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Advances in dermatology and venereology Acta Dermato-Venereologica
Hydroa Vacciniforme-like Skin Lesions in Epstein-Barr-Virus-associated T-cell Lymphoproliferation with Subsequent Development of Aggressive NK / T-cell Lymphoma
Atiye TOKSOY 1, Susanne STRIFLER 2, Sandrine BENOIT 1, Götz U. GRIGOLEIT 2, Stefan KNOP 2, Stephan MIELKE 2, Kristina BUDER-BAKHAYA 1, Sabine ROTH 3, Matthias GOEBELER 1, Andreas ROSENWALD 3, Eva GEISSINGER 3 and Marion WOBSER 1 Departments of 1 Dermatology, Venereology, and Allergology and 2 Internal Medicine II, University Hospital Würzburg, Josef-Schneider- Straße 2, DE-97080 Würzburg, 3 Institute of Pathology and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. E-mail: Toksoy _ a @ ukw. de Accepted Nov 8, 2016; Epub ahead of print Nov 9, 2016
Worldwide, more than 95 % of adults over the age of 40 years are seropositive for Epstein-Barr virus( EBV). Most EBV infections are asymptomatic and occur during childhood. An acute EBV infection in adolescence presents as infectious mononucleosis and usually heals without sequelae. However, some EBV-infected individuals develop chronic active EBV infection( CAEBV) resulting from continuous latent infection of T cells, NK cells, B cells, or epithelial cells( 1 – 3). In particular, immunodeficient and Asian patients carry an increased risk of CAEBV. The clinical presentation of CAEBV is variable, and is characterized by fever, hepatic dysfunction, splenomegaly, lymphadenopathy and thrombocytopaenia. In addition, some of these patients show hydroa vacciniforme-like skin eruptions with oedematous swelling of the face and eyelids( 4 – 10). CAEBV is a disease with potentially life-threatening complications, such as EBV-associated lymphomas, which are associated with a high morbidity and mortality( 3, 5). We report here such a case.
CASE REPORT
A 45-year-old Turkish woman presented with persistent swelling of the face, erosive facial papules and small oral ulcers that had developed 5 years previously( Fig. 1). As granulomatous cheilitis and Morbihan disease / oedematous rosacea had been suspected prior to first presentation at our department, the patient had been treated with several, mainly immunomodulating, therapies, including systemic corticosteroids, dapsone, methotrexate, fumarates and the tumour necrosis factor( TNF) antagonist adalimumab, without success. The clinical course was complicated by the development of diplopia and excessive B-symptoms( weight loss, night sweats and a reduced condition). Computed tomography( CT) scans revealed splenomegaly, cervical and mediastinal lymphadenopathy, hilar and para-aortal consolidations and oedematous ocular muscles.
Fig. 1. Clinical features.( a) Oedematous swelling of the eyelids and the lips. Disseminated crusty papules of the facial skin.( b) Intraoral aphthous ulcers( arrows).
Histological examination of biopsies obtained from the upper lip mucosa and facial skin showed a variable dense lymphoid infiltration. EBV + T cells were identified within the infiltrate by EBV RNA in situ hybridization in conjunction with conventional immunohistochemical, as well as double and triple immunofluorescence staining. These EBV + T cells were mostly CD4 +( Fig. S1a – c 1), although, in addition, a population of CD8 + EBV-infected T cells, and few CD79a + B cells, could be detected( Fig. S1d 1). Molecular clonality analyses were consistent with oligoclonal EBV + T-cell proliferation( Fig. S2 1). Subsequent lymph node and bone marrow biopsies revealed the same oligoclonal EBV + T-cell proliferation. Blood analysis revealed increased levels of EBV DNA( 6,000 copies / ml) and the presence of IgG antibodies against EBV antigens( EBNA-1, VCA p18, VCA p23, BZLF1, EA p138, EA p54). CAEBV infection associated with T-cell lymphoproliferation in multiple organ systems was diagnosed.
With respect to the known high risk for progression into an aggressive EBV-associated lymphoma, treatment with 2 cycles of CHOP( cyclophosphamide( 375 mg / m 2), doxorubicin( 50 mg / m 2), vincristine( 2 mg), prednisone( 100 mg) for 5 days) were given every 3 weeks; however, there was no clinical response and a considerable EBV load persisted in the blood( 3,000 copies / ml). Therefore, the anti-CD20 antibody rituximab( 375 mg / m 2) was added to the protocol( R-CHOP) for a total of 4 cycles, with the aim of also specifically targeting the B-lymphocyte compartment. The patient responded to this approach( reduction in B symptoms, improvement in intraoral aphthous lesions, regression of lymphadenopathy and splenomegaly). However, the EBV load of 6,000 copies / ml only partially improved to a viral load of 1,000 copies / ml, while the hydroa vacciniforme-like skin lesions further progressed( not shown).
Seven months after the primary diagnosis of CAEBV and more than 4 years after the onset of first cutaneous indicator lesions, a follow-up CT scan revealed newly developed hepatic infiltration. A liver biopsy showed a dense infiltrate of atypical CD56 – / CD3 – / CD8 + and EBV + highly proliferative cells, classified as extranodal EBV-associated NK / T-cell lymphoma( Fig. S1 1).
Normal distribution of NK- / T and B cells without detection of an NK / T-cell lymphoma could be observed in repetitive flow cytometric analyses of the peripheral blood and the bone marrow. Hence, an intensified chemotherapy protocol( SMILE) was initiated comprising high-dose methotrexate( 2,000 mg / m 2), etoposide( 100 mg / m 2), ifosfamide( 1,500 mg / m 2) and PEG-asparaginase( 2,000 IE / m 2). After re-induction of a partial response, the patient finally underwent reduced-intensity conditioning with fludarabine and busulfan, followed by human leukocyte antigen-matched allogeneic stem cell transplantation from a sibling donor. Day + 100 staging revealed complete remission. The patient later developed limited chronic graft-versus-host disease, requiring topical and systemic immunosuppressive treatment that resolved completely. At time of writing, 18 months after transplantation, the patient is alive in complete remission and free of immunosuppressive drugs.
1 https:// www. medicaljournals. se / acta / content / abstract / 10.2340 / 00015555-2564
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2564 Acta Derm Venereol 2017; 97: 379 – 380