Cancer surveillance in patients with primary sclerosing cholangitis

Authors


  • Potential conflict of interest: Dr. Lindor received grants from Axcan.

  • This work was supported by National Institutes of Health Grants DK59427 (to G.J.G.), DK056924 (to K.D.L.), and T32 DK007198 (to N.R.) and the Mayo Foundation.

Abstract

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)

Abbreviations

AASLD, American Association for the Study of Liver Diseases; CA 19-9, carbohydrate antigen 19-9; CCA, cholangiocarcinoma; CD, Crohn's disease; 95% CI, 95% confidence interval; CRC, colorectal carcinoma; EASL, European Association for the Study of the Liver; ERCP, endoscopic retrograde cholangiopancreatography; FISH, fluorescence in situ hybridization; GBC, gallbladder cancer; HCC, hepatocellular carcinoma; HGD, high-grade dysplasia; HR, hazard ratio; IBD, inflammatory bowel disease; LGD, low-grade dysplasia; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; OLT, orthotopic liver transplantation; OR, odds ratio; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid.

Epidemiology of Primary Sclerosing Cholangitis

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

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

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

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.

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.

GBC in Patients with PSC

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.

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.

HCC in Patients with PSC

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

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).

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.

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

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

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.

Ancillary