Rheumatoid Arthritis-related Lymphadenopathy



Rheumatoid Arthritis-related Lymphadenopathy


L. Jeffrey Medeiros, MD





Key Facts


Terminology



  • Lymphadenopathy accompanying rheumatoid arthritis (RA)


Etiology/Pathogenesis



  • Smoking is risk factor


  • Infectious agent may act as antigenic trigger of RA


  • Genetic susceptibility and impaired T-cell function are involved in RA


Clinical Issues



  • Lymphadenopathy occurs in ˜ 75% of RA patients at some point in their clinical course


  • Can be localized or systemic


Microscopic Pathology



  • Marked follicular hyperplasia in cortex and medulla of lymph node



    • “Starry sky” pattern within germinal centers


    • Hyaline-like eosinophilic deposits(+/-)


  • Interfollicular areas show marked plasmacytosis


  • Capillary endothelial hyperplasia


Ancillary Tests



  • Immunophenotype



    • Polytypic B cells and plasma cells; normal T cells


  • EBER(+) in ˜ 20% of RA-related lymph nodes


  • No monoclonal Ig or TCR gene rearrangements


Diagnostic Checklist



  • It is unusual for RA-related lymphadenopathy to be initial manifestation of RA


  • Clinical history is often available to support diagnosis



    • Joint symptoms &/or physical manifestations


    • Laboratory results supporting diagnosis of RA





TERMINOLOGY


Definitions



  • Lymphadenopathy accompanying rheumatoid arthritis (RA)


ETIOLOGY/PATHOGENESIS


Environmental Exposure



  • Smoking is risk factor



    • Increases risk of developing RA


    • Correlates with increased disease severity


Autoimmune Disease



  • Infectious agent may act as antigenic trigger of RA



    • Possible/suspected organisms include



      • Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Parvovirus


      • Rubella virus, Mycoplasma species


  • Genetic susceptibility is involved in RA



    • Association with HLA-DR1 and HLA-DR4


    • Recently reported loci at chromosomes 10p15, 12q13, and 22q13


  • T-cell function is impaired in RA


  • RA is mediated by inflammatory mediators and cytokines released by macrophages and synovial lining cells



    • Activated by CD4(+) T helper cells


    • Important cytokines: Tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6


    • Bone and cartilage destruction mediated by prostaglandins, matrix metalloproteinases, RANKL


CLINICAL ISSUES


Epidemiology



  • Incidence



    • RA affects 0.8% of world population


  • Age



    • ˜ 80% of patients develop RA between 35-50 years


    • Can affect patients at any age


  • Gender



    • Male to female ratio = 1:3-5


Site



  • Most common sites of lymphadenopathy: Cervical, supraclavicular, axillary



    • Any lymph node group can be affected


Presentation



  • RA usually has insidious onset



    • 10% of patients have acute onset with rapid polyarticular involvement


  • Initial symptoms may be nonspecific and generalized



    • Fatigue, weakness, anorexia, fever, musculoskeletal pain


  • Joint involvement often follows generalized symptoms



    • Small joints in hands and feet are affected before large joints


    • Typically symmetric


  • Lymphadenopathy occurs in ˜ 75% of RA patients at some point in their clinical course



    • Can be localized or systemic


  • Felty syndrome = RA, splenomegaly, and autoimmune neutropenia


  • In 1987, American Rheumatism Association proposed criteria to help establish diagnosis of RA



    • Total of 4 of 7 criteria support diagnosis of RA



      • Morning stiffness


      • Arthritis in 3 or more joints


      • Arthritis of hand joints


      • Symmetric arthritis


      • Rheumatoid nodule(s)


      • Serum rheumatoid factor (RF)(+)


      • Typical radiographic changes


Laboratory Tests



  • Rheumatoid factor (RF)




    • RF = immunoglobulins that react with Fc portion of IgG molecules



      • Most standard tests detect IgM


    • ˜ 60% of patients with RA have elevated RF in serum


    • RF can be elevated in other autoimmune diseases



      • Sjögren syndrome, systemic lupus erythematosus


    • Serum RF levels can be positive in healthy individuals



      • ˜ 5%; positivity tends to increase with age


  • Anti-cyclic citrullinated peptide antibodies (anti-CCP)



    • Positive 80-85% of RA patients; more sensitive than RF


    • Higher specificity for RA (90-96%) than RF (50-80%)


Natural History



  • RA is progressive disease that can be crippling in untreated patients


  • RA-related lymphadenopathy can wax and wane


Treatment



  • Drugs



    • Immunomodulator agents



      • Methotrexate is commonly used


      • Anti-TNF α and other recently developed biological therapies


    • Therapies used more commonly in the past



      • Azathioprine


      • Gold


Prognosis



  • Patients with RA have increased risk of malignant lymphoma



    • Risk is ˜ 2x greater than general population


    • Increased risk of lymphoma is attributable to RA itself



      • Highest risk in patients who are serum RF(+)


      • Can be detected after 5 years of follow-up


    • Therapy of RA patients also may increase risk of developing lymphoma


  • Common types of lymphoma that occur in RA patients



    • Diffuse large B-cell lymphoma (DLBCL) is most common



      • ˜ 60-70% of all lymphomas in RA patients


    • Classical Hodgkin lymphoma (HL)



      • Nodular sclerosis or mixed cellularity most often reported


    • Other lymphoma types reported with some frequency in RA patients



      • Follicular lymphoma


      • Mantle cell lymphoma


      • Marginal zone B-cell lymphomas


      • Peripheral T-cell lymphoma not otherwise classified


    • Evidence of EBV present in subset of DLBCL and classical HL of RA patients



      • ˜ 20% of DLBCLs are EBV(+)


IMAGE FINDINGS


Radiographic Findings



  • Joints show juxtaarticular osteopenia and bone erosion with narrowing of joint spaces


  • Lymphadenopathy can be detected by various imaging methods


MICROSCOPIC PATHOLOGY


Histologic Features



  • Marked follicular hyperplasia in cortex and medulla of lymph node



    • Follicles of various sizes and shapes


    • “Starry sky” pattern within reactive germinal centers


    • ± hyaline-like eosinophilic deposits in germinal centers



      • Can be extensive and replace lymph node parenchyma


      • Dystrophic calcification can occur


      • PAS(+), Congo red(-)


    • “Cracking artifact” around follicles in poorly fixed tissues



  • Interfollicular areas



    • Plasmacytosis is present and often prominent



      • Small aggregates or sheets of plasma cells without atypia


      • Cytoplasmic globules of Ig in plasma cells (Russell bodies)


    • Capillary endothelial hyperplasia


  • Neutrophils in sinuses and interfollicular areas


  • ± sarcoid-like granulomas


  • After immunosuppressive therapy lymph nodes often show



    • Reduced follicular hyperplasia


    • Expanded interfollicular regions and paracortical hyperplasia


  • After gold therapy lymph nodes may show



    • Nonbirefringent crystalline structures throughout parenchyma



      • Free within spaces or in histiocyte cytoplasm


  • RA patients can develop lymphoplasmacytic infiltrates of lung



    • Interstitial or nodular pattern


    • ± reactive germinal centers


    • Aggregates of small lymphocytes and plasma cells


    • Can be associated with amyloid


    • Rheumatoid nodules can occur in lung ± lymphoplasmacytic infiltrate


Cytologic Features



  • Very few reports in literature of fine needle aspiration findings of RA-related lymphadenopathy


ANCILLARY TESTS


Immunohistochemistry

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Rheumatoid Arthritis-related Lymphadenopathy

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