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*1Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada2Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada3Department of Radiology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada

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 symp-

toms, 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 2005Wiley-Liss, Inc.

Key words: intravascular lymphoma; bowel; angiotropic lymphoma

INTRODUCTION

Intravascular lymphoma (IVL), also referred to asintravascular lymphomatosis or angiotrophic lym-phoma, is a rare form of non-Hodgkin lymphoma char-acterized by massive proliferation of large, neoplasticmononuclear cells within small- and medium-sizedblood vessels. First described as an endothelial neoplasmby Pfleger and Tappeiner in 1959, they suggested theterm ‘‘angioendotheliomatosis proliferans systemisata’’[1]. Subsequently, various terms have been used todescribe this entity, including ‘‘proliferating endothelio-sis’’ [2], ‘‘angioendotheliomatois proliferans’’ [3], and‘‘neoplastic endotheliosis’’ [4]. The origin of the malig-nant cell in intravascular lymphoma was debated untilrecent immunohistochemical studies confirmed a lym-phoid origin [5]. Most IVL cases are B-cell tumors, withfifteen reports of T-cell IVL described in the literature[6–9]. The reason for the intravascular predilection ofthese cells is not known, but lack of specific adhesion

molecules, such as lymphocyte function-associated anti-gen 1, on the neoplastic cells may be important [10].IVL is a systemic condition that commonly affects the

nervous system, presenting as multifocal cerebrovascu-lar events, paraparesis, encephalopathy, and peripheralneuropathies due to occlusion of blood vessels [11] anddirect neuronal infiltration [12]. Cutaneous involvementis also common [13]. Unlike in other lymphomas, lymphnodes and bone marrow are rarely affected [14]. Sys-temic symptoms including fever and weight loss arecommon. Patients are typically middle-aged to elderly,

*Correspondence to: Stephen Couban, Department of Medicine,Dalhousie University and Queen Elizabeth II Health Sciences Centre,Room417,BethuneBuilding,1278TowerRoad,Halifax,NovaScotia,CanadaB3H 2Y9. E-mail: stephen.couban@cdha.nshealth.ca

Received for publication 9 December 2003; Accepted 21 July 2004

Published online inWiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.20253

American Journal of Hematology 78:207–211 (2005)

ª 2005 Wiley-Liss, Inc.

although IVL has been described in a stillborn [15] and ateenager [7]. The variable and nonspecific presentationmay delay diagnosis, which is often made at autopsy.Combination chemotherapy has resulted in long-termremissions in some patients [15,16].We report a 23-year-old man with T-cell IVL who

presented with acute abdominal pain due to ischemicbowel. To our knowledge, this is the first case of IVLpresenting as an acute abdomen in an immunocompe-tent individual. We have also reviewed five additionalcases of IVL from our institution from the past 10 years.

METHODS

We reviewed all cases of IVL diagnosed at the QueenElizabeth II Health Sciences Centre in Halifax, NovaScotia, between August 1992 and August 2002. A lit-erature review and bibliographic search of referenceswas also undertaken with standard internet searchengines using key words: ‘‘intravascular lymphoma,’’‘‘angiotropic lymphoma,’’ and ‘‘T-cell.’’ T-cell clonalitywas assessed using a PCR-based method described byDiss et al. [17]. Two reactions with primers VgI andVgIII/IV and Jg1/2 are reported to detect 80% of T-cellgamma gene rearrangements. B-cell clonality was simi-larly assessed using nested PCRwith consensus primersfor the variable and joining regions as described byReed et al. [18]. This approach is reported to detect83% of immunoglobulin heavy chain rearrangements.

RESULTS

Case Report

A 23-year-old previously healthyman presented witha 4-day history of lower abdominal and lumbosacralback pain. The patient was febrile and had a markedlytender lower abdomen. There was no lymphadeno-pathy or hepatosplenomegaly. Complete blood countand lactate dehydrogenasewere normal. The initial clin-ical diagnosis was acute diverticulitis, and the patientwas admitted for intravenous antibiotics. He did notimprove, and a CT of the abdomen and pelvis revealedchanges suggestive of inflammation with mucosalthickening of the right and transverse colon (Fig. 1).Peritoneal signs developed, and the patient was takento laparotomy.At laparotomy, a small amount of clear fluid was

found in the abdomen. The bowel wall was inflamedwith small bowel distension and atony. There was noevidence of Crohn disease. Colotomy of the trans-verse colon showed a granular appearance with nodefinite ischemia. The bowel was abnormal from thecaecum to the splenic flexure, suspicious for a toxicprocess such as ulcerative colitis. A subtotal colect-omy with ileostomy was performed. The patient did

well post-operatively and was discharged, returning2 weeks later with recurrent abdominal and back painand watery discharge from his ileostomy. Abdominalfilms did not suggest new pathology, and these symp-toms improved with chemotherapy.Pathology revealed infiltration of colonic vessels by

large lymphoid cells (Fig. 2A,B) with immunohisto-chemical featuresofT-cell (CD3+,CD5+)non-Hodgkinlymphoma (Fig. 2C). The pathology is typical of intra-vascular lymphoma. Although hepatosplenic T-cell lym-phoma can also be sinusoidal, the clinical presentation isdifferent, with splenic involvement and medium-sizedcells rather than large-sized cells in that disorder. Bowelwall ischemia with necrosis was present. Mesentericlymph nodes were negative for lymphoma. Interestingly,DNA extracted from the paraffin-embedded colondemonstrated evidence of an immunoglobulin heavychain gene rearrangement, but no T-cell receptor generearrangementwas found. Peripheral smear showedonlynormocytic anemia, and a bone marrow aspirate andbiopsy were negative for lymphoma. CT thorax, abdo-men, and pelvis did not reveal any nodal involvement.MRI head was normal. The patient was diagnosed witha T-cell intravascular non-Hodgkin lymphoma andreceived 8 cycles of CHOP chemotherapy followed by8 treatments of prophylactic intrathecal methotrexate.He remains well with no clinical or radiologic evidenceof disease 16 months following completion of therapy.

Case Series

We identified five additional cases of IVL in asystematic review of 1192 cases of lymphoma at our

Fig. 1. CT scan demonstrates marked mucosal thickeninginvolving the hepatic flexure of the colon (arrows) as well asabnormal enhancement throughout the transverse colon(arrowheads). The abnormal wall thickening extends fromthe cecum to just proximal to the splenic flexure.

208 Case Report: Williams et al.

institution over a 10-year period (1992–2002) (Table I):2 males and 3 females with a median age at presentationof 64 years (range 38–73 years). Three patients pre-sented with neurological symptoms. Two patients hadleg weakness, one of which progressed to paraparesis,while the other developed tremor and migraine-likeheadaches. Two patients presented with abdominalpain, one due to mesenteric ischemia and the seconddue to multiorgan visceral involvement. Two patientswere diagnosed postmortem. Two cases were of T-cellimmunophenotype and three were of B-cell immuno-phenotype, as assessed using immunohistochemistry(CD3+ and CD5+ for T cells and CD20+ for B-cells).The median survival from presentation of the 3 patientswho were diagnosed prior to death was 8 months (range2–10 months). Both patients with T-cell IVL died within4 months of presentation. Bone marrow involvementwas found in one patient, and no patient had clinical,radiologic, or pathologic evidence of lymph nodeinvolvement. Lactate dehydrogenase was elevated inall but one case. Three patients in whom autopsy wasperformed showedmultiorgan involvement with sparingof bone marrow, spleen, and lymph nodes.

DISCUSSION

Intravascular lymphoma is a rare type of non-Hodg-kin lymphoma, which may be of either B- or T-cellimmunophenotype. First described in 1959 as an un-usual cutaneous small vessel neoplasm [1], it has sincebeen reported in various extranodal sites. Several reportsusing standard immunohistochemical techniques haveconfirmed the lymphoid origin of the malignant cells[5], and while the etiology is unclear, associations withEpstein-Barr virus [19] and human T-cell lymphotropicvirus [20] have been suggested in individual cases.Intravascular lymphoma cells are usually not found

extravascularly, and bone marrow and lymph nodeinvolvement is rare [14]. The reason for the intravascu-lar predilection of these cells is not known. It may resultfrom an abnormal interaction between homing recep-tors of lymphocytes and cell adhesion molecules ofendothelial cells within high endothelial venules [10].Lack of expression of a lymphocyte adhesion moleculemay impair these cells’ ability to exit from blood vesselsand reach interstitial tissues. LFA-1 (lymphocyte func-tion-associated antigen-1), a lymphocyte adhesionmolecule, was not detectable in intravascular lymphomacells [21]. However, this antigen is also decreased orabsent in other B-cell lymphomas, suggesting that addi-tional abnormalities must account for the unique intra-vascular predilection of the malignant cells.T-cell IVL has usually been described in patients

between 50 and 70 years of age. One case has beenreported in a young adult [7] and one in a stillbirth

Fig. 2. (A) Mucosal ulcer overlying the fatty submucosa ofthe ileocecal valve. Note the granulation tissue at the basewith exudate on the surface. Vessels in the lower right aredistended and occluded by neoplastic cells (hematoxylin-eosin stain, original magnification 2·). (B) Distended, thin-walled vessel filled with large malignant cells (hematoxylin-eosin, original magnification 40·). (C) Vessels containingneoplastic cells with an immunostain against CD3 (originalmagnification 25·).

Case Report: Intravascular Lymphoma 209

[15]. Prognosis is poor, and only two reported cases ofsurvival beyond 1 year have been described [9,11]. Therehave been two reports of autologous bone marrowtransplantation in patients with IVL, and both patientsremained in remission at the time of publication of thereports [22,23]. Most cases of T-cell IVL have presentedwith neurologic or cutaneous involvement or fever ofunknown origin [11]. Other presentations include inter-stitial lung disease [6] and infiltration of a testis [19].Postmortem studies have shown that most cases havemultiorgan involvement. Renal involvement is particu-larly common, suggesting that renal biopsy may be botha means of diagnosis and to follow response to treat-ment [24]. Random skin biopsies were used as a meansfor 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 notpreviously been described in an immunocompetentindividual. Interestingly, a review of cases at our insti-tution revealed another patient with T-cell IVL whoalso presented with abdominal pain. A case of T-cellIVL of the appendix has also been reported in a teen-ager with HIV [9]. This raises the question of whetherT-cell IVL may have a particular predilection for thevascular system of the gastrointestinal tract and sug-gests that it should be considered as a very rare cause ofacute abdominal pain. The young age of our patient atpresentation and his response to therapy are also not-able features of this case. Molecular analysis revealeda monoclonal immunoglobulin heavy-chain gene rear-rangement, and polyclonality of the T-cell receptorgamma gene appears to be inconsistent with the posi-tive immunohistology staining for T cells. This PCRanalysis, however, does not detect approximately 20%of T-cell clones. Furthermore, it is well documentedthat a small proportion of T-cell lymphomas have rear-ranged immunoglobulin and T-cell receptor genes [25].A systematic review of consecutive cases of lymphoma

at our institution revealed five additional cases with IVLover a 10-year period. These cases are comparable withthose reported in the literature, except for the relativelyhigh (3/6) proportion of T-cell IVL. The proportion ofpatients with T-cell IVL in our series is unusual because

only 15 cases of T-cell IVL have been published. Theimmunophenotype of most cases of IVL is usuallyestablished using immunohistochemical studies, and sev-eral studies have identified more than one population oflymphoid cells, with the predominant cell type reportedas the IVL cell of origin. Few studies have confirmedclonalitywithPCRtechnique [26]. Thismay indicate thatthe T-cell phenotype is either under-reported or not dis-tinguished from B-cell phenotype on pathology.In summary, T-cell IVL is an aggressive disease that

is difficult to diagnose because of the variable presenta-tion, which may include acute abdominal pain. Thescarcity of cases limits the ability to establish standardtreatment modalities. In addition, unlike other types ofnon-Hodgkin lymphoma, IVL has an intravascularpredilection, which presents difficulty in monitoringdisease progression and response to treatment. Furtherstudies are warranted to expand our knowledge andunderstanding of this interesting lymphoma.

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TABLE I. Summary of Index Case and Case Series

Patient

Age

(years) Presentation Immunophenotype

Interval from diagnosis

to death (weeks) Treatment

K.C. (index case) 23 Abdominal pain T-cell N/A (in remission

for >100 weeks)

CHOP

B.V. 62 Right upper quadrant pain T-cell Postmortem diagnosis None

O.G. 73 Progressive leg weakness T-cell 8 CHOP

R.S. 64 Paraplegia B-cell 40 CHOP+cranial radiation

C.K. 38 Migraine headache and tremor B-cell 32 CHOP

H.B. 67 Fatigue and epigastric pain B-cell Postmortem diagnosis None

210 Case Report: Williams et al.

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