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983
T g/d Hepatosplenic Lymphoma in a Heart Transplant
Patient after an Epstein–Barr Virus Positive
Lymphoproliferative Disorder
A Case Report
Madeleine D. Kraus, M.D.1
David F. Crawford, M.D., Ph.D.2
Zahid Kaleem, M.D.1
Shalini Shenoy, M.D.2
Craig A. MacArthur, M.D., Ph.D.1,2
Janina A. Longtine, M.D.3
BACKGROUND. An unusual case of a peripheral T-cell lymphoma of T g/d hepatos-
1
Department of Pathology, St. Louis Children’s
Hospital, Washington University School of Medicine, St. Louis, Missouri.
2
Department of Pediatrics, St. Louis Children’s
Hospital, Washington University School of Medicine, St. Louis, Missouri.
3
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts.
plenic type (Tg/dHSL) that arose in a child 5 years after she received a heart
transplant and 9 months after she developed Epstein-Barr virus (EBV) positive, Bcell lymphoid hyperplasia involving the tonsils is presented. The majority of the
reported cases of Tg/dHSL have been described in young adult men without antecedent immunodeficiency; several well documented cases of Tg/dHSL in the posttransplant setting have been described previously, but none has been described in
a child (or an adult) with a previously diagnosed EBV/ B-cell lymphoid hyperplasia.
METHODS. Standard histologic, immunohistochemical, flow cytometric, and molecular genetic techniques were used in the evaluation of diagnostic material.
RESULTS. The patient’s Tg/dHSL involved the spleen in a predominantly cordal
pattern, and infiltrated the liver in an exclusively sinusoidal distribution. Bone
marrow involvement was focal and interstitial. In all locations, malignant cells
were of intermediate or large size and had oval nuclei with coarse chromatin, with
a scant or moderate amount of eosinophilic cytoplasm. This Tg/dHSL expressed
the characteristic CD2/, CD3/, [CD40 CD80], Td1/ phenotype, and malignant
cells also expressed the natural killer cell marker CD56. Cytogenetic studies demonstrated isochromosome 7q with the addition of trisomy 8 as the tumor progressed.
Southern blot analysis demonstrated clonal rearrangements of the g, d, and b loci
of the T-cell receptor but did not identify EBV DNA within the tumor cells.
CONCLUSIONS. This case highlights the fact that a full range of lymphoid proliferations is possible in the posttransplantation period, and that a prior diagnosis of a
B-cell disorder does not preclude the development of a subsequent T-cell posttransplant lymphoproliferative disorder (PTLD), which should be formally evaluated, especially if clinical circumstances appear atypical for a PTLD of the ‘‘usual’’
(EBV-related, B-cell) type. Cancer 1998;82:983–92.
q 1998 American Cancer Society.
KEYWORDS: spleen, lymphoma, T-cell, transplantation, Epstein–Barr virus, g/d.
P
Address for reprints: Madeleine D. Kraus, M.D.,
Department of Pathology, (Box 8118), Washington University School of Medicine, 660 South
Euclid Avenue, St. Louis, MO 63110.
Received June 19, 1997; revision received September 19, 1997; accepted September 19, 1997.
osttransplant lymphoproliferative disorders (PTLDs) almost are
invariably of B-cell lineage, and frequently demonstrate an association with Epstein – Barr virus (EBV) infection.1 Rarely, patients with
either solid organ or bone marrow transplants develop a lymphoproliferative disorder that proves to be of T-cell lineage, and these, like
most peripheral T-cell lymphomas (PTCL), commonly are of either
T-helper (CD4/ ) or a T-cytotoxic (CD8/ ) phenotype and express
the a/b T-cell receptor heterodimer.2,3 Recently, attention has been
directed to a distinctive clinicopathologic form of PTCL that exhibits
q 1998 American Cancer Society
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the dual eccentricity of 1) a predominant hepatosplenic tissue distribution and 2) expression of the
g/d T-cell receptor heterodimer, two features that account for the designation of T g/d hepatosplenic
lymphoma (Tg/dHSL). An aggressive lymphoproliferative disorder, Tg/dHSL affects a predominantly young
adult male population, most with an intact immune
system. Occasional cases have been reported after
solid organ transplantation, though no relation with
EBV infection has yet been identified. We present a
case of Tg/dHSL arising in a child after heart transplantation, and discuss the pathogenic implications of
the immunophenotypic, cytogenetic, and molecular
profile of this disease.
Case Report
The patient, a female child, had received a heart transplant at 9 days of age for left ventricular hypoplasia,
and was found to have a 45, XO karyotype during evaluation for that condition. The surgery and the postoperative convalescence were uneventful and uncomplicated by rejection. Five years after transplant, the patient developed symptoms related to oropharyngeal
obstruction caused by a discrete left-sided tonsillar
mass, but no peripheral adenopathy or cytopenia.
Tonsillectomy was performed, the histologic features
of which included an immunoblast-rich, EBV positive
atypical lymphoid proliferation. Because of the localized nature of disease, the immunosuppressive regimen was not altered. After a 4-month asymptomatic
period, the patient developed fever, malaise, night
sweats, abdominal distension, anorexia, a diffuse maculopapular rash, and hepatosplenomegaly without peripheral adenopathy. Pancytopenia with elevated lactate dehydrogenase (LDH), uric acid, and cyclosporine
levels were noted on laboratory evaluation. An endomyocardial biopsy demonstrated ISHT Grade 1A rejection,4 and a bone marrow biopsy was remarkable for
erythrophagocytosis and an atypical lymphoid infiltrate. A liver biopsy demonstrated both actively phagocytic cells and a mild lymphoid infiltrate. Cyclosporine
and azathioprine were withdrawn and a brief trial of
corticosteroids and etoposide for presumed virus-associated hemophagocytic syndrome was initiated. Despite resolution of systemic symptomatology and pancytopenia, the organomegaly persisted and the LDH
level remained elevated. A laparoscopic splenectomy
with liver biopsy was performed for both diagnostic
and therapeutic reasons. A diagnosis of lymphoma was
made, and a repeat bone marrow biopsy demonstrated involvement. The patient was treated initially
with chemotherapy comprised of cyclophosphamide,
doxorubicin, vincristine, and prednisone with inexorable disease progression; she died 6 weeks after diagno-
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sis after intensive therapy with prednisone, doxorubicin, methotrexate, cyclophosphamide, and etoposide;
and cytarabine, bleomycin, vincristine, and methotrexate.
MATERIALS AND METHODS
Informed consent for all procedures was obtained
from the patient’s parents, who were her legal guardians. Portions of all specimens had been processed
routinely for light microscopy. The morphologic and
phenotypic criteria used for the diagnosis of EBV-related PTLDs reflect the morphologic principles articulated by Hanto et al.1 and Frizzera5 and are in accordance with recommendations of the Society for Hematopathology6; special reference to the classification
scheme proposed by Knowles et al. also is made.7
Tissue section immunophenotypic studies were
performed on paraffin embedded tissue using the avidin-biotin complex technique with microwave antigen
retrieval according to standard methods. Fresh, disaggregated cells obtained from the spleen, bone marrow,
and peripheral blood were studied via dual color flow
cytometric analysis according to standard methods
(Coulter XL-MCL Instrument, Coulter Cytometry, Hialeah, FL).
Karyotypic analysis was performed according to
standard techniques for Giemsa-banded karyotyping
of direct harvest and 24-hour cultures of bone marrow
and splenic tissue obtained at the time of diagnosis
and during the course of therapy.8 Molecular genotypic studies using standard procedure for antigen receptor gene rearrangement analysis were performed
on high molecular weight DNA extracted from splenic
tissue via Southern blot hybridization. Approximately
10 mg of DNA was digested with restriction endonucleases BamHI, Bgl II, Hind III, or XBA-I (Gibco BRL,
Gaithersburg, MD), electrophoresed in 0.8% agarose
gels, transferred to nylon membranes (Oncor Inc.,
Gaithersburg, MD), baked and hybridized with 32Plabeled probes for the joining region of the T-cell receptor-b, the first and third joining regions of T-cell
receptor-d (kindly provided by Dr. Michael Krangel,
Duke University Medical Center, Durham, NC), and
the joining region of T-cell receptor-g chains and the
terminal repeat unit of EBV, the methodology of which
has been described previously.9 – 11 After appropriate
washing, autoradiography was performed for 3 days
at minus 80 7C.
RESULTS
Macroscopic Findings
The right and left tonsils had smooth, glistening mucosa and a pale-tan cut surface with lobulations but
without distinct nodularity. The splenectomy speci-
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985
these large cells were B cells (Fig. 2A) and positive for
a marker of EBV infection, latent membrane protein
(LMP) (Fig. 2B), but not positive for the T-cell markers
CD3, CD45RO, or CD43. LMP positive cells were present in high density in the areas of diffuse effacement
(average 18/X40 field, range, 8 – 45; 20 fields counted).
Bone Marrow Biopsies
A bone marrow core biopsy performed 2 months before the splenectomy was remarkable for moderate
hypocellularity and relative erythroid hyperplasia. Also
present were erythrophagocytic histiocytes and a minor (õ10% of the overall cellularity) interstitial proliferation of small and intermediate size lymphocytes. A
bone marrow core needle biopsy performed 3 days
after splenectomy was mildly hypercellular with a relative erythroid hyperplasia, and contained increased
numbers of atypical lymphocytes. Definite localization
to the marrow sinusoids could not be discerned in the
lymphoid infiltrates in this or any of the bone marrow
biopsies. Data from flow cytometric studies are summarized and compared with phenotypic results from
other specimens in Table 1.
FIGURE 1.
Diffuse effacement of the normal architecture was present
in the tonsillectomy specimen, as was a generalized interfollicular expansion in areas with preserved germinal centers. Large, transformed
lymphoid elements, including occasional Reed-Sternberg-like forms, were
present throughout the diffusely effaced areas.
men, in large fragments after laparoscopic resection,
weighed 270 g in aggregate. The cut surface had a
homogenous, deep maroon appearance, and a soft,
nonfibrotic consistency. Malpighian corpuscles were
indistinct, and a delicate vascularity was evident on
close inspection.
Light Microscopic and Tissue Section
Immunohistochemical Findings
Tonsils
Sections of the tonsils were notable for areas of diffuse
architectural effacement (Fig. 1) as well as florid follicular hyperplasia. In diffuse areas an atypical lymphoid
infiltrate was present and was comprised of a spectrum of transformed lymphoid cells, the latter including immunoblasts and Reed-Sternberg-like cells. Plasmacytoid cells, although present, represented a minor
constituent of the overall cell population. Tissue section immunohistochemical studies demonstrated that
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Liver Biopsies
Sections of the first liver biopsy demonstrated focal
increase in the number of small lymphocytes and occasional intermediate size lymphocytes with irregular
nuclear contour within the sinusoids almost exclusively in single-file array (Fig. 3A) Neither immunoblasts nor the very large cells with lobated nuclei
such as those noted in the tonsils were observed. A
portal infiltrate was not evident, and the hepatic parenchyma was uninvolved by a primary hepatitic process. Immunohistochemical studies demonstrated reactivity for the T-cell markers CD3 and CD43 but not
for the B-cell marker CD20. In the second liver biopsy,
performed at the time of splenectomy, the hepatic sinusoids were distended by a monotony of atypical
lymphocytes, both in single file array and also in aggregates of seven to eight cells (Fig. 3B). Immunohistochemical studies performed again demonstrated reactivity for the T-cell markers CD3 and CD43 but not for
the B-cell marker CD20.
Spleen
The red pulp was markedly expanded (Fig. 4) by atypical lymphocytes that localized preferentially to the
splenic cords, although an intrasinusoidal component
was present as well. Cytologically, the malignant infiltrate was comprised of intermediate and occasional
large cells with oval to irregular nuclei, distinct
nucleoli, and scant to moderate pale-staining cytoplasm (Fig. 5). Reed-Sternberg-like cells such as those
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CANCER March 1, 1998 / Volume 82 / Number 5
FIGURE 2. (A) The large transformed lymphoid elements exhibited strong reactivity for the B-cell marker CD20. Reactivity for T-cell markers was not
identified in these cells. (B) These cells also exhibited strong reactivity for latent membrane protein, a marker of infection by Epstein–Barr virus, and
were present in increased number throughout the tonsillar tisue (Immunoperoxidase stains, avidin-biotin complex method).
TABLE 1
Immunophenotypic Data from Flow Cytometric Analysis of Bone Marrow, Blood, and Splenic Tissue from a Patient
with T g/d Hepatosplenic Lymphoma
Specimen type
Timing of
biopsy relative
to splenectomy
Percentage of gated cells expressing indicated antigen
CD2
CD3
CD4
CD8
CD5
CD7
CD20
CD3/CD56/
Td-1
Bone marrowa
Splenectomy
Bone marrow
Peripheral blood
2 months prior
0
3 days after
3 days after
35.1
92.7
91.6
97.4
27.0
81.8
70.3
79.8
8.8
0.6
4.5
6.1
5.2
2.5
7.5
6.8
12.4
0.7
0.6
0.9
16.1
45.0d
84.7
97.1
1.4
6.0
1.2
0.0
ND
85.3
71.3
77.9
ND
70.4
69.2
76.5
ND: not done.
a
Histologic features of malignancy not present.
observed in the tonsil were not present. Tissue section
immunohistochemical studies revealed that tumor
cells were reactive for the T-cell markers CD3 and
CD43 but not for CD45RO or the B-cell marker CD20.
Flow cytometric data are compared with phenotypic
results from other specimens in Table 1.
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Peripheral Blood
A peripheral blood smear obtained immediately after
splenectomy contained rare large lymphoid cells with
round or irregular nuclei, delicate chromatin, distinct
nucleoli, and pale blue-staining cytoplasm, and represented approximately 2% of the overall leukocyte pop-
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987
FIGURE 3. (A) The tumor cells that infiltrated the hepatic sinusoids were intermediate in size and had coarse chromatin and a notched nuclear contour.
(B) The second liver biopsy, performed 2 months later, contained an extensive sinusoidal infiltrate with aggregates of tumor cells distending hepatic
sinusoids (CD43, avidin-biotin complex method).
ulation. Cytoplasmic granularity was not appreciated
on this preparation. Data from flow cytometric studies
on this specimen are summarized and compared with
phenotypic results from other specimens in Table 1.
Flow Cytometric Immunophenotypic Findings
In all specimens studied tumor cells were reactive for
the T-cell markers CD2 and CD3, and exhibited an
aberrant ‘‘double-negative’’ [CD40CD80 ] phenotype
(Table 1). Surface expression of Td-1 was high in the
spleen, second bone marrow biopsy, and peripheral
blood, as was coexpression of the T-cell marker CD3
and the natural killer cell marker CD56. Expression
of CD5 was õ1% in all diagnostic specimens. CD7
expression was diminished (45%) and dim in the splenectomy specimen, but was expressed at a high level
in the second bone marrow and the peripheral blood.
A minor polytypic population of cells reactive for the
B-cell markers CD19 and CD20 also was present.
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Cytogenetic Findings
In addition to the patient’s known 45,XO karyotype,
cytogenetic analysis identified an isochromosome
7(q10) in 3 of the 13 metaphases studied from bone
marrow obtained at the time of presentation. Analysis
of involved bone marrow obtained after the initiation
of treatment and as the disease manifested resistance
to chemotherapy, demonstrated iso 7(q10) in 6 of 23
metaphases. In two of these six metaphases a derivative chromosome that involved the attachment of the
majority of the long arm of a chromosome 8 to the
short arm of chromosome 10 also was identified
[t(8; 10)(q11; p11)] an abnormality that produced a
functional partial trisomy for the long arm of chromosome 8.
DNA Analysis
Clonal rearrangements of TcR-g and TcR-b and TcRd were identified via Southern blot analysis. EBV DNA
was not detected in the extracted tumor DNA.
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FIGURE 4. The splenic architecture was distorted by a malignant infiltrate that expanded the red pulp extensively and produced a near-total
effacement of white pulp structure.
FIGURE 5. Cytologic features of this lymphoma were typical of Tg/d
hepatosplenic lymphoma: cells were intermediate to large in size and had
oval shaped nuclei with irregular contour, coarse chromatin, and moderate
pale cytoplasm. Large atypical cells reminiscent of those observed in the
tonsils are not identified.
DISCUSSION
T g/d hepatosplenic lymphoma, a rare lymphoid neoplasm even in large referral centers, is a well characterized malignancy with distinctive clinical and histopathologic features.12 Fewer than 30 fully documented
cases have been reported to date (Table 2); strictly
defined, these are not simply PTCL with documented
splenic and hepatic involvement, but rather CD2/,
CD3/ [CD40CD80] peripheral T-cell lymphoid malignancies that express the g/d rather than the more
common a/b T-cell receptor molecule.12 The neoplasm displays an exquisite but as yet unexplained
trophism for the liver and spleen until late in the disease course, with a preferential localization to hepatic
sinusoids and splenic red pulp. Peripheral adenopathy
is uncommon and hepatosplenomegaly is the sole
consistent clinical finding at presentation in immunocompetent transplant patients. Exceptional in both
childhood and the posttransplantation state, Tg/dHSL
is most common in young adults, with nearly 90% of
reported cases occurring in males. It appears to be
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a highly aggressive lymphoproliferative disorder with
inexorable clinical course and short survival in spite
of aggressive treatment with multiagent chemotherapy
protocols (Table 3).
To our knowledge, the current case of Tg/dHSL is
the first occurring in a pediatric recipient of a heart
allograft in whom an EBV positive B-cell lymphoproliferative disorder previously had developed. In the absence of fresh tissue for the documentation of clonality, the precise classification of this B-cell process is
open to interpretation, for it contains histologic features that overlap an EBV-driven lymphoproliferative
disorder and focal nonspecific tonsillitis. The discrete
asymmetric tonsillar mass formation, diffuse architectural effacement, marked cytologic atypia with ReedSternberg-like cells, and extensive expression of LMP
support a diagnosis of B-cell PTLD over an infectious
mononucleosis-like reaction6 and the lesion is best
classified morphologically as either polymorphous B-
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T g/d Hepatosplenic Lymphoma/Kraus et al.
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TABLE 2
Clinical, Molecular Genetic, and Cytogenetic Data for 24 Patients with T g/d Hepatosplenic Lymphoma for Whom Clinical Data Are Available
Demographics
Follow-up
Cytogenetics
Case
Age
(yrs)
Gender
Tx?
EBV
status
TcR rearr
Chemotherapy
1
2
3
4
5
6
30
23
32
48
45
28
m
m
m
f
m
m
no
no
no
no
no
no
nd
nd
nd
nd
nd
nd
g, d, b
g, d
g, d, b
d
b, ?d
b germline
7
32
m
renal
nd
b
8
9
10
11
12
13
14
15
8
32
15
20
65
23
19
39
m
m
m
m
m
f
m
m
no
no
no
no
no
no
no
no
nd
EBV0
EBV0
EBV0
EBV0
EBV0
EBV0
EBER0
d
g
g
g
nd
g
nd
g, b (partial)
16
17
18
19
20
21
18
25
19
21
23
29
m
m
m
m
m
m
no
no
renal
no
no
no
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
22
23
m
no
nd
nd
23
31
m
renal
EBV0
g, b
24
20
5
m
f
no
heart
nd
EBV0
d
g, d, b
CHOP
A-MACOP/BMT
AMACOP
CTX/CHL/CHOP-E
VACOP-B
CHOP/OP / MTX / L-asp/
Ara-C / Cisplt. / Dex
CHOP / ETOPO / MTX/
AraC / L-asp/INF
CTP
CHOP
Multiagent
Multiagent
Multiagent
Multiagent
2CDA/CHOP/BMT
mBACOP/Pro-MACECytaBOM
CHOP
BMT
CHOP
BMT
CHOP
Doxorubicin-containing
regimen
Doxorubicin-containing
regimen
HOP / L-asparaginase/
AraC, Mitoxantrone
MACOP-B/DICE
CHOP/ProMACE CytaBOM
Interval
(mos)
Condition
iso7
tri8
37
24
42
14
42
9
DOD
DOD
DOD
DOD
DOD
Alive
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
29
3, 23, 29, 30
3, 23, 29, 30
31
32
33
12
DOD
nd
nd
24
24
8
25
8
36
3
24
25
DOD
AWD
DOD
DOD
AWD
DOD
AWD
AWD
nd
nd
/
nd
/
nd
nd
0
nd
nd
0
nd
/
nd
nd
0
44,0Y,011,022,/mar
34, 35
36
36
36
36
36
36
13, 37
10
1
11
2
9
6
DOD
DOD
DOD
Alive
DOD
DOD
/
/
/
/
/
/
/
/
/
/
/
/
0Y
add 6q27
0Y
25
25
25
25
38, 39
38
2
AWD
/
/
3
DOD
0
0
t(7;9) and t(13;14)
26
10
1.5
AWD
DOD
/
/
0
/
0Y
XO
40
Current
study
Other
/8,/21,/psudic(13;16)
Reference
38
Tx?: transplant patient?; EBV: Epstein-Barr virus; TCR: T-cell receptor; rearr: rearrangement; iso7: isochromosome 7q; tri8: trisomy 8; m: male; f: female; nd: not done; 0: negative; CHOP: cyclophosphamide,
doxorubicin, vincristine, and prednisone; AMACOP; methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone; BMT: bone marrow transplantation; CTX: cyclophosphamide; CHL: chlorambucil; CHOPE: cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide; VACOP-B: etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; OP: vincristine, prednisone; MTX:
methotrexate; L-asp: L-asparaginase; Ara-C: cytarabine; Cisplt: cisplatin; Dex: dexamethasone; ETOPO: etoposide; INF: interferon; CTP: cytosine triphosphate; 2CDA: 2-chlorodeoxyadenosine; mBACOP: methotrexate,
cyclophosphamide, vincristine, prednisone; HOP: doxorubicin, vincristine, and prednisone; DICE: dexamethasone, doxorubicin, ifosfamide, carboplatin, etoposide; DOD: dead of disease; AWD: alive with disease;
/: positive.
TABLE 3
Summary of Clinical Data on 24 Previously Reported Cases of T g/d
Hepatosplenic Lymphoma
Mean age (yrs)
Male:female ratio:
Outcome
Dead of disease
27.8
22:2
(median, 24; range, 8–65)
16
(Mean survival, 19.6 mos;
median, 11.5 mos)
(mean follow-up, 17.5 mos;
median, 17.0 mos)
(mean follow-up, 5.5 mos;
median, 5.5 mos)
Alive with disease
6
Alive, in treatment
2
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cell hyperplasia (P-BCH) or as polymorphous B-cell
lymphoma in the terminology of Knowles et al.7; we
note that localized forms of B-cell PTLD in the oropharynx are are well represented in the literature.13 – 15
Although gene rearrangement studies were not performed on this specimen, the morphology and immunophenotype are diagnostic of a B-cell PTLD, and the
clinical outcome (lack of recurrence after resection of
the tonsillar mass) suggest that this likely represented
a P-BCH.
The clinical features that first raised suspicion that
the patient’s subsequent pancytopenia and hepatosplenomegaly related to something other than a B-cell
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lymphoproliferative disorder included 1) the absence
of appreciable peripheral adenopathy in the presence
of a deteriorating clinical course; 2) the intrasinusoidal
aggregation of cytologically atypical T-lymphocytes in
the first liver biopsy, and 3) the presence of actively
phagocytic macrophages in both initial bone marrow
and liver biopsies. This latter finding in particular
prompted consideration of a virus-associated hemophagocytic syndrome, a diagnostic consideration
whose definitive exclusion required splenectomy. Immunophenotypic studies on the splenectomy specimen were decisive in the subtyping of this PTCL, for
this tumor expressed the g/d T-cell receptor heterodimer and manifested a CD2/, CD3/, CD56/,
[CD40CD80] ‘‘double negative’’ profile rather than
the typical a/b/, [CD4/CD80], or [CD40CD8/] phenotype associated with most PTCL, including those
that arise in the posttransplant setting.16 – 20
In view of the high mortality rate of this
lymphoma, early diagnosis is a cornerstone to optimal
outcome. However, subtle involvement of a liver core
biopsy by Tg/dHSL (as exemplified by the first biopsy
in this case) may simulate the lymphoid infiltrate observed in association with the acute hepatitis of cytomegalovirus and EBV infection.21,22 Limited bone marrow involvement by this special type of lymphoma
may be difficult to detect because, as this case illustrates, bone marrow involvement is not necessarily
heralded by a distinctively sinusoidal pattern of localization,23 even when involvement is overt. Consequently, early diagnosis of Tg/dHSL via bone marrow
biopsy is unlikely to be possible on morphologic
grounds alone in a bone marrow specimen, and a specific diagnosis based on flow cytometric analysis of
aspirated bone marrow would require prescience in
the selection of a panel of antibodies weighted toward
the unlikely possibility of a g/d-expressing T-cell
lymphoma. Based on experience from this case as well
as the experience recorded in other reports, it would
appear that (in the absence of splenectomy) careful
examination of a liver biopsy may provide the most
useful clue to suggest a specific diagnosis of Tg/dHSL
over a lymphoproliferative disorder of another sort,
particularly if specialized flow cytometric panels are
not available.
The absence of clonal EBV genome in this tumor
provided a strong argument against a direct relationship between this patient’s lymphoma and the antecedent B-cell PTLD, and supports the notion that Tcell PTLD may arise by other means. Cytogenetic studies may be informative in this regard because in addition to the case in the current study, 10 of the 12
previously karyotyped Tg/dHSL contained isochromosome 7q, a finding that lends credence to the percep-
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tion that the distinctive clinical and histopathologic
features of Tg/dHSL reflect a specific biologic abnormality. This translocation is associated with the loss
of one T-cell receptor-g allele (normally located at
7p15) and the duplication of one T-cell receptor-b allele (at 7q35); the implications of these genetic
changes are unclear.
The curious predilection of this tumor for males
has yet to be explained. The current case, which to
our knowledge is the first Tg/dHSL in a female patient
to be karyotyped, perhaps is notable because it arose
in a child with a previously documented 45,XO karyotype. The functional partial trisomy 8 identified in this
patient’s neoplastic cells as the disease progressed is
an interesting evolution of karyotype that has been
observed in 8 of the 12 previously karyotyped cases of
Tg/dHSL. In three of these eight patients trisomy 8
was not identified in karyotypes performed at diagnosis, but, like in the the patient presented in this report,
developed subsequently during treatment. Although
both isochromosome 7q and trisomy 8 have been described separately in a diverse array of hematolymphoid and solid tumor neoplasms, their occurrence
together in the same tumor appears to be unique to
Tg/dHSL during disease progression through chemotherapy. In the case described here, the functional trisomy involved only a portion of the long arm of chromosome 8, a finding that focuses attention on the role
that duplicated loci from this particular portion of
chromosome 8 may play in the evolution of this type
of lymphoma.
With only a few Tg/dHSL fully described in the
literature, it is notable that, including the current case,
four arose subsequent to solid organ transplantation,24 – 26 such an association lends itself to speculation
that the chronic antigenic stimulation and immunosuppression of these patients may unmask T-cell
clones with a selective proliferative advantage. Such
cells, if of the g/d subset, would be expected to home
preferentially to tissues normally enriched in this Tcell subtype, such as the spleen.27 In this light, it is
particularly interesting to note reports of the disproportionate representation of the g/d subset of benign
T cells in the peripheral blood of some transplant patients being studied for graft versus host disease.28
The histologic, phenotypic, genotypic, and karyotypic features of the case in the current study are characteristic of Tg/dHSL. However, its occurrence in the
posttransplant setting after the development of an
EBV-related B-cell PTLD is unusual and merits recognition not only to draw attention to Tg/dHSL in childhood, but also to underscore the importance of rebiopsy and rephenotyping tissue from patients with
EBV-related B-cell lymphoid proliferations when the
W: Cancer
T g/d Hepatosplenic Lymphoma/Kraus et al.
subsequent clinical course appears unusual for that
disorder. Although the precise mechanism of lymphomagensis for Tg/dHSL is not yet apparent, a heightened awareness of its morphology and phenotype will
facilitate further advances in this area.
16.
17.
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