Objectives: Hepatitis C virus infection has a 10.5% frequency in liver
transplant posttransplant lymphoproliferative disorders. Studies have suggested
that hepatitis C virus infection plays a role in developing posttransplant
lymphoproliferative disorders. Pooling data of posttransplant
lymphoproliferative disorders developing in liver recipients from the literature,
we analyzed and compared characteristics, behavior, and prognoses of
posttransplant lymphoproliferative disorders arising in hepatitis C virus-positive
versus negative liver graft recipients.
Materials and Methods: We conducted a search for the available data though
PubMed and Google Scholar for reports of posttransplant lymphoproliferative
disorders and hepatitis C virus infection in liver transplant recipients.
Overall, 29 studies were found and their data are included in the analyses.
Results: Overall, data of 212 liver transplant patients were included. Sixty-three
percent were male. No difference was found between hepatitis C virus-positive
liver transplant patients with posttransplant lymphoproliferative disorders
compared to their hepatitis C virus-negative counterparts regarding sex, time
from transplant to lymphoma development, lymphoma cell type, remission,
mortality rate, multiorgan involvement, disseminated posttransplant
lymphoproliferative disorders, and histopathologic evaluations (P > .1 for all).
Hepatitis C virus-positive liver transplant recipients representing
posttransplant lymphoproliferative disorders who were concomitantly positive for
Epstein-Barr virus were significantly more likely to develop lymphomas in the
early posttransplant period (26 [67%] vs 16 [40%]; P = .024) and to complicate liver (19 [63%] vs 8 [30%];
P = .017) than hepatitis
C virus-/Epstein-Barr virus+ patients.
Conclusions: Hepatitis C virus infection alone has no significant effect on
lymphoproliferative disorders after liver transplant; but when combined with
Epstein-Barr virus infection, it represents some significant different
presentations of the disease. However, no survival effect was found for
hepatitis C virus with or without simultaneous Epstein-Barr virus infection, in
the posttransplant lymphoproliferative disorders setting. Future prospective
studies are needed for confirming our results.
Key words: Posttransplant lymphoproliferative disorders, PTLD, Liver transplant, EBV, Hepatitis C virus
The term posttransplant lymphoproliferative disorder (PTLD) is a well-known
complication of organ transplants comprising a wide spectrum of clinically
relevant lymphatic disorders ranging from plasmacytic hyperplasia to malignant
monoclonal non-Hodgkin lymphoma. This entity was first reported by Penn and
associates1 in 1969, in a patient who had undergone living-related kidney
transplant. Since then, several reports have been published indicating a high
incidence of PTLD among recipients of all types of organs, including the liver.
The reported incidence of PTLD in organ transplanted patients is 1% to 20%2-4 with an incidence rate of 2% to 4% in adult liver allograft recipients.5-7 It is
shown that the rate of PTLD development has unequivocal associations with the
type of organ transplanted, the intensity of the immunosuppression, underlying
disease, age, and the occurrence of viral infections, particularly Epstein-Barr
virus (EBV).8-10 It also has been suggested that hepatitis C virus (HCV) and/or
cytomegalovirus, as cofactors of EBV infection, may increase the risk of PTLD.11-12
Hepatitis C virus has been associated with several extrahepatic manifestations,
most of which are through immunologic pathways.13 There are overwhelming data
indicating a powerful association between HCV infection and essential mixed
cryoglobulinemia, which is generally considered as a low-grade non-Hodgkin
lymphoma.14-17 Hepatitis C virus-specific antibodies have been found in up to
98% of mixed cryoglobulinemia patients.18 It also has been demonstrated that HCV
can induce clonal proliferation of B lymphocytes and has been shown to be
involved in the pathogenesis of B-cell lymphoproliferation.19, 20
Hepatitis C virus has a 10.5% frequency in liver transplant PTLD patients.8 Evidence suggests that HCV infection plays a significant role in development of
PTLD, and reports indicate that the incidence of PTLD in HCV-positive liver
graft recipients is higher than that in HCV-negative patients.21 Most of the
available data on the above-mentioned issues are based on case reports and small
series. In fact, such cases are only included in bigger series and have not
received enough attention. Moreover, there is no mention about any specificity
associated with HCV-induced PTLD, including histopathological features, any
priorities in organ involvement, and rates of disseminated disease, remissions,
and survival. Pooling data of HCV-positive PTLD liver recipients from the
existing literature, we sought to analyze and compare characteristics, behavior,
and prognosis of PTLD arising in HCV-positive versus negative liver graft
Materials and Methods
Approach to the study
We conducted a comprehensive search for the available data though PubMed and
Google Scholar for reports of PTLD and HCV infection in liver transplant (LT)
recipients. Search terms used were “lymphoproliferative disorders +
transplantation + liver + hepatitis C virus,” “lymphoproliferative disorders +
transplantation + liver + HCV,” “PTLD + liver + hepatitis C virus,” and “PTLD +
liver + HCV.” In some cases, we were unable to obtain the full text of the
articles, e-mails were sent to the corresponding authors requesting the article
file. Of the full texts obtained, we included studies in which data on each
patient was presented separately. Hepatitis C virus-negative PTLD LT controls
also were included for comparisons. For inclusion of controls, we only used
cases for which HCV negativity was definitely reported, and cases with no
presented data on HCV serology/polymerase chain reaction (PCR) analyses were
excluded. A standard questionnaire was developed to collect data from different
published studies. The time between transplant and PTLD onset was defined as the
period between the engraftment and the first signs of PTLD or diagnosis,
depending on the study’s approach.
Twenty-nine international published studies8, 22-49 met our criteria (Table 1).
A total of 212 cases of PTLD LT patients were included in the analysis; of whom
68 (32%) were HCV-positive PTLD, and the remaining 144 patients (68%) developed
HCV-negative PTLD LT. Epstein-Barr virus was documented in 145 patients (68%),
of whom, 112 (77%) were reported positive.
Because methodologies differed among the published studies, not all our measures
were available for all patients. We recorded disseminated PTLD when it was
reported by the study authors, or if at least 3 different organs were involved
by the PTLD (different lymph node areas were excluded from the analysis owing to
the lack of knowledge on how to categorize; unless they were concomitant with
other organ involvements; or other authors specifically presented them as having
disseminated disease). According to the above-mentioned, disseminated disease
was reported for 28 patients (23%; 91 missing data). Multiorgan involvement,
defined as involvement of more than 1 organ (the second organ could be a
lymphatic region), was available in 49 patients (38%; 84 missing data).
At PTLD LT onset, all patients were under immunosuppressive regimens consisting
of varying combinations of azathioprine, prednisone, cyclosporine, mycophenolate
mofetil, ATG/ALG, and OKT3. A rather uniform approach was used to manage most of
the included PTLD LT. On diagnosis of PTLD, the first step in almost all reports
was to decrease or discontinue immunosuppressive therapy; various regimens of
chemotherapy with or without surgical interventions also were used for some
Response to treatment
We defined response to treatment as any favorable change both in PTLD measures
as well as the patient’s clinical condition. Data on response to treatment was
reported for 75 patients (35%), of whom 68 (91%) responded to treatment. To
create a common standard across the studies, we defined a remission episode as
when a patient was alive 24 months after PTLD onset (because all reported cases
meeting this criterion had at least 1 confirmed remission episode) and as no remission when a patient died within the first month after PTLD onset
there were no patients dying in the first posttransplant month that were
reported to have any remission episodes). According to these criteria, data on
remission were available for 99 patients (47%), of whom 86 (87%) had at least 1
response to treatment, irrespective of their future disease course. Data on
mortality were available for 160 patients (75.5%), of whom 67 died (42%). We
defined death owing to PTLD LT when the authors stated it, when death was within
6 months after onset, or death was reported to be owing to PTLD LT treatment
complications. Death beyond this time was not labeled as PTLD-free mortality,
unless it was defined by authors. Based on these criteria, 33 patients (49% of
reported deaths, 24% of patients for whom mortality data was reported) died
owing to PTLD.
Statistical analyses were performed with SPSS software (SPSS: An IBM Company,
version 13.0, IBM Corporation, Armonk, New York, USA). Statistical comparisons
between patient subgroups were performed using chi-square and Fisher exact tests
for proportions, and the t test for continuous data. Survival analysis was done
with life tables, Kaplan-Meier method and log-rank test. A P value of .05 was
taken as the threshold for significance.
Overall, 212 cases of PTLD LT were found. There were 113 male (63%) and 66
female patients (31%) (33 missing data). Mean age at transplant was45.3 ▒ 15.7
years. The mean interval between transplant and the onset of PTLD LT was 31.8 ▒
36.3 months, and the mean follow-up after onset of PTLD was 24.0 ▒ 29.0 months.
Characteristics of PTLD LT patients with and without HCV infection are
summarized in Table 2. A chi-square test showed that HCV positive-PTLD LT
patients were comparable to HCV-negative PTLD in sex (P = .19), time from
transplant to PTLD LT development (P = .633), lymphoma cell type (P = .17), remission (P = 1.0), mortality rate (P = 1.0), multiorgan involvement (based on
our definition; P = .23), and disseminated PTLD (based on our definition;
.35). Histopathologic evaluations also were not significantly different between
the 2 groups (P = .11). Hepatitis C virus-positive PTLD LT patients were
significantly younger at the time of transplant (P = .002).
Table 3 compares HCV-positive versus-negative LT recipients respecting organ
involvement by PTLD. No differences were seen regarding priorities in organ
involvements for the 2 patient groups. At the last follow-up, 68 patients (42%
of reported; 51 missing data) died. Using death by any cause as the outcome, log-rank
test did not show any difference between the 2 groups in survival (P = .96; Figure 1). Nor was any difference seen between the 2 groups when death only
owing to PTLD (based on our definition) was used as the outcome (P = .58). One-
and 5-year survival rates for HCV-positive PTLD LT patients were 65% and 62%,
compared to 70% and 56% for HCV-negative PTLD LT patients.
In an attempt to find out whether a coinfection of HCV and EBV has any effect on
PTLD, we introduced 2 patient groups according to their HCV and EBV test results:
(1) EBV positive and HCV positive (HCV+/EBV+), and (2) EBV positive and HCV
negative (HCV-/EBV+). Group 1 was significantly more likely to develop PTLD in
the early posttransplant period (26 [67%] vs 16 [40%]; P = .024); moreover, HCV+/EBV+
PTLD LT patients were significantly more likely to complicate liver (19 [63%] vs
8 [30%]; P = .017) than HCV-/EBV+ patients. Other study parameters were
comparable between the 2 groups (data not shown).
Posttransplant lymphoproliferative disorders comprise a spectrum of significant
lymphatic disorders that induce a wide range of morbidity and mortality to organ
transplant recipients; it has emerged as a serious complication that needs a
huge amount of attention on exploring predictive and interfering factors. The
incidence, features, and prognosis of PTLD varies between different transplant
patients owing to several parameters including the transplanted organ,
immunoşsuppression intensity, the use of antibody induction, and viral
infections, most notably, EBV infection.50
In a nontransplant setting, hepatophil viruses are shown to have stimulating
roles in inducing lymphoproliferative disorders. Several reports have suggested
an exceeding prevalence of HCV51-53 or of hepatitis B virus54, 55 infection in
patients with non-Hodgkin lymphomas. Hepatitis C virus can induce clonal
expansion of B lymphocytes and has been involved in the pathogenesis of B-cell
lymphoproliferative disorders.19, 20 It has been demonstrated that HCV
nonstructural proteins (NS3 and HCV core protein) can induce cell transformation
in nude mice, and that HCV core protein is capable of effecting cellular proto-oncogenesis
regulation and stimulating B-cell secreting cryoglobulin, which potentially can
result in clonal expansion and lymphoma.56-58 Hepatitis C virus RNA or proteins
also have been found in epithelial cells of parotid lymphoma, and in bone marrow
and lymph nodes of patients with B-cell non-Hodgkin lymphomas.59, 60 Other
studies have demonstrated that HCV replicates blood cells including B-lymphocytes
and CD34+ hematopoietic progenitor cells.16, 59, 61 Other evidence for a
potential association between HCV infection and lymphoma is provided by
observations suggesting regression of monoclonal B-cell expansion in patients
with lymphoproliferative disorders after clearance of HCV following
In this era of transplant, it is also believed that chronic HCV infection may
lead to the development of PTLD by stimulating lymphoid tissue and clonal B
cells proliferation.10 One reason for this risk enhancement is reportedly the
immunosuppressive treatment in these patients, owing to preventing rejection
episodes that can lead to activation of chronic infections including HCV. In
this study of international data, we pooled the existing data from HCV-infected
PTLD LT to find any potential associations between HCV infection in PTLD
patients and disease features, behavior, and prognosis. The unexpected finding
of this study is that we found no significant difference between HCV-positive
and -negative PTLD LT patients.
Because our study deals with the largest patient population in the current
literature, we think that this finding is not only due to the limited number of
included patients, but the methodology of our study, which reviews and gathers
data from different reports, despite some disadvantages, can be used precisely
in several cases. For example, if HCV infection could have a provocative role
for development of PTLD, at least we should expect a shorter time from
transplant to PTLD in HCV-positive PTLD LT patients compared to HCV-negative
controls, as we can observe it in EBV-positive setting.65, 66 Moreover, no
disparities also were found in the behavior of the PTLD between HCV-positive and
-negative liver recipients including remission rates and survival rates. This
finding suggests that even if HCV has any role in the development of the PTLD,
its role is not significant.
It also has been suggested that some viruses, including HCV, can act as
cofactors of EBV infection, and may increase the risk of PTLD.11, 12 Because we
have not found any associations between HCV infection and PTLD, we tried to find
out whether a coinfection of HCV and EBV can be different from that in only HCV-infected
At first, we introduced 4 patient groups according to their HCV and EBV test
results. We found that patients with EBV-positive tests had a significantly
shorter time to PTLD development. To censor the effect of EBV infection, we
recategorized our patients to 2 groups: (1) EBV-positive and HCV-positive, and
(2) EBV-positive and HCV-negative. New categorization showed that HCV-positive
PTLD patients with a simultaneous positive result for EBV were significantly
more likely to develop PTLD in the early posttransplant period; moreover, HCV+/EBV+
PTLD LT patients were significantly more likely to complicate liver than HCV-/EBV+
patients. These findings confirm previous studies’ findings in which authors
have speculated HCV as a predictor for PTLD only as a cofactor for EBV infection.
Potential criticisms may arise over our study. First, our study population was
gathered from different reports with inconsistent approaches. We also believe
that this is the unique major limitation for this study leading to substantial
missing data for some of study variables and thus, decreasing the power of our
analyses. This limitation was most prominent for special data that are not
typically included in reports on PTLD patients.
Another limitation owing to the inconsistencies available between the included
studies was that results of different studies were not presented in the same way.
For example, report of any response to treatment was presented very dissimilar
in different studies; while in 1 study, partial and complete remission was used
to translate the results; in another, only “response to treatment” was used, and
in some others, no specific terminology was used. So, we ought to invent new
methods to cumulate the existing data for analysis.
We conclude that, HCV infection alone has no significant effect on
lymphoproliferative disorders after LT; but when it is combined with EBV
infection, it represents some significant different presentations of the disease.
However, no survival effect was found for HCV with or without simultaneous EBV
infection, in the PTLD setting. Future prospective studies are warranted to
confirm our findings.
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Volume : 10
Issue : 2
Pages : 141-147
From 1The Internist Research Center, Department of Internal Medicine,
Baqiyatallah University of Medical Sciences, and the 2Dr Taheri Medical Research
Group, Tehran, Iran
Address reprint requests to: Hossein Khedmat, Floor 9, The Internist Research
Center, Department of Internal Medicine, Baqiyatallah Hospital, Mollasadra St,
Vanak Sq, Tehran, Iran
Table 1. List of the included studies and their share
in case and control groups.
Table 2. Characteristics of the included PTLD LT
patients regarding HCV test results.
Table 3. Frequency of involved organs in PTLD LT
patients with respect to their HCV test results.
Figure 1. Survival curves of HCV-positive and -negative
PTLD LT patients (Outcome: death irrespective of the reason)
Abbreviations: HCV, hepatitis C virus; PTLT, posttransplant lympho
- proliferative disorder