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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