Classification of diseases with increased immunoglobulins

From Wikilite

Jump to: navigation, search


SECTION 10 - Practical aspects

Classification of diseases with increased immunoglobulins


  • Serum free light chains can be used in the classification of monoclonal and polyclonal gammopathies.
    1. Monoclonal gammopathies: MGUS, asymptomatic MM (SMM), MM, NSMM, plasmacytomas and plasma cell leukaemia.
    2. Polyclonal gammopathies: connective tissue diseases, liver diseases, chronic infections, lymphoproliferative disorders, other haematologic conditions and more.

29.1. Monoclonal gammopathies

A. New classification

In May 2003, The International Myeloma Working Group published a review of the criteria for the diagnosis and classification of monoclonal gammopathies, multiple myeloma (MM) and related disorders [1]. The aim was to standardise and simplify previous classification systems and provide easy definitions based on routinely available investigations. A uniform approach should facilitate comparisons of therapeutic trial data. The disease groups are as follows and their definitions are found in the respective chapters of this book.

  1. Monoclonal gammopathy of undetermined significance (MGUS). (Chapter 19)
  2. Smouldering (asymptomatic) multiple myeloma (SMM) or Durie and Salmon Stage I). (Chapter 14)
  3. Symptomatic MM. (Chapters 8, 9, 10, 11, 12 and 13)M
  4. Nonsecretory multiple myeloma (NSMM). (Chapter 9)
  5. Solitary plasmacytoma of bone. (Chapter 18.1)
  6. Extramedullary plasmacytoma. (Chapter 18.2)
  7. Multiple solitary plasmacytoma. (Chapter 18.3)
  8. Plasma cell leukaemia. (Chapter 18.4)

B. Old classification

This classification includes the diseases indicated above and other types of monoclonal gammopathies. The distribution of clinical diagnoses in patients with monoclonal gammopathies is discussed further in Section 2. The co-occurrence of monoclonal immunoglobulins with non-malignant conditions is uncommon but a proportion of such patients will contain chance associations with MGUS.

  1. MGUS
    1. Benign (IgG, IgA, IgD, IgM and FLCs)
    2. Biclonal and triclonal gammopathies
  2. Malignant Monoclonal Gammopathies
    1. MM (IgG, IgA, IgD, IgE and free λ or λ light chains)
      1. Overt MM
      2. SMM
      3. Plasma cell leukaemia
      4. NSMM
      5. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; osteosclerotic myeloma)
    2. Plasmacytoma
      1. Solitary plasmacytoma of bone
      2. Extramedullary plasmacytoma
    3. Malignant lymphoproliferative disorders
    4. Waldenström’s macroglobulinemia (primary macroglobulinemia)
    5. Malignant Lymphoma
    6. Chronic lymphocytic leukemia or lymphoproliferative disorders
    7. Heavy chain diseases
      1. γ heavy chain disease
      2. α heavy chain disease
      3. μ heavy chain disease
    8. Amyloidosis
      1. Primary amyloidosis
      2. With MM (secondary, localised, and familial amyloidosis have no monoclonal protein)

    Non-malignant disorders associated rarely with monoclonal proteins (usually MGUS)

    1. Dermatological diseases Lichen myxoedematosus (IgG1), scleroderma, pyoderma gangrenosum, necrobiotic xanthogranuloma, discoid lupus erythematosus, psoriasis, cutaneous lymphoma
    2. Immunosuppression AIDS and HIV infection, renal transplantation, bone marrow transplantation
    3. Liver diseases Chronic hepatitis, cirrhosis, primary biliary cirrhosis
    4. Miscellaneous Rheumatoid arthritis, inflammatory seronegative polyarthritis, polymyositis (IgGκ), polymyalgia rheumatica, myasthenia gravis, angioneurotic oedema (C1 inactivator deficiency)

    29.2. Polyclonal gammopathies

    Chronic infections, autoimmune diseases and many tumours cause increases in polyclonal immunoglobulins and presumably polyclonal FLC concentrations (Chapter 21). Skin, pulmonary and gut diseases are more likely to cause increases in IgA concentrations while systemic infections will increase all immunoglobulins but particularly IgG. The percentages indicate the frequency of the various disorders from a retrospective cohort study of 148 patients with polyclonal gammopathy at The Mayo Clinic [2]. Clearly, results will vary in different parts of the world.

    1. Connective tissue diseases (22%)
      Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, overlap syndrome, juvenile rheumatoid arthritis, progressive systemic sclerosis, ankylosing spondylitis, fibrosing alveolitis, CREST syndrome, temporal arteritis, Raynaud’s phenomenon, cutaneous vasculitis, familial mediterranean fever, eosinophilic fasciitis and inclusion body myositis.
    2. Liver diseases (61%)
      Autoimmune hepatitis, viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cryptogenic cirrhosis, primary hemochromatosis, ethanol-induced liver injury and α1-antitrypsin deficiency.
    3. Chronic Infections (6%)
      Subacute bacterial endocarditis, renal abscess, cystic fibrosis, Whipple's disease, brucellosis, Lyme disease, malaria, worm infestations, tropical splenomegaly syndrome, mycobacterium tuberculosis, mycobacterium leprae, Leishmania organisms, Trypanosoma cruzi, Toxocara canis, HIV-1, varicella and vaccinia.
    4. Lymphoproliferative disorders (5%)
      Pseudolymphoma, Kikuchi disease, malignant lymphoma, Castleman disease, angioimmunoblastic lymphadenopathy with dysproteinemia, large granular lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, plasma cell leukaemia, histiocytosis X, sinus histiocytosis with massive lymphadenopathy, cutaneous eruptive histiocytoma, intracranial plasma cell granulomata, systemic cutaneous plasmacytosis, proteinaceous lymphadenopathy with hypergammaglobulinemia, chronic active EBV infection syndrome and severe autoimmune lymphoproliferative syndrome.
    5. Other haematological conditions
      Myelodysplastic syndromes, idiopathic neutropenia, idiopathic thrombocytopenic purpura, severe hemophilia A, Thalassemia major, Sickle cell anemia, benign hypergammaglobulinemic purpura of Waldenström, cryoglobulinemia and Fanconi anemia.
    6. Non-hematological malignancies (3%)
      Gastric carcinoma, lung cancer, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer and chondrosarcoma.
    7. Neurological conditions
      Acquired chronic dysimmune demyelinating polyneuropathy, HTLV-1-associated myelopathy, chronic progressive sensory ataxic neuropathy, pure motor neuron disease and plasma cell dyscrasia and microangiopathy of vasa nervorum in dysglobulinemic neuropathy.
    8. Diseases with associated immune system abnormalities
      Graves’ disease, chronic ulcerative colitis, chronic autoimmune pancreatitis, sarcoidosis, syndrome of IgG2 subclass deficiency, hyper IgE syndrome, hyperimmunoglobulinemia D and periodic fever syndrome.
    9. Drugs
      Aminophenazone, asparaginase, ethotoin, hydralazine hydrochloride, mephenytoin, methadone, oral contraceptives, phenylbutazone and phenytoin.
    10. Miscellaneous conditions
      Gaucher’s disease, Meniére’s disease, cardiac myxoma, asbestos exposure, cryptogenic organising pneumonitis, lymphoid interstitial pneumonia, distal renal tubular acidosis and hyperimmunisation.
      Chapter 28 Back to Contents Page Chapter 30


      1. Kyle R, Child JA, Anderson K, Barlogie B, Bataille R, Bensinger W, et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–57 PMID: 12780789
      2. Dispenzieri A, Gertz MA, Therneau TM, Kyle RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc 2001;76:476–87 PMID: 11357794 is an online educational resource provided by The Binding Site Group Ltd and is intended for our UK customers. To read our disclaimer and full terms and conditions, please visit Chapter 35.
Personal tools