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Angioimmunoblastic T-Cell Lymphoma


Definition

Angioimmunoblastic T-cell lymphoma (AITL) is a systemic lymphoproliferative disorder characterized by generalized lymphadenopathy, hepatosplenomegaly, constitutional symptoms, rash, anemia, and polyclonal hypergammaglobulinemia. Histologically, the normal architecture of the lymph node is effaced by a polymorphic cellular infiltrate composed of lymphocytes, plasma cells, eosinophils, histiocytes, and immunoblasts. A hallmark of the disease is a prominent proliferation of high endothelial venules with arborization and a diffuse proliferation of follicular dendritic cells, usually with the disappearance of follicles and germinal centers. Initially, AITL was thought to represent an abnormal immune reaction characterized morphologically as atypical lymphoid hyperplasia with a high risk for progression to malignant lymphoma. However, subsequent gene-rearrangement studies have shown clonal rearrangement of the T-cell receptor (TCR) genes in the majority of cases ; therefore, AITL is regarded as the prototype of peripheral T-cell lymphoma derived from the follicular helper T cell (T FH ) population of the germinal center. Terms frequently used in the past to describe this disease include angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), immunoblastic lymphadenopathy, lymphogranulomatosis X, and AILD-type T-cell lymphoma . In the Revised European American Lymphoma (REAL) classification, this entity was recognized as angioimmunoblastic T-cell lymphoma.

Epidemiology

AITL accounts for approximately 1% to 2% of non-Hodgkin's lymphomas. It is the second most common specific subtype of peripheral T-cell lymphoma (PTCL) worldwide, but it appears more prevalent in Europe (29% of cases) than in North America or Asia, where the prevalence is approximately 16% to 18% of cases. AITL is most frequently observed in middle-age and older adult patients, with a peak incidence in the sixth and seventh decades of life, although young adults may rarely be affected. The male-to-female ratio is 1 : 1; however, some studies have reported a slight male predominance.

Etiology

The cause of AITL is unknown. Originally, this disorder was thought to be triggered by the administration of drugs, most commonly antibiotics, or to occur after an infectious disease, suggesting that AITL represented the manifestation of an abnormal immune reaction. Subsequent work explored the role of Epstein-Barr virus (EBV) in the pathogenesis of AITL. EBV has been detected by in situ hybridization in 80% to 96% of lymph nodes involved by the disease. In most cases, the EBV-infected cells represent transformed B cells; only rarely in older reports has it been suggested that T cells are infected by EBV. The prevalence of infected B cells in AITL patients may amount to 1 in 10 to 1 in 500 B cells in lymph nodes. In contrast, in healthy EBV carriers, EBV resides in B cells at a frequency of approximately 1 in 10 6 to 1 in 10 7 . Despite the obvious pathogenetic role of EBV in a variety of other lymphomas, it is currently thought that the presence of EBV in AITL is not causative; it most likely reflects the underlying immunodeficiency that is characteristic of the neoplastic process, although a more direct role for EBV in driving the T-cell proliferation has been postulated.

Follicular Helper T Cells

T FH cells are a distinct functional subset of effector T-helper cells that reside in the germinal center and are specialized in providing help to B cells during the germinal-center reaction. T FH cells promote B-cell survival, immunoglobulin class-switch recombination, and somatic hypermutation, ultimately yielding high-affinity plasma cells and memory B cells. T FH differentiation is dependent upon the transcriptional repressor BCL6 and the expression of CXCR5, which are first detectable in T cells at the border between the T-zones and the follicles (T : B border) soon after T-cell priming and before germinal-center formation. BCL6 expression in T cells is able to downregulate CCR7 and upregulate CXCR5, inducible costimulator (ICOS), programmed death 1 (PD1), interleukin (IL)-21R, and IL-6R. The expression of ICOS also seems to play an important role in the initial stage of T FH differentiation at the time of T-cell priming by antigen-presenting dendritic cells. These CD4-positive, CXCR5-positive, BCL6-positive T cells, so called pre-T FH cells, are essential for the initiation of the germinal-center and extrafollicular antibody responses. The T FH -specific secretory profile, including IL-21, CXCL13 chemokine, and its receptor CXCR5, are critical to recruit and localize T FH cells in the germinal center. CXCR5 enables the migration of T FH cells into CXCL13-rich areas in B-cell follicles. Once T FH cells are located in the germinal center, they upregulate the expression of PD1, IL-21, CD84, and ICOS. These markers, which are characteristic of T FH cells, can be used in diagnostic practice either by flow cytometry or by immunohistochemistry on routinely formalin-fixed tissue.

Clinical Features

The clinical presentation of AITL is unique among malignant lymphomas, and the diagnosis is frequently suspected on clinical grounds. Most patients present with generalized peripheral lymphadenopathy, hepatosplenomegaly, and prominent systemic symptoms including fever, weight loss, and rash, often with pruritus. One third of patients present with edema, especially in the upper extremities and face; pleural effusion; arthritis; and ascites. Polyclonal hypergammaglobulinemia and Coombs-positive hemolytic anemia are frequently present. Bone marrow is commonly involved. Approximately 30% of patients present with eosinophilia, and 10% present with plasmacytosis. Laboratory studies reveal the presence of cold agglutinins, circulating immune complexes, anti–smooth muscle and antinuclear antibodies, positive rheumatoid factor, and cryoglobulins. The evolution of the disease is often complicated by intercurrent infections with conventional and opportunistic microorganisms. There is no consensus regarding the best therapeutic approach to patients with AITL. Patients may respond initially to steroids or mild cytotoxic chemotherapy, but progression usually occurs. Derivation from T FH cells explains many of the distinctive clinical characteristics of AITL including hypergammaglobulinemia, autoimmune phenomena, and clonal B-cell proliferations, suggesting that the malignant T FH cells, like their normal counterpart, can stimulate B-cell proliferation.

Morphology

In contrast to other peripheral T-cell lymphomas, AITL displays some unique morphologic features in involved lymph nodes ( Box 36-1 ). At low magnification, the lymph node architecture is usually effaced. There is a polymorphic infiltrate of small to medium-sized lymphocytes intermingled with granulocytes, eosinophils, plasma cells, fibroblast-like dendritic cells, histiocytes, and epithelioid cells predominantly occupying the paracortical or interfollicular area ( Fig. 36-1 ). Occasionally a neoplastic T-cell population can be readily identified on morphologic grounds. In these cases, there is an infiltration of atypical T cells characterized by round to irregular nuclear contours and broad, clear cytoplasm with distinct cell membranes (clear cells) ( Fig. 36-2, A ). Cytologic atypia of the lymphoid cells, although frequently observed, is not a prerequisite for diagnosis (see Fig. 36-2, B ). The proportion of atypical T cells may vary greatly from small foci to large confluent sheets, sometimes posing problems in the differential diagnosis with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Noteworthy is that medium-sized to large basophilic blasts of B-cell phenotype may be present, some of them reminiscent of Hodgkin cells ( Fig. 36-3 ).

Box 36-1
Diagnostic Criteria for Angioimmunoblastic T-Cell Lymphoma

Morphology

  • Usually effaced lymph node architecture

  • Perinodal extension of infiltrate, with sparing of sinuses

  • Polymorphic infiltrate of lymphocytes, granulocytes, plasma cells, and immunoblasts

  • T cells with abundant clear cytoplasm (clear cells)

  • Proliferation of FDCs

  • Proliferation of arborizing high endothelial venules

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