Angioimmunoblastic T-Cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL) is a neoplasm of mature T follicular helper (TFH) cells characterized by systemic disease, a polymorphous infiltrate involving lymph nodes, with a prominent proliferation of high endothelial venules and follicular dendritic cells (Swerdlow et al. 2017).
Presenting features and sites of involvement
In typical cases, AITL presents as a subacute or acute systemic illness which may manifest after administration of drugs (especially antibiotics) or after a viral infection. Therefore, AITL may masquerade as an infectious process or a systemic inflammatory disease. Several reports also mentioned an association with various bacterial or fungal infections, likely reflecting the consequences of immune deregulation in AITL patients, rather than a causal relationship.
Frequency of clinical and laboratory features in AITL patients
Sex ratio (male to female)
General clinical features
Advanced stage (III/IV)
LDH > normal
Performance status >1
High-risk IPI (4–5)
Bone marrow involvement
Positive Coombs test
Laboratory tests often disclose a variety of hematological, biochemical, and/or immunologic abnormalities. Anemia (often hemolytic and Coombs positive), polyclonal hypergammaglobulinemia, and hypereosinophilia are the most common alterations seen at diagnosis. Lymphopenia, thrombocytopenia, and the presence of various autoantibodies (rheumatoid factor, antinuclear factor, anti-smooth muscle, etc.), of cryoglobulins or cold agglutinins, are other common findings.
The course of AITL is variable, with occasional spontaneous remissions, but overall it portends a poor prognosis even when treated intensively, with a median survival <3 years and a 5-year overall survival around 30–35%. However, AITL is not always lethal with 30% of long-term survivors.
Lymph nodes are often mildly to moderately enlarged (<1 to 3 cm) and present a homogeneous fleshy texture, similar to other lymphomas.
The lymphoma cells are medium-sized cells with round or slightly irregular nuclei and abundant clear cytoplasm and tend to form small clusters around high endothelial venules. In less typical cases, the neoplastic cells are smaller with only slight pleomorphism and atypia and without striking clear cell component.
Varying numbers of small B cells and polytypic plasma cells are distributed randomly as single cells or as small clusters in association with FDC aggregates. In addition, a population of large B blasts, which may sometimes mimic Reed–Sternberg cells, usually infected by EBV, is almost invariably present.
Variant Architectural Patterns
Three architectural patterns are recognized: pattern I (AITL with hyperplastic follicles), pattern II (AITL with depleted follicles), and pattern III (AITL without follicles, as described above), the latter being the most frequently encountered (Attygalle et al. 2014).
In pattern II (AITL with depleted follicles), occasional depleted follicles are present.
In contrast with pattern III, FDCs are normal or only minimally increased in patterns I and II. Patterns I to III have been documented in consecutive biopsies and are thought to represent progressive stages of the disease and to reflect morphologic evolution rather than clinical progression, as patients with pattern I usually show advanced-stage disease.
Morphologic Variants According to Cell Content
A subset of AITL contain a high proportion of large B-cell blasts (>25%) (B-cell-rich AITL), which are usually but not always infected by EBV. In some cases, the proliferation of EBV-positive B-cell blasts may be so prominent to form diffuse confluent sheets; in these cases, a diagnosis of EBV-positive lymphoproliferation or EBV-positive diffuse large B-cell lymphoma may be rendered. This complication occurs most commonly during the evolution of the disease, but more rarely can be the presenting histologic picture. EBV-negative large B-cell lymphoma or plasma cell proliferations can also occur occasionally.
Bone marrow involvement is often subtle, appearing as small single or multiple nodular or interstitial foci of infiltration in a paratrabecular or non-paratrabecular distribution. The infiltrates have a mixed composition of T and B cells, including atypical clear cells, and are associated with blood vessel proliferation. Massive tumor replacement of hematopoietic tissues is exceptional.
In addition, secondary reactive marrow changes (polyclonal plasmacytosis, erythroid hyperplasia, eosinophilia, myelofibrosis, or hematophagocytosis) are frequently observed. They may obscure the lymphomatous foci and be misdiagnosed as other proliferative or reactive hematopoietic conditions.
Different histopathologic aspects can be seen in skin biopsies, ranging from subtle nonspecific mild perivascular lymphocytic infiltrate to, more rarely, an overtly lymphomatous infiltration. In most instances, eosinophils, vascular hyperplasia, and large immunoblasts are not obvious. EBV-positive cells are rarely demonstrated. A florid epithelioid or granulomatous reaction has been described in occasional cases, which may mimic sarcoidosis or an infectious process.
The distribution of the atypical lymphoid infiltrates in other organs is less well characterized. Tonsillar involvement may be subtle with preservation of reactive follicles and may be difficult to demonstrate. Splenic involvement occurs in the form of nodules in the white and/or the red pulp. Not all symptomatic manifestations may result from direct tumor infiltration; for example, effusions are usually nonneoplastic in nature, and their cause is poorly understood.
In general, successive biopsies harvested at relapses tend to show a stable histologic picture or, more rarely, a progression in histologic pattern. Transformation into a T-cell lymphoma with a high content of large pleomorphic neoplastic T cells resembling PTCL, not otherwise specified (PTCL, NOS), is rare and does not seem to impact outcome. Conversely, features of “high-grade” lymphoma are usually represented by a secondary B-cell proliferation. The incidence of this complication is poorly documented, and in fact how to place the border between AITL rich in B-cell blasts and AITL with superimposed B-cell lymphoma is not established. Interestingly, whereas an increased large B-cell component does not seem to impact the clinical outcome, the prognosis following the occurrence of overt diffuse large B-cell lymphoma or an EBV-positive lymphoproliferation is quite variable. From a therapeutic standpoint, in these circumstances, the administration of rituximab might be recommended.
TR and IG Clonality Tests
Using sensitive PCR techniques, the detection of monoclonal or oligoclonal rearrangement of the T-cell receptor (TR) genes is found in the vast majority of cases (95% in the series reported by the BIOMED-2 consortium using multiplex strategies targeting the β, γ, and δ TR loci). In one recent study, sequence analysis of the rearranged TRB genes showed overrepresentation of the BV17S1 family compared to the use of other Vβ segments.
In addition to TR rearrangement, a clonal or oligoclonal rearrangement of the immunoglobulin (IG) gene(s) is also found in up to one third of patients. B-cell clonality tends to be evidenced in cases comprising increased numbers of B-cell blasts. Intriguingly, most EBV-infected B cells show ongoing mutational activity while carrying hypermutated IG genes with destructive mutations, suggesting that in AITL alternative pathways operate to allow the survival of these mutating “forbidden” (Ig-deficient) B cells.
Gene Expression Signature
At the gene expression level, the molecular profile of AITL is dominated by a strong microenvironment imprint, including overexpression of B-cell- and FDC-related genes, chemokines and chemokine receptors, and genes related to extracellular matrix and vascular biology. The signature contributed by the neoplastic cells, albeit quantitatively minor, is enriched in genes normally expressed by TFH cells. This demonstration of molecular similarities between AITL tumor cells and TFH cells at a genome-wide level definitively established the cellular derivation of AITL from TFH cells, initially suspected on the basis of expression of single TFH markers in AITL tumor cells, in particular the CXCL13 chemokine.
Genetic and Molecular Alterations
By conventional cytogenetic analysis, detection of clonal aberrations – most commonly trisomies of chromosomes 3, 5, and 21, gain of X, and loss of 6q – has been reported in up to 90% of the cases.
The mutational landscape of AITL encompasses recurrent mutations in TET2, IDH2, and DNMT3A, which are involved in the regulation of DNA +/− histone methylation/hydroxymethylation. They are mutated in about 80%, 30%, and 25% of the cases, respectively. Mutations in TET2 and DNMT3A are mono- or biallelic and inactivating, while virtually all IDH2 mutations are gain-of-function missense mutations at R172 residue, inducing the production of an oncometabolite (2-hydroxyglutarate) which inhibits TET2 and other deoxygenases.
Hotspot somatic RHOA mutations encoding a p.Gly17Val occur in 50–70% of AITL (Palomero et al. 2014). RHOA encodes a small GTPase that regulates a variety of biological processes by regulating the actin cytoskeleton and cell adhesion. Mechanistically, the Gly17Val RHOA mutant does not bind GTP and inhibits wild-type RHOA function. This RHOA mutant also has the ability to bind to and activate VAV1 and subsequent T-cell receptor (TCR) signaling. Virtually all RHOA mutations occur in TET2-mutated cases, suggesting that the cooperation between impaired RHOA function and preceding TET2 loss of function contributes to AITL pathogenesis.
In addition to epigenetic modifiers and RHOA mutations, activation of genes related to TCR signaling and costimulatory pathways is present in about half of the cases, affecting various genes, most commonly CD28, PLCG1, FYN, VAV1, CARD11, and others.
RNA fusions involving CD28 and ICOS (or less commonly CTLA4) are found in 6–7% of AITL, mutually exclusive to CD28 mutations.
The differential diagnosis of AITL encompasses several reactive conditions and lymphoma entities.
AITL Versus Reactive Hyperplasia
The distinction between early involvement by AITL and reactive T-zone hyperplasia (in viral infections or dysimmune conditions) may be difficult. The presence of atypical clear cells positive for CD10 and/or TFH markers, minimal FDC expansion, and clonal TR (and IG) gene rearrangements are criteria favoring AITL. Rimming of the germinal centers by atypical cells with intense expression of CD10 and TFH markers is particularly helpful in distinguishing AITL pattern I from reactive follicular and paracortical hyperplasia.
Reactive lymphadenitis due to EBV comprises paracortical expansion and EBV-positive B cells, but the majority of T cells are CD8+ and polyclonal.
There is some overlap between the pattern II of AITL and Castleman’s disease, but the expansion of the mantle zones seen in the latter is absent in the regressed follicles of AITL.
The epithelioid variant of AITL can suggest a granulomatous disease, but identification of atypical neoplastic T cells is the clue to the correct diagnosis.
AITL Versus Hodgkin Lymphoma
The B blasts in AITL are often EBV positive and CD30 positive and may show Reed–Sternberg-like morphology and even partial CD15 expression in some cases, which is a source of confusion with classical Hodgkin lymphoma (cHL). However, in cHL, prominent arborizing venules and FDC expansion are absent, and the T cells, which are reactive in nature, lack atypia and are polyclonal.
AITL Versus T–Cell–/Histiocyte–Rich Large B–Cell Lymphoma
The presence of scattered large B cells in a background of T cells and histiocytes is a feature common to AITL, especially the epithelioid variant, and T-cell-/histiocyte-rich large B-cell lymphoma; however, in the latter, the neoplastic B cells are EBV negative, while the T cells lack atypia and are polyclonal.
AITL Versus Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL, NOS), and Versus Other Nodal Lymphomas of T Follicular Helper (TFH)-Cell Origin
The diagnosis of PTCL, NOS is an exclusion diagnosis requiring that the neoplastic cells do not express TFH immunophenotype (defined as the expression of 2 or more TFH markers). The WHO classification recognizes two other forms of nodal lymphomas of TFH-cell origin, namely nodal PTCL with TFH phenotype and follicular PTCL.
In common with AITL, F-PTCL is composed of CD4+ CD10+ T cells expressing an extensive TFH immunophenotype (BCL6+ CXCL13+ PD1+ ICOS+) and variably contains neoplastic clear cells and/or EBV-positive blasts. In addition, F-PTCL may present biological and clinicopathological features overlapping with those of AITL, therefore questioning its relationship to AITL, inasmuch as patients with F-PTCL may present with recurrent lesions as AITL and vice versa. A chromosomal translocation t(5;9)(q33;q22) involving ITK and SYK tyrosine kinases is found in about 20% of F-PTCL and is rare in AITL. ITK-SYK has transforming properties in vitro and induces a T-cell lymphoproliferative disease in mice through a signal that mimics TCR activation.
Extranodal Involvement by AITL
The identification of AITL in extranodal localizations may be difficult because of the scarcity of neoplastic cells, especially in the absence of established diagnosis. Immunohistochemistry for CD10 and TFH markers is helpful to identify the neoplastic elements, and molecular genetic studies may demonstrate clonal TR rearrangement. In the bone marrow and skin infiltrates, CXCL13 may be more useful than CD10 which also stains the stroma and may be difficult to interpret. However, TFH markers are not entirely specific for AITL. Indeed, a BCL6+ PD1+ CXCL13+ immunophenotype has also been reported in primary cutaneous CD4+ small-/medium-sized T-cell lymphoproliferative disorder.
References and Further Reading
- Attygalle, A., Cabeçadas, J., Gaulard, P., et al. (2014). Peripheral T- and NK-cell lymphomas and their mimics: Taking a step forward – Report on the lymphoma workshop of the XVI meeting of the European Association for Haematopathology in Lisbon 2012. Histopathology, 64(2), 171–199.CrossRefPubMedCentralGoogle Scholar
- Dobay, M. P., Lemonnier, F., Missiaglia, E., Bastard, C., Vallois, D., Jais, J. P., et al. (2017). Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica, 102(4), e148–ee51.CrossRefPubMedCentralGoogle Scholar
- Mourad, N., Mounier, N., Brière, J., et al. (2008). Groupe d’Etude des Lymphomes de l’Adulte. Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte (GELA) trials. Blood, 111(9), 4463–4470.CrossRefPubMedCentralGoogle Scholar
- Patsouris, E., Nöel, H., & Lennert, K. (1989). Angioimmunoblastic lymphadenopathy–type of T-cell lymphoma with a high content of epithelioid cells. Histopathology and comparison with lymphoepithelioid cell lymphoma. American Journal of Surgical Pathology, 13(4), 262–275.CrossRefPubMedCentralGoogle Scholar
- Swerdlow, S. H., Campo, E., Harris, N. L., Jaffe, E. S., Pileri, S., Stein, H., et al. (2017). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer.Google Scholar