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Federico
Perfetto, Roberto Tarquini, Francesco Mancuso, Giacomo Laffi,
Department of Internal Medicine, University of Florence, Italy
Simonetta di Lollo, Silvia Tozzini, Department of Human Pathology
and Oncology, University of Florence, Italy
Giampiero Bellesi, Department of Hematology, University of Florence,
Italy
Correspondence to: Professor Giacomo Laffi, Department of
Internal Medicine, University of Florence, Viale Pieraccini, 18, Zip
Code 50139 Firenze, Italy. g.laffi@mednuc2.dfc.unifi.it
Telephone: +39-55-4223549
Fax: +39-55-4223549
Received: 2002-10-10
Accepted: 2002-11-04
Abstract
We reported a case of non-Hodgkin's
lymphoma where liver involvement
was the predominant clinical manifestation. A 27-year old man
presented wiht markedly elevated serum aspartate aminotrasferase,
alanine aminotransferase and lactate dehydrogenase, reduced
prothrombin activity, thrombocytopenic purpura and
hepato-splenomegaly without adenopathy. Viral, toxic, autoimmune and
metabolic liver diseases were excluded. Bone marrow biopsy showed an
intracapillary infiltration of T-lymphocytes with no evidence of
lipid storage disease. Because of a progressive spleen enlargement,
splenectomy was performed. Histological examination showed
lymphomatous intrasinuses invasion of the spleen.
Immunohistochemical investigation revealed the T phenotype of the
neoplastic cells: CD45+, CD45RO+, CD3+, CD4-, CD8-, TIA1-. About 50
% of the lymphoid cells expressed CD56 antigen. The diagnosis of
hepatosplenic T cell lymphoma was done. The patient was treated with
chemotherapy, which induced a complete remission.
Eighteen months later, he had a first relapse with increased
aspartate aminotransferase, alanine aminotransferase, lactate
dehydrogenase, thrombocytopenic purpura and blast in the peripheral
blood. In spite of autologous bone marrow transplantation, he died
twenty months after the diagnosis. Even in the absence of a mass
lesion or lymphoadenopathy, hepatosplenic T-cell lymphoma should be
considered in the differential diagnosis of a patient whose clinical
course is atypical for acute hepatic dysfunction.
Perfetto
F, Tarquini R, Mancuso F, di Lollo S, Tozzini S, Bellesi G, Laffi G.
Hepato-splenic lymphoma: a rare entity mimicking acute hepatitis: A
case report. World J Gastroenterol
2003; 9(6): 1381-1384
http://www.wjgnet.com/1007-9327/9/1381.asp
INTRODUCTION
Liver and splenic involvement is commonly seen during a
malignant lymphoma, but rarely occurs as a prominent clinical
feature at diagnosis. Hepatosplenic lymphoma is a rare and poorly
recognized entity[1] characterized by neoplastic
proliferation of T-cell bearing a gd or, more rarely, ab clonal
rearrangement of the receptor (TCR). This lymphoma shows a specific
morphological pattern characterized by a preferential hepatic
sinusoids and splenic red pulp involvement without lymphoadenopathy
and discrete or absent bone marrow involvement. Moreover the
diagnosis is complicated in several cases by the presence of
misleading symptoms. We reported the case of a young man without
palpable lymphoadenopathy and clinical and laboratory presentations
resembling an acute liver disease.
CASE
REPORT
A 27-year old caucasian man was admitted in an Internal Medicine
unit in February 1999 because of fever (38 °C), malaise, anorexia, and erythematous macules and papules on the
face, trunk and arms. The patient referred similar but transient
cutaneous lesions in the previous two-months. Laboratory
investigations yielded the following results: aspartate
aminotransferase (AST) 240 IU/L (normal range: 0-37 IU/L), alanine
aminotransferase (ALT) 520 IU/L (normal range: 0-40 IU/L), g-glutamyl-transpeptidase (g-GT) 46 IU/L (normal range: 11-43 IU/L), alkaline phosphatase
(ALP) 298 IU/L (normal range: 60-270 IU/L) and platelets 120109 /L
(normal range: 130-400109/L). Serological tests for Ebstein Barr
virus (EBV) showed a positivity for nuclear antigen (IgG 248 ACU/ml)
(normal value: <56 ACU/ml) whereas serology for hepatitis A (HAV),
hepatitis B (HBV) and hepatitis C (HCV) viruses was negative.
Physical examination showed a mild hepato-splenomegaly. There was no
palpable lymphoadenopathy.
Two
weeks later he was transferred to our Internal Medicine unit with
the clinical diagnosis of "acute
hepatitis with hepato-splenomegaly and recidivant purpuric
exanthema". Physical examinations showed an enlarged tender
liver (2 cm below the rib border) and splenomegaly (2 cm below the
rib border) without peripheral lymphoadenopathy. The cutaneous
lesions of the trunk and the face were already present as purpuric
palpable papules. Fever was absent. Abdominal ultrasonography
revealed a mild hepatomegaly and splenomegaly (major axis of 18 cm),
without ascite and abdominal lymphoadenomegaly. Doppler sonography
revealed an increased blood flow in the spleen and the portal vein
without obstruction of the main hepatic veins. An upper
gastrointestinal endoscopy did not reveal esophageal varices. Chest
x-rays at the time of admission yielded normal findings. Liver
function test showed AST 498 IU/L, ALT 958 IU/L, g-GT 49 IU/L, ALP 426 IU/L, total bilirubin 1.15 mg/dl (normal
range: 0.2-1.0 mg/dl) and lactate dehydrogenase (LDH) 1 234 U/L
(normal range 190-450 IU/L). Peripheral blood counts showed
hemoglobin 16.1 g/dl, hematocrit 45 %, leukocytes 4.9×109 /L with normal
differential count and platelets 80×109/L. Coagulation indices
showed prothrombin activity 53 % (normal range: 90-100 %),
international normal ratio 1.4, activated partial thromboplastin
time 53 sec (normal range: 25-40 sec) and fibrinogen 267 mg/dl
(normal range: 200-400 mg/dl). Albumin levels were 4.25 g/dl (normal
range: 3.3-5.1 g/dl) and g-globulin were 1.44 g/dl (normal range: 0.84-1.44 g/dl).
Serological tests were negative for HAV, HBV, HCV, cytomegalovirus
and human herpes simplex N 1, 2, and 6. EBV serologic findings were
heterophile test (heterophile antibody) negative, viral capsid
antigen (VCA) immunoglobulin IgM negative and IgG positive.
Serological tests exploring infective agents able to induce an acute
hepatitis such as Chlamydia pneumoniae, Bartonella spp, Borrelia
Burgdorferi, Toxoplasma Gondii, Coxsackie virus groups A and B
(N1-6) and Echovirus, were negative as well as the serological test
for Rickettsie and Parvovirus B19. Results of serology for human
immunodeficient virus (HIV) 1 and 2 including cDNA Polymerase Chain
Reaction and the screening of the antigen p24 of HIV1 were negative.
Serum g-fetoprotein and carcinoembryonic antigens were within the normal
range. To exclude autoimmune disease, serological tests for
anti-nuclear, anti-mitochondrial, anti-liver/kidney microsomial (LKM),
and anti-smooth muscle (ASM) were performed but the results were
negative; cryoglobulins and circulating immune complexes were
absent. Serum ceruloplasmine levels, circulating serum copper
levels, 24-h urine excretion of copper and a
1-antitrypsin levels were in the normal range and Kayser Fleischer
rings were absent on slit-lamp examination. To exclude a
thrombocytopenia induced by EDTA (pseudothrombocytopenia) blood was
drawn on test tube with sodium citrate as anticoagulant but the
result confirmed the presence of a true thrombocytopenia.
Anti-platelet antibodies were negative in two consecutive different
samples and reticulate platelets were in the normal range. Toxic
(including also ingestion of hepatotoxic mushrooms such as Amanita
Phalloides) and drugs inducing hepatitis were excluded by a careful
and detailed personal and family history. During the following
weeks, patient complained increasing fatigue and tenderness in the
upper left quadrant and physical examination revealed an enlarged
spleen that extended his lower pole 4-cm below the rib border. Liver
function tests continued to rise with AST 658 IU/L, ALT 1 074 IU/L, g-GT 72 IU/L, ALP 473 IU/L, and LDH 1 365 U/L. Serum b-2 microglobulin levels were 2.4 mg/dl; (normal range: 1.2-2.5
mg/dl). Coagulation indices showed prothrombin activity 51 %,
international normal ratio 1.4, fibrinogen 146 mg/dl and activated
partial thromboplastin time 42.4 sec without serological evidence of
circulating anticoagulants such as lupus anticoagulant or
anticardiolipin antibodies. A decreased activity of coagulation
factor II (57 %; normal range: 70-120 %), VII (58 %; normal range:
70-120 %) and X (41 %; normal range: 70-120 %) were also
demonstrated, despite i.v. Vitamin K treatment; factor VIII activity
was also reduced (63.9 %; normal range: 70-150). The bleeding time
was slightly prolonged (8 minutes and 20 seconds; normal range: 3-7
min.) Because of coagulopathy and thrombocytopenia percutaneous
liver biopsy was not performed. Biopsy of the skin showed neither
vasculitis findings nor lymphoproliferative disease. An abdominal CT
scan revealed a massive enlargement of the spleen (20 cm of sagittal
diameter and 14 cm of antero-posterior diameter) and mild
hepatomegaly without either focal lesions or abdominal
lymphoadenomegaly. Thorax and neck CT scan yielded normal findings.
Although in type 1 Gaucher disease the liver function tests were not
so seriously altered, the presence of hepatomegaly with a
progressive and massive splenomegaly together with thrombocytopenia
prompted us to undergo the patient to bone morrow examination and to
a measurement of acid b-glucosidase activity in circulating leukocyte cells. Although b-glucosidase activity was slightly decreased (5.5 nmol/mg/h;
normal range: 8-15.1 nmol/mg/h), the bone marrow examination did not
reveal the presence of the characteristics of Gaucher cells with the
typical "wrinkled
paper" cytoplasm. However, an intracapillary T-lymphocytes
infiltration was observed. The circulating leukocytes were 14.6109/L
(normal range: 4.8-8.5) with absolute lymphocytosis (8.8×109/L, normal range:
1.6-2.4). Immunophenotype of circulating lymphocytes showed that CD3
positive lymphocytes were about 5.4×109/L (normal range:
1.1-1.7), CD4 positive lymphocytes were 2.5×109/L (normal range:
0.65-1.4), CD8 positive lymphocytes were 3.01×109/L (normal range:
0.32-0.90) with CD4 to CD8 ratio of 0.8 % (normal range: 1-1.5 %)
and CD19 positive lymphocytes were 1.23109/L (normal range:
0.2-0.4). Circulating T lymphocytes (65 % of overall; 5.65×109/L) bearing the ab type of
TCR were 92.5 % (normal range: 90-95 %) while circulating T
lymphocytes bearing gd TCR were about 7.5 % (normal range: 5-10 %).
Over half (60 %) of circulating leukocytes were small to
medium sized lymphoid cell with moderate amount of pale, agranular
cytoplasm without villous projections. Some lymphocytes showed round
or folding nucleus, with moderate clumped chromatin surrounding a
small nucleolus. In spite of the opportunity to perform a
transjugular liver biopsy, the presence of massive splenomegaly with
pain in the left upper abdominal quadrant and early satiety, urged
us to do splenectomy which was performed in April 1999. The
histologic examination of the spleen revealed a hepatosplenic
lymphoma. After the splenectomy, skin lesions disappeared, liver
enzyme values progressively decreased and coagulation indices showed
normalization in one week. As expected, platelets count increased
until 738109 /L one week after the splenectomy and decreased to
417109/L one month later. In the post surgical period, patient was
treated with 4 cycles of chemotherapy (Fi2/89; epirubicine,
vincristine, bleomycine and cyclophosphamide). This resulted in a
complete clinical remission with negative bone marrow biopsy. In
view of autologous bone marrow transplantation (ABMT) he was treated
with 2 cycles of chemotherapy (BAVEC-MiMA; BiCNU, adriblastine,
vepeside, vincristine, mitoxantrone, methotrexate and cytosine
arabinoside). In January 2000, he was submitted to three consecutive
leukapheresis but, unfortunately, the number of peripheral
circulating levels of CD34 positive cells was not sufficient for the
ABMT and the patient refused new leukapheresis. Two other cycles of
BAVEC-MiMA chemotherapy were performed as intensive consolidation
therapy after the remission. One month later (May 2000), the patient
was admitted to a hematological unit because of fatigue, malaise and
erythematous papules of the face and trunk similar to those that
characterized the beginning of the disease. Significant laboratory
values included AST 225 IU/L, ALT 255 IU/L, LDH 1773 U/L, platelets
46×109/L and leukocytes 27.9×109/L, the latter
characterized by medium and large size lymphocytes with cleaved and
folding nucleus. The immunophenotype of circulating lymphocytes was
NK (CD16+, CD56+, CD2+, CD7+; CD8 were expressed on about 63 % of NK
population while CD3 was negative). He was treated with four weekly
infusions of chemotherapy (MACOP-B; vincristine, adriamicine,
bleomycine, cyclophosphamide, methotrexate and prednisone) with
normalization of liver enzyme values, peripheral blood counts and
skin lesions. The second relapse occured 10 weeks later. Patient was
readmitted in the same hematological unit for salvage ABMT.
One-month later, he developed an acute leukemia. The patient died in
December 2000, twenty months after the diagnosis. Post-mortem
examination was not performed.
MATERIALS
AND METHODS
Informed consent for all procedures was obtained from the
patient. Bone marrow specimen was fixed in 10 % buffered formalin
and processed according to standard technique. Paraffin sections
were stained with hematoxylin-eosin, Giemsa, PAS and Gomori method.
Biopsy of the skin and specimens of the spleen were fixed in 10 %
buffered formalin, and in B5; paraffin sections were stained with
hematoxilin-eosin, Giemsa and PAS. An immunohistochemical
investigation was performed on bone marrow and spleen sections
according to streptavidin-biotin method. Monoclonal antibodies were
used for detection of CD45, CD20, CD79a, CD10, CD45RO, CD30, CD15,
CD56, CD8, CD4, TIA-1, AE1/AE3, EMA, HMB45, MIB1 antigens, and
polyclonal antibodies for CD3 and S-100 protein detection. The
positive reaction was revealed using diaminobenzidin as chromogen.
Histologic
findings
Biopsy of the skin showed a moderate aspecific lymphoid
infiltration of perivascular space associated with erythrocytes.
Bone marrow biopsy showed intense eritroid and megakaryocytic
hyperplasia and a mild hypoplasia of myeloid compartment. Moreover
an important intracapillary infiltration of medium-sized
T-lymphocytes (CD45+, CD3+, scattered CD56+, CD 20- ) was observed
(Figure 1). The spleen weight was 3 000 g. Microscopic examination
showed the presence of a diffuse intrasinuses infiltrate in the red
pulp of medium-sized T-lymphoid cells with round to irregular nuclei
and moderately abundant pale cytoplasm (Figure 2). All neoplastic
cells expressed CD45, CD45RO and CD3 membrane antigens (Figure 3),
whereas they were CD4-, CD8- and TIA-1-. CD56 antigen was positive
on about 50 % of the T-lymphoid cells (Figure 4). The diagnosis of
hepatosplenic T cell lymphoma was done. Because of the
unavailability of frozen sections, the analysis of gd TCR expression
was not done.
Figure
1 Immunohistochemical
analysis of the bone marrow: the neoplastic cells within sinuses
were CD3 positive and scattered CD56 positive (insert).
Figure 2
Clusters of medium-sized cells seeped through the red pulp of
spleen.
Figure 3
The neoplastic cells were CD3 positive in the spleen.
Figure 4
The neoplastic cells were scattered CD56 positive (arrows) in
the spleen.
DISCUSSION
Lymphomatous involvement of the liver has been described in
three clinical situations: disseminated disease, primary liver
lymphoma and hepatosplenic T-cell lymphoma. Secondary hepatic
involvement by lymphoma is relatively common and indicates advanced
disease. Non-Hodgkin's primary
lymphoma of the liver is an uncommon entity, often clinically
indistinguishable from more commonly occurring primary carcinoma and
metastatic neoplasms; the correct diagnosis is based on liver biopsy
or even on post-mortem examination because of lacking of suggestive
clinical or imaging features. The hepatosplenic T-cell lymphoma has
been recognized by Farcet et al. in 1990[1] as a
distinct entity characterized by a gd T lymphocytes sinusal infiltration of the red pulp of the
spleen and by sinusoidal infiltration of the liver without lymph
node involvement[2]. Because of its striking uniformity
with respect to clinical, morphological and immunophenotypical
features, this lymphoma was listed as a provisional entity in the
Revised European-American Lymphoma (REAL) classification[3].
Later on, it has been incorporated as a distinct entity in the WHO
classification of lymphoid neoplasms[4] and termed
hepatosplenic gd T-cell lymphoma. Since then, to our knowledge, 45 cases have
been described[5]. According to Weidmann revision,
clinical symptoms at presentation are hepato-splenomegaly,
constitutional symptoms and less frequently jaundice due to hepatic
involvement. The predominant laboratory findings are reduced
peripheral blood cells ranging from hemolytic anemia (Coombs
negative) to thrombocytopenia or pancytopenia, high levels of LDH
and mild increase of liver enzymes. Moreover, recently, 14 cases of
hepatosplenic lymphoma expressing a
b TCRs have
been described[6].
These
a
b lymphomas
fulfill all the clinical, morphological and immunophenotypical
criteria required for the diagnosis of hepatosplenic lymphoma, with
the exception of the female preponderance (11/14 patients) and age
of distribution (more wide than the gd counterpart). Early diagnosis of this lymphoma, even if
mandatory, is complicated in several cases because of the absence of
lymphoadenomegaly, not specific bone marrow involvement and normal
peripheral blood cell counts. The diagnosis of hepatosplenic T-cell
lymphoma in the case we reported had considerable difficulties
because its clinical and laboratory features were similar to acute
hepatitis. As a matter of fact, the liver chemistry evaluation was
typical of hepatic inflammatory disease with hepatocellular necrosis
(about tenfold increase of AST and ALD and threefold increase of LDH)
and impaired synthesis of liver coagulation factors whereas, the
mild increase of ALP level together with normal levels of serum b-2 microglobulin and g-GT were unusual for a lymphoproliferative disease of the liver.
Probably these unusual laboratory findings were related to the quite
exclusive sinusoidal infiltration by lymphoid cells without or with
minimal portal involvement. However, this clinical presentation
prompted us to exclude all causes of acute liver diseases such as
viral hepatitis drugs, toxins, chemical ingestion and/or exposition,
vascular abnormalities, autoimmune hepatitis and metabolic diseases.
As the present case illustrated, an early diagnosis of hepatosplenic
lymphoma was unlikely to be possible on bone marrow specimen alone.
According to Galaurd[7] even when the hepatosplenic
involvement is clear, the presence of few T-cells within bone marrow
sinus is neither specific nor conclusive without a molecular
analysis on frozen tissue. Liver biopsy, which is another way to
confirm the diagnosis of hepatosplenic T-cell lymphoma, was not
performed in this case because of the presence of coagulopathy and
thrombocytopenia. Nevertheless, the presence of an intracapillary
infiltrate by T lymphocytes on the bone marrow specimen as well as
the progressive and symptomatic enlargement of the spleen prompted
us to suspect the presence of a lymphoprolipherative disease and
consequently to perform splenectomy. As reported in literature,
splenectomy was the cornerstone for the diagnosis of hepatosplenic
T-cell lymphoma. Immunophenotype studies on the spleen specimens
showed the typical pattern of hepatosplenic T-cell lymphoma
characterized by expression of CD45 and CD3 antigens and by double
negativity for CD4 and CD8 antigens. The NK cell associated antigen
CD56 expression has been reported in approximately 70-100 % of
hepatosplenic T-cell lymphoma[8, 9]. The presence in the
bone marrow of T-lymphocytes bearing the CD56 antigen could explain
the late involvement of peripheral blood by lymphoid cell with NK
immunophenotype. Furthermore,
in contrast with other previous investigations, in all specimens of
the spleen examined, neoplastic cells were negative for TIA-1
(restricted intracellular antigen, also called granular membrane
protein of 17 Kd, GMP 17), a very sensitive marker of cytosol
granules independent of their activation status. Concerning the
recurrence of cutaneous skin lesions, a skin biopsy, performed early
in the course of disease, showed only a moderate and aspecific
lymphoid infiltration of perivascular spaces, without the
morphological and immunophenotypical findings that characterized the
peripheral lymphoma involving the skin. Although thrombocytopenia
was not severe, a complete remission of skin lesions was achieved
after its correction. It seems likely to ascribe these purpuric
lesions to the reduced number of circulating platelets, but a
cytotoxic activity of cutaneous T lymphocytes could have a role in
the pathogenesis of these skin lesions. As the present case
illustrated that the prognosis for this type of lymphoma is poor.
Complete remission was reported only in few patients after
chemotherapy (second and third generation regime for high-grade
lymphomas), followed by autologous and allogenic bone marrow or
peripheral stem cell transplantation. The median survival time was 8
months (range 0-42 month)[5].
In
conclusion, the current report described the unusual clinical
presentations of hepatosplenic lymphoma. This patient, in fact,
shared several distinctive features including: 1) the initial
clinical presentations mimicking an acute hepatitis, 2) the presence
of cutaneous lesions, contemporary with the hepatosplenic
involvement and 3) a negativity of TIA-1 expression of lymphoid T
cells. Even in the absence of a mass lesion or lymphoadenopathy,
hepatosplenic T-cell lymphoma should be included in the differential
diagnosis of an acute hepatic dysfunction in young patient who shows
no evidence of viral, toxic, autoimmune or metabolic liver disease.
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Edited
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XQ and Zhu LH
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