INTRODUCTION — The peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas (NHLs) in adults [1,2]. (See "Classification of hematopoietic neoplasms".)
Among these, in decreasing frequency of occurrence, are:
●Peripheral T cell lymphoma, not otherwise specified
●Anaplastic large cell lymphoma, primary systemic type
●Angioimmunoblastic T cell lymphoma
●Extranodal NK/T cell lymphoma, nasal type
●Subcutaneous panniculitis-like T cell lymphoma
●Enteropathy associated T cell lymphoma
●Hepatosplenic T cell lymphoma
Angioimmunoblastic T cell lymphoma (AITL) is one of the more common PTCLs and is thought to arise from a subset of peripheral CD4 positive T cells corresponding to follicular helper T cells [3-5]. Patients typically present with the acute onset of a systemic illness and lymph node biopsy demonstrates a polymorphous infiltrate with a prominent proliferation of high endothelial venules and follicular dendritic cells.
In the past, AITL was thought to arise from an abnormal immune reaction, frequently accompanied by dysproteinemia. This was referred to as "angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)." It has since been realized that essentially all cases of AILD have clonal rearrangements of T cell receptor genes and represent a frank T cell lymphoma rather than a benign entity with high risk for transformation to one. Moreover, genomic sequencing of AITL has revealed the presence of acquired "driver" mutations in genes previously linked to the pathogenesis of other hematologic cancers.
The clinical presentation, pathologic features, and diagnosis of AITL will be discussed here. The other T cell lymphomas, including the NK/T cell types, and the pathobiology and treatment of the PTCLs are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified" and "Initial treatment of peripheral T cell lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type" and "Treatment of extranodal NK/T cell lymphoma, nasal type".)
EPIDEMIOLOGY — Angioimmunoblastic T cell lymphoma (AITL) is one of the more common peripheral T cell lymphomas (PTCL) encountered in Western countries. Incidence varies by geography. The highest incidence rates are in Europe (28 percent of PTCL), while lower rates are seen in North America (15 percent of PTCL) and Asia (17 percent of PTCL) [6,7]. In the United States the incidence is approximately 0.05 cases per 100,000 person years [8].
In the United States, the incidence is higher among Asian/Pacific Islanders and Hispanic White Americans and lowest among non-Hispanic White and Black Americans [9]. It is uncommon in Native Americans and Alaska natives.
AITL usually affects older adults; the median age is approximately 60 to 65 years (range 20 to 86 years) [10-13]. Some reports have noted a slight male predominance [10-13].
CLINICAL FEATURES — Patients with angioimmunoblastic T cell lymphoma (AITL) typically present with the acute onset of a systemic illness. Less commonly, patients may present with asymptomatic lymphadenopathy.
Symptoms frequently include [11,13-17]:
●Generalized lymphadenopathy (76 to 95 percent)
●Hepatomegaly (50 to 70 percent)
●Splenomegaly (70 percent)
●Systemic B symptoms of fevers, night sweats, or weight loss (70 to 85 percent)
●Rash (20 to 60 percent)
●Polyarthritis (20 percent)
●Ascites/effusions (20 to 35 percent)
●Symptoms related to anemia (20 to 50 percent)
The rash is usually pruritic and may demonstrate lymphohistiocytic vasculitis on biopsy. The vast majority (90 percent) of patients present with advanced (stage III/IV) disease. The bone marrow is involved in 30 to 60 percent of cases. While extranodal involvement is present in approximately one-quarter, it is uncommon for AITL to present at a single, isolated extranodal site [13].
Laboratory abnormalities are common and include [11,14-17]:
●Elevated serum lactate dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR), seen in approximately 70 and 45 percent of cases, respectively.
●Polyclonal hypergammaglobulinemia, present in 30 to 80 percent of cases; other cases may demonstrate hypogammaglobulinemia or a monoclonal gammopathy.
●Positive Coombs test, with or without hemolysis, seen in up to 30 percent of cases.
●Elevated beta-2 microglobulin (22 to 65 percent of cases).
●Lymphopenia, anemia, and thrombocytopenia, seen in approximately 45 percent, 30 to 50 percent, and 20 to 25 percent of cases, respectively. Hypereosinophilia is noted in another 30 to 40 percent.
●Approximately half of patients demonstrate hypoalbuminemia.
Immunologic abnormalities are common and can include plasmacytosis, polyclonal hypergammaglobulinemia, and a positive Coombs test [18]. AITL can be associated with autoimmune phenomena including hemolytic anemia, vasculitis, polyarthritis, rheumatoid arthritis, and thyroid disease [13,17]. Cold agglutinins and cryoglobulins can also be seen. These autoimmune features are thought to stem from immune dysregulation of both B cells and T cells that result in immunodeficiency and risk of opportunistic infections before and during treatment.
PATHOLOGIC FEATURES
Morphology
Growth pattern — Involved lymph nodes demonstrate partial or complete effacement of the normal architecture by a predominantly paracortical infiltrate of atypical lymphoid and inflammatory cells [1]. Follicles may be hyperplastic, depleted, or absent. Peripheral sinuses are typically open or even dilated, and the abnormal infiltrate usually does not extend beyond the capsule into perinodal tissue.
There is prominent neovascularization with arborizing high endothelial venules (HEV), many of which show thickened or hyalinized walls (picture 1). This can be particularly well appreciated with a Periodic Acid Schiff (PAS) stain. Clusters of epithelioid histiocytes and numerous eosinophils and plasma cells may be present. Expanded aggregates of follicular dendritic cells, best appreciated in sections immunostained for dendritic cell markers, surround the proliferating blood vessels, and may have the appearance of "burned-out" germinal centers.
Cell morphology — The infiltrating cells are a mixture of variably sized lymphocytes, immunoblasts, polyclonal plasma cells, eosinophils, histiocytes, epithelioid cells, and medium-sized atypical lymphoid cells with round or irregular nuclei and moderately abundant clear cytoplasm (picture 2). In the past, this polymorphous mixture of cell types was interpreted to be a reactive process (angioimmunoblastic lymphadenopathy with dysproteinemia). As the neoplasm progresses, lymphoid cells with clear cytoplasm tend to increase in number and efface the lymph node. In most cases, these clear cells are closely associated and intermingled with the expanded follicular dendritic cell (FDC) network. B immunoblasts may be numerous in areas between the FDCs and often harbor Epstein-Barr virus (EBV). The malignant T cells and the background reactive component generally do not penetrate beyond the lymph node capsule, but infiltration into the perinodal fat is sometimes seen. B immunoblasts that are EBV-positive are sometimes very prominent and occasionally give rise to secondary EBV-positive diffuse large B cell lymphoma (DLBCL). Occasionally, binucleated or multinucleated cells that resemble the Reed-Sternberg (RS) cells of Hodgkin lymphoma may be observed. These RS-like cells are usually EBV-positive and may be akin to similar appearing cells that are found on occasion in lymph nodes of patients with infectious mononucleosis. However, the inflammatory background that is characteristic of true classic Hodgkin lymphoma is absent.
Bone marrow involvement — Bone marrow involvement in angioimmunoblastic T cell lymphoma (AITL) usually takes the form of paratrabecular and interstitial polymorphous infiltrates containing cytologically atypical lymphocytes mixed with histiocytes and eosinophils [19]. The lymphomatous infiltrate in some marrow specimens contains numerous small or scattered large B cells, resembling either benign lymphoid aggregates or T cell rich large B cell lymphoma. Secondary changes such as trilineage hyperplasia of marrow elements and polyclonal plasmacytosis are frequent and may present independent of marrow involvement.
Immunophenotype — AITL tumor cells appear to be the malignant counterparts of CD4-positive T follicular helper (Tfh) cells, which normally provide T cell help to germinal center B cells. The tumor cells express pan T cell antigens (ie, CD3, CD2, and CD5) and almost always express CD4 (picture 3); CD3 expression may be dim or absent, particularly in the peripheral blood, which shows low-level involvement in approximately half of patients [20]. Many reactive CD8-expressing T cells are often present. An expanded follicular dendritic cell (FDC) network expressing CD21, CD23, and CD35 is usually present, often in areas where malignant T cells with abundant pale cytoplasm are seen (picture 4) [21,22]. This feature is useful in distinguishing this disorder from other T cell lymphomas, which do not contain expanded populations of FDCs [7].
The malignant T cells frequently express CD10, CXCL13, PD-1, BCL6, and ICOS, markers that are expressed by normal Tfh cells [1,23-25]. As an example, in one study, CD10 positive T cells were found in 27 of 30 cases of AITL [23]. In contrast, no CD10 positive T cells were present in 10 cases of other peripheral T cell lymphomas or 10 cases of reactive lymphoid hyperplasia. Single cell studies indicated that the CD10 positive cells belonged to the neoplastic clone.
Genetic features — T cell receptor genes are clonally rearranged in 75 to 90 percent of cases; immunoglobulin heavy chains may be clonally rearranged in up to 25 percent, corresponding to the secondarily expanded Epstein-Barr virus-positive B cell clones [22,26]. Human herpes virus-6 (HHV6) genomes also are detected in many cases and may be present in either T or B cells [27-29].
Many genetic abnormalities have been reported, but there is no single cytogenetic change that is typical or diagnostic of AITL. The most common cytogenetic abnormalities are trisomy 3, trisomy 5, and/or an additional X chromosome [1,30]. There is also an unusually high incidence of subclones with distinct chromosomal aberrations; the mechanism underlying the apparent genomic instability is unknown. Gene expression profiling demonstrates a pattern similar to that expressed by follicular helper T cells [5,31].
Of interest, among peripheral T cell lymphomas, AITL is particularly likely to have mutations in the genes TET2, IDH2, DNMT3A, and RHOA [31-34]. In one study, TET2 mutations were identified in 40 of 86 AITLs (47 percent) [32], while a second study identified IDH2 mutations in 20 to 45 percent of AITLs [33]. Unlike in acute myeloid leukemia (AML), IDH2 mutations preferentially occur at R172 and coexist with TET2 mutations more frequently than in AML [31]. The pathogenic significance of these mutations in AITL is uncertain, but it is of interest that mutations in the same genes in myeloid neoplasms lead to changes in DNA methylation and appear to increase the self-renewal capacity of hematopoietic stem cells. AITL may originate from mutated hematopoietic stem cells (rather than peripheral T cells) because B cells from patients with AITL often contain the same TET2 and/or DNMT3A mutations as are found in AITL cells [35,36].
RHOA, a gene that encodes a small GTP-binding protein, is mutated in roughly at least half of cases, often in association with TET2 mutation; a glycine to valine substitution in residue 17 in RHOA, dominates in AITL [37-39]. Consistent with a central role for this mutation, studies in mice have shown that expression of RHOA G17V in CD4+ T cells induces Tfh cell specification, PI3k and Mapk signaling, increased proliferation and, when combined with Tet2 loss, results in development of AITL [40]. In another mouse model of AITL, it is proposed that interactions between malignant T cells and adjacent B lymphocytes are necessary for tumor progression; if extended to human AITL, these observations may provide novel therapeutic opportunities [41]. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Pathogenesis'.)
DIAGNOSIS — The diagnosis of angioimmunoblastic T cell lymphoma (AITL) is best made by excisional tissue biopsy, most commonly a lymph node interpreted in the context of the clinical presentation. Lymph node evaluation includes assessment of the morphology and immunophenotyping, which are essential to make the diagnosis (table 1). In difficult cases, PCR-based tests to look for the presence of clonal T cell receptor rearrangements can be helpful.
As described above, tissue sections reveal effaced nodal architecture, prominent arborizing high endothelial venules, and a polymorphous infiltrate including reactive lymphocytes, immunoblasts, plasma cells, inflammatory cells, and small to large atypical lymphocytes that are positive for CD3 and CD4. Many cases also are positive for markers that are expressed by normal Tfh cells, such as BCL6, CD10, CXCL13, PD-1, and ICOS. As with other peripheral T cell lymphomas, the tumor cells may lose a subset of pan-T cell markers and exhibit an aberrant immunophenotype. Follicular dendritic cells (FDCs) are inconspicuous in routinely stained sections, but immunohistochemical staining for markers such as CD21 usually demonstrates irregularly shaped expansions of these cells.
When clusters of atypical T cells with abundant clear cytoplasm are present, they are typically found within the expanded FDC network. In most cases, Epstein-Barr virus (EBV) positive B immunoblasts, best detected by in situ hybridization for small nuclear EBV RNAS (EBERs), are present in areas between the FDCs. (See "Virology of Epstein-Barr virus", section on 'EBER-1 and EBER-2'.)
DIFFERENTIAL DIAGNOSIS
Other peripheral T cell lymphomas — Both angioimmunoblastic T cell lymphoma (AITL) and other peripheral T cell lymphomas (PTCLs) typically express pan T cell associated antigens (ie, CD3, CD2, and CD5) and demonstrate T cell receptor gene rearrangements. AITL is distinguished from most other PTCLs by expression of BCL6, CD10, CXCL13, PD-1, and ICOS and the presence of expanded meshworks of follicular dendritic cells (FDCs) expressing CD21, CD23, and CD35. FDCs are not expanded in other PTCLs.
In the 2016 revision of the WHO classification, the category of peripheral T cell lymphoma includes two provisional entities in addition to AITL that, like AITL, appear to share an origin from T follicular helper cells [2]:
●Follicular T cell lymphoma
●Nodal peripheral T cell lymphoma with T follicular helper (Tfh) phenotype
Such tumors have neoplastic cells that express at least two Tfh-related antigens, including CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP, and CCR5. Patients with follicular T cell lymphoma usually present with localized disease and few symptoms, whereas nodal peripheral T cell lymphomas with TFH phenotypes encompass cases that lack histologic features typical of AITL. In addition to phenotypic similarities to AITL, tumors in these provisional categories also share many of the same somatic mutations, including mutations in the genes TET2, IDH2, DNMT3A, RHOA, and CD28.
Hodgkin lymphoma — Occasionally, binucleated or multinucleated cells that resemble the Reed-Sternberg (R-S) cells of Hodgkin lymphoma (HL) may be observed in angioimmunoblastic T cell lymphoma. These cells can even exhibit the immunophenotypic characteristics of true R-S cells, making distinction from HL difficult. However, unlike in HL, clonal T cell receptor gene rearrangements are present in most cases of AITL. The prominent vascular proliferation and the proliferation of atypical T cells with clear cytoplasm are absent in HL.
EBV-positive diffuse large B cell lymphoma, NOS — EBV-positive diffuse large B cell lymphoma, not otherwise specified, is a subtype of B cell lymphoma characterized by the presence of numerous large EBV+ B cells and that often involves extranodal sites. Vascular invasion by the tumor cells may produce tissue necrosis. The EBV+ B cells in AITL are usually scattered, but in instances where small biopsies are taken, EBV+ B cells (usually detected by in situ hybridization for EBV EBER RNAs) can be sufficiently numerous to cause diagnostic confusion. The keys to making the distinction are recognition of the underlying T cell proliferation and performance of gene rearrangements studies, which typically show a polyclonal B cell population in AITL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive DLBCL, NOS'.)
TREATMENT — The treatment of angioimmunoblastic T cell lymphoma (AITL) is discussed separately. (See "Initial treatment of peripheral T cell lymphoma", section on 'Angioimmunoblastic T cell lymphoma' and "Treatment of relapsed or refractory peripheral T cell lymphoma".)
PROGNOSIS — AITL is generally an aggressive disease, although occasional spontaneous remissions are seen. The AITL prognostic score [42], which is based on clinical and laboratory features [42] appears to have greater discriminant power than either the International Prognostic Index (IPI) (table 2) or the Prognostic Index for T cell lymphomas (PIT) [13,24,43,44]. The course of disease is not reliably predicted by the histologic appearance, but outcomes are associated with gene expression patterns.
The international prospective T-cell Project (NCT01142674) reported outcomes for 282 patients with AITL and developed and validated a prognostic score (AITL score) based on clinical and laboratory features [42]. Median age of patients was 64 years, 90 percent had advanced-stage disease, 81 percent received anthracycline-based chemotherapy, and 13 percent underwent consolidative autologous hematopoietic cell transplantation (HCT) in first complete remission (CR1). Five-year overall survival (OS) and progression-free survival (PFS) were 44 and 32 percent, respectively, and outcomes were more favorable for patients who underwent autologous HCT in CR1. Multivariate analysis reported that age ≥60 years, Eastern Cooperative Oncology Group (ECOG) performance status >2, elevated C-reactive protein, and elevated beta 2 microglobulin were associated with inferior outcomes. A prognostic score based on these factors (AITL score) defined subgroups with distinct five-year OS: low-risk (63 percent), intermediate-risk (54 percent), and high-risk (21 percent). In addition, progression of disease within 24 months (POD24) was a powerful prognostic factor, with 63 percent five-year OS for patients without progression, compared with 6 percent for patients with POD24.
A retrospective analysis from Japan of 207 patients with AITL with a median follow-up of 42 months reported three-year OS and PFS rates of 54 and 38 percent, respectively [45]. Three-year OS according to IPI score was 81, 69, 53, and 35 percent for patients with low-, low-intermediate-, high-intermediate-, and high-risk IPI, respectively.
Analysis of gene expression studies in 66 patients with AITL reported that cases enriched for B lymphocytes had a more favorable prognosis [46]. The study detected the RHOA G17V mutation in one-third of patients and multivariate analysis reported that expression of a B cell signature (TCL1A, PNOC, CD19, CD20, and SPIB) was an IPI-independent prognostic factor. The B cell pattern segregated patients into high-risk and a low-risk categories that had distinct OS and time to progression (TTP). For the high-risk group, OS and TTP at 32 months were 30 percent and 20 percent, respectively, while for the low-risk group, the corresponding rates for OS and TTP were 75 percent and 70 percent. Compared with median OS, the hazard ratios (HR) for OS for the high-risk group was 0.35 (95% CI 0.14-0.85) compared with 2.73 (95% CI 1.37-6.86) for the low-risk group. The prognostic significance for OS and TTP was confirmed in a validation cohort of 27 patients with AITL.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)
SUMMARY
●Angioimmunoblastic T cell lymphoma (AITL) – AITL is one of the more common peripheral T cell lymphomas and is thought to arise from CD4+ T follicular helper cells.
●Clinical features – Patients typically present with the acute onset of a systemic illness characterized by generalized lymphadenopathy, hepatosplenomegaly, systemic B symptoms (ie, fever, night sweats, weight loss), with or without a rash. It can also be associated with immunologic abnormalities, such as autoimmune hemolytic anemia, plasmacytosis, or polyclonal hypergammaglobulinemia. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of AITL is best made by excisional tissue biopsy, most commonly a lymph node interpreted in the context of the clinical presentation (table 1). The histology reveals effaced nodal architecture, prominent arborizing high endothelial venules, and a polymorphous infiltrate including small to large atypical lymphocytes that are positive for T cell markers and markers of T follicular helper cells. Expanded networks of follicular dendritic cells are also characteristically present and can be demonstrated by staining for markers such as CD21. (See 'Pathologic features' above and 'Diagnosis' above.)
●Differential diagnosis – AITL should be distinguished from other peripheral T cell lymphomas, Hodgkin lymphoma, and Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL). (See 'Differential diagnosis' above.)
●Prognosis – Outcomes for patients have been associated with clinical and laboratory features (AITL score) and with patterns of gene expression. (See 'Prognosis' above.)
