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


RegisterSign in


  • Access throughyour institution

Volume 60, Issue 10,

December 2006

, Pages 663-672


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.


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].

(Video) Virtual Patient Conference: CD30+ Lymphoproliferative Disorders

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.


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

References (44)

  • C.P. Hans et al.Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray



  • R. Blanco et al.Systemic lupus erythematosus-associated lymphoproliferative disorder: report of a case and discussion in light of the literature

    Hum. Pathol.


  • M. Kojima et al.Idiopathic multicentric Castleman’s disease. A clinicopathologic and immunohistochemical study of five cases

    Pathol. Res. Pract.


  • G. Niedobitek et al.Patterns of Epstein–Barr virus infection in non-neoplastic lymphoid tissue



  • M. Kojima et al.Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases

    Pathol. Res. Pract.


  • O.W. Kamel et al.Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein–Barr virus and other features associated with immunosuppression

    Hum. Pathol.


  • D.P.M. SymmonsNeoplasms of the immune system in rheumatoid arthritis

    Am. J. Med.


  • H.A. Isomäki et al.Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis

    J. Chronic Dis.


    (Video) Sjogren's Syndrome: Beyond Dry Eyes and Mouth by Frederick Vivino, MD

  • M. Kojima et al.Atypical lymphoplasmacytic and immunoblastic proliferation from rheumatoid arthritis. A case report

    Pathol. Res. Pract.


  • M. Kojima et al.Autoimmune disease-associated lymphadenopathy with hiostological appearance of T-zone dysplasia with hyperplastic follicles. A clinicopathologic analysis of nine cases

    Pathol. Res. Pract.


  • V. Kumar et al.
  • A.G. Motulsky et al.

    Lymph nodes in rheumatoid arthritis

    Arch. Intern. Med.


  • J.S. Nosanchuk et al.

    Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis. A clinicopathologic study



  • K. Henry

    Connective tissue disorders/autoimmune diseases

  • W.G. McCluggage et al.

    Lymph node hyalinization in rheumatoid arthritis and systemic sclerosis

    J. Clin. Pathol.


  • G. Frizzera

    Atypical lymphoproliferative disorders

  • H.L. Ioachim et al.

    Ioachim’s lymph node pathology. 3rd ed


  • E. Ben-Chetrit et al.

    Multicentric Castleman’s disease assocoiated with rheumatoid arthritis: a possible role of hepatitis B antigen

    Ann. Rheum. Dis.


  • C.H. Koo et al.

    Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy)

    Medicine (Baltimore)


  • E. Thomas et al.

    Risk of malignancy among patients with rheumatic conditions

    Int. J. Cancer


  • M.J. Leandro et al.

    Rheumatic diseases and malignancy-is there an association

    Scand. J. Rheumatol.


  • O.W. Kamel et al.

    Hodgkin’s disease and lymphoproliferations resembling Hodgkin’s disease in patients receiving long-term low-dose methotrexate therapy

    Am. J. Surg. Pathol.


  • Cited by (38)

    • Patients with autoimmune diseases have an altered activity of the PD-1 pathway and proportions of Epstein-Barr virus infected cells in benign lymphadenopathies

      2021, Immunobiology

      Patients with autoimmune diseases (AD) have an increased risk to develop benign lymphadenopathies compared to patients without AD. The aim with this study was to determine the role of the PD-1 pathway and the number of cells harboring Epstein-Barr virus (EBV) in benign lymphadenopathies in patients with AD (cases) compared to patients without AD (controls). Pathology registries were screened to identify patients with biopsies diagnosed as benign lymphadenopathy and medical journals were reviewed for information on AD. Immunohistochemical stainings (PD-1 and PD-L1) and EBER in situ hybridization for EBV were applied on lymph node biopsies in patients with AD (n=22) and patients without AD (n=57). The case group was compared with the control group with Wilcoxon-signed rank, chi-square and Fischeŕs exact test. There was a statistically significantly higher proportion of PD-1+ cells and a tendency for a lower prevalence of PD-L1+ and EBV+ cells in cases compared to controls. Apparently, patients with AD have an altered immune response as revealed in benign lymphadenopathies compared to patients without AD. If this association might be a piece of the puzzle for the increased risk of development of lymphomas in patients with AD remains to be determined.

    • Castleman Disease

      2019, Surgical Pathology Clinics

      In these cases, the differential diagnosis can be challenging. Lymph nodes in patients with autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, adult-onset Still disease, and juvenile idiopathic arthritis can show features of PC-CD.69,70 This observation suggests that a subset of cases of unicentric or multicentric PC-CD cases have an autoimmune etiology, or at least an autoimmune component in their pathogenesis.

      (Video) Systemic and Inflammatory Disease of the Larynx - Dr. Matthew Naunheim
    • Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells

      2019, Blood

      CD30 is expressed on a variety of B-cell lymphomas, such as Hodgkin lymphoma, primary effusion lymphoma, and a diffuse large B-cell lymphoma subgroup. In normal tissues, CD30 is expressed on some activated B and T lymphocytes. However, the physiological function of CD30 signaling and its contribution to the generation of CD30+ lymphomas are still poorly understood. To gain a better understanding of CD30 signaling in B cells, we studied the expression of CD30 in different murine B-cell populations. We show that B1 cells expressed higher levels of CD30 than B2 cells and that CD30 was upregulated in IRF4+ plasmablasts (PBs). Furthermore, we generated and analyzed mice expressing a constitutively active CD30 receptor in B lymphocytes. These mice displayed an increase in B1 cells in the peritoneal cavity (PerC) and secondary lymphoid organs as well as increased numbers of plasma cells (PCs). TI-2 immunization resulted in a further expansion of B1 cells and PCs. We provide evidence that the expanded B1 population in the spleen included a fraction of PBs. CD30 signals seemed to enhance PC differentiation by increasing activation of NF-κB and promoting higher levels of phosphorylated STAT3 and STAT6 and nuclear IRF4. In addition, chronic CD30 signaling led to B-cell lymphomagenesis in aged mice. These lymphomas were localized in the spleen and PerC and had a B1-like/plasmablastic phenotype. We conclude that our mouse model mirrors chronic B-cell activation with increased numbers of CD30+ lymphocytes and provides experimental proof that chronic CD30 signaling increases the risk of B-cell lymphomagenesis.

    • Castleman Disease Pathogenesis

      2018, Hematology/Oncology Clinics of North America

      Autoimmune diseases can demonstrate clinical and histopathologic features that are identical to iMCD. Nearly all lymph nodes of patients with rheumatoid arthritis and 15% to 30% of lymph nodes from patients with systemic lupus erythematosus display CD histopathologic features.36,37 Patients with iMCD respond to therapies used to treat autoimmune disease, such as anti–IL-6 receptor therapy and cyclosporine.38

    • Reactive Lymph Nodes and Castleman Disease

      2018, Hematopathology: A Volume in the Series: Foundations in Diagnostic Pathology

      Lymph nodes and lymphoid tissue in various extranodal sites can be involved by a variety of reactive processes. In many cases, the histologic changes are nonspecific, and a particular cause cannot be assigned; in other cases, the findings are suspicious for, or even diagnostic of, a certain entity. This chapter focuses on histologically distinctive lymphoid hyperplasias and lymphadenitides and on their differential diagnosis. A number of types of reactive lymphoid hyperplasias can have histologic features that are atypical, distorting the nodal architecture and potentially mimicking a lymphoproliferative disorder. Familiarity with the range of changes that may be seen in reactive lymph nodes can help prevent a misdiagnosis of lymphoma.

    • International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease

      2017, Blood

      Human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

    View all citing articles on Scopus

    Recommended articles (6)

    • Research article

      Secukinumab for ankylosing spondylitis

      The Lancet, Volume 383, Issue 9919, 2014, p. 780

    • Research article

      (Video) Autoimmune Neurology: Paraneoplastic Disorders and Beyond

      Secukinumab for ankylosing spondylitis

      The Lancet, Volume 383, Issue 9919, 2014, p. 780

    • Research article

      Hypofibrinogénémie et thrombopénie persistantes induites par le tocilizumab. Commentaire de l’article: «Hypofibrinogénémie induite par le tocilizumab: 7cas» de Martis et al., Revue du rhumatisme 2017. DOI: 10.1016/j.rhum.2017.07.019

      Revue du Rhumatisme, Volume 84, Issue 6, 2017, pp. 562-563

    • Research article

      A case of Merkel cell carcinoma development under treatment with a Janus kinase inhibitor

      JAAD Case Reports, Volume 3, Issue 6, 2017, pp. 498-500

    • Research article

      A Cutoff Value Based on Analysis of a Reference Population Decreases Overestimation of the Prevalence of Nocturnal Polyuria

      The Journal of Urology, Volume 188, Issue 3, 2012, pp. 869-874

      We sought criteria for nocturnal polyuria in asymptomatic, nonurological adults of all ages by reporting reference values of the ratio of daytime and nighttime urine volumes, and finding nocturia predictors.

      Data from a database of frequency-volume charts from a reference population of 894 nonurological, asymptomatic volunteers of all age groups were analyzed. The nocturnal polyuria index and the nocturia index were calculated and factors influencing these values were determined by multivariate analysis.

      The nocturnal polyuria index had wide variation but a normal distribution with a mean ± SD of 30% ± 12%. The 95th percentile of the values was 53%. Above this cutoff a patient had nocturnal polyuria. This value contrasts with the International Continence Society definition of 33% but agrees with several other reports. On multivariate regression analysis with the nocturnal polyuria index as the dependent variable sleeping time, maximum voided volume and age were the covariates. However, the increase in the nocturnal polyuria index by age was small. Excluding polyuria and nocturia from analysis did not alter the results in a relevant way. The nocturnal voiding frequency depended on sleeping time and maximum voided volume but most of all on the nocturia index.

      The prevalence of nocturnal polyuria is overestimated. We suggest a new cutoff value for the nocturnal polyuria index, that is nocturnal polyuria exists when the nocturnal polyuria index exceeds 53%. The nocturia index is the best predictor of nocturia.

    • Research article

      Paraoxonase 1 activity and level of antibodies directed against oxidized low density lipoproteins in a group of an elderly population in Poland – PolSenior study

      Archives of Gerontology and Geriatrics, Volume 60, Issue 1, 2015, pp. 153-161

      The aim of this study was to assess two factors influencing the amount of oxidized LDL-paraoxonase 1 (PON1) activity and the level of anti-oxidized LDL antibodies (anti-ox LDL) in a large group of elderly individuals in Poland. The effects of cognitive status, hypertension and metabolic syndrome and of selected serum lipids and inflammation indicators on PON1 activity and anti-ox LDL level were also examined.

      The investigated population consisted of 3154 individuals aged 65 and more – participants of the population-based PolSenior project.

      PON1 arylesterase activity was determined spectrophotometrically, anti-ox-LDL antibodies using ELISA method.

      PON1 activity significantly decreased with advancing age, was lower in males than in females and decreased in persons with impaired cognition. Individuals with hypertension and high lipid levels showed higher PON1 activity. Lower PON1 activity was related to higher level of inflammation indicators – hsCRP and IL-6. The significant association of PON1 activity with age, HDL-C, LDL-C, sex and IL-6 was confirmed in multivariate analysis.

      Anti-ox LDL antibodies level was significantly higher in the two oldest subgroups of males. It was significantly lower in males than in females. It was decreased in persons with higher serum triglycerides. No relationship of anti-ox LDL level with cognition, hypertension, metabolic syndrome, inflammation indicators and serum lipid levels was observed. In some persons very high levels of anti-ox LDL were stated, most frequently in the oldest persons, particularly in men.

      (Video) Rheumatoid Arthritis: Early Diagnosis and Treatment

      Both investigated antioxidant factors – PON1 activity and anti-ox LDL level, could play an important role in aging.

    View full text

    Copyright © 2006 Elsevier Masson SAS. All rights reserved.


    1. Radiography of Arthritis, 2018 Refresher
    (Chris Beaulieu)
    2. Reactive Non Neoplastic Lymph Nodes Pt 1
    (Pushing Glass Coast 2 Coast)
    3. Virtual T-Cell Lymphoma Patient Forum - July 10, 2021
    (T-Cell Leukemia Lymphoma Foundation)
    4. Lecture-71: Management of Psoriasis and its variants
    5. Dr. Peter Vadas - CME Presentation: Mast Cells Gone Wild - Mast Cell Activation Disorders
    (The ILC Ehlers Danlos & Chronic Pain Foundation)
    6. STR Cardiothoracic Case Webinar 6/19/2014
    (Jeffrey Kanne)

    You might also like

    Latest Posts

    Article information

    Author: Saturnina Altenwerth DVM

    Last Updated: 06/07/2022

    Views: 6288

    Rating: 4.3 / 5 (64 voted)

    Reviews: 87% of readers found this page helpful

    Author information

    Name: Saturnina Altenwerth DVM

    Birthday: 1992-08-21

    Address: Apt. 237 662 Haag Mills, East Verenaport, MO 57071-5493

    Phone: +331850833384

    Job: District Real-Estate Architect

    Hobby: Skateboarding, Taxidermy, Air sports, Painting, Knife making, Letterboxing, Inline skating

    Introduction: My name is Saturnina Altenwerth DVM, I am a witty, perfect, combative, beautiful, determined, fancy, determined person who loves writing and wants to share my knowledge and understanding with you.