Hepatosplenic T-Gammadelta Lymphoma in a Patient withCrohn’s Disease Treated with Azathioprine

JOSE-TOMAS NAVARROa, JOSEP-MARIA RIBERAa,*, JOSE-LUIS MATEb, ISABEL GRANADAa, JORDI JUNCAa,MONTSERRAT BATLLEa, FUENSANTA MILLAa and EVARIST FELIUa

aDepartment of Haematology, Hospital Universitari Germans Trias i Pujol. Badalona, Universitat Autonoma de Barcelona, Barcelona, Spain;bDepartment of Pathology Hospital Universitari Germans Trias i Pujol. Badalona, Universitat Autonoma de Barcelona, Barcelona, Spain

(Received 28 June 2002)

Hepatosplenic gd T-cell lymphoma (HSgdTCL) is an uncommon type of peripheral T-cell lymphoma,which has been associated in some cases with immunosuppression, mainly after solid organ transplants.We describe a case of HSgdTCL with a leukaemic course in a patient with Crohn’s disease who hadreceived azathioprine during the previous 55 years. Sinusoidal infiltration by atypical lymphocytes wasobserved in the liver, spleen and bone marrow and the typical cytogenetic abnormalities(isochromosome 7 and trisomy 8) were found. The patient did not respond to intensive chemotherapy.This case shows the importance of ruling out HSgdTCL in patients with hepatosplenomegaly,B-symptoms and any immunosuppressive condition.

Keywords: Gammadelta T-cell lymphoma; Hepatosplenomegaly; Crohn’s disease; Azathioprine

INTRODUCTION

Hepatosplenic T-cell lymphoma is a rare entity, which

comprises less than 5% of peripheral T-cell lymphomas and

usually expresses the gd T-cell receptor. It has recently

been considered as a distinct entity in the new WHO

classification [1]. Patients are usually young males

presenting with hepatosplenomegaly, without lymphade-

nopathy, frequent B-symptoms and aggressive clinical

course despite treatment [2]. The main laboratory findings

are cytopenias and pathologic liver parameters. Almost one

fourth of the reported cases of hepatosplenic gd T-cell

lymphomas (HSgdTCL) arise in immunocompromised

patients, mainly after solid organ transplantation [3]. The

presence of this type of lymphoma in other immunosup-

pressive conditions has been less described and, to our

knowledge, the association of Crohn’s disease and

HSgdTCL has not been previously reported (MEDLINE

search from 1990 to June, 2002 and PubMed search, key

words hepatosplenic lymphoma, Crohn’s disease, inflam-

matory bowel disease).

CASE DESCRIPTION

A 35-year-old male was admitted because of hepatosple-

nomegaly detected on an outpatient visit. He also

complained of malaise and night sweats. The patient had

been diagnosed with Crohn’s disease at the age of 20.

Treatment included salazopyrine and several corticoste-

roid cycles for 10 years and azathioprine (150 mg/day)

during the 67 months prior to admission (total dose

301.125 g).

On examination, pethechiae on both sides of the

abdomen were observed and hepatomegaly of 3 cm and

splenomegaly of 11 cm were palpable. The haemoglobin

level was 113 g/l, WBC count 9.9 £ 109/l (neutrophils

50%, lymphocytes 39%, monocytes 8%, eosinophils 1%,

metamyelocytes 2%) with 2 erythroblasts per 100

leucocytes and platelet count 95 £ 109/l. On examination

of peripheral blood smears, 20% of lymphoid cells of

blastic appearance with irregular shaped nuclei of

immature chromatin and visible nucleoli and scarce

basophilic cytoplasm were identified. The liver

ISSN 1042-8194 print/ISSN 1029-2403 online q 2003 Taylor & Francis Ltd

DOI: 10.1080/1042819021000035662

*Corresponding author. Address: Servicio de Hematologıa. Hospital Unversitari Germans Trias i Pujol. Ctra. de Canyet s/n. 08916 Badalona. Spain.Tel.: þ34-93-4978987. Fax: þ34-93-4978995. E-mail: jmribera@ns.hugtip.scs.es

Leukemia & Lymphoma, 2003 Vol. 44 (3), pp. 531–533

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laboratory parameters showed: AST 85 U/l, ALT 90 U/l,

alkaline phosphatase 343 U/l and normal serum bili-

rubin. Serum LDH was 561 U/l (normal up to 270),

b2-microglobulin 4.3 mg/l (normal ¼ 0.7 – 3.4) and

CA-125 103 U/l (normal , 35 U/l). Bone marrow

aspirate showed an infiltration of 17% by atypical

lymphoid cells with the same characteristics as those in

peripheral blood. Bone marrow biopsy showed an

interstitial and intrasinusoidal infiltration by atypical

lymphoid cells (Fig. 1). Paratrabecular reticulin fibrosis

was observed. The immunophenotypic study of the

peripheral lymphoid cells by cytofluorometry showed

positivity (.20% of cells) for CD45, CD3, CD8,

CD11c, CD16, CD56 and TCRgd. On the other hand,

CD19, CD20, CD5, CD4 y TCRab were negative.

Cytogenetic study of peripheral blood revealed:

47,XY,i(7)(q10), þ 8[12]/46,XY[18]. Rearrangements of

gamma and delta genes were demonstrated by RT-PCR

with restriction for the families g1 and d3. CT scan of

the thorax and abdomen showed an enlarged liver and

spleen, but no lymphadenopathies were observed.

Sinusoidal infiltration by small atypical lymphocytes

was observed in the liver biopsy (Fig. 2). Immunoper-

oxidase study showed positivity for CD3, CD7, CD8 and

CD56.

The patient received 6 complete alternating cycles of

high-dose CHOP (cyclophosphamide 2 g/m2, hydroxy-

doxorubicin 90 mg/m2, vincristine 1.4 mg/m2 and pred-

nisone 60 mg/m2 for 5 days) and ESHAP (etoposide

40 mg/m2 for 4 days, cytarabine 2 g/m2 on day 1, cisplatin

25 mg/m2 for 4 days and prednisone 200 mg for 5 days)

with intrathecal prophylaxis with methotrexate (15 mg) in

each chemotherapy cycle, without response. Splenectomy

was performed and a bone marrow allotransplantation was

programmed. In the histopathologic study of the spleen, a

sinusoid infiltration by lymphoid cells with the same

immunophenotypic profile as that of the liver and

peripheral blood was observed. During the postoperative

period, the patient developed a subphrenic abscess and

died.

DISCUSSION

Hepatosplenic T-cell lymphoma is a rare extranodal T-cell

lymphoma, mainly affecting males in the second or third

decade of life. Some of the cases have been described in

transplanted patients, mainly of the kidney. The typical

histological pattern shows intrasinusoidal infiltration by

lymphoma cells in the involved organs. Bone marrow

involvement is frequent and different patterns have been

described, including exclusively sinusoidal, interstitial

and mixed interstitial and sinusoidal [4], as in the case

reported herein. The neoplastic cells are usually of small

or medium size, different from the larger size and more

blastic appearance of the cells when seen in peripheral

blood or in aspirate smears. In half of the cases a

leukaemic course has been described [2]. The common

phenotype in HSgdTCL is CD2 þ , CD3 þ , CD4 2 ,

CD5 2 , CD7 þ , CD8 2 , TCRgd, although some CD8

positive cases have been described. As in our case, NK-

related antigens CD16 and CD56 are frequently

expressed. Isochromosome 7 [i(7)(q10)] is the typical

chromosomal alteration [5,6], often associated with

trisomy 8 as a secondary alteration, both being present

in the karyotype of our patient. The combination of both

chromosomal abnormalities seems to be exclusive of

HSgdTCL [2]. The course of this type of T-cell lymphoma

is aggressive and only a few cases with complete

remission have been reported in spite of different

treatment approaches.

Several cases of HSgdTCL have been described arising

in immunocompromised patients, most of whom had

undergone a kidney transplantation [3,7]. Although data

regarding the risk of lymphoma in inflammatory bowel

disease are controversial, several studies show that there is

not an increased risk of non-Hodgkin’s lymphoma in these

patients [8,9]. However, an increased incidence of

lymphoma in those patients on immunosuppressive

therapy with azathioprine or 6-mercaptopurine has been

reported [8–11]. In the patient referred herein, the

treatment with azathioprine of more than 5 years may have

FIGURE 1 Intrasinusoidal infiltration of neoplastic lymphoid cells inthe bone marrow (Giemsa, original magnification £ 400).

FIGURE 2 Sinusoidal infiltration of the liver of atypical lymphoid cells(Hematoxylin and eosine, original magnification £ 400).

J.-T. NAVARRO532

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played a role in the lymphomagenesis, apart from the

controversial influence of the underlying Crohn’s disease.

On the other hand, most lymphomas described in patients

with inflammatory bowel disease are of the B-cell

phenotype. We did not find any reports on the association

of LHSgdTC in patients with Crohn’s disease in the

literature. The case described in this paper shows the

importance of considering the diagnosis of LHSgdTC in

patients with hepatosplenomegaly, B-symptoms and any

immunosuppressive condition.

Acknowledgements

Supported in part with the grant P-EF/01 from the

Fundacion Internacional Jose Carreras para la Lucha

contra la Leucemia.

The authors wish to thank Dr Dolores Jaraquemada

(Immunology Department of Hospital Universitari

Germans Trias i Pujol) for performing the RT-PCR tests.

References

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[2] Weidmann, E. (2000) “Hepatosplenic T cell lymphoma. A reviewon 45 cases since the first report describing the disease as a distinctlymphoma entity in 1990”, Leukemia 14, 991–997.

[3] Khan, W.A., Yu, L., Eisenbrey, A.B., Crisan, D., Al Saadi, A.,Davis, B.H., Hankin, R.C. and Mattson, J.C. (2001) “Hepatosplenicgamma/delta T-cell lymphoma in immunocompromised patients.

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[4] Vega, F., Medeiros, L.J., Bueso-Ramos, C., Jones, D., Lai, R.,Luthra, R. and Abruzzo, L.V. (2001) “Hepatosplenic gamma/deltalymphoma in bone marrow. A sinusoidal neoplasm with blasticcytologic features”, American Journal of Clinical Pathology 116,410–416.

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[6] Wlodarska, I., Martin-GarcIa, N., Achten, R., De Wolf-Peeters, C.,Pauwels, P., Tulliez, M., de Mascarel, A., Briere, J., Patey, M.,Hagemeijer, A. and Gaulard, P. (2002) “Fluorescence in situhybridization study of chromosome 7 aberrations in hepatosplenicT-cell lymphoma: isochromosome 7q as a common abnormalityaccumulating in forms with features of cytologic progression”,Genes Chromosomes and Cancer 33, 243–251.

[7] Steurer, M., Stauder, R., Grunewald, K., Gunsilius, E., Duba, H-C.,Gastl, G. and Dirnhofer, S. (2002) “Hepatosplenic gd-T-celllymphoma with leukemic course after renal transplantation”,Human Pathology 33, 253–258.

[8] Loftus, Jr., E.V., Tremaine, W.J., Habermann, T.M., Harmsen, W.S.,Zins, A.R. and Sandborn, W.J. (2000) “Risk of lymphoma ininflammatory bowel disease”, American Journal of Gastroenterol-ogy 95, 2308–2312.

[9] Lewis, J.D., Bilker, W.B., Brensinger, C., Deren, J.J., Vaughn, D.J.and Strom, B.L. (2001) “Inflammatory bowel disease is notassociated with an increased risk of lymphoma”, Gastroenterology121, 1080–1087.

[10] Lewis, J.D., Schwartz, J.S. and Lichtenstein, G.R. (2000)“Azathioprine for maintenance of remission in Crohn’s disease:benefits outweigh the risk of lymphoma”, Gastroenterology 118,1018–1024.

[11] Farrell, R.J., Ang, Y., Kileen, P., O’brien, D.S., Kelleher, D.,Keeling, P.W. and Weir, D.G. (2000) “Increased incidence of non-Hodgkin’s lymphoma in inflammatory bowel disease patients onimmunosuppressive therapy but overall risk is low”, Gut 47,514–519.

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