Case report

Successful treatment of mediastinallymphomatoid granulomatosis withrituximab monotherapy

Lymphomatoid granulomatosis (LYG) was origin-ally described by Liebow et al. (1) as an angiocen-tric and angiodestructive lymphoproliferativedisease involving extranodal sites. Pulmonarymanifestation is most common, followed by skin(50%), nervous system (25%), kidneys, and liver.Lymph nodes, spleen, and bone marrow are usuallyspared until late in the course of illness (2, 3).The diagnosis is based on the following histo-

logical triad (4):

• Nodular polymorphic lymphoid infiltrate.• Angiitis because of transmural infiltration ofarteries and veins by lymphocytes.

• Granulomatosis with central necrosis withinthe lymphoid nodules and no granulomaformation.

While the pathogenesis of this rare disease is stillunknown, recent studies demonstrate that patientswith LYG show an impaired humoral and cell-mediated immune response to viral infections, in

particular, to Epstein–Barr virus (EBV) (5). Thus,LYG bears similarities with EBV-positive post-transplant B-cell lymphoproliferative disorders(PTLD) (3, 6). The clinical course of LYG islargely unpredictable with reports of spontaneousregressions as well as rapid, lethal progressions(7, 8). Various treatment approaches for LYG havebeen reported in the literature ranging fromimmunomodulatory therapy to high-dose chemo-therapy with bone marrow or stem-cell transplan-tation (7–10). However, no treatment modality hasdemonstrated convincing, long-lasting efficacy.

We present the case of a young patient withlymphomatoid granulomatosis with a mediastinalbulk that was successfully treated with the mono-clonal anti-CD20 antibody rituximab.

Case report

A 21-yr-old Caucasian woman was admitted tothe Department of Hematology/Oncology of the

Jordan K, Grothey A, Grothe W, Kegel T, Wolf H-H, Schmoll H-J.Successful treatment of mediastinal lymphomatoid granulomatosis withrituximab monotherapy.Eur J Haematol 2005: 74: 263–266. � Blackwell Munksgaard 2005.

Abstract: Lymphomatoid granulomatosis is a rare Epstein–Barr virus(EBV)-positive-B-cell lymphoproliferative disorder. Treatment optionsinclude corticosteroids, antiviral therapy, interferon-alpha and chemo-therapy. However, long-term prognosis is poor and no therapeuticstandard has been established yet. In a 21-year-old woman, a biopsy ofmediastinal mass revealed lymphomatoid granulomatosis. Combinedtherapy with valganciclovir and interferon-alpha proved ineffective. Inview of the CD20 expression of the tumor cells, monotherapy withrituximab was intiated. After 3 months a complete remission wasachieved. Rituximab was continued for another 6 months withsubsequent consolidation radiotherapy. This is the first report of anenduring complete remission (20 months) of a non-CNS lymphomatoidgranulomatosis treated with rituximab.

Karin Jordan, Axel Grothey,Wilfried Grothe, Thomas Kegel,Hans-Heinrich Wolf, Hans-JoachimSchmollInternal Medicine IV, Hematology/Oncology, Martin-Luther-University Halle/Wittenberg, Halle/Saale,Germany

Key words: lymphomatoid granulomatosis; liebowgranulomatosis; rituximab; EBV-associatedlymphoproliferative disease; CD20; mediastinal bulk

Correspondence: K. Jordan MD, Internal Medicine IV,Hematology/Oncology, Martin-Luther-University Halle/Wittenberg, Ernst-Grube-Str. 40, 06120 Halle/Saale,GermanyTel: +49 345 557 2924Fax: +49 345 557 2950e-mail: karin.jordan@medizin.uni-halle.de

Accepted for publication 12 September 2004

Eur J Haematol 2005: 74: 263–266All rights reserved

Copyright � Blackwell Munksgaard 2005

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University of Halle for further evaluation of a mass(50 · 60 mm) in the upper mediastinum that wasdiagnosed in May 2002 by chest X-ray. At initialpresentation, the patient was free of symptomsexcept for a chronic, non-productive cough forseveral weeks. A biopsy of the mediastinal masswas performed which showed a diffuse infiltrateconsisting of a mixture of small lymphocytes,blasts, macrophages, and epitheloid cells. The areasof necrosis and the cellular infiltrate destroyed thenormal tissue structure and showed a clear relationto vascular structures with an angiocentric andangiodestructive pattern consistent with lympho-matoid granulomatosis (Fig. 1). The proliferationindex was high with 60–70%. Immunhistochemi-cally, the lymphoid cells were positive for CD20and CD30. In addition, EBV antigens (LMP1 andEBNA2) were detected in tumor cells suggestingEBV-associated lymphoproliferative disease. In thiscase, the mediastinal lesion was consistent withlymphomatoid granulomatosis grade II. Bronchos-copy demonstrated mucosal lesions suspect forlymphoid infiltration, however, histologic andcytologic evaluation failed to demonstrate malig-nant cells. Bone marrow biopsy showed no lym-phoid infiltration. Computed tomographic scans ofchest and abdomen revealed no hilar and abdom-inal lymphadenopathy and no involvement ofinternal organs. Magnetic resonance imaging ofthe brain did not show any neurologic lesions.

As the patient was almost completely asympto-matic and in view of the presumed EBV associationand the lack of any standard therapy for thisdisease, we initiated treatment with valganciclovir,an oral-formulated antiviral drug. After 2 monthsof continued treatment and no change of themediastinal mass in MR imaging, interferon-alphaat a dose of 5 Mio IE three times a week was added.Under this combination therapy the patient res-ponded shortly for 1 month showing a moderate

decrease of the tumor mass. However, magneticresonance imaging (MRI) of the thorax in October2002 (Fig. 2A) showed progression of the medias-tinal mass from 50 · 60 mm inMay to 80 · 60 mm.Corresponding to this, a positron emission tomo-graphy (PET) scan visualized a 10.2 · 6 · 7.2 cmfocus of high tracer uptake in the left mediastinum(Fig. 2B). At this time the patient was still asymp-tomatic except for flu like symptoms associated withthe interferon-alpha treatment. Various therapeuticoptions were considered including high-dose che-motherapy. However, in view of the absence ofclinical symptoms in this young patient alternative,less toxic therapeutic approaches appeared justified.The documented expression of CD20 on the lym-phoid cells formed the rationale for initiatingtreatment with rituximab, a humanized monoclonal

Fig. 1. Angiocentric and angiodestructive polymorphouslymphoid infiltrate (grade II lesion) in the upper media-stinum.

Fig. 2. Magnetic resonance imaging of thorax (panel A) andPET scan (panel B), October 2002. A mediastinal mass withhigh glucose uptake can be identified.

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anti-CD20 antibody, in October 2002. During thefirst month the patient received rituximab on aweekly basis at a dose of 375 mg/m2, subsequentlythe treatment was continued with monthly applica-tions. After 3 months of treatment the chest MRI(Fig. 3A) showed an impressive remission of thetumor bulk from 80 · 60 mm to a residual tumor of10 · 15 mm. This shrinkage was mirrored by adramatically decreased glucose-uptake in a PETscan performed in February 2003 (Fig. 3B). Duringthe whole treatment period the patient did notexperience any therapy-associated side-effects andwas able to work full time as a nurse. In March 2003

a consolidating involved-field irradiation of theinitial tumor region was started (36 Gy); rituxi-mab was continued for another 6 months untilSeptember 2003. As of June 2004 the patient is stillin complete remission, 20 months after initiation ofrituximab therapy.

Discussion

The pathogenesis of LYG is unknown; however,recent studies have showed overwhelming evidencethat LYG is a distinctive type of malignantlymphoma associated with immunosuppression.The lesions are mainly extranodal, involving lungs,brain, and skin in most cases reported (1–3, 11). Inrare cases, the disease has a fluctuating activityincluding a spontaneous and complete regressionwithout treatment (12, 13). In the initial report byLiebow two-third of the patients died from thedisease and the median survival was 14 months (1).A standard therapeutic approach and optimalmanagement of LYG have not been defined yet.In various small studies and case reports, therapyhas ranged from observation to treatment withprednisone or aggressive chemotherapy. In thelargest study of 152 patients no significant differ-ence in mortality or disease-free survival was foundbetween treatment options, and the disease-relatedmortality exceeded 50% (14). In view of theassociation of LYG with EBV and the similarityto post-transplant lymphoma (6), the use of anti-viral drugs combined with immunosuppressivetherapy with prednisone/cyclophosphamide hasbeen suggested (7). Although more than 50% ofthe patients responded to this treatment, recurrenceis very common in prednisone- treated patients withtransformation into refractory disease or progres-sion to high-grade lymphoma (2). When LYGprogresses to high-grade lymphoma, combinationchemotherapy has frequently been used, butresponse rates are poor at this stage (8).

Experimental treatment approaches have inclu-ded antiviral therapy with interferon-alfa or ganci-clovir (9). One patient with LYG and positive EBVserology after stem cell transplant for multiplemyeloma was reported to have complete radiologi-cal remission following 2 wk of ganciclovir therapy(15). Based on this observation we initially startedtreatment in our asymptomatic, young patientusing an antiviral therapy with oral ganciclovir.However, as we did not observe any signs ofremission within the first month, interferon-alphawas added to the treatment, a drug with antiviral,antiproliferative, and immunomodulatory proper-ties. It is of note that four patients with LYGtreated with interferon-alpha in the literatureresponded. Three of these patients showed a

Fig. 3. Magnetic resonance imaging of thorax (panel A) andPET scan (panel B) in January 2003, after 4 months of rit-uximab monotherapy. The mediastinal mass is dramaticallyreduced in size and in metabolic activity.

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complete response at 3 months and were disease-free after 36, 43 and 60 months; one patientachieved a partial response for 16 months, butdiscontinued therapy and died from lymphoma (8,9). In our case, the patient showed a modest tumordecrease after 1 month, however, eventuallyprogressed substantially after 2 months. Theexpression of CD20 on the lymphoid cells and thewell-documented efficacy of rituximab in otherCD20-positive lymphomas (16) were the rationalefor the use of rituximab in our patient. Rituximabis approved in the USA and Europe for the treat-ment of aggressive non-Hodgkin lymphoma (NHL)when combined with standard chemotherapy.While the function of CD20 itself is not fullyunderstood, the mechanism of rituximab’s activityincludes complement-dependent lysis (17), effectorcell-mediated lysis (18), induction of apoptosis andinterference with calcium influx into the cell (19).

To our knowledge, this is the first report of asuccessful therapy of non-CNS LYG with an anti-CD20 antibody Based on our observation, ritux-imab should be considered as a valid first-linetreatment option of LYG. Further evaluation ofrituximab in a larger patient population with LYGis warranted.

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