Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Angioimmunoblastic T-Cell Lymphoma

  • Laurence de LevalEmail author
  • Bettina Bisig
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3862-1

Synonyms

Definition

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).

Clinical Features

  • Incidence

According to a retrospective study published in 2008, AITL represents the second most common form peripheral T-cell lymphoma (PTCL) worldwide, accounting for 18.5% of the cases. The disease is more common in Europe (representing 29% of the cases) than in North America or Asia where its prevalence is estimated to be 16% and 18% of the cases, respectively. According to recent publications reporting on the findings derived from the Lymphopath network in France, AITL represents the most common form of noncutaneous PTCL (>35% of the cases) in France. Yet, no risk factors or etiologic agent(s) have been identified, and no racial predisposition is recognized.
  • Age

AITL affects elderly adults in their sixth or seventh decades, at a median age ranging from 59 to 65 years in published series.
  • Sex

A slight or marked male predominance is repeatedly reported.
  • 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.

The frequency of clinical and laboratory features in AITL patients summarized from 16 clinical series published between 1975 and 2017, comprising each 10–243 patients (total approximately 1250 subjects), is presented in Table 1. Generalized lymphadenopathy is almost constant, often accompanied by constitutional symptoms such as fever and weight loss. A high proportion of patients have hepatomegaly and/or splenomegaly. Bone marrow involvement has been reported in up to 70% of the cases and tends to correlate with a higher frequency of B symptoms, hepatosplenomegaly, laboratory abnormalities, and the presence of circulating tumor cells. Up to half of the patients have skin rash and/or pruritus, prior to or concurrent with the diagnosis of lymphoma or at relapse. Nodular skin lesions, plaques, purpura, and urticarial lesions can also be seen. Other clinical signs and symptoms (arthralgias or arthritis, pleural effusions, ascites and/or edema, lung involvement, neurologic manifestations, gastrointestinal involvement) are less common with a wide variation in their reported frequency. Overall, most patients have concomitant extranodal disease, and the disease is stage III or IV in more than 80% of cases (de Leval et al. 2010).
Table 1

Frequency of clinical and laboratory features in AITL patients

Sex ratio (male to female)

0.7–6/1

Median age

57–68 years

General clinical features

 

Advanced stage (III/IV)

68–94%

LDH > normal

46–86%

Performance status >1

29–57%

B symptoms

51–86%

Bulky mass

1–26%

High-risk IPI (4–5)

21–52%

Organ involvement

 

Generalized

84–100%

Lymphadenopathy

 

Bone marrow involvement

12–70%

Hepatomegaly

9–83%

Splenomegaly

35–73%

Skin rash

9–58%

Effusion/edema/ascites

25–53%

Polyarthritis/arthralgias

16–18%

Lung involvementa

3–10%

Neurologic manifestationsb

10%

Gastrointestinal involvementc

1–4%

Laboratory tests

 

Anemia

33–88%

Positive Coombs test

27–75%

Lymphopenia

17–52%

Thrombocytopenia

9–53%

Hypereosinophilia

24–50%

Hypergammaglobulinemia

30–83%

The data are summarized from 16 clinical series published between 1975 and 2017 comprising each 10–243 patients (total approximately 1250 subjects). Not all parameters were recorded for each patient

Adapted from Ascani et al. (1997), Cho et al. (2009), Federico et al. (2013), Frizzera et al. (1975), Kaneko et al. (1988), Kao et al. (2016), Lachenal et al. (2007), Li et al. (2017), Mourad et al. (2008), Nakamura and Suchi (1991), Niitsu et al. (2008), Patsouris et al. (1989), Pautier et al. (1999), Siegert et al. (1995), Tobinai et al. (1988), Tokunaga et al. (2012)

aX-ray patterns showing diffuse patchy infiltrates or interstitial pneumonia

bVarious manifestations reported: confusion, polyneuritis, loss of hearing or vision, apathy, regressive hemiparesis, cerebellar syndrome, tinnitus, aphasia

cLesions consist of mucosal ulcers which may resemble those of Crohn’s disease or tuberculous colitis and manifest as bleeding and diarrhea

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.

Peripheral blood leukocytosis with lymphocytosis is rare; however, careful examination of blood smears can reveal a small population of atypical lymphoid cells in many patients, the presence of which is highlighted by flow cytometry disclosing an aberrant cell surface immunophenotype (most commonly CD10+ and/or sCD3− or dim).
  • Treatment

First-line therapy of AITL typically consists of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOE (etoposide) P chemotherapy given for four to six cycles. Other regimens are experimental. Patients achieving complete remission (CR) or partial remission (PR) may benefit from high-dose therapy followed by autologous stem cell transplantation. However, there is no randomized study supporting this practice. Unfortunately, about one third of patients show progression of disease during first-line treatment. These patients should immediately be switched to an alternative chemotherapy regimen (DHAP (dexamethasone, high-dose cytarabine, cisplatin), GemOxDex (gemcitabine, oxaliplatin, dexamethasone), or others) and scheduled for allogeneic transplantation.
  • Outcome

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.

Macroscopy

Lymph nodes are often mildly to moderately enlarged (<1 to 3 cm) and present a homogeneous fleshy texture, similar to other lymphomas.

Microscopy

The hallmark features of AITL are (1) a diffuse polymorphous infiltrate including variable proportions of atypical neoplastic T cells, admixed with small lymphocytes, histiocytes or epithelioid cells, immunoblasts, eosinophils, and plasma cells; (2) prominent arborizing high endothelial venules; and (3) irregular proliferation of follicular dendritic cells (FDCs). Lymph nodes involved by AITL are in general characterized by complete loss of architecture, often with capsular and perinodal infiltration sparing the peripheral sinus, and absence of residual B-cell follicles (pattern III; see below) (Figs. 1, 2, and 3).
Fig. 1

Low-power view of a lymph node involved by angioimmunoblastic T-cell lymphoma. The architecture is effaced and there is extension of the lymphoproliferation beyond the open peripheral sinus (“sinus sign”)

Fig. 2

Lymph node involvement by angioimmunoblastic T-cell lymphoma pattern III showing numerous branching vessels and a diffuse lymphoproliferation

Fig. 3

At high magnification, angioimmunoblastic T-cell lymphoma comprises a polymorphous lymphoproliferation comprising small to medium atypical lymphoid cells (white arrows), large blastic cells (black arrows), plasma cells, and eosinophils

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.

Expanded FDC meshworks, typically associated with vessels, can be seen by morphology alone when prominent (Fig. 4) and are best highlighted by immunohistochemistry using classical FDC markers (CD21, CD23, CNA.42, and/or CD35), among which CD21 appears to be most sensitive.
Fig. 4

Numerous pale oval nuclei in a perivascular distribution are indicative of a prominent proliferation of follicular dendritic cells in this case of angioimmunoblastic T-cell lymphoma

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 I (AITL with hyperplastic follicles) (Fig. 5), the lymph node has a partially preserved architecture and contains hyperplastic follicles with poorly developed mantles, merging into the paracortex expanded by a polymorphous infiltrate comprising often inconspicuous neoplastic cells, which tend to distribute around the follicles.
Fig. 5

Angioimmunoblastic T-cell lymphoma, pattern I: a reactive germinal center is surrounded by a cuff of atypical lymphoid cells with clear cytoplasm that positively stain for CD10

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

In some cases, the neoplastic cells are small lymphocytes with minimal atypia. The clear cell-rich variant of AITL designates a subset of cases comprising an overt lymphomatous proliferation of sheets of “clear” neoplastic cells. The epithelioid variant of AITL is characterized by a high content of epithelioid cells in small, poorly defined clusters (Fig. 6).
Fig. 6

Morphologic variants of angioimmunoblastic T-cell lymphoma: (a) small cell variant; (b) clear cell-rich variant; (c) epithelioid cell-rich variant

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

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.

Extranodal Involvement

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.

Relapses

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.

Immunophenotype

In the typical type III pattern, the disturbed architecture is highlighted by immunostains for follicular dendritic cell, B-cell, and T-cell markers (Fig. 7). The neoplastic cells (Fig. 8) are mature αβ CD4+ CD8− T cells that frequently show aberrant loss or reduced expression of CD7, surface CD3, and/or CD4 and may show partial CD30 expression in up to one third of the cases. Aberrant coexpression of CD20 is also reported. Expression of CD10 by the neoplastic cells is observed in around 80% of the cases, but is often heterogeneous. AITL tumor cells express several markers of follicular helper T cells (TFH): CXCL13, CXCR5, CD154, programmed cell death-1 (PD-1) (a member of the CD28 costimulatory receptor family resulting in negative regulation of T-cell activity), inducible costimulator (ICOS) (a CD28 homologue with costimulatory function in T-cell activation and expansion), and cytoplasmic SAP (SLAM-associated protein). Expression of BCL6, a transcription factor characteristic of the TFH subset of CD4+ cells, is another phenotypic marker of AITL tumor cells. On tissue sections, the distribution and intensity of the immunostainings observed for the different TFH markers tend to correlate and, similar to CD10, to show a relationship to the FDC meshwork. For diagnostic purposes, CXCL13, PD1, ICOS, and BCL6 currently represent the most useful and robust immunohistochemical TFH markers.
Fig. 7

Immunoarchitecture of angioimmunoblastic T-cell lymphoma, pattern III. CD21 highlights a diffuse proliferation of follicular dendritic cells. CD20 shows aggregates of B cells at the periphery of the lymph node and scattered large blastic cells. The majority of the cells in the lymph node are T cells positive for CD3, including atypical elements. The T cells comprise a majority of CD4+ cells (including the neoplastic cells) but also a significant component of CD8+ cells

Fig. 8

Immunophenotypical characterization of the neoplastic cells in angioimmunoblastic T-cell lymphoma. The neoplastic cells are positive for one or several pan-T-cell antigens (shown here CD3) and may show aberrant loss of one or more of these (here CD7 negative). The neoplastic cells stain for one or several markers of TFH differentiation, such as PD1 and CXCL13. In this case, the T cells aberrantly coexpressed CD20 and were partly positive for CD30 (also strongly positive on the large B-cell blasts, arrow)

Molecular Features

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.

Differential Diagnosis

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.

Nodal PTCL with TFH phenotype, also referred to as PTCL, NOS with TFH-like features in several publications (Fig. 9), has in common the mutational landscape of AITL (Dobay et al. 2017). It remains to be defined which criteria should be used to define the borders of AITL entity. In that respect, whether clinical and/or laboratory features should be taken into account in borderline cases requires further investigation (Gaulard and de Leval 2014).
Fig. 9

Nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. This lymphoma composed of medium to large cells shows no morphologic features characteristic of angioimmunoblastic T-cell lymphoma. However, upon immunophenotyping, there is evidence of some follicular dendritic cell proliferation and expression of TFH markers (ICOS and PD1)

Follicular PTCL (F-PTCL) is a rare and peculiar form of PTCL, whose designation refers to a pattern of growth intimately related to follicular structures. It comprises cases with a truly follicular pattern, mimicking follicular lymphoma, and cases resembling progressive transformation of germinal centers (Fig. 10).
Fig. 10

Follicular peripheral T-cell lymphoma. In this case, the lymphoma proliferation appeared as aggregates of clear cells in expanded mantle zones (progressive transformation of germinal center-like pattern) and sheets of pale lymphoid cells with perifollicular distribution

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

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Institute of PathologyUniversity Hospital Lausanne CHUVLausanneSwitzerland