Excerpt from Angioimmunoblastic Lymphadenopathy With Dysproteinemia

Synonyms, Key Words, and Related Terms: AILD, angioimmunoblastic T-cell lymphoma, diffuse plasmacytic sarcomatosis, immunoblastic lymphadenopathy, lymphogranulomatosis X, immunologic aberrations in idiopathic reticulosis, angioimmunoblastic lymphadenopathy, AIL

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Background

In 1974, Frizzera et al¹ described angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). In some classifications, similar atypical lymphoproliferative disorders were later grouped as lymphogranulomatosis X or immunoblastic lymphadenopathy.

AILD is a type of peripheral T-cell lymphoma that is clinically characterized by high fever and generalized lymphadenopathy that sometimes has cutaneous involvement. As AILD progresses, hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia may develop. The skin is involved in approximately 40-50% of patients. Patients are usually aged 40-90 years. In one series, other symptoms included weight loss (58%), hepatomegaly (60%), polyclonal hyperglobulinemia (65%), and generalized adenopathy (87%).

AILD may represent a spectrum of disease ranging from a hyperplastic but still benign immune reaction to frank malignant lymphoma. Because clonal expansion of T cells has been demonstrated in most but not all cases of AILD, subclassification has been introduced and comprises 3 subsets of the disease: AILD with no evidence of clonal lymphoid proliferation; AILD-type dysplasia with inconsistent findings regarding the clonality of the proliferating cells; and AILD-type lymphoma with strong evidence of clonality by immunohistochemical tests, rearrangement analysis, and cytogenetic studies. However, AILD-type dysplasia with an oligoclonal T-cell pattern has frequently been shown to progress into AILD-type lymphoma. Thus, subclassification may reflect the existence of stages in the development of the disease rather than independent disease entities.

Krenacs et al² have suggested that the phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma appears consistent with the phenotype of activated follicular B-helper T cells.

Pathophysiology

Evidence exists that AILD develops in a serial fashion. The initial reaction may be an unbalanced immune response to an unknown antigen. This stage is followed by an oligoclonal phase that is driven by persistence and ineffective handling of the primary and initial stimulus. Further events, assumed to take place on a molecular level, may then evolve into malignant monoclonal disease. In AILD, the factors that result in the serial evolution into malignant lymphoma have yet to be defined. Patients frequently pass through a phase of atypical immune reactions, such as an allergic drug reaction or an allergic reaction to an arthropod bite. Moreover, latent infections with Epstein-Barr virus (EBV) or human cytomegalovirus (CMV) as evidenced by data from in situ hybridization and polymerase chain reaction tests, may also be involved.

AILD, specifically angioimmunoblastic T-cell lymphoma, is mainly derived from CD2⁺CD3⁺CD4⁺CD5⁺CD7^- mature T-helper cells with varying expression and partial loss of detectable CD4. A significant number of non-neoplastic T cells (resting CD4⁺ T cells and activated small- or medium-sized CD8⁺ lymphocytes) may coexist with a minor neoplastic T-cell population.

A deletion mutant of the LMP1 oncogene of EBV is associated with the evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.

Dunleavy et al³ noted that over expression of the chemokine CXCL13 and vascular endothelial growth factor-A in angioimmunoblastic T cell lymphoma suggests that it may be derived from follicular helper T cells.

Using immunohistochemistry, Grogg et al⁴ noted CD10 and CXCL13 staining in bone marrow samples in a subset of patients with AILD. The lymphomatous infiltrate in some bone marrow specimens from these AILD patients contained numerous small or scattered large B cells, and these cells resembled either benign lymphoid aggregates or T-cell–rich large B cell lymphoma, respectively. Trilineage hematopoietic hyperplasia and plasmacytosis were other changes noted by Grogg et al.

Murakami et al⁵ noted that, similarly to multiple myeloma, c-Maf expression occurs in persons with angioimmunoblastic T-cell lymphoma.

Frequency

United States

The exact incidence is not known. However, it is well reported. Approximately 1-2% of non-Hodgkin lymphomas are associated with AILD.

International

The exact incidence is not known. In one case series in Korea, 1 of 78 cases of lymphoma was diagnosed as AILD. In a series of 3194 cases of lymphoma in Japan, 2.35% were diagnosed as AILD.

Mortality/Morbidity

Treatment of AILD is suboptimal, with approximately 25% of patients achieving complete and sustained remission when combined chemotherapy agents are used. However, in most patients, the condition eventually evolves into AILD-type lymphoma.

Race

This disease has been reported in Asia, the United States, and Europe. Few reports in the literature describe this disease in African American and Hispanic persons.

Sex

In 2000, in a series of 10 patients, Martel et al⁶ reported 7 women and 3 men. In 1995, Siegert et al⁷ reported a female-to-male ratio of 1:1.4 in a series of 62 patients.

Age

Most patients are middle aged or elderly. AILD has been reported in children. In 1995, Siegert et al⁷ reported a median patient age of 64 years (range, 21-87 y) in a series of 62 patients.

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