Lymphoma & related disorders
Mature T/NK cell disorders
T follicular helper phenotype
Angioimmunoblastic
Topic Completed: 1 June 2017
Minor changes: 26 March 2021
Copyright: 2001-2021, PathologyOutlines.com, Inc.
PubMed search: angioimmunoblastic T cell [title] lymphoma
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Flow cytometry images | Electron microscopy description | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review style answer #1Cite this page: Yang G. Angioimmunoblastic. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBAITL.html. Accessed April 16th, 2021.
Definition / general
- Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma characterized by systemic disease, a polymorphous infiltrate involving lymph nodes, and a prominent proliferation of high endothelial venules and follicular dendritic cells (WHO 2008)
- According to the 2016 revision of the World Health Organization classification of lymphoid neoplasms, AITL now resides under the umbrella category of nodal T cell lymphomas with T follicular helper (TFH) phenotype (Blood 2016;127:2375)
Essential features
- Nodal architecture partially to completely effaced
- Follicular dendritic cell proliferation
- Prominent high endothelial venules
- CD4+, CD10+, PD1+, CXCL13+ T cell immunoblasts, CD21+ FDCs, EBV+ B cells
- TCR and IGH gene rearrangements
Terminology
- Originally described in 1974 as a nonneoplastic abnormal immune reaction (Lancet 1974;1:1070)
- Formerly termed angioimmunoblastic lymphadenopathy with dysproteinemia, immunoblastic lymphadenopathy, lymphogranulomatous X and immunodysplastic disease (Hsi: Hematopathology, Second Edition, 2012)
- Acknowledged entity since the 1994 Revised European American Lymphoma (REAL) Classification (Blood 1994;84:1361)
Epidemiology
- 1-2% of non-Hodgkin lymphoma (NHL), 15-20% of peripheral T cell lymphoma (PTCL)
- Geographically more prevalent in Europe (28.7% of all PTCL) > Asia (17.9%) > North America (16.0%) (J Clin Oncol 2013;31:240)
- 0.05 new cases diagnosed per 100,000 patients in the United States per year (Hematol Oncol Clin North Am 2017;31:223)
- Median age 65 years (J Clin Oncol 2013;31:240)
- No gender predisposition (Hsi: Hematopathology, Second Edition, 2012)
Sites
- Virtually all cases of AITL present with generalized lymphadenopathy and advanced stage
- Extranodal sites such as the lungs, skin or bone marrow are frequently involved at presentation (Orazi: Knowles' Neoplastic Hematopathology, Third Edition, 2013)
Etiology
- The neoplastic cell in AITL is a follicular T helper (TFH) cell
- Cellular components of the microenvironment include high endothelial venules (HEVs), EBV+ B cells and TFH
- Dysregulation of the TFH cell leads to germinal center anarchy and subsequent development of AITL
- The B cell activation leads to autoimmune hemolytic anemia (AIHA) and hypergammaglobulinemia (Blood 2017;129:1095)
- Described mutations in AITL: TET2 , DNMT3A , IDH2 , RHOA , CD28 , PLCG1 and TNFRSF21 (DR6) (Hematol Oncol Clin North Am 2017;31:223, Oncotarget 2017;8:17763)
Clinical features
- Generalized lymphadenopathy (stage III or IV disease), hepatosplenomegaly, and skin rash
- B symptoms: fever, night sweats, weight loss (Hsi: Hematopathology, Second Edition, 2012)
- Less common: arthralgias or arthritis, pleural effusion, ascites, pulmonary involvement, neurological involvement and gastrointestinal involvement
- Polyclonal hypergammaglobulinemia and autoimmune hemolytic anemia may develop with progression (Hsi: Hematopathology, Second Edition, 2012)
- May be complicated by a second lymphoma (EBV associated large B cell lymphoma > Hodgkin lymphoma (HL) > high grade T cell lymphoma (Gorczyca: Atlas of Differential Diagnosis in Neoplastic Hematopathology, Third Edition, 2014)
Diagnosis
- Best made by excisional biopsy, usually a lymph node, interpreted withi clinical presentation
- Testing for clonal T cell receptor rearrangement can be helpful (eMedicine)
Laboratory
- Polyclonal hypergammaglobulinemia and autoimmune hemolytic anemia (Hsi: Hematopathology, Second Edition, 2012)
- Eosinophilia, thrombocytopenia, lymphopenia, elevated lactate dehydrogenase serum levels, elevated erythrocyte sedimentation rate and an array of autoantibodies (rheumatoid factor, antinuclear antibody, anti-smooth muscle antibody) (Semin Hematol 2014;51:52)
Prognostic factors
- Five year overall and failure free survivals were 33% and 18%, respectively
- Poor prognostic factors: age > 60 years, performance status ≥ 2, extranodal sites > 1, B symptoms, platelet count < 150 × 109/L (J Clin Oncol 2013;31:240)
- Other prognostic factors: anemia, elevated white blood cell count and IgA levels (Gorczyca: Atlas of Differential Diagnosis in Neoplastic Hematopathology, Third Edition, 2014)
Case reports
- 43 year old woman with pure red cell aplasia (Cancer Res Treat 2010;42:115)
- 48 year old woman with composite tumor with diffuse large B cell lymphoma (Am J Clin Pathol 2002;118:848)
- 49 year old woman with treatment refractory, CD3-, CD4+ T cell associated Gleich syndrome (Leuk Lymphoma 2015;56:1891)
- 59 year old man with secondary cutaneous Epstein Barr virus associated diffuse large B cell lymphoma (Diagn Pathol 2012;7:7)
- 67 year old woman with cutaneous trunk lesions with prominent granulomas (Am J Surg Pathol 2003;27:699)
- 67 year old man with nephrotic syndrome (Ann Hematol 2004;83:455)
- 74 year old woman with long term remission of 11 years after chemotherapy (Ann Hematol 2015;94:347)
- 77 year old man with aggressive colonic involvement (Gastroenterological Endoscopy 2015;57:154)
- 80 year old man with central nervous system involvement by B cell lymphoma following AITL (J Hematop 2015;8:235)
Treatment
- First line: anthracycline containing regimens
- Consolidative autologous transplantation
- Romidepsin, belinostat, brentuximab, vedotin, lenalidomide seem active in pretreated patients (Hematol Oncol Clin North Am 2017;31:223)
Clinical images
Images hosted on other servers:
Violaceous erythema and bullae of the foot
Macular erythema on the trunk
Confluent lesions over the back
Microscopic (histologic) description
- Lymph nodes:
- Partial effacement of lymphonodular architecture, often with perinodal infiltration but with preservation of subcapsular and trabecular sinuses
- Prominent arborizing high endothelial venules with thickened, hyalinized PAS+ walls surrounded by CD21+ follicular dendritic cells and irregular homogenous eosinophilic material
- Burnt out germinal centers with increased follicular dendritic cell meshworks (mediated through expression of CXCL13 by neoplastic follicular helper T cells)
- Predominantly paracortical aggregates of polymorphic small to medium sized cells with clear / pale cytoplasm, distinct cell membranes and minimal cytologic atypia
- Small clusters of neoplastic cells around follicles and high endothelial venules, variable numbers of small reactive lymphocytes, eosinophils, plasma cells, histiocytes
- Paracortical expansion of B immunoblasts linked to the functional properties of neoplastic follicular helper T cells
- Three different histologic patterns described, I - III, with increasing degrees of architectural effacement, commonly coexisting in the same specimen, arbitrary cutoffs
- Bone marrow:
- Focal or diffuse marrow involvement
- Focal lesions have indistinct margins
- Contain polymorphous infiltrate of lymphocytes, immunoblasts, plasma cells, histiocytes, eosinophils and neutrophils
- Often vascular proliferation with prominent endothelial cells and fibroblasts
- Perivascular clustering of neoplastic clear cells in 41%
- Variable epithelioid histiocytes
- Usually no amorphous PAS+ material (found in nodal lesions)
- Uninvolved marrow may be hypercellular
- Peripheral blood:
- Reactive lymphocytes, immunoblasts, immunocytes, increased eosinophils, various cytopenias, rouleaux
- May also see circulating lymphoma cells
- Skin:
- Subtle infiltrate with nonspecific mild perivascular accumulation of lymphocytes; overtly lymphomatous infiltration uncommon
- Eosinophils, vascular proliferation and large immunoblasts not obvious
- Rare EBV+ cells (Gorczyca: Atlas of Differential Diagnosis in Neoplastic Hematopathology, Third Edition, 2014)
Microscopic (histologic) images
AFIP Images
Various images
Images hosted on other servers:
Atypical lymphoid cells
Atypical, polymorphic infiltrate
Peripheral blood,
bone marrow
and lymph node
specimens
CD3+
CD4 weak
BCL6+
Various images
Cytology description
- Small to large cells with moderate to faint basophilic cytoplasm without azurophilic granules and sometimes with microvacuoles, often irregular or indented nuclei, moderately condensed chromatin
Cytology images
Images hosted on other servers:
Peripheral blood: atypical lymphocytes
Positive stains
- Lymph nodes:
- Pan T cell antigens: CD2, CD3, CD5 and CD7 with frequent aberrant loss of one or more of these antigens
- T helper cell marker: CD4
- Follicular T helper cell markers: CD10, BCL6, CXCL13 (more specific), PD-1 (CD279), ICOS
- Follicular dendritic cell networks: CD21, CD23, CD35, CNA.42 or clusterin
- Scattered B cells: EBV+ (Miranda: Atlas of Lymph Node Pathology (Atlas of Anatomic Pathology), 2013 Edition, 2013)
- Bone marrow:
- Uncommon expression of CD10 (25%)
- Lack of CXCL13 expression
- PD-1 in 85%
- BCL6 / CD3 dual staining (Hum Pathol 2010;1:79)
Flow cytometry images
Images hosted on other servers:
Immunophenotypic features
Electron microscopy description
- Lymphocytes with cytoplasmic vacuoles thought to correspond to neoplastic cells
- High endothelial venules: swollen endothelial cells with walls thickened by basement membrane-like material and immunoglobulin deposition
- Intercellular collagen and immunoglobulins correspond to the eosinophilic PAS+ material
Molecular / cytogenetics description
- Clonal rearrangement of T cell receptor genes (75 - 90%)
- Monoclonal IgH gene rearrangements (30%): expansion of B cells or EBV+ proliferations
- Most frequent cytogenetic abnormalities: +3, +5, +X and 1p alterations
- Other: +22q, +19, +11q13, -13q (Miranda: Atlas of Lymph Node Pathology (Atlas of Anatomic Pathology), 2013 Edition, 2013)
- t(5;9)(q33;q22)/ITK-SYK reported in one AITL case (Am J Surg Pathol 2013;37:1456)
- Common mutations in AITL: TET2 , DNMT3A , IDH2 , RHOA , CD28 , PLCG1 and TNFRSF21 (DR6) and VAV1 (Hematol Oncol Clin North Am 2017;31:223, Oncotarget 2017;8:17763, Blood 2016;128:4104)
Differential diagnosis
- Castleman disease
- Drug reactions
- Classical Hodgkin lymphoma, mixed cellularity: no aberrant T cell phenotype, no TCR gene rearrangements
- Infectious mononucleosis
- Peripheral T cell lymphoma: CD10-, EBV-, no clear cells
- Reactive lymphoid hyperplasia: may also have CD10+ T cells (Mod Pathol 2003;16:879)
Board review style question #1
Follicular dendritic cell proliferation and prominent high endothelial venules are classic features of which of the following lymphoma/condition?
- Angioimmunoblastic T cell lymphoma
- Atypical T zone hyperplasia
- Classical Hodgkin lymphoma
- Peripheral T cell lymphoma, not otherwise specified
Board review style answer #1
A. Follicular dendritic cell proliferation and prominent high endothelial venules are classic features of angioimmunoblastic T cell lymphoma.
(Hsi: Hematopathology, Second Edition, 2012)
- Incorrect: these two features are usually absent in atypical T zone hyperplasia.
- Incorrect: these two features are usually absent in classical Hodgkin lymphoma.
- Incorrect: although high endothelial venules can occasionally be seen in peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), follicular dendritic cell proliferation is usually absent in PTCL, NOS.
(Hsi: Hematopathology, Second Edition, 2012)
