Review Article

POST TRANSPLANT MALIGNANCY – A BRIEF REVIEW

Veena Malhotra, Sumaid Kaul and Deep Shikha Arora

Senior Consultants, Department of Histopathology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Correspondence to: Dr Veena Malhotra, Senior Consultant, Department of Pathology, Indraprastha Apollo Hospitals,
Sarita Vihar, New Delhi 110 076, India
E-mail: veena_m@appollohospitals.com

Immunosuppressed allograft recipients have three to five folds increase in cancer risk as compared to age
matched general population. The most common malignancies encountered are Non Melanotic Skin Cancer,
Post Transplant Lymphoproliferative Disorder and Kaposi’s Sarcoma. Duration of immunosuppressive
therapy and/or type of immunosuppressive agents are important controllable factors which have an impact in
the development of tumors. Oncogenic viruses have an important role in the development of these
malignancies.
Key words: Post transplant malignancy, Immunosuppressive agents.

INTRODUCTION INCIDENCE

Solid organs transplant is the only life saving modality
for end stage disease of various organs. In past few decades
great advances have been made in the field of organ
transplant. Availability of excellent infrastructure in leading
hospitals, advancement of surgical techniques, growing
research and development of various safe options for
immunosuppression have lead to improvement in graft
survival, increased life expectancy and morbidity free post
transplant life in recipients. This has resulted in notable
increase in number of solid organ transplants. Currently
survival rate of renal transplant recipients is 95% at 1 year
and about 90% at 5 years [1].
Recipients of solid organ transplant are exposed to
prolonged immunosuppression which increases potential
risk of post transplant malignancies (PTM). In addition,
relatively older individuals are being considered for
transplants who carry inherent risk of malignancies. Thus
PTM is now a major challenge in patients successfully
treated by organ transplantation. Compared to general
population, several types of malignancies occur more
commonly in transplant recipients and are often more
aggressive with far worse prognosis [2].
In 1968, Starzl and Penn described the first case of Post
Transplant Lymphoproliferative Disorder (PTLD). Penn
established a voluntary Transplant Tumor Registry in 1969,
which was posthumously renamed as Israel Penn
International Transplant Tumor registry (IPITTR) in honour
of his life’s commitment to the study of transplant
malignancies [3].
Immunosuppressed allograft organ recipients have 3 to
5 fold increase in cancer risk as compared to age matched
general population [4]. The most common malignancies
encountered in post transplant recipients are non melanotic
skin cancers (NMSC - upto 82 %), PTLD (upto 11%) and
Kaposi’s sarcoma (KS) (about 6%) [5-7]. Besides these
malignancies, other tumors showing higher frequency are
renal cell carcinoma, in-situ carcinoma of uterine cervix,
hepatobiliary carcinoma, anogential cancer and
gastrointestinal tumors [8]. US Renal Data System
(USRDS) database showed that incidence of common
cancers such as colon, lung, prostate and breast is two times
higher in post transplant recipients as compared to age
matched population, while the increase in incidence ranges
from 3 fold for bladder and testicular malignancies, 15 fold
for kidney malignancies and 20 fold for lymphomas and
NMSC [9].
Netherland study showed that skin malignancy
developed in 53% of patients after renal transplant and 48%
of this subsequently developed second malignancy. PTLD
developed in 11% of patients, of which 65% presented with
lymphoma. Skin malignancies usually have good
prognosis, PTLD has variable prognosis and GIT
malignancies have poor prognosis[6].
Post transplant malignancies are a problem for
recipients of all types of organ transplants. The risk of
PTLD being more after small bowel, heart and lung
transplant than renal and liver transplants [10]. Reported
incidence of cancer in renal transplant recipients is 2.3-

169 Apollo Medicine, Vol. 7, No. 3, September 2010

Review Article
31 % in published series [11]. Data from registry of
International Heart and Lung Transplantation (ISHLT)
shows that amongst the heart transplant recipients, 3.1% of
surviving patients develop some form of malignancy after 1
year, which increased to 16.1% in 5 years survivors and
26.2% in 8 years survivors. Data from lung transplant
recipients showed the same trend [12]. USRDS data
showed that in renal transplant recipients cumulative
incidence of cancer excluding NMSC is 3.3% at 1 year and
7.5% at 3 years [13].
Pathogenesis
All human beings are continuously being exposed to
carcinogens or mutagens. These mutations are dealt with by
immune surveillance mechanism. Immunosuppressive
therapy resulting in lack of adequate immune surveillance
plays a key role in development of post transplant
malignancies. This is coupled with conventional
predisposing factors for development of tumors. Common
risk factors are increasing age of patient, cigarette smoking,
exposure to ultraviolet light, total sun burden, latent
oncogenic viruses, previous exposure to carcinogens and
analgesic abuse [14]. Geographical factors such as
predisposition to certain malignancies in some countries i.e.
liver tumors in South East Asia and GI malignancies in
Japan, also play a role. Genetic predisposition for certain
malignancies also contributes [15]. The duration of
immunosuppressive therapy, and/or type of
immunosuppressive agents are the important controllable
factors which have an impact on the development of PTM.
In development of post transplant malignancies
potentially oncogenic viruses play a major role. Human
Herpes Virus-8 (HHV8) is associated with Kaposi’s
sarcoma, Human Papilloma Virus (HPV) 8 and 19 with skin
cancer, HPV58 with Bowen disease, Epstein Barr Virus
(EBV) with PTLD, Hepatitis B and C virus with
hepatocelullar carcinoma [16] . PTLD in particular is
related to EBV with 98% of cases related with latent EBV
infection [17].
It has been suggested that duration and type of
immunosuppressive agent used can affect cancer risk.
Number of studies demonstrate that incidence of PTM
increase after the introduction of the calcineurin inhibitor
(cyclosporin), whereas a few studies report no increase in
the risk of cancer [17-19]. An induction regimen that
contains lymphocyte depleting antibodies such as OKT3
and antithymocyte globulin is a well documented risk factor
for the development of PTLD [16]. Cyclosporin may cause
cancer progression through direct cellular effect and also by
increased expression of transforming growth factor B
(TGF-B) [20]. In addition, a role for cyclosporin in
Apollo Medicine, Vol. 7, No. 3, September 2010 170
stimulating angiogenesis mediated by Vascular Endothelial
Growth Factor (VEGF) has also been demonstrated [20]. In
vitro studies have suggested that cyclosporin induces
malignancy by reduction in p53 induced apoptosis and
suppression of UV induced DNA repair [16]. Purine
analogues such as azathioprin, have also been used in post
transplant patients. Post transplant patients treated with
Purine analogues have a much more rapid development of
skin cancer in comparison those treated with cyclosporine
[16,21].
Potential role of newer immunosuppressive agents that
is proliferation signal inhibitors (PSIs), Siromulus and
Everolimus, in prevention of PTM is increasingly being
evaluated. These new immunosuppressive agents have a
role in prevention, modification and even treatment of post
transplant malignancies [14]. In addition to
immunosuppression, they have antiproliferative effect by
their action on cell cycle. In vitro and vivo studies have
demonstrated that PSI’s can prevent growth of transformed
cells, increase rate of apoptosis in tumor cells, decrease
angiogenesis and thus tumor progression [22-24].
Post Transplant Lymphoproliferative Disorder
(PTLD)
PTLD is that most common malignancy after skin
cancer in solid organ recipients [25]. It is more common in
pediatric patients [26]. WHO has classified PTLD as; (i)
Early lesion characterized by reactive plasmacytic
hyperplasia or infectious mononucleosis type picture; (ii)
Polymorphic PTLD showing full range of B cell maturation
from immunoblast to plasma cell, small to medium
lymphocytes and cells resembling centrocytes and (iii)
Monomorphic PTLD which includes B cell neoplasms like
diffuse large B cell lymphoma, Burkitt’s lymphoma, plasma
cell myeloma, T cell lymphoma and Hodgkin’s lymphoma
[27].
The relationship of PTLD with Epstein Barr Virus
(EBV) is well recognized. Immunosuppressive drugs used
in post transplant period can lead to decrease in EBV
specific T cell surveillance and proliferation. Recipients
who are EBV negative and receive graft form EBV positive
individuals are at highest risk for developing PLTD.
Early lesions are most often seen in children and young
adults and usually occur within the first year post
transplantation, while second and third group i.e.
polymorphic and monomorphic PTLD are seen later post
transplantation [10]. In one study, relative risk of
lymphomia in the first 6 months after transplant was 13.8
which decreased to 3.46 between 2.5 to 3 years[17].
Incidence of PTLD is between 5-20 % after heart, lung and
small bowel transplant. However, the incidence after kidney

transplant recipient is much lower i.e.1-3% as kidney
transplant recipients require relatively less severe
immunosuppressive treatment [16].
Vast majority of PTLD are host derived. However some
cases can be derived from donor lymphocytes transplanted
within the graft [28]. Sites of predilection for PTLD are
extranodal. Trasplanted organ and digestive tract are most
frequent sites [29]. CNS is frequently involved in up to 30%
cases [30]. PTLD arising within one year of transplant is
usually associated with EBV infection and commonly
involves graft. This may suggest permissive role of graft
microenviorment in the pathogenesis [31].
Most of the PTLD are B cell type, T cell lymphomas are
only about 15% of these. T cell lymphomas tend to occur
late and affect extranodal sites. HTLV-1 virus has been
implicated in pathogenesis of T cell lymphoma. [32].
Duration, degree and type of immunosuppressive agent
used greatly influence development of PTLD. Introduction
of triple therapy i.e. cyclosporin, OKT3 antibody and
antithymocyte globulin is associated with increased risk
[33]. There is higher risk of PTLD with tacrolimus than
cyclosporin therapy in kidney transplant recipient [34].
Efforts have been made to identify patient at high risk of
developing PTLD by monitoring EBV-DNA load. No
threshhold values predictive of development of PTLD have
been identified [35]. However, a rising trend of EBV- DNA
in a particular patient may define patient at risk [36]. Serial
raised IL-10 levels and a unique monoclonal serum protein
has been identified in patients who developed
PTLD [37,38]. Vaccine against EBV may provide
protection to post transplant patients [39].
Reduction in immunosuppression is first line of
treatment in the management of patients with PTLD.
Complete regression of early lesions and polymorphic
PTLD usually occurs as a result. No standard guidelines
exist, but decreasing cyclosporin/tacrolimus by 50% and
discontinuing azathioprin or mycophenolate is
recommended [40]. Immunosuppression should be reduced
to minimal possible safe level keeping in mind graft
survival. Twenty five to 50% patients respond to reduction
in immunosuppression alone. Beneficial effect of antiviral
agents such as cyclovir is doubtful [25].
For last few years monoclonal antibody therapy
(rituximab) directed against B cell receptor (CD20) has
been introduced in treatment of B cell PTLD with promising
results [41-44]. Whether demonstration of CD20
expression in biopsy is prerequisite for starting treatment is
not well established. When to start rituximab therapy is
another issue. Whether the treatment should be initiated
171
Review Article
after absence of response to reduction in
immunosuppression treatment or simultaneously is still
debated [29].
It is suggested that in monomorphic PTLD, starting
rituximab at the same time as reducing immunosuppression
is a justified approach, which increases the chances of
complete remission [29]. In cases which are refractive to
first line treatment by rituximab, it is yet unclear whether
extended treatment by rituximab is appropriate or whether
polychemotherapy should be initiated. Because of higher
rate of treatment related morbidity and mortality, use of
rituximab has become more common [45]. Case series have
described response rate with single agent rituximab of
around 60% [45]. Finally, adoptive T-cell immunotherapy,
via infusion of EBV- specific CTLs in patients with EBV-
positive PTLD has shown promise [45].
PSIs have shown promising results in the treatment of
PTLD [46]. Data from centers in Europe of nineteen post
renal transplant patients with PTLD have been pooled. In
these patients calcineurin inhibitor was withdrawn in
eighteen and minimized in one with simultaneous
conversion to PSIs. Concomitant CHOP was given in six
and rituximab in another six. Fifteen out of eighteen patients
showed remission which was maintained for 6 to 56 months
[46]. Radiation therapy is method of treatment for CNS
lymphoproliferative disease [30].
Kaposi’s Sarcoma (KS)
The incidence of Kaposi’s Sarcoma (KS) in transplant
patients may be as high as 500 times than in healthy
individuals [7,47]. In renal transplants it is seen in upto 6%
of recipients though recent data demonstrates a lower
overall incidence of 8.8 cases of KS per 1,00,000 person
years [5]. Prevalence of KS in transplant recipients depends
on geographical location, ranging from 0.5% in western
countries such as USA to 5.3% in Saudi Arabia. Majority of
cases occur in patient from Mediterranean, Jewish, Arabic,
Caribbean or African ethnic groups [7,47]. The median time
from transplantation to diagnosis of KS is about 1.5 years
[48]. KS presents as cutaneous involvement in about 80%
cases. Visceral involvement is seen in 20% cases. Lungs,
GIT and lymphoid tissue can be involved [47, 49]. The
pathogenesis of KS is related to the use of immuno-
suppressive drugs and subsequent viral infection [45].
HHV-8 is implicated in the pathogenesis of tumor
development.
The first association of KS and HHV-8 was made when
virus was isolated from KS tissue in AIDS patients [50].
Various mechanisms may be involved in HHV-8 induced
tumor development. HHV-8 proinflammatory proteins
might directly inhibit apoptosis and there by promote cell
Apollo Medicine, Vol. 7, No. 3, September 2010
Review Article
transformation [51]. The virus might also modulate the
major histocompatibity class 1 antigen presentation
pathway making infected host cells invisible to cytotoxic T
lymphocyte surveillance [51]. Development of KS may
involve initial latent HHV-8 infection of endothelial cells
and subsequent conversion in spindle cells. This is followed
by proliferative phase and expression of a lytic protein, viral
G protein coupled receptor (vGPCD). In endothelial cells
vGPCR oncoprotein increases secretion of VEGF and
plays a pivotal role in development of tumor [52 ].
Immunosuppresion is the key contributing factor for
development of tumors. Use of cyclosporin as an
immunosuppressive drug in post transplant patients is
associated with a higher incidence of Kaposi’s sarcoma.
[47]. Reduction or discontinuation of immunosuppresssion
is the first line treatment for KS.
Conversion of cyclosporin to low therapeutic doses of
mycophenolate mofetil can lead to regression of KS [53].
PSIs (sirolimus and everolimus) through specific effect on
VGEF may provide advantage of both immunosuppressive
and antineoplastic activity [54]. PSIs impair VEGF
production and limit response of endothelial cells to VEGF
in animal models [54, 55]. Recurrence after reduction or
change in immunosuppresion has been treated by
chemotherapy, Anthracycline based chemotherapy is the
usual line of treatment [45]. Paclitaxel has also shown
success in two phase II trials [56]. Imatinib (C-kit inhibitor)
and antiangiogenic agents like bevacizumab may also have
a role in treating KS [56-58].
NON MELANOTIC SKIN CANCER
Non melanotic skin cancer (NMSC) affects large
number of organ transplant patients. Basal cell carcinoma
(BCC) and squamous cell carcinoma (SCC) account for
more than 90% of NMSC in transplant recipients [7].
Squamous cell carcinoma is the most common form of skin
cancer in these patients occurring at an incidence 65- 250
times greater than general population while incidence of
BCC is increased 10 fold after transplant [7]. This indicates
that normal ratio of 4:1 of BCC to SCC is reversed in
transplant recipients [7,59].
Overall cumulative incidence of NMSC after
transplantation ranges from 2-24% after 5 years and 7-33 %
after 10 years [60]. Lifelong immunosuppression is the most
important factor in the pathogenesis of NMSC. In addition,
UV exposure, HPV infection, and genetic factors also play a
role. Mutations of p53 and proto-oncogenes may occur [7].
Fair skinned people living in countries with hot climate
and high ultra violet exposure are more at risk of developing
post transplant NMSC [61]. Ultraviolet radiations, in
Apollo Medicine, Vol. 7, No. 3, September 2010 172
addition to its role as mutagen, have immunosuppressive
properties in the skin [7, 60]. Older age, male sex, presence
of permalignant lesions such as actinic keratosis and
cigarette smoking has also been associated with SCC and
BCC [60].
Transplant recipients should be warned about sun
exposure. Studies have demonstrated beneficial effect of
systemic retinoid chemoprophylaxis in transplant recipients
[45, 62]. However, a rebound effect with higher incidence of
NMSC after discontinuation of therapy is also reported.
Standard therapy for NMSC includes Mohs’ micrographic
surgery, superficial ablative therapy, cytotherapy and
photodynamic therapy along with attenuation of
immunosuppresion [63].
Consensus guidelines for immunosuppression
reduction have been developed [64]. Extent of
immunosuppression and type of immunosuppressive agents
used may play a critical role. A recent study indicated that
incidence NMSC increased from 19% at less than 5 years to
47% after more than 20 years of immunosuppressive
therapy [65]. A study in liver transplant receipient showed
mycophenolate mofetil (MMF) was associated with
increased risk of NMSC although this risk didn’t remain
after multivariate anlaysis [66], PSIS like sirolimus have
potential for reducing the incidence of NMSC [67].
Compared with 5% incidence of NMSC in cyclosporin
treated patients, no malignancies were observed in patients
receiving sirolimus as base therapy [68]. Thus cyclosporin
free sirolimus based immunotherapy may reduce incidence
of post transplant skin malignancy.
CONCLUSION
• Allograft organ recipients have three to five folds
increase in cancer risk as compared to age matched
general population.
• Post transplant immunosuppressive therapy resulting
in impaired cancer surveillance and facilitating the
action of oncogenic substances including oncogenic
viruses are key factors in pathogenesis.
• The most common malignancies encountered in post
transplant recipients are NMSC (upto 82%), PTLD
(upto 11%) and KS (upto 6%).
• PTLD has been classified by WHO as (i) early lesion
characterized by infectious mononucleosis type
picture or plasma cell proliferation, (ii) polymorphic
PTLD and; (iii) monomorphic PTLD. EBV has
important role in causing PTLD.
• Prevention of post transplant malignancies by
judicious use of immunosuppressive agents and early

detection is important.
• Early lesions of PTLD regress by withdrawing
immunosuppressive agents.
• Newer agents like PSIs have been shown to have
simultaneous immunosuppressive and antitumor
properties and may play a promising role in
management of post transplant patients.
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Apollo Medicine, Vol. 7, No. 3, September 2010