The Role of Infectious Agents in B-cell Lymphomas
Moderators: Dr. Miguel A. Piris and Dr. Steven H. Swerdlow
Section 6 -
Age-related Epstein-Barr Virus-Associated B-cell Lymphoproliferative Disorders
Department of Pathology and Clinical Laboratories
Nagoya University Hospital
Department of Clinical Oncology
Aichi Cancer Center
Department of Hematology and Cell Therapy
Aichi Cancer Center
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, 
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.  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
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).
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
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.
- 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