Primary spleen extranodal NK/T cell lymphoma, nasal type, with bone marrow involvement and CD30 positive expression: a case report and literature review
Primary spleen extranodal NK/T cell lymphoma, nasal type, with bone marrow involvement and CD30 positive expression: a case report and literature review
Qinghua Cao 0
Yan Huang 1
Ziyin Ye 0
Ni Liu 0
Shuhua Li 0
Tingsheng Peng 0
0 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University , 58, Zhongshan Road II, Guangzhou 510080 , China
1 Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University , 26, Yuancun Erheng Road, Guangzhou 510655 , China
Aims: Primay spleen NK/T cell lymphoma is very rare. We report a case of 39-years-old male of primary splenic NK/T cell lymphoma with bone marrow involvement and CD30 positive expression. Case description: The patient had high fever for 2 months, and CT scan revealed a diffuse splenomegaly without hepatomegaly. The diagnosis was established by splenectomy specimen and bone marrow biopsy. Normal spleen structure was destroyed by the diffusely infiltrated neoplastic cells, and one of the splenic hilar lymph nodes was involved. The lymphomatous cells were mainly medium-sized, mixed with small and large cells with pleomorphic nuclei and conspicuous nucleoli. Angiocentric growth pattern was present, with mitotic figures and apoptotic bodies easily being found. These neoplastic cells demonstrated a typical immunophenotype of CD2, CD3, CD7, CD4, CD56, TIA-1, Granzyme B, CD30 positive, and CD5, CD8, CD20, CD79a negative. The Epstein-Barr virus encoded RNAs (EBERs) genomes were also found in tumor cells by in situ hybridization, while no clonal rearrangement of the T cell receptor- genes (TCRG) was found. Biopsy of bone marrow revealed scattered atypical cells presented with a predominantly intrasinusoidal distribution. A diagnosis as primary spleen NK/T cell lymphoma, nasal type (ENKTL) with CD30 expression and bone marrow involvement was finally made. The patient received chemotherapy and was still alive 6 months after splenectomy. Clinical significance: Primary spleen ENKTL is very rare, it should be made with the combination of clinical feature, PET-CT image, and pathological characteristics, and should be distinguished from other lymphomas or leukemia involved in spleen. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/ vs/13000_2014_169 2014 Cao et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Extranodal NK/T cell lymphoma, nasal type, is an
uncommon tumor that occurs with a higher prevalence among
Asians, and the native American population of Mexico,
Central America and South America . It is well known
as an aggressive tumor that is characterized by angiocentric
and angiodestructive growth pattern, coagulative necrosis
mixed with apoptotic bodies, cytotoxic phenotyhpe, and
associated with Epstein-Barr Virus (EBV). The most
common site of involvement is upper aerodigestive tract (nasal
cavity, nasopharynx, paranasal sinuses, palate). Preferential
sites of extranasal involvement include the skin, soft
tissue, gastrointestinal tract, and testis [1-3]. Rare sites
of involvement such as prostate , pancreas  and
adrenal glands  have been reported. Primary spleen
NK/T cell lymphoma is very rare. Herein, we report a
case of primary spleen extranodal NK/T cell lymphoma,
nasal type, with bone marrow involvement and CD30
A 39-year-old man presented a 2-month history of
discontinuous fever peaked up to 39C without obvious cause,
and no response to antibiotic. An ultrasonography and a
computed tomography (CT) showed a diffuse splenomegaly
without a concrete mass, and lymphadenopathy and
hepatomegaly was not detected. FDG PET/CT scan showed
significant splenomegaly (long arrow) and hepatic portal
lymphadenopathy (short arrow) with increased FDG
metabolism (Figure 1). The SUV value reached 7.2 and
2.8 respectively. He denied symptoms of cough,
expectoration, erythrism and abdominal pain. Endoscope failed to
find lesion in nasal cavity.
Laboratory data showed a leukocyte count of 3.63
109/L, haemoglobin 160 g/L, platelet count 208 109/L
after admission. Bone marrow smear found 2% atypical
cells, which was not detected in peripheral blood smear.
Unfortunately, the count of platelet decreased quickly to
20 109/L within ten days, strongly indicating that the
patient had suffered from a highly aggressive tumor in
the bone marrow.
Bone marrow biopsy specimen was obtained firstly. A
few large atypical cells with T cell immunophenotype were
found with intrasinusoidal distributive manner, which
provide the clue of the possibility for bone marrow
involvement of T/NK tumor cells. For the purpose as diagnostic
therapy, the patient received spenoectomy. As the final
pathologic diagnosis was spenic NK/T cell lymphoma,
nasal type, the patient received five circle chemotherapy
afterwards. The patient is alive without recurrence
6 months after the splenectomy.
Material and methods
The specimen was fixed in a 10% neutral formalin solution
and embedded in paraffin. Four micrometer-thick sections
were prepared and stained with hematoxylin-eosin. An
Envision two-step assay was used for the
immunohistochemistry staining. Commercially available monoclonal
antibodies were employed CD20 (Mouse mAb(L26);1:200),
Figure 1 PET-CT images: FDG PET/CT scan showed the patient had marked splenomegaly (long arrow) and hepatic portal
lymphadenopathy (short arrow) with increased FDG metabolism. The SUV value of the spleen reached 7.2, and that of the hepatic portal
lymph node was 2.8, respectively.
CD79a (Mouse mAb (JCB117);1:200), CD2 (Mouse mAb
(AB75);1:200), CD3 (Mouse mAb (F7.2.38);1:200), CD5
(Mouse mAb(CD5/54/F6);1:200), CD7 (Mouse mAb
(CBC.37);1:200), CD4 (Mouse mAb(4B12);1:200), CD8
(Mouse mAb(C8/144B);1:200), CD56 (Mouse mAb
(123C3);1:200), Granzyme B (Mouse mAb(GrB-7);1:200),
CD30 (Mouse mAb(Ber-H2);1:200), ALK (Mouse mAb
(ALK1);1:200), MPO(Rabbit pAb;1:200),Ki-67 (Mouse
mAb(MIB-1);1:200). All the above primary antibodies
and HRP-conjugated secondary antibodies were obtained
from DAKO Inc., Denmark. The primary antibodies of
TdT(Mouse mAb(SEIV28);1:200), TIA-1(Mouse mAb
(2G9A10F5);1:200) were from Zhongshan company. The
primary antibody of CD123(Mouse mAb(BR4MS);1:400)
was from Novocastra.
In situ hybridization (ISH) with Epstein-Barr virus
(EBV)-encoded small RNA (EBER) oligonucleotides was
performed to test the specimens for the presence of EBV
small RNA in formalin-fixed, paraffin-embedded sections
using a hybridization kit (DAKO).
For cytogenetic analysis, the paraffin tissue DNA was
prepared with a tissue DNA extraction and purification
kit (Dneasy TM Tissue Kit, Qiagene, CA). T-cell receptor
rearrangement studies were performed. The detection
process was conducted by methods described previously .
Grossly, the splenectomy specimen measured 18 cm
15 cm 10 cm. Surface and cut surface showed diffuse
graywish crimson without nodules. Hemorrhage and
necrosis were absent (Figure 2).
Microscopically, the structure of normal spleen white
pulp and red pulp was destroyed by the diffusely infiltrated
neoplastic cells. The lymphomatous cells were mainly
Figure 2 Macroscopic appearance of the significantly enlarged
18 cm 15 cm 10 cm spleen. Surface and cut surface showed
diffuse graywish crimson without nodules.
medium-sized, mixed with small and large cells, containing
moderate pale cytoplasm. Most of them had irregular
folded hyperchromatin nuclei and small inconspicuous
nucleoli, while the large tumor cells had vesicular pleomorphic
nuclei and conspicuous nucleoli (Figure 3A, 3B). Mitotic
figures and apoptotic bodies were easily found. The tumor
cells were accompanied with an admixture of inflammatory
cells as small lymphocytes, plasma cells, and so forth. Many
splenic arteries were infiltrated and destroyed by the
neoplastic cells (Figure 3C), and geographic coagulative
necrosis were also observed. Hemophagocytosis could be found
throughout the tumor. The section from the peripheral
spleen remained the structure of white pulp and red pulp
with expanded sinuses. Neoplastic cells were also found in
the cords and sinuses of the expanded red pulp, as well as
around splenic arteriolar sheath.
Immunohistochemically, the neoplastic cells were CD2+
(Figure 3D), CD3 + (Figure 3E), CD7+, CD56+ (Figure 3F),
CD4+ (Figure 3G), Granzyme B+, TIA-1+, CD20-, CD79a-,
CD5-, CD8- (Figure 3H), ALK-, TdT-, MPO-, and CD123-.
Specially, most of the neoplastic cells were CD30 positive
(Figure 3I). The proliferation index was approximately 90%,
assessed by Ki-67 staining. In situ hybridization (ISH)
for EBERs study showed strong positive signals in most
of the abnormal large and giant cells (Figure 3J). Based
on these results, the diagnosis as spleen exnodular NK/
T cell lymphoma, nasal type, with CD30 expression was
made. No clonal rearrangement of the T cell receptor
gamma (TCRG) genes was found in the lesion by
Polymerase Chain Reaction heteroduplex analysis (PCR-HA)
and polyacrylamide gel electrophoresis (PAGE).
In addition, five splenic hilar lymph nodes from 0.3 cm to
0.5 cm and one hepatic portal lymph node as 2.8 cm were
detected. One of the splenic hilar lymph nodes was involved
by the lymphomatous cells with morphology and size
similar to which infiltrated into the spleen, while there was
lymphoid tissue hyperplasia rather than tumor involvement
in the hepatic portal lymph node. The microscopic findings
of the bone marrow biopsy revealed scattered atypical cells
presented with a predominantly intrasinusoidal distribution.
The atypical cells were also medium to large sized, with
pale cytoplasm and pleomorphic irregularly folded nuclei
(Figure 3K). The scattered atypical cells were stained
immunohistochemically as CD2, cytoplasmic CD3, CD7, CD56
(Figure 3L), CD30 positive, while CD5, CD20, CD79a,
MPO negative. At the same time, EBERs signals were
detected in nuclei of the atypical cells. Based on these
morphological and immunohistochemical features, it was
considered that the bone marrow was involved by the
lymphomatous cells of the spleen ENKTL.
Figure 3 Microscopic features of the spleen tumor and the bone marrow with immunohistochemical and in situ hybridization staining.
(A) The structure of spleen white and red pulp was destroyed by the diffusely infiltrating neoplastic cells (HE 100), (B) The size of the neoplastic cells
were from medium to large with irregular pleomorphic hyperchromatin nuclei and conspicuous nucleoli. Giant tumor cells and apoptotic bodies were
easily observed (HE 200); (C) A splenic artery was infiltrated and destroyed by the lymphomatous cells (HE 40); Tumor cells were postitive for CD2
(D), CD3 (E), CD56 (F), CD4 (G), CD8 (H), and CD30 (I) (Envision 100); (J) Tumor cells were positive for EBERs by in situ hybridization; (K) Bone
marrow biopsy showed scattered medium-sized tumor cells(arrow) (HE 100); (L) Tumor cells of bone marrow were positive for CD56 (Envision 100).
involvement of only the spleen and splenic hilum. PSL is
very rare, which is much less common than the secondary
involvement of spleen, accounting for less than 1% of all
lymphomas . PSL usually represents non-Hodgkin
lymphoma of B cell origin. Shimizu-Kohno K et al.
classified 184 specimens of the spleen, 115 were determined
to be lymphoid neoplasm (62.5%). The most common
subtype of lymphoid neoplasm was diffuse large B-cell
lymphoma (DLBCL) (46 cases), followed by splenic
marginal zone lymphoma (SMZL) (28 cases), follicular
lymphoma (FL) (11 cases), splenic B-cell lymphoma,
unclassifiable (SBL-U) (6 cases) and peripheral T-cell
lymphoma, not otherwise specified (4 cases, nearly 3.5%)
. Hence, T/NK cell lymphoma primarily occurring in
spleen is very rare. To our knowledge, this is the first
reported case of a primary spleen extranodal NK/T-cell
lymphoma, nasal type. The symptoms of the patient were
fever, hypocytosis, and splenomegaly, without
hepatomegaly and peripheral lymphadenopathy. The neoplastic cells
destroyed normal spleen structure, showed typical
angiocentric and angiodestructive growth pattern, notable
atypical cell morphology, a typical immunophenotype
expression of CD56, CD2, CD3, and EBERs positive
detection with ISH. Additionally, One of the splenic
hilar lymph nodes was involved by the lymphomatous
cells similar to which infiltrated into the spleen. In this
manner, the primary extranodal NK/T cell lymphoma of
spleen was confirmed. The bone marrow biopsy revealed
scattered atypical cells with NK/T cell immunophenotype
and EBERs signals, which highlight the diagnosis as the
spleen ENKTL with bone marrow involvement.
The cell morphology of ENKTL is variety. Most cases
comprise middle cells mixed a few small- and large-sized
cells, and usually do not have nucleoli. In this case the
tumor was composed of small to large or anaplastic cells
containing several nucleoli. This tissue change may
indicate a poor prognosis . And CD30, an important
marker for Hodgkins lymphoma and Anaplastic large
cell lymphoma, is not rarely expressed in ENKTL, which
is usually focal and not so intense. Moreover, it was
speculated that ENKTL with large cells were prone to
express CD30 and indicate a worse prognosis [4,11,12].
On the other hand, there were inverse views as that
ENKTL patients with CD30 expression even tended to
have more favorable outcome , or there was no
difference of survival according to CD30 expression . As for
the diverse outcome, further study with large number of
patients should be performed to evaluated the prognostic
value of CD30 expression in NK/T-cell lymphoma. Since
there were many CD30 postive lymphomatous cells in this
case, the target therapy with Brentuximab (anti-CD30
antibody) might be useful for the clinical trial .
ENKTL should be distinguished from other lymphomas
or leukemia involved in spleen. Except for the notable
atypical cell morphology, ENKTL neoplastic cells have
typical immunophenotype expression as CD56, CD2,
CD3, but usually CD5 negative, and exceptionally CD20
positive . Epstein-Barr virus (EBV) expression is one
of the most important factors, and it has been proved that
latent membrane protein (LMP) 1 and LMP2A encoded
by EBV are also associated with prognostic indicators of
survival in patients with ENKTL .
The most important differential diagnosis is Aggressive
NK-cell leukemia (ANKL), which has been described in
a case with jaundice and spontaneous splenic rupture by
Gao et al.  recently. The immunophenotype of ANKL
is identical to that of ENKTL neoplastic cells, and ANKL
has been suggested to represent the leukaemic
manifestation of ENKTL . But ANKL has a younger median age
by more than a decade, and high frequency of
hepatosplenic and BM involvement, tumor cells have monomorphic
and medium size with irregular nuclei. A fulminant
clinical course frequently complicated by multi-organ failure,
coagulopathy and haemophagocytic syndrome, and the
median survival is less than 2 months. In this case, the
patient had only splenomegaly without hepatomegaly,
the morphology of neoplastic cells were various, and
only a few tumor cells had involved the bone marrow. The
clinical course also supported the diagnosis as ENKTL
because the patient were still alive for 6 month after the
splenectomy and chemotherapy. According to WHO
(2008 version), other disorders of NK cell system as Blastic
NK-cell lymphoma (BNKL) is also named as Blastic
plasmacytoid dendritic cell neoplasm. While actually, there
are still difference between real NK-cell lymphoma and
Blastic plasmacytoid dendritic cell neoplasm, because of the
morphology of the tumor cells, the sites of involvement,
the immunophonotype and association with EBV .
Hepatosplenic T-cell lymphoma (HSTL) is another rare
T-cell lymphoma needing to be distinguished. HSTL cells
usually derive from a functionally immature cytotoxic
T cell,and usually occurs in adolescents and young adults
(68%) . Patients initially present with fever, fatigue,
weight loss, and abdominal discomfort due to
splenomegaly and hepatomegaly. The neoplastic cells involve the
cords and sinuses of the splenic red pulp, with a reduction
or complete atrophy of the white pulp. Hepatomegaly can
be found in approximately 50% of the patients, and the
liver also shows a predominant sinusoidal infiltration.
The cells of HSTL are monotonous, with medium-sized
nuclei and a rim of pale cytoplasm. The neoplastic cells
are CD3+, and usually TCR1+, TCR-, CD56+/,
CD4-,CD8/+,TIA-1+,GranzymeB-, and EBV is generally
negative. Cases of origin show a biallelic rearrangement
of TRG genes, and TRB genes are arranged in cases
. In this case, all of the features including the tumor
morphology, immunophenotype, EBERs positive
expression, and TCRG negatively rearrangement did not support
the diagnosis as HSTL.
Since some of the tumor cells were large and anaplastic
with CD30 positive staining, Anaplastic large cell
lymphoma (ALCL) should also be distinguished. All cases of
ALCL contain a variable proportion of hallmark cells
with eccentric, horseshoe- or kidney-shaped nuclei often
with an eosinophilic region near the nucleus. The tumor
cells are positive for CD30 on the cell membrane and in
the Golgi region, and usually ALK positive. ALCL are
also consistently negative for EBV (EBER or LMP1) .
In this case, the morphology of the neoplastic cell were
different from ALCL, and the tumor cells were
ALKand EBER+. Hence, the diagnosis of ALCL in spleen
should be excluded.
Spleen and peripheral lymph nodes can also be affected
by Peripheral T-cell lymphoma, NOS (PTCL,NOS). The
PTCL neoplastic cells are medium-sized and/or large cells
with irregular, pleomorphic, hyperchromatic or vesicular
nuclei, prominent nucleoli and many mitotic figures. The
lymphomatous cells are usually T-cell phenotype positive
with downregulation of CD5 and CD7, TCR F1 positive
and EBV negative. PTCL, NOS is a diagnosis with the
exclusion of other specific T/NK cell lymphoma . In
this case, the tumor cells morphology, immunophenotype
and EBER positive improve the diagnosis as an ENKTL.
The rearrangement TCR genes is an important
supplement to the diagnosis of T-cell non-Hodgkin lymphoma.
TCR genes are clonally rearranged in most cases of
PTCL, NOS , while only a small proportion of ENKTL
show clonal rearrangement [21,22]. According to all of the
characteristics of the tumors morphology,
immunophenotype, EBERs ISH, and TCR rearrangement in this case,
other type of lymphomas as Hodgkin lymphoma (HL) and
diffuse large B cell lymphoma (DLBCL) could be ruled out
from the differential diagnosis.
The case reported a rare primary NK/T cell lymphoma
in spleen. As spleen can be involved by other types of
lymphomas, the final diagnosis should be made with the
combination of clinical feature, PET-CT image, pathological
morphology, immunophenotype, and genetic features. The
prognosis of those tumors comprised of big cells with
CD30 positive expression are quite unclear. As agrressive
NK cell leukemia shared similar morphology and
immunophenotype features with ENKTL, sites of involvement and
clinical course may serve as important clues to make the
distinction between them.
Written informed consent was obtained from the patient
for publication of this Case Report and any accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
PSL: Primary spleen lymphoma; ANCL: Aggressive NK cell leukemia;
ALCL: Anaplastic large-cell lymphomas; HL: Hodgkin lymphoma;
DLBCL: Diffuse large B cell lymphoma; SMZL: Splenic marginal zone
lymphoma; FL: Follicular lymphoma.
QC participated in pathological investigations, drafted the manuscript and
performed the literature review; YH carried out pathological examination and
collected the patients clinical information; ZY participated in pathological
investigations and helped to draft the manuscript. NL carried out the
immunohistochemical staining; SL carried out the FISH staining; TP gave and
reviewed the final histopathological diagnosis, and revised the manuscript.
All authors have read and approved the final manuscript.
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