De Novo Malignancies After Liver Transplantation With 14 Cases

at a Single Center
Z.-N. Liu, W.-T. Wang*, and L.-N. Yan, for the Liver Surgery Group
Liver Surgery, West China Hospital of Sichuan University, Chengdu, China

ABSTRACT
Objective. To analyze the clinical characteristics, risk factors, and prevention of de novo
malignant tumors after liver transplantation.
Methods. Fourteen patients who underwent liver transplantation were identified as
having de novo malignancies. The clinical characteristics and survival of these patients were
retrospectively reviewed.
Results. Fourteen cases of de novo malignancies after liver transplantation occurred for
an incidence rate of 1.94% (14/722), including 11 men (78.6%, mean age, 48 y) and 3
women (21.4%, mean age, 50 y). The mean period from transplantation to cancer diagnosis
was 55
35 months. The distribution of tumor histologic types included colon cancer, lung
cancer, esophageal cancer, nasopharyngeal cancer, liver cancer, parotid carcinoma, bone
cancer, post-transplantation lymphoproliferative disorder, stomach cancer, bladder cancer,
and laryngeal cancer. Twelve cases (85.7%) had hepatitis B. Five patients (35.7%)
underwent operations, and the other 9 patients underwent chemotherapy or
radiotherapy. During a mean follow-up period of 37
26 months after the diagnosis of
de novo malignancy, 8 patients (57.1%) died, with only 1 dying of causes not related to
the de novo malignancy. The survival analysis showed 1-, 5-, and 7-year survival rates of
85.7%, 71.4%, and 42.9%, respectively.
Conclusions. De novo malignancies after organ transplantation have been suggested to be a
major cause of late mortality. De novo malignancy after orthotopic liver transplantation was
found to be related to smoking, sex, and low immune function due to immunosuppressive
agents. Solid tumors should be removed, and the patient should receive chemotherapy or
radiotherapy as early as possible. Early diagnosis and treatment are very important for
improving the prognosis.

S INCE the first successful human liver transplantation

(LT) in humans by Thomas Starzl in 1963 [1], it has
become the best therapeutic option for cancer, cirrhosis,
surgical technique have increased the number of long-term
survivors, de novo malignancies are frequently found during
extended follow-up and are currently the 2nd leading cause
end-stage liver diseases, and severe hepatitis. In general, the of death, after cardiovascular complications [3]. Indeed, the
surgical technique, intensive care treatment, donor and incidence of de novo malignancies in liver transplant re-
recipient conditioning, and immunosuppressive regimens cipients is w10% at 10 years [4], and the risk of de novo
have been improved, and better control of secondary com-
plications has also been achieved. These positive de-
velopments have resulted in current overall 10-year survival Funding: National Sciences and Technology Major Project of
rates of w60% after liver transplantation [2]. Furthermore, China (2012Zx10002-016 and 2012Zx10002-017).
the survival rate in the 1st year after transplantation has *Address correspondence to W.-T. Wang, MD, PhD, Liver
increased to >90% in many transplant centers [2]. Despite Surgery, West China Hospital of Sichuan University, Chengdu
the fact that advances in both medical management and 610041, China. E-mail: wwt0223@163.com

ª 2015 by Elsevier Inc. All rights reserved. 0041-1345/15

360 Park Avenue South, New York, NY 10010-1710 http://dx.doi.org/10.1016/j.transproceed.2015.08.008

Transplantation Proceedings, 47, 2483e2487 (2015) 2483

2484 LIU, WANG, AND YAN

malignancy is 3e7-fold higher than in the normal population rate of 1.94% (14/722). This rate is clearly higher than that
[5]. Although de novo malignancy has become the 2nd in the general population. Herrero et al [6] reported the
leading cause of death, recent studies suggest that the highest incidence of post-transplantation malignancies, at
incidence of deaths from malignancy is increasing faster 26% in a cohort of 187 orthotopic LT recipients. The 14
than those from cardiovascular complications [3]. The adult LT recipients in the present study consisted of 11 men
increased incidence of malignancies in these patients re- (78.6%; mean age, 48 y), 5 of whom were heavy alcohol
flects factors related to demographics, chronic viral in- consumers and 4 of whom were smokers before the trans-
fections, and exogenous immunosuppressive drugs [5e7]. plantation, and 3 women (21.4%; mean age, 50 y). A total of
Tumor incidence in transplant patients depends on the 12 patients (85.7%) had hepatitis B; 8 underwent living-
length of follow-up and the time period in which the donor LT (57.1%) and 6 deceased-donor LT (42.9%). At
transplantation was performed [8]; in addition, recipient age 1 year, 22% of the patients were receiving only 1 immuno-
and smoking history have been reported as potential risk suppressive drug; 1 case was treated with cyclosporine, and,
factors for the development of cancer [7,8]. The majority of 4 cases with cyclosporine combined with mycophenolate
malignancies related to solid organ grafting are related to mofetil. However, in 2 of these patients, the cyclosporine
viral infections, such as post-transplantation lymphoproli- was changed to tacrolimus because of side effects. In addi-
ferative disorders (PTLDs) related to Epstein-Barr virus tion, 2 patients were administered tacrolimus and 7 patients
(EBV) [9], skin cancer including squamous cell carcinoma, tacrolimus combined with mycophenolate mofetil. One pa-
and Kaposi sarcoma related to herpesvirus 8 [7,9]. tient had premalignant conditions of ulcerative colitis that
The aim of the present retrospective study was to analyze developed into colorectal cancer at 10 months after LT. The
the incidence and course of de novo malignancies in a series patients were diagnosed with a de novo malignancy after a
of 14 patients who underwent LT at a single institution. We mean period of 55
35 months. The demographic and
also analyzed patient outcomes regarding patient survival, clinicopathologic features of the 14 patients are described in
tumor type, and prognosis. Table 1. None of them had >1 malignancy. Eleven types of
de novo malignancies were identified, the most frequent
MATERIALS AND METHODS being lung cancer (n ¼ 3; 27.3%) and PTLD (n ¼ 2; 18.2%)
Study Population that were detected by endoscopy or bone marrow pathologic
evaluation. Patients with de novo malignancies of the upper
Data were collected from case histories, follow-up visits, and tele-
digestive tract were evaluated with the use of endoscopy and
phone interviews. In this retrospective study, data from the clinical
records of 722 consecutive patients who underwent LT from April biopsy. The histologic findings demonstrated 1 squamous cell
2002 to March 2009 at a single Chinese center were analyzed. The carcinoma, 1 gastric adenocarcinoma, and 1 pharyngeal carci-
median age of the recipients at the time of transplantation was 50 noma. All 14 patients received aggressive cancer treatment,
years (range, 19e68), and 507 (70%) of the recipients were male. The including surgery, chemotherapy, and radiotherapy. A total of 5
main indications for liver transplant were hepatitis B (HBV) cirrhosis. patients (35.7%) underwent an operation, and the other pa-
The observation period ended on August 31, 2014, or at the time of tients were administered chemotherapy or radiotherapy. Eight
patient death. Recipients who were followed for <3 months or died patients (57.1%) died during a mean follow-up period of 37

within 3 months after transplantation, those <18 years old, and those 26 months after the diagnosis of de novo malignancy. Only 1
with carcinoma recurrence were excluded from the present study. died of causes not related to the de novo malignancy. The
Cyclosporine or tacrolimus with steroids or mycophenolate mofetil
survival analysis showed 1-, 5-, and 7-year survival rates of
were the standard immunosuppressive regimens. After discharge, the
patients were evaluated twice a week in the 1st and 2nd months. They 85.7%, 71.4%, and 42.9%, respectively.
then attended clinic visits every 3 months in the 1st year after trans-
plantation and thereafter every 4e6 months.
DISCUSSION
All liver grafts were obtained from brain-dead or living donors.
Both the living and deceased donations were voluntary in all cases, Patterns of malignancy differ among the various organ
were approved by the West China Hospital Ethics Committee, and transplants. There is a greater incidence in LT patients of
complied with the ethical guidelines of the Declaration of Helsinki. carcinoma of the skin, lung cancer, PTLD, and Kaposi
sarcoma. Some studies have shown that skin cancers are the
Statistical Analysis
most common de novo malignancies after organ trans-
The patients’ baseline characteristics were expressed as median plantation [2]; indeed, the overall incidence of skin cancer
(range) for continuous data, and as n (%) for categoric data. after LT was reported in a large case series to be 0.9%e
Numeric data are presented as mean
SD or median. Patient 3.2% [2], compared with 0.02% in the general population.
survival rates were estimated with the use of the Kaplan-Meier
Nonmelanoma skin cancer was found to be the most
method. All analyses were performed with the use of SPSS 19.0
statistical software (IBM, Armonk, New York).
commonly reported cancer of all skin cancers after trans-
plantation. The common risk factors include sex, age, and
sunlight exposure, with the immunosuppressive agent
RESULTS (duration, type) also being related. One study found that
A total of 14 cases of de novo malignancies after liver male sex was an independent risk factor for the develop-
transplantation occurred in our series, with an incidence ment of skin cancer after LT [7].
DE NOVO MALIGNANCIES AFTER LIVER TRANSPLANTATION 2485

Table 1. Demographic and Clinic Pathologic Features of the 14 Patients With De Novo Malignancy
LT to
Patient Age Cancer Post-transplantation
No Sex (y) Diagnosis Type Immunosuppression (mo) De Novo Malignancy Treatment Follow-Up (mo) Status

1 M 49 HBV LC DDLT CsA/FK þ MMF 28 Parotid cancer RTx þ CTx 67 Alive

2 M 42 HBV LC DDLT CsA þ MMF 35 Nasopharyngeal cancer RTx þ CTx 82 Dead
3 M 43 HBV LC DDLT CsA/FK þ MMF 48 Laryngeal carcinoma RTx þ CTx 63 Dead
4 M 48 HBV LC LDLT FK þ MMF 18 Colorectal cancer Surgery þ CTx 28 Alive
5 F 47 HBV LC DDLT CsA þ MMF 61 Lung cancer CTx 23 Dead
6 M 62 HBV LC LDLT FK þ MMF 80 Esophageal cancer RTx þ CTx 49 Dead
7 M 38 HBV LC DDLT FK þ MMF 99 PTLD CTx 10 Dead
8 M 34 ALD DDLT FK 108 PTLD CTx 10 Alive
9 F 62 Toxic hepatitis LDLT FK þ MMF 60 Liver cancer Surgery 19 Alive
10 F 42 HBV LC LDLT CsA 98 Bone cancer Surgery 1 Dead
11 M 55 HBV LC LDLT FK þ MMF 99 Stomach cancer Surgery 9 Alive
12 M 59 HBV LC LDLT FKþMMF 7 Bladder cancer Surgery þ CTx 62 Dead
13 M 48 HBV LC LDLT FK þ MMF 16 Lung cancer CTx 68 Alive
14 M 54 HBV LC LDLT FK 32 Lung cancer CTx 37 Dead
Abbreviations: ALD, alcoholic liver disease; CsA, cyclosporine; CTx, chemotherapy; DDLT, deceased-donor liver transplantation; EMR, endoscopic mucosal
resection; FK, tacrolimus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LC, liver cirrhosis; LDLT, living-donor liver transplantation;
LT, orthotopic liver transplantation; MMF, mycophenolate mofetil; PTLD, post-transplantation lymphoproliferative disease; RTx, radiotherapy.

The second most common cancer in LT recipients is PTLD, transplants for nonalcoholic indications (P ¼ .001). In a study
with an incidence that varies from 0.9% to 2.6% in large case by Jonas et al [13], 2 of 33 cancers detected after LT were
series in adult LT populations [8], compared with 0.03% in the tongue cancers, both of which occurred in patients with a
general population. PTLD account for 20%e50% of de novo history of smoking. However the effects of smoking and
tumors after LT, and the high incidence of lymphomas is partly alcohol have been difficult to separate, because long-term
related partly to the more intense immunosuppressive therapy alcohol use has been shown to potentiate the carcinogenic
administered to hepatic allograft recipients and partly to the effects of cigarette smoke [14] and heavy drinkers also tend
large percentage of pediatric patients with a high incidence of to be heavy smokers [15].
primary EBV infection. The development of PTLD is related The incidence of lung cancer in LT recipients has been re-
to immunosuppression, specifically the use of OKT3, as well as ported to be from 0 to 1.2% [16], compared with 0.06% in the
to hepatitis C virus and EBV infection. Regression of lym- general population. However, the incidence of de novo lung
phoma can occur after treatment with acyclovir and reductions tumors after LT ranged from 0.1% to 2.2% in several reported
in immunosuppression [9]. series [17]. Smoking as a cause of lung cancer in the general
The incidence of colorectal cancer in the LT population population has been well established, and it appears that
has been reported to be 0%e0.6% [8]. Interestingly, patients smoking history would also predispose LT recipients given their
who underwent LT for primary sclerosing cholangitis immunosuppressed state. Lung tumors after LT are usually
appeared to be at an additional increased risk for devel- diagnosed at advanced stages, which are usually unresectable
oping de novo malignancy compared with LT recipients for and have a poor response to chemo- and/or radiotherapy [6,17].
other causes, with an incidence as high as 9.6%. This was confirmed in our series, in which 2 patients (66.6%)
The incidence of head and neck cancers (HNC) in LT were classified as stage IV and 1 patient (33.3%) as stage IIIB.
recipients has been reported to range from 0.1% to 2% in In the transplant population there is also a clear preponderance
large retrospective trials, compared with 0.01% in the gen- of lung tumors in male patients, explained by the higher rate of
eral population [10]. Nelissen [11] reported that of 5,255 men undergoing LT for alcoholic cirrhosis usually associated
organ transplant recipients, 48 (0.9%) developed HNC with routine tobacco consumption [18].
during the post-transplantation follow-up period. LT re-
cipients showed the highest risk compared with other trans-
plant groups: 14 of 965 LT patients (1.45%) were diagnosed Major Risk Factors and Predisposing Conditions
with HNC. In comparison, 5 of 536 heart recipients (0.93%), Recent research has shown that tobacco use may have
27 of 3,057 renal transplant patients (0.88%), and 2 of 697 important implications for surgical and clinical outcomes
(0.29%) lung recipients developed HNC [11]. A large [19]. There is further evidence that cigarette smoking may
portion of these HNCs are squamous cell carcinomas (SCC) contribute to poor graft function, cardiovascular disease,
of the lip or oropharynx, and a history of alcohol use appears and the development of secondary malignancies after
to predispose LT recipients to oropharyngeal cancer. Indeed, transplantation. A retrospective cohort study of 326 LT
in a study by Duvoux et al [12], the incidence of oropharyn- patients by van der Heide et al [20] showed that at 10 years,
geal cancer among patients receiving transplants owing to smoking increased an LT recipient’s risk of nonskin malig-
alcohol complications was 16.7% vs 0 in patients receiving nancies from 2.1% to 12.7% (P ¼ .019). Pungpapong et al
2486 LIU, WANG, AND YAN

[21] reported that 27% of patients were actively smoking and might have a more protective effect against certain tumor
within the 2 years before their pre-LT evaluation and that types. Second, long-term immunosuppression also puts the
57% of patients had a lifetime prevalence of smoking. Acute patient at a higher risk of infection with an oncovirus such as
alcohol intoxication has been shown to decrease natural human papillomavirus (HPV) or EBV [35]. Third, the drugs
killer cell activity, which plays an important role in tumor used for immunosuppression could also directly play a role.
surveillance in vivo, and the suppression of this activity Indeed, long-term use of calcineurin inhibitors is associated
could promote tumorigenesis [22]. A study by Jimenez et al with post-transplantation tumors because of the aberrant pro-
[23] showed that patients who underwent transplantation duction of cytokines that regulate processes promoting tumor
for alcoholic cirrhosis had higher rates of lung cancer than growth, metastasis, and angiogenesis [33]. Some retrospective
those who underwent transplantation for other causes studies have suggested a dose-dependent relationship with de
(4.3% vs 0.7%; P < .001). This result could be confounded novo malignancy. A study by Benllochet al [36] found that the
by the fact that patients who drink alcohol are more likely to use of azathioprine was an independent risk factor for a higher
smoke cigarettes; in fact, 73.3% of the de novo lung cancer incidence of de novo malignancies. Dantal et al [37] showed
patients in the present study were both heavy drinkers and that renal transplant patients on low-dose cyclosporine (trough
intermediate or heavy smokers. range, 75e125 ng/mL) had lower rates of malignancy than those
Haagsma et al [24] showed that age >40 years at trans- on high-dose cyclosporine (trough range, 150e250 ng/mL),
plantation is an independent risk factor for de novo though they also had higher rates of graft rejection; however, no
neoplasia, with a relative risk of 5.8 compared with younger mortality was observed.
patients. This point is important to consider because the Frequently, oncogenic viruses such as EBV, human
mean age of LT candidates increased progressively during herpesvirus 8, human papillomavirus (HPV), and Merkel cell
the past decade, indicating that de novo tumor risk currently polyoma virus are involved [38]. EBV-associated PTLD,
involves the majority of LT recipients. More recent studies Kaposi sarcoma, and Merkel cell cancer may involve the lower
have shown that male LT patients older than 40 years and gastrointestinal tract and the anogenital region [39]. Most of
female older than 51, respectively, at the time of transplant the data supporting the role of EBV in the development of
exhibited an independent risk for de novo malignancy [25]. PTLD are found in the pediatric transplant literature; children
However, a statistically significant difference between men have a higher likelihood of exhibiting EBV seroconversion
and women regarding the development of de novo tumor after transplantation (because most donor livers are EBV
has been shown in a single center study [13]. positive), which, along with the required immunosuppression,
Given the role of the immune system in tumor surveil- appears to place younger people at considerably higher risk
lance, it is likely that LT recipients with premalignant con- for PTLD [40].
ditions before LT could be at a higher risk for developing CMV-negative patients who receive a CMV-positive liver
malignant disease in the setting of immunosuppression. A have a 4e6-fold higher risk of PTLD, indicating that CMV
slightly increased risk for developing colon carcinoma in LT seroconversion may be a risk factor for PTLD in adults as
recipients with UC (ulcerative colitis) was found compared well [41]. Bellnoch et al found that HCV was an indepen-
with other patients with UC [26]. In addition, Fabia et al dent risk factor for the development of PTLD, and this has
[27] reported an 8% incidence of adenocarcinoma in been supported by other reports [42].
transplanted patients who had UC, but 0.1% incidence in LT recipients are exposed to a risk of de novo malig-
non-UC transplant patients. Patients with Barrett esoph- nancy. The age of LT candidates, virus infection after LT,
agus are at an increased risk of developing esophageal the parallel increase in the duration of exposure to immu-
cancer [28]. Myeloproliferative disorder (MPD) is a risk nosuppressive drugs, and exposure to alcohol and tobacco
factor for leukemia that commonly presents as Budd-Chiari as major indications of LT indicate that the prevention,
syndrome, and Dousett et al [29] reported 2 cases of rela- detection, and treatment of de novo tumors should become
tively late progression of MPD to leukemia (29 and 31 mo). major goals of LT recipient follow-up.
Over all, 3 cancers were determined to have developed from Pre-transplantation cessation of alcohol and tobacco
premalignant conditions: cervical carcinoma in situ (cervical consumption as early as possible, and a reduction in
atypia), esophageal carcinoma (Barrett esophagus), and immunosuppression or implementing the lowest level of
colon cancer (colonic polyp and UC) [30]. immunosuppression are consistent with good graft function.
Another important point to consider is the impact of However, the prevention of skin cancers is currently based
immunosuppression on de novo malignancies. First, impaired on sun protection measures, and annual screening for skin
immunosurveillance itself can stimulate oncogenesis by means cancer, especially in high-sunlight areas, is recommended.
of independent processes. This is especially the case for calci- Furthermore, the early detection of the tumors by yearly
neurin inhibitors, such as cyclosporine, that potentially pro- screening with computerized tomographic scanning should
mote carcinogenesis through complex pathways involving contribute to increasing to more resectability.
increased angiogenesis, suppressed apoptosis of damaged cells, In patients receiving transplants for premalignant disease,
DNA damage and altered DNA repair [31]. Other immuno- such as Barrett esophagus, annual clinical examination of
suppressive agents, such as mycophenolate mofetil [32], rapa- the mouth and throat, combined with esophagoscopy and
mycin [33] and tacrolimus [34], have antiproliferative activity chest X-rays, appears to be effective. In patients receiving
DE NOVO MALIGNANCIES AFTER LIVER TRANSPLANTATION 2487

transplants for gastric ulcer or UC, annual surveillance co- [20] van der Heide F, Dijkstra G, Porte RJ, Kleibeuker JH,
lonoscopy is recommended. In women, regular gynecologic Haagsma EB. Smoking behavior in liver transplant recipients. Liver
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associated with an increased incidence of vascular complications
after liver transplantation. Liver Transpl 2002;8:582e7.
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