Section 6 -

Age-related Epstein-Barr Virus-Associated B-cell Lymphoproliferative Disorders Shigeo Nakamura Department of Pathology and Clinical Laboratories Nagoya University Hospital Nagoya, Japan Takashi Oyama Department of Clinical Oncology Aichi Cancer Center Nagoya, Japan Kazuhito Yamamoto Department of Hematology and Cell Therapy Aichi Cancer Center Nagoya, Japan

In the past few decades, human malignancies associated with Epstein-Barr virus (EBV), including a variety of malignant lymphomas and carcinomas, have been well documented; our knowledge of these diseases is now greatly expanded. As the epidemiology of EBV-associated (EBV-positive) human diseases is quite complex, the true contribution of EBV to the pathogenesis of these diseases remains to be elucidated. According to the World Health Organization (WHO) classification of lymphoid tumors, [1] disease entities, such as endemic Burkitt lymphoma, lymphomatoid granulomatosis, and extranodal NK/T-cell lymphoma of nasal type, reveal a high prevalence of EBV positivity. This virus is also clearly involved in the pathogenesis of the majority of B-cell lymphomas arising in patients with iatrogenic or congenital immunosuppression. The association of EBV is heterogeneous in conventional diffuse large B cell lymphomas (DLBCL), peripheral T cell lymphomas, and Hodgkin lymphomas (HL). The clinicopathologic significance of EBV in these diseases remains to be clarified. Age-Related Epstein-Barr Virus-Associated B-cell Lymphoproliferative Disorders In 2003, we reported 22 cases of EBV-associated (EBV-positive) B cell LPDs in patients without any predisposing immunodeficiencies. [2] All of these patients were over 60 years of age, with a median age of 76 years. This condition was accompanied by extranodal involvement in 18 cases (82%). Biopsied specimens contained varying numbers of centroblasts, immunoblasts, and Hodgkin and Reed-Sternberg (HRS)-like giant cells. Necrosis and an angiocentric pattern were also frequently seen. The cases were divided into two groups based on the morphology of the malignancy. Thirteen cases were of the polymorphic subtype, showing a polymorphous composition and inflammatory background. Nine patients had a large-cell lymphoma subtype with diffuse proliferation of large lymphoid cells, although the patients constituted a continuous spectrum of pathology. The tumor cells typically expressed CD20 and/or CD79a; in situ hybridization revealed an association with EBV. LMP1 was detected in all of the cases, while EBNA2 was seen in seven cases (32%), indicating latency II and III status, respectively. Eight of the 18 patients who received chemotherapy with a CHOP regimen showed an aggressive disease progression within a year of diagnosis. Although the clinicopathologic profile of this series was analogous to that seen in immunodeficiency-associated B cell LPDs, none of the patients showed any evidence of underlying immunodeficiencies. It was speculated that this disease may be related to an immunological deterioration or the senescence in the immune system derived from the aging process as such in these patients. Therefore, this group has been denominated as senile EBV-associated B-cell lymphoproliferative diorders. We subsequently searched the EBV harboring on 1546 large B-cell LPD cases, mainly consisting of DLBCL, from the files of 6 collaborating institutions ( Fukushima Medical College , Tokyo University , Okayama University , Fukuoka University , Saitama Cancer Center and Aichi Cancer Center ) during the period from January 1990 and December 2003 by EBERs in situ hybridization. The positive signals were detected on many cells of 213 cases (14%), containing 134 cases without any predisposing immunodeficiency. The age distribution of these EBV-associated B-cell LPD cases and their percentages for all cases examined are shown in Figure 1. A bimodal age distribution with an incidence peak in the 10-19 years range and a second peak in older adult aged 70 to 79 was evident for EBV-positive B-cell LPD patients without predisposing immunodeficiency (Fig. 1A). The positive percentages of this group for all cases examined became higher in parallel with the elder patient populations (>50 years), showing the highest peak at ages >90 years (Fig. 1B). In the present series, 8 patients having no documentation for predisposing immunodeficiency were found to be less than 50 years old of age, although it remains to be adequately elucidated about their relationship with chronic active EBV infection and/or primary immune disorders. In taking these rare cases into the consideration, the term of "age-related" may be more appropriate than that of "senile" for further understanding the overall age distribution of EBV-positive B-cell LPDs without predisposing immunodeficiency. The overall clinicopathologic profiles of the patients with age-related EBV-associated B-cell LPDs are currently under investigation in details. The clinical data of the 76 patients of this unique disorder are preliminarily available. Briefly, there were 39 male and 37 female patients, with ages ranging from 50 to 92 years old and a median age of 71 years. According to the definition of the disease, all patients were negative for anti-human immunodeficiency virus antibodies and did not have any of the clinical symptoms that would suggest immunodeficiency. Specimens were obtained from lymph nodes in 43 patients, the stomach in seven cases, Waldeyer's ring in six patients, the skin in five individuals, the lung in four cases, the nasal cavity in four patients, and other sites in seven individuals. Morphologically, the patients were subdivided into 31 cases with polymorphic subtype disease and 45 cases with large cell lymphoma (LCL) subtype disease with supportive data of CD20 and/or CD79a positivity and EBV association. There was a significant difference in prognosis between patients with polymorphic and LCL subtypes (median survivals of 40 vs. 9 months, respectively, P = 0.04). Conclusions Age-related EBV+ B-cell lymphoproliferative disorders (LPDs) were pathologically characterized by varying numbers of Hodgkin and Reed-Sternberg (HRS)-like giant cells, often posing a diagnostic problem differentiating this condition from Hodgkin lymphoma (HL). Recent studies, however, have indicated that HL and non-Hodgkin lymphoma (NHL) may be more closely related than previously implied, promoting the general consensus that HRS cells are derived from B cells in most HL cases. The relationship between EBV+ HL and EBV+ B-cell LPDs remains to be clarified. Further investigations are necessary to clarify the interrelationship, including their overlapping morphological and biological features. A B Figure 1. Age distribution of the patients with EBV-associated B-cell lymphoproliferative disorders. Figures A and B show the number of the cases and the positive percentages for all cases examined, representatively. White bars represent all cases with EBV-positive B-cell lymphoproliferative disorders (LPDs), and, among those, black bars (EBV, not otherwise specified [NOS]) do only the EBV-associated B-cell LPDs without predisposing immunodeficiency. References Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haemotopoietic and Lymphoid Tissues. Lyon, IARC press, 2001 Oyama T, Ichimura K, Suzuki R, et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol 2003;27:16-26