ARTICLE
Auteur(s) : Yukiko Nitta1, Keiji
Iwatsuki2, Hiroshi Kimura3, Seiji
Kojima3, Tsuneo Morishima4, Kazuhide
Tsuji2, Takashi Oono2
1Department of Dermatology, National Hospital
Organization Nagoya Medical Center, Nagoya 460-0001, Japan
2Department of Dermatology, Okayama University Graduate
School of Medicine and Dentistry, 2-5-1 Shikata-cho Okayama
700-8558, Japan Fax: (+81) 86 235 7283
3Departments of Pediatrics, Nagoya University School of
Medicine, Nagoya 466-8560, Japan
4Okayama University Graduate School of Medicine and
Dentistry, Okayama 700-8558, Japan
accepté le 21 Mars 2005
Epstein-Barr virus (EBV) is a causative agent of infectious
mononucleosis and is also associated with Burkitt’s lymphoma,
nasopharyngeal carcinoma, and various types of lymphoproliferative
disorders. Patients with EBV-associated natural killer (NK) or
T-cell lymphoprolifarative disorders present with clinical features
including hypersensitivity to mosquito bites (HMB) [1-4], chronic
active Epstein-Barr virus infection (CAEBV) [5, 6],
virus-associated haemophagocytic syndrome (VAHS) [7], hydroa
vacciniforme (HV)-like eruptions [8-12] and nasal lymphoma [13].
These diseases have been reported in Asians, mostly from Japan, in
contrast to few reports in Western literature [14]. The levels of
EBV-DNA in the plasma and peripheral blood mononuclear cells are
usually elevated in these patients [5], and many of them have high
antibody titres to lytic-cycle viral proteins such as viral capsid
antigens (VCA) and early antigens (EA) [1, 5, 6], suggesting a
booster phenomenon to the repetitive reactivation of EBV.We
experienced a 14-year-old Japanese girl who sequentially developed
HMB at 2 years old, VAHS at 3, HV-like eruptions at 4, CAEBV at 7,
and fatal nasal NK cell lymphoma at 14. We studied the pathogenic
significance of EBV-infected NK/T cells in the development of
cutaneous manifestations and confirmed the spectrum of
EBV-associated lymphoproliferative disorders.
Case report
A 2-year-old-girl was admitted to our hospital in July 1987, with a
6-week history of intense skin reactions at mosquito-bitten sites.
Each lesion began as an edematous erythema on the extremities,
became a bulla several hours after the bites, and evolved into a
deep ulcer ( (figure 1A,
B) ). The patient also had a high fever and general
malaise, but she did not show generalized reactions of an
anaphylactic type. Other family members were in good health. At the
time of the initial admission, the patient’s white blood count
(WBC) was 7.0×109 L–1 with 7% eosinophils,
and IgE was 4165 U mL–1 without any symptom suggestive
of atopic dermatitis. No IgE antibody was detected against mosquito
antigens. IgG and IgM antibodies for Aedes albopictus were
positive. A skin biopsy from the ulcer demonstrated dense
infiltrates composed of lymphoid cells and a few eosinophils in the
deep dermis and subcutaneous tissue ( (figure 1C) ), together
with a sparse infiltration of mononuclear cells positive for
EBV-encoded small nuclear RNA (EBER). The patient was diagnosed as
having severe HMB and treated with prednisolone. Over the summer
seasons from 1987 to 1999, she experienced the same episodes
following mosquito bites many times.
In January 1988, at the age of 3 years, the patient developed a
high fever and exhibited hepatosplenomegaly and generalized
lymphadenopathy associated with leukocytopenia of
2.5×109 L-1 with 6% eosinophils, and
thrombocytopenia of 5.00×1010 L-1. A red
blood cell (RBC) count was 3.84×1012 L–1. The
bone marrow aspiration showed hypoplasia of granulocytoid and
erythroid lineage, and megakaryocytic hyperplasia. Histiocytes
phagocytizing RBCs and neutrophils were observed in the bone marrow
smears ( (figure
1D) ). Elevated levels of serum asparate aminotransferase
(AST) of 234 IU L–1 (normal 0-41), alanine
aminotransferase (ALT) of 335 IU L–1 (normal 0-45), and
IgE of 4930 U mL–1 were found. Anti-EBV antibody titres
disclosed anti-VCA IgG, 1: 2560; VCA IgM, 1:< 10; VCA IgA, 1:20;
EA-DR IgG, 1:20; EA-DR IgA, 1:10; and EBNA, 1:20. Under the
diagnosis of EBV-associated haemophagocytic syndrome, the patient
was treated with gamma-globulin with a remarkable benefit. She had
two recurrent episodes in 1990 and 1991.
In February 1989, at the age of 4, the patient began to develop
umbilicated vesiculopapules with small necrotic centres on the
face, cheeks, and buttocks ( (figure 2A, B) ). These
eruptions occurred on both sun-exposed and sun-protected areas
without relation to seasons. Routine laboratory study results were
normal for blood cell counts, urinalysis, liver function, and
erythrocyte porphyrin levels. Histopathologic findings of the
vesiculopapule were consistent with those of hydroa vacciniforme,
showing necrotic epidermis and perivascular patchy cell
infiltration of T-cells without CD56+ cells and a few histiocytes
and eosinophils in the dermis and fatty tissues ( (figure 2C) ).
Approximately 25% of the infiltrating lymphocytic cells were
positive for EBER ( (figure 2D) ). Similar
eruptions sometimes recurred and then resolved spontaneously in a
few weeks, leaving slightly depressed scars, and these eruptions
continued until the patient died.
At the age of 7, the patient was hospitalized for
hepatosplenomegaly and a high fever of unknown origin. Laboratory
test results disclosed a white blood cell count of
4.0×109 L–1 with 20.7% eosinophils; RBC,
4.46×1012 L–1; platelets,
10.4×1010 L–1; IgG, 1221 mg dL–1;
IgA, 78 mg dL–1; IgM, 125mg dL–1; and IgE,
1357 U mL–1. Liver dysfunction was found by AST of 425
IU L–1 and ALT of 524 IU L–1. Virological
studies excluded the infections of cytomegalovirus, and hepatitis B
and C. Antibody titres to EBV revealed an active latent EBV
infection, showing anti-VCA IgG, 1:640~2560; VCA IgM, below 1:10;
VCA IgA, 1:40; EA-DR IgG, 1:40~640; EA-DR IgA, 1:40; and EBNA,
1:20~40. A high amount of EBV-DNA was detected in the plasma by
quantitative polymerase chain reaction assay. The NK cell
population determined by CD16+ and CD56+
cells was increased, and EBER+ cells were detected in
approximately 60% of NK cells in the peripheral blood. The patient
was diagnosed as having severe CAEBV and treated with aciclovir 250
mg day-1. She frequently complained of headaches during
her hospitalization. T1-weighted magnetic resonance image (MRI)
revealed a high signal in the bilateral pallidum. No abnormal
signals were seen on T2-weighted MRI. Head computed tomography (CT)
without contrast showed a high-density area in the basal ganglia,
indicating symmetric calcification in the bilateral basal
ganglia.
In September 1998, at 13 years, the patient had a slight snuffle
and was diagnosed with chronic paranasal sinusitis. There were no
abnormalities in the head X-ray or CT images. In July 1999, she
presented with edema on the eyelids and the bottom of the nose, and
was suffering from nasal obstruction. MRI scanning disclosed a
tumourous shadow in the left nasopharyngeal lesion ( (figure 3A) ). A biopsy
specimen taken from the tumour showed dense infiltration of
atypical lymphocytes and necrosis ( (figure 3B) ). Surface
markers of the infiltrating atypical cells were positive for CD2,
CD16, CD45RO, CD56, and granzyme B, and negative for CD3, CD20 and
CD30 ( (figure
3C) ). The tumor cells were positive for EBER. No
chromosomal changes were detected on cells obtained from bone
marrow by G-banding assay. On 10 November 1999, allogenic
bone-marrow transplantation was carried out under the diagnosis of
nasal NK cell lymphoma. One week later, however, the patient
developed MRSA sepsis and intracranial hemorrhage, and she died on
17 December 1999 ( (figure 4) ).
Discussion
Primary infection with EBV in childhood is generally asymptomatic
but often causes overt diseases such as infectious mononucleosis
and lymphoproliferative disorders (LPD) [14]. Most EBV-associated
LPD arising in immunocompromised hosts are of B-cell lineage, but T
or NK cell lymphomas may occur in Asians without apparent
immunodeficiency [9, 13-15]. Extranodal NK/T-cell lymphoma, nasal
type, is a prototype of such lymphomas, and it usually affects the
nasopharynx, palates, skin, soft tissues, gastrointestinal tract,
and testis [13]. In addition to the prototypic type, other
EBV-associated cutaneous lymphomas exhibit characteristic clinical
features, including HV-like lymphoma in children and young adults,
eyelid swelling with intramuscular infiltration, and
panniculitis-like plaque associated with high fever and
haemophagocytosis [9, 14, 15]. Unlike the de novo, adult-onset of
EBV-associated lymphomas, those arising in children or young adults
are often preceded by various EBV-related complications [1, 14].
Our patient developed a fatal nasal NK-cell lymphoma 12 years after
the initial episode of EBV-related disease. In the clinical course,
she presented with a crop of EBV-associated symptoms, including
HMB, VAHS, HV-like eruptions, CAEBV, and calcification of basal
ganglia. These symptoms, therefore, might be included in the
spectrum of EBV-associated diseases [14]. As pointed out previously
[5, 6], elevated levels of EBV-DNA in the blood might be one of the
predictive signs of disease progression.
Among EBV-associated symptoms, NK-cell lymphocytosis is closely
related to the occurrence of HMB, [1] and EBV-infected
CD8+ T-cells are responsible for the occurrence of
haemophagocytic syndrome [17, 18]. In our previous study, we noted
that both typical HV and vesiculopapular eruptions mimicking HV are
induced by EBV-infected T-cells without infiltration of CD56+ (NK)
cells [10]. Although a dominant NK-cell clone infected with EBV was
often detected in the peripheral blood, latent EBV infection is
usually observed in various cell types including NK- and T-cells,
and patients with CAEBV with T-cell-dominant infection had
significantly poorer outcomes [6]. These observations, therefore,
suggest that a variety of clinical manifestations in our case were
induced by different EBV-infected lymphocyte subsets rather than
solely by a dominant clone.
Patients with typical HV are observed worldwide and independent
of race, but HV-like lymphomas and other EBV-associated
complications with poor prognosis occur preferentially in Asian
countries and Latin America [14]. We believe, therefore, that a
defect in genetic immunological responses against the latent-cycle
EBV antigens might be responsible for the development of
EBV-associated NK/T-cell lymphomas [16].
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research
(B) (KI; No.14370261), a Grant-in-Aid for Scientific Research
(C)(2) (KT; No.16591099) from the Japan Society for the Promotion
of Science, and a Grant-in-Aid for Exploratory Research (KI;
No.14657200) from the Ministry of Education, Culture, Sports,
Science and Technology in Japan.
References
1 Tokura Y, Ishhara S, Tagawa S, Seo N,
Ohshima K, Takigawa H. Hypersensitivity to mosquito bites
as the primary clinical manifestation of a juvenile type of
Epstein-Barr virus associated natural killer cell
leukemia/lymphoma. J Am Acad Dermatol 2001; 45: 568-9.
2 Tsuge I, Morishita T, Morita H, Kimura H,
Kuzushima K, Matsuoka H. Characterization of Epstein-Barr
(EBV)-infected natural killer (NK) cell proliferation in patient
with severe mosquito allergy; establishment of an IL-2-dependent
NK-like cell line. Clin Exp Immumol 1999; 115: 385-92.
3 Satoh M, Oyama N, Akiba H, Ohtsuka M,
Iwatsuki K, Kaneko F. Hypersensitivity to mosquito bites
with natural-killer cell lymphocytosis: the possible implication of
Epstein-Barr virus reactivation. Eur J Dermatol 2002; 12:
381-4.
4 Asada H, Miyagawa S, Sumikawa Y,
Yamaguchi Y, Itami S, Suguri S, et al. CD4+
T-lymphocyte-induced Epstein-Barr virus reactivation in a patient
with severe hypersensitivity to mosquito bites and Epstein-Barr
virus-infected NK cell lymphocytosis. Arch Dermatol 2003; 139:
1601-7.
5 Kimura H, Hoshino Y, Kanegane H, Tsuge I,
Okamura T, Kawa K, Morishima T. Clinical and
virologic characteristics of chronic active Epstein-Barr virus
infection. Blood 2001; 15(98): 280-6.
6 Kimura H, Morishima T, Kanegane H, Ohga S,
Hoshino Y, Maeda A, et al., Japanese Association for
Research on Epstein-Barr Virus and Related Diseases. Prognostic
factors for chronic active Epstein-Barr virus infection. J Infect
Dis 2003; 187: 527-33.
7 Imashuku S. Clinical features and treatment strategies of
Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis.
Crit Rev Oncol Hematol 2002; 44: 259-72.
8 Oono T, Arata J, Masuda T, Ohtsuki Y.
Coexistence of hydroa vacciniforme and malignant lymphoma. Arch
Dermatol 1986; 122: 1306-9.
9 Iwatsuki K, Ohtsuka M, Harada H, Ham G,
Kaneko F. Clinicopathologic manifestations of Epstein-Barr
virus associated cutaneous lymphoproliferative disorders. Arch
Dermatol 1997; 133: 1081-6.
10 Iwatsuki K, Xu Z, Takata M, Iguchi M,
Ohtsuka M, Akiba H. The association of latent
Epstein-Barr virus infection with hydroa vacciniforme. Br J
Dermatol 1999; 140: 715-21.
11 Cho KH, Kim CW, Lee DY, Sohn SJ. An
Epstein-Barr virus-associated lymphoproliferative lesion of the
skin presenting as recurrent necrotic papulovesicles of the face.
Br J Dermatol 1996; 134: 791-6.
12 Magana M, Sangueza P, Gil-Beristain J,
Sanchez-Sosa S, Salgado A, Romon G, et al.
Angiocentric cutaneous T-cell lymphoma of children (hydroa-like
lymphoma): A distinctive type of cutaneous T-cell lymphoma. J Am
Acad Dermatol 1998; 38: 574-9.
13 Harabuchi Y, Yamanaka N, Kataura A,
Imai S, Kinoshita T, Mizuno F, et al.
Epstein-Barr virus in nasal T-cell lymphomas in patients with
lethal midline granuloma. Lancet 1990; 335: 128-30.
14 Iwatsuki K, Yamamoto T, Tsuji K,
Suzuki D, Fujii K, Matuura H, et al. A spectrum
of clinical manifestations caused by host immune responses against
Epstein-Barr virus infections. Acta Med Okayama 2004: 169-80.
15 Ohtsuka M, Iwatsuki K, Kaneko R, Akiba H,
Kikuchi S, Harada H, et al. Epstein-Barr
virus-associated lymphoid hyperplasia of the eyelid characterized
by intramuscular infiltration. Br J Dermatol 1999; 140: 358-9.
16 Cho KH, Lee SH, Kim CW, Jeon YK,
Kwon IH, Cho YJ, et al. Epstein-Barr
virus-associated lymphoproliferative lesions presenting as a hydroa
vacciniforme-like eruption: an analysis of six cases. Br J Dermatol
2004; 151: 372-80.
17 Yachie A, Kanegane H, Kasahara Y. Epstein-Barr
virus-associated T-/natural killer cell lymphoproliferative
diseases. Semin Hematol 2003; 40: 124-32.
18 Kasahara Y, Yachie A, Takei K,
Kanegane C, Okada K, Ohta K, et al.
Differential celluar targets of Epstein-Barr virus (EBV) infection
between acute EBV-associated haemophagocytic lymphohistiocytosis
and chronic active EBV infection. Blood 2001; 98: 1882-8.
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