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
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
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
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)
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)