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Japanese Journal of Clinical Oncology Pages 84-90

Malignant Lymphoma in Patients with Rheumatic Diseases other than Sjögren's Syndrome: a Clinicopathologic Study of Five Cases and a Review of the Japanese Literature
Introduction
Materials And Methods
Results
   Clinical findings
   Histological, immunohistochemical and ebv findings
   Clinical findings
   Pathological findings
Discussion
References

Malignant Lymphoma in Patients with Rheumatic Diseases other than Sjögren's Syndrome: a Clinicopathologic Study of Five Cases and a Review of the Japanese Literature

Malignant Lymphoma in Patients with Rheumatic Diseases other than Sjögren's Syndrome: a Clinicopathologic Study of Five Cases and a Review of the Japanese Literature Masaru Kojima1,2, Shigeo Nakamura3, Naoki Futamura4, Yoshiyuki Kurabayashi2, Satoshi Ban2, Hideaki Itoh2, Katsue Yoshida2,6, Takashi Joshita2 and Taizan Suchi3

1Department of Pathology and Clinical Laboratories, Ashikaga Red Cross Hospital, Ashikaga, 2Department of Clinical Laboratories, Gunma University School of Medicine, Maebashi, 3Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya, 4First Department of Surgery, Gifu University School of Medicine, 5Department of Pathology, Maebashi Red Cross Hospital, Maebashi, 6Department of Pathology and Clinical Laboratories, Kiryu Welfare General Hospital, Kiryu, Japan

We conducted clinicopathologic and immunohistochemical analysis of five patients with malignant lymphoma complicating rheumatic diseases other than Sjögren's syndrome, and reviewed 26 cases of similar lesions reported in the Japanese literature over a 17-year period. All five patients were women ranging in age from 31 to 74 years (mean 55 years). Two of them fulfilled the diagnostic criteria for systemic lupus erythematosus, two for dermatomyositis and one for progressive systemic sclerosis. The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in four patients. All the biopsied or resected specimens showed non-Hodgkin's lymphoma of B-cell phenotype. Three were nodal in origin (one diffuse mixed, one diffuse large cell and one immunoblastic) and two were extranodal (one low-grade B-cell lymphoma of mucosa- associated lymphoid tissue and one diffuse large cell). In three of four cases examined, Epstein-Barr virus-encoded small RNAs were identified in a small to large number of the lymphoma cells by in situ hybridization. Our study showed that the clinicopathological features of malignant lymphomas complicating rheumatic disease in Japan were similar to those in England and the USA. Furthermore, our findings suggested no evidence for a causative association between iatrogenic immunosuppression due to methotrexate therapy and the development of EBV-related lymphoid neoplasms.

Key Words: malignant lymphoma - rheumatic disease - clinicopathologic study - Epstein-Barr virus

INTRODUCTION

The range of autoimmune disease types extends from organ-specific (e.g., Hashimoto's thyroiditis) to non-organ-specific and generalized (e.g., systemic lupus erythematosus [SLE]) types (1,2). Sjögren's syndrome also manifests both organ-specific and non-organ-specific features with localized pathological changes, and systemically distributed autoantigens (1,2). It is well known that the development of malignant lymphoma in the thyroid and salivary glands is closely related to a background of Hashimoto's thyroiditis and Sjögren's syndrome respectively (1,2). In patients with other rheumatic diseases such as SLE and rheumatoid arthritis (RA), there has been considerable controversy in the literature about a possibily increased risk of developing lymphoproliferative disorders (3-10). On the other hand, in patients with acquired immunodeficiency syndrome or solid organ transplantation, immunosuppression-related lymphomas have been shown to be characterized by a large or polymorphous form, the presence of Epstein-Barr virus (EBV) and extranodal location (11-13). Based on this background, Kamel et al. (10) recently described that a proportion of lymphoid neoplasms in patients with RA and dermatomyositis (DM) exhibited features similar to those of immunosuppression-related lymphomas, suggesting that this phenomenon might be partly attributable to the treatment received, especially methotrexate administration.

In the present study, we investigated the clinicopathologic and EBV findings of malignant lymphomas developing in five patients with systemic rheumatic diseases other than Sjögren's syndrome, and reviewed 26 Japanese cases reported in the literature for comparison with those in England and the USA (3-5,10,14-33).

MATERIALS AND METHODS

The study materials were biopsied or surgically resected specimens obtained from five patients with malignant lymphomas associated with systemic rheumatic diseases other than Sjögren's syndrome at Gunma University Hospital between 1978 and 1994. Clinical information was obtained from the patient records and attending physicians. The clinical staging of malignant lymphoma was based on the criteria of the Ann Arbor classification (34).


Figure 1.Diffuse large cell lymphoma. The tumor cells have large round nuclei, with small nucleoli apposed to the nuclear membrane. Numerous histiocytes are intermingled with tumor cells. Case 2.

Sections 3 µm thick were cut from formalin-fixed paraffin- embedded tissue and stained with hematoxylin-eosin, Giemsa, PAS and silver impregnation (Watanabe) techniqes. For immunohistochemical studies, sections were stained by the indirect immunoperoxidase method using human immunoglobulin subclasses L26 (CD20), DFT-1 (CD43), UCHL-1 (CD45RO) (Dako, A/S, Denmark) and LN-1 (CDw75) (Techniclone, Santa Ana, USA). In four cases (nos. 2, 3, 4 and 5), the presence or absence of EBV small RNAs was determined by in situ hybridization(ISH) using EBV-encoded small RNA (EBER) oligonucleotides on formalin-fixed paraffin-embedded sections (35). Briefly, the Dako hybridization kit was used with a cocktail of fluorescein isothiocyanate (FITC)-labeled EBER oligonucleotides (one oligonucleotide corresponding to EBER-1 and one to EBER-2, both 30 bases long) (Dako A/S code Y 017). The hybridization products were detected using mouse monoclonal anti-FITC (Dako M878) and a Vectastain ABC kit (Vector, Burlingame, CA). EBV-negative lymphoid tissues and RNAase (Boehringer, Mannheim, Germany) or DNAase I (Pharmacia, Brussels, Belgium) pretreatment were used as controls, and one case of infectious mononucleosis served as a positive control.

The non-Hodgkin's lymphomas (NHLs) were classified according to the Working Formulation for clinical usage (36). One case of gastric lymphoma was diagnosed as low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) according to Isaacson and Spencer (37).

We reviewed the records of 26 patients with malignant lymphomas that followed systemic rheumatic diseases other than Sjögren's syndrome, which have been described in 21 different reports in the Japanese literature between 1978 and 1994 (7,14-33). We focused especially on: 1, the patient's age at the time of lymphoma onset; 2, sex; 3, the type of rheumatic disease; 4, the site of disease; 5, the disease stage according to the Ann Arbor system (34); 6, the interval between the onset of rheumatic disease and that of lymphoma; 7, any history of immunosuppressive therapy before the onset of the lymphoma; 8, treatment of the lymphoma; 9, survival time; 10, histologic and immunohistochemical features. The original histologic diagnosis in the literature was converted to the terminology used in the Working Formulation (36).


Figure 2. Immunoblastic lymphoma. The tumor cells have large prominent central nucleoli. Some of the cells show plasmacytic differentiation. Case 3.

RESULTS

Clinical findings

The clinical data for the five patients are shown in Table 1. Two patients fulfilled the 1982 revised diagnostic criteria for SLE (38), two fulfilled the Bohan and Peter diagnostic criteria for DM (39) and one met the diagnostic criteria of the American Rheumatism Association for progressive systemic sclerosis (PSS) (40). All five patients were women and their ages ranged from 30-74 years (mean 55). At the time of development of the malignant lymphomas, the systemic rheumatic diseases were inactive except in one patient with DM (Case 3). The interval between the onset of rheumatic disease and that of malignant lymphoma ranged from 6 months to 13 years (mean 5.9 years). Malignant lymphomas were found at extranodal sites in two patients (Cases 1 and 5), and the disease was in the advanced stage in two patients (Cases 2 and 4). Use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in four patients (Cases 1, 2, 3 and 5). Three patients (Cases 2, 3 and 4) were treated by chemotherapy. One (Case 1) underwent resection of a cecal tumor and chemotherapy, and one (Case 5) underwent gastrectomy. Three patients (Cases 1, 2 and 3) died of malignant lymphoma and two (Cases 4 and 5) are currently alive and disease-free.

Table 1 . Clinical findings in the present five cases
No

 Age/Sex

 Dis.

 Activity

 Sign

 Site of
lymphoma		 Stage

 Dur.

 Immunosup.
drug		 Therapy

 Outcome
1

 30/F

 SLE

 Inactive

 Abdominal
pain		 Cecum,
regional LN		 IIE

 9yr

 Predonine,
Endoxan		 Resection
+ CHOP		 46moD(+)
2

 53/F

 SLE

 Inactive

Fever,
neck tumor		 Systemic LN

 III

 5yr

 Predonine

 COP

 2moD(+)
3

 53/F

 DM

 Active

Fever

 Inguinal,
retro LN		 II

 6mo

 Predonine

 VEPA

 11moD(+)
4

 59/F

 PSS

 Inactive

Inguinal
tumor		 Systemic LN
liver, spleen, tonsil		 VI

 13yr

 (-)

 MCNU-VEPA

 42moA(-)
5 74/F DM inactive (-) Stomach IE 2yr Predonine Resection 38moA(-)
Dis., systemic rheumatic disease; Activity, activity of rheumatic disease; Dur., duration from onset of rheumatic disease to onset of lymphoma; Immunosup. drug, immunosuppressive drugs used before onset of lymphoma; SLE, systemic lupus erythematosus; DM, dermatomyositis; PSS, progressive systemic sclerosis; LN, lymph nodes; retro, retroperitoneal; yr, years; mo, months; CHOP, cyclophosphamide, adriamycin, vincristine, predonine; COP, cyclophosphamide, vincristine, predonine; VEPA, vincristine, cyclophosphamide, predonine, adriamycin; MCNU, ranimustine; D, dead; A, alive; (+), with disease; (-), without disease.

Histological, immunohistochemical and ebv findings

Histological, immunohistochemical and EBV findings in the five cases are shown in Table 2.

Histologically, all five lesions were NHLs and all showed a diffuse growth pattern. According to the Working Formulation (36), two (Cases 1 and 2) were diffuse large cell (Fig. 1), one (Case 3) was immunoblastic (Fig. 2), one (Case 4) was diffuse mixed and one (Case 5) of the gastric lymphomas was a low-grade MALT lymphoma (Figs. 3 and 4) (37). None of the five cases showed cellular polymorphism including small and large lymphocytes, plasma cells and immunoblasts, geographic tumor necrosis or single cell necrosis.


Figure 3. Low grade B-cell lymphoma of the mucosa-associated lymphoid tissue. Low magnification shows neoplastic cells diffusely infiltrating the gastric mucosa. Case 5.


Figure 4. High-power field of Fig. 3. A lymphoepithelial lesion is evident. Case 5.

Immunohistochemically, all five lesions exhibited a B-cell phenotype. All were positive for L26 and four (Cases 1, 2, 3 and 4) were positive for LN-1. Intracytoplasmic immunoglobulin was positive in one patient (Case 3; IgG, kappa).

In three of the four cases examined, EBERs were identified. In one (Case 3), nearly all the tumor cells contained EBV (Fig. 5), but in two (Cases 2 and 5), fewer than 30% of the tumor cells contained EBV.Analysis of reports in the japanese literature

A summary of the 26 cases reported in the Japanese literature is shown in Table 3.

Table 2 . Pathological findings in the present five cases
No. Histology L26 LN-1 UCHL-1 DFT-1 Cytoplasmic Ig EBER
1 Diffuse large + + - - - ND
2 Diffuse large + + - - - +
3 Immunoblastic + + - - Kappa, IgG +
4 Diffuse mixed + + - - - -
5 MALT lymphoma + - - - - +
Ig, immunoglobulin; ND, not done; MALT, low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.


Figure 5. Immunoblastic lymphoma. In situ hybridization shows Epstein-Barr virus RNA (black nuclear staining) in the tumor cells (Case 3).

Clinical findings

Seven patients were male and 19 were female. Their age at the time of diagnosis of malignant lymphoma ranged from 27 to 80 years (mean 58). Eighteen cases of lymphoma occurred in RA, four in SLE, three in polymyositis (PM) and one in RA + SLE. The site of the lymphoma was recorded in 24 patients. In nine cases (Nos. 9, 13, 14, 21, 23, 25, 26, 28 and 29), the lymphoma developed at an extranodal site, and six cases (Nos. 7, 9, 20, 21, 23 and 25) were in the localized stage. The use of immunosuppressive drugs before onset of the lymphoma was recorded in seven cases (Nos. 9, 20, 25, 26, 27, 28 and 29). The interval between the onset of rheumatic disease and that of lymphoma ranged from 6 months to 36 years (mean 11.4 years). One case (No. 16) was associated with gastrointestinal amyloidosis and one (Case 17) with Waldenström's macroglobulinemia. Treatment was recorded in 23 cases. Thirteen patients (Cases 9, 10, 11, 12, 13, 15, 16, 17, 19, 20, 22, 29 and 30) received combination chemotherapy, three (Cases 24, 27, 28) received predonine alone, two (Cases 25 and 26) underwent primary tumor resection, combination chemotherapy and radiation therapy, one (Case 14) underwent primary tumor resection and combination chemotherapy, one (Case 21) received combination chemotherapy and radiation therapy, and one (Case 23) was given radiation therapy alone. Two patients (Cases 18 and 31) had no treatment. Follow-up data were obtained from 24 cases. Sixteen patients (Cases 6, 8, 9, 10, 12, 17, 18, 19, 20, 23, 24, 26, 27, 28, 29 and 31) died of malignant lymphoma, and the diagnosis of malignant lymphoma was made at autopsy in four of them (Cases 18, 27, 28, 31). One patient (Case 25) died of gastrointestinal bleeding, and no residual lymphoma cells were detected at autopsy. Seven patients (Cases 11, 13, 14, 15, 16, 22, 30) are still alive, two of them (Cases 11 and 16) with disease and the other five (Cases 13, 14, 15, 22 and 30) without.

Pathological findings

The type of malignant lymphoma in two (Cases 15 and 31) of these patients was Hodgkin's disease (HD), while in the other 24 it was NHL. Based on the Working Formulation (53), 10 cases (Nos 6, 7, 10, 11, 12, 14, 18, 19, 20 and 23) were diffuse large cell, six (Nos 13, 22, 26, 27, 28 and 30) were diffuse small cleaved cell, four (Nos 9, 21, 24 and 29) were diffuse mixed, two (Nos 17 and 25) were immunoblastic, one (No. 8) was follicular small cleaved and one (No. 16) was follicular large cell lymphoma. Immunophenotypic analysis was performed by immunohistochemical staining on 21 NHLs, revealing that 15 (Nos 7, 9, 13, 14, 16, 18, 19, 20, 21, 22, 23, 26, 27, 28 and 30) of the lesions had a B-cell phenotype and four (Nos 17, 24, 25 and 29) had a T-cell phenotype. In two cases (Nos 10 and 12), cellular lineage was undetermined. In three cases (Nos 6, 8 and 11), the lymphoma cells were considered to be of B-cell origin based on their morphologic features.

DISCUSSION

Thirty-one Japanese cases including our present five were reviewed in the this study, and compared with four reports dealing with a large number of cases in England and the USA (Table 4) (3-5,10) The clinicopathologic features of the Japanese cases were essentially similar to those in the four foreign reports in the following respects: 1, rheumatic disease almost invariably preceded the development of lymphoid neoplasms; 2, more than half of the patients were diagnosed as having RA; 3, a striking female predominance was noted, reflecting the sex ratio of patients with RA and SLE; 4, the interval between diagnosis and the development of lymphoma was more than 12 months in most cases; 5, more than half of the NHLs had high-grade histology; 6, follicular lymphoma and Hodgkin's disease were recognized in a only few cases.

Table 3 . Clinicopathological features of Japanese patients with malignant lymphoma developing after systemic rheumatic disease
No

 Age/
Sex		 Dis.

 Site of
lymphoma		 Stage

 Im.
Sup		 Dur.

 Therapy

 Outcome

 Histol.

 Cell
type		 Ref
6 27/F RA+ SLE (U) (U) (U) 11yr (U) 5moD(+) DL B 14
7 45/F RA Lt. neck I (-) 9yr (U) (U) DL B 15
8 52/M RA (U) (U) (U) 16yr (U) 27moD(+) FSC B 14
9 60/F RA Skin IIE P 10yr Chem. 31moD(+) DMx B 16
10

 61/F

 RA

 Systemic LA,
pleura, liver		 IV

 (-)

 22yr

 Chem.

 13moD(+)

 DL

 UD

 17
11 62/F RA Systemic LN III (-) 17yr Chem. 13moA(+) DL B 18
12 62/F RA Systemic LN III (-) 36yr Chem. 3moD(+) DL UD 17
13 64/M MRA Spleen, LN IIIE (-) 7yr Chem. 45moA(-) DSC B 19
14 65/M RA Lung, LN IIIE (U) 15yr O+Chem. 48moA(-) DL B 20
15 65/F RA Systemic LN III (-) 8yr Chem. 6moA(-) Hodgkin UD 18
16 66/F RA Systemic LN III (-) 15yr Chem. 6moA(+) FL B 21
17



 67/F



 RA



 Systemic LN,
skin, liver,
bone marrow
spleen		 IV



 (-)



 3.5yr



 Chem.



 10moD(+)



 IB



 T



 22
18

 67/F

 RA

 LN, kidney,
spleen		 IV

 (U)

 27yr

 (-)

 *D

 DL

 B

 23
19

 68/F

 RA

 Systemic LN

 III

 (-)

 10yr

 Chem.

 14moD(+)

 DL

 B

 17
20

 70/F

 RA

Pharynx,
Rt. Neck LN		 II

 P

 21yr

 Chem.

 6moD(+)

 DL

 B

 17
21

 72/M

 RA

 Skin

 IE

 (-)

 6yr

 Chem.
+RT		 (U)

 DMx

 B

 24
22


 73/F


 RA


 Axilla,
inguinal LN,
skin, liver		 IV


 (U)


 10yr


 Chem.


 6moA(-)


 DSC


 B


 25
23

 76/F

 RA

 Skin
(multiple)		 IIE

 (U)

 20yr

 RT

 6moD(+)

 DL

 B

 26
24

 80/F

 RA

 Systemic LN

 III

 (-)

 15yr

 P

 1moD(+)

 DMx

 T

 27
25

 30/M

 SLE

 Liver

 IE

 P

 3.5yr

 O+Chem+RT

 18moD(-)

 IB

 T

 28
26

 34/F

 SLE

 Spinal cord,
bone marrow		 IVE

 P

 4yr

 O+Chem+RT

 4moD(+)

 DSC

 B

 7
27

 47/F

 SLE

 Systemic LN

 III

 P+AZ

 5.5yr

 P

 *D

 DSC

 B

 29
28

 51/F

 SLE

 CNS

 IVE

 P+CPM

 6mo

 P

 *D

 DSC

 B

 30
29

 32/M

 PM

 Spinal cord,
stomach, soft
tissue		 IVE

 P

 3yr

 Chem.

 5moD(+)

 DMx

 T

 31
30

 49/M

 PM

 Systemic LN,
bone marrow		 IV

 (-)

 6mo

 Chem.

 1moA(-)

 DSC

 B

 32
31

 67/F

 PM

 Systemic LN,
liver, spleen		 IV

 (-)

 6mo

 (-)

 *D

 Hodgkin

 UD

 33
Im.Sup., use of immunosuppressive drugs before onset of lymphoma.; Dur., period between onset of rheumatic disease and onset of lymphoma; Histol, histology; Ref, references; RA, rheumatoid arthritis; (U), unknown; MRA, malignant rheumatoid arthritis; SLE, systemic lupus erythematosus; PSS, progressive systemic sclerosis; DM, dermatomyositis; PM, polymyositis; LN, lymph node; CNS, central nervous system; retro,retroperitoneum; P, predonine; CPM, cyclophosphamide; AZ, azathioprine; yr, years; mo, months; O, operation; Chem., combination chemotherapy; P, predonine; RT, radiation therapy; A,alive; D, died; (+), with disease; (-), without disease; *Malignant lymphoma was diagnosed at autopsy.; DL, diffuse large; FSC, follicular small cleaved; Dmx, diffuse mixed; FL, follicular large; DSC, diffuse small cleaved; IB, immunoblastic; UD, undetermined. Case 13 was associated with bladder cancer, Case 16 was associated with amyloidosis and case 17 with macroglobulinemia.

In one study, MALT lymphomas occounted for 20% of all NHLs associated with Sjögren's syndrome (41). However, in our series, MALT lymphoma was found in only one (3%) of 31 cases of NHLs associated with rheumatic diseases other than Sjögren's syndrome.

Several hypotheses have been proposed to explain the association between lymphoid neoplasms and rheumatic diseases (2-10). These include 1, treatment of rheumatic disease produces lymphoid neoplasms; 2, susceptibility to both diseases is due to genetic predisposition or a single causative agent such as a virus; 3, chronic immune stimulation causes malignant transformation of B cells; 4, proliferation of a forbidden clone of lymphocytes produces both diseases.

The pathogenetic role of immunosuppressive therapy in the development of lymphoproliferative disorders in patients with systemic rheumatic diseases other than Sjögren's syndrome has been a subject of debate (3-10). Recently, Kamel et al. reported 18 patients with RA or DM who developed lymphoid neoplasms (10). EBV was detected in six (33%) of the 18 lymphoid neoplasms and five (83%) of the six EBV-associated lesions occurred in patients who had received methotrexate (14). It was therefore suggested that therapeutic immunosuppression, especially with methotrexate, may have contributed to this phenomenon, since their cases showed clinicopathologic features common to immunosuppression-associated lymphoma such as an extranodal location, a large cell or polymorphous form, geographic necrosis, presence of EBV and the occurrence of spontaneous regression after withdrawal of immunosuppressive therpapy (11-13).

In the present study, we investigated the clinicopathologic and EBV features of malignant lymphoma in five patients with rheumatic diseases other than Sjögren's syndrome. These five cases also shared some of the clinicopathologic features of immunosuppression-associated lymphomas (11-13): 1, all five lymphomas exhibited a B-cell phenotype; 2, three (60%) showed a large cell or immunoblastic morphology; and 3, EBV was found in three (75%) of four cases examined. To our knowledge, there has been no description in the Japanese literature regarding the frequency of EBV in malignant lymphomas occurring in patients with rheumatic disease. In spite of the small number of cases in our series, this rate of EBV association was much higher than that (12.5%) of B-cell-phenotype NHLs in Japanese with no underlying disorders (42). In our series, the frequency of EBV detection was higher than that reported by Kamel et al., although none of our patients received methotrexate. Our results indicated that, at least in patients with rheumatic disease in Japan, EBV-related lymphoid neoplasms were unrelated to immunosuppression with methotrexate. Furthermore, it appears that the pathogenic role of EBV in the development of these lymphoid neoplasms cannot yet be completely accepted, because EBV was often found in only a minor proportion of the lymphoma cells in both our cases and those reported by Kamel et al. (10).

In contrast to the general pattern of NHLs in Japan (43), our study showed that >90% of the NHLs had a B-cell phenotype and that extra-nodal lymphomas occurred in only 30% of cases. These findings seem to be chacteristic of rheumatic disease-associated lymphoma in Japan, although further study is needed to confirm this.

Table 4 . Clinicopathological features of Japanese patients with malignant lymphoma developing after systemic rheumatic disease

Green
et al.(3)		 Banks
et al.(4)		 Symmons
et al.(5)		 Kamel
et al.(10)		 Current
study
Total no of cases 11 14 17 18 31
RA   13 17 15 18
SLE 11 1     6
PSS         1
DM/PM       3 5
RA+SLE         1
M: F ratio 0:11 4:10 6:11 2:16 7:24
Age range (yr) 28-65 51-86 40-74 15-87 27-80
(average) (46) (64) (62) (63) (57)
Duration (yr) 1/6-36* 1/3-63[dagger] 3-24* NM 1/2-36*
(average) (10) (15) (14)   (11)
Immunosup Tx 11 NM NM 15[Dagger] 11
Site of lymphoma
nodal 8 NM NM 8 18
extranodal 2     10 11
unknown 1       2
Histology
Hodgkin's 4   4 2 2
SL 1 1 4 2  
Follicular 2 2 1 4 2
DSC   2     6
DMx 1   1 1 5
DL&IB 3 9 6 9 15
Others     1   1
Cell type NE NE NE    
T       1 4
B       13 23
Undetermined       4 4
No, number; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; DM/PM, dermatomyositis/polymyositis; M:F, male to female; Immunosup Tx, immunosuppressive therapy (suppressive therapy before onset of lymphoma); SL, small lymphocytic; DSC, diffuse small cleaved; DMx, diffuse mixed; DL, diffuse large; IB, immunoblastic; *duration between onset of rheumatic disease and onset of lymphoma; [dagger]duration between diagnosis of rheumatic disease and onset of lymphoma; [Dagger]11 of 15 cases were treated with methotrexate before onset of lymphoma; NM, not mentioned; NE, not examined.

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Received August 22, 1996; accepted November 7, 1996
For reprints and all correspondence: Masaru Kojima, Department of Pathology and Clinical Laboratories, Ashikaga Red Cross Hospital, 3-2100 Honjo, Ashikaga, Tochigi 326, Japan.
Abbreviations: EBV, Epstein-Barr virus; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; DM, dermatomyositis; ISH, in situ hybridization; EBER, EBV-encoded small RNA; FITC, fluorescein isothiocyanate; NHL, non-Hodgkin's lymphoma; MALT, mucosa-associated lymphoid tissue; PSS, progressive systemic sclerosis; PM, polymyositis; HD, Hodgkin's disease;

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