Autoimmune Hemolytic Anemia in Lymphoproliferative Disorders
AIHA is a typical, relatively common immune-mediated, paraneoplastic syndrome in LPD. It occurs in almost all histologic subtypes of NHL, but there is no correlation between the frequency of lymphoma and the risk of AIHA. AIHA is relatively most common in SMZL and angioimmunoblastic T-cell lymphoma (Table 1). In most cases of LPD, wAIHAs is predominant. Most wAIHAs, particularly in CLL, seem to be polyclonal. The proportion of patients with wAIHAs is highest in CLL and Hodgkin lymphoma; in other malignancies, the ratio of wAIHAs to cAIHAs is 2:1. In lymphoplasmacytic lymphoma (LPL), almost all antibodies are clonal cAIHAs.
Table1. Secondary Autoimmune Hemolytic Anemia in Malignancies
Autoimmune Hemolytic Anemia as a Risk Factor for Lymphoproliferative Disorder
In various population-based studies, AIHA emerged as a risk fac tor for subsequent development of diffuse, large B-cell lymphoma, LPL, CLL, monoclonal gammopathy with unknown significance (MGUS), and multiple myeloma. Data regarding the type of AIHA and a possible influence of treatment were not available in these studies. It is uncertain whether autoimmune disorder per se is the causal factor or whether these patients had a clinically silent clonal disorder at the time of AIHA.
Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia
The prevalence of AIHA is highest in CLL, ranging from 4.3% to 9%. The prevalence is highest in poor-risk patients (Binet stage B or C, increased ZAP70 expression, unmutated IgVH status, and CD38 positivity) and patients who had already been treated. However, AIHA may also occur in very early stages of CLL, including B-cell monoclonal lymphocytosis. In a large group of non-treated CLL patients, the prevalence of positive DAT result (with or without anemia) was 14%. Most CLL patients with AIHA are men. The vast majority of patients have (presumably) polyclonal wAIHAs, but in all studies, there is small number of cases with cAIHA (specificity anti-I), often with IgM paraproteinemia.
Autoimmune Hemolytic Anemia in Monoclonal Gammopathy With Unknown Significance and Lymphoplasmacytic Lymphoma
The clinical picture of primary chronic CAD suggests the presence of “idiopathic,” or primary cAIHAs, but in fact, most of these patients have a clonal disease with either only clonal IgMk (IgM-MGUS) or LPL with IgM paraproteinemia, MYD88 mutation and bone marrow infiltration (or Waldenström macroglobulinemia). Traditionally, the latter category would be classified as secondary AIHA (CAS). More than 90% of patients with CAD have a monoclonal IgMκ; 7% had IgG or IgA monoclonal immune globulin with λ chains. The course of CAD is usually indolent. Fewer than half of patients require trans fusions and the risk for progression to highly malignant lymphomas is small.
Autoimmune Hemolytic Anemia in Other Lymphoproliferative Diseases and Myeloma
The prevalence of AIHA is low in NHL, ranging from 0.23% to 2.6%. AIHA has been described in all histologic subtypes of NHL. Based on the prevalence of NHL, the association with AIHA is highest with SMZL, LPL, angioimmunoblastic T-cell lymphoma, and γ heavy-chain disease. The antibody may be either a warm (two-thirds) or a cold (one-third) antibody. In NHL, there seems to be a relatively frequent association of AIHA with LA, C1-esterase deficiency, or essential cryoglobulinemia.
A number of predominant wAIHAs have been described in IgG and IgA myelomas.
Autoimmune Hemolytic Anemia in Myeloid Disorders
Generally, AIHA is rare in patients with myeloid malignancies. A number of cases have been reported in myelodysplastic syndromes, particularly chronic myelomonocytic leukemia. Very few cases were described in acute myelogenous and lymphoblastic leukemia, myelofibrosis, and polycythemia.
Autoimmune Hemolytic Anemia in Solid Tumors
A special, rare, but highly interesting cause of wAIHA is an ovarian dermoid cyst. These patients respond very poorly to drug therapies, but the AIHA resolves completely and the DAT result becomes negative a few weeks after ovariectomy. The same behavior has been described in microcystic adenoma of the pancreas and dermoid cyst of the mesentery, both associated with AIHA.
AIHA is rarely but definitely associated with solid tumors. It is a very rare complication of lung, renal cell, and ovarian cancer. In some cases of renal-cell cancer, AIHA resolved after curative surgery.
