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Intravascular T-cell lymphoma with bowel involvement Case report and literature review.

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American Journal of Hematology 78:207–211 (2005)
Intravascular T-Cell Lymphoma With Bowel Involvement:
Case Report and Literature Review
Geoffrey Williams,1 Ann Foyle,2 Darrell White,1 Wenda Greer,2 Steven Burrell,3
and Stephen Couban1*
1
Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
3
Department of Radiology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
2
Intravascular lymphoma (IVL) is a rare form of non-Hodgkin lymphoma characterized by
massive proliferation of large, neoplastic cells in small- and medium-sized blood vessels.
Most cases of IVL are of B-cell immunophenotype; fewer than 15 cases of T-cell IVL have
been reported. A 23-year-old male presented with acute abdominal pain, fever, and tender
lower abdomen. Pathology at laparotomy revealed infiltration of colonic vessels with large
lymphoid cells compatible with IVL. We reviewed all cases of IVL diagnosed at the Queen
Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, from August 1992 to August
2002. A literature review was also performed. Five additional cases of IVL were identified at
this institution during a 10-year period. Three patients presented with neurological symptoms, and two with abdominal pain. In 4 of 5 cases, patients died of lymphoma within
3 months of presentation; one patient experienced a 10-month remission. While visceral
involvement with IVL is common at autopsy, IVL presenting as an acute abdomen in an
immunocompetent patient has not previously been described. Among the 15 cases of T-cell
IVL reported in the literature, only two occurred in people under age 30. Given the rarity of
T-cell IVL, it is remarkable that three cases of T-cell IVL have been diagnosed at our
institution during a 10-year period. Am. J. Hematol. 78:207–211, 2005. ª 2005 Wiley-Liss, Inc.
Key words: intravascular lymphoma; bowel; angiotropic lymphoma
INTRODUCTION
Intravascular lymphoma (IVL), also referred to as
intravascular lymphomatosis or angiotrophic lymphoma, is a rare form of non-Hodgkin lymphoma characterized by massive proliferation of large, neoplastic
mononuclear cells within small- and medium-sized
blood vessels. First described as an endothelial neoplasm
by Pfleger and Tappeiner in 1959, they suggested the
term ‘‘angioendotheliomatosis proliferans systemisata’’
[1]. Subsequently, various terms have been used to
describe this entity, including ‘‘proliferating endotheliosis’’ [2], ‘‘angioendotheliomatois proliferans’’ [3], and
‘‘neoplastic endotheliosis’’ [4]. The origin of the malignant cell in intravascular lymphoma was debated until
recent immunohistochemical studies confirmed a lymphoid origin [5]. Most IVL cases are B-cell tumors, with
fifteen reports of T-cell IVL described in the literature
[6–9]. The reason for the intravascular predilection of
these cells is not known, but lack of specific adhesion
ª 2005 Wiley-Liss, Inc.
molecules, such as lymphocyte function-associated antigen 1, on the neoplastic cells may be important [10].
IVL is a systemic condition that commonly affects the
nervous system, presenting as multifocal cerebrovascular events, paraparesis, encephalopathy, and peripheral
neuropathies due to occlusion of blood vessels [11] and
direct neuronal infiltration [12]. Cutaneous involvement
is also common [13]. Unlike in other lymphomas, lymph
nodes and bone marrow are rarely affected [14]. Systemic symptoms including fever and weight loss are
common. Patients are typically middle-aged to elderly,
*Correspondence to: Stephen Couban, Department of Medicine,
Dalhousie University and Queen Elizabeth II Health Sciences Centre,
Room 417, Bethune Building, 1278 Tower Road, Halifax, Nova Scotia,
Canada B3H 2Y9. E-mail: stephen.couban@cdha.nshealth.ca
Received for publication 9 December 2003; Accepted 21 July 2004
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.20253
208
Case Report: Williams et al.
although IVL has been described in a stillborn [15] and a
teenager [7]. The variable and nonspecific presentation
may delay diagnosis, which is often made at autopsy.
Combination chemotherapy has resulted in long-term
remissions in some patients [15,16].
We report a 23-year-old man with T-cell IVL who
presented with acute abdominal pain due to ischemic
bowel. To our knowledge, this is the first case of IVL
presenting as an acute abdomen in an immunocompetent individual. We have also reviewed five additional
cases of IVL from our institution from the past 10 years.
METHODS
We reviewed all cases of IVL diagnosed at the Queen
Elizabeth II Health Sciences Centre in Halifax, Nova
Scotia, between August 1992 and August 2002. A literature review and bibliographic search of references
was also undertaken with standard internet search
engines using key words: ‘‘intravascular lymphoma,’’
‘‘angiotropic lymphoma,’’ and ‘‘T-cell.’’ T-cell clonality
was assessed using a PCR-based method described by
Diss et al. [17]. Two reactions with primers VgI and
VgIII/IV and Jg1/2 are reported to detect 80% of T-cell
gamma gene rearrangements. B-cell clonality was similarly assessed using nested PCR with consensus primers
for the variable and joining regions as described by
Reed et al. [18]. This approach is reported to detect
83% of immunoglobulin heavy chain rearrangements.
RESULTS
Case Report
A 23-year-old previously healthy man presented with
a 4-day history of lower abdominal and lumbosacral
back pain. The patient was febrile and had a markedly
tender lower abdomen. There was no lymphadenopathy or hepatosplenomegaly. Complete blood count
and lactate dehydrogenase were normal. The initial clinical diagnosis was acute diverticulitis, and the patient
was admitted for intravenous antibiotics. He did not
improve, and a CT of the abdomen and pelvis revealed
changes suggestive of inflammation with mucosal
thickening of the right and transverse colon (Fig. 1).
Peritoneal signs developed, and the patient was taken
to laparotomy.
At laparotomy, a small amount of clear fluid was
found in the abdomen. The bowel wall was inflamed
with small bowel distension and atony. There was no
evidence of Crohn disease. Colotomy of the transverse colon showed a granular appearance with no
definite ischemia. The bowel was abnormal from the
caecum to the splenic flexure, suspicious for a toxic
process such as ulcerative colitis. A subtotal colectomy with ileostomy was performed. The patient did
Fig. 1. CT scan demonstrates marked mucosal thickening
involving the hepatic flexure of the colon (arrows) as well as
abnormal enhancement throughout the transverse colon
(arrowheads). The abnormal wall thickening extends from
the cecum to just proximal to the splenic flexure.
well post-operatively and was discharged, returning
2 weeks later with recurrent abdominal and back pain
and watery discharge from his ileostomy. Abdominal
films did not suggest new pathology, and these symptoms improved with chemotherapy.
Pathology revealed infiltration of colonic vessels by
large lymphoid cells (Fig. 2A,B) with immunohistochemical features of T-cell (CD3+, CD5+) non-Hodgkin
lymphoma (Fig. 2C). The pathology is typical of intravascular lymphoma. Although hepatosplenic T-cell lymphoma can also be sinusoidal, the clinical presentation is
different, with splenic involvement and medium-sized
cells rather than large-sized cells in that disorder. Bowel
wall ischemia with necrosis was present. Mesenteric
lymph nodes were negative for lymphoma. Interestingly,
DNA extracted from the paraffin-embedded colon
demonstrated evidence of an immunoglobulin heavy
chain gene rearrangement, but no T-cell receptor gene
rearrangement was found. Peripheral smear showed only
normocytic anemia, and a bone marrow aspirate and
biopsy were negative for lymphoma. CT thorax, abdomen, and pelvis did not reveal any nodal involvement.
MRI head was normal. The patient was diagnosed with
a T-cell intravascular non-Hodgkin lymphoma and
received 8 cycles of CHOP chemotherapy followed by
8 treatments of prophylactic intrathecal methotrexate.
He remains well with no clinical or radiologic evidence
of disease 16 months following completion of therapy.
Case Series
We identified five additional cases of IVL in a
systematic review of 1192 cases of lymphoma at our
Case Report: Intravascular Lymphoma
209
institution over a 10-year period (1992–2002) (Table I):
2 males and 3 females with a median age at presentation
of 64 years (range 38–73 years). Three patients presented with neurological symptoms. Two patients had
leg weakness, one of which progressed to paraparesis,
while the other developed tremor and migraine-like
headaches. Two patients presented with abdominal
pain, one due to mesenteric ischemia and the second
due to multiorgan visceral involvement. Two patients
were diagnosed postmortem. Two cases were of T-cell
immunophenotype and three were of B-cell immunophenotype, as assessed using immunohistochemistry
(CD3+ and CD5+ for T cells and CD20+ for B-cells).
The median survival from presentation of the 3 patients
who were diagnosed prior to death was 8 months (range
2–10 months). Both patients with T-cell IVL died within
4 months of presentation. Bone marrow involvement
was found in one patient, and no patient had clinical,
radiologic, or pathologic evidence of lymph node
involvement. Lactate dehydrogenase was elevated in
all but one case. Three patients in whom autopsy was
performed showed multiorgan involvement with sparing
of bone marrow, spleen, and lymph nodes.
DISCUSSION
Fig. 2. (A) Mucosal ulcer overlying the fatty submucosa of
the ileocecal valve. Note the granulation tissue at the base
with exudate on the surface. Vessels in the lower right are
distended and occluded by neoplastic cells (hematoxylineosin stain, original magnification 2·). (B) Distended, thinwalled vessel filled with large malignant cells (hematoxylineosin, original magnification 40·). (C) Vessels containing
neoplastic cells with an immunostain against CD3 (original
magnification 25·).
Intravascular lymphoma is a rare type of non-Hodgkin lymphoma, which may be of either B- or T-cell
immunophenotype. First described in 1959 as an unusual cutaneous small vessel neoplasm [1], it has since
been reported in various extranodal sites. Several reports
using standard immunohistochemical techniques have
confirmed the lymphoid origin of the malignant cells
[5], and while the etiology is unclear, associations with
Epstein-Barr virus [19] and human T-cell lymphotropic
virus [20] have been suggested in individual cases.
Intravascular lymphoma cells are usually not found
extravascularly, and bone marrow and lymph node
involvement is rare [14]. The reason for the intravascular predilection of these cells is not known. It may result
from an abnormal interaction between homing receptors of lymphocytes and cell adhesion molecules of
endothelial cells within high endothelial venules [10].
Lack of expression of a lymphocyte adhesion molecule
may impair these cells’ ability to exit from blood vessels
and reach interstitial tissues. LFA-1 (lymphocyte function-associated antigen-1), a lymphocyte adhesion
molecule, was not detectable in intravascular lymphoma
cells [21]. However, this antigen is also decreased or
absent in other B-cell lymphomas, suggesting that additional abnormalities must account for the unique intravascular predilection of the malignant cells.
T-cell IVL has usually been described in patients
between 50 and 70 years of age. One case has been
reported in a young adult [7] and one in a stillbirth
210
Case Report: Williams et al.
TABLE I. Summary of Index Case and Case Series
Patient
Age
(years)
Presentation
Immunophenotype
K.C. (index case)
23
Abdominal pain
T-cell
B.V.
O.G.
R.S.
C.K.
H.B.
62
73
64
38
67
Right upper quadrant pain
Progressive leg weakness
Paraplegia
Migraine headache and tremor
Fatigue and epigastric pain
T-cell
T-cell
B-cell
B-cell
B-cell
[15]. Prognosis is poor, and only two reported cases of
survival beyond 1 year have been described [9,11]. There
have been two reports of autologous bone marrow
transplantation in patients with IVL, and both patients
remained in remission at the time of publication of the
reports [22,23]. Most cases of T-cell IVL have presented
with neurologic or cutaneous involvement or fever of
unknown origin [11]. Other presentations include interstitial lung disease [6] and infiltration of a testis [19].
Postmortem studies have shown that most cases have
multiorgan involvement. Renal involvement is particularly common, suggesting that renal biopsy may be both
a means of diagnosis and to follow response to treatment [24]. Random skin biopsies were used as a means
for diagnosing IVL in two patients [13].
The case of T-cell IVL we have described is unique
since the presentation with an acute abdomen has not
previously been described in an immunocompetent
individual. Interestingly, a review of cases at our institution revealed another patient with T-cell IVL who
also presented with abdominal pain. A case of T-cell
IVL of the appendix has also been reported in a teenager with HIV [9]. This raises the question of whether
T-cell IVL may have a particular predilection for the
vascular system of the gastrointestinal tract and suggests that it should be considered as a very rare cause of
acute abdominal pain. The young age of our patient at
presentation and his response to therapy are also notable features of this case. Molecular analysis revealed
a monoclonal immunoglobulin heavy-chain gene rearrangement, and polyclonality of the T-cell receptor
gamma gene appears to be inconsistent with the positive immunohistology staining for T cells. This PCR
analysis, however, does not detect approximately 20%
of T-cell clones. Furthermore, it is well documented
that a small proportion of T-cell lymphomas have rearranged immunoglobulin and T-cell receptor genes [25].
A systematic review of consecutive cases of lymphoma
at our institution revealed five additional cases with IVL
over a 10-year period. These cases are comparable with
those reported in the literature, except for the relatively
high (3/6) proportion of T-cell IVL. The proportion of
patients with T-cell IVL in our series is unusual because
Interval from diagnosis
to death (weeks)
N/A (in remission
for >100 weeks)
Postmortem diagnosis
8
40
32
Postmortem diagnosis
Treatment
CHOP
None
CHOP
CHOP + cranial radiation
CHOP
None
only 15 cases of T-cell IVL have been published. The
immunophenotype of most cases of IVL is usually
established using immunohistochemical studies, and several studies have identified more than one population of
lymphoid cells, with the predominant cell type reported
as the IVL cell of origin. Few studies have confirmed
clonality with PCR technique [26]. This may indicate that
the T-cell phenotype is either under-reported or not distinguished from B-cell phenotype on pathology.
In summary, T-cell IVL is an aggressive disease that
is difficult to diagnose because of the variable presentation, which may include acute abdominal pain. The
scarcity of cases limits the ability to establish standard
treatment modalities. In addition, unlike other types of
non-Hodgkin lymphoma, IVL has an intravascular
predilection, which presents difficulty in monitoring
disease progression and response to treatment. Further
studies are warranted to expand our knowledge and
understanding of this interesting lymphoma.
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