Angioimmunoblastic T-Cell Lymphoma

Updated: Apr 24, 2020
  • Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

In 1974, Frizzera et al [1] described angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). In some classifications, similar atypical lymphoproliferative disorders were later grouped as lymphogranulomatosis X or immunoblastic lymphadenopathy. The disorder is now classified as angioimmunoblastic T-cell lymphoma (AITL). Both terms are in common use.

AITL is a type of peripheral T-cell lymphoma (PTCL) that is clinically characterized by high fever and generalized lymphadenopathy. Approximately 40-50% of patients also have cutaneous involvement. As the disorder progresses, hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia may develop. In one series, other symptoms included weight loss (58%), hepatomegaly (60%), polyclonal hyperglobulinemia (65%), and generalized adenopathy (87%). Patients are usually aged 40-90 years.

AITL 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 AITL, the following three subclassifications have been introduced:

  • AITL with no evidence of clonal lymphoid proliferation
  • AITL-type dysplasia with inconsistent findings regarding the clonality of the proliferating cells
  • AITL-type lymphoma with strong evidence of clonality by immunohistochemical tests, rearrangement analysis, and cytogenetic studies

AITL-type dysplasia with an oligoclonal T-cell pattern has frequently been shown to progress into AITL-type lymphoma. Thus, this subclassification may reflect the existence of stages in the development of the disease rather than independent disease entities.

Krenacs et al have suggested that the phenotype of neoplastic cells in AITL appears consistent with the phenotype of activated follicular B-helper T cells. [2] It has become clear that AITL is a clonal T-cell disorder involving deregulation of B-cells and endothelial cells against a background involving a unique malignant microenvironment.

Biopsies of the bone marrow, lymph node, and skin are key in diagnosing AITL (see Workup). Many agents have been used to treat AITL, but none has proved universally or consistently effective (see Treatment and Management).

AITL can occur with other neoplasms. AITL has been reported to occur concurrently with plasma cell leukemia. [3] AITL has also been noted to manifest with a leukemic presentation. [4]

For other discussions on lymphoma, see the overview topic Non-Hodgkin Lymphoma.

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Pathophysiology

Evidence exists that angioimmunoblastic T-cell lymphoma (AITL) 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 AITL, 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. Latent viral infection may also be involved (see Etiology).

AITL 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.

Dunleavy et al noted that overexpression of the chemokine CXCL13 and vascular endothelial growth factor–A in AITL suggests that it may be derived from follicular helper T cells. [5]

Using immunohistochemistry, Grogg et al noted CD10 and CXCL13 staining in bone marrow samples in a subset of patients with AITL. [6] The lymphomatous infiltrate in some bone marrow specimens from these AITL 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 al reported that the oncogene c-Maf was expressed in the majority of AITLs studied. [7] c-Maf is also overexpressed in approximately half of multiple myelomas.

Tripodo et al have suggested that mast cells have a role in the proinflammatory microenvironment of AITL. [8] They observed that mast cells, which preferentially occurred in AITL cases, directly synthesized interleukin 6 and correlated with the presence of interleukin 17–producing T cells.

In late 2013, Kashara et al reported on 85 cases of AITL with 219 genes from the United States and Europe. All cases had TET2 mutations. In addition, loss-of-function mutations were noted: 4 in TP53, 3 in ETV6, 2 in CCND3, and 5 in EP300. Gain-of-function mutations were also found: 2 in JAK2, and 4 in STAT3 (n=4). [9]

In a separate study, somatic RHOA mutations that encoded a p.Gly17Val alteration were found in 68% of AITL samples. Interestingly, whenever the mutation p.Gly17Val occurred, the TET2 mutation occurred as well. [10]

Elevated absolute monocyte numbers can predict unfavorable outcomes in AITL. [11]

Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) and their clinicopathological implications were investigated in peripheral T-cell lymphoma (PTCL), including AITL. [12]

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Etiology

Data from in situ hybridization and polymerase chain reaction tests suggest that angioimmunoblastic T-cell lymphoma (AITL) may be linked to latent infection with a variety of viruses, such as Epstein-Barr virus (EBV), [13] cytomegalovirus (CMV), and herpesvirus type 6. A deletion mutant of the LMP1 oncogene of EBV is associated with the evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.

The body's immune system is also thought to misapprehend some antigens, resulting in the cascade of cytokines and gene expression that underlies AITL. The actual proximate cause is not known. The role of EBV infection in skin lesions is not clear.

Patients with Sjögren syndrome are at increased risk for developing lymphoma. Although most lymphomas in these patients are of the B-cell variety, AITL constitutes the majority of T-cell lymphomas associated with Sjögren syndrome. [14]

Medications linked to the induction of AITL include salazosulfapyridine, azithromycin, and doxycycline.

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Epidemiology

The exact incidence of angioimmunoblastic T-cell lymphoma (AITL) is not known. In the United States, approximately 1-2% of non-Hodgkin lymphomas are associated with AITL. In one case series in Korea, 1 of 78 cases of lymphoma was diagnosed as AITL. In a series of 3194 cases of lymphoma in Japan, 2.35% were diagnosed as AITL.

The female-to-male ratio in AITL remains uncertain. In 2000, in a series of 10 patients, Martel et al reported 7 women and 3 men. [15] In 1995, Siegert et al reported a female-to-male ratio of 1:1.4 in a series of 62 patients. [16]

Although AITL has been reported in children, most patients are middle aged or elderly. Siegert et al reported a median patient age of 64 years (range, 21-87 y) in a series of 62 patients. [16]

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Prognosis

Overall, angioimmunoblastic T-cell lymphoma (AITL) has a moderately aggressive course, with occasional spontaneous remissions or protracted responses to therapy. The median survival is 24 months. AITL can evolve into high-grade lymphomas of T- or B-cell type, Epstein-Barr virus (EBV)–positive B-cell lymphomas, and chronic lymphatic leukemia (CLL), among other kinds of lymphoma and leukemia. Most patients eventually die of infections due to immunologic compromise.

A univariate analysis by Siegert et al showed that survival was significantly related to the following [16] :

  • Age
  • Stage
  • Rash/pruritus
  • Edema
  • Ascites
  • Number of clinical symptoms
  • LDH level
  • Hemoglobin level

Schlegelberger et al found that certain cytogenetic findings were associated with a significantly lower incidence of therapy-induced remissions and a significantly shorter survival duration. [17] These cytogenetic findings included the following:

  • Aberrant metaphases in unstimulated cultures
  • Clones with an additional X chromosome
  • Structural aberrations of the short arm of chromosome 1, preferentially involving 1p31-32
  • Complex aberrant clones with more than four aberrations
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Patient Education

Patients and their families must understand that angioimmunoblastic T-cell lymphoma (AITL) is usually a fatal disease and is accompanied by many potentially serious infections.

For patient education information, see the Cancer Center, as well as Lymphoma and Skin Cancer.

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