Benign, atypical and malignant lymphoproliferative disorders in rheumatoid arthritis patients (2022)

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Volume 60, Issue 10,

December 2006

, Pages 663-672

Abstract

Lymphadenopathy, which may be associated with systemic symptoms, is frequently associated with rheumatoid arthritis (RA). Reactive non-neoplastic tissue comprises the majority of the lymph node lesions. However, several cohort studies have demonstrated that RA has an increased risk of non-Hodgkin's lymphomas (NHLs). Since the early 1990s, an atypical or malignant lymphoproliferative disorders (LPD) in patients immunosupressed with methtorexate (MTX) therapy for RA has been emphasized, namely MTX-associated LPDs. Epstein–Barr virus (EBV) has received attention in connection with the etiology of RA. The present review describes the clinicopathologic and immunohistochemical findings of reactive, atypical and malignant LPDs associated with RA along with the presence or absence of EBV in LPDs using the in situ hybridization (ISH) method. The majority of reactive lymph node lesions exhibit reactive follicular hyperplasia with interfollicular polyclonal plasmacytosis. Atypical LPDs rarely appears in RA patients. However, these cases occasionally pose difficult problems in the differential diagnosis from malignant lymphomas associated with RA or atypical and malignant LPDs showing RA-like clinicopathological findings. Clinicopathologically, three types of atypical LPDs have delineated, i.e. (i) resembling multicentric Castleman’s disease (MCD); (ii) atypical paracortical hyperplasia with lymphoid follicles (APHLF) and; (iii) atypical lymphoplasmacytic immunoblastic proliferation. Malignant lymphoma associated with RA is characterized by; (i) predominance of elderly cases; (ii) usually female predominance, reflecting the sex ratio of RA; (iii) longstanding history of RA; (iv) relatively frequent advanced stage of disease; (v) majority of the patients had the B-cell phenotype; and (vi) an increased frequency of diffuse large B-cell lymphoma (DLBCL) in RA. It is unlikely that EBV is the causative agent of either reactive or atypical LPD. Among malignant lymphomas, EBV-associated lymphoma comprised only a small fraction of all NHLs in the general RA patient population.

Introduction

Rheumatoid arthritis (RA) is a chronic disease in which non-suppurative inflammation of the synovium is frequently associated with a variety of extra-articular manifestations [1].

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Lymphadenopathy, which may be associated with systemic symptoms such as fever and weight loss, is frequently found in patients with RA [2]. In various studies, the number of patients exhibiting lymphadenopathy has ranged from 50% to 75% [2], [3], [4], and distinctive histological characteristics are evident in the sampled lymph node. Histologically, reactive lymphoproliferative disorders (LPDs) associated with RA usually demonstrate reactive follicular hyperplasia and polyclonal plasma cell infiltration in the interfollicular area [3], [4]. Rarely, the lymph node lesion contains sarcoid-like granuloma [5].

A category of LPDs has recently emerged, and has been designated atypical LPDs because these disorders closely mimic malignant lymphomas, both clinically and pathologically, but do not demonstrate all of the characteristics of malignancy (e.g. monoclonality) [6], [7]. Although, atypical LPDs have rarely been described in association with RA [4], reports have included multicentric Castleman's disease (MCD) [8], atypical paracortical hyperplasia with lymphoid follicles (APHLF) [9] and atypical lymphoplasmacytic immunoblastic proliferation in lymph nodes [10], [11].

An increased risk of hematological malignancies including non-Hodgkin's lymphoma (NHL) in patients with RA was suggested in the 1970s [12], [13], [14], [15]. There is strong evidence from case-control morbidity studies suggesting that patients with RA have an increased risk for spontaneous development of NHLs [12], [13], [14], [15]. Moreover, in the early 1990s, it was shown that patients with RA have an increased risk of developing atypical or malignant LPD [7], [16], [17], [18], [19]. Although the reason for this association remains controversial, immunosuppressive therapy particularly low-dose methotrexate (MTX) therapy, as well as Epstein–Barr virus (EBV) infection may contribute to the development of these LPDs [7], [16], [17], [18], [19]. The histomorphological and immunohistochemical features of malignant lymphoma associated with RA including MTX-associated LPDs have been well discussed in the literature from western countries, particularly the USA. [7], [16], [17], [18], [19], [20], [21], [22], [23]. However, in Japan, little is known about the clinicopathological and immunohistological findings of malignant lymphomas associated with RA including MTX-associated LPD [24], [25], [26].

Although the pathogenesis of RA remains unclear, it is currently believed that RA is triggered by exposure of arthrogenetic microbial antigens. Among the causative antigens, EBV has received attention in the connection with the etiology of RA [27]. Serologic data has been proposed to implicate of EBV in the etiology of RA. However, whether synovial tissue in RA is specifically infected by EBV remains controversial. We also examined the presence and distribution of EBV+ cells using EBV-encoded small RNA (EBER)-specific in situ hybridization (ISH) in reactive, atypical and malignant LPDs using formalin-fixed paraffin-embedded sections treated with Ventana automated (BenchMark™) stainer.

In this review, we described clinicopathological and immunohistochemical and EBV findings of reactive, atypical and malignant LPDs based on findings in cases we have encountered.

Firstly, the clinicopathologic and immunohistologic features of reactive follicular hyperplasia with interfollicular plasmacytosis of the lymph node have been described. Secondly, the present review focuses on the histopathological, immunohistochemical and genotypic findings of atypical LPDs in lymph nodes from RA patients, and their differential diagnostic problems.

Finally, we describe clinicopathologic and immunohistochemical findings in 24 Japanese cases of malignant lymphomas associated with RA occurring in north east Japan.

The findings of EBER+ cells were also described along with the histological and immunohistological findings of reactive, atypical and malignant LPDs.

Section snippets

Clinical findings (Table1)

In our 22 cases including four cases with malignant RA (MRA), there were five males and 17 females with a broad age distribution (27–75years; mean, 57; median 57) [28]. Joint disease of varying severity was present in all patients, systemic symptoms in 8, elevated erythrocyte sedimentation rate in all 17 tested cases, and polyclonal hyper gamma-globulinemia was found in 12 of 15 cases. These findings indicated that lymph node lesions in RA patients might be associated with active disease.

Atypical LPDs anditsdifferential diagnostic problems

We describe here, histopathological and immunohistochemical findings of atypical LPDs. Three distinct clinicopathological subtypes of atypical LPDs associated with RA have been delineated; i.e. (i) resembling MCD; (ii) APHLF; (iii) and atypical lymphoplasmacytic and immunoblastic proliferation. As we have previously described, atypical LPDs associated with RA usually exhibit multicentric lymphadenopathy, constitutional symptoms and abnormal laboratory findings [9], [11] (Table2). These cases

Malignant lymphoma inpatients with RA

The main clinicopathological, immunohistochemical and EBV findings in our 24 cases are shown in Table4 [25], [26] and compared with five reports describing with a large number of cases in Table5.

Conclusion

Previous review emphasized an association of malignant LPDs and RA. However, this review focused on clinicopathological findings of reactive or atypical LPDs associated with RA patients along with their differential diagnostic problems. EBV has received attention in connection with the etiology of RA [27]. However, using the ISH method, we indicated that EBV-associated LPDs occupied only a small fraction of benign, atypical and malignant LPDs associated with RA.

In the majority of cases, the

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