Distribution of Epstein-Barr Virus in Systemic Rheumatic Disease (Rheumatoid Arthritis,Systemic Lupus Erythematosus,Dermatomyositis) With Associated Lymphadenopathy: A Study of 49 Cases

Abstract

Among systemic rheumatic diseases (SRDs), lymphadenopathy is frequently found in patients with rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) may occur in patients following methotrexate therapy for RA and dermatomyositis (DM). However, little is known about the distribution of EBV in reactive LPDs in patients with SRDs who had no history of methotrexate therapy. We analyzed 49 such patients (SLE=25, RA=23, DM=1) for the presence and distribution of EBV+ cells using Epstein-Barr virus (EBV)-encoded small RNA (EBER) specific in situ hybridization. A positive signal for EBERs was identified in 9 (SLE=5, RA=4) (18%) of 49 cases, and 3 main distribution patterns of EBER+ cells could be delineated: pattern A, more than 500 EBER-positive cells were located in the germinal centers as well as interfollicular area (SLE=2); pattern B, EBER + cells were located in a few germinal centers (RA=2); and pattern C, up to 100 EBER+ cells were located in the interfollicular area (SLE=3, RA=2). Recent EBV infection may be a cause of lymph node lesion in only 2 cases of patients with pattern A. However, the pathognomonic significance of pattern B and pattern C EBER+ cell distribution patterns still remains unclear. Our study indicates that the underlying immune deficits of patients with SRDs may also play an important role in the development of EBV-associated LPDs in SRDs, as previously suggested by several authors.

Keywords

systemic rheumatic disease rheumatoid arthritis systemic lupus erythematous dermatomyositis reactive lymphoproliferative lesion Epstein-Barr virus in situ hybridization

Get full access to this article

View all access options for this article.

References

Henry K . Connective tissue disorders/autoimmune diseases. In Henry K , Symmers WStC (eds): Thymus, lymph nodes, spleen and lymphatics. Systemic pathology, 3rd ed. vol. 7. Churchill Livingstone, Edinburgh, pp. 255-263, 1992

Kojima M , Hosomura Y , Itoh H , Johshita T , Yoshida K , Nakamura S , Suchi T . Reactive proliferative lesions in lymph node from rheumatoid arthritis patients. A clinicopathological study and immunohistochemical study. Acta Pathol Jpn 40:249-254 1990

Kojima M , Nakamura S , Morishita Y , Itoh H , Yoshida K , Ohno Y , Oyama T , Asano S , Joshita T , Mori S , Suchi T , Masawa N . Reactive follicular hyperplasia in the lymph node lesions from systemic lupus erythematosus patients. A clinicopathological study of 21 cases. Pathol Int 50:304-312 2000

Koo CH , Nathwani BN , Winberg CD , Hill LR , Rappaport H . Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy. Medicine (Baltimore) 63:274-290 1984

Blanco R , McLaren B , Davis B , Steele P , Smith R . Systemic lupus erythematosus-associated lymphoproliferative disorder: Report of a case discussion in light of the literature. Hum Pathol 28:980-985 1997

Koima M , Nakamura S , Yamane Y , Tanaka H , Masawa N . Autoimmune disease-associated lymphadenopathy from dermatomyositis. A case report. Pathol Res Pract 199:691-694 2003

Kamel OW , van de Rijn M , LeBrun DP , Weiss LM , Warnke RA , Dorfman RF . Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: Frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol 25:638-643 1994

Kamel OW , Weiss LM , van de Rijin , Colby TV , Kingma DW , Jaffe ES . Hodgkin’s disease in patients with long-term low-dose methotrexate therapy. Am J Surg Pathol 20:1279-1287 1996

Salloum E , Cooper DL , Howe G , Lacy J , Tallini G , Grouch J , Shultz M , Murren J . Spontaneous regression of lymphoproliferative disorders in patients with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14:1943-1949 1996

10.

Kamel OW . Iatrogenic lymphoproliferative disorders in nontransplantation setting. Semin Diag Pathol 14:27-34 1997

11.

Knowles DM . Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol 12:200-217 1999

12.

Harris NL , Swerdlow SH . Methotrexate-associated lymphoproliferative disorders. In Jaffe ES , Harris NL , Stein H , Vardiman JW (eds): Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARCPress, Lyon, pp. 270-271, 2003

13.

Ioachim HL . Ioachim’s Lymph node pathology, 3rd ed. JB Lippincott, Philadelphia, pp. 261-263, 2003

14.

Kojima M , Nakamura S , Itoh H , Yoshida K , Suchi T , Masawa N . Lymph node necrosis in systemic lupus erythematosus. A histopathological and immunohistochemical study of four cases. APMIS 109:141-146 2001

15.

Kojima M , Nakamura S , Oyma T , Motoori T , Itoh H , Yoshida K , Suchi T , Masawa N . Autoimmune disease-associated lymphadenopathy with histologic appearance of T-zone dysplasia with hyperplastic follicles. A clinicopathologic analysis of nine cases. Pathol Res Pract 197:237-244 2001

16.

Kojima M , Nakamura S , Itoh H , Shimizu K , Murayama K , Iijima M , Hosomur Y , Ohno Y , Yoshida K , Mtoori T , Sakata N , Masawa N . Clinical implication of florid reactive follicular hyperplasia in Japanese patients 60 years or older. A study of 46 cases. Int J Surg Pathol 13, 2005 (in press)

17.

Trainor KJ , Brisco MJ , Was JH , Neoh S , Grist S , Moriey AA . Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction. Blood 78:192-196 1991

18.

Arnett FC , Edworthy SM , Bloch DA , McShane DJ , Fries JF , Cooper NS , Healey LA , Kaplan SR , Liang MH , Luthra HS , Medsger TA Jr , Mitchell DM , Neustadt DH , Pinals RS , Schaller JG , Sharp JT , Wilder RL , Hunder GG . The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324 1988

19.

Kumar V , Corton RS , Robbins SL . Basic pathology, 7th ed. WB Saunders, Philadelphia, pp. 103-164, 2003

20.

Hochberg MC . Updating the American Colledge of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, 1997

21.

Bohan A , Peter JB . Polymyositis and dermatomyositis (first of two parts). N Engl J Med 292:344-347 1975

22.

Flendrig JA . Benign giant lymphoma: clinicopathologic correlation study. In Clark RL , Gumley RW (eds): The year book of cancer. Year Book Medical Publishers, Chicago, pp. 296-299, 1970

23.

Osborne BM , Butler JJ , Viriakojis D , Kott M . Reactive lymph node hyperplasia with giant follicles. Am J Clin Pathol 78:493-499 1982

24.

Kurth J , Hansmann M-L , Rajewsky K , Küppers R . Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in germinal center reaction. Proc Natl Acad Sci USA 100:4730-4735 2003

25.

Niedobitek G , Herbst H , Young LS , Brooks L , Masucci MG , Crocker J , Rickinson AB , Stein H . Patterns of Epstein-Barr virus infection in nonneoplastic lymphoid tissue. Blood 79:2520-2526 1992

26.

Deamant FD , Albúgar PF , Chen Y-Y , Weiss LM . Epstein-Barr virus distribution in nonneoplastic lymph nodes. Mod Pathol 6:729-732 1993

27.

Kobayashi R , Takeuchi H , Sasaki M , Hasegawa M , Hirai K . Detection of Epstein-Barr virus infection in the epithelial cells and lymphocytes of nonneoplastic tonsils by in situ hybridization and in situ PCR. Arch Virol 143:803-813 1999