The patient is a 32-year-old man with cystic fibrosis, who is
Epstein-Barr virus naive and underwent a bilateral lung transplant in January
2006. He was readmitted to the hospital one and a half months after his lung
transplant for intussusception. He required surgical intervention, with the
pathologic specimen revealing hyperplasia of Peyers patches.
The patient recovered but had persistent abdominal discomfort and
nutritional issues. Approximately seven months after his transplant, he was
admitted to the hospital with the onset of new gastrointestinal symptoms and
escalating abdominal pain. He underwent a laparoscopically-assisted small bowel
resection for intussusception. The ileal specimen contained a 2 cm ulcer that
showed a posttransplant lymphoproliferative disorder (large B-cell lymphoma)
that was EBV positive. A small lymphocytic infiltrate was identified at the
At the time of evaluation after recovery from surgery, the patient had
no known fevers or infections. He reported true night sweats that have been
present for years. He had occasional nausea and vomiting, precipitated
primarily by coughing spells. His bowels had been somewhat loose.
- Past medical history: Cystic fibrosis with accompanying
pancreatic insufficiency and diabetes, hypertension, nephrolithiasis.
- Medications: Reglan (metoclopramide hydrochloride), CellCept
(mycophenolate mofetil), dapsone, enalapril, eszopiclone (Lunesta, Sepracor),
metoprolol, prednisone, tacrolimus (Prograf, Astellas), pantoprazole sodium
(Protonix, Wyeth), voriconazole (Vfend, Pfizer), sertraline hydrochloride
(Zoloft, Pfizer), multivitamins.
- Social history: Married without children. No tobacco, rare
A physical examination demonstrated normal vital signs with oxygen
saturations of 100% on room air. He had no scleral icterus and no
lymphadenopathy. His heartbeat was regular and his lungs clear. The abdomen was
scaphoid with a liver span of 9 cm. An abdominal incision was healing. There
was evidence of clubbing.
A MUGA demonstrated normal cardiac function. Bone marrow biopsy was
negative. PET/CT scan revealed a new finding of an ileal intussusception with a
focal area of hypermetabolic activity that was not obstructive. EBV studies
show an IgG antibody of 1.04 (equivocal) and an IgM of 0.5 (not detectable).
EBNA is 0.62 (not detectable), and there were fewer than 1,000 copies of EBV in
the blood. Hepatitis B serologies were negative.
A. Repeat surgical resection of the ileum.
Single agent rituximab (Rituxan, Genentech) therapy.
D. Reduction in immunosuppression and treatment with
Posttransplant lymphoproliferative disorders (PTLD) are a rare but
serious complication following solid organ and bone marrow transplant.
Initially described in 1969, it has been observed that the risk of malignancies
in recipients of solid organ transplants is up to 100 times that of the general
population when matched by age. The most common malignancies are skin or lip
carcinomas followed by lymphoproliferative disorders. Lymphoproliferative
disorders have been found to have a different histology, to be more clinically
aggressive and, in general, to result in poorer outcomes than de
novo non-Hodgkins lymphomas.
The development of PTLD is felt to be bimodal. There are a group of
cases that are typically EBV-related that develop within the first year after
transplant (ranging from three to five months after solid organ transplant).
There are a group of cases, typically EBV-negative, that develop late after
transplant (range 50 to 77 months). The outcome is felt to be similar in both
It has been thought for many years that EBV plays a key role in the
pathogenesis and the development of PTLD. The role of EBV was initially
suspected when transplant recipients were found to have increased oropharyngeal
shedding of the virus and had symptoms of primary and secondary EBV infection.
Since that time, the association of EBV has been demonstrated by
immunohistochemistry and EBV-DNA hybridization studies in patients with PTLD.
It is felt that EBV is a polyclonal stimulator of B-cell
proliferation. In a normal host, B cells are defected by the TH1 immune
response. Additionally, infected cells display latency and are lysed by
EBV-specific cytotoxic T lymphocytes (CTLs), resulting in memory cells. In
solid organ transplant recipients, six months after transplant, there is a
complete loss of EBV-specific CTLs. Although it is unknown why this occurs,
EBV-specific CTL activity will increase to pretransplant levels beginning six
months after transplant. However, during the time period where EBV-specific
CTLs are lacking, CD4+ cells predominate and no CD56+ natural killer cells are
detected. As a result, the B-cells proliferate. Additionally, many of the
immunosuppressants that transplant recipients are taking to prevent organ
rejection, such as tacrolimus, cyclosporine and azathioprine, either interfere
with T-cell activation or block the T-cell response. This also allows the B
cells to proliferate.
EBV infection clearly has a role in the pathogenesis of EBV-positive
PTLD. However, this type of PTLD only develops in some patients; not all
patients develop PTLD. It suggests that a few EBV-infected cells have the
capacity to proliferate. Some investigators have suggested cofactors in the
development of PTLD such as chronic antigenic stimulation by the allograft,
IL-4, IL-10 and IL-6 that may promote B-cell growth. It has also been
hypothesized that late-onset PTLD may have a different pathogenic mechanism
involving secondary oncogenic events such as BCL-2 rearrangements,
C-MYC mutations, N-RAS and p53 mutations and LMP1
deletions that are responsible for de novo lymphoma.
With the pathologic heterogeneity, the clinical presentation of PTLD
can vary significantly. Early lesions are typically found incidentally and
asymptomatically. In one series, lung transplant recipients with PTLD were most
commonly picked up asymptomatically on chest X-ray. In contrast, in late
disease, patients typically present with bulky, extranodal lymphadenopathy.
Fifty-six percent presented with involvement of the gastrointestinal tract
(nonhealing ulcers, bowel perforation). Involvement of the central nervous
system and the bone marrow at the time of presentation is rare in solid organ
A reduction in immunosuppression has been shown to be helpful in
selected patients with variable response rates of 31% to 75%. However, it is
usually only successful in patients with early lesions. Surgical resection and
radiotherapy have been implemented and shown to be effective, primarily in
patients with limited-stage disease. In the 1980s, antiviral therapies with
acyclovir were evaluated and shown to have some benefit in individuals with EBV
infection. However, a large review demonstrated that the survival rate for
transplant recipients treated with acyclovir was similar to the overall
survival rate in similar patients not treated with acyclovir. In addition,
acyclovir inhibits viral replication, not EBV-induced B-cell transformation.
Therefore, acyclovir and other antivirals would not be expected to be effective
in EBV-PTLD when the vast majority of cells are latently infected with EBV.
Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin,
vincristine, and prednisone) with or without rituximab can provide effective
results; however, the toxicities of these therapies in patients that are
already immunosuppressed is too great, particularly in those who develop late
PTLD. Dotti et al evaluated 30 patients with PTLD that developed more than one
year from transplant, of whom 55% had stage III or IV disease. Of those
patients, 33% that were treated with chemotherapy had a response. However, 50%
died of toxicities to the chemotherapy, either infectious complications or
multisystem organ failure.
More recently, immunotherapy with monoclonal antibodies such as
rituximab (anti-CD20) has demonstrated some efficacy, offering a potentially
safe and effective treatment. Overall response rates with single agent
rituximab vary from 37% to 69% with median survivals of 14 months. In general,
it has been felt that single agent rituximab is better tolerated than systemic
chemotherapy. It also appears that patients who have failed treatment with
single agent rituximab can still respond well to systemic chemotherapy.
Our patient was treated with single agent rituximab 375
mg/m2 weekly for four weeks, given on an every six month basis. He
is now two years out from diagnosis with no evidence of recurrent
Anne H. Blaes, MD, is a Fellow at the University of Minnesota and a
member of the HemOnc Today Editorial Board.
For more information:
- Blaes AH. Cancer. 2005;104:1661-1667.
- Dotti G. Transplantation. 2002;74:1095-1102.
- Hanto DW. NEJM. 1982;306:913-918.
- Ho M. J infect Dis. 1985;152:876.
- Jain AB. Transplantation. 2005;80:1692-1698.