From the time of the first liver transplantation (LT) reported by Starzl et al. in 1963 and the emergence of transplantation as a field of medicine in the 1980s, significant improvement in outcomes has been witnessed over the course of the last four decades (1). The median survival time has increased nearly fourfold for deceased donor LT recipients, and one-year survival has increased from around 30% to 92% (2-4). The long-term survival, however, has not significantly improved during the last two decades (4). Most of the long-term post-LT mortality is attributed to chronic immunosuppression, and malignancy is one of the leading cause of death among these patients, accounting for 16.4% of deaths (4). Post-LT malignancy in 1-year LT survivors was found to be the cause of death in 15% between 1987 and 1990 compared to 27% between 2011 and 2016 (4). A rising trend of de novo malignancies in long-term survivors has also been documented, and they account for approximately 30% of all 10-year post-LT mortalities (5). The incidence of de novo malignancies among transplant patients is two to fourfold higher than their healthy counterparts (6). These neoplasms exhibit aggressive behavior, appear at a younger age and have higher mortality in LT recipients (7). With solid organ malignancies, skin malignancies, and post-transplant lymphoproliferative disorders being at the top of the list, head and neck cancers, Kaposi sarcoma, lung, gynecological, genitourinary, colorectal, and gastrointestinal cancers have all been reported (6,8,9).
The high mortality rate of pancreatic cancer is well known. With 458,918 new cases and 432,242 deaths globally in 2018, pancreatic cancer was the 12th most common cancer and the 7th leading cause of cancer-related death worldwide with an incidence of 7.6 per 100,000 population in North America (10,11) and 7.7 per 100,000 population in Europe (11). It is more common in men (5.5 per 100,000) compared to women (4.0 per 100,00) (11), while the incidence for both sexes increases with age (10,11). Although the underlying reason for this disparity is unclear, it can be speculated that either women are less likely to be exposed to risk factors for pancreatic cancer or may be less susceptible to this type of cancer (11-13). Alcohol, smoking, obesity, and hepatitis C virus infection are significant risk factors for pancreatic cancer (5,14-17). As alcohol, obesity and hepatitis C virus infection are common causes of cirrhosis, pancreatic cancer is an important malignancy to be aware of post-LT.
Most of the data in the literature about LT and pancreatic cancer are focused on pancreatic neuroendocrine tumor. We sought to specifically describe the incidence and impact of post-LT pancreatic adenocarcinoma compared to pancreatic adenocarcinoma in our general population. We present the following article in accordance with the AME Case Series reporting checklist (available at https://dx.doi.org/10.21037/apc-21-4).
The Vanderbilt University Medical Center (VUMC) electronic health record (EHR) system was established in 1990 and includes data on billing codes from the International Classification of Diseases, 9th and 10th editions (ICD-9 and ICD-10), Current Procedural Terminology (CPT) codes, laboratory values, reports, and clinical documentation. The de-identified mirror of the EHR, known as the Synthetic Derivative, includes patient records on more than 2.8 million individuals.
Pancreatic adenocarcinoma cases were identified by the presence of any pancreatic adenocarcinoma ICD code (ICD-9: 157.X or ICD-10: C.25.X) in their EHR. Liver transplant cases were identified by the presence of the LT CPT code: 47135.
The prevalence of pancreatic adenocarcinoma was determined separately within the entire Synthetic Derivative sample and excluding individuals who received an LT. Next, the incidence of pancreatic adenocarcinoma after LT was determined by finding the number of individuals whose first pancreatic adenocarcinoma code occurred after their LT code.
The study included all adult (age 18 and above) LT recipients transplanted at VUMC from January 1, 1990, to December 31, 2019, who were diagnosed with pancreatic adenocarcinoma. A retrospective review of the VUMC EHR of LT recipients to identify patients with a diagnosis of pancreatic adenocarcinoma after LT was performed through text-search using the terms “pancreas”, “pancreatic”, “malignancy”, “malignant”, “tumor”, “cancer”, and “carcinoma”. We collected demographic, clinical, laboratory, and radiological data utilizing the EMR database and VUMC radiology database. The final diagnosis of pancreatic adenocarcinoma and inclusion of patients in our study was determined after a review of biopsy/surgical specimen pathology reports. All data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at VUMC (18,19); REDCap is a secure, web-based software platform designed to support data capture for research studies. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Vanderbilt University Medical Center Institutional Board Review (IRB#192061) and individual consent for this retrospective analysis was waived.
Continuous variables were summarized as medians and interquartile ranges (IQR), and categorical variables were summarized as frequencies and percentages. Statistical analysis was performed using IBM SPSS Statistics 26 software (IBM Corp., Armonk, NY, USA).
The VUMC Synthetic Derivative contained ICD information on 2,484,772 individuals, including 5,033 individuals who had pancreatic adenocarcinoma and 1,711 who received an LT. Among LT recipients, eight also had a pancreatic adenocarcinoma code (two had their first pancreatic adenocarcinoma code prior to LT, and six had their first pancreatic adenocarcinoma code after LT). The prevalence of pancreatic adenocarcinoma in the entire Synthetic Derivative was 0.20%. Within individuals who did not receive an LT, the prevalence of pancreatic adenocarcinoma was 0.20%. The incidence of pancreatic adenocarcinoma after LT was 0.35%.
Six patients who developed pancreatic adenocarcinoma after LT were identified. Based on Organ Procurement and Transplantation Network data, 2,232 LTs in adults were performed in our institution between 1990 and 2019, leading to an incidence of 0.27%. Detailed patient characteristics and outcomes are presented in Table 1. The median age at the time of pancreatic adenocarcinoma diagnosis was 66.0 years (IQR, 57.8–71.8 years). Four patients were male (66.7%), the median body mass index was 23.7 (IQR, 21.4–26.2), 5 had a history of smoking (83.3%), and 4 had a history of alcohol abuse (66.7%). All patients remained abstinent of alcohol use post-LT and patients received standard immunosuppression with a calcineurin inhibitor, steroids and mycophenolate mofetil. The patients’ clinical manifestations are presented in Table 2. The median time from LT to pancreatic adenocarcinoma diagnosis was 8.9 years (IQR, 4.7–16.2 years), the median size on imaging was 3.2 cm (IQR, 3.1–4.7 cm), and all tumors were located on the head of the pancreas. The initial diagnosis was established via computed tomography (CT) scan in all but one patient. This one patient was found to have endoscopic findings consistent with malignancy, but the CT scan failed to identify any pancreatic lesions. Carbohydrate antigen 19-9 level was requested in three patients and was found to be elevated (mean, 110 U/L; range, 40–236 U/L). Three patients underwent surgical resection (one with adjuvant FOLFOX chemotherapy), two underwent palliative care, and one palliative chemotherapy with gemcitabine and abraxane. Over a median follow-up of 220.5 days (IQR, 144.8–399.5 days), all six patients died due to disease progression (100%).
|Patient No. [year of LT]||LT diagnosis||Age (years)/sex||BMI (kg/m2)||Smoking history||Alcohol abuse history||DM||Year of diagnosis||Tumor size on imaging (cm)||Management||Last disease extent||Status||Survival after diagnosis (days)|
|1 ||HBV, hereditary hemochromatosis||71/M||21.8||No||No||Yes||2014||3.2||Resection + chemotherapy||M1 intraoperatively||Dead||360|
|2 ||Alcoholic liver disease||74/F||25.3||Yes||Yes||No||2018||4||Palliative care||M1||Dead||154|
|3 ||HCV, HCC (explant)*||66/M||20.2||Yes||Yes||Yes||2019||3||Palliative care||SMA invasion||Dead||260|
|4 ||HCV, Alcoholic liver disease||48/M||22.1||Yes||Yes||No||2013||3.1||Resection||R1 resection, leading to M1||Dead||117|
|5 ||HCV, iCCA (explant)*||66/F||27.3||Yes||Yes||No||2019||5.3||Palliative chemotherapy||SMA, SMV and celiac axis invasion||Dead||181|
|6 ||NASH, HCC||61/M||25.8||Yes||No||Yes||2018||NA||Resection → palliative care||Disease-free → M1||Dead||518|
*, HCC and iCCA were identified on explant pathology and not pre-operatively. BMI, body mass index; DM, diabetes mellitus; F, female; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; LT, liver transplantation; M, male; M1, metastatic disease; MMF, mycophenolate mofetil; NA, not available; NASH, nonalcoholic steatohepatitis; R1, positive-margin resection; SMA, superior mesenteric artery; SMV, superior mesenteric vein.
|Elevated bilirubin||5 (83.3)|
|Abdominal pain||3 (50.0)|
|Weight loss||3 (50.0)|
|Elevated glucose||1 (16.7)|
Our single institution series shows that the incidence of pancreatic adenocarcinoma after an LT is comparable to that of our hospital population (0.27–0.35% vs. 0.20%), yet it is higher than that reported in the general population of North America (0.0076%) (10,11). The incidence of pancreatic adenocarcinoma in our hospital population is different from that of the general population, as our center is a large tertiary care referral center and therefore, many patients are referred for advanced care of complex disease processes, and they represent a subgroup with a higher incidence of comorbidities.
Improved outcomes following LT has led to patients living longer following LT. This increased longevity has highlighted the significance of de novo malignancies. The incidence of de novo malignancies among LT recipients is 2–4 times higher than in the general population (20,21). A recent systematic review showed that post-transplant lymphoproliferative diseases and skin tumors are the most commonly seen malignancies after LT (6). The incidence of de novo solid-organ malignancy following LT ranges from 3–15% (22). Reported risk factors for the development of de novo malignancy include increasing age, male sex, white race, and prior malignancy (23). Importantly, survival with de novo malignancy in LT patients is worse when compared to the general population and to the population of cancer-free LT recipients (24).
There are no large studies in the literature reporting incidence or outcomes of LT recipients with pancreatic malignancies except for single case reports or small case series, also suggesting that pancreatic adenocarcinoma is not among the most common post-LT malignancies. When examining the SRTR database from 1987–2015, Bhat et al. found that de novo pancreatic cancer was reported in only 0.18% of the LT population. These patients were grouped with other rare malignancies as “Other” and not analyzed (23). Most pancreatic tumors reported in the literature are neuroendocrine type while only a handful of cases of adenocarcinoma are reported (5,25-29) (Table 3).
|First author, year||LT diagnosis||Age (years)/sex||Interval between LT and diagnosis||Tumor size on imaging (cm)||Management||Last disease extent||Status||Survival after diagnosis|
|Abbasoglu, 1997, (26)||NA||NA||NA||NA||NA||NA||Died||NA|
|Kelly, 1998, (27)||NA||66/NA||2 years||NA||NA||NA||Died||1 month|
|Stauffer, 2009, (25)||Alpha-1 antitrypsin deficiency||56/M||3.8 years||>4||Resection||Disease-free → recurrence||NA||21 months|
|Sutcliffe, 2010, (28)||PSC||40/M||3 years||3||Resection + chemotherapy||Disease-free locoregional recurrence with retroperitoneal lymphadenopathy||Dead||10 months|
|Ester, 2018, (5)||HCV||66/M||1–2 years||4||Palliative chemotherapy||Progression with compression and dilation of biliary system||NA||NA|
|Kobayashi, 2018, (29)||Alcoholic liver disease||59/F||4 years||NA||Chemotherapy||Progression||Died||4 months|
|HCV||60/M||13 years||NA||Resection||Lymph node metastasis → peritoneal dissemination||Died||4 months|
HCV, hepatitis C virus; LT, liver transplantation; M, male; NA, not available; PSC, primary sclerosing cholangitis.
Post-LT pancreatic adenocarcinoma poses a significant diagnostic challenge, as symptoms of obstructive jaundice are usually attributed to biliary strictures or allograft dysfunction, and thus, the diagnostic workup is commonly directed towards these entities (30). This can potentially lead to a diagnostic delay. This particularly holds true for patients with primary sclerosing cholangitis (PSC), who are also at a higher risk of developing pancreatic adenocarcinoma than the general population (31). Although PSC was not the transplant diagnosis for any of the six patients in our study, these patients may potentially be in a higher risk of delayed cancer diagnosis, due to their high incidence of biliary complications (32). Our case series, as well as previously published cases, shows there is often a relatively long time between the LT surgery and diagnosis of pancreatic adenocarcinoma, emphasizing the importance of long-term follow-up in this patient population. The overlap in clinical presentation and laboratory data abnormalities of pancreatic adenocarcinoma and LT complications requires ongoing vigilance, especially in patients with unexplained hyperbilirubinemia and history of tobacco and/or alcohol use, to prevent this potential delay in diagnosis and management.
When a patient is diagnosed with resectable pancreatic post-LT, the prior transplant and immunosuppression will render pancreatic resection and postoperative recovery more complex and challenging. The anatomy of the hepatoduodenal ligament is altered during the LT, making it technically more challenging to perform pancreaticoduodenectomy without harming the liver allograft. Knowledge and familiarity with a patient’s LT anatomy and the surgeon’s experience in dealing with reoperation scenarios after LT are of utmost importance. Anastomotic leak is a relatively common complication after pancreaticoduodenectomy (33), and the immunosuppressive state in LT recipients only increases this risk. Additionally, higher dose of tacrolimus has been associated with increased risk for post-LT solid organ malignancy (34). Data suggest that LT recipients on tacrolimus-based immunosuppression demonstrated a two-fold higher risk of de novo malignancy post-LT compared to LT recipients on cyclosporine-based immunosuppression (35). Further multi-center studies are required to unveil whether decreasing or even halting immunosuppression in these patients may be sound. In many of these cases the immunosuppression regimen is likely already minimized because of the long time period between LT and development of pancreatic adenocarcinoma.
Certain limitations should be taken into consideration when interpreting the results of our study. One of these is the retrospective, single-center nature of our study. The small size of our study population may also preclude generalization of our results to other populations. Additionally, there may be LT recipients who were transplanted at our center but may have been later diagnosed with pancreatic adenocarcinoma in other centers that we could not identify and include in our analysis.
In conclusion, although uncommon, there is an increased incidence of pancreatic adenocarcinoma following LT when compared to the general population, with a long lag time between LT and development of pancreatic adenocarcinoma. Timely diagnosis requires long-term vigilance, and management requires expertise and familiarity with LT, pancreatic resection, and immunosuppression management.
Part of the findings have been presented at the Virtual American Transplant Congress May 30, 2020–June 3, 2020.
Funding: Partially supported by NIH/NCATS grant support (UL1 TR000445) for REDCap (Vanderbilt University).
Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://dx.doi.org/10.21037/apc-21-4
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apc-21-4). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Vanderbilt University Medical Center Institutional Board Review (IRB#192061) and individual consent for this retrospective analysis was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
- Starzl TE, Marchioro TL, Vonkaulla KN, et al. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659-76. [PubMed]
- Rana A, Godfrey EL. Outcomes in Solid-Organ Transplantation: Success and Stagnation. Tex Heart Inst J 2019;46:75-6. [Crossref] [PubMed]
- Lim KB, Schiano TD. Long-term outcome after liver transplantation. Mt Sinai J Med 2012;79:169-89. [Crossref] [PubMed]
- Rana A, Ackah RL, Webb GJ, et al. No Gains in Long-term Survival After Liver Transplantation Over the Past Three Decades. Ann Surg 2019;269:20-7. [Crossref] [PubMed]
- Ester C, Gheorghe L, Becheanu G, et al. Early detection of advanced pancreatic cancer after DAA-induced virological cure in a liver transplant recipient with hepatitis C recurrence. J Gastrointestin Liver Dis 2018;27:104-5. [Crossref] [PubMed]
- Manzia TM, Angelico R, Gazia C, et al. De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature. World J Gastroenterol 2019;25:5356-75. [Crossref] [PubMed]
- Verran DJ, Mulhearn MH, Dilworth PJ, et al. Nature and outcomes of the increased incidence of colorectal malignancy after liver transplantation in Australasia. Med J Aust 2013;199:610-2. [Crossref] [PubMed]
- Rademacher S, Seehofer D, Eurich D, et al. The 28-year incidence of de novo malignancies after liver transplantation: A single-center analysis of risk factors and mortality in 1616 patients. Liver Transpl 2017;23:1404-14. [Crossref] [PubMed]
- Fung JJ, Jain A, Kwak EJ, et al. De novo malignancies after liver transplantation: a major cause of late death. Liver Transpl 2001;7:S109-18. [Crossref] [PubMed]
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
- Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol 2019;10:10-27. [Crossref] [PubMed]
- Parkin DM, Boyd L, Walker LC. 16. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br J Cancer 2011;105:S77-S81. [Crossref] [PubMed]
- Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-403. [Crossref] [PubMed]
- El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology 2009;49:116-23. [Crossref] [PubMed]
- Korc M, Jeon CY, Edderkaoui M, et al. Tobacco and alcohol as risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2017;31:529-36. [Crossref] [PubMed]
- Pandol SJ, Apte MV, Wilson JS, et al. The burning question: why is smoking a risk factor for pancreatic cancer? Pancreatology 2012;12:344-9. [Crossref] [PubMed]
- Xu M, Jung X, Hines OJ, et al. Obesity and Pancreatic Cancer: Overview of Epidemiology and Potential Prevention by Weight Loss. Pancreas 2018;47:158-62. [Crossref] [PubMed]
- Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377-81. [Crossref] [PubMed]
- Harris PA, Taylor R, Minor BLThe REDCap consortium, et al. Building an international community of software platform partners. J Biomed Inform 2019;95:103208 [Crossref] [PubMed]
- Herrero JI. De novo malignancies following liver transplantation: impact and recommendations. Liver Transpl 2009;15:S90-4. [Crossref] [PubMed]
- Herrero JI. Screening of de novo tumors after liver transplantation. J Gastroenterol Hepatol 2012;27:1011-6. [Crossref] [PubMed]
- Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl 2012;18:1277-89. [Crossref] [PubMed]
- Bhat M, Mara K, Dierkhising R, et al. Gender, Race and Disease Etiology Predict De Novo Malignancy Risk After Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance. Transplantation 2019;103:91-100. [Crossref] [PubMed]
- Taborelli M, Piselli P, Ettorre GM, et al. Survival after the diagnosis of de novo malignancy in liver transplant recipients. Int J Cancer 2019;144:232-9. [Crossref] [PubMed]
- Stauffer JA, Steers JL, Bonatti H, et al. Liver transplantation and pancreatic resection: a single-center experience and a review of the literature. Liver Transpl 2009;15:1728-37. [Crossref] [PubMed]
- Abbasoglu O, Levy MF, Brkic BB, et al. Ten years of liver transplantation: an evolving understanding of late graft loss. Transplantation 1997;64:1801-7. [Crossref] [PubMed]
- Kelly DM, Emre S, Guy SR, et al. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 1998;83:1237-43. [Crossref] [PubMed]
- Sutcliffe RP, Lam W, O'Sullivan A, et al. Pancreaticoduodenectomy after liver transplantation in patients with primary sclerosing cholangitis complicated by distal pancreatobiliary malignancy. World J Surg 2010;34:2128-32. [Crossref] [PubMed]
- Kobayashi N, Goto R, Yabe S, et al. Two cases of de novo pancreatic cancer after living donor liver transplantation. Japanese J Transplant 2018;53:365-71.
- Villa NA, Harrison ME. Management of Biliary Strictures After Liver Transplantation. Gastroenterol Hepatol (N Y) 2015;11:316-28. [PubMed]
- Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321-7. [Crossref] [PubMed]
- Hildebrand T, Pannicke N, Dechene A, et al. Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis. Liver Transpl 2016;22:42-52. [Crossref] [PubMed]
- Nathan H, Cameron JL, Goodwin CR, et al. Risk factors for pancreatic leak after distal pancreatectomy. Ann Surg 2009;250:277-81. [Crossref] [PubMed]
- Carenco C, Assenat E, Faure S, et al. Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship. Am J Transplant 2015;15:678-86. [Crossref] [PubMed]
- Wimmer CD, Angele MK, Schwarz B, et al. Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients. Transpl Int 2013;26:999-1006. [Crossref] [PubMed]
Cite this article as: Rauf MA, Ziogas IA, Sealock JM, Davis LK, Izzy M, Alexopoulos SP, Matsuoka LK. Pancreatic adenocarcinoma in liver transplant recipients: a case series. Ann Pancreat Cancer 2021;4:6.