Eur J Pediatr (2007) 166:589–593 DOI 10.1007/s00431-006-0290-1
ORIGINAL PAPER
Simultaneous manifestation of fulminant infectious mononucleosis with haemophagocytic syndrome and B-cell lymphoma in X-linked lymphoproliferative disease Boris Hügle & Itziar Astigarraga & Jan-Inge Henter & Anna Porwit-MacDonald & Alfons Meindl & Volker Schuster
Received: 11 March 2006 / Revised: 15 August 2006 / Accepted: 17 August 2006 / Published online: 21 October 2006 # Springer-Verlag 2006
Abstract X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months. The results of bone marrow biopsy and autopsy indicated a histological diagnosis of both high-grade B-cell lymphoma and virus-associated haemophagocytic syndrome, thereby confirming the simultaneous presence of two different manifestations of X-linked lymphoproliferative disease (XLP) in this patient. The family history revealed four close male relatives dying under similar circumstances, one of whom died following a vaccination against measles. Molecular genetic studies identified a B. Hügle (*) : V. Schuster Department of Pediatrics, University of Leipzig, Oststrasse 21-25, 04317 Leipzig, Germany e-mail:
[email protected] I. Astigarraga Pediatric Oncology Unit, Hospital de Cruces, Barakaldo, Spain J.-I. Henter Childhood Cancer Research Unit, Karolinska University Hospital, Stockholm, Sweden A. Porwit-MacDonald Department of Pathology, Karolinska University Hospital, Stockholm, Sweden A. Meindl Department of Obstetrics and Gynaecology, Technical University, Munich, Germany
novel mutation in the SH2D1A gene in several members of the family, establishing the diagnosis of XLP. Fatal EBV infection in male infants is highly indicative of XLP. Virusassociated haemophagocytic syndrome and B-cell lymphoma can occur concomitantly and may be difficult to distinguish due to their similar histological pictures. Keywords X-linked lymphoproliferative disease . SH2D1A . Lymphoma . VAHS . Measles Abbreviations AIM acute infectious mononucleosis EBV Epstein-Barr virus HLH haemophagocytic lymphohistiocytosis VAHS virus-associated haemophagocytic syndrome VCA viral capsid antigen XLP X-linked lymphoproliferative disease
Introduction Most Epstein-Barr virus (EBV) infections of infants and young children are asymptomatic or show non-specific symptoms. Acute infectious mononucleosis (AIM) usually manifests in adolescents and adults as a self-limiting lymphoproliferative disease with a very good prognosis. X-linked lymphoproliferative disease (XLP, McKusick’s OMIM no. 308 240) is a rare immunodeficiency presenting in two thirds of all cases as fulminant and mostly fatal AIM at an unusually low age [15]. It is associated with a variety of additional clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma [4, 19]. The gene causing XLP, when defective, was identified and described in 1998 and termed SH2D1A or SAP [for
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signaling lymphocyte activation molecule (SLAM)-associated protein] [2]. This gene encodes a protein which interacts with the SLAM (or CD150, a T-cell surface marker and self-ligand) and several related receptors [18]. Experiments using animal models have shown that the absence of SH2D1A leads to an overwhelming and uncontrolled TH1shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture [23]. Virus-associated haemophagocytic syndrome (VAHS) is a distinct clinical entity characterized by generalized lymphohistiocytic proliferation with macrophage activation and marked haemophagocytosis. VAHS occurs in males with XLP and fulminant AIM in >90% of cases [20]. Unlike other, more benign manifestations, VAHS due to EBV infection is associated with a poor prognosis [13]. Lymphoma in XLP affects approximately one third of all patients, manifesting at a median age of 4–6 years [10, 21]. Nearly all lesions are B-cell in origin, and approximately half of these can be classified as Burkitt lymphoma [3]. Typical manifestations are extra-nodal, with the majority being found in the ileocoecal region. The risk of developing lymphoproliferative disease is higher for patients with XLP than for any other primary immunodeficiency [4]. This case report describes a patient from a Spanish family (Fig. 1), with several cases of XLP, presenting with both severe VAHS and B-cell lymphoma.
Case report A 4-year-old boy was admitted to hospital with typical, although severe, signs of infectious mononucleosis:
Fig. 1 Family tree of the 4-year old patient. The index patient (IV:5) is indicated with an arrow; other affected members (II:1, II:2, III:6, IV:3) are marked by black circles (female) and squares (male). The tested female carriers (III:2 and III:5) carried the SH2D1A mutation c146insG are marked with a dot inside the circle. A diagonal line through the circle or square indicates the family member has died; family member IV:2 died in an accident
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extensive adenopathy, marked hepatosplenomegaly, skin rash and high fever starting 9 days previously. The results of serology analyses indicated an acute infection with EPV [anti-EBV viral capsid antigen (VCA) IgM positive] and showed a marked increase in ferritin (1643 ng/mL, normal range for age: 12–65) and triglycerides (317 mg/dL; normal range for age: 48–130) with only slightly elevated levels of C-reactive protein (2.7 mg/dL; normal range for age: 0–2.2). Biopsy of a lymph node showed the destruction of the nodular structure by an infiltration of highly differentiated, monomorphous, medium-sized lymphocytes together with a ‘starry sky’ image. Immunohistological staining revealed a diffuse pattern of 20% CD20+ B-cells, 50% CD3+ T-cells and abundant CD68+ histiocytes. At that time, this was interpreted as diffuse high-grade lymphoma suggestive of Burkitt`s lymphoma. Bone marrow biopsy failed to show any lymphoma cells. However, associated with the bone marrow infiltration with lymphocytes were plasma cells and histiocytes with signs of haemophagocytosis and hypocellularity (Fig. 2). The cerebrospinal fluid showed a high content of protein (130 mg/dL) and 150 cells/μL, with 64% plasma cells and 34% lymphocytes (93% CD3+CD79−TdT−). Immunological investigations of the peripheral lymphocytes showed a decreased CD4/CD8-ratio of 0.21 (CD3+ T-cells: 63%; CD4+ T-cells:10%; CD8+ T-cells: 47%; CD19+ B-cells: 17%). Immunoglobulin serum levels were elevated with an IgG level of 2093 mg/dL (normal range for age: 510– 1100 mg/dL), IgA, 710 mg/dL (40–190 mg/dL) and IgM, 717 mg/dL (37–140 mg/dL). The patient developed severe hepatic failure accompanied by coagulopathy and pancytopenia. Treatment followed the guidelines of the Histiocyte Society and the HLH-94 protocol for haemophagocytic lymphohistiocytosis
Fig. 2 Bone marrow aspirate of the patient showing macrophage activation. Visualized is a macrophage in the process of phagocytosis of two erythroblasts and one lymphocyte. (Magnification ×1000)
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(HLH): etoposide and dexamethasone with added cyclophosphamide for administered for the B-cell lymphoma, which resulted in only a partial response with respect to the hepatic and hematological symptoms [5]. Concomitant bacterial infections were treated with adequate levels of antibiotics. The patient developed increasing neurological impairment with tetraplegia and medullary infarction and an increasing hydrocephalus. Death ensued 50 days after admission due to severe intracranial hypertension. The autopsy showed macroscopic signs of severe necrosis and edema as well as an acute necrotic lesion in the spinal cord. A whitish tumour with a diameter of 6 cm was found within the posterior surface of the cerebellum. Analysis of the cerebellum and the meninges revealed infiltration of a diffuse large cell B-cell lymphoma with large pathological cells and irregular nuclei (CD20+ and CD79a+), which was consistent with diffuse large cell B-cell lymphoma (Fig. 3). Immunohistology analysis also showed high proliferative activity (Ki67+) and clonal expression of cytoplasmic immunoglobulin lambda light chain (Fig. 4). In addition, visceral HLH was observed in the spleen, lymph nodes, bone marrow and liver. Biopsy of a lymph node demonstrated the presence of CD8+ T cells with high proliferative activity and reduced expression of Bcl-2 in addition to B-cell immunoblasts and abundant macrophages. Cytoplasmic staining for the EBV-latent membrane protein 1 (LMP-1) showed positive cells in the lymph node and also a few positive cells in the cerebellar tissue (Fig. 3). An investigation of the family history of the patient showed five male relatives presenting with similar symp-
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Fig. 4 Immunostaining for immunoglobulin lambda chain of meningeal infiltrate shows strong cytoplasmic signal for the lymphoma cells. The insert shows immunostaining for the immunoglobulin kappa chain with one positive plasma cell as control
toms in early infancy (Fig. 1). Both an uncle and two grand uncles of the patient had died of hepatic failure and fever aged 2–4 years. A half brother of the patient (Fig. 1, IV-3) was admitted to hospital 2 weeks after vaccination against measles with fever, cervical adenopathy and a rash. At the time of admission, monospot testing was negative. The patient died a few days later with meningitis and pulmonary bleeding. The index patient has an older brother with EBVpositive serology (VCA-IgG positive) and a half-sister, both healthy to date. Material for genetic analysis was regrettably not obtained prior to the death of the patient. However, mutation screening for SH2D1A in the mother and a maternal aunt of the patient showed the presence of a novel mutation in the SH2D1A gene (see below, Fig. 1, III-2 and III-5). Thus, these two family members were identified as carriers, thereby confirming the diagnosis of XLP in the family. Two other family members at risk do not carry the mutation (Fig. 1, IV-1 and IV-4).
Discussion
Fig. 3 Histological preparation of cerebellar lymphoma. Diffuse large cell B-cell lymphoma with large pathological cells, irregular nuclei (HE staining) and high proliferative (Prolif.) activity (Ki67/MIB-1 staining), positive for B-cell antigens CD20 and CD79a. Note some lymphoma cells with strong cytoplasmic expression of EBV-latent membrane protein LMP-1
At first sight, this patient presented with a severe manifestation of X-linked lymphoproliferative disease – virus-associated haemophagocytic syndrome – which is associated with infectious mononucleosis in XLP in approximately 90% of cases [20]. Obvious signs of hemophagocytosis were found in the bone marrow of the
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patient (Fig. 2), and typical histopathological findings of haemophagocytic lymphohistiocytosis dominated the visceral infiltration in the autopsy findings. In addition, however, a cerebellar tumorous growth was found to be densely infiltrated with cells identified as high-grade B-cell lymphoma, an additional manifestation of XLP described in one third of all XLP patients [21]. The histological picture of diffuse lymphocytic infiltration combined with that of highly differentiated cells with interspersed macrophages is compatible with both lymphoproliferative disease and VAHS. To distinguish between VAHS and a high-grade B-cell lymphoma in the cerebellar tissue sample was possible only after extensive microscopic and immunohistological investigations. Previously, only one case report has described the close similarity between the histopathological pictures of VAHS and B-cell lymphoma, and the concomitant presentation reported here further complicated diagnostic efforts [8]. The data available does not allow definite conclusions to be drawn regarding the question of whether the observed lymphoma was a pre-existing condition or whether it developed rapidly after contact with EBV. On the one hand, patients with onset of lymphoproliferative disease prior to EBV infection have been described, even at an early age [1]. However, the observed expression of the EBV latent membrane protein LMP1 in the cerebellar tissue would certainly argue for involvement of the EBV. A similar occurrence of VAHS and rapidly developing lymphoma in a 4-year-old girl without known immunodeficiency reported previously supports this hypothesis [7]. In rare cases, B-cell lymphomas have even been known to cause haemophagocytic syndrome, although these cases are considered not to be related to EBV infection [12]. The mutation found in this family leads to an insertion of a guanine nucleotide in exon 2 of the SH2D1A gene at position 146 (c146insG), resulting in a frame shift with the formation of a stop codon at position 67, a mutation not described previously. Any translation product of the gene would be truncated and, considering the small size of the SH2D1A protein (128 amino acids), almost certainly non-functional. The family history with several cases of fulminant AIM is remarkably homogeneous. XLP families usually exhibit a more diverse range of disease manifestations in the affected individuals, ranging from lymphoma to agammaglobulinaemia [19]. Although anecdotal, the fulminant AIM clinical presentation following a vaccination against measles described in the family history presents an intriguing point, as recent research has shown that SLAM functions as the receptor for the morbilli virus [22]. Thus, patients with XLP might also be susceptible to unusual reactions to measles infections, as reported in three boys with XLP [16, 17]. Particles suggestive of morbilli virus were seen at the
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autopsy in the atrophic lymphoid tissue of two of these patients. In one of these XLP patients, hypogammaglobulinaemia and measles pneumonitis had preceded EBV infection. As shown for subject IV:3 in the family reported here, vaccination with a live, attenuated measles strain might also trigger a fatal lymphoproliferative complication. Therefore, similar to other severe immunodeficiencies, live vaccines are contraindicated in patients with XLP. To the best of our knowledge, no severe immunological reactions in XLP patients following measles vaccination have been reported to date. The immune reaction described here would argue for a role of SH2D1A in interactions of lymphocytes with the morbilli virus. Therapy options in XLP patients with VAHS are limited and may induce merely transient remissions [6, 19, 20]. Two patients with fulminant infectious mononucleosis and VAHS were successfully treated recently with Rituximab, suggesting that early reduction of EBV-infected B-cells will diminish both antigenic stimulation and expansion of activated defective T cells [11]. Some patients with XLP have been successfully treated with etoposide, dexamethasone and cyclosporine according to the HLH-94 protocol [5, 6]. Allogeneic stem cell transplantation, in the same way as described for familial haemophagocytic lymphohistiocytosis (HLH) in the HLH-94 protocol, is the only curative measure currently available. It has been proven successful even in XLP patients with similarly severe clinical courses [9, 14]. In conclusion, this is – to the best of our knowledge – the first reported case of two concomitant manifestations of X-linked lymphoproliferative disease: a manifestation of B-cell lymphoma of the cerebellum and fulminant AIM with VAHS. As both diseases present a very similar histological picture, extensive investigations were necessary to differentiate these two diseases. Taking into account the possibility of a rapid proliferation of the B-cell lymphoma following EBVexposure, other cases of concomitant manifestations could well have been missed previously. Thus, the rate of lymphoproliferative disease in XLP might currently be underestimated.
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