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primary sclerosing cholangitis. Screening with ultrasound and HCG biomarker test-
ing for HCC in the setting of post-transplant HBV and/or HCV infection is advised
every 6–12months indenitely.
10.4.10 Colorectal Cancer
Solid organ transplant recipients have a 1- to 3-fold increased risk of colorectal
cancer (CRC) [9, 81, 94]. Diagnosis of CRC typically is made during the sixth
decade and lung transplant recipients are at greatest risk (SIR 2.34) [95]. In a large
population-based study, solid organ transplant recipients had a slightly increased
risk of colon cancer compared to the general population (SIR 1.12) after a median
follow-up of 3.7years. Most of the cancers were located in the proximal colon
(52%) and proximal CRC had the highest risk compared to the general population
(SIR 1.69). This excess risk of proximal CRC rises with increased time since trans-
plantation with a risk 2–3 times higher than age-matched controls 12 or more years
after transplant (SIR 2.68). In contrast, CRC in the distal colon and rectum were not
seen more frequently [95]. CRC in solid organ transplant recipients age<50years
was increased in proximal colon (SIR 2.52) and distal colon (SIR 1.77) but not the
rectum, whereas older patients had increased risk only in the proximal location (SIR
1.64) [95]. The propensity for proximal location and increased risk in patients under
the age of 50years for post-transplant CRC may have implications when screening
this population. When considering CRC screening options, one should consider
screening at the earliest recommended age (currently age 45 [96], lacking evidence
to support screening at an earlier age in solid organ transplant recipients despite
their higher risk) and using colonoscopy rather than stool-based testing such as fecal
immunochemical testing or DNA-based testing, as colonoscopy is better able to
detect proximal lesions [97].
Underlying medical conditions contribute to the increased risk of CRC.Patients
with lung or liver transplantation performed for a condition known to confer
increased CRC risk have an even greater risk of CRC after transplant. Patients with
cystic brosis have an elevated risk of colon cancer at baseline [98] and this is fur-
ther increased after lung transplantation (SIR 27.0) [95]. Similarly, patients who
received liver transplantation for primary sclerosing cholangitis (PSC) had a signi-
cantly increased risk (SIR 4.49) of CRC.This additional risk was seen even in the
absence of known inammatory bowel disease.
Oncogenic risk from immunosuppressive medications is also seen with
CRC.Maintenance immunosuppression regimens with cyclosporine and azathio-
prine are associated with greater risk of proximal CRC when compared to regimens
using tacrolimus and MMF (incidence rate ratio, IRR 1.53) [95].
Limited information is available regarding survival following a diagnosis of
CRC in solid organ transplant recipients. In a retrospective review from the Mayo
Clinic, median overall survival after diagnosis was 30.8months. Stage-specic sur-
vival at 5years for stage 1, stage 2, stage 3 and stage 4 disease was 77%, 50%,
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
318
42.3%, and 0%, respectively. Compared to patients with CRC but no history of
transplantation, solid organ transplant recipients with CRC had increased cancer-
specic mortality (adjusted HR 1.77) [13].
10.4.11 Kaposi’s Sarcoma
Kaposi’s sarcoma, a cutaneous malignancy associated most frequently with HIV
infection, is caused by human herpes virus 8 (HHV8). Solid organ transplant recipi-
ents, as with patients with HIV, also have a signicantly increased risk of Kaposi’s
sarcoma (SIR 61.45, EAR 15.2) [9]. HHV8 is endemic in certain regions and thus
Kaposi’s is more likely to occur in Mediterranean than Western populations. In a
large population-based cohort of solid organ transplant recipients in the USA, the
highest risk for Kaposi’s sarcoma was associated with male gender, nonwhite race,
non-US citizenship, lung transplantation, and a prior diagnosis of cutaneous squa-
mous cell carcinoma. The highest incidence occurred in the rst year following
transplantation [99].
10.5 Cancers Without anApparent De Novo Increased Risk
Following Solid Organ Transplantation
10.5.1 Non-HPV Associated Gynecologic Cancers
Endometrial and ovarian cancer incidence was not increased in large cohort study in
the USA [9] or in a meta-analysis of studies in worldwide [42].
10.5.2 Breast Cancer
Breast cancer is the most common cancer among women in the USA.The overall
risk of breast cancer in solid organ transplant recipients varies across studies but is
likely similar to age- and gender-matched controls [9, 100]. In some studies, the
incidence of breast is actually lower than the general population [9]. Unfortunately,
the risk may be higher in some populations including younger women (aged
<35years) and men [100], and outcomes for those who develop breast cancer are
less favorable. Once a solid organ transplant recipient is diagnosed with breast can-
cer, the risk of dying from breast cancer may be twice that in the general population,
especially in kidney transplant recipients [13, 100]. In part, poorer outcomes reect
the more aggressive and advanced nature of these cancers at the time of diagnosis,
but also uncertainties in treatment options for solid organ transplant recipients with
C. J.Wong andC. D.Blosser
319
breast cancer. Interactions between cancer therapies and immunosuppression, con-
cerns for rejection and graft loss as well as other patient-specic factors must be
considered when developing a treatment regimen for these patients and may limit
use of more novel biologic and immunologic agents [100].
Breast cancer screening recommendations in solid organ transplant recipients are
the same as the general population. Women of average risk should be screened every
1–2years beginning at age 40 and continuing through age 74 [101], although guide-
lines vary. It is not known whether women who have had solid organ transplantation
would benet from earlier or more frequent screening. When considering the use of
screening tests, factors such as life expectancy should be taken into consideration.
Some patients with relatively short life expectancy due to chronic conditions and
other complications of transplantation may not benet from screening.
10.5.3 Prostate Cancer
Although prostate cancer is the most common cancer in men, it is not increased in
solid organ transplant recipients, and may even be less common compared to the
general population (EAR -11.3 [9], SIR 0.68 [2]) possibly due to pre-transplant
screening. Prostate cancer, when it does occur in solid organ transplant recipients,
is associated with either no difference in outcomes [102] or with a lower mortality
compared to the general population (SMR 0.58) [12].
10.6 Cancer Screening andPrevention Pre-Transplantation
It is important that transplant recipients are free of most cancers prior to transplanta-
tion, with the potential exceptions of low risk prostate, thyroid, and breast cancers.
On the other hand, it is not clear that pre-transplant cancer screening reduces the
risk of post-transplantation malignancy. Screening guidelines generally mimic
guidelines for the general population with the addition of screening based on indi-
vidual risk factors. A thorough skin, oral cavity and physical examination, age- and
gender-appropriate breast, cervical, and colorectal cancer screening, and lung can-
cer screening if meets criteria, is typically recommended. Risk reduction strategies
include vaccinations, smoking cessation, and alcohol reduction.
Pre-renal transplant screening for malignancies that are more common in the
population with ESRD and dialysis, such as skin cancer, renal cell carcinoma, and
multiple myeloma may be appropriate. Patients with ESRD are at increased risk of
renal and other urothelial cancers, partially due to acquired cystic disease of the
kidneys and analgesic overuse, and some have advocated for screening prior to
transplantation in patients who have been on dialysis for >3years [103]. Potential
screening tests proposed by the American Society of Transplantation include uri-
nalysis, urine cytology and imaging of the native kidneys in high-risk patients [104].
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
320
10.6.1 Pre-transplant Evaluation ofPatients withPrior Cancer
Patients with a history of pretransplant malignancy (PTM) unrelated to the trans-
plant indication make up 7% of solid organ transplant recipients in population-based
studies [36], have roughly a 5% risk of cancer recurrence [36], and may be at greater
risk of cancer-related death than solid organ transplant recipients without a prior
history of cancer [105–109]. In a Swedish study of 10,448 solid organ transplant
recipients, 4% had a history of PTM.These patients were three times more likely to
die from cancer than patients without a history of pretransplant malignancy (HR
3.6) [107]. Cancers most likely to recur include breast, kidney, urothelial, hemato-
logic, and gastrointestinal malignancies [107, 110]. As another example, among
21,415 patients receiving a kidney transplant in Australia and New Zealand, 3% had
a history of PTM. 3.5% of these patients had post-transplant cancer recurrence and
8.7% developed a second primary cancer compared to 13.2% of cancer-free patients
who developed a rst cancer after transplantation. Cancer recurrence was seen most
frequently with urinary tract cancers, breast cancer and melanoma. Cancer-related
death was not more common in the patients with a prior history of cancer in this
study [111].
A history of malignancy is not an absolute contraindication for transplantation
[107]. The waiting period prior to solid organ transplant listing varies based on the
type, stage and aggressiveness of the cancer as well as the urgency and indication
for transplant. Most guidelines recommend disease-free intervals for specic can-
cers [110]. Waiting periods prior to transplantation have come under increased scru-
tiny [112]. In Norway, where the waiting period is 1year, there was no difference in
overall survival in kidney transplant recipients with or without a prior cancer history
[105]. Recent consensus expert opinion statements have been released with updated
multidisciplinary input in an effort to update waiting times [32, 113, 114]. Further
data-driven studies are needed to clarify cancer-specic risk of recurrence, cancer-
specic death and waiting times. Consultation with the patient’s oncologist is
appropriate.
10.7 Screening andPrevention Post-Transplantation
Given the increased risk of cancer following solid organ transplantation compared
to the general population, strategies to reduce cancer risk and identify malignancy
in early stages are important. Education regarding the role of diet, exercise, weight
control, sun protection, sexually transmitted disease prevention, smoking absti-
nence and limited alcohol intake are essential. Routine cancer screening recommen-
dations have been developed for identication of pre-cancerous lesions and early
stage diagnosis when possible. Cancer screening in solid organ transplant recipients
must be individualized, taking into account the patient’s overall health, life
C. J.Wong andC. D.Blosser
321
expectancy and goals to avoid excess testing, over-diagnosis, and unnecessary treat-
ment. Cancer screening in solid organ transplant recipients is addressed in Chap. 14.
10.8 Multidisciplinary Cancer Centers forSolid Organ
Transplant Recipients
The general population is aging with chronic diseases, resulting in more cancer and
solid organ transplantation. As such, there is a growing number of people with both
of these conditions for two reasons. First, solid organ transplant recipients (SOTRs)
have a 2–4 times greater risk of cancer due to older age, oncogenic viruses (e.g.,
Epstein–Barr Virus) and immunosuppression to prevent transplant rejection.
Second, an increasing number of patients with cancer are presenting with the need
for solid organ transplantation. These individuals have a higher risk for post-
transplant cancer. The combination of cancer and solid organ transplantation pres-
ents signicant challenges for patients, including increased risk of death and the
need for intensive and invasive treatments.
Oncology is rapidly developing new therapies, including immunotherapies, such
as immune checkpoint inhibitors (ICIs). ICIs are approved for nearly half of adult
cancer patients with advanced solid tumors. Yet, ICIs signicantly increase the risk
of organ transplant rejection, off-target effects, and cancer progression in SOTRs.
Much remains unknown for safe use of ICIs and other immunotherapies in SOTRs,
especially in racial and ethnic minority populations who experience lower access to
transplant and worse transplant and patient survival. These poorer outcomes are
possibly due to social determinants of health (SDOH), including economic stability,
education, neighborhood and the built environment, social and community context,
and health and health care access. Yet, the impact of SDOH on SOTRs at risk for or
with cancer is largely unknown.
Unfortunately, clinical care has been delivered in silos of distinct clinic and hos-
pital spaces which limits the quality of care, especially for patients with complex
health conditions. Patients and providers see a need for greater collaboration in
clinical care delivery to enhance the outcomes of patients with cancer before and
after organ transplant. There are a small number of multidisciplinary clinics in the
USA that focus on the complex needs of these patients.
The rst and most comprehensive is the Cancer and Organ Transplant Clinic
(COTC) at the Fred Hutch Cancer Center in Seattle, WA.The COTC provides inte-
grated expert consultation to pre- and post-transplant patients living with or who
have a history of cancer. Each patient is seen by a cancer-specic oncologist (e.g.,
skin, lymphoma, myeloma, kidney, GI, GU, and so on) and transplant physician
(e.g., kidney, liver, lung, heart, and so on), based on the patient’s condition. The
personalized recommendations are collectively shared with the patient and their
referring providers.
10 Cancer Risk intheAdult Solid Organ Transplant Recipient
322
A more specialized clinic is the Immunosuppression and Skin Cancer (ISC)
Clinic at the Dana Farber Cancer Center in Boston, MA.An expert group of derma-
tologists is focused on secondary prevention and treatment of skin cancer in these
high-risk patients.
These clinics highlight potential approaches to effectively care for complex
patients in efcient and meaningful ways and are models for multidisciplinary
future care.
10.9 Conclusion
Cancer is the second leading cause of death in solid organ transplant recipients [5].
It is essential for the primary care provider who takes care of solid organ transplant
recipients to have knowledge of this increased incidence and consider the possible
presentations of cancer in this population. Because patients may present many years
after transplantation with symptoms localizing to areas of the body distant to the
allograft, patients may not recognize that they may have a transplant-related condi-
tion and are likely to present to primary care. A high index of suspicion is critical to
making a timely diagnosis and expediting the appropriate treatment.
Acknowledgments The authors thank Deborah Greenberg, MD, for authoring the rst edition of
this chapter.
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