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Slide 1 Post-Transplant Malignancies
In 1963, Israel (Sol) Penn, MD, joined the
transplantation program at the University of
Colorado in Denver under the direction of Thomas
E. Starzl, MD. Over the ensuing years, Dr Penn
noticed the increased frequency of lymphoma
development in transplant recipients and reported
this observation in 1968 at the inaugural meeting
of the Transplantation Society, in Paris. At that
meeting, other investigators reported similar
experiences with malignancies noted at greater
frequency in transplantation patients than in the
general population. In 1969, Dr Penn started the
Denver Transplant Tumor Registry to examine this
phenomenon.  Subsequently, Dr Penn moved to
Cincinnati as chief of surgery at the Cincinnati
Veterans Administration Hospital, and the
registry was renamed the Cincinnati Transplant
Tumor Registry. After Dr Penns death, in 1999,
the registry was renamed the Israel Penn
International Transplant Tumor Registry (IPITTR)
in his honor. To date, more than 7000 US cases
and 9000 international cases have been reported
to this registry. A registry Web site
(www.IPITTR.uc.edu) has been created for
submission of data on donor, de novo, and
preexisting malignancies, as well as for
obtaining consultations, based on registry data,
regarding the management of donor and recipient
malignancies. 
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Slide 2 Post-Transplant Malignancies
Cancers of the skin and post-transplant
lymphoproliferative disorder (PTLD) make up and
post-transplant lymphoproliferative disorder
(PTLD) make up approximately 50 of the cancers
reported to the IPITTR. Post-transplant
malignancies have been reported in recipients of
all types of solid organs. De novo malignancies
have been reported most commonly in renal
transplant recipients, the largest and the
longest monitored group of transplant recipients
in the United States.1,2 Thus, patients who
received kidneys account for the majority (62.1)
of cases reported to the registry. This group is
immediately followed in order of cancer incidence
by cardiac transplant recipients. Patients with
cardiac transplants make up a significantly
smaller proportion of US organ recipients than
those with hepatic transplants (12.2 vs 19.6,
respectively)3 yet account for a greater
proportion of post-transplant malignancies
reported to the IPITTR (24.3 vs 7.9,
respectively). These data demonstrate the
possible link between not only duration but also
intensity of immunosuppression and the
post-transplant incidence of cancer. Lung and
pancreas recipients constitute the smallest
segments of reported patients (1.4 and 0.5,
respectively). Cancers that occur with an
increased relative frequency in transplant
recipients compared with the general population
include PTLD, cancer of the hepatobiliary system,
Kaposis sarcoma (KS), renal cell cancer, vulvar
and perineal cancers, solid neuroendocrine
sarcomas, Merkel cell tumors, and carcinoids.
1,2,4-7
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Slide 3  Post-Transplant Malignancies
De novo post-transplant malignancies have been
associated with the long-term administration of
immunosuppressive agents. Notably,
immunosuppressed patients, including those with
human immunodeficiency virus infection as well as
transplant recipients, have had a high reported
incidence of virally stimulated malignancies,
such as KS (human herpesvirus 8 HHV-8) and PTLD
(Epstein-Barr virus EBV). These malignancies
have been reported as early as 1 month, but may
be identified as late as 25 years, after
transplantation.1  In the cases reported to the
IPITTR, the mean time to the development of
post-transplant malignancy is 63 months after
transplantation (median time, 47 months).
Kaposis sarcoma occurs at the shortest interval
post-transplantation, a mean of 21 months
(median, 13 months). Next earliest in occurrence
is PTLD, at a mean of 35 months (median, 13
months). Epithelial malignancies, including skin
cancers, have been reported after a mean of 66
months (median, 51 months) following the
transplant procedure. Cancer of the vulva,
uterus, or cervix has the longest latency,
occurring after a mean interval from
transplantation of 114 months (median, 51
months).
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Slide 4  Post-Transplant Malignancies
This abdominal computed tomographic scan shows
hepatic PTLD (arrow) that developed in a female
patient 1 year post-transplantation. Her
immunosuppressive regimen comprised cyclosporine,
mycophenolate mofetil, and corticosteroids, with
OKT3 induction. Treatment consisted of
immunosuppression reduction to corticosteroids
only and radiation therapy. The patient also
required endoscopic retrograde cholangiopancreatog
raphy for placement of a common bile duct stent
and a portal vein stent for hilar
compression. Post-transplant lymphoproliferative
disorder occurs with far greater frequency in the
immunosuppressed transplant recipient than do
lymphomas in the general population.1,8,9
Morphologically, PTLD appears as large-cell
lesions 85 are of B-cell, and 15 of T-cell
origin.1 The pathologic spectrum of the B-cell
lesions ranges from lymphoid hyperplasia to true
lymphoma. From 90 to 95 of the B-cell tumors
are thought to arise from EBV co-stimulation.8  Mo
re than 70 of transplant recipients with PTLD
have extranodal disease, and involvement of the
allograft by the PTLD is frequently encountered.1
This may lead to diagnostic confusion with acute
rejection at the site. Post-transplant
lymphoproliferative disorder also has a higher
incidence of central nervous system (CNS)
involvement (21) than lymphomas in the general
population, which are associated with
CNS-confined disease in approximately 1 of
patients.1  Like PTLD itself, the therapeutic
options for the disease span a continuum, ranging
from antiviral therapy to reduction or withdrawal
of immunosuppressive agents, anti-CD20 monoclonal
antibody, or cytotoxic chemotherapy. Invasive
procedures, including radiation therapy and
surgical excision, are additional therapeutic
modalities, with unclear efficacy.18. Penn I.
Post-transplant malignancy the role of
immunosuppression. Drug Saf. 200023101-113.9.
Buell JF, Hanaway MJ, Trofe J, et al.
Post-transplant lymphoproliferative disorder in
liver transplant recipients a report from the
Israel Penn International Transplant Tumor
Registry. Liver Transpl. 20017C-71.
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Slide 5  Post-Transplant Malignancies
There is a relationship that has been shown
between the intensity of immunosuppression and
the time to development of PTLD.10 In patients
reported to the IPITTR who had PTLD and had been
treated with azathioprine and steroids, the mean
time to development of the disease was 50 months.
After the introduction of cyclosporine, this
interval declined to 13 months, and if induction
with OKT3 was included, the mean time
post-transplantation to the development of PTLD
was 7 months. Moreover, these 3 immunosuppressive
regimens have an impact on how early PTLD
develops. It occurred within the first 4 months
after transplantation in only 12 of the
azathioprine-and-prednisonetreated patients, in
31 of patients after addition of cyclosporine,
and in 59 of patients when OKT3 was given.
Development of PTLD has been reported with all
the different immunosuppressive agents used, and
it appears to be related not to any single agent
but to the degree of immunosuppression
induced. 10. Trofe J, Buell JF, First MR,
Hanaway MJ, Beebe TM, Woodle ES. The role of
immunosuppression in lymphoma. Paper presented
at 3rd Symposium on Immunodeficiency and
Malignancy February 16-17, 2001 Berlin,
Germany.
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Slide 6  Post-Transplant Malignancies
Skin cancer is the most common malignancy
reported after transplantation.1 There are many
differences between skin cancers in transplant
recipients and those in the general population.
The most common skin cancer in the general
population is basal cell cancer, with a ratio of
basal cell to squamous cell cancers of 5 to 1. In
transplant recipients, however, squamous cell
carcinoma is the most commonly encountered skin
cancer, with a ratio to basal cell carcinoma of
1.8 to 1.1 The frequency of malignant melanoma is
almost twice as high in transplant recipients as
in the general population.11 The mean age of
development of skin cancer in transplant
recipients is 30 years, compared with 65 years in
the general population.1 The skin cancers
encountered in transplant recipients are much
more aggressive than those in the general
population and are frequently multicentric in
origin.1,12 Lymph node metastasis has been
reported in approximately 6 of transplant
patients and mortality resulting from the
dissemination of skin cancer, in approximately
5.1 Lymph node metastasis and death from skin
cancers are rare in the general population,
except in cases of malignant melanoma.13 The
development of squamous cell carcinoma of the
skin after organ transplantation has been clearly
related to exposure to UV light, with the highest
incidence being reported in transplant recipients
in Australia.1 11. Penn I. Malignant melanoma
in organ allograft recipients. Transplantation.
199661274-278.12. Buell JF, Trofe J, Hanaway
MJ, et al. Malignancies of the skin after liver
transplantation a report from the Israel Penn
International Transplant Tumor Registry. Liver
Transpl. 20017C-40.13. Shelton RM. Skin
cancer a review and atlas for the medical
provider. Mt Sinai J Med. 200168243-252.
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Slide 7  Post-Transplant Malignancies
  The most common womens malignancies reported
to the IPITTR include breast cancer followed by
cervical/uterine, vulvar, and ovarian cancer.
Like the majority of malignancies reported to the
registry, cancers in women occurred most often in
renal allograft recipients. Most breast
malignancies in registry patients are intraductal
(65), as in the general population, with the
remainder lobular and a small percentage
inflammatory. One fourth of these malignancies
presented with nodal involvement. Conservative
resection and radiation were used in a
significant proportion (35) of patients, while
simple or modified radical mastectomy remained
the principal procedure in most reported
patients.  Human papillomavirus and condylomata
have been associated as an etiologic factor in
the development of vulvar cancer (35 of cases in
the IPITTR). A significant proportion of female
recipients of transplants had second vulvar
malignancies, which consisted of in-field
recurrences as well as second primary cancers.
Nevertheless, overall vulvar cancer mortality was
exceedingly low (4). Ovarian cancer is a common
malignancy in the general population14 however,
in immunosuppressed transplant recipients, it
appears to be seldom encountered. 14. Runnebaum
IB, Stickeler E. Epidemiological and molecular
aspects of ovarian cancer risk. J Cancer Res Clin
Oncol. 200112773-79.
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Slide 8  Post-Transplant Malignancies
   Kaposis sarcoma accounts for 0.02 to 0.07
of all cases of cancer in the general population
and is responsible for between 5 and 6 of the
post-transplant malignancies reported to the
IPITTR.1,15 Two forms of KS exist the
nonvisceral type, which is localized to the skin,
mouth, and oropharynx, and the visceral type,
with involvement of the gastrointestinal tract,
lymph nodes, and lungs.  Comparison of IPITTR
data on US and international recipients of organ
allografts in whom post-transplant KS developed
reveals differences between the 2 groups.15 While
the gender ratio and visceral KS survival rate
are the same or similar in both groups, the US
patients are older, more commonly receive
antibody induction therapy, less frequently have
visceral-type disease, and appear to have better
survival with cutaneous KS. Complete remission of
both the nonvisceral and visceral types of KS has
been reported when immunosuppression reduction or
discontinuation has been the only therapy.
Patients with the visceral form of the disease
more frequently need adjunctive chemotherapy,
radiation therapy, and/or surgery.115. Buell J,
Hanaway M, Trofe J, Beebe T, First MR, Woodle ES.
Kaposis sarcoma in transplant recipients
differential features between US and European
patients. Paper presented at 2001 A Transplant
Odyssey August 23, 2001 Istanbul, Turkey.
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Slide 9  Post-Transplant Malignancies
 Early experiences in transplantation included
the use of organs from donors with active
malignancies. This practice resulted in the
transmission of malignancy to transplant
recipients. The largest group of donor
malignancies in the United States is CNS
cancers.16,17  Several risk factors have been
associated with donor malignancy transmission,
including high-grade malignancy, especially
astrocytoma, glioblastoma, and medulloblastoma. A
history of shunt surgery, extensive surgical
resection, chemotherapy, or radiation is also
associated with an increased incidence of
transmission. Melanoma and choriocarcinoma are
associated with the highest incidence of
transmission and clearly should be considered
donor exclusion criteria.16  Renal cell cancer is
also encountered with a high frequency in the
evaluation of donors. In the instance of isolated
intraparenchymal renal cell cancer without
vascular invasion, multiple cases have been
reported to the registry in which the
contralateral kidney was transplanted without
transmission. In a small group of patients,
malignancies were excised with adequate margins,
and the kidneys were implanted without a single
incidence of transmission. However, in those
cases with extracapsular invasion, vascular
invasion, or metastatic disease, a high incidence
of donor transmission has been observed. Donors
with an unclear etiology for intracranial
bleeding should be autopsied after donation to
avoid the transplantation of high-risk
organs.1616. Buell JF, Trofe J, Hanaway MJ, et
al. Transmission of donor cancer into
cardiothoracic transplant recipients. Surgery.
2001130660-668.17. Buell JF, Trofe J, Hanaway
MJ, et al. Can patients with CNS tumors safely be
used in expanding the donor pool? Am J
Transplantation. 20011220.