HEMATOPATHOLOGY
Case Report
Gamma/Delta T-Cell Posttransplantation
Lymphoproliferative Disorder
Primarily in the Spleen
CHARLES W. ROSS, MD, 1 BERTRAM SCHNITZER, MD, 1 SUSAN SHELDON, P H D , 1
DANIEL K. BRAUN, MD, P H D , 2 AND CURTIS A. HANSON, MD 1
A 31-year-old renal transplant recipient developed an unusual T-cell
lymphoproliferative disorder 3 years after transplantation. The neoplasm involved the spleen, without concomitant hepatomegaly, lymphadenopathy, or obvious bone marrow involvement. Peripheral blood
involvement developed after splenectomy. Immunophenotypically, the
neoplastic cells expressed CD2, CD3, CD7, CD16, CD45, CD56, and
the 7/6 T-cell receptor on the surface membrane. The neoplastic cells
were negative for surface membrane CD4, CD5, and CD8. Serologic
and/or DNA analyses for viruses, including Epstein-Barr virus, human
T-cell lymphotropic virus-1, human immunodeficiency virus, and human herpesvirus-6, were negative. Cytogenetic findings included a
translocation breakpoint at chromosome 7pl5, consistent with involvement of the T-cell receptor 7-chain locus. Although 7/6 T-cell lymphomas have been reported to have a predilection for hepatosplenic localization, this is the first well-documented case to be described in the setting
of posttransplantation immunosuppression. (Key words: 7/6 T-Cell receptor; T-Cell lymphoma; Spleen; Transplantation) Am J Clin Pathol
1994;102:310-315.
Organ transplant recipients are known to have an increased
risk of developing non-Hodgkin's lymphomas, usually of the
B-cell type.1'2 Only rare cases of T-cell lymphomas have been
described in this setting.3"8 In this report, we describe an unusual 7/5 T-cell lymphoma that developed in an immunosuppressed renal transplant recipient. The clinical, virologic, immunophenotypic, genotypic, and cytogenetic findings are
discussed in the context of the limited literature available on
this subject.
bacterial, mycobacterial, and fungal cultures of blood, sputum, and
urine were negative. Cytomegalovirus cultures of blood and urine were
negative. Results of serologic studies for hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus, human T-cell lymphotropic
virus-1, rheumatoid factor, antinuclear antibody, and cold agglutinins
were negative. Epstein-Barr virus (EBV) serologicfindingswere as follows: viral capsid antigen IgM < 1:10, viral capsid antigen IgG >
1:1024, early-antigen IgG 1:128, and nuclear antigen ) 1:32, consistent
with past infection at an undetermined time.
Over the next 7 weeks, fevers persisted, splenomegaly increased, and
the peripheral blood cytopenias worsened. A diagnostic and therapeuCASE REPORT
tic splenectomy was performed. The spleen was diffusely involved by a
large-cell lymphoproliferative process. Within days after splenectomy,
On initial examination, a 31-year-old man had a 4-week history of
a rapidly progressive neoplastic lymphocytosis emerged in the periphfatigue, dry cough, and fever. He had a history of renal failure due to
eral blood. By the sixth week after splenectomy, the white blood cell
Alport's syndrome, treated by cadaveric renal transplantation 3 years
count had increased to 144.0 X 109/L, and the platelet count had depreviously. The medical history included hypertension, gout, and hycreased to 79 X 109/L. The patient had persistent fevers, night sweats,
perparathyroidism. Medications included cyclosporine A, azathioand right-upper-quadrant pain. There was still no lymphadenopathy.
prine, and enalapril.
Chemotherapy was given, including prednisone, vincristine, daunoruPhysical examination disclosed splenomegaly, but no lymphadenopbicin, and L-asparaginase. The maintenance dose of cyclosporine A
athy or hepatomegaly. Computerized tomography of the thorax, abdowas reduced by two thirds. Within 2 days, the white blood cell count
men, and pelvis revealed no lymphadenopathy. Hematologic findings
had fallen to the normal range.
included a normocytic anemia (hemoglobin 9.6 g/dL), a normal white
Four weeks later, the fever and neoplastic lymphocytosis had reblood cell count (6.7 X 109/L), and a normal platelet count. Routine
curred. The patient then underwent treatment with cytosine arabinoside and mitoxantrone. His course was complicated by pancreatitis and
profound neutropenia, and 3 months after splenectomy the patient
From the Departments of Pathology and2Internal Medicine, Univer- died of fungal septicemia. No autopsy was performed.
sity of Michigan Hospitals, Ann Arbor. Michigan.
Manuscript received April 30, 1993; revision accepted August 11,
1993.
Supported in part by United States Public Health Service Grant
AI27960 (D.K.B.).
Address correspondence to Dr. Ross: University of Michigan Medical School, Department of Pathology/M5242 Med Sci I, 1301 Catherine Road, Ann Arbor, MI 48109-0602.
MATERIALS A N D METHODS
Morphologic
Examination
Peripheral blood and bone marrow aspirate smears were
stained with the Wright or Wright-Giemsa stain. Bone marrow
310
ROSS ET AL.
y/8 T-Cell Posttransplantation Lymphoma
TABLE 1. FLOW CYTOMETRIC IMMUNOPHENOTYPING
RESULTS: PERIPHERAL BLOOD
Cluster
Designation
2
3
4
5
7
8
10
lie
14
16
19
20
22
25
34
38
45
56
57
Antibody
Leu5b
Leu4
Leu3a
Leul
Leu9
Leu2a
J5
LeuM5
LeuM3
Leullc
B4
Leu 16
Leu 14
IL-2R
HPCA-2
Leu 17
HLe-1
Leu 19
Leu7
Ig heavy (G, A, M, D)
Ig light (k, X)
a/(3 WT31 (TCR-1)
TCRT/6-1
Source
% Positive
B-D
B-D
B-D
B-D
B-D
B-D
C
B-D
B-D
B-D
C
B-D
B-D
B-D
B-D
B-D
B-D
B-D
B-D
Dako
B-D
B-D
B-D
94.6
79.0
1.6
11.2
43.4
10.0
11.3
22.6
0.0
92.2
9.5
0.4
1.3
0.8
1.5
47.5
99.0
51.1
0.7
Negative
Negative
6.8
69.3
B-D = Bccton-Dickinson. San Jose. CA; C = Coulter Corporation. Hialcah. FL: Dako =
Dako Corporation. Carpintcria. CA.
trephine biopsy specimens werefixedin B5 and briefly decalcified. Bone marrow aspirate clots werefixedin neutral buffered
formalin. Spleen, splenic hilar lymph nodes, liver, and kidney
tissues werefixedin B5 or neutral buffered formalin. Histologic
sections were stained with hematoxylin and eosin.
Immunofluorescence Phenotyping
Heparinized peripheral blood and bone marrow were immunophenotyped according to flow cytometric methods described previously.910 Surface immunophenotyping was performed with a broad panel of monoclonal antibodies (Table 1).
Nuclear terminal deoxynucleotidyl transferase was assayed by
indirect immunofluorescence microscopy.
3_n
to standard procedures.12 DNA was digested using BamHl,
£coRI, and Hindlll restriction enzymes. The digested DNA
was size-fractionated by agarose gel electrophoresis, transferred
to a nylon membrane, and then analyzed with radiolabeled
probes according to standard methods.1213
T-Cell receptor gene rearrangement analysis was carried out
with a probe for the constant regions of the T-cell receptor
(3-chain gene14 and a probe for the joining region of the T-cell
receptor 7-chain gene.15 Human placental DNA was used as a
germline control.
Viral genomic studies were carried out for two herpesviruses
that have been associated with chronic lymphoproliferative
disorders.16"18 Epstein-Barr virus probe pT65 was made from a
cDNA containing the EBNA-LP and EBNA-2 genes of the
virus." Probe pH6Z101 for the Z29 strain of human herpesvirus-6 (HHV-6) was kindly provided by P. Pellett (Centers for
Disease Control, Atlanta, GA). According to P. Pellett, this
probe has been shown to have no cross reactivity with the five
previously known human herpesviruses (personal communication).
Polymerase Chain Reaction Analysis for Epstein-Barr
Virus and Human Herpesvirus-6
DNA extracted from peripheral blood and bone marrow
mononuclear cells was used as template material for polymerase chain reaction. Oligonucleotide primers corresponded to
sequences in the internal repeat fragment {BamHl W-fragment) of the EBV genome20 or near the left end of the unique
component of the genome of the Z29 strain of HHV-6.21 The
polymerase chain reaction was performed as described elsewhere.20 Positive control material was DNA extracted from a
known EBV-positive posttransplantation lymphoproliferative
disorder or Molt3 cells infected with the Z29 strain of HHV-6.
Negative controls contained sterile water in place of template
DNA. Polymerase chain reaction products were electrophoresed on 2% agarose gels containing ethidium bromide and then
examined and photographed by ultraviolet illumination.
Cytogenetic Analysis
Presplenectomy bone marrow and postsplenectomy peripheral blood specimens were cultured for 2-24 hours and then
analyzed by standard cytogenetic techniques.22
Immunohistochemical Analysis
RESULTS
Paraffin-section immunohistochemical analysis was performed on B5- and formalin-fixed tissues. An avidin-biotinperoxidase complex technique" was used with all antisera. Primary antibody specificities included CD3 (Dako, Carpinteria,
CA), CD20 (L26, Dako), CD43 (Leu22, Becton-Dickinson,
San Jose, CA), CD45 (leukocyte common antigen, Dako),
CD45RO (UCHL-1, Dako), CD68 (KP1, Dako), CD74 (LN2,
BioGenex, San Ramon, CA), CDw75 (LN1, BioGenex), immunoglobulin light chains (Dako), and SI00 protein (Dako). Appropriate positive and negative controls were used for all immunohistochemical studies.
Genomic DNA Analyses
DNA for gene rearrangement analysis and viral probing was
extracted from peripheral blood mononuclear cells according
Morphologic and Immunohistochemical
Findings
The spleen weighed 948 g, and the splenic parenchyma was
maroon and homogeneous in texture. The splenic white pulp
was inconspicuous. Two small accessory spleens at the hilum
had a similar gross appearance. Histologic sections of the
spleen and accessory spleens revealed a diffuse red pulp infiltrate of intermediate-to-large lymphoid cells (Fig. 1). Most of
these lymphoid cells had a high nuclear-to-cytoplasmic ratio,
noncleaved nuclei, open chromatin, and one or two nucleoli.
The splenic red pulp was congested. Scattered small white pulp
areas were still intact. Histologic examination of two small
splenic hilar lymph nodes was negative for involvement by the
lymphoproliferative process.
Immunohistochemical analysis was performed on paraffin
Vol. 102-No. 3
312
HEMATOPATHOLOGY
Case Report
sections of the spleen (Fig. 2). The neoplastic lymphoid infiltrate was positive for common leukocyte antigen, CD3 (in formalin-fixed tissue but not in B5-fixed tissue), and CD43
(Leu22); the neoplastic infiltrate was negative for CD20 (L26),
CD45RO (UCHL1), CD68 (KP1), CD74 (LN2), CDw75
(LN1), immunoglobulin light chains, and S100 protein.
A neoplastic lymphocytosis was manifest in the peripheral
blood within days after splenectomy (Fig. 3). The abnormal
lymphoid cells were medium to large, with a moderate amount
of gray-blue cytoplasm and no cytoplasmic granules. The nuclei were round or oval with some contour irregularities. Only a
few nuclei were deeply clefted or lobulated. The chromatin was
moderately clumped. Nearly all of the circulating neoplastic
cells had one or two prominent nucleoli.
Bone marrow biopsy specimens and aspirate smears obtained at 6 and 4 weeks before splenectomy showed trilinear
hematopoiesis without obvious evidence of neoplastic infiltration. A bone marrow specimen obtained 2 weeks after splenectomy was hypercellular as a result of erythroid hyperplasia;
only occasional abnormal lymphoid cells were noted in the
marrow aspirate, consistent with minimal neoplastic infiltration or peripheral blood contamination.
A needle biopsy specimen of the liver, obtained 4 weeks before splenectomy, showed expanded sinusoids containing neoplastic lymphocytes and increased numbers of Kupffer cells
(Fig. 4). Paraffin-section immunohistochemical analysis documented the same neoplastic T-cell phenotype in the liver as was
FIG. 2. Immunohistochemical staining of spleen with Leu22 (CD43).
Red pulp (upper) is densely infiltrated by Leu22-positive neoplastic
cells. Residual white pulp area contains only a few positive cells (immunoperoxidase, X 400).
shown in the spleen (Fig. 5). There was no hepatocyte necrosis,
and no viral inclusions were seen in the liver sections.
A kidney specimen, obtained by open biopsy performed 4
weeks before splenectomy, showed moderate-to-severe acute
and chronic cellular and vascular rejection. There was no neoplastic lymphoid infiltrate in the kidney biopsy specimen.
Immunofluorescence
Phenotyping
Immunophenotypic analysis was performed on a sample of
heparinized blood collected 2 weeks after splenectomy. The
white blood cell count at that time was 27 X 109/L with 64%
lymphoid cells. Nuclear terminal deoxynucleotidyl transferase
was negative. The neoplastic lymphoid cells had the following
immunophenotype (also see Table 1): CD2+, CD3+, CD4—,
C D 5 - , CD7+, CDS-, C D 1 0 - , C D l l c + , CD16+, C D 2 5 - ,
C D 3 4 - , C D 3 7 - , CD38+, CD45+, CD56+, C D 5 7 - . In addition, these cells were positive for surface expression of the 7/6
T-cell receptor (detected by monoclonal antibody T C R Y / 5 - 1 ) ;
the monoclonal antibody a/fi WT31, which binds to the a//3
T-cell receptor, did not stain the cells. The same aberrant T-cell
phenotype was identified in a bone marrow aspirate specimen
sampled 3 days earlier.
Genomic DNA
FIG. 1. Splenic red pulp (upper) distorted by neoplastic lymphoid infiltrate. Uninvolved white pulp area (lower) adjacent to an arteriole (hematoxylin and eosin, X 400).
Analyses
Monoclonal T-cell receptor gene rearrangements were found
with probes for both the T-cell receptor -/-chain gene and the
A.J.C.P.-September 1994
ROSS ET AL.
7/6 T-Cell Posttransplantation
313
Lymphoma
°Q#5*UJJK,
SAO
FIG. 3. Neoplastic lymphocytosis, peripheral blood (Wright stain, X
1250).
T-cell receptor 0-chain gene. The 7-chain gene probe demonstrated a single nongermline band in each of the three restriction enzyme digests. The 0-chain gene probe revealed a single
nongermline band in the BamHl and Hindlll digests. Genomic probing for EBV and HHV-6 DNA was negative.
Polymerase Chain Reaction Analysis
Virus and Human
Herpesvirus-6
for
FIG. 4. Neoplastic lymphoid infiltrate in hepatic sinusoids (hematoxy| j n a n ( j e o s j n x 640)
DISCUSSION
It is estimated that fewer than 5% of human T cells express
the y/8 receptor.23 y/b T cells usually are negative for both CD4
and CD8 but frequently express natural killer cell-associated
Epstein-Barr
No EBV or HHV-6 DNA was detected by polymerase chain
reaction amplification of template DNA derived from this patient's mononuclear cells. The positive control material yielded
a polymerase chain reaction product of the appropriate size for
each virus, visualized on ethidium bromide-stained agarose
gels.
Cytogenetic
Analysis
Cytogenetic analysis of a bone marrow aspirate obtained 6
weeks before splenectomy yielded a normal male karyotype.
Analysis of peripheral blood cells sampled 3 weeks after splenectomy (white blood cell count 38.4 X 109/I_, 49% lymphocytes) revealed an abnormal clone: 45,XY, t(7;9)(pl5;ql3),
t(13ql4q). This karyotypic abnormality was found in 24 of 24
cells analyzed.
FIG. 5. Neoplastic cells, positive for CD43 (Leu22), fill hepatic sinusoids (immunoperoxidase, X 400).
Vol. 102-No. 3
314
HEMATOPATHOLOGY
Case Report
antigens. The role of this T-cell subset in humans is not well
defined, but it is believed to have immune function that is not
restricted by major histocompatibility complexes. These cells
are found throughout the human lymphoid system. Frozensection immunoperoxidase studies have shown a relatively
higher proportion of 7/5 T cells localized in the gastrointestinal
mucosa, skin, and splenic red pulp. 24
The patient described in this manuscript had a very unusual
7/5 T-cell lymphoproliferative disorder occurring in the setting
of posttransplantation immunosuppression. Morphologic classification of this neoplasm was difficult. The prominent nucleoli and the lack of cytoplasmic granules excluded the diagnosis of a large granular (T-7) lymphoproliferative disorder.
The clumped nuclear chromatin, terminal deoxynucleotidyl
transferase negativity, and lack of bone marrow involvement
argued against a diagnosis of T-cell acute lymphoblastic leukemia. T-Cell prolymphocytic leukemia was a serious diagnostic
consideration, but the immunophenotype and the lack of significant bone marrow involvement were not typical for that disease.25
Hanson and colleagues16 have described an aggressive T-cell
chronic lymphoproliferative disease characterized by hepatosplenomegaly (without lymphadenopathy), prominent splenic
red pulp infiltration, and a leukemic presentation with sinusoidal involvement of liver and lymph nodes. Neoplastic cells in
that entity expressed mature T-cell antigens (but no CD4 or
CD8), natural killer cell-associated antigens, an a//3 T-cell receptor and SI 00 protein. An association of that disorder with
HHV-6 infection has been postulated.' 6,26 Although the pattern of hepatosplenic infiltration was similar, the case reported
here had a y/d T-cell receptor, was negative for SI00 protein,
did not manifest a leukemic phase until after splenectomy, and
was negative for HHV-6 by molecular analysis of peripheral
blood mononuclear cells.
Perhaps this neoplasm is best described as a diffuse large-cell
lymphoma with predominant involvement of the splenic red
pulp and lesser infiltration of the liver. There was no associated
lymphadenopathy, and it is remarkable that peripheral blood
involvement did not become manifest until after splenectomy;
bone marrow involvement remained minimal despite an impressive peripheral blood lymphocytosis.
Gaulard and colleagues have described a subset of T-cell
lymphomas that express the 7/5 receptor and are characterized
by hepatosplenic localization.27,28 They reported five such cases
with primary involvement of the splenic red pulp, hepatic sinusoids, and, to a lesser extent, the bone marrow. 27 Lymphadenopathy was inconspicuous or absent. The tumor cells were
described as monomorphic and medium sized. The surface immunophenotype was CD2+, CD3+, C D 4 - , and C D 8 - . Three
of their five cases also expressed the natural killer cell-associated antigen CD56. Our case report extends the observations
of Gaulard and colleagues27,28 by demonstrating that the same
type of T-cell lymphoproliferative disease may occur in the
setting of posttransplantation immunosuppression. Too few of
these unusual neoplasms have been reported to draw any
meaningful conclusions about prognosis.
In immunosuppressed transplant recipients, the risk of developing non-Hodgkin's lymphomas is increased.' The majority
of these have been B-cell lymphomas, and EBV has been implicated in their pathogenesis.2 T-Cell posttransplantation lymphoproliferative disorders have been documented, 3 " 8 but they
are rare. It is noteworthy that increased numbers of y/8 T cells
have been found in the peripheral blood of renal allograft recipients, 29 but the relation of that observation to the pathogenesis
of this case is purely conjectural. Thus far, there is no evidence
to indicate that 7/5 T cells have a definitive role in allograft
acceptance or rejection.29,30
There has been only one other case report 3 of a patient with
clinical, histologic, and immunophenotypic findings similar to
our case. That patient was a 32-year-old man who had been on
an immunosuppressive regimen of azathioprine and methylprednisolone for 10 years after renal transplantation when he
developed fever, pancytopenia, and splenomegaly. A diffuse
mixed peripheral T-cell lymphoma was found in the splenic
red pulp and hepatic sinuses. The immunophenotype was
CD2+, CD3+, C D 4 - , and C D 8 - . A monoclonal rearrangement of the T-cell receptor |8-chain gene was documented, but
7/5 receptor phenotyping and genetic analysis was not done.
The clinical course was aggressive, with death within 1 year
after initial presentation. Serologic assays for human immunodeficiency virus and human T-cell lymphotropic virus-1 were
negative, as they were in our case. In addition, we found no
evidence of EBV DNA in the peripheral blood mononuclear
cells of our patient.
This patient's karyotype included a translocation involving
the centromeric regions of chromosomes 13 and 14; it was not
clear whether 14ql 1, the T-cell receptor a/5-chain locus, was
involved in this translocation. The patient also had a
t(7;9)(pl5;ql3). The breakpoint at 7pl5 is consistent with involvement of the T-cell receptor 7-chain locus; gene rearrangement of this locus was observed by Southern blot. The latter
cytogenetic abnormality, described with some frequency in
acute T-cell disorders,31 appears to be seen more rarely in the
chronic disorders. As is well documented in other T-cell disorders, a cellular oncogene may be juxtaposed with the T-cell
receptor 7 gene locus and thereby may be transcribed constitutively. This patient, like those described by Pittman and coworkers,32 had a complex, clonal cytogenetic abnormality and
aggressive disease, in contrast to patients with a normal karyotype and a more indolent clinical course.
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