Colorectal cancer after orthotopic liver transplantation

Critical Reviews in Oncology/Hematology 56 (2005) 147–153

Colorectal cancer after orthotopic liver transplantation Michael A. Silva, Periyathambi S. Jambulingam, Darius F. Mirza ∗ The Liver Unit, 3rd Floor, Nuffield House, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK Accepted 14 December 2004

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The incidence of colorectal cancer after LT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Colorectal adenomas in LT candidates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Colorectal adenoma post-LT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSC and CRC in post-LT patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. IBD in PSC patients post-LT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-LT surveillance for CRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of CRC in post-LT patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147 148 148 148 149 149 151 151 151 152 152 153

Abstract There is an increased incidence of de novo malignancies in post-liver transplant patients, commonly associated with chronic viral infection comprising lymphoproliferative disease and skin cancers, including squamous cell carcinoma and Kaposi’s sarcoma. The overall incidence of colorectal cancer however in this population seems to be no different to the age and sex matched general population. In identified high risk patients like those with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the incidence of colorectal cancer appears to be higher. In IBD, like other pre-malignant conditions, the risk of developing malignancy increases exponentially with time, raising the question of whether the apparent increase in the incidence of colorectal cancer is the result of liver transplantation and immunosuppression or due to the natural history of IBD. For these PSC recipients, pre-transplant screening with colonoscopy and posttransplant surveillance for malignant change in the large bowel is crucial. The behaviour of inflammatory bowel disease post-liver transplant is largely unpredictable despite immunosuppression. Colorectal cancer when it occurs in the post-liver transplant patient should be managed according to current guidelines, stage for stage as for the population in general coupled with reduction in immunosuppression treatment. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Inflammatory bowel disease; Primary sclerosing cholangitis; Colorectal adenoma; Post-liver transplant surveillance

1. Introduction Aetiological factors that determine susceptibility for malignancy depend on complex interactions between environmental variables, genetic pre-disposition, oncologenic viral ∗

Corresponding author. Tel.: +44 121 697 8391; fax: +44 121 414 1833. E-mail address: [email protected] (D.F. Mirza).

1040-8428/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2004.12.013

factors and the immune status of the patient. The demographic make up of liver transplant (LT) recipients, as compared with the general population, results in an increased incidence of de novo malignancies. In the LT recipient pre-existent risk factors for colorectal cancer (CRC) like primary sclerosing cholangitis (PSC) and its association with inflammatory bowel disease (IBD), the greater incidence of chronic viral infection and the impact of long-term immunosuppression must

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153

148

play a role in oncogenesis. It is however uncertain whether the increased incidence of de novo malignancies in LT recipients is influenced by the type of immunosuppressive therapy or related to the cause of the underlying liver disease [1,2]. In LT recipients, post-transplant lymphoproliferative disease, skin cancers including squamous cell carcinoma and Kaposi’s sarcoma account for the majority of de novo malignancies [1,3–5]. The incidence of CRC in these patients was similarly thought to be increased. However, studies have shown that there was no apparent increase in risk for LT recipients matched for age, sex and length of follow up, for CRC in this group of patients [3,6,7]. This review examines the risks of CRC in LT recipients, and in subsets of recipients with increased risk factors for CRC like PSC and IBD. An attempt is made to review the role immunosuppression plays on the adenoma/cancer sequence in post-LT recipients and suggested screening surveillance in high risk patients.

lowing LT [10]. There however is a suggestion that the CRC when it does occur in the post-LT population occurs at an earlier age (mean, 41 years) when compared to the general population [3,10]. This reduction of age at presentation was not apparent in more recent studies, which describe age at diagnosis of CRC at a mean of 55 years [1,11]. This could also be as a result of the mean age at LT being greater than 41 years in most centres globally. The immunosuppresion therapy in LT centres is relatively standard at present, primarily based on calcineurin inhibitors (cyclosporine or tacrolimus). Toxic consequences of steroids are ameliorated by early steroid withdrawal where possible without risk of rejection or immunological graft loss [12]. It is therefore unlikely that differences in immunosuppression protocols result in variation in the incidence of CRC after LT between centres.

3. Colorectal adenomas in LT candidates 2. The incidence of colorectal cancer after LT The majority of information on malignancies after LT is from registry reports: the Isreal Penn International Transplant Tumour Registry (IPITTR; formerly the Cincinnati Transplant Tumour Registry) and the Australian Combined Liver Transplant Registry. Registry data however have limitations, which include voluntary reporting, unspecified total at-risk population and the failure of all post-transplant neoplasms being reported uniformly. Therefore, large single centre data in which at risk populations are specified may offer a better picture of the relative risk of CRC post-LT. The reported overall incidence of CRC in post-LT patients is listed in Table 1. LT recipients compared with the general population matched for age, gender and length of follow up have a similar relative risk of developing CRC [1,6–9]. Comparative malignancy incidence expressed as a standardized incidence ratio (SIR; ratio of the observed number of malignancy to the expected number of cases) was found to be 1.01, an SIR value greater than 1 indicating excess risk [7]. The IPITTR too confirms that there is no increased CRC incidence folTable 1 The incidence of colorectal cancer in post-liver transplant patients

There is a view that screening for pre-malignant conditions should be included in pre-transplant evaluation of a potential recipient [13]. The prevalence of colorectal adenomas is estimated at 29% in asymptomatic, average risk persons who are 50 years of age and over [14]. Little is known however about the prevalence of colorectal adenomas in liver transplant candidates. A study examining the diagnostic yield of colonoscopy in lung transplant candidates concluded recently that screening did not alter the management of such patients significantly [15]. In a non-controlled retrospective study on 71 liver transplant candidates, screening using sigmoidoscopy for colorectal carcinoma was assessed [16]. Twenty-one (30%) were found to have colorectal polyps; 6 (9%) hyperplastic, 15 (21%) adenomatous [16]. There were no CRC’s detected in this study. This does not appear to vary greatly from that in the general population [14,16–18]. One hundred and forty-three colonoscopies would however be required to detect one CRC in an average risk person aged 50 years or over [14]. The studies done so far with screening endoscopies in the pre-transplant population may therefore lack the power to draw conclusions on the issue of screening for pre-malignant colorectal lesions.

Author, Ref., country (city)

No. of Pts in study

No. diagnosed with CRC

Percentage incidence (%)

3.1. Colorectal adenoma post-LT

Vera et al. [11], UK (Birmingham) Kelly et al. [6], UK (London) Jain et al. [7], USA (Pittsburgh) Frezza et al. [55], USA (New York) Sanchez et al. [5], USA (Dallas) Haagsma et al. [4], Netherlands (Groningen)

1336

15

11

888

3

0.33

1000

4

0.4

1657

9

0.54

1421

8

0.56

174

3

1.7

A study examining the incidence of adenomatous colorectal polyps in 98 cardiac transplant recipients concluded that long-term immunosuppression did not increase the risk for such lesions in the colon [19]. There is however a paucity of data on the prevalence or incidence of colorectal adenomas in LT recipients. Although the majority of transplant recipients are highly motivated to maintain their recovered health status, surveillance for malignancy is not protocol based at most centres [20]. It is not known whether the immunosuppressed post-LT patients go through the same adenoma/carcinoma sequence as immunocompetent subjects [21]. In a retrospec-

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153

149

tive study, 25 patients who had post-transplant colonoscopy 41 ± 19 months following LT were compared with 50 controls undergoing routine colonoscopy [21]. Patients younger than 45 years, those who survived less than 3 years following LT and those with a history of IBD or colonic tumours were not included in this study. In both groups, the diagnosis of adenoma was confirmed pathologically. Seven (28%) post-LT recipients and 4 (8%) controls were found to have colorectal adenoma (p = 0.049). No malignant polyps were detected in both groups [21]. LT recipients with a history of PSC were included into the study group. It is however unclear how many of these PSC patients went on to subsequently develop polyps.

Table 2 Liver transplant for PSC patients at the Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham—NHS Trust, Birmingham UK, 1986–March 2004)

4. PSC and CRC in post-LT patients

not found to be statistically significant [34]. In a recent series, Vera et al. reported our units experience with PSC patients and the incidence of CRC post-LT [11]. A total of 1336 liver transplantations were performed between 1986 and 2000, at the Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. This included a total of 152 patients with PSC. CRC occurred in 7 (0.6%) out of 1184 non-PSC recipients. The patients transplanted for PSC were examined in three groups; those with PSC without IBD (n = 52), PSC patients having undergone colectomy for IBD (pre LT and at LT, n = 17) and PSC patients with IBD having intact colons (n = 83). CRC was found to occur in 8 (5.3%) of those who under went LT for PSC. CRC did not occur in the PSC group without IBD at LT and all 8 patients who developed CRC had IBD at LT with intact colons (8/83–9.6%) [11]. The incidence of CRC in patients transplanted to date at our centre for PSC from 1986 is given in Table 2.

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown aetiology, leading to inflammation and fibrosis of the biliary tree [22,23]. The prevalence of IBD in patients with PSC is in the range of 55–75% [24–26]. About 2.5–7.5% of patients with ulcerative colitis (UC) develop cholestatic liver disease with 40% of these developing PSC [24,25,27]. PSC is found less often in Crohn’s disease where it usually is associated with colonic involvement [24]. Studies have found an increased prevalence of colonic dysplasia and cancer in patients with PSC and ulcerative colitis compared with UC alone [28,29]. Colonic dysplasia and cancer has also been reported to occur more commonly in the proximal colon [30]. The high proportion of right-sided cancers has been attributed to ‘backwash ileitis’ with secondary bile acids increasing the likelihood of cancer in the proximal colon [30]. The occurrence of ileal pouch malignancy in these patients, following total colectomy is likely to be due to similar factors [30]. The incidence of CRC and colorectal dysplasia is reportedly higher in LT patients with the combined history of PSC and IBD compared with recipients of LT for PSC alone or for those transplanted for other indications [26,31,32]. Indeed, some studies have suggested that there may be a higher incidence of colorectal cancer in the first 2 years post-liver transplant [26,31]. This maybe related to the higher doses of immunosuppression used during this period [24]. The mechanism by which PSC increases the risk of colonic neoplasia is however unknown [24]. Cholangiocytes and colonocytes may share autoantigens or bacterial products, such as formyl peptides, which may ascend the portal vein to excite hepatobiliary change in susceptible patients [24]. In the first published report on the risk of colon cancer after LT in patients with PSC, 31 patients with UC and PSC had an incidence of 6.5% [31]. In a retrospective study of 1,085 LT recipients, the incidence of CRC was found to be 8% in patients with IBD versus 0.1% in transplant recipients without IBD [33]. Among 57 patients with intact colons who underwent LT for PSC with coexistent IBD, the risk factor was found to rise fourfold for CRC, but this difference was

Description

Number (%)

Incidence of CRC

Total LT (1986–March 2004) Total non-PSC LT Total No. PSC LT Total LT for PSC without IBD Total LT for PSC with colectomy at transplant Total LT for PSC + IBD with intact colon

1593 1550 195 64 23

18 (1.1%) 8 (0.5%) 10 (5.1%) Zero 1 (3.7%)a

106

9 (8.5%)

a Pt had subtotal colectomy in 1976, ileal pouch in 1986, LT for PSC + IBD 1994.

4.1. IBD in PSC patients post-LT Retrospective studies have established that the clinical course of UC seems to be independent of the natural history and progress of hepatobiliary disease [35]. The majority of patients are treated with immunosuppressive agents post-LT, and hence it could be expected that the course of IBD would be controlled or improve post operatively. The post-LT course of IBD in PSC patients however is largely unpredictable, with variable data shown in published studies (Table 3). Furthermore, comparison is made more difficult since the assessment of IBD activity seems to differ between studies. In studies where steroids have also been used in the maintenance immunosuppression regimens, a favourable course of IBD is described with a majority of patients showing an improvement of clinical course [36,37]. Some studies have shown little or no change in colitis activity [38,39], while others have described increased disease activity [25,26,40,41], despite immunosuppression, which included steroids. Dvorchik et al. in Pittsburgh USA, using unique statistical methodology has recently shown that LT and the concomitant use of immunosuppression actually accelerates the progression of IBD [42]. This highly variable activity of IBD following LT is also

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153

150

Table 3 The course of IBD in PSC patients post-liver transplantation Reference

Maintenance immunosuppression

Pre-OLT IBD activity

No. of patients

IBD course after OLT number (%) Same

Better

Worse

Gavaler et al. [38]

Cyclosporin + prednisolone

Total Quiescent Active

23 6 17

9(39) 6(100) 3(18)

14(61) 0 14(82)

0 0 0

Shaked et al. [41]

Cyclosporin or tacrolimus + azathioprine/ prednesalone

Total Quiescent Active

24 13 11

12(50) 9(69) 3(28)

4(17) 0 4(36)

8(33) 4(31) 4(36)

Stephens et al. [36]

Cyclosporin or tacrolimus + azathioprine/ prednesalone Cyclosporin or tacrolimus + azathioprine/ prednesalone

Total

27

4(15)

18(67)

5(18)

Total

23

12(52)

11(48)

0

Quiescent Active

6 17

6(100) 6(35)

0 11(65)

0 0

Total Quiescent Active

16 12 4

8(50) 8(67) 0

0 0 0

8(50) 4(33) 4(100)

Befeler et al. [37]

Papatheodoridis et al. [25]

Cyclosporin or tacrolimus ± azathioprine

described in a recent study of 69 patients, which showed a third of patients improving, a third remaining stable while in the remaining third the disease state worsened [43]. IBD is also known to occur de novo in LT recipients transplanted for PSC, having being free of its association pre-transplant [25]. Aminosalicylates, including both sulfasalazine and mesalamine, are the most commonly prescribed antiinflammatory agents in patients with IBD. On balance, the body of literature to date suggests that aminosalicylates confer some protection against the development of colonic neoplasia in patients with IBD and in a variety of models, including the non-inflamed gut [44]. Ursodeoxycholic acid too is believed to confer a similar chemoprotective role [45]. Randomized, placebo-controlled studies are however

yet to demonstrate the chemoprotective role of ursodeoxycholic acid [45]. The findings that aminosalicylates may have a chemoprotective role in non-inflamed colons are of particular interest especially in the post-transplant patient. Further studies however need to be conducted in this setting to ascertain its benefit conclusively. It should be noted that in most studies the course of posttransplant UC has been compared only with the clinical status of colitis in the immediate pre-transplant period [46]. Current evidence therefore suggests that IBD could worsen or develop for the first time in patients on corticosteroids and other immunosuppressive agents. There is no obvious answer to the cause of these findings. It has been suggested that depressed T cell function with advanced liver disease improves after grafting, creating a new balance in immunoregulation [25].

Fig. 1. Post-LT comparative patient survival: patients with PSC and no ulcerative colitis, PSC colectomy and PSC with UC and intact colon.

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153

Alternatively, altered bile salt concentrations post-LT may alter the milieu within the colon [24]. The impact of colectomy pre-, during and post-LT has been described by Vera et al. [11]. PSC patients with their colon removed pre- or during LT have shown a better survival than those with intact colons at the time of the transplant (10year survival 87% versus 55%; NS), reflecting the fact that the CRC and colitis related morbidity had been avoided (Fig. 1) [11]. Previous studies demonstrating the risk of colonic dysplasia and CRC in PSC patients post-LT, however have failed to show such survival benefit [31,34,47]. Although these have been smaller studies, whether proctocolectomy should be considered prophylactically before, during or after LT remains an unresolved issue for PSC patients with active IBD. Colectomy pre- or during LT has been found not to impact early (<30 days) post-liver transplant outcome [11]. Perioperative technical factors at transplantation (operation time, blood loss, ITU and hospital stay) in both the pre-LT colectomy and simultaneous LT and colectomy groups were no different compared with the non-colectomy group [11]. This indicates that colectomy in selected cases did not represent a significant additional mortality. Furthermore, studies have also shown that post-transplant colectomy where indicated too does not affect patient survival adversely [11,23]. Liver transplantation does not seem to alter the course of pouchitis, a complication encountered in patients with ileal pouch–anal anastomosis following proctocolectomy, although the pathogenesis of pouchitis may be different to that of IBD [48].

151

PSC and UC has been reported to be increased with an incidence of approximately 1% per person per year [34]. Many publications have therefore supported the inclusion of an annual surveillance colonoscopy for this subset of LT recipients [19,26,31,34,43,50,51]. This risk has been considered clinically important by the British Society of Gastroenterology, which recommends an annual surveillance colonoscopy in the post-transplant period for PSC patients with IBD [52]. One limitation of most studies on CRC in PSC patients post-LT is the common assumption that the risk for these patients to develop CRC is distributed uniformly over time. This is however unlikely to be true since as is the case for most pre-malignant conditions, the risk increases exponentially with time. With duration, the risk of CRC in PSC patients with IBD post-LT, increases dramatically, but does not differ from the risk of CRC in patients with IBD who do not undergo LT [42]. The evidence for this could be drawn from the recent publication by Vera et al. who describe three variables contributing significantly, following multivariate analysis, to the risk of developing CRC in PSC patients with IBD undergoing LT; the duration of colitis more than 10 years (p = 0.002), pancolitis (p = 0.004) and dysplasia post-LT (p = 0.0003). Thus, the incidence of CRC will always be greater after LT than before simply due to the longer duration of IBD in LT recipients, rather than a true increased risk of CRC in patients with this underlying disorder.

6. Management of CRC in post-LT patients 5. Post-LT surveillance for CRC In a study on the role of endoscopic colon surveillance in the general transplant population, Parikshak et al. recently described that these patients had an equivalent incidence of adenomatous polyps compared with the general population [49]. This was following a retrospective analysis of 229 transplant recipients who were age and gender matched to a control group, with a 3-year follow up. Therefore, it would seem that post-transplant colorectal surveillance should not be more frequent than that for the age matched general population [49]. Although Tamer and Thuluvath in their recent study have shown that comparatively liver transplant recipients appear to have an increased risk for developing colorectal adenoma post operatively, they failed to show a similar increase in incidence of colorectal dysplasia or malignancy [21]. It is also established that in comparison with the general population matched for age, gender and length of follow up LT recipients with no history of PSC have a similar relative risk of developing CRC [1,6–9]. Hence the non-PSC post-LT recipients too should not require more frequent surveillance than the age-matched population in general. It is however presently well established that CRC appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC [50]. The risk of CRC following LT in patients with

The management of CRC in post-LT recipients are based on the same principles as would be for CRC alone. As stated earlier, colectomy post-LT has been shown to be a relatively safe procedure when associated with PSC and IBD and does not affect patient survival adversely [11,23]. Adjuvant pharmacotherapy with drugs like oxaliplatin too have been shown to be well tolerated in patients with all levels of liver dysfunction and have been used in the post-LT setting as well [53]. Prophylactic colectomy in selected patients with PSC and IBD with two or more identified risk factors for CRC like long-term IBD (>10 years pre-LT), severe colitis (pancolitis, servere dysplasia) and age more than 40 years may also help reduce the risk of CRC in these patients in the first place [11,54].

7. Conclusions The incidence of CRC in the LT recipient with no identifiable risk factors is similar to that of the general population. These patients therefore should undergo screening for colorectal cancer according to current guidelines for the age and sex matched general population. Studies had done so far have not shown conclusively that the potential LT recipient benefits by additional screening for CRC pre-transplantation.

152

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153

The incidence of CRC in patients with PSC and IBD appears to be greater than the age and sex matched general population. In patients with PSC alone with no evidence of coexistent IBD, the incidence of CRC is not however increased. Studies have shown that IBD could occur de novo post-LT in patients with PSC who were found to be free of the disease at transplant, although it is unclear if this subgroup of patients are at higher risk of developing CRC with time. Patients with PSC therefore require pre-LT screening with colonoscopy for the diagnosis of IBD (if not already diagnosed), staging of extent and severity of IBD, and for identification of pre-malignant lesions. Newly emerging data suggest that identified risk factors for CRC like duration of IBD more than 10 years, pancolitis and severe colitis with dysplasia are indications for pre or peri LT colectomy. Studies have also shown that colectomy during or post-liver transplant is not associated with increased risk of morbidity or mortality. It is recommended that patients with PSC and a history of IBD who have intact large bowel post-LT undergo yearly colonoscopic surveillance for pre-malignant and malignant changes. Colorectal cancer if diagnosed in the post-LT recipient needs to be treated stage for stage as for CRC in the general population. Reviewers Rudolf Steininger, Professor, Department of Surgery, Division of Transplantation, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Roger W.G., Dr., Chapman, Consultant Gastroenterologist, Oxford Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. Philippe Morel, Professor, Clinique et Policlinique de Chirurgie Digestive, Hˆopitaux Universitaires de Gen´eve, Rue Micheli-du-Crest, Ch-1211 Geneva-14, Switzerland.

References [1] Saigal S, Norris S, Muiesan P, Rela M, Heaton N, O’Grady J. Evidence of differential risk for post-transplantation malignancy based on pre-transplantation cause in patients undergoing liver transplantation. Liver Transpl 2002;8:482–7. [2] Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530–4. [3] Fung JJ, Jain A, Kwak EJ, Kusne S, Dvorchik I, Eghtesad B. De novo malignancies after liver transpantation: a major cause of late death. Liver Transpl 2001;7:S109–18. [4] Haagsma EB, Hagens VE, Schaaoveld M, et al. Increased risk after liver transplantation: a population-based study. J Hepatol 2001;34:84–91. [5] Sanchez EQ, Marubashi S, Jung G, et al. De novo tumours after liver transplantation: a single institute experience. Liver Transpl 2002;8:285–91. [6] Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA. Liver transplant recipients are not at increased risk for non-lymphoid soilid organ tumours. Cancer 1998;83:1237–43.

[7] Jain AB, Yee LD, Nalesnik MA, et al. Comparative incidence of de novo non-lymphoid malignancies after liver trasnaplantation under tacrolimus using surveillance epidemiologic end result data. Transplantation 1998;66:1193–200. [8] Penn I. The problem of cancer in transplant recipients. Transplant Sci 1994;4:23–32. [9] Penn I. Malignancy after immunosuppressive therapy: how can the risk be reduced. Clin Immunother 1995;9:207–8. [10] Penn I. Cancer in the immunosuppressed organ recipient. Transplant Proc 1991;23:1771–2. [11] Vera A, Gunson BK, Ussatoff V, et al. Colorectal cancer in patients with infalmmatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 2003;75:1983– 8. [12] Everson GT, Trotter JF, Kugelmas M, Forman L. Immunosuppression in liver transplantation. Minerva Chir 2003;58:725–40. [13] Menachem Y, Safadi R, Ashur Y, Ilan Y. Malignancy after liver transplantation in patients with pre-malignant conditions. J Clin Gastroenterol 2003;36:436–9. [14] Rex DK. Colonoscopy: a review of its yeild for cancers and adenomas by indication. Am J Gatroenterol 1995;90:253–60. [15] Singer LG, Weinacker AB, Levin L, Doyle RL, Theodore J. Diagnostic yield of screening colonoscopies in lung transplant candidates. Transplantation 2001;72:530–2. [16] Zaman A, Hapke R, Flora K, Rosen H, Benner K. Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation. Am J Gatroenterol 1999;94:895–9. [17] Rex DK, Lehman GA, Hawes RA, Ulbright TM, Smith JJ. Screening colonoscopy in asymptomatic average-risk persons with negative fecal occult blood tests. Gatroenterology 1991;100: 64–7. [18] Verne JECW, Aubrey R, Love SB, Talbot IC, Northover JMA. Population based randomised study of uptake and yield of screening by flexible sigmoidoscopy compared with screening by faecal occult blood testing. BMJ 1998;317:182–5. [19] Rodriguez-Larrain JM, Ziebertt JJ, Kfoury AG, Kuwada S, Taylor D, Renlund DG. Incidence of adenomatous colorectal polyps in cardiac transplant recipients. Transplantation 1997;64:528–30. [20] Zeldin GA, Maygers J, Klein A, Thuluvath PJ. Vaccination, screening for malignancy and health maintenance of the liver transplant recipient. J Clin Gastroenterol 2001;32:148–50. [21] Tamer A, Thuluvath PJ. Risk of colorectal adenoma in liver transplant recipients compared to immunocompetent control population undergoing routine screening colonoscopy. J Clin Gastroenterol 2003;37:72–3. [22] Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;332:924–33. [23] Goss JA, Shackleton CR, Farmer DG, et al. Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience. Ann Surg 1997;225:472–81. [24] Chapman RW. The colon and PSC: new liver, new danger. Gut 1998;43:595–6. [25] Papatheodoridis GV, Hamilton M, Mistry PK, Davidson B, Rolles K, Burroughs AK. Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis. Gut 1998;43:639–48. [26] Knechtle SJ, D’Alessandro AM, Harmes BA, Pirsch JD, Belzer FO, Kalayoglu M. Relationship between sclerosing cholangitis, inflammatory bowel disease and cancer in patients undergoing liver transplantation. Surgery 1995;118:615–9. [27] Olsson R, Danielsson A, Jarnerot G, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991;100:1319–23. [28] Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis—a risk factor for the development of dysplasia and DNA aneuploidy. Gatroenterology 1992;102:1877–80.

M.A. Silva et al. / Critical Reviews in Oncology/Hematology 56 (2005) 147–153 [29] Gurburz AK, Giardiello FM, Bayless TM. Colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Dis Colon Rectum 1995;36:908–12. [30] Marchesa P, Lashner BA, Lavery IC, et al. The risk of cancer and dysplasia among ulcerative colitis patients with primary sclerosing cholangitis. Am J Gatroenterol 1997;92:1285–8. [31] Higashi H, Yanaga K, Mash JW, Tzakis A, Kakizoe S, Starzl TE. Devepolpment of colon cancer after liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Hepatology 1990;11:477–80. [32] Brentnall TA, Haggitt RC, Rabinovitch PS, et al. Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1996;110:331–8. [33] Fabia R, Levy MF, Testa G, et al. Colon carcinoma in patients undergoing liver transplantation. Am J Surg 1998;176(3):265–9. [34] Loftus EVJ, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998;27:685–90. [35] Balan V, LaRusso NF. Hepatobiliary disease in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:647–69. [36] Stephens J, Goldstein R, Crippin J, et al. Effects of orthotopic liver transplantation and immunosuppression on inflammatory bowel disease in primary sclerosing cholangitis. Transplant Proc 1993;25:1122–3. [37] Befeler AS, Lissoos TW, Schiano TD, et al. Clinical course and management of inflammaory bowel disease after liver transplantation. Transplantation 1998;65:393–6. [38] Gavaler JS, Delemos B, Belle SH, et al. Ulcerative colitis disease activity as subjectively assessed by patient-completed questionnaires following orthotopic liver transplantation for sclerosing cholangitis. Dig Dis Sci 1991;36:321–8. [39] van de Vrie W, de Man RA, van Buuren HK, Schouten WR, Tilanus HW, Metselaar HJ. Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2003;15:657–63. [40] Miki C, Harrison JD, Gunson BK, Buckels JAC, McMaster P, Mayer AD. Inflammatory bowel disease in primary sclerosing cholangitis: an analysis of patients undergoing liver transplantation. Br J Surg 1995;82:1114–7. [41] Shaked A, Colonna JO, Goldstein LI, Busuttil RW. The interrelation between sclerosing cholangitis and ulcerative colitis in patients undergoing transplantation. Ann Surg 1992;215:598–603. [42] Dvorchik I, Subotin M, Demetris AJ, et al. Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis. Hepatology 2002;35:380–4. [43] MacLean AR, Lilly L, Cohen Z, O’Connor B, McLeod RS. Outcome of patients undergoing liver transplantation for primary sclerosing cholangitis. Dis Colon Rectum 2003;46:1124–8. [44] Ryan BM, Russel MGVM, Langholz E, Stockbrugger RW. Aminosalicylates and colorectal cancer in IBD: A not-so bitter pill to swallow. Am J Gatroenterol 2003;98:1682–7. [45] Ochsenkuhn T, Marsteller I, Hay U, Diebold J, Paumgartner G, et al. Does ursodeoxycholic acid change the proliferation of the colonic mucosa? A randomized, placebo-controlled study. Digestion 2003;68:209–16. [46] Narumi S, Roberts JP, Emond JC, Lake J, Ascher NL. Liver transplantation for sclerosing cholangitis. Hepatology 1995;22:451–7. [47] Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing colangitis. Gastroenterolgy 1989;96:790–4.

153

[48] Zins BJ, Sandborn WJ, Penna CR, et al. Pouchitis disease course after orthotopic liver transplantation with primary sclerosing cholangitis and an ileal pouch–anal anastomosis. Am J Gatroenterol 1995;90:2177–81. [49] Parikshak M, Pawlak SE, Eggenberger JC, Lee CS, Szilagy EJ, Marg DA. The role of endoscopic colon surveillance in the transplant population. Dis Colon Rectum 2002;45:1655–60. [50] Gow PJ, Chapman RW. Liver transplantation for primary sclerosing cholangitis. Liver 2000;20:97–103. [51] Bleday R, Lee E, Jessurun J, Heine J, Wong WD. Increased risk of early colorectal neoplasms after hepatic transplant in patients with inflammatory bowel disease. Dis Colon Rectum 1993;36:908– 12. [52] Eaden JA, Mayberry JF. Colorectal cancer screening: guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 2002;51:v10–2. [53] Doroshow JH, Synold TW, Gandara D, et al. Pharmacology of oxaliplatin in solid tumour patients with hepatic dysfunction: a priliminary report of the National Cancer Institute Organ Dysfunction Working Group. Semin Oncol 2003;30:14–9. [54] Levin B. Risk of cancer in ulcerative colitis. Gasterointest Endosc 1999;49:S60–2. [55] Frezza EE, Fung JJ, Van Thiel DH. Non-lymphoid cancer after liver transplantation. Hepat-Gastroenterology 1997;44:1172–81.

Biographies Michael A. Silva M.S., FRCS Ed., is a higher surgical trainee attached as a research fellow to the Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK. His research interests are the metabolic events related to preservation and ischemia reperfusion injury of the liver during transplantation. Periyathambi S. Jambulingam M.S., FRCS Ed., FRCS (Gen) is a Specialist Registrar attached to the Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK. His training is in upper gastrointestinal surgery with a special interest in oesophago-gastric surgery. Darius F. Mirza M.S. FRCS Ed., FRCS (Glas), is Consultant Hepatobiliary and Liver Transplant Surgeon at the Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Edgbaston, Birmingham B15 2TH, UK. His research interests are the use of ‘marginal livers’ in transplantation and ischemia reperfusion injury related to liver surgery. He has published on a wide range of hepatobiliary and liver transplant topics. His operative commitments in addition to adult heptobiliary, pancreatic and liver transplant surgery, include paediatric liver and small bowel transplantation at the Birmingham Children’s Hospital. He is currently the secretary of the European Liver Transplant Association.