07a Deeper technical material for liver cancer readers

1. Cancer incidence after liver transplantation
   Solid-organ transplantation and subsequent chronic immunosuppression have been long associated with an increased risk for the development of cancer. Patients are at increased risk for hematologic malignancies as well as solid cancers. Concerning solid malignancies, several studies have demonstrated a higher incidence of both cutaneous and non-cutaneous solid malignancies in LT recipients compared with the general population. The reported rates in various studies range from 3 to 17%. The reported neoplasia rates are likely to be elevated due to the presence of screening bias among this population of patients where close medical surveillance is routine. These studies are also limited due to heterogeneity in terms of many important variables such as cohort size, patient population, indication for LT, era of transplantation, immunosuppressive regimen and length of follow-up.
   
   
2. Recurrent malignancies
   Liver transplantation is considered to be the treatment of choice for patients with hepatocellular carcinoma (HCC) and decompensated cirrhosis [19]. Despite the use of established criteria for selecting LT candidates with the lowest risk of HCC recurrence, HCC has been reported to recur after LT in approximately 10% of patients [20–22]. After the adoption of the model for end-stage liver disease (MELD) score for organ allocation among LT candidates in the USA, the number of patients undergoing LT for HCC tripled during the first year. Subsequently, a number of patients were identified whose diagnosis of HCC could not be rigorously verified and thus a reduction in assigned MELD score was performed. Nonetheless, the proportion of patients undergoing LT who have HCC continues to rise, the number of patients with recurrent HCC is expected to increase (OPTN Data 2004) [21]. The natural history of recurrent HCC is not well established, although given concomitant immunosuppression, recurrent cancer may run a more aggressive course. In a series of 132 LT recipients from three Italian transplant centers, Regalia et al. reported a 15.9% HCC recurrence rate. Ninety percent of patients developed recurrence within 2 years of transplantation. The authors identified tumors greater than 3 cm in diameter, the presence of a peri-tumoral capsule and tumors, which exceeded the Milan criteria for LT as independent risk factors for post-transplantation recurrence. TNM (American Joint Committee on Cancer Tumor, Nodal Involvement and Metastasis classification system) stage, vascular invasion, pre-transplantation chemoembolization and serum alpha-fetoprotein level did not independently predict HCC recurrence in this study [23]. More recently, among a cohort of 67 patients undergoing LT for HCC complicating HCV-related liver disease at a single US center, 11 patients (16.4%) developed a cancer recurrence. Subsequently, eight deaths occurred from recurrent HCC. The majority of patients (81%) had cancer recurrence within 1 year of transplantation. Both patients who had late (O3 years after LT) recurrence presented with lung metastases. TNM staging, vascular invasion, and pre-operative tumor diagnosis (as opposed to donor melanoma to an LT recipient) have been reported [26]. LT recipients, particularly those in sunny climates, should be counseled on photoprotection and require cancer surveillance with regular dermatologic examinations.

3. De novo malignancies
   3.1. Skin cancer
   Cutaneous malignancies are the most commonly occurring cancers after LT. The prevalence of cutaneous malignancies is increased in transplant recipients and varies with the degree of immunosuppression. The majority of cutaneous malignancies are non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma. While basal cell carcinomas are the most common cutaneous malignancy in the general population, squamous cell skin cancer is more common among transplant recipients. The rate of developing squamous cell skin cancer is estimated to be increased over 60-fold in LT recipients compared to the general population. Fortunately, mortality rates from skin cancer in LT recipients are low with melanoma as the major cause of death [9,25]. While the transmission of donor-related tumors is rare, malignant melanoma is the most commonly transmitted tumor. Transplant recipient mortality due to the transmission of  an important role in the pathogenesis of lymphoproliferative disorders [32]. Among 660 patients undergoing LT at Mayo Clinic, Zein et al. found no link between HCV infection and the development of PTLD [33]. Given the small numbers of patients who developed PTLD and the differences in immunosuppressive regimens used at different institutions, the link between HCV infection and PTLD remains unclear [28,33].
   
   3.2. Post-transplant lymphoproliferative disorder (PTLD)
   Post-transplant lymphoproliferative disorders (PTLD) comprise a spectrum of abnormal lymphoid tissue proliferation among organ transplant recipients. PTLD is associated with chronically immunosuppression and is frequently associated with Epstein–Barr virus (EBV) infected B-lymphocytes. PTLD has been reported to occur with a prevalence of 1.7–4% of LT recipients. While many cases of PTLD respond to a reduction in the level of immunosuppression, PTLD can present as an aggressive B-cell lymphoma [27–29]. PTLD frequently involves the liver allograft with allograft PTLD (accounting for approximately 44%) and carries a mortality rate of approximately 50% despite therapy [13,28]. Among recipients of LT, infection with the hepatitis C virus may represent an additional risk for the development of PTLD. This is of concern given the universal recurrence of HCV after LT. The hepatitis C virus may induce B-cell proliferation either independently or through a synergistic effect with the EBV virus. In one study of 480 consecutive French LT recipients, multivariate analysis identified age (older than 50 years), the use of antilymphocyte antibody therapy, and LT for either hepatitis C related cirrhosis or alcoholic cirrhosis as risk factors for the subsequent development of PTLD. The relative risk of developing PTLD among HCV-infected LT recipients was 8.7 (95% CI 1–78.3, PZ0.015) compared to patients transplanted for non-HCV, non-alcoholic liver diseases [30]. A case-control study of 57 HCV-infected LT recipients, the odds ratio of developing PTLD was 9.5 (PZ0.02) among HCV-infected patients compared to non-HCV infected LT recipients [31]. In another study of 157 LT recipients, PTLD was more common in HCV-infected patients than in non-infected patients (10.5% vs 1.7%; PZ0.03). Patients undergoing LT for HCV-related ESLD were more likely to have received anti-thymocyte globulins. However, among patients who received anti-thymocyte globulins, PTLD seemed to occur more frequently among those HCV-related disease (27.1% vs 6.4%, PZ0.08) [28]. In contrast, PTLD is a relatively uncommon disease, and the studies which find an increased risk among HCV infected LT recipients are limited by small numbers of patients. In a prospective study of 394 patients with lymphoproliferative disorders (including 164 patients with non-Hodgkin’s lymphoma), Hausfater and colleagues found a low prevalence rate of HCV infection (2.79 and 1.83%, respectively). While patients with lymphoproliferative disorders did have a higher prevalence of HCV compared to controls (2.79% vs 0.43%), the authors concluded that the low rate of HCV infection suggests that HCV does not play an important role in the pathogenesis of lymphoproliferative disorders [32]. Among 660 patients undergoing LT at Mayo Clinic, Zein et al. found no link between HCV infection and the development of PTLD [33]. Given the small numbers of patients who developed PTLD and the differences in immunosuppressive regimens used at different institutions, the link between HCV infection and PTLD remains unclear [28,33].
   
   3.3. Solid-organ malignancies
   Multiple studies have reported an increased risk for developing solid organ malignancy after LT. Data from the International Transplant Tumor Registry (formerly the Cincinnati Transplant Tumor Registry) demonstrates a significantly increased risk of cancers such as skin cancer, Kaposi’s sarcoma, cervical, vulvar and anal squamous cell carcinomas among organ transplant recipients compared to the general population. Among liver transplant recipients, 324 patients developed 329 cancers after LT. When compared to a cohort of 7200 renal transplant recipients with cancer, LT recipients had a higher rate of lymphoma (57% vs 12% of cancers). In LT recipients both solid tumors (27 vs 72 months) and lymphomas (15 vs 46 months) occurred earlier in the post-transplant course compared to renal transplant recipients. The higher proportion of pediatric LT recipients and the longer follow-up of renal transplant recipients may explain the observed differences [13]. A population-based study of 174 transplant recipients from the Netherlands who survived more than 1 year from LT revealed an increased relative risk of developing solid organ malignancy compared to expected rates in the Dutch population. The relative risk of developing any noncutaneous, solid organ malignancy was 2.7, with the relative risk being highest for colon and renal cell carcinomas (12.5 and 30.0, respectively). Of note, renal cell carcinoma was noted incidentally in two of three cases and none of the three patients who developed colorectal neoplasia had underlying PSC or IBD. Age greater than 40 years was identified as an important risk factor for post-transplant cancer [8]. Based on center-specific practices, a number of LT recipients may be evaluated longitudinally to ensure stable allograft function and for the prevention of immunosuppression-related medical complications. However, the use of cancer surveillance methods in this setting does not appear to guarantee the prospect of early detection time based on annual visits or problem-specific issues. Herrero and colleagues reported a retrospective review of 187 Spanish LT recipients who survived beyond 3 months after transplantation. Despite an aggressive pre-and post-LT cancer screening protocol (including upper and lower GI endoscopy, thoracic and abdominal computed tomography, magnetic resonance neuroimaging and otorhinolaryngology evaluation for smokers), 27 patients developed 28 noncutaneous malignancies (including nine PTLD and one Kaposi’s sarcoma). The majority of solid organ malignancies were diagnosed at advanced stages (50% of upper aerodigestive tract tumors diagnosed at stage IV, 66% of non-small cell lung cancers and 71% of abdominal and genitourinary tract tumors diagnosed at stages III-IV). Multivariate analysis identified only age and a history of smoking or history of alcohol abuse as risk factors for post-LT non-cutaneous malignancy [9].
   
   3.4. Colorectal neoplasia
   Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD) with 60–80% of patients with PSC having concurrent IBD. Patients with IBD are at risk for developing colorectal carcinoma (CRC) and coexisting PSC may be an additional cancer risk, although this association remains controversial [34]. Studies have also examined the continued risk for CRC in patients undergoing LT for PSC in the setting of inflammatory bowel disease. Vera et al. reviewed 100 patients with PSC and IBD who underwent transplantation at a single center in the UK. Among 83 patients with intact colons after LT, five patients subsequently developed dysplasia requiring colectomy and an additional eight patients developed CRC. Among patients developing CRC, three were diagnosed with stage I disease, one with stage II disease, three with stage III disease and two patients had metastatic (stage IV) disease at diagnosis. Patients with CRChad a decreased 5-year survival compared to other LT recipients with PSC and IBD (53% vs 73%); four patients with CRC died during the study period [35]. In contrast, data from the Mayo Clinic found no survival difference among patients who developed CRC complicating LT for PSC. Among 108 patients undergoing LT for PSC with coexisting IBD in 81 patients, the cumulative risk for CRC was 4% at 5 years. While there was a higher incidence of colorectal neoplasia (dysplasia and carcinoma) among LT recipients compared to historical controls, there was no excess mortality attributed to CRC in this study [36]. Routine surveillance for neoplasia and subsequent colectomy for dysplasia may account for the low mortality from CRC in LT patients with IBD [8].
   
   3.5. Upper aerodigestive tract malignancies
   Upper aerodigestive tract malignancies, such as oral, laryngeal and esophageal carcinoma, have been reported to be more common in patients after LT. In an analysis of 1000 consecutive LT patients treated with a tacrolimus-based immunosuppressive regimen, the incidence of oropharyngeal cancer was dramatically increased compared to SEER (Surveillance Epidemiology End Result) data (standardized incidence ratio 7.6; P!0.01). Among the seven cases of oropharyngeal cancer, four patients were smokers and five patients underwent transplantation for alcoholic liver disease [10].  Among 772 Spanish patients who underwent LT, upper aerodigestive cancers were the most commonly occurring malignancy after skin cancers. A prior history of alcohol use was noted to be an independent risk factor for the development of cancer [2]. Similar findings were noted in a smaller study of LT recipients in France. All five patients who developed upper aerodigestive tract cancers had been transplanted for alcoholic liver disease and had a higher incidence of tobacco abuse [4].
   
   3.6. Effect of immunosuppressive therapy
   In general, the immunocompromised host is at risk for the development of certain malignancies. The degree of intensity with immunosuppression is commonly related to developing PTLD in susceptible hosts. With increasingly powerful immunosuppressive therapy, including a growing array of biologic agents, available studies have examined their effects on cancer incidence among LT recipients. In a study of 500 German LT recipients enrolled in various immunosuppressive protocols, there was no difference in the development of de novo malignancy noted over a median follow-up of 50 months. Thirty-three patients developed cancer including seven lymphomas. The only degree of immunosuppression as measured by a low CD4C/CD8C lymphocyte regimen and a positive T-cell crossmatch were associated with an increased relative risk of malignancy [12]. In a more recent study of 772 LT recipients, the use of azathioprine (RR 3.8, 95% CI 1.67–8.6, PZ0.004) and a history of rejection (RR 2.0, 95% CI 1–3.97, PZ0.04) were identified as independent risk factors for the development of de novo malignancies. Additionally, the authors noted a trend toward more frequent and earlier tumors among the cohort of patients transplanted during the tacrolimus era. Their conclusion was that more profound immunosuppression may further increase the risk of cancer [2]. Population-based data has identified the use of pre-LT immunosuppressive therapy for greater than 1 year in association with a significantly higher rate of de novo malignancy after LT (RR 2.93, PZ0.018). While there was only one patient who developed PTLD, approximately half of the patients who were treated with immunosuppressives prior to LT subsequently developed cancer [8].

Reference 1.
Journal of Hepatology 44 (2006) 13–38
Forum on Liver Transplantation Special Section Editor and Associate Editor: Pierre-Alain Clavien w

Reference 2.
With excellent long-term survival rates, the causes of morbidity and mortality of liver transplant (LT) recipients are primarily cardiovascular diseases, renal insufficiency, and de novo neoplasm, the latter of which account for almost 30% of deaths at 10 years post transplantation. Apart from hepatic causes, neoplasm has been reported as the most common cause of death in patients surviving at least 1 year after LT, and is responsible for approximately 40% of deaths[1,2]. Overall, it is estimated that in LT recipients the incidence of neoplasms is between 3.1% and 14.4%, and the cancer-related mortality rate is between 0.6% and 8.0%[3,4].

Although the risk of some neoplasms including breast cancer (1.9 times lower) and genitourinary cancer (1.5 times lower) in women seem to be reduced compared to those of the general population[5], in general terms, the status of transplant recipient is associated with an increased risk of developing de novo neoplasm. As shown in a study analyzing 1000 consecutive LT recipients in Pittsburgh and comparing this population’s incidence of neoplasms compared to the general population, the former have a significantly elevated risk for developing neoplasm, which is 7.6 times higher for oropharyngeal cancer and 1.7 times higher for respiratory malignancies (Table  (Table11).

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades.

Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.

Read more: Neoplastic disease after liver transplantation: Focus on de novo neoplasms

Source:
World Journal of Gastroenterology : WJG

Article information

World J Gastroenterol. 2015 Aug 7; 21(29): 8753–8768.
Published online 2015 Aug 7. doi: 10.3748/wjg.v21.i29.8753
PMCID: PMC4528018
PMID: 26269665
Patrizia Burra and Kryssia I Rodriguez-Castro
Patrizia Burra, Kryssia I Rodriguez-Castro, Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, PD, Italy
Author contributions: Burra P designed and outlined the review, performed the research and a critical revision of the manuscript; and Rodriguez-Castro KI performed the review and wrote the manuscript.
Correspondence to: Patrizia Burra, MD, PhD, Professor, Head of the Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, PD, Italy. ti.dpinu@arrub