Review Article

Postrenal Transplant Malignancy: An Update for Clinicians

Renuka Soni, Priyadarshi Ranjan1*
Clinical Research Associate, Meliora Kidney and Urology Institute, Shalby Multispeciality Hospital, 1Director, Meliora Kidney and Urology Institute,
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW

Shalby Multispeciality Hospital, Mohali, Punjab, India

Abstract
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024

When compared to the general population, solid organ transplant patients had a 2–3 times higher overall risk of cancer. The third most frequent
cause of mortality in kidney transplant patients is posttransplant malignancy, with certain malignancies (melanoma, renal cell carcinoma, and
posttransplant lymphoproliferative disease) occurring at significantly greater rates than in the general population. Longer lifespans for kidney
transplant recipients necessitate close monitoring for posttransplant cancer. Immunosuppressant medicine and oncogenic infections appear to be
significant factors in the development of cancer. With the existing arsenal of pharmacotherapy and the possibility for immunologic surveillance
in the future, posttransplant treatment might be tailored to reduce the risk of posttransplant malignancy without affecting graft survival. This
manuscript gives an outline of the occurrence, causative factors, surveillance, diagnosis, and treatment of posttransplant malignancy. The review
focuses on the most prevalent cancers and the patients who are most at risk of developing them, including an overview of pathogenesis, the
association of immunosuppressive medications with the development of cancer, and several proposed processes that explain why transplant
recipients have a higher cancer risk.

Keywords: Immunosuppression, Kaposi sarcoma, kidney transplant, posttransplant lymphoproliferative disease, posttransplant malignancy,
renal cell carcinoma

Introduction Pre‑transplant recipient and donor evaluation, recipient

screening, and monitoring posttransplant are important
Malignancy is the third leading cause of mortality among solid
considerations for reducing overall tumor burden among kidney
organ transplant recipients after infection and cardiovascular
transplanted recipients. When an immunocompromised patient
complications. Malignancy after transplantation often
has a potentially curable cancer, online calculators can help
manifests as a more severe illness and is linked to a greater
with oncological counseling and treatment decision‑making
incidence of recurrence when compared to the normal
by estimating the likelihood of recurrence and survival using
population. The prevalence of certain malignancies is
patient and tumor information.[2] Individualized immune
higher in transplant recipients and significantly impacts the
system dysfunction is the contributing factor which may have
recipient’s survival and quality of life after transplant. It
a detrimental effect on how well cancer is controlled and
carries a two‑fold mortality risk among kidney transplant
treated. Furthermore, it is essential to create new treatment
recipients because of specific characteristics such as type
strategies for transplant recipients based on mechanistic
of malignancy, oncogenic viral infections, and use of strong
understandings of how cancer cells arise in the presence of
immunosuppressants.[1,2] The most dangerous cancers are
immunosuppression.[2,4,5] The best future therapeutic option for
those caused by viruses (Kaposi sarcoma and posttransplant
lymphoproliferative disease [PTLD]), anti‑rejection
Corresponding Author: Dr. Priyadarshi Ranjan,
medications themselves, like skin and lip cancers augmented Director, Meliora Kidney and Urology Institute, Shalby Multispeciality
by weakened immune systems which fail to keep a check on Hospital, Mohali, Punjab, India.
malignant proliferative cells. The types of cancers linked E‑mail: drp.ranjan1978@gmail.com
to immunological inadequacies differ from those that are
prevalent in the nontransplant population, such as colorectal, Received: 22 May 2023; Revised: 21 July 2023;
Accepted: 22 July 2023; Published: 29 December 2023
prostate, breast, and lung cancer.[3]

This is an open access journal, and articles are distributed under the terms of the Creative
Access this article online
Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
Quick Response Code: remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
Website: is given and the new creations are licensed under the identical terms.
www.ijtonline.in
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

DOI:
10.4103/ijot.ijot_60_23 How to cite this article: Soni R, Ranjan P. Postrenal transplant malignancy:
An update for clinicians. Indian J Transplant 2023;17:389-96.

© 2023 Indian Journal of Transplantation | Published by Wolters Kluwer ‑ Medknow 389

 Soni and Ranjan: Malignancy in renal transplant recipients
reducing risk of malignancy posttransplant is the development
of novel (tolerogenic) treatments that will minimize the need
for immunosuppression. This review gives an outline on the
occurrence, causative factors, surveillance, diagnosis, and
treatment of posttransplant malignancy. The manuscript also
highlights the most prevalent cancers and the patients who
are most at risk of developing them, including an overview of
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
pathogenesis, association of immunosuppressive medications
with the development of cancer, and several proposed processes
that explain why transplant recipients have a higher cancer risk.
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
Epidemiology and Risk Factors
Immunosuppressive medications used for preventing rejection
limit the ability of immune cells to distinguish between
normal and cancerous cells, encouraging virus‑associated
malignancies, thus setting a pro‑tumorigenic milieu in transplant
recipients. The incidence of vulvovaginal, hepatobiliary, and
cervical cancers, leukemia, and melanoma is increased by a
factor of five, whereas the risk of renal cell carcinoma (RCC),
non‑Hodgkin’s lymphomas (NHL) a part of PTLD, Kaposi’s
sarcoma (KS), and nonmelanoma skin cancer is elevated by
a factor up to twenty. For prevalent malignancies such as
breast, colon, prostate, and lung, a relatively moderate two‑fold
increase is found.[6,7] Many cancers are overrepresented among
chronic kidney disease/kidney failure populations, including
multiple myeloma and RCC.
Recipients who have previously undergone treatment for a
pretransplant malignancy are at increased risk of developing
cancer posttransplant than those without any malignancy,
though the cause of death may not always be a cancer recurrence.
Several risk variables, including sex (males are more at risk
than females), race, patient age, pretransplant cancer history,
type and intensity of net immunosuppression, dialysis duration
prior to transplant, sun exposure, viral or bacterial infection,
are associated with the onset and development of the different
types of cancer posttransplant [Table 1].[8‑10]
Posttransplant malignancies have a complex etiology that may
be roughly divided into the following groups: infection‑related,
donor‑derived, modifiable, and unmodifiable recipient‑derived,
pre‑ and posttransplant drug therapy [Table 2].[10] Also, different
types of malignancies tend to have different latency periods,
such as skin cancer, which has a latency period of 69 months,
whereas Kaposi Sarcoma and Lymphoma have latency periods
of 13–21 months and 32 months, respectively. The latency
period of occurrence of malignancy depends on the age of the
recipient. Younger recipients have a longer latency period.[11,12]
Pathogenesis
Cancer pathogenesis is a complex process that includes genetic,
immunological, and environmental viral components. Tumor
development can be influenced by control of cell proliferation,
prolonged angiogenesis, mutations in tumor suppressor genes
and oncogenes, abnormalities in DNA repair, and resistance
to apoptosis.[13]
390 Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
Table 1: Risk factors associated with different types of
malignancies posttransplant
Type of cancer Risk factors
Skin cancer Gender (males > females), race, age, pretransplant
skin cancer, HPV infection, and UV radiation
exposure (UVA and UVB are oncogenic)
Renal cell Long‑term dialysis, infections, acquired renal cystic
carcinoma disease, toxins, obstructions
Cervical cancer HPV infection, age, and immunosuppression
Bladder cancer BKV infection
Prostate cancer BKV infection
PTLD EBV infection, CMV infection, recipient or donor
origin ethnicity, age, immunosuppressive drugs, length
of time posttransplant
HPV: Human papillomavirus, UV: Ultraviolet, UVA: Ultraviolet A,
UVB: Ultraviolet B, CMV: Cytomegalovirus, EBV: Epstein–Barr virus,
BKV: BK virus, PTLD: Posttransplant lymphoproliferative disease
Table 2: Etiological classification of posttransplant
malignancy
Etiology Factors involved
Donor- Cancer history, undiagnosed cancer in donor.
derived Confirmation done by comparing donor and recipients
FISH, tumor histopathology
Recipient- Modifiable factors include smoking, tobacco intake,
derived obesity, and UV radiation exposure. Unmodifiable factors
include cancer history, age, kidney failure, dialysis vintage
Infection EBV, HPV, HHV‑8, BKV, CMV
Donor factors Age, ethnicity, gender
Drug therapy Pre‑ and posttransplant drug therapy, cytotoxic, steroids,
dialysis
UV: Ultraviolet, EBV: Epstein–Barr virus, BKV: BK virus, HPV: Human
papillomavirus, HHV‑8: Human herpesvirus‑8, CMV: Cytomegalovirus,
FISH: Fluorescence in situ hybridization
Patients with cellular and humoral immunological inhibition
have a higher chance of developing cancer, proving the
importance of a healthy immune system in preventing
cancer. Research studies provide more concrete evidence that
some tumors can be successfully treated by interfering with
molecules that typically slow or stop immune responses.[3,14]
Consequently, a healthy immune system is probably more
likely to check and inhibit cancer cells.
Immunosuppression is required following kidney
transplantation to avoid allograft rejection. Although it is widely
understood that total immunosuppression dosage is related to
increased cancer risk after transplantation, the contribution
of individual immunosuppressive drugs is unknown. There
are numerous mechanisms linking immunosuppression dose
to increased cancer incidence, including decreased immune
surveillance of tumors, decreased antiviral responses resulting
in a specific increase in virus‑induced tumors, and possibly the
direct carcinogenic effect of immunosuppressive drugs such
as cyclosporine and azathioprine.[15]
Also, taking immunosuppressive medications for the rest
of life can lead to secondary issues in transplant recipients,
 Soni and Ranjan: Malignancy in renal transplant recipients

such as an increased risk of contracting viral infections that
are closely linked to the development of cancer [Figure 1
and Table 3].[16] Normal tumor surveillance involves the
destruction of the development of tumor cells. Most likely,
surveillance targets viruses rather than tumors. The evidence
for this is that there is an increased frequency of tumors
in immunocompromised people, which are most likely
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
to promote tumor angiogenesis by inhibiting DNA repair
mechanisms.[8,17‑19]
Pathogenesis of Epstein–Barr virus (EBV) infection in solid
organ transplant recipients arises in either, latent, acute, or
acquired settings from the allograft. EBV early RNA, EBV
latent membrane protein, and EBV DNA are all present in
PTLD that is associated with EBV. B‑cells are infected via

linked with oncogenic viruses. Immunosuppressive drugs their CD21 receptor during the latency phase, during which
inhibit the immune cells synthesis, and as a result, T cells viral DNA remains in the nuclei of B lymphocytes without
are unable to produce cytokines necessary for destruction, being lysed. After EBV‑encoded non‑translational RNAs are
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024

such as tumor necrosis factor‑alpha, interleukin 2, and
interferon‑gamma as a result of immunosuppression, which
reduces the number, quality, and fighting ability of T cells
against tumor [Figure 2]. Additional risk factors in transplant
recipients include potential direct effects of medications,
such as cyclosporine and azathioprine, that have been shown
transcribed, infected B‑cells differentiate into memory cells,
Immunosuppressive treatment following transplantation
results in a chain of consequences prompting diminished
Lymphocyte capabilities, uncontrolled viral replication,
extension of EBV‑tainted B‑cells, EBV oncogene articulation,
expansion and, eventually, malignancy. The other additional
factors that contribute to the pathogenesis of EBV infection in
transplant recipients include epigenetic modifications of tumor
suppressors and oncogenes [Figure 3].[20,21]

Table 3: Virus‑associated posttransplant malignancy

Virus Cancer type SIR
HBV, HCV HCC SIR >4 (high risk)
HHV‑8 Kaposi’s sarcoma SIR >4 (high risk)
HPV Skin and Tonsillar Skin cancer with SIR >4 (high risk)
cancer Cervical cancer SIR 1–4
Cervical cancer (moderate risk)
Penile cancer
Vulvar cancer
EBV PTLD SIR >4 (high risk)
BKV Bladder cancer, No increased risk in prostate
prostate cancer cancer, bladder cancer SIR 1–2
SIR: Standard incidence ratio, HBV: Hepatitis B virus, HCV: Hepatitis
C virus, HHV‑8: Human herpesvirus‑8, HPV: Human papillomavirus,
Figure 1: Factors involved in the tumorigenesis posttransplant. UV: EBV: Epstein–Barr virus, BKV: BK virus, HCC: Hepatocellular
Ultraviolet carcinoma, PTLD: Posttransplant lymphoproliferative disorder

Figure 2: Pathogenesis of virus‑induced posttransplant malignancy. VEGF: Vascular endothelial factor, TGF-β: Transforming growth factor-β,
IL‑6: Interleukin‑6, RAS: Rat sarcoma-rapidly accelerated fibrosarcoma, PTLD: Posttransplant lymphoproliferative disease, EBV: Epstein–Barr virus

Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023 391

 Soni and Ranjan: Malignancy in renal transplant recipients
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
Figure 3: Pathogenesis of posttransplant lymphoproliferative disease in kidney transplant recipients. PTLD: Posttransplant lymphoproliferative disease,
EBV: Epstein–Barr virus
Viral Infection Associated Cancers
Skin cancer
Skin malignancies such as Kaposi sarcoma, basal cell
carcinoma, cutaneous squamous cell carcinoma, and
malignant melanoma, are the most frequently reported skin
cancers in kidney transplant patients [Figures 4 and 5].
Ninety to ninety‑five percent of these skin cancers arise from
keratinocytes. Several risk variables, including sex (males
are more at risk than females), race, age, pretransplant skin
cancer, human papillomavirus (HPV) infection, and exposure
to ultraviolet (UV) radiation (UVA and UVB are oncogenic)
interact in a complicated way throughout the pathogenesis
of skin carcinoma. Additionally, immunosuppressive drugs,
primarily cyclosporine and azathioprine, amplify their
carcinogenic effects.[16,22‑24] It is advised for transplant patients
to take basic precautions against the onset of skin cancer.
Proper counseling, both before and after transplantation, is
among them. Avoiding prolonged exposure to the sun, using
high‑factor sunblocks with SPF 50+ regardless of the weather,
and wearing sun‑protective clothes (such as fine‑weave silk
apparel) are all recommended. Avoid the midday sun and the
1–2 h before and after it, and provide patients with tailored
information to encourage them to evaluate their skin and
protect it from the sun. Retinoids and nicotinamide may be
considered for chemoprophylaxis in patients having either
benign or malignant form of squamous cell carcinoma.
Chemotherapy and systemic immunotherapy are advised in
case of metastatic cutaneous squamous cell carcinoma.[22]
Kaposi sarcoma
Human herpesvirus 8 (HHV‑8) is the causative agent
of KS, an angioproliferative cutaneous malignancy in
immunocompromised hosts. They present as purple‑red‑bluish
lesions that appear as macules, papules, or other nonpruritic,
painful lesions or nodules. Patients who have received a
renal transplant develop KS more frequently, affecting up to
5% of transplant patients from Central Europe, Africa, and
Mediterranean ethnic groups. The incidence of Kaposi sarcoma
is more than 100 times in these ethnic groups as compared to
the general population.
392 Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
KS has a stronger association with calcineurin
inhibitors (CNIs)[25] so the first line of management is the
modification of immunosuppression by reducing the dose
or changing the drug. With modified immunosuppressive
medication, around one‑third of patients get full remission,
while another third of patients pass away 3 years after
diagnosis.[25,26] The cornerstone of treatment is to lower the
dosage or switch immunosuppressive drugs to an mammalian
target of rapamycin (mTOR) inhibitor. After switching from
CNIs to sirolimus, Kaposi sarcoma has been shown to regress
by recovering effector and memory T‑cell immunological
function against human herpesvirus 8 and malignancy rates
were significantly lower in 12 and 24 months.[27]
Posttransplant lymphoproliferative disease
PTLD is the most serious and life‑threatening, despite being
a rare disorder, it signifies poor outcomes in postsolid organ
recipients. It is linked to EBV infection that infects B‑cells
on a long‑term basis and promotes their multiplication.
Immunosuppression prevents T cells from controlling
EBV‑infected B‑cells, which may lead to their unchecked
proliferation. [28] The pathogenesis of PTLD in kidney
transplant recipients is demonstrated in Figure 2. Multiple
lymphoid disorders like multiple myeloma, lymphomas (both
Hodgkin and NHL), and Lymphoid leukemia are included in
the PTLD. PTLD is divided into four groups by the World
Health Organization (WHO): Early lesions, polymorphic,
monomorphic, and classical Hodgkin’s lymphoma. At 10 years
after transplant, the incidence rate of PTLD is 1.8%, and
pediatric transplant recipients are more likely to experience it.
The risk of PTLD is at its maximum when an EBV‑negative
recipient receives a transplant from an EBV‑positive donor.[28]
PTLD may develop at any time after transplant, NHL, the
most aggressive and frequent form, happens within the 1st year
following transplant, when net immunosuppression is maximum
and viral infectivity is at its peak. Recent data indicate that the
time between disease onset and the posttransplant course is
between 48 and 81 months. The proliferation of lymphoid cells
might be restricted to lymph nodes affecting the transplanted
organ and other organs including the central nervous
 Soni and Ranjan: Malignancy in renal transplant recipients
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
Figure 4: Squamous cell carcinoma ©Skin Therapy Letter
system (CNS). The gastrointestinal tract is the most typical
site for PTLD in people who have had kidney transplants.[29]
Lymphadenopathy, night sweats, lethargy, anorexia, weight
loss, and chills are the common initial clinical presentation,
whereas fever, weight loss, protein‑losing enteropathy, bowel
obstruction or perforation, and gastrointestinal bleeding are
severe manifestations in case of gastrointestinal involvement.
Immunosuppression is reduced as part of treatment, and
B‑cell‑specific chemotherapy is frequently used.[29] Once
PTLD has been identified, the standard immunosuppressive
regimens call for discontinuing the adjuvant agent, reducing/
eliminating the exposure to the CNI, and taking 5‑10 mg of
prednisone daily. Reduced immunosuppression, rituximab
immunotherapy (for CD20‑positive PTLD), radiation therapy,
chemotherapy, and a combination of these treatments are
further therapeutic options. Rituximab monotherapy, an
Anti‑CD20 Monoclonal Antibody, provides response rates
of 44%–59% in patients with PTLD who have received solid
organ transplants.[29] Rituximab binds to CD‑20 expressed
B‑cell and kills them via antibody‑dependent cell‑mediated
cytotoxicity and phagocytosis. Rituximab treatment is followed
by chemotherapy (cyclophosphamide, doxorubicin, vincristine,
and prednisone) i.e. R CHOP therapy is the most common
treatment for CD20 negative PTLD. Other immunomodulatory,
antiviral, and chemotherapeutic strategies (intravenous
immunoglobulin, interleukin‑6, interferon‑alpha, and
EBV‑specific T‑cell therapy) are used to manage rare subtypes
of PTLD and relapsed PTLD.[29,30] Another strategy to treat
PTLD is via EBV‑specific cytotoxic T‑lymphocytes or donor
lymphocyte infusion to inhibit the EBV‑induced B‑cell
proliferation. This therapeutic strategy is referred to as adoptive
immunotherapy. It has shown about 75% potential in the
prevention and remission of EBV‑induced PTLD.
Some cases of PTLD primarily manifest in the CNS, referred
to as systemic PTLD. CNS‑PTLD has been linked to several
viral factors, the most prominent of which is EBV. There is
a wide range of neurological symptoms, including increased
intracranial pressure, seizures, headache, nausea, vomiting,
Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
Figure 5: Basal cell carcinoma ©HealthJade.com
drowsiness, and visual problems. By WHO standards,
most CNS‑PTLD cases are monomorphic, but some are
polymorphic. Monomorphic CNS‑PTLD usually has a
B‑cell phenotype and resembles aggressive diffuse large‑cell
lymphomas. CNS‑PTLD cases start presenting within the
1st year after the immunosuppression with a median time to
occurrence of around 4–5 years. However, cases that occur
more than 10 years after the initial transplantation do occur.
The treatment of CNS‑PTLD constantly includes diminishing
or withdrawal of immunosuppressive treatment followed by
rituximab and/or cytarabine therapy.[20,31]
Anogenital cancers
Patients receiving kidney transplants have reported a 14–50‑fold
higher prevalence of anogenital malignant neoplasms and
HPV infection is a crucial factor in the development of these
tumors. Malignancies of the cervical, vulvar, vaginal, penile,
and anal regions are among them. With a low rate of cytologic
alterations detected on pap tests, kidney transplant recipients
have an HPV infection prevalence of 17%–45%. Most vulvar
malignancies following transplantation are HPV‑related, like
cervical cancer, with high‑risk HPV strains being the main
contributors to the pathogenesis. Cervical cancer is more likely
to develop in younger kidney transplant recipients (18–34 years
old), whereas data by some researchers show the occurrence
of vulvar cancer after 5 years posttransplantation. The choice,
intensity, and duration of immunosuppressive agents influence
the occurrence and progression of gynecological cancers.
According to Schiffman et al. 2016, immunosuppression
may let latent HPV infections, especially the reactivation
of high‑risk oncogenic HPV strains. An increase in in‑situ
carcinoma was noted, but no increase in invasive cervical
cancers was reported in a US‑based study of 187,649 Solid
organ transplant recipients (64% of whom had received renal
transplants). This may be due to very close follow‑up because
of chronic immunosuppression, which led to earlier detection
of noninvasive cervical lesions. Individual choices should
be made about immunosuppression withdrawal or reduction
following a gynecologic malignancy.[32] Also, the Centre for
Disease Control and Prevention recommends all solid organ
transplant recipients (males and females) aged 9–26 years to
393
 Soni and Ranjan: Malignancy in renal transplant recipients
get vaccinated against HPV, though its safety among transplant
recipients is still controversial.
Bladder and prostate cancer
Bladder and Prostate cancer are one of the least prevalent
malignancies among transplant recipients, with very few
reported studies. However, compared to the general population,
the risk of bladder carcinomas is around four times higher
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
among organ transplant recipients and four to eleven times
for BKV‑infected recipients. There is no difference in the
incidence of prostate cancer among the general and solid organ
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
transplant population. Vascular endothelial factor and Flk‑1/
KDR receptor are expressed more frequently when the immune
system is suppressed, thus promoting the spread of bladder
cancer. mTOR inhibitor may be used instead of a CNI to treat
organ transplant patients who develop malignancy, potentially
extending survival time. Chemotherapy posttransurethral
resection is recommended to manage the bladder tumor.[33,34]
Renal cell carcinoma
RCC is discovered in 3.4%–3.9% of individuals who undergo
screening for asymptomatic renal transplant candidates.
Long‑term dialysis use, obstructive, uropathy, toxic, or
infectious etiologies for renal disease and acquired cystic
kidney disease have all been recognized as risk factors in the
onset of RCC in end‑stage renal disease patients. In high‑risk
transplant candidates for RCC, screening urinalyses, urine
cytology, and radiologic investigations should be considered.
There are no regulations for RCC posttransplant monitoring.
Although a higher risk is observed in known patients with
acquired cystic kidney disease, they must undergo routine
screening before a transplant, though the prevalence of this
condition appears to go down after kidney transplantation.[35,36]
Surveillance Strategies
Pre‑transplant cancer screening
Cancer patients who undergo transplants are subjected to
unwarranted surgery and immunosuppression‑related adverse
side effects that may increase the risk of mortality and
morbidity. The reasonable general guideline is to start with
a history and physical examination to check for lymphoid,
testicular, anogenital, thyroid, oral, and different skin cancers.
Repeated tests may be necessary, especially for people who
have been on the waitlist for a long time. In higher‑risk
patients, there are specific screening options, such as in the
case of kidney transplantation; a chest radiograph (CXR) for
lung cancer screening is recommended.[37,38] In individuals
with toxic, infectious, obstructive, or acquired cystic illness,
it is recommended to have an ultrasound for abdominal
examination or computerized tomography prior to a transplant
to minimize the chance of any native kidney cancer.[10]
Waiting period for transplantation postcancer
Prior to transplantation, few patients would have a history
of malignancy. The danger of mortality among solid organ
transplant recipients is 30% more in people having a cancer
394 Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
history. Kidney transplant recipients having a cancer history
had a 3.7‑fold increased risk of dying from the disease so a
waiting period is recommended for such recipients. However,
according to the study by Battstrom, in recipients with cancer
history, extended waiting periods had no effect in preventing
the reoccurrence of cancer and its associated death rate.[36,39]
The waiting period needed before transplantation in case of
the prevalence of different types of cancer in recipients is
mentioned in Schreiber et al., 2022 [Table 4].[40]
Posttransplant cancer screening
Even though the chances of cancer occurrence following
a kidney transplant are high, there isn’t much data to back
up screening recommendations in this complex patient
population. In case of persistent HBV infection and underlying
liver disease, serum‑alpha fetoprotein levels and abdominal
ultrasounds are examined every 6 months to diagnose any
onset of cancer. Skin evaluation of transplant recipients
should be done periodically as they are highly susceptible to
it. Ultrasonographic screening of the native kidneys is done in
patients with a family history of smoking and use of long‑term
analgesics and who are highly susceptible to RCC. Noncontrast
computed tomography chest and whole abdomen should be
considered yearly, especially in pediatric patients.[5,41,42] The
screening strategies of cancer in postrenal transplant patients
are described in Table 5.
Therapeutic strategies for the management of posttransplant
malignancy
Reducing immunosuppression is the cornerstone in the
management of posttransplant malignancy. The best treatment
regimen depends on the type, organ of origin, and severity of
the cancer. The advantages of reducing immunosuppression
in the battle against the disease must be balanced against the
risk of graft rejection. In the presence of malignancy, targeting
a lower immunosuppressive medication level is usual, and a
switch from a CNI to mTOR inhibitors (particularly in skin
malignancies) is recommended. According to research, early
conversion (4 months postkidney transplant) from CNIs to
mTOR inhibitors is related to better renal function and has a
protective effect on the development of malignancy.[43] In the
Table 4: Waiting time for kidney transplant postcancer
treatment (Schreiber et al., 2022)
Type of cancer Waiting time (years)
Renal carcinoma 2–5
Lung cancer 2–5
Cervical 2–5
Colorectal 5
Breast cancer Benign: 2; Advanced: 5
NHL 3–5
Thyroid cancer Stage 1: No waiting time; Stage 2–4: 2–5
Melanoma 5
Prostate cancer Gleason ≤6: No waiting time; Gleason 7–10: 2–5
Bladder cancer 2
NHL: Non‑Hodgkin lymphoma
 Soni and Ranjan: Malignancy in renal transplant recipients
Table 5: Posttransplant cancer screening strategy (Cavaliere et al., 2010)[31]
Type of cancer Screening test
PTLD‑virus related Viral nucleic acid dosage
Renal Ultrasonography
Cervical Pelvic examination and cytological cervical cancer screening
Hepatocellular α‑fetoprotein and ultrasound
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
Gastric and colorectal Esophagogastroduodenoscopy
Breast (women) Mammography
Prostate PSA measurement and rectal examination
Skin Self‑examination every month and skin expert examination
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
PTLD: Posttransplant lymphoproliferative disease, PSA: Prostate‑specific antigen
case of the use of azathioprine, it is replaced with mycophenolate
mofetil (MMF) because azathioprine metabolites make the skin
sensitive to UV radiation, increasing the risk of skin cancer.
MMF lowers the relative risk of various cancers, including skin
cancer and PTLD, benefiting people already on azathioprine.
In kidney transplant recipients, malignancy is treated via
a reduction in immunosuppression using mTOR inhibitors
specifically. [16,35,44] Stomatitis, Interstitial pneumonitis,
inadequate wound healing, dyslipidemia, posttransplant
diabetes mellitus, hyperglycemia, bone marrow suppression,
and proteinuria are some of the clinical presentations associated
with the use of mTOR inhibitors.[45]
Retransplantation posttransplant malignancy
Most solid organ transplant recipients have undergone a
large reduction in immunosuppression, with or without
additional medication, which can result in PTLD regression,
including the rejection and loss of the allograft. As a result,
it is important to question when to perform retransplant after
the recipient has survived the cancer. There are numerous
challenges for those requiring renal retransplant, including
first graft nephrectomy and whether the site of retransplant
should be ipsilateral or contralateral, whether to perform
pre-emptive retransplant or wait while on dialysis, additional
immunologic factors, immunosuppression after retransplant.
Despite the higher relative risks of retransplantation, patients
benefit from improved quality of life and lower health care
expenses as compared to being on dialysis after the graft loss
due to malignancy or PTLD.[46] According to the study reported
by Karras et al. prolonged interval between the PTLD and
re transplantation maximize success as this provides time to
determine the biological behaviour of the PTLD and restore the
patient’s own immune system prior to retransplantation.[47,48]
Future directions
Immunotherapy is now at the forefront of cancer treatment. In
some cases, chemotherapy is employed depending on the type
of cancer diagnosed in the posttransplant recipient. Therapeutic
strategies such as immune‑checkpoint inhibitors targeting
the CD28‑CD80/86 axis, immune system activation, and the
interaction of cytotoxic T‑lymphocyte‑associated protein‑4
Ig with programmed death ligand‑1 have revolutionized the
cancer treatment offering better results than the prior standard
of care against malignancies. However, due to the risk of
Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
Duration
Every month for 6 months posttransplant, and then every 12 months
Every 6–12 months
Annually
Bi‑annually
Annually
Annually
Annually
Annually
rejection from nonspecific immune system activation, the use
of checkpoint inhibitors is restricted in transplant recipients.
Even though checkpoint inhibitors are successful in managing
RCC, non‑small cell lung cancer, and melanoma in the general
community, their potential in the kidney transplant recipients
needs more research in a large cohort group.[5]
Summary
The overall morbidity and mortality of transplant recipients are
anticipated to be increasingly affected by cancer. The younger
patients will be the most at risk. More investigation is required
to pinpoint more precise immunosuppressive therapies, to
identify patients who are overly immunosuppressed and would
benefit from a long‑term reduction in immunosuppressants, and
to choose the best pre‑ and posttransplant screening methods
for recipients with malignancies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH,
Law M, et al. Cancer incidence before and after kidney transplantation.
JAMA 2006;296:2823‑31.
2. Piselli P, Serraino D, Segoloni GP, Sandrini S, Piredda GB, Scolari MP,
et al. Risk of de novo cancers after transplantation: Results from a
cohort of 7217 kidney transplant recipients, Italy 1997‑2009. Eur J
Cancer 2013;49:336‑44.
3. Geissler EK. Post‑transplantation malignancies: Here today, gone
tomorrow? Nat Rev Clin Oncol 2015;12:705‑17.
4. D’Arcy ME, Coghill AE, Lynch CF, Koch LA, Li J, Pawlish KS, et al.
Survival after a cancer diagnosis among solid organ transplant recipients
in the United States. Cancer 2019;125:933‑42.
5. Al‑Adra D, Al‑Qaoud T, Fowler K, Wong G. De novo malignancies after
kidney transplantation. Clin J Am Soc Nephrol 2022;17:434‑43.
6. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney
transplantation in the United States. Am J Transplant 2004;4:905‑13.
7. Rama I, Grinyó JM. Malignancy after renal transplantation: The role of
immunosuppression. Nat Rev Nephrol 2010;6:511‑9.
8. Acuna SA, Sutradhar R, Kim SJ, Baxter NN. Solid organ
transplantation in patients with preexisting malignancies in
remission: A propensity score matched cohort study. Transplantation
2018;102:1156‑64.
9. Viecelli AK, Lim WH, Macaskill P, Chapman JR, Craig JC, Clayton P,
395
 Soni and Ranjan: Malignancy in renal transplant recipients
et al. Cancer‑specific and all‑cause mortality in kidney transplant
recipients with and without previous cancer. Transplantation
2015;99:2586‑92.
10. Wu C, Shapiro R. Post‑transplant malignancy: Reducing the risk in kidney
transplant recipients. Expert Opin Pharmacother 2011;12:1719‑29.
11. Medeiros E, Merhi B. Malignancy after renal transplantation: A review.
R I Med J (2013) 2021;104:25‑30.
12. Miao Y, Everly JJ, Gross TG, Tevar AD, First MR, Alloway RR, et al.
De novo cancers arising in organ transplant recipients are associated
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
with adverse outcomes compared with the general population.
Transplantation 2009;87:1347‑59.
13. Martinez OM, de Gruijl FR. Molecular and immunologic mechanisms
of cancer pathogenesis in solid organ transplant recipients. Am J
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024
Transplant 2008;8:2205‑11.
14. Gatti RA, Good RA. Occurrence of malignancy in immunodeficiency
diseases. A literature review. Cancer 1971;28:89‑98.
15. Stallone G, Infante B, Grandaliano G. Management and prevention
of post‑transplant malignancies in kidney transplant recipients. Clin
Kidney J 2015;8:637‑44.
16. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation.
Transplantation 2005;80:S254‑64.
17. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer
immunoediting: From immunosurveillance to tumor escape. Nat
Immunol 2002;3:991‑8.
18. Thoms KM, Kuschal C, Oetjen E, Mori T, Kobayashi N, Laspe P, et al.
Cyclosporin A, but not everolimus, inhibits DNA repair mediated by
calcineurin: Implications for tumorigenesis under immunosuppression.
Exp Dermatol 2011;20:232‑6.
19. Hofbauer GF, Attard NR, Harwood CA, McGregor JM, Dziunycz P,
Iotzova‑Weiss G, et al. Reversal of UVA skin photosensitivity and DNA
damage in kidney transplant recipients by replacing azathioprine. Am J
Transplant 2012;12:218‑25.
20. Kempf C, Tinguely M, Rushing EJ. Posttransplant lymphoproliferative
disorder of the central nervous system. Pathobiology 2013;80:310‑8.
21. Lim WH, Russ GR, Coates PT. Review of Epstein‑Barr virus
and post‑transplant lymphoproliferative disorder post‑solid organ
transplantation. Nephrology (Carlton) 2006;11:355‑66.
22. Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J
Transplant 2017;17:2509‑30.
23. Greenberg JN, Zwald FO. Management of skin cancer in solid-organ
transplant recipients: A multidisciplinary approach. Dermatol Clin
2011;29:231-41, ix.
24. Brem R, Li F, Karran P. Reactive oxygen species generated by
thiopurine/UVA cause irreparable transcription‑blocking DNA lesions.
Nucleic Acids Res 2009;37:1951‑61.
25. Campistol JM, Schena FP. Kaposi’s sarcoma in renal transplant
recipients – The impact of proliferation signal inhibitors. Nephrol Dial
Transplant 2007;22 Suppl 1:i17‑22.
26. Sunil M, Reid E, Lechowicz MJ. Update on HHV‑8‑associated
malignancies. Curr Infect Dis Rep 2010;12:147‑54.
27. Al‑Mansour Z, Nelson BP, Evens AM. Post‑transplant
lymphoproliferative disease (PTLD): Risk factors, diagnosis, and
current treatment strategies. Curr Hematol Malig Rep 2013;8:173‑83.
28. Morton M, Coupes B, Roberts SA, Klapper PE, Byers RJ, Vallely PJ,
et al. Epidemiology of posttransplantation lymphoproliferative
disorder in adult renal transplant recipients. Transplantation
2013;95:470‑8.
29. Jagadeesh D, Woda BA, Draper J, Evens AM. Post transplant
lymphoproliferative disorders: Risk, classification, and therapeutic
396 Indian Journal of Transplantation ¦ Volume 17 ¦ Issue 4 ¦ October‑December 2023
recommendations. Curr Treat Options Oncol 2012;13:122‑36.
30. Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM,
Vandenberghe P, et al. Efficacy and safety of rituximab in B‑cell
post‑transplantation lymphoproliferative disorders: Results of a
prospective multicenter phase 2 study. Blood 2006;107:3053‑7.
31. Cavaliere R, Petroni G, Lopes MB, Schiff D, International Primary
Central Nervous System Lymphoma Collaborative Group. Primary
central nervous system post‑transplantation lymphoproliferative
disorder: An international primary central nervous system lymphoma
collaborative group report. Cancer 2010;116:863‑70.
32. Schiffman M, Doorbar J, Wentzensen N, de Sanjosé S, Fakhry C,
Monk BJ, et al. Carcinogenic human papillomavirus infection. Nat Rev
Dis Primers 2016;2:16086.
33. Gupta G, Kuppachi S, Kalil RS, Buck CB, Lynch CF, Engels EA.
Treatment for presumed BK polyomavirus nephropathy and risk of
urinary tract cancers among kidney transplant recipients in the United
States. Am J Transplant 2018;18:245‑52.
34. Wallerand H, Ravaud A, Ferrière JM. Bladder cancer in patients after
organ transplantation. Curr Opin Urol 2010;20:432‑6.
35. Chertow GM, Paltiel AD, Owen WF Jr., Lazarus JM. Cost‑effectiveness
of cancer screening in end‑stage renal disease. Arch Intern Med
1996;156:1345‑50.
36. Brattström C, Granath F, Edgren G, Smedby KE, Wilczek HE.
Overall and cause‑specific mortality in transplant recipients with a
pretransplantation cancer history. Transplantation 2013;96:297‑305.
37. National Lung Screening Trial Research Team, Aberle DR, Adams AM,
Berg CD, Black WC, Clapp JD, et al. Reduced lung‑cancer mortality
with low‑dose computed tomographic screening. N Engl J Med
2011;365:395‑409.
38. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D,
et al. The evaluation of renal transplantation candidates: Clinical
practice guidelines. Am J Transplant 2001;1 Suppl 2:3‑95.
39. Schwarz A, Vatandaslar S, Merkel S, Haller H. Renal cell carcinoma in
transplant recipients with acquired cystic kidney disease. Clin J Am Soc
Nephrol 2007;2:750‑6.
40. Schreiber B, Abdelrahim M, Abudayyeh A, Murakami N. Emerging
concepts in managing malignancy in kidney transplant patients. Semin
Nephrol 2022;42:63‑75.
41. Wong G, Howard K, Tong A, Craig JC. Cancer screening in people
who have chronic disease: The example of kidney disease. Semin Dial
2011;24:72‑8.
42. Wong G, Chapman JR, Craig JC. Cancer screening in renal
transplant recipients: What is the evidence? Clin J Am Soc Nephrol
2008;3 Suppl 2:S87‑100.
43. Ireland R. Transplantation: Early switch from calcineurin inhibitors
to mTOR inhibitors leads to improved renal graft function. Nat Rev
Nephrol 2011;7:243.
44. AlBugami M, Kiberd B. Malignancies: Pre and post transplantation
strategies. Transplant Rev (Orlando) 2014;28:76‑83.
45. Pallet N, Legendre C. Adverse events associated with mTOR inhibitors.
Expert Opin Drug Saf 2013;12:177‑86.
46. Bakr MA, Denewar AA, Abbas MH. Challenges for renal retransplant:
An overview. Exp Clin Transplant 2016;14:21‑6.
47. Hanto DW. Retransplantation after post‑transplant
lymphoproliferative diseases (PTLD): When is it safe? Am J
Transplant 2004;4:1733‑4.
48. Karras A, Thervet E, Le Meur Y, Baudet-Bonneville V, Kessler M,
Legendre C. Successful renal retransplantation after post-transplant
lymphoproliferative disease. Am J Transplant. 2004;4:1904-9.
Downloaded from http://journals.lww.com/ijjt by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 02/22/2024