Cutaneous lymphoproliferative disorders associated with Epstein–Barr virus infection: a clinical overview
Introduction
Epstein–Barr virus (EBV), or human herpesvirus 4 is a member of γ herpesviruses. Primary infection usually causes a mild, self-limited illness or infectious mononucleosis, and less frequently induces Gianotti–Crosti syndrome and virus-associated hemophagocytic syndrome (Table 1) [1], [2]. Recent advantages in diagnostic procedures enabled us to find the association of EBV infection in various disorders with unknown etiology. Various types of lymphoproliferative disorders occur in patients with congenital or acquired immune deficiency including X-linked lymphoproliferative disorder (Duncan disease), acquired immunodeficiency syndrome (AIDS), and recipients with an organ transplantation [1], [2], [3], [4], in which EBV-transformed B-cells may proliferate either in a polyclonal or monoclonal fashion. Latent EBV infection, however, has been associated with a variety of malignant conditions without immunodeficiency, including African Burkitt's lymphoma, nasopharyngeal carcinoma, peripheral T-cell lymphomas, NK/T-cell lymphoma, chronic active EBV infection, gastric cancer, and pyothorax-associated pleural lymphoma [1], [2], [5], [6], [7], [8], [9], [10], [11]. In these conditions, EBV has evolved a number of skilful strategies to escape from the host immune surveillance system [1], [2], [12], [13], [14], [15]. From a clinical viewpoint, the recent observations on EBV-associated lymphoproliferative disorders and the pathogenic role of EBV infection are reviewed.
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Primary EBV infection and host immune response
Primary EBV infection begins in oropharyngeal epithelium, where EBV virions are replicated and released from the epithelial cells to saliva [1], [2], [14], [15]. The virions carrying gp350/220 infect B-cells via CD21 molecules, or receptors for the C3d in the oropharyngeal areas, and form an episome in the nucleus (Fig. 1). Although major target cells of EBV are human B-cells, human epithelial cells, salivary gland duct cells, T-cells, NK cells, macrophages/monocytes, smooth muscle cells and
Molecular mechanisms leading to latent infection and tumor development
Latent EBV infection has an essential role in induction of malignant phenotypes and transformation for the virus-infected cells [17]. Some viral gene products associated with latent infection have biological properties relating to cell immortalization (Table 2, Fig. 1) [1], [2], [18], [19], [20]. It has been postulated that many viruses can use an array of evasion mechanisms from host immune responses to establish latent infection [20], [21]: (1) inhibition of viral antigen expression; (2)
Serological analysis
In cases of primary EBV infections such as infectious mononucleosis and Gianotti–Crosti syndrome, positive IgM and IgG antibodies to viral capsid antigens (VCA) are commonly noted, whereas no IgG antibody to EBNA is found in early stage of the primary infections. Both IgG anti-VCA and anti-EBNA antibodies persist for life-long. Increased IgG antibody titers to VCA and early antigens (EA) indicate activation of EBV [1], [2]. In cases with chronic active EBV infection, extremely high titers of
Clinical subtypes of EB virus-associated cutaneous lymphomas
Our screening test results demonstrated certain types of cutaneous lymphomas containing latent EBV infection (Table 5) [38], [39]. The extremely high association rate (more than 80%) was observed in hydroa vacciniforme-related lymphomas and CD56+ lymphomas, or angiocentric lymphomas. Four of six patients (67%) with subcutaneous lymphoma contained a considerable number of EBER+ cells. While the number of cases was small, EBV infection was found in other cases with unique clinical features as
Association of latent EBV infection with hydroa vacciniforme
We found that all six children with clinically and histologically typical HV had EBER+ T-cells in 3–10% of the dermal infiltrates (Fig. 7) [47]. No EBER+ cells were detected in lesions from other inflammatory skin disorders including photosensitivity dermatitis and lymphomatoid papulosis. Furthermore, the PCR amplification test confirmed the presence of EBV DNA sequences in five of six biopsy specimens from typical HV. These results indicate that the cutaneous lesions of typical HV are
Prognosis and treatment
In our series, some patients with EBV-associated lymphoma became fatal in a few months, whereas others showed chronic or smoldering conditions for several years or more. Some patients belonging to each of the above-mentioned categories presented with the overlapping manifestations in their clinical course, and progressed to other clinical types. For instance, two patients with eyelid or facial swelling turned into a subcutaneous lymphoma with rearrangement of T-cell receptor beta chain gene and
Conclusions and a perspective
It is intriguing to note that patients with typical and atypical HV had eventually 100% association with EBV infection. Similar patients with atypical HV and malignant potential have been reported from Asia [38], [44], [45], [46] and Mexico [42], [43]. Patients with CD56+ lymphoma also showed more than 80% association rate with EBV infection.
The pathogenic role as well as the exact incidence of EBV infection has been a controversial issue in lymphoid malignancies [57], [58]. In order to clarify
Acknowledgements
We thank for generous donation of tissue sections from the following institutes: Departments of Dermatology, Kanazawa University (Dr M. Takata), Tohoku University (Drs H. Tagami, M. Iguchi, N. Tabata, and M. Tanaka), Sapporo Medical College (Dr S. Sugiyama), Aichi Medical College (Drs T. Ikeya, and Y. Nitta), Teikyo University (Dr I. Ando), Ohita Medical College (Drs S. Takayasu and H. Terashi), Yamaguchi Red-Cross Hospital (Dr K. Nishioka), Fujinomiya General Hospital (Drs H. Igarashi, and A.
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