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K. O’Connor and C. J. Wong
299© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
C. J. Wong (ed.), Primary Care of the Solid Organ Transplant Recipient,
https://doi.org/10.1007/978-3-031-98076-3_10
Chapter 10
Cancer Risk intheAdult Solid Organ
Transplant Recipient
ChristopherJ.Wong andChristopherD.Blosser
10.1 Introduction
The eld of solid organ transplantation has seen remarkable advances in care that
have resulted in impactful reductions in the risks of early mortality due to rejection
and infection. However, with increased longevity also comes an increase in condi-
tions such as cardiovascular disease and cancer [1]. Despite improvements in gen-
eral population screening and treatments, cancer has not improved for over the past
30years and remains a leading cause of morbidity and death in solid organ trans-
plant (SOT) recipients [2–5]. In this chapter, we review the risk of cancer in solid
organ transplant recipients.
10.2 Epidemiology
10.2.1 Cancer Incidence
The absolute incidence of cancers in solid organ transplant recipients is high. In the
USA, the 5-year cumulative incidence of cancer (excluding nonmelanoma skin can-
cers) is estimated at 4.4%, using data between 2000 and 2008. This incidence was
higher than that of an earlier cohort (1987–1999) and coincided with a concomitant
C. J. Wong (*)
Division of General Internal Medicine, Department of Medicine, University
of Washington, Seattle, WA, USA
e-mail: cjwong@uw.edu
C. D. Blosser
Division of Nephrology, Department of Medicine, University of Washington,
Seattle, WA, USA
e-mail: CBlosser@nephrology.washington.edu
300
decrease in death, graft failure, and retransplantation [6]. Longer-term cohort stud-
ies have also shown a high cumulative risk of cancer: liver transplant recipients in
France were found to have an incidence of 6.8% at 5years and 14.5% at 10years
[7], while a study of kidney transplant recipients in Spain reported a 20.7% cumula-
tive incidence of cancer at 20years [8].
In addition to estimating the absolute incidence of cancer, researchers have
sought to quantify the risk of cancer in solid organ transplant recipients in compari-
son to the general population. This increased risk of cancer is often expressed as the
excess absolute risk (EAR)—the rate of cancer in solid organ transplant recipients
minus the rate of cancer in the general population, or the standardized incidence
ratio (SIR)—the number of observed cancers in solid organ transplant recipients
divided by the expected number of cases in the general population (Table10.1).
A study in the USA comprising approximately 40% of all solid organ transplants
reported an EAR of 719 per 100,000 person-years (or 0.7% per year), with an SIR
of 2.10 [9]. A meta-analysis in 2020 found an even higher overall SIR of 2.68 [10].
A study in Finland reported an overall SIR of 3.6, and an SIR of 2.2 with nonmela-
noma skin cancers excluded [11].
10.2.2 Cancer Mortality
In a study of over 600,000 solid organ transplant recipients in the USA using data
from the Scientic Registry of Transplant Recipients (SRTR), the cancer mortality
rate was 603 per 100,000 person-years. Cancer was responsible for 13% of all
deaths [12].
The increased mortality risk may be expressed as the standardized mortality
ratio (SMR)—the observed number of cancer deaths in solid organ transplant recip-
ients compared to the number expected in the general population (Table10.1). The
SMR for cancer mortality following solid organ transplantation has generally been
consistent across studies: 2.8 in Canada [5], 2.3 in the USA [12], and 2.5 in
Finland [11].
C. J.Wong andC. D.Blosser
Table 10.1
Terms for increased risk of cancer
Excess Absolute Risk
(EAR)
(Rate of cancer in solid organ transplant recipients)–(Rate of cancer in
general population)
Standardized
Incidence Ratio (SIR)
Number of observed cancers in solid organ transplant recipiients
Number of expected cancers in the general populati
()
oon
()
Standardized
Mortality Ratio
(SMR)
Number of observed cancer deaths in solid organ transplant recipients
Number of expected cancer deaths in the gene
()
rral population
()
301
Expressed as survival, the overall survival following the diagnosis of malignancy
in the post-transplantation setting is poor. In a study of liver transplant recipients,
10-year overall survival was 49.4% in patients who developed cancer compared to
88.3% who did not [7].
10.2.3 Timing
The median time to develop post-transplant solid tumors varies depending on can-
cer type and between studies but is approximately 4–6years post-transplantation.
For example, a cohort of solid organ transplant recipients in Canada was found to
have a median time to diagnosis of de novo cancers after transplantation of 5.2years
[5]. Liver transplant recipients in France were reported to have a mean time to diag-
nosis of 6years [7].
Time since transplantation is associated with increased mortality for certain
types of cancers (lung cancer) but decreased mortality for other types (liver cancer);
non-Hodgkin lymphoma is characterized by a bimodal pattern [12].
10.2.4 Types ofCancers
Incidence: The cancers with the greatest increased incidence are skin cancer, post-
transplant lymphoproliferative disorders (PTLD), and solid tumors of the lung,
liver and kidney [9].
Mortality: The numerically most common causes of death due to cancer for solid
organ transplant recipients in the USA are lung cancer, liver cancer, and non-
Hodgkin lymphoma [12]. In addition, the Transplant Cancer Match Study dem-
onstrated that there is an increased risk of cancer deaths in transplant recipients
compared to non-transplant recipients, with the largest increases seen in mela-
noma, breast cancer, bladder cancer, and colorectal cancer (adjusted hazard
ratios of 2.59, 1.88, 1.85, and 1.77, respectively) [13]. In contrast, another
U.S. study reported the highest SMRs for nonmelanoma skin cancer (including
Merkel cell carcinoma), liver cancer, non-Hodgkin lymphoma, kidney cancer,
soft tissue/heart cancers, and melanoma (23.4, 6.93, 5.17, 3.40, 3.37, and 3.27,
respectively), and did not nd an increased mortality risk for breast cancer [12].
10.3 Risk Factors
Immunosuppression is one of the major risk factors for the development of cancer
following solid organ transplantation. However, while the increased risk of several
types of cancers is similar to that of other immunosuppressed populations such as
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
302
Table 10.2
Risk factors for cancer in solid organ transplant recipients
Age • Increased age associated with increased incidence of and mortality
due to cancer as with the general population
Gender • Most studies suggest an increased risk in men; studies vary
Immunosuppression
• Calcineurin inhibitors and azathioprine are associated with
increased risk
• Cumulative exposure associated with increased risk
• Higher doses of immunosuppression
• Younger age at time of transplantation (increases lifetime risk)
• Longer duration of time since transplantation
• Lymphoma associated with muromonab-CD3 and ATG induction
therapies
Type of transplant • Lung transplantation is associated with higher overall cancer risk
Exposures • Cigarette smoking
• Alcohol
• Sunlight/ultraviolet light
Underlying medical
conditions
Examples:
• End-stage renal disease (ESRD)—native kidneys are left in place in
kidney transplant recipients
• Single-lung transplantation: native lung has increased risk of
malignancy if indication for transplant was due to a smoking-
related condition
Presence of oncogenic
infections
• Epstein–Barr Virus (EBV)
• Human Papillomavirus (HPV)
• Hepatitis B Virus (HCV)
• Merkel cell polyomavirus
• Human Herpes Virus 8 (HHV-8)
Previous cancer
• Increases the risk of recurrence for certain cancers post
transplantation
people living with HIV, transplant recipients have increased susceptibility to other
malignancies, including colorectal and thyroid cancers, which are not increased in
the patients with HIV.Additional risk factors include age, the specic type of immu-
nosuppression, oncogenic viruses, exposures, and the type of transplant.
10.3.1 Age
The incidence of the most common cancers following solid organ transplantation
increases with age, with the exception of non-Hodgkin lymphoma which exhibits a
bimodal pattern [9]. Patients transplanted at a younger age have the greatest overall
increased risk of cancer (15–30 times the risk of peers) compared to patients trans-
planted later in life (2 times greater risk if transplanted at age> 65 years) [14]
(Table10.2).
Age at time of transplantation is also a risk factor for mortality due to cancer [12].
C. J.Wong andC. D.Blosser
303
10.3.2 Gender
Most studies found an increased cancer risk in men [9, 15], although a study of
kidney transplant recipients in Spain found a signicant increased risk in women
only (SIR 1.18) [8]. Mortality of the most common cancers has been shown to be
increased in men compared to women [12].
10.3.3 Immunosuppression
The need for therapeutic immunosuppression to prevent graft rejection following
solid organ transplantation likely plays the largest role in the increased cancer inci-
dence seen in solid organ transplant recipients. Immunosuppression magnies
known behavioral risk factors for cancer such as cigarette smoking, alcohol intake,
and sun exposure, and promotes malignant conversion in the setting of oncogenic
viral infections. Certain immunosuppressant medications may also be carcinogenic
themselves. A variety of mechanisms have been proposed, including imbalance in
the immune response and direct DNA damage. The type, intensity and duration of
immunosuppressive agents contribute to the risk of malignancy (Table10.2).
10.3.3.1 Calcineurin Inhibitors (CNIs)
Calcineurin inhibitors (CNIs) contribute to malignancy development following
solid organ transplantation largely through their impact on T cells. CNIs inhibit
calcineurin, a phosphatase involved in T-cell activation [16]. With CNIs, speci-
cally cyclosporine and tacrolimus, this effect appears to be dose-dependent and
cumulative [17]. A higher mean blood concentration of calcineurin inhibitor or a
greater cumulative dose is associated with a greater risk of post-transplant malig-
nancy. In a study of 247 liver transplant recipients, patients with the highest tacroli-
mus blood mean concentrations were twice as likely to develop solid organ
tumors [7].
10.3.3.2 Antimetabolites: Azathioprine
andMycophenolate/Mycophenolic Acid
Azathioprine is an anti-proliferative agent that impairs DNA repair mechanisms and
boosts photosensitivity. Azathioprine has been implicated in the promotion of
malignancy in solid organ transplant recipients, with an elevated risk of nonmela-
noma skin cancers [18] and PTLD [19]. In contrast, mycophenolate mofetil (MMF)
and its active metabolite, mycophenolic acid (MPA), have not been associated with
an increased risk of cancer in solid organ transplant recipients [20].
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
304
10.3.3.3 mTOR Inhibitors
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, may be associated
with a lower risk of post-transplant malignancy. mTOR inhibitors may have an anti-
neoplastic effect in some settings and provide primary prevention for basal cell
carcinoma and secondary prevention of squamous cell skin cancer in high risk post-
transplantation populations [21–27].
10.3.3.4 Induction Immune Suppression
Many transplant protocols commonly use an induction treatment to reduce the risk
of acute rejection, including anti-thymocyte globulin (ATG); non-depleting inter-
leukin- 2 receptor antagonists (IL-2RA) and alemtuzumab (anti-CD52). The use of
these agents varies by transplant type and center.
Data on the cancer risk due to these induction therapies vary. The risk is thought
to be greatest for PTLD, and associated with ATG, alemtuzumab and historically
with muromonab-CD3 (OKT3®), but not IL-2RAs [28]. In one study, muromonab-
CD3 was associated with a ve-fold increased risk of early non-Hodgkin lymphoma
[19]. Contemporary studies have shown an increased risk of ATG compared to
IL-2RA regimens [1, 29]. Additional use of ATG for rejection treatment further
amplies the risk of cancer [30].
10.3.4 Type ofTransplant
Lung transplant recipients have the highest cumulative incidence of non-cutaneous
malignancy followed by heart, liver, and kidney recipients [6]. Types of cancer vary
based on transplant type [9, 31–34].
Mortality may also vary by type of solid organ transplant: in an SRTR-based
study, compared to heart or lung transplant recipients, kidney transplant recipi-
ents had a lower cancer mortality while liver transplant recipients had a higher
cancer mortality but mainly due to their increased risk of liver cancer. When
liver cancer deaths were excluded (because almost all patients had a diagnosis
of liver cancer prior to transplantation), liver transplant recipients also had a
lower overall cancer mortality compared to heart and lung transplant recipients
[12]. Similarly to liver transplant recipients and liver cancer mortality, lung
transplant recipients had a higher lung cancer SMR and kidney transplant recip-
ients had a higher kidney cancer SMR—however, most of these cancer diagno-
ses occurred post transplantation [12].
C. J.Wong andC. D.Blosser
305
10.3.5 Underlying Medical Conditions andBehaviors
Certain underlying chronic medical conditions for which the patient may undergo
solid organ transplantation such as end-stage renal disease (ESRD), cirrhosis, and
chronic obstructive pulmonary disease (COPD) are themselves associated with an
increased risk of malignancy. Patients treated with dialysis for end-stage renal dis-
ease (ESRD) are at signicantly increased risk for cancers of the kidney, bladder,
thyroid, liver, skin, and lungs, as well as multiple myeloma, even without kidney
transplantation [35, 36]. Patients with COPD are at higher risk for lung cancer and
colorectal cancer (CRC) compared to the general population. In a Swedish study,
patients with COPD were at signicantly increased risk of post-lung transplantation
skin (SIR 27), lung (SIR 19.8), CRC (SIR 11.4), and non-Hodgkin lymphoma
(NHL) (SIR 39) compared to those without COPD [37].
Smoking and alcohol use are risk factors for malignancy in the general popula-
tion, especially for cancers of the head and neck, esophagus, lungs, kidney, and
urinary tract. Solid organ transplant recipients who used signicant amounts of
tobacco or alcohol prior to transplantation or who resume use following transplanta-
tion are at increased risk for de novo malignancy. Patients who received a liver
transplant for alcoholic liver disease and those with a prior history of alcohol use
disorder have a 2- to 3-fold increased risk of de novo solid tumors following trans-
plantation [17, 38, 39]. A history of prior smoking or active smoking are also inde-
pendent risk factors (RR 8.5 and 4.4, respectively) for post-liver transplant de novo
smoking-related (lung, oral, esophageal, urinary tract) cancers [17, 39, 40].
Obesity has been identied as an independent risk factor for de novo malignancy
following liver transplantation, especially in non-smoking related malignancies [17].
10.3.6 Oncogenic Infections
Multiple viruses have been implicated as risk factors for cancer in solid organ trans-
plant recipients.
Human papillomavirus (HPV), a sexually transmitted, double-stranded DNA
virus which infects mucosal and cutaneous epithelial cells, is typically held in check
by T cell-mediated immunity. Certain high-risk strains (hrHPV), especially 16 and
18, are felt to be a causative agent and promote growth of certain types of oral, cer-
vical, vaginal, vulvar, penile and anal cancers. Loss of cell-mediated immunity due
to post-transplant immunosuppressive medications leads to viral reactivation in
latently infected cells, reduces a patient’s ability to spontaneously clear new HPV
infections, and subsequently leads to malignant transformation and promotion in
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
306
mucosal and cutaneous epithelial cells [40]. As a consequence, HPV-related precan-
cerous and cancerous lesions are seen more frequently in solid organ transplant
recipients [9, 41]. The role of HPV in squamous cell carcinoma of the skin in post-
transplant patient is less clear but may be a contributing factor [41].
Epstein–Barr virus (EBV) is a major contributor in most cases of post-transplant
lymphoproliferative disorder (PTLD) [42]. Iatrogenic immunosuppression leads to
poor immune control of EBV, B cell transformation, and proliferation through a
variety of mechanisms [43].
Merkel cell carcinoma is a rare form of skin cancer associated with Merkel cell
polyomavirus. Its incidence is much greater in the transplant population, with an
SIR of 24.7 [44, 45].
Kaposi sarcoma is associated with human herpes virus 8 (HHV-8), with a known
association with immune suppression in people with HIV.In solid organ transplant
recipients, the SIR for Kaposi sarcoma was found to be extraordinarily high at
61.46, consistent with its rarity in the general population [9].
The role of cytomegalovirus (CMV) in causing malignancy is less certain. While
smaller studies have shown a potential association, the largest study of over two
hundred thousand patients did not nd any association between CMV and risk of
cancer in solid organ transplant recipients [46].
Hepatitis B (HBV) may recur after liver transplantation and poses an increased
risk of hepatocellular carcinoma (HCC); however, the risk of recurrence may be
reduced by appropriate antiviral therapy and screening for HCC post transplanta-
tion, including in non-liver transplant recipients who have HBV infection [47].
Hepatitis C can recur after transplantation; if recurrence leads to cirrhosis, then
hepatocellular carcinoma may develop. Hepatitis C is now readily treated with mod-
ern antiviral regimens, leading to the use of HCV-positive donors for solid organ
transplantation [48].
10.4 Cancers Associated withanIncreased Risk inSolid
Organ Transplant Recipients
Solid organ transplant recipients have been found to be at risk for the cancers given
in Table10.3 and discussed below.
10.4.1 Donor Transmitted Cancer
Rare reports of cancers thought to be transmitted by the donor organ have occurred.
Living donors are screened based on age and gender-appropriate guidelines. Despite
adequate screening, donor-derived cancers may occur as frequently as once per
5000 living donations [2].
C. J.Wong andC. D.Blosser