Oculomucosal and gastrointestinal involvement in Epstein-Barr virus-associated hydroa vacciniforme

ARTICLE

ejd.2012.1665

Auteur(s) : Takenobu Yamamoto go-yama@med.kawasaki-m.ac.jp, Yoji Hirai, Tomoko Miyake, Osamu Yamasaki, Shin Morizane, Keiji Iwatsuki

Department of Dermatology, Okayama Graduate School of Medicine, 2-5-1 Shikata-cho Kita-Ku, 700-8558 Okayama, Japan

Reprints: T. Yamamoto

Recent studies have shown that cutaneous disorders such as hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB) are mediated by Epstein-Barr virus (EBV)-infected T and NK cells [1-4]. Furthermore, HV-like vesiculopapular eruptions may occur in patients with EBV-associated T cell lymphoproliferative disorders [5]. A total of 63 patients have been referred to us from Japan and Asian countries between 1998 and 2010. In a series of patients with HV and HMB, we noticed that some patients with HV and HMB present with aphthous stomatitis, and develop ulcerative mucosal or gingival lesions in their clinical course. We reviewed the incidence of oculomucosal and gastrointestinal complications in our series of patients.

Patients and Methods

Patients with typical HV fulfilled the following criteria, as described elsewhere [1]:

• 1). repetitive vesiculopapular eruptions on exposed areas including the face, lips, cheeks and extensor surfaces of the hands and arms,
• 2). histologic features of reticulated degeneration of epidermis or blister formation associated with dense lymphocytic infiltration,
• 3). the exclusion of hereditary photosensitivity disorders.

A positive photo-provocation test result was not included in the indispensable criterion for typical HV because HV patients do not always present positive reactions [6]. In contrast, patients with ‘severe’ HV present with one or more of the following clinical and histopathologic findings in addition to the HV-like eruptions:

• 1). high-grade fever,
• 2). liver damage,
• 3). ulcerative indurated lesions,
• 4). edematous swelling of the cheeks, eyelids, ears and lips [7, 8].

HMB has been defined as ulceronecrotic skin lesions with infiltration of EBV-encoded small nuclear RNA (EBER)⁺ cells induced by mosquito bites, insect bites, or vaccination [9].

Thirty-two patients with typical HV alone, 16 with severe HV, 6 with both HV and HMB, and 9 with HMB alone were enrolled in the present study. Clinical characteristics of these patients are listed in table 1. The diagnoses were confirmed by the presence of EBER⁺ cells in the cutaneous lesions by in situ hybridization, or the presence of EBER-1 transcripts in the tissues by reverse transcription-polymerase chain reaction (RT-PCR) [1, 2]. Oral and ocular lesions were checked every time in the clinic. The endoscopic screening was done when gastrointestinal symptoms, such as diarrhea and abdominal pain, occurred. All tissue materials were obtained for diagnostic or therapeutic purposes and utilized for the present study with approval of the ethical committee in Okayama University Hospital (No. 993).

Table 1 Clinical characteristics in patients with HV and/or HMB

LN : Lymph node HPS : Hemophagocytic syndrome

Results

All patients had an increased EBV DNA load in the peripheral blood mononuclear cells (PBMC). Patients with typical HV showed no complications and good prognosis compared to other diseases (table 1).

Oral lesions were observed in 11 (17.5%) of 63 patients with HV and/or HMB (figure 1, table 2), including aphthous stomatitis in 10 patients, and ulcerative gingivitis in 3 patients. Oral lesions were observed more frequently in the severe HV group than the typical HV group: 5 (31.3%) of 16 patients with severe HV vs 5 (15.6%) of 32 patients with typical HV. Three (6.3%) of 48 patients with typical and severe HV presented with iritis, conjunctival hyperemia, or corneal erosions associated with HV lesions, although no ocular lesions were observed in patients with HMB.

Table 2 Oculomucosal and gastrointestinal involvement in patients with HV and/or HMB

Overlapped with iritis*, and aphtous stomatitis**

Two patients (12.5%) with severe HV had gastrointestinal tract involvement. One case of severe HV was complicated with punched-out erosions in the colon by endoscopic examination, in which dense infiltration of mononuclear cells was present (figure 2A). In this case, the infiltrates contained many CD3⁺ and CD8⁺ cells, a small number of CD4⁺ cells, and a lesser number of CD20⁺ cells, but no CD56⁺ cells, and approximately 80% of the infiltrating cells were positive for EBER (figure 2B-C). Another patient with severe HV and fatal hemophagocytic syndrome presented with multiple punched-out erosions with EBER⁺ cell infiltration in the esophageal and gastrointestinal tract as well as oral aphthae. In this case, the esophageal lesion showed dense infiltration of CD3⁺, CD4⁺ and CD8⁺ cells without CD56 expression, and approximately 50% of the infiltrates were strongly positive for granulysin, and weakly positive for granzyme B.

Discussion

The present study indicates that patients with EBV-related HV and/or HMB often present with aphthous stomatitis and/or ulcerative gingivitis, and ocular symptoms such as iritis, conjunctival hyperemia, and corneal erosions. The gastrointestinal lesions contained many EBER⁺ T-cells, and reactive T cells expressing CD8 and cytotoxic molecules in severe HV. A small number of B-cells were present in the mucosal lesions, but CD56⁺ cells were absent or at a background level. Since EBV DNA was detected by PCR amplification even in healthy adults, the detection of EBER⁺ cells or latency-associated EBER-1 transcripts by in situ hybridization or RT-PCR is required to determine the pathogenic significance of EBV [10].

Although EBV has been suggested as a possible etiological agent of ulcerative colitis, Crohn disease, and other inflammatory bowel diseases [11], the clinicopathological findings of our patients were distinct from those of such diseases: macroscopic findings of our patients were characterized by punched-out or herpetic vesicles, and the majority of infiltrating cells were EBER⁺ T-cells, while EBER⁺ B-cell infiltration is dominant in ulcerative colitis and Crohn disease.

Chronic active EBV infection is an EBV-associated T/NK cell lymphoproliferative disorder characterized by increased numbers of large granular lymphocytes (LGL) containing azurophilic granules in the blood as well as concomitant occurrence of HV and/or HMB [12]. A previous report has shown that intestinal perforation and oral ulcers were present as complications in 4 and 18 of 30 patients with chronic active EBV infection, respectively [5]. Complications of aphthosis and oral ulcers are observed in patients with HV [13] and T cell LGL leukemia [14, 15]. Our data, together with the previous reports, suggest that both aphthous stomatitis and gastrointestinal lesions can be included among the digestive tract complications related to EBV⁺ T/NK-cell lymphoproliferative disorders, with gastrointestinal lesions occurring in patients with the severe form.

Disclosure

Ackoledgements: This work was made possible by referral of patients to us from Drs. Makoto Kawashima, Tokyo Women's Hospital, Junichi Hasegawa, Shinonoi General Hospital, and Hideaki Imamura, University of Miyazaki Hospital, Japan. Financial support: This work was supported by Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (#20390307) and Grant-in-Aid for Exploratory Research (#22659205). Conflict of interest: none.

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