BRIEF REPORTSuccessful Treatment of Monoclonal, Aggressive Epstein-Barr Virus-Associated

B-Cell Lymphoproliferative Disorder in a Child With AcuteLymphoblastic Leukemia

Mikko Perkkio, MD,1* Pekka Riikonen, MD,1 Raija Seuri, MD,2 andMartine Vornanen, MD3

Key words: acute lymphoblastic leukemia; Epstein-Barr virus; child;lymphoproliferative disorder; cyclophosphamide

Epstein-Barr virus–associated B-cell lymphoprolifera-tive disorder (EBV B-cell LPD) is an uncommon andoften fatal complication of patients with inherited or ac-quired immune deficiency [1]. It has been reported infive children with acute lymphoblastic leukemia (ALL)treated without bone marrow transplantation [2–5]. Threepatients survived, all through discontinuation of chemo-therapy; one was in addition treated with local radiationtherapy [4] and another with alpha-interferon, intrave-nous immunoglobulin (IVIG), and acyclovir [5]. Giventhe rarity of the problem, our experience with such apatient may be helpful to others.

He was a 7-year-old boy when first seen with an un-usual occurrence of aggressive, monoclonal EBV B-cellLPD after chemotherapy for ALL. In December 1990, hewas diagnosed with ALL showing FAB L1 morphology,and a positive test for common ALL (CD 10) antigen. Hewas treated with the standard-risk ALL protocol for 3years according to the recommendations of the NordicSociety of Pediatric Hematology and Oncology. Themaintenance therapy for the last two years included onlyoral mercaptopurine daily and methotrexate weekly. Atthe discontinuation of the ALL chemotherapy, his serumlevels of IgA, IgM, IgG, and the IgG subclasses wereappropriate to the age. The distribution of the lympho-cyte subpopulations and the stimulation test with phyto-hemagglutin and poke weed mitogens were normal.

In January 1994, a month after the cessation of theALL chemotherapy, he presented with fever, cough, andincreasing dyspnea. Chest radiography and computer to-mography (CT) revealed several round nodules in alllobes of the lungs (Fig. 1), but a normal-sized mediasti-num and normal abdominal organs. Bone marrow aspi-rates and biopsies from both iliac crests showed no evi-dence of LPD. An open lung biopsy showed on histologya necrotic tumor nodule composed of various lympho-cytes. The infiltrate was mainly perivascular and mor-

phologically quite pleomorphic. Almost all forms of lym-phocytes were present from plasma cells to very atypicalReed Sternberg (R-S)–like cells. There were also numer-ous mitotic figures (Fig. 2). With immunostaining, mostof the lymphocytes, even the R-S–like cells, stainedstrongly positively with B-cell markers (L26/CD20Dako). The infiltrate was found to be polyclonal withlambda and kappa stains as well as monoclonal, at places70%–80% of the cells being kappa-positive [6]. An EBVgenome was detected by polymerase chain reaction andin situ hybridization techniques [6]. IgG antibody titeragainst EBV capsid antigen (VCA) in serum was low,and no anti-VCA IgM antibodies were detected.

Empirical therapy, until the diagnosis of LPD wasconfirmed, consisted of broad-spectrum antibiotics, andamphotericin-B without any clinical response. Acyclovirwas started after the detection of EBV. Due to progres-sive expiratory bronchial obstruction, the patient wastreated with methylprednisolone 2 mg/kg daily for 2weeks. Intravenous immunoglobulin at a dose of 1 g/kgwas given twice. However, multiple tumor infiltratesprogressed, causing respiratory insufficiency, and the pa-tient was treated with mechanical ventilation in the in-tensive care unit. Cyclophosphamide 1,000 mg/m2 wasinfused on 2 consecutive days, followed by hematopoi-etic growth factor (G-CSF 5mg/kg for 10 days) to reduce

1Department of Pediatrics, Kuopio University Hospital, Kuopio, Fin-land2Department of Clinical Radiology, Kuopio University Hospital, Kuo-pio, Finland3Department of Clinical Pathology, Kuopio University Hospital, Kuo-pio, Finland

*Correspondence to: Dr. Mikko Perkkio¨, Kuopio University Hospital,Department of Pediatrics, FIN-70211 Kuopio, Finland.E-mail: mikko.perkkio@kuh.fi

Received 12 September 1998; Accepted 10 November 1998

Medical and Pediatric Oncology 32:447–449 (1999)

© 1999 Wiley-Liss, Inc.

the bone marrow toxicity combined with interferon-alpha(1.5 million units daily) for 3 months. After a prolongedtreatment of 5 weeks in the intensive care unit, the patientshowed signs of recovery and the pulmonary infiltrateson lung CT began to disappear. Acyclovir was continuedfor 6 months. Presently, 4 years later, the patient is well,showing no signs of leukemia or LPD recurrence.

DISCUSSION

The polymorphic, partly monoclonal, lymphocytic in-filtration present in the lung tissue of our patient had allthe features of EBV B-cell LPD [6]. Clinically, the tumorwas very aggressive with growth progression in spite oftherapy with acyclovir, methylprednisolone, and IVIG.Finally, the tumor progression was stopped by treatment

with high-dose cyclophosphamide combined with alpha-interferon and acyclovir.

Maintenance chemotherapy for ALL, consisting oforal mercaptopurine daily and methotrexate weekly, wasthe only predisposing factor for LPD.

Immunosuppression causing impaired T-cell functionis considered an important factor in the development ofEBV LPD in organ transplant recipients [1,6]. Low-intensity maintenance chemotherapy was the probablepredisposing factor in four of the five earlier EBV LPDchildren with ALL, the fifth presenting on reinductionchemotherapy for leukemia relapse [2–5].

The clinical findings and pathological features of EBVLPD in children with leukemia are similar to those foundin other immunocompromised patients [5,6]. The post-transplantation EBV LPDs are a morphologically hetero-geneous group of varying clonal composition [5,6]. Pre-viously defined morphologic categories do not correlatewith clonality, and neither morphology nor clonality pre-dicts the clinical behavior of LPDs [7]. However, in thereport of Fischer et al. [8], none of the seven bone mar-row and organ transplantation patients with monoclonalB-cell LPD responded to any type of treatment.

In conclusion, minimal maintenance chemotherapyconsisting of daily mercaptopurine and weekly metho-trexate can render children with ALL susceptible to life-threatening EBV-associated LPD. The principal treat-ment in these cases is discontinuation of chemotherapy.In nonresponding progressive tumors, however, systemicchemotherapy should be strongly considered. A furtherpotential treatment modality would be anti–B-cell mono-clonal antibodies used successfully in patients with oli-

Fig. 2. Lung biopsy showing a poly-morphic lymphocytic tumoral infiltra-tion with cells ranging from plasmacells (asterisk) to atypical Reed-Sternberg–like cells with a high mi-totic frequency (stars). Hematoxylin-eosin stain, ×400.

Fig. 1. Computed tomography of the chest showing several roundedtumor infiltrates in both lungs.

448 Perkkio et al.

goclonal LPDs following bone marrow and organ trans-plantation [8].

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