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Posttransplantation Lymphoproliferative Disorder Initially Seen as Iris Mass and Uveitis
Todd Cook, MD;
Richard J. Grostern, MD;
Neal P. Barney, MD;
Monte D. Mills, MD;
Robert Judd, MD;
Daniel M. Albert, MD
Arch Ophthalmol. 2001;119:768-770.
ABSTRACT
Primary ocular posttransplantation lymphoproliferative disorder is rare.
Epstein-Barr virus is implicated as the cause as a result of systemic immunosuppression
after transplant surgery. We studied a patient who developed ocular posttransplantion
lymphoproliferative disorder after orthotopic liver transplantation. Slitlamp
and light microscopic photographs confirmed the diagnosis.
INTRODUCTION
Inflammatory nodules of the iris in children are unusual. An immunosuppressed
child with the development of iris nodules and uveitis is suspicious for secondary
malignancy, infectious agents, and posttransplantation lymphoproliferative
disorder. Secondary malignancy is commonly lymphoma or leukemic infiltrate,
but only rarely is the eye reported as a solitary organ with development of
posttransplantation lymphoproliferative disorder.
REPORT OF A CASE
A 4-month-old girl with a history of primary biliary atresia underwent
orthotopic liver transplant in April 1995. Six months later, she developed
persistent diarrhea and vomiting. Biopsy specimens of the stomach and duodenum
demonstrated hyperplastic lymphoid nodules, and a positive serum Epstein-Barr
virus (EBV) titer was identified. The diagnosis of posttransplantation lymphoproliferative
disorder (PTLD) associated with immunosuppression and EBV was made. Her antirejection
medication, tacrolimus, was discontinued, her prednisone dosage was decreased,
and treatment was started with ganciclovir. Her symptoms resolved, but she
developed biopsy-proved rejection of the liver transplant, which required
cyclosporine in addition to prednisone and ganciclovir.
In April 1996, the patient had an elevated EBV titer associated with
gastrointestinal distress that resolved with oral acyclovir. In March 1998,
the patient developed tonsillitis and underwent tonsillectomy. Histologic
analysis failed to definitively diagnose PTLD.
In November 1999, the patient had sand thrown into her right eye. Her
ophthalmologist diagnosed a corneal abrasion with reactive anterior uveitis.
The abrasion healed rapidly, but the uveitis persisted. Three days after the
injury, the patient was referred to the University of Wisconsin–Madison
pediatric eye clinic for evaluation.
When first seen by us, the patient's medications included oral cyclosporine,
0.7 mg twice daily; oral prednisone, 5 mg every other day; 5% homatropine
hydrobromide, 1 drop in the right eye 4 times daily; ciprofloxacin hydrochloride,
1 drop in the right eye every 3 hours; and prednisolone acetate, 1 drop in
the right eye every 2 hours. On examination, the best-corrected visual acuity
was 20/30 in the right eye and 20/20 in the left. Ocular motility was normal,
as were the results of external examination. There was anisocoria, with the
right pupil greater than left, without a relative afferent pupillary defect.
Slitlamp examination disclosed normal conjunctiva and sclera in both
eyes. Large mutton-fat keratic precipitates were seen bilaterally, more severe
in the right eye than the left (Figure 1). Seven to 10 inflammatory cells per 2-mm slit beam were seen in the right anterior
chamber, and 5 to 7 were seen in the left. Examination of the irises showed
prominent nodularity in the right eye at the 6, 9, and 12 o'clock positions,
while the iris in the left eye was normal (Figure 1). The lenses were clear bilaterally. Funduscopic examination
disclosed a few anterior vitreous cells in the right eye, a clear vitreous
in the left eye, and normal optic nerves and retinas. Anterior segment ultrasonography
was consistent with iris masses in the right eye.
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Figure 1. Slitlamp photograph showing keratic
precipitates (black arrow) and iris nodule at the 6-o'clock position (white
arrows).
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In this immunosuppressed child with iris nodules, there was suspicion
of infectious uveitis, secondary malignancy (leukemia or lymphoma), or posttransplantation
lymphoproliferative disorder. A joint decision was made with the transplant
team and the pediatric oncology service to pursue further workup, to include
a cerebrospinal fluid analysis, bone marrow aspiration biopsy, and iris biopsy
of the right eye.
The bone marrow was normal. The cerebrospinal fluid showed a mild lymphocytosis
with normal-appearing lymphocytes. Results of physical examination were normal,
as was a complete blood cell count and a computed tomographic scan of the
pelvis, abdomen, and chest. A biopsy of the right iris was performed with
the patient under general anesthesia.
A 2 x 2 x 1-mm piece of iris tissue was received for histopathologic
examination. Microscopic examination showed a dense infiltrate of the iris
stroma, consisting predominantly of plasma cells, with accompanying lymphocytes
with mild atypia (Figure 2). Immunohistochemical
staining was strongly positive for  light chains and negative for 
light chains (Figure 3). The CD3
staining was moderately intense and the CD20 staining was moderate (Figure 4).
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Figure 2. Iris biopsy specimen showing infiltrate
of inflammatory cells, composed predominantly of plasma cells with an admixture
of lymphocytes (hematoxylin-eosin, original magnification x100).
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Figure 4. Iris biopsy specimen showing weakly
positive CD3 (A) and CD20 (B) staining within iris stroma (immunohistochemical
staining, original magnification x100).
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The immunohistochemical staining was interpreted as follows: The strong
positivity for light chains and the negative light chains
indicate monoclonality of the predominant population of cells, the plasma
cells. The positive CD3 and CD20 staining represents the polymorphism of the
infiltrate and the accompanying T (CD3-positive) and B (CD20-positive) cells.
The final diagnosis was of a polymorphic infiltrate with a predominant monoclonal
plasma cell population consistent with PTLD of the iris. No studies for evidence
of EBV were performed on the iris specimen.
COMMENT
Posttransplantation lymphoproliferative disorder develops in approximately
3% of patients who receive systemic immunosuppression for liver transplantation.1 The association between immunosuppression after organ
transplantation and lymphoproliferative disorders has been known since the
early 1970s; however, most of these tumors were originally diagnosed as non-Hodgkin
lymphoma. In 1977, Hertel et al2 were the first
to present these tumors as a lymphoproliferative disorder unique to patients
who have undergone organ transplantation. In the 1980s, Hanto et al3-5 fully described the
syndrome of PTLD.
Three distinct varieties of PTLD have been described. The first is a
mononucleosislike syndrome of fever, adenopathy, tonsillitis, and sore throat,
which is self-limited. The second variety of PTLD consists of widespread lymphoproliferative
disease that usually leads to death. Our patient was initially seen by us
with localized organ involvement, the third variety of PTLD. Localized PTLD
most commonly affects the gastrointestinal tract, central nervous system,
tonsils, and salivary glands.6-7
Epstein-Barr virus is implicated as the cause of PTLD. One theory suggests
that EBV causes B-cell proliferation, which would normally be down-regulated
by cytotoxic T cells and natural killer cells. Posttransplantation immunosuppressive
medications inhibit T-cell function, and thus B-cell proliferation goes unchecked.
Serologic evidence supporting the association between EBV and PTLD was strongly
supported by Ho et al.8
Histopathologically, PTLD usually consists of a B-lymphocyte or plasma
cell proliferation. The spectrum ranges from polyclonal benign typical-appearing
B-cell proliferations to monoclonal aggressive atypical-appearing B-cell and
plasma cell proliferations. Occasionally T-cell lymphomas are recognized as
PTLD. In a histopathologic study of 83 specimens in 43 cases of PTLD by Nalesnik
et al,7 most (71 of 83) were classified as
polymorphic or minimally polymorphic, whereas only 12 of 83 were monomorphic.
In the same study, clonality was determined in 30 cases. Twelve were monoclonal,
13 were polyclonal, and 5 cases had separate lesions that were both monoclonal
and polyclonal. The case presented here is consistent with the most common
type of PTLD, a polymorphic infiltrate with a monoclonal predominant subpopulation.
Treatment of PTLD consists of systemic ganciclovir and lowering the
dosage(s) of immunosuppressive agents to achieve a balance between organ rejection
and PTLD. Surgical resection of localized PTLD tumors or systemic antilymphoma
agents are options in select cases.
Outcomes vary depending on the type and extent of the tumor. Previous
reports of ocular occurrence of PTLD exist,9-13
2 of which were first seen as iris masses,9-10
2 as vitreitis mimicking lymphoma,11, 13
and 1 as an orbital mass.12
AUTHOR INFORMATION
Accepted for publication October 27, 2000.
Corresponding author: Neal P. Barney, MD, Department of Ophthalmology
and Visual Sciences, University of Wisconsin, 2870 University Ave, No. 206,
Madison, WI 53705 (e-mail: npbarney{at}facstaff.wisc.edu).
From the Departments of Ophthalmology and Visual Sciences (Drs Cook,
Grostern, Barney, Mills, and Albert) and Gastroenterology (Dr Judd), University
of Wisconsin, Madison.
REFERENCES
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1. Strazzabosco M, Corneo B, Iemmolo RM, et al. Epstein-Barr virus–associated post-transplant lympho-proliferative
disease of donor origin in liver transplant recipients. J Hepatol. 1997;26:926-934.
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2. Hertel BF, Rosai J, Dehner LP, Simmons RL. Lymphoproliferative disorders in organ transplant recipients [abstract]. Lab Invest. 1977;36:340.
3. Hanto DW, Frizzera G, Purtilo DT, et al. Clinical spectrum of lymphoproliferative disorders in renal transplant
recipients and evidence for the role of Epstein-Barr virus. Cancer Res. 1981;41(11, pt 1):4253-4261.
4. Hanto DW, Frizzera G, Gajl-Peczalska KJ, et al. Epstein-Barr virus–induced B-cell lymphoma after renal transplantation:
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disorders. Curr Probl Surg. 1988;25:367-472.
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7. Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of post-transplant lymphoproliferative disorders occurring
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ABSTRACT
8. Ho M, Miller G, Atchison RW, et al. Epstein-Barr virus infections and DNA hybridization studies in posttransplantation
lymphoma and lymphoproliferative lesions: the role of primary infection. J Infect Dis. 1985;152:876-886.
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9. Brodsky MC, Casteel H, Barber LD, et al. Bilateral iris tumors in an immunosuppressed child. Surv Ophthalmol. 1991;36:217-222.
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10. Clark WL, Scott IU, Murray TG, et al. Primary intraocular posttransplantation lymphoproliferative disorder. Arch Ophthalmol. 1998;116:1667-1669.
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recipient. Ophthalmology. 1992;99:987-992.
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12. Pomeranz HD, McEvoy LT, Lueder GT. Orbital tumor in a child with posttransplantation lymphoproliferative
disorder. Arch Ophthalmol. 1996;114:1422-1423.
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13. Kheterpal S, Kirkby GR, Neuberger JM, et al. Intraocular lymphoma after liver transplantation. Am J Ophthalmol. 1993;116:507-508.
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SECTION EDITOR: W. RICHARD GREEN, MD
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