninvasive imaging modalities suggest a worrisome finding or if there has been a change in serum cholestatic parameters.

Approach to High-Grade Dysplasia.

A dysplasia-carcinoma sequence is substantiated by an expanding body of evidence in PSC.35-37 However, a clinical approach to high-grade dysplasia (HGD) detected on conventional cytologic evaluation still represents a very controversial issue. According to available studies, dysplasia is present in 0%-58% of liver tissue with and without CCA.22, 38-42 Up to 36% of patients with low-grade dysplasia (LGD) and HGD are found to have CCA in liver explants.43 Therefore, there are advocates for preemptive liver transplantation in those patients with HGD found on biliary biopsy.43, 44 HGD, which can be considered carcinoma in situ, often represents a field defect throughout the biliary tree, making segmental resection an unattractive option. Therefore, liver transplantation in this setting may be considered a logical therapeutic approach. In the United States, such patients are not, however, prioritized for liver transplantation. Diligent monitoring at short time intervals (e.g., 3-4 months) with repeat ERCP-directed brushings and biopsies until CCA can be established is likely the only approach for these patients in the United States. Clearly, this is an area that requires intense investigation.

Current Treatment Options for CCA.

The extremely poor prognosis of CCA brings a high level of anxiety to physicians taking care of patients with PSC. Surgical treatment with negative tumor margins can be appropriate for early stage of disease in patients with reasonably preserved liver function, but is still associated with a 3-year survival rate of less than 20%.45 A contemporary treatment with a combination of neoadjuvant chemotherapy followed by liver transplantation is likely the best option available and leads to a 5-year survival rate above 70%. Unfortunately, it can be offered to less than 10% of a highly select group of patients at specialized transplant centers.45 Hence, the advantage of making an early diagnosis of CCA in PSC patients, and its cost-effectiveness in a population of PSC patients, is unclear if transplantation is not available. At the individual patient/physician level, the patient desires an early diagnosis and any chance of survival is usually seen by patients as superior to no chance.

Pragmatic Clinical Approach for CCA Surveillance in PSC.

Despite the absence of high-quality evidence, an interval follow-up with a combination of a MRI/MRCP or ultrasound, plus a serum CA 19-9 determination on an annual basis, is rational for CCA surveillance in patients with PSC (Fig. 1). ERCP with brush cytology should be reserved for patients with dominant strictures, an increase in cholestatic biochemistries, rising CA 19-9, pruritus, or bacterial cholangitis. Patients with an early diagnosis of CCA appear to be best served by referral to centers experienced in hepatobiliary surgery and liver transplantation. The suggested interval of follow-up at 1 year is not well supported by data and, ideally, should be based on tumor doubling time, which can be very challenging in a disease with the pattern of growth of CCA. Cost-effectiveness studies for this approach are desired, but because of overall low prevalence of disease can be accomplished only by multicenter and, likely, international collaborations.

thumbnail image

Figure 1. Recommendations for decision process for CCA surveillance in PSC. Abbreviations: CCA, cholangiocarcinoma; PSC, primary sclerosing cholangitis; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; CA 19-9, carbohydrate antigen 19-9; ERCP, endoscopic retrograde cholangiopancreatography; FISH, fluorescence in situ hybridization.

Download figure to PowerPoint

GBC in Patients with PSC

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Epidemiology and Risk Factors for GBC in PSC.

PSC patients have an increased frequency of gallbladder mass lesions, with an estimated prevalence of 3%-14% versus 0.35% in the general population.46-48 Males represent more than 60% of those with GBC among PSC patients, which is the opposite of studies in the general population demonstrating a female predominance.49, 50 Patients with PSC and GBC tend to be younger than GBC patients without PSC; 70% of PSC/GBC patients are less than 60 years of age, with a median age at diagnosis of 5850 versus 70 years in the general population.51

Risk factors for presence of GBC within a polyp in non-PSC patients are in size more than 0.8 cm, especially if the lesion is sessile and rapidly growing, displaying imaging features of local invasion, vascularity on Doppler ultrasound or contrast-enhancement on cross-sectional imaging studies, simultaneous presence of gallstones, and older age at time of polyp diagnosis.52-56 Likely, these same risk factors apply to PSC patients. Chronic inflammation caused by stones or infection, such as from Salmonella, is a risk factor in non-PSC patients, and, presumably, the chronic inflammation of PSC involving the gallbladder also leads to carcinogenesis. Although PSC by itself is also a risk factor for gallbladder stones,57 gallstones are present only in approximately one-quarter of PSC patients with GBC47, 58 versus 65%-90% of patients with GBC without PSC.51, 59

Association of GBC With Other Malignancies in PSC.

An association of GBC with bile duct dysplasia and CCA has been reported.35, 60 IBD with colonic dysplasia may also be more prevalent in patients with GBC,21, 61, 62, and cases of concurrent GBC and HCC are described.63

Management of Gallbladder Lesions in PSC and Its Controversies.

Current treatment options for GBC include potentially curative surgery with cholecystectomy for localized early-stage disease comprising only 10% of non-PSC cases.64, 65 Survival in patients with GBC is closely related to depth of tumor invasion, CA 19-9 level before surgery, and gross morphology66 and is still very dismal. Overall 5-year survival is less than 10%59, and for stage 3-4 disease, is less than 5%.67

Because of awareness that up to 56% of mass lesions of the gallbladder might harbor cancer or dysplasia,68 as well as the poor prognosis of GBC, the general consensus has been to recommend cholecystectomy for all gallbladder lesions in PSC patients independent of their size.11, 69 This suggestion is based on reports of adenocarcinoma, the most common histological type of GBC, in lesions ranging in size from 6 to 35 mm.46, 68, 70 Moreover, several studies identified adenocarcinoma concurrently with different grades of dysplasia in the background gallbladder epithelium.35, 46, 71 Analysis of cholecystectomy samples from liver explants also revealed the presence of gallbladder dysplasia in up to 37% of cases.35 The last two observations might, in fact, support the hypothesis of adenoma-carcinoma sequence similar to those in patients with IBD and CRC and prompt most physicians to be even more comfortable with cholecystectomy for any gallbladder polyps in PSC patients. Although liver transplantation for GBC has been proposed by some groups,60 it is not yet well evaluated, and we are not aware of any published outcome data for this indication.

The AASLD guidelines support the cholecystectomy strategy for any size polyps in patients with PSC.11 However, the approach may be challenged by studies with retrospective examination of early postoperative and long-term clinical outcomes and the predictors of malignancy in PSC patients with gallbladder polyps.50, 52 These data suggest that a polyp size ≥0.8 cm has utility in predicting the presence of gallbladder neoplasia with a sensitivity of 100% and specificity of 70% in PSC patients (Table 1).52 The leading cause of death in >10% of patients postcholecystectomy was reported to be liver-related complications.50, 52 This information also may help clinical decision making, given the complexity of surgery for patients with PSC, particularly if liver function is compromised.

Suggestions for GBC Surveillance in PSC.

Both the AASLD and European Association for the Study of the Liver (EASL) recommend annual abdominal ultrasound for the detection of gallbladder pathology.11, 69 Ultrasound seems to be an appropriate modality for surveillance, which, despite the lack of cost-effectiveness studies, is likely to be the most available and acceptable surveillance modality. MRI/MRCP also can be potentially utilized for GBC surveillance purposes and has the advantage of providing surveillance for CCA, as well. For patients with PSC with a concurrent small gallbladder polyp, regular imaging studies at intervals of 3-6 months is also rational and has been reported to result in an earlier diagnosis of GBC.72 Although lesions less than 0.8 cm may be at a lower risk for GBC, performing a cholecystectomy in patients without cirrhosis is also reasonable, even in patients with smaller polyps (Fig. 2). The natural history of small polyps in PSC, tumor doubling time, and outcomes of patients with PSC postcholecystectomy are yet to be well defined.

thumbnail image

Figure 2. Recommendations for decision process for GBC surveillance in PSC. Abbreviations: GBC, gallbladder cancer; PSC, primary sclerosing cholangitis; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography.

Download figure to PowerPoint

HCC in Patients with PSC

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

There is certainly a signal for an increased risk for HCC in patients with PSC.10 This is not surprising, because virtually all causes of cirrhosis are associated with a risk for HCC development. Cost-benefit analysis suggests that an HCC incidence of up to 1.5% is sufficient to justify screening in cirrhotic stage disease.73 However, the incidence of HCC for PSC cirrhotics has not been well studied, and most experienced clinicians believe it to be well below the 1.5%/year threshold required to institute HCC surveillance strategies. Nevertheless, cross-sectional imaging studies, such as MRI/MRCP or ultrasound, conducted for a purpose of surveillance for CCA and GBC might assist in detecting HCC, as well (Table 1).73, 74

CRC in Patients with PSC

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Epidemiology and Characteristics of IBD and CRC in PSC.

IBD is observed in up to 80% of patients with PSC. Meanwhile, only 2%-7.5% of the population with IBD develops PSC.75 Approximately 80% of IBD is represented by UC, 10% by Crohn's disease (CD), and 10% described as an indeterminate colitis.75 For UC associated with PSC (PSC/UC), compared with UC alone, OR for CRC development, is 4.6.76 The cumulative incidence of development of CRC or dysplasia in PSC/UC patients versus UC alone is 9% and 2% after 10 years and 20%-31% and 5% after 20 years of disease duration, respectively.26, 77-79 CD associated with PSC rarely has all the classic features of CD and tends to involve primarily the colon,80 and many cases classified as CD may, in fact, represent a specific subtype of IBD characteristic for PSC (i.e., colitis with rectal sparing and backwash ileitis).75, 81 Patients with IBD and PSC are younger at IBD diagnosis,82, 83 and, in most patients, the diagnosis of IBD precedes the diagnosis of PSC.

IBD in PSC is often quiescent or even inapparent by history,75, 84, 85 and many patients with PSC are diagnosed with IBD by active screening with colonoscopy. Even more worrisome, patients may already have dysplasia at the initial surveillance colonoscopy.85 Colonic neoplasia, including dysplasia, in PSC patients with colitis is most prevalent in the proximal colon (65%).86 One study also suggested that patients with PSC and dominant stricture on biliary tree imaging have an increased risk for both colorectal and hepatobiliary malignancies.87

Risk of CRC After Orthotopic Liver Transplantation.

A separate issue involves management of IBD in patients with PSC undergoing orthotopic liver transplantation OLT. Though, in the past, prophylactic proctoclectomy was advocated by some in light of an increased colorectal neoplasia incidence post–liver transplantation,88 this strategy cannot be supported, based on later studies. Despite the trend for an increased rate of CRC in patients after OLT, compared with those without OLT (OR = 4.4; 95% confidence interval [CI]: 0.9-12.8), 5-year survival of patients who underwent proctocolectomy before OLT did not differ from the survival of PSC/UC patients with an intact colon and OLT (86% for both groups).89 None of the deaths in the intact colon group were related to CRC. Thus, the risk of colonic neoplasia alone is not sufficient to justify a proctocolectomy in PSC/IBD patients undergoing, or status, post–liver transplantation. Surveillance in these patients is the same as for nontransplant patients.

Management of PSC/IBD After Neoplasia Diagnosis.

Colorectal neoplasia complicating colitis represents a range of pathology from indefinite dysplasia to advanced adenocarcinoma. For patients with IBD alone, even the presence of LGD often prompts a recommendation for total proctocolectomy.90, 91 The risk of progression from LGD to HGD or even adenocarcinoma may be increased in PSC/IBD patients (hazard ratio [HR]: 10.4; 95% CI: 0.94-115)92, in support of advocates of proctocolectomy for PSC/IBD patients with colonic LGD and, certainly, for HGD, which has been confirmed by two independent pathologists. However, there are higher rates of pouchitis with ileal pouch-anal anastamosis and difficult-to-treat peristomal varices after Brooke ileostomy in PSC/UC patients.93

In addition, PSC patients may have compromised hepatic function, and several studies have evaluated the safety of a proctocolectomy in this patient population. Indeed, PSC patients with cirrhosis have a worse prognosis postproctocolectomy than those without cirrhosis (38% early postoperative death versus 0%, respectively).94 The risk of death in patients with cirrhosis who underwent elective colectomy was 3.7 times higher, compared with those without cirrhosis.95 Moreover, 25% of patients who underwent a proctocolectomy in the setting of UC died or required liver transplantation within 2.6 years after the surgical procedure.96 These retrospective observations suggest that a proctocolectomy may adversely affect the natural history of PSC. Lower albumin and platelet levels preoperatively were predictors of poor outcomes (OR = 0.99 and 0.05, respectively, with P < 0.05).96 Besides high rates of pouchitis and peristomal varices, this recent data suggest that PSC patients undergoing a proctocolectomy also should be informed of potential hepatic decompensation and be monitored closely or even be evaluated for liver transplantation before surgery.

Current Recommendations for CRC Surveillance.

A long preclinical course of IBD, extensive colitis, presence of dysplasia diagnosed on first endoscopic examination, absence of association between disease severity and colorectal neoplasia development, and higher prevalence of right-sided neoplasia—which is often harder to detect—all justify CRC surveillance with colonoscopy in patients with IBD starting promptly from time of PSC diagnosis. Colonoscopy every 1-2 years is recommended and advocated by both the AASLD and EASL guidelines.11, 69 Importantly, the value of these recommendations was reassessed in a recent study.86 Indeed, this study demonstrated that the frequency of CRC development within 2 years of PSC/IBD diagnosis is the same as colorectal neoplasia development within 8-10 years of concurrent diagnosis. Notably, in those with CRC, more than 50% had greater than stage 3 disease at diagnosis. These data further support the AASLD and EASL guidelines. The role of chromoendoscopy, narrow band-imaging technique, and confocal endomicroscopy to augment the diagnostic ability of white light colonoscopy is to be determined.97 However, given the potential for development of proctocolectomy-related complications, these studies, especially chromoendoscopy, may be considered for patients with LGD, rather than proceeding to surgery (Fig. 3). In some patients, these techniques identify “flat lesions” with LGD, which may be amenable to endoscopic therapy (e.g., endoscopic mucosal resection).

thumbnail image

Figure 3. Recommendations for decision process for CRC surveillance in PSC. Abbreviations: CRC, colorectal cancer; PSC, primary sclerosing cholangitis; IBD, inflammatory bowel disease; HGD, high-grade dysplasia; LGD, low-grade dysplasia.

Download figure to PowerPoint

Summary of Our Current Knowledge Regarding Management of and Surveillance for CRC in PSC/IBD.

Surveillance colonoscopy is recommended every 1-2 years starting at the time of PSC diagnosis. Proctocolectomy is recommended in patients with dysplasia and/or cancer; however, patients should be monitored closely for hepatic decompensation after the procedure and informed of surgery-related complications. Outcome studies for indefinite and colorectal LGD in patients with PSC/IBD are desirable to protect patients from potentially unnecessary surgical intervention, which might lead to no improvement in overall survival, especially if cirrhosis is present.

The Role of UDCA in Chemoprevention

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

Multiple potential disease-modifying agents have been studied in PSC, including corticosteroids, colchicine, penicillamine, cyclosporine, tacrolimus, azathioprine, pentoxifylline, pirfenidone, and methotrexate, without encouraging results.98-100 Experience with another cholestatic liver disorder, primary biliary cirrhosis, prompted an interest in UDCA for treatment in patients with PSC. The UDCA dose evaluation was done in a “step up” fashion. First, a randomized, controlled trial with 13-15 mg/kg of UDCA per day showed improvement in the biochemical profile associated with PSC, but with no modification of primary outcomes, such as death, liver transplantation, histological progression, development of cirrhosis complications, and symptoms.101 The next step was an evaluation of UDCA at 20 mg/kg per day.102 Improvement in biochemical and histological profiles and the absence of significant side effects were very promising, but long-term survival was not evaluated. Meanwhile, over a 5-year study period, no statistically significant difference was found between UDCA (at the dose of 17-23 mg/kg/day) and placebo groups in outcomes, including survival and CCA incidence in another study.103 A more recent randomized, controlled trial, employing high-dose UDCA (28-30 mg/kg a day), was terminated prematurely. Compared with the placebo group, primary end-points (e.g., death, liver transplantation, cirrhosis, ascites, varices, and CCA) were reached 2.3 times (P < 0.01) and death, transplantation, and minimal listing criteria 2.1 times (P = 0.038) more often in the treatment group. Disconcerting also was the fact that liver tests often improved, which masked the toxicity of UDCA. As anticipated, poor outcomes were more common in patients with a higher Mayo risk score and advanced histological stage, regardless of treatment allocation.104 More interesting, subgroup analysis demonstrated a higher rate of adverse outcomes in the UDCA treatment group versus placebo (14 versus 4; P = 0.0151) for patients with earlier histological stage (stage 1-2).105

Meanwhile, a study from Brandsaeter et al. suggested that no treatment with UDCA was an independent predictor of hepatobiliary malignancy in patients listed for liver transplantation.61 Other studies additionally demonstrated a decrease in the risk of CRC and dysplasia development in PSC/UC patients treated with UDCA.106, 107 However, a recent analysis demonstrated an increased incidence of CR neoplasia in patients treated with high doses UDCA (28-30 mg/kg/day). Indeed, an HR of 4.44 (95% CI: 1.30-20.1; P = 0.02) for development of colorectal cancer and dysplasia, mainly LGD, in patients receiving UDCA versus placebo, is worrisome!108

Summary on UDCA Use in PSC Patients.

Certainly, high doses of UDCA (>28 mg/kg/day) should not be used because of increased risk of poor long-term hepatic outcomes and risk of colorectal neoplasia. We, in general, do not advocate the use of UDCA as a chemopreventive agent. The data simply are not compelling in the absence of properly designed trials with end-points of either CCA or CRC.

Other Promising Chemopreventive Agents in PSC.

Reports from studies focused on 5-aminosalicylic acid preparations differ. Sulfasalazine therapy is described to pose an increased risk for dysplasia in PSC/UC.107 However, mesalamine, alone or in combination with UDCA, had been shown to have some protective effect.107, 109, 110 An observation that some 5-aminosalicylic acid preparations might have protective effects in PSC/IBD patients deserves additional attention.

Conclusion

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References

To establish the best practice for cancer surveillance in our patients with PSC patients, we need to remind ourselves of the principles of surveillance, be abreast of the current status of medical knowledge regarding the problem, and apply them to each individual situation. This analysis must take into account costs of surveillance, therapies available, and their impact on the patients. Surveillance strategies for CCA are still in evaluation, and cost-effectiveness studies do not support routine surveillance for HCC limited to PSC cirrhotics, whereas surveillance for GBC and CRC is more straightforward.

References

  1. Top of page
  2. Abstract
  3. Epidemiology of Primary Sclerosing Cholangitis
  4. Cancer Risk in Patients With PSC
  5. Principles of Disease Surveillance
  6. CCA in Patients With PSC
  7. GBC in Patients with PSC
  8. HCC in Patients with PSC
  9. CRC in Patients with PSC
  10. The Role of UDCA in Chemoprevention
  11. Conclusion
  12. References
  • 1
    Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003; 125: 1364-1369.
  • 2
    Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998; 33: 99-103.
  • 3
    Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007; 102: 1042-1049.
    Direct Link:
  • 4
    Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology 2004; 126: 1929-1930.
  • 5
    Escorsell A, Pares A, Rodes J, Solis-Herruzo JA, Miras M, de la Morena E. Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J Hepatol 1994; 21: 787-791.
  • 6
    Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY. Clinical profile of primary sclerosing cholangitis in Singapore. J Gastroenterol Hepatol 2002; 17: 908-913.
  • 7
    Lindkvist B, Benito de Valle M, Gullberg B, Bjornsson E. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology 2010; 52: 571-577.
  • 8
    Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36: 321-327.
  • 9
    Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004; 99: 523-526.
    Direct Link:
  • 10
    Harnois DM, Gores JG, Ludwig J, Steers JL, LaRusso NE, Wiesner RH. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997; 27: 512-516.
  • 11
    Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51: 660-678.
  • 12
    Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2011: CD001877.
  • 13
    Kopans DB. The 2009 US Preventive Services Task Force (USPSTF) guidelines are not supported by science: the scientific support for mammography screening. Radiol Clin North Am 2010; 48: 843-857.
  • 14
    Lin K, Lipsitz R, Miller T, Janakiraman S. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med 2008; 149: 192-199.
  • 15
    Helzberg JH, Peterson JM, Boyer JL. Improved survival with promary sclerosing cholangitis. A review of clinicopathologic features and comparison of symptomatic and asymptomatic patients. Gastroenterology 1887; 92: 1869-1875.
  • 16
    Farrant JM, Hayllar KM, Wilkinson ML, Karani J, Portmann BC, Westaby D, Williams R. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991; 100: 1710-1717.
  • 17
    Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 1997; 32: 1042-1045.
  • 18
    Rosen CB, Nagorney DM. Cholangiocarcinoma complicating primary sclerosing cholangitis. Semin Liver Dis 1991; 11: 26-30.
  • 19
    Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38: 610-615.
  • 20
    Melum E, Karlsen TH, Schrumpf E, Bergquist A, Thorsby E, Boberg KM, Lie BA. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 2008; 47: 90-96.
  • 21
    Broome U, Lofberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995; 22: 1404-1408.
  • 22
    Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27: 311-316.
  • 23
    Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000; 31: 7-11.
  • 24
    Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128: 620-626.
  • 25
    Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002; 37: 1205-1211.
  • 26
    Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009; 50: 158-164.
  • 27
    Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48: 1106-1117.
  • 28
    Sinakos E, Saenger AK, Keach J, Kim WR, Lindor KD. Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma. Clin Gastroenterol Hepatol 2011; 434-449.e1.
  • 29
    Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004; 24: 139-154.
  • 30
    Moreno Luna LE, Kipp B, Halling KC, Sebo TJ, Kremers WK, Roberts LR, et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 2006; 131: 1064-1072.
  • 31
    Fritcher EG, Kipp BR, Halling KC, Oberg TN, Bryant SC, Tarrell RF, et al. A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology 2009; 136: 2180-2186.
  • 32
    Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol 2004; 99: 1675-1681.
  • 33
    Bangarulingam SY, Bjornsson E, Enders F, Barr Fritcher EG, Gores G, Halling KC, Lindor KD. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology 2010; 51: 174-180.
  • 34
    Bangarulingam SY, Gossard AA, Petersen BT, Ott BJ, Lindor KD. Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol 2009; 104: 855-860.
  • 35
    Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol 2007; 31: 907-913.
  • 36
    Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobil Pancreat Surg 2003; 10: 265-281.
  • 37
    Shimonishi T, Sasaki M, Nakanuma Y. Precancerous lesions of intrahepatic cholangiocarcinoma. J Hepatobil Pancreat Surg 2000; 7: 542-550.
  • 38
    Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP. Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2001; 34: 360-365.
  • 39
    Bergquist A, Glaumann H, Stal P, Wang GS, Broome U. Biliary dysplasia, cell proliferation, and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma. J Intern Med 2001; 249: 69-75.
  • 40
    Ludwig J, Wahlstrom HE, Batts KP, Wiesner RH. Papillary bile duct dysplasia in primary sclerosing cholangitis. Gastroenterology 1992; 102: 2134-2138.
  • 41
    Katabi N, Albores-Saavedra J. The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis. Am J Surg Pathol 2003; 27: 349-355.
  • 42
    Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma. Am J Surg Pathol 2010; 34: 27-34.
  • 43
    Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2006; 45: 568-574.
  • 44
    Sharma RR, London MJ, Magenta LL, Posner MC, Roggin KK. Preemptive surgery for premalignant foregut lesions. J Gastrointest Surg 2009; 13: 1874-1887.
  • 45
    Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int 2010; 23: 692-697.
  • 46
    Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol 2002; 97: 1138-1142.
    Direct Link:
  • 47
    Said K, Glaumann H, Broome U, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 2007; 46: 256.
  • 48
    Paolucci V, Schaeff B, Schneider M, Gutt C. Tumor seeding following laparoscopy: international survey. World J Surg 1999; 23: 989-995; discussion, 996-987.
  • 49
    Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001; 51: 349-364.
  • 50
    Treeprasertsuk S, Sinakos E, Keach J, Lindor KD. Outcome of gallbladder polyps in patients with primary sclerosing cholangitis. Submitted 2011.
  • 51
    Malik IA. Gallbladder cancer: current status. Expert Opin Pharmacother 2004; 5: 1271-1277.
  • 52
    Eaton JE, Thackeray EW, Lindor KD. Outcomes following cholecystectomy in primary sclerosing cholangitis: removing small gallbladder polyps are not worth the risk. Submitted 2011.
  • 53
    Zielinski MD, Atwell TD, Davis PW, Kendrick ML, Que FG. Comparison of surgically resected polypoid lesions of the gallbladder to their pre-operative ultrasound characteristics. J Gastrointest Surg 2008; 13: 19-25.
  • 54
    Mainprize KS, Gould SW, Gilbert JM. Surgical management of polypoid lesions of the gallbladder. Br J Surg 2000; 87: 414-417.
  • 55
    Shinkai H, Kimura W, Muto T. Surgical indications for small polypoid lesions of the gallbladder. Am J Surg 1998; 175: 114-117.
  • 56
    Lee JS, Lee KT, Jung JH, Ok SW, Choi SC, Lee KH, et al. [Factors associated with malignancy in gallbladder polyps without gallbladder stone]. Korean J Gastroenterol 2008; 52: 97-105.
  • 57
    Silveira MG, Lindor KD. Primary sclerosing cholangitis. Can J Gastroenterol 2008; 22: 689-698.
  • 58
    Brandt DJ, MacCarty RL, Charboneau JW, LaRusso NF, Wiesner RH, Ludwig J. Gallbladder disease in patients with primary sclerosing cholangitis. AJR Am J Roentgenol 1988; 150: 571-574.
  • 59
    Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol 2003; 4: 167-176.
  • 60
    Karlsen TH, Schrumpf E, Boberg KM. Gallbladder polyps in primary sclerosing cholangitis: not so benign. Curr Opin Gastroenterol 2008; 24: 395-399.
  • 61
    Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, et al. Liver transplantation for primary sclerosing cholangitis: predictors and consequences of hepatobiliary malignancy. J Hepatol 2004; 40: 815-822.
  • 62
    Klingenberg-Noftz RD, Homann N, Bos I, Bruch HP, Ludwig D. Simultaneous detection of synchronous colonic and biliary carcinoma by abdominal ultrasonography in two patients with ulcerative colitis. Dig Dis Sci 2004; 49: 1922-1929.
  • 63
    Schmitt TM, Hughes CB, Bonatti H, Harnois DM, Nguyen JH, Dickson RC, et al. Gallbladder cancer and liver transplantation. Transpl Int 2005; 18: 52-55.
  • 64
    Kiran RP, Pokala N, Dudrick SJ. Incidence pattern and survival for gallbladder cancer over three decades—an analysis of 10,301 patients. Ann Surg Oncol 2007; 14: 827-832.
  • 65
    Fong Y, Wagman L, Gonen M, Crawford J, Reed W, Swanson R, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg 2006; 243: 767-771; discussion, 771-764.
  • 66
    Park JS, Yoon DS, Kim KS, Choi JS, Lee WJ, Chi HS, Kim BR. [Analysis of prognostic factors after curative resection for gallbladder carcinoma]. Korean J Gastroenterol 2006; 48: 32-36.
  • 67
    Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder. Histologic types, stage of disease, grade, and survival rates. Cancer 1992; 70: 1493-1497.
  • 68
    Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 2008; 48: 598-605.
  • 69
    Beuers U, Boberg KM, Chapman RW, Chazouillères O, Invernizzi P, Jones DE, et al. collaborating on behalf of the European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51: 237-267.
  • 70
    Zielinski MD, Atwell TD, Davis PW, Kendrick ML, Que FG. Comparison of surgically resected polypoid lesions of the gallbladder to their pre-operative ultrasound characteristics. J Gastrointest Surg 2009; 13: 19-25.
  • 71
    Leung UC, Wong PY, Roberts RH, Koea JB. Gall bladder polyps in sclerosing cholangitis: does the 1-cm rule apply? ANZ J Surg 2007; 77: 355-357.
  • 72
    Yamamoto T, Uki K, Takeuchi K, Nagashima N, Honjo H, Sakurai N, et al. Early gallbladder carcinoma associated with primary sclerosing cholangitis and ulcerative colitis. J Gastroenterol 2003; 38: 704-706.
  • 73
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2010; 000: 1-35.
  • 74
    Khalili K, Kim TK, Jang HJ, Haider MA, Khan L, Guindi M, Sherman M. Optimization of imaging diagnosis of 1-2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol 2011; 54: 723-728.
  • 75
    Loftus EV, Jr., Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54: 91-96.
  • 76
    Soetikno R, Lin O, Heidenreich P, Young H, Blackstone M. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002; 56: 48-54.
  • 77
    Broome U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006; 26: 31-41.
  • 78
    Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990; 323: 1228-1233.
  • 79
    Leidenius MH, Farkkila MA, Karkkainen P, Taskinen EI, Kellokumpu IH, Hockerstedt KA. Colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis. Scand J Gastroenterol 1997; 32: 706-711.
  • 80
    Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 1991; 11: 31-39.
  • 81
    Faubion WA, Jr., Loftus EV, Sandborn WJ, Freese DK, Perrault J. Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with psc. J Pediatr Gastroenterol Nutr 2001; 33: 296-300.
  • 82
    Brackmann S, Andersen SN, Aamodt G, Langmark F, Clausen OP, Aadland E, et al. Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease. Scand J Gastroenterol 2009; 44: 46-55.
  • 83
    Joo M, Abreu-e-Lima P, Farraye F, Smith T, Swaroop P, Gardner L, et al. Pathologic features of ulcerative colitis in patients with primary sclerosing cholangitis: a case-control study. Am J Surg Pathol 2009; 33: 854-862.
  • 84
    Lundqvist K, Broome U. Differences in colonic disease activity in patients with ulcerative colitis with and without primary sclerosing cholangitis: a case control study. Dis Colon Rectum 1997; 40: 451-456.
  • 85
    Broome U, Lofberg R, Lundqvist K, Veress B. Subclinical time span of inflammatory bowel disease in patients with primary sclerosing cholangitis. Dis Colon Rectum 1995; 38: 1301-1305.
  • 86
    Thackeray EW, Charatcharoenwitthaya P, Elfaki D, Sinakos E, Lindor KD. Colon neoplasms develop early in the course of inflammatory bowel disease and primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2011; 9: 52-56.
  • 87
    Rudolph G, Gotthardt D, Kloeters-Plachky P, Rost D, Kulaksiz H, Stiehl A. In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival. J Hepatol 2010; 53: 313-317.
  • 88
    Higashi H, Yanaga K, Marsh JW, Tzakis A, Kakizoe S, Starzl TE. Development of colon cancer after liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Hepatology 1990; 11: 477-480.
  • 89
    Loftus EV, Jr., Aguilar HI, Sandborn WJ, Tremaine WJ, Krom RA, Zinsmeister AR, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998; 27: 685-690.
  • 90
    Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994; 343: 71-74.
  • 91
    Nguyen GC, Frick KD, Dassopoulos T. Medical decision analysis for the management of unifocal, flat, low-grade dysplasia in ulcerative colitis. Gastrointest Endosc 2009; 69: 1299-1310.
  • 92
    Pekow JR, Hetzel JT, Rothe JA, Hanauer SB, Turner JR, Hart J, et al. Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis. Inflamm Bowel Dis 2010; 16: 1352-1356.
  • 93
    Loftus EV, Sandborn WJ, Lindor KD, LaRusso NF. Interactions between chronic liver disease and inflammatory bowel disease. Inflamm Bowel Dis 1997; 3: 288-302.
  • 94
    Post AB, Bozdech JM, Lavery I, Barnes DS. Colectomy in patients with inflammatory bowel disease and primary sclerosing cholangitis. Dis Colon Rectum 1994; 37: 175-178.
  • 95
    Csikesz NG, Nguyen LN, Tseng JF, Shah SA. Nationwide volume and mortality after elective surgery in cirrhotic patients. J Am Coll Surg 2009; 208: 96-103.
  • 96
    Treeprasertsuk S, Bjornsson E, Abbas G, Sinakos E, Keach J, Lindor KD. Outcome of patients with primary sclerosing cholangitis and ulcerative colitis. Submitted 2011.
  • 97
    Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 746-774, 774.e741-744; quiz, e712-743.
  • 98
    LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 1988; 95: 1036-1042.
  • 99
    Knox TA, Kaplan MM. A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994; 106: 494-499.
  • 100
    Olsson R, Broome U, Danielsson A, Hagerstrand I, Jarnerot G, Loof L, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology 1995; 108: 1199-1203.
  • 101
    Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 1997; 336: 691-695.
  • 102
    Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001; 121: 900-907.
  • 103
    Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 2005; 129: 1464-1472.
  • 104
    Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009; 50: 808-814.
  • 105
    Imam MH, Sinakos E, Gossard AA, Kowdley KV, Luketic VA, Harrison ME, et al. Increased risk of adverse outcomes in primary sclerosing cholangitis patients receiving high dose ursodeoxycholic acid is confined to early stage of disease. Submitted 2011.
  • 106
    Pardi DS, Loftus EV, Jr.; Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003; 124: 889-893.
  • 107
    Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, Kowdley KV, Brentnall TA. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001; 134: 89-95.
  • 108
    Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011 May 10. doi:10.1038/ajg.2011.156.
  • 109
    Smith T, Swaroop P. Mesalamine reduces the rate of colorectal dysplasia in patients with inflammatory bowel disease and primary sclerosing cholangitis who are on ursodeoxycholic acid [abstract]. Gastroenterology 2006; 130( Suppl2): A-653.
  • 110
    Chan EP, Lichtenstein GR. Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease. Gastroenterol Clin North Am 2006; 35: 675-712.