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Hepatocellular carcinoma (HCC) is among the top ten most frequently diagnosed cancers in the United States, with liver transplantation widely accepted as the best treatment option for long term outcomes. The risk of HCC recurrence after liver transplantation is a growing concern among the medical community due to the scarcity of available organs for transplant. Scholars desire to understand HCC biology and risk factors associated with recurrence, for more accurate predictions of HCC recurrence in the future. A retrospective review from Oregon Health and Science University (OHSU) examined 69 HCC patients from February 27, 2002 to December 31, 2011. Data was collected and statistically analyzed for significant connections to incidence of HCC recurrence (p<0.05). No statistical difference was observed between ten of the eleven risk factors and incidence of recurrence: age, ethnicity, gender, initial imaging, explant pathology, AFP levels, MELD scores, ischemia time, diagnoses, and donor type. A statistically significant association was identified between Milan criteria and HCC recurrence (p=0.004). The incidence of HCC recurrence from the OHSU data set was 15.9%. The Milan findings support the nationwide acceptance of the risk factor, which underlies the MELD exception scores for transplantation. The other ten risk factors supported the lack of consensus among the research community and the idea that HCC biology is still not fully understood. This thesis determines POST-TRANSPLANTATION HEPATOCELLULAR CARCINOMA RECURRENCE 4 how data from OHSU compares to nationally reported data, in terms of similarities, differences, and future focuses of research. Introduction/Background Cancer is one of the leading causes of death in the United States, affecting millions of individuals each year. In 2015, 1,658,370 new diagnoses of cancer were predicted to affect individuals across the country (American Cancer Society, 2015). Cancer of the liver, specifically hepatocellular carcinoma (HCC), is among the ten most frequently diagnosed cancers, and is the fifth leading cancer that contributes to death in American males (American Cancer Society, 2015). Of the limited treatment options available, the most successful and durable treatment for HCC is liver transplantation. However, as with most malignancies, an underlying concern for recurrence after transplantation persists for HCC. Multiple authors have examined this issue, in an attempt to identify possible risk factors and to understand the underlying causes of recurrence. In this thesis, I will identify the incidence of and risk factors associated with HCC recurrence after liver transplantation. Furthermore, I will compare published literature to data collected from Oregon Health and Science University (OHSU). Screening and Surveillance Prior to diagnosis of HCC, patients considered at risk undergo screening and surveillance. Screening focuses on a wide array of patients without HCC risk factors, while surveillance focuses on an array of individuals with known risk factors for HCC (Bruix and Sherman, 2010). The goal of screening and surveillance is to identify early stage rather than late stage HCC. HCC development often stems from precursor diseases. Hepatitis B and C are common pathways for the development of cirrhosis, which is ultimately the biggest risk factor for HCC development POST-TRANSPLANTATION HEPATOCELLULAR CARCINOMA RECURRENCE 5 (Zarrinpar and Busuttil, 2013). Bruix and Sherman (2010), mention, “hepatitis B carriers were 100 times more likely to develop HCC than uninfected persons,” demonstrating the impact these diseases have on the likelihood of developing HCC. According to the American Cancer Society (2015), individuals with a high risk for developing precursor diseases are those with a history of intravenous drug use, excess alcohol consumption, and those unvaccinated for hepatitis B. Alcohol consumption, an environmental risk factor, serves as another pathway to cirrhosis, which can lead to the development of HCC. Other environmental risk factors exist, but most are rare and are not a large area of focus. Serological and radiological tests are used to screen at risk patients for HCC. Serological tests refer to biochemical markers, primarily alpha-fetoprotein (AFP), while radiological tests refer to the use of various imaging techniques (Bruix and Sherman, 2010). These include ultrasound, computerized tomography (CT) scan, and magnetic resonance imaging (MRI). For more accurate early detection, both ultrasonography and AFP tests should be performed, which is done approximately every 6-12 months (Bruix and Sherman, 2010). Surveillance continues after an individual is diagnosed with HCC, with the time interval changing depending on the treatment option chosen. Diagnosis Diagnosis of HCC increased by 3.4% between 2007 and 2011, with the rate predicted to continue climbing in the near term (American Cancer Society, 2015). The most widely accepted diagnostic algorithm for the detection of HCC uses a combination of radiology, biopsy, and serology tests (Bruix and Sherman, 2010). Radiology techniques test for HCC with the use of an MRI or a CT scan. In addition to radiology tests, biopsies are performed to examine the pathology for a section of the affected liver tissue when classic imaging characteristics are not POST-TRANSPLANTATION HEPATOCELLULAR CARCINOMA RECURRENCE 6 present. Serological testing refers to the use of AFP, an indicator for tumor growth when present in high concentrations. AFP testing is not sensitive or specific, so it must be combined with the radiological and biopsy tests to make an accurate diagnosis of HCC (Bruix and Sherman, 2010). AFP levels can indicate treatment response, so it is important to measure levels prior to and after treatment. Tumor Classification The stage of a tumor is determined “based on the size of or extent of the primary tumor and whether it has spread to nearby lymph nodes or other areas of the body” (American Cancer Society, 2015). A major concern regarding HCC is metastasis, the spread of cancer to locations in the body that differ from the original location (Roberts, 2005). Metastasis is common among patients with HCC recurrence, with death occurring shortly after. Vascular invasion is often an early predictor of local and distant recurrence, which is why individuals may be unqualified for many treatments. Individuals eligible for liver transplantation based on the results from the previously described tests, will be placed on a transplant waitlist with a score to reflect the state of their disease. The Model for End-Stage Liver Disease (MELD) was designed “as a severity index for patients with end-stage liver disease awaiting liver transplantation” (Kamath et al., 2001). The original goal of the MELD scoring system was to provide an objective ranking system within a group of heterogeneous individuals having liver dysfunction (Kamath et al., 2001). This original model did not include adjustments for HCC or other ailments involving diseases without liver dysfunction. In February 2002, the MELD score incorporated exception scores, which enabled patients without liver dysfunction to have MELD scores among individuals with liver dysfunction (Heimbach et al., 2015). The adjustments for HCC patients are often higher due to POST-TRANSPLANTATION HEPATOCELLULAR CARCINOMA RECURRENCE 7 specific HCC disease processes, including tumor size and vascular invasion. An individual’s MELD score is updated every three months, which allows for adjustments based on the risk of progression of the tumor, which increases with time. The MELD score is a reflection of the risk of death in the patient, meaning it is possible for patients to be dropped from the list, depending on the severity of tumor progression (Heimbach et al., 2015). The MELD system measures the mortality risk of patients, while several scoring systems have been developed to predict the likelihood of HCC recurrence after liver transplantation. The extents of Milan and University of California at San Francisco (UCSF) criteria are well established and accepted as methods for predicting HCC recurrence. Despite controversy regarding the relative efficacy of these criteria, these guidelines are widely accepted nationwide. To be within the Milan criteria a patient must have a single tumor ≤ 5 cm or up to 3 nodules ≤ 3 cm (Mazzaferro et al., 1996). The UCSF criteria states that patients within the criteria must have a single tumor ≤6.5 cm or up to three nodules ≤4.5 cm and a total diameter ≤8 cm (Bonadio et al., 2015). Individuals with vascular invasion, regardless of tumor size, do not fit within either criterion. Treatment Treatment options for HCC vary depending on the nature of the tumor and the predicted survival rate of the patient. Prior to opting for organ transplantation, multiple methods to limit tumor growth or even to downstage are applied. In the latter, tumors that are larger than Milan or UCSF criteria may undergo up front treatment such that the tumor(s) shrink and fall into these classification schemas. One method of up front treatment involves transarterial chemoembolization (TACE) a process which blocks blood flow to the tumor (American Cancer Society, 2015). Another preoperative treatment is radiofrequency ablation (RFA), which “causes POST-TRANSPLANTATION HEPATOCELLULAR CARCINOMA RECURRENCE 8 the ablation of tumor tissue through heat or local ischemic necrosis” (Wang et al., 2015). Resection involves operations to remove a section of normal liver along with the tumor. These procedures are considered for patients within the Milan and UCSF criteria that have enough healthy liver tissue that can tolerate the stress of surgery (American Cancer Society, 2015). Patients with combined poor life expectancy and tumors exceeding the Milan and UCSF criteria, are given the medication Sorafenib, which can temporarily extend survival time (Zarrinpar and Busuttil, 2013). Patient

Hepatocellular Carcinoma Recurrence After Liver Transplantation: An Analysis of Risk Factors and Incidence from Oregon Health Science University