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Educational Theme | AITL: Pathophysiology, diagnostic challenges, and current and future treatment of a rare T-cell lymphoma subtype

Nov 24, 2021
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Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of mature peripheral T-cell lymphoma (PTCL) that has undergone several name changes over the years, having been called angioimmunoblastic lymphadenopathy with dysproteinemia, immunoblastic lymphadenopathy, and lymphogranulomatosis X, before finally settling into its current moniker. The name is not the only thing that has changed, however: early descriptions of AITL suggested that the entity was a nonmalignant, hyperimmune reaction or possibly a premalignant condition. Decades later, aided by diagnostic staining techniques, we now know that AITL is indeed a malignant lymphoma.1 This rare T-cell lymphoma arises from a subset of peripheral mature CD4+ T follicular helper (TFH) cells and is an aggressive lymphoid malignancy that generates intense systemic inflammatory and immune reactions.2,3

Pathobiology of AITL

Morphology

Morphologically, AITL lymph nodes demonstrate a loss of architecture due to a polymorphic lymphoid infiltrate comprised of tumor and inflammatory cells (including lymphocytes, eosinophils, macrophages, and plasma cells), as well as increased vascular arborization and extra-follicular proliferation of follicular dendritic cells (FDCs). Neoplastic cells are medium sized with clear cytoplasm and minimal atypia and are often found adjacent to the proliferative vasculature (called high endothelial venules [HEVs]). Morphologic diagnosis is challenging, as these features are often seen in association with reactive conditions, and malignant cells—in addition to being well-differentiated—are often few in number: in approximately 30% of cases, morphologically distinct clear cells are not identifiable.3,4

There are three histologic patterns that have been described in AITL (Table 1). These patterns have some overlap, and most cases of AITL are Pattern II (occasional regression of follicles) or Pattern III (complete effacement with no residual follicles); Pattern I (largely intact nodal architecture with hyperplastic follicles) is uncommon and can be difficult to identify due to a morphology that appears more reactive than overtly neoplastic.5

Table 1. Histologic patterns of AITL*

Type

Pattern I

Pattern II

Pattern III

Nodal architecture

Largely preserved

Partially or largely effaced

Completely effaced

B-cell follicles

Hyperplastic follicles with attenuated mantle cuffs

Scattered follicles, generally with regressive changes

Largely absent, atretic follicles limited to far cortex

FDC meshwork

Minimal expansion of FDCs around germinal centers

Prominent extrafollicular proliferation of FDCs, usually surrounding HEVs

Irregular proliferation of FDCs, usually surrounding HEVs

Neoplastic cells

Atypical T cells with predominantly perifollicular distribution

Aggregates of atypical T cells within the paracortex

Large aggregates/sheets of atypical T cells

Background

Perifollicular polymorphic infiltrate

Polymorphic paracortical infiltrate; RS-like cells may be present

Diffuse polymorphic infiltrate; RS-like cells may be present

AITL, angioimmunoblastic T-cell lymphoma; FDC, follicular dendritic cell; HEV, high endothelial venule; RS, Reed-Sternberg.
*Adapted from Xie et al 5

Immunohistochemistry (IHC)

TFH cells in AITL are characterized by the expression of CD3, CD4, and CD10, and aberrant loss of CD5 and/or CD7; in up to 70% of cases, CD7 is not detectable.1,3 Other variably positive TFH cell markers include CXCL13, programmed cell death-1 (PD-1), B-cell lymphoma 6 (BCL6), and inducible T-cell co-stimulator (ICOS).

According to the 2016 World Health Organization (WHO) classification guidelines for TFH lymphomas, diagnosis requires positive immunostaining for at least two, and ideally three, of the following antigens3:

  • CD10
  • BCL6
  • PD-1
  • CXCL13
  • CXCR5
  • ICOS
  • Signaling lymphocytic activation molecule-associated protein (SAP)

AITL, like natural killer/T-cell lymphoma, has close ties to the Epstein-Barr virus (EBV), with the majority of AITL cases demonstrating active EBV infection. Interestingly, it is the reactive B cells rather than the malignant TFH cells that are EBV positive.1 These EBV-positive B immunoblasts have the potential to develop into an EBV-positive diffuse large B-cell lymphoma (DLBCL) which can occur as a composite lymphoma or may arise at a later phase of AITL (and can further complicate diagnosis and treatment).3

Mutations and AITL development

A number of genetic mutations have been identified in relation to AITL as outlined in Table 2.

Table 2. AITL genetic mutations*

Mutation

Frequency

Functional Change

Other Information

TET2

~80%

Loss of function of the TET2 enzyme, enhancing BCL6 expression and promoting differentiation to TFH cells

Most frequently mutated gene in AITL

Many cases exhibit TET2 mutations

RHOAG17V

50‒70%

Glycine to valine substitution at amino acid 17, ultimately resulting in preferential commitment of RHOAG17V-expressing naïve CD4+ T cells to TFH cells

The presence of RHOAG17V enhances both TCR and ICOS signaling and specifies TFH lineage

RHOA mutations (at other hotspots) are seen in other lymphomas

IDH2R172

20‒30%

Upregulation of TFH-associated genes (such as chromosome 5 gain) and increased vascularization due to increased expression of VEGF

Identified almost exclusively alongside TET2 mutations

DNMT3A

20‒39%

DNMT3A mutations are likely involved in clonal hematopoiesis, though the involvement in TFH differentiation is unclear

Most DNMT3A mutations occur with TET2 mutations

TCR-related
(PLCG1, CD28, VAV1, FYN, ITK)

~50%

Increased TCR signaling that broadly influences T-cell activities (including proliferation, migration, and resistance to apoptosis)

Most of these TCR-related mutations are not specific to AITL, occurring in ATLL and PTCL-NOS

AITL, angioimmunoblastic T-cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; CD28, cluster of differentiation 28; DNMT3A, DNA methyltransferase 3 alpha; FYN, fyn proto-oncogene; IDH2, isocitrate dehydrogenase type 2; ICOS, inducible T-cell costimulator; ITK, IL2 inducible T cell kinase; PLCG1, phospholipase C gamma 1; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; RHOA, ras homolog family member A; TCR, T-cell receptor; TET2, tet methylcytosine dioxygenase 2; TFH, T follicular helper cell; VAV1, vav guanine nucleotide exchange factor 1.
*Adapted from Chiba et al.3

Diagnosis

Epidemiology

AITL is a rare lymphoma, comprising 1‒2% of non-Hodgkin lymphomas (NHL). It is the second most common type of PTCL (after PTCL-NOS), representing one in five of PTCL diagnoses.1,3 The median age at diagnosis is 65 years, with men and women affected equally. Notably, unlike other PTCL subtypes, AITL is more common in Europe (28.7% of all PTCL diagnoses) than in Asia (17.9%), although this may be due to the higher incidence of NK/T-cell lymphoma in Asia.1

Signs and symptoms

Patients with AITL often report nonspecific symptoms associated with systemic inflammation; signs are nonspecific as well, and the road to diagnosis can be a long one, spanning weeks or months. The chief complaints are fever, unintentional weight loss, and night sweats—the so-called B symptoms—and generalized non-bulky lymphadenopathy. Other findings include1,3,5:

  • Bone marrow involvement in approximately 70% of cases
  • Later stage at diagnosis (Ann Arbor Stage III/IV) in 80‒90% of cases
  • Rash in up to 50% of patients, with a wide range of manifestations
  • Hepatosplenomegaly
  • Dysproteinemia (generally a polyclonal gammopathy rather than monoclonal)
    • In some cases, circulating plasma cells may be seen on peripheral smear
  • Warm autoimmune hemolytic anemia
  • Polyarthritis
  • Vasculitis
  • Laboratory abnormalities such as elevated lactate dehydrogenase (LDH), cytopenias, and eosinophilia

The nonspecific nature of the signs and symptoms associated with AITL, combined with the difficulties associated with diagnosis based on morphology, lends to a rather lengthy list of potential diagnoses. See Table 3 for a description of other lymphoma entities that are often included in the differential diagnosis of AITL.

Table 3. Differential diagnosis of AITL*

Disease entity

Confusing features

Features favoring diagnosis of disease entity

Features favoring diagnosis of AITL

RPH

Paracortical expansion
Immunoblastic proliferation.
Extrafollicular T cells with variable/weak PD-1 positivity.
Increased vascularity.

No definite cytologic atypia.
Strong CD10- or PD-1-positive cells confined to germinal centers.
No FDC meshwork outside germinal centers.
No clonal rearrangement.

Atypical clear cells at outer rim of germinal centers or around HEVs.
CD10 and PD-1 strongly expressed on interfollicular or perifollicular atypical T cells.
FDC meshwork outside germinal centers.
EBV+ immunoblasts and RS-like cells.
Oligoclonal or monoclonal TCR rearrangement.
Monoclonal IG rearrangement sometimes present.

cHL

RS-like cells, frequently EBV+.
Polymorphic background.

Bands of fibrosis.
Nodular growth pattern.
No atypical T-cell population.
TFH markers show a single layer of reactive T cells forming rosettes around RS cells.
CD30 staining restricted to RS cells.
No clonal TCR rearrangement.

Open peripheral sinuses. prominent arborizing HEVs.
TFH markers show aggregates of atypical T cells surrounding RS-like cells.
Neoplastic T cells may express variable CD30.
Monoclonal TCR rearrangement.

PTCL-NOS

Atypical T-cell population with frequent loss of T-cell antigens.

Lack of characteristic TFH phenotype.
Lack of extrafollicular FDC meshwork or prominent
arborizing HEVs.

Polymorphous infiltrate. extrafollicular FDC meshwork.
Prominent arborizing HEVs.
Expression of ≥2 TFH markers.
Occasional EBV+ immunoblasts.

DLBCL

Large B-cell proliferation.
Monoclonal IgG rearrangement.

Cohesive sheets of large B cells.
No atypical T-cell population in the
background.
No clonal TCR rearrangement.

Atypical T cells with TFH phenotype in the background.
Extrafollicular FDC meshwork.
Prominent arborizing HEVs.
Monoclonal TCR rearrangement.

Nodal MZL

B cell proliferation.
Monoclonal plasma cells may be present.
Extrafollicular T cells with variable/weak PD-1 positivity.
Monoclonal IgG rearrangement.

No atypical T-cell population in the
background.
No clonal TCR rearrangement.

Atypical T cells with TFH phenotype in the background.
Extrafollicular FDC meshwork.
Monoclonal TCR rearrangement.
EBV+ immunoblasts and RS-like cells.

AITL, angioimmunoblastic T-cell lymphoma; cHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FDC, follicular dendritic cell; HEV, high endothelial venules; IG, immunoglobulin; IgG, immunoglobulin G; MZL, marginal zone lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; RPH, reactive paracortical hyperplasia; RS, Reed-Sternberg; TCR, T-cell receptor; TFH, T follicular helper.
*Adapted from Xie et al. 5

Prognosis

Though the natural history of the disease is variable, AITL has a median survival of 5 years, with a 5-year overall survival (OS) rate of 30% and a 5-year event-free survival (EFS) rate ranging from 18% to 38%.3,5 There is a survival advantage for patients with an international prognostic index (IPI) score of 0/1, which is associated with a 5-year OS of 56% compared with 25% for an IPI score of 4/5, although it should be noted that the IPI was developed for aggressive B-cell NHL. Attempts at a clinically-applicable prognostic index for AITL have not yet been successful.1

AITL treatment

Based on what we have discussed so far, it is not terribly surprising that, in addition to being difficult to diagnose, AITL is also difficult to treat. Frontline treatment is similar to that used to treat other PTCLs, while further lines of treatment depend on whether or not the patient will undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT).6

Induction regimens

Currently, there is no gold standard frontline chemotherapy regimen for patients with newly diagnosed AITL. For most patients, initial treatment is with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). While CHOP has relatively high complete response (CR) rates as upfront therapy in nodal PTCLs (up to 39%), its efficacy in AITL is unclear, and relapse rates are high.1,5

Other agents have been investigated in combination with CHOP (in PTCL):

  • Etoposide + CHOP (CHEOP) has demonstrated higher CR rates (51%) and may allow for deeper remissions in patients who are candidates for allo-HSCT.1,5,6
    • In elderly patients (>60 years), the toxicity associated with the addition of etoposide negated any survival benefits over CHOP alone.6
  • Alemtuzumab + CHOP has induced responses in a small number of patients with AITL across several phase II trials and appears to potentially improve CR compared with CHOP alone, though infectious complications are a concern.1
  • Bortezomib + CHOP demonstrated an overall response rate (ORR) of 76% and a CR rate of 65% in a phase II trial in which patients with AITL represented 17% of the study population. When compared with non-AITL populations, AITL had an improved 3-year OS advantage.1
  • Belinostat + CHOP demonstrated response rates of 86% (ORR) and 71% (CR) in a phase III trial of 23 patients with PTCL (10 of whom had AITL); nevertheless, serious adverse events (AEs) occurred in 43% of patients.7
  • Romidepsin + CHOP (Ro-CHOP) demonstrated similar response rates, progression-free survival (PFS), and OS when compared with CHOP in a phase III study of patients with PTCL.8
  • Brentuximab vedotin + cyclophosphamide, doxorubicin, and prednisone (BV + CHP) demonstrated superiority over CHOP in patients with CD30-positive PTCL in the phase III ECHELON-2 trial, with median PFS of 48.2 months vs 20.8 months as well as an OS benefit in patients who received BV + CHP.9

Non-CHOP-based regimens have also been explored as potential frontline therapy for AITL. In a retrospective study that included patients with PTCL, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) was found to be superior to CHOP, although this regimen requires intense consolidation following the induction phase.1 Other regimens that have thus far failed to demonstrate improvements over CHOP-based regimens include6:

  • Etoposide, ifosfamide, and cisplatin alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine
  • Cisplatin, etoposide, gemcitabine, and solumedrol
  • Gemcitabine, etoposide, and cisplatin

Upfront consolidation with allo-HSCT

While there is no evidence from randomized clinical trials to support the use of consolidation with allo-HSCT in first remission for patients with PTCL (including AITL), and the identification of transplant eligible patients is fraught, the use of this treatment modality has gained popularity. Patients who are chemo-sensitive by computed tomography (CT) or positron emission tomography (PET)/CT have a survival advantage over those who are not in at least partial remission at the time of transplantation.1,6 Results from a prospective phase II study showed a 5-year OS and PFS of 51% and 44%, respectively, in patients with AITL who underwent upfront consolidation and allo-HSCT, and results from retrospective and registry-based studies are similar.6

Relapsed/refractory (R/R) AITL

Due to the potential for the development of DLBCL—which, again, may occur concomitantly with AITL or at relapse—repeating biopsy is necessary. Once the etiology of relapse has been confirmed, a decision must be made as to whether the goal of treatment is cure or palliative care.6

While the data are limited, they in general do not support the utility of autologous transplantation for R/R AITL. Allo-HSCT, however, is more promising, with reports of PFS as high as 81% in AITL. In patients with controlled disease, consolidation with allo-HSCT is an excellent option.6

For patients who have been selected to undergo allo-HSCT, an intensive regimen such as ifosfamide, carboplatin, and etoposide (ICE) can be used as bridging therapy, as this regimen is associated with high response rates. For patients who are ineligible for transplant, however, sustained disease control rather than a quickly induced response is the goal. Table 4 summarizes some of the agents that may be used as continuous therapy for patients with R/R AITL.6

Table 4. Agents for continuous therapy in R/R AITL*

Agent

AITL/PTCL
(n)

ORR/CR
(AITL), %

ORR/CR
(all PTCL), %

Median PFS
(months)

Median DOR
(months)

Romidepsin

27/130

30/19

25/15

4

17

Belinostat

22/129

45/18

26/10

NA

8.3

5-azacitidine

12/19

75/42

53/26

NA

NA

Pralatrexate

13/111

8/NR

29/13

3.5

10.5

Bendamustine

32/60

NR

50/28

3.6

3.5

Brentuximab vedotin

13/22

54/38

41/24

2.6

7.6

Gemcitabine

NR/20

NR

55/30

NR

NR

Lenalidomide

7/23

29/0

30/0

3.2

5.7

Cyclosporine A

12/NA

67/25

NA

NA

NA

AITL, angioimmunoblastic T-cell lymphoma; CR, complete response; DOR, duration of response; NA, not applicable; NR, not reported; ORR, overall response rate; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory.
Adapted from Moskowitz et al.6

Future directions

Brentuximab vedotin, an anti-CD30 antibody with an antimitotic payload, has demonstrated efficacy in the treatment of CD30-positive AITL, identifying CD30 as an important therapeutic target in this disease. Other potentially important targets in AITL include the phosphoinositide-3-kinase (PI3K) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways1,6.

Case study

  • Age: 71 years
  • Sex: Female
  • The patient had a history of generalized lymphadenopathy, and polymyalgia rheumatica that had been treated with low-dose steroids for 2 years.
  • An axillary lymph node was biopsied5
    • On hematoxylin and eosin (H&E) stained tissue, there was a diffuse infiltrate of atypical lymphoid cells with effacement of the nodal architecture, focal follicles with regressive changes, and prominent arborizing neovascularization in the paracortex. Some Reed-Sternberg (RS)-like cells were seen
    • Flow cytometry showed an atypical T-cell population that was positive for CD2, CD4, CD5, and CD7, and negative for CD8, with loss of surface CD3. It was also observed that 45% of the T cells were positive for CD10
    • IHC confirmed a TFH phenotype, with the atypical lymphocytes expressing PD-1 and ICOS and resetting the RS-like cells, which were EBV-positive

While Hodgkin RS-like cells were present, the background of atypical lymphocytes did not support a diagnosis of classic Hodgkin lymphoma (cHL). Clonal rearrangement of TCR genes was detected via polymerase chain reaction (PCR), confirming a T-cell lymphoma diagnosis. In this case, there was a marked expansion of CD21 dendritic cells surrounding clusters of atypical lymphocytes, and this feature, combined with the presence of EBV-positive B cells, favor a diagnosis of AITL rather than nodal PTCL with TFH phenotype.5

Conclusion

AITL is a rare T-cell lymphoma that has long been misunderstood due to its infrequency and its variable and atypical presentations. Symptomatology is often non-specific and can mimic autoimmune diseases and other causes of systemic inflammation, and the histologic picture can add to the confusion, with the presence of RS-like cells and an atypical B-cell population. The high incidence of EBV positivity in AITL means that the development of DLBCL is a possibility, one that can heighten the uncertainty.1-6

Decades of treating patients with AITL using protocols developed for other PTCLs has likely not served this patient population well, though advances in our understanding of this complex disease have led to the identification of therapeutic targets. Brentuximab vedotin, the anti-CD30 antibody-drug conjugate, has shown impressive efficacy in patients with CD30-positive AITL, and other agents and pathways are under investigation. Continued research regarding new targets will lead to the development of AITL-specific treatment regimens, and molecular profiling will hopefully be used to individualize therapy and improve outcomes in this patient population.1-6

  1. Lunning MA & Vose JM. Angioimmunoblastic T-cell lymphoma: The many-faced lymphoma. Blood. 2017;129(9):1095-1102. DOI: 1182/blood-2016-09-692541
  2. Cheng S, Zhang W, Inghirami G, et al. Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking. eLife. 2021;29;10:e66395. DOI: 7554/eLife.66395
  3. Chiba S & Sakata-Yanagimoto M. Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia. 2020;34(10):2592-2606. DOI: 1038/s41375-020-0990-y
  4. Bal M, Gujral S, Gandhi J, et al. Angioimmunoblastic T-cell lymphoma: A critical analysis of clinical, morphologic and immunophenotypic features. Indian J Pathol Microbiol. 2010;53(4):640-645. DOI: 4103/0377-4929.72010
  5. Xie Y & Jaffe ES. How I diagnose angioimmunoblastic T-cell lymphoma. Am J Clin Pathol. 2021;156(1):1-14. DOI: 1093/ajcp/aqab090
  6. Moskowitz AJ. Practical treatment approach for angioimmunoblastic T-cell lymphoma. J Oncol Pract. 2019;15(3):137-143. DOI: 1200/JOP.18.00511
  7. Johnston PB, Cashen AF, Nikolinakos PG, et al. Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma. Exp Hematol Oncol. 2021;10(1):15. DOI: 1186/s40164-021-00203-8
  8. Bachy E, Camus V, Thieblemont C, et al. Final analysis of the Ro-CHOP phase III study (conducted by LYSA): romidepsin plus CHOP in patients with peripheral T-cell lymphoma. 2020;136(Supplement 1):32-33. DOI: 10.1182/blood-2020-134440
  9. Horwitz SM, O’Connor OA, Pro B, et al. The Echelon-2 trial: 5-year results of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma. 2020;136(Supplement 1):3-5. DOI: 10.1182/blood-2020-134398

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