Angioimmunoblastic T Cell Lymphoma

Definition

• T cell lymphoma of probable germinal center T cell origin, characterized by a polymorphous infiltrate with a prominent proliferation of high endothelial venules and follicular dendritic cells, frequently with marked constitutional symptoms

Alternate/Historical Names

• Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-type T cell lymphoma
• Angioimmunoblastic-type T cell lymphoma
• Immunoblastic lymphadenopathy
• Lymphogranulomatosis X

Historical note

• Angioimmunoblastic lymphadenopathy was originally felt to be a precursor lesion that in some cases evolved into T cell lymphoma
• Presence in most cases of clonal T cell receptor gene rearrangements has led to re-classification as T cell lymphoma, even when the malignant T cell population is not histologically evident

Diagnostic Criteria

• Loss of normal lymph node architecture
• Atretic or absent germinal centers
• Prominent arborizing high endothelial venules with PAS positive amorphous perivascular material
• Patent subcapsular sinus, even in the presence of extracapsular extension
• Diffuse polymorphous paracortical infiltrate including lymphocytes, immunoblasts,plasma cells, histiocytes, and eosinophils
• Follicular dendritic cell proliferation outside germinal centers/around high endothelial venules (usually requires immunohistochemistry)
• Neoplastic T cell population often obscured by reactive infiltrate
• Small to medium-sized but occasionally large cells
• Abundant clear cytoplasm and irregular nuclear contour
• Often appear in clusters around high endothelial venules
• Often requires immunohistochemistry
• An early form shows hyperplastic germinal centers
• Germinal centers lack mantle zones, have irregular borders
•  Subtle sprouts of follicular dendritic cells extend from germinal centers (usually requires immunohistochemistry)
• Many cases show accompanying B cell proliferation
• About 70% are EBV related
• May be polymorphic or monmorphic, immunoblastic or plasmacytic
  • Diagnosis of diffuse large B cell lymphoma requires sheets of monoclonal large B cells
  • Diagnosis of plasmacytoma requires sheets of monoclonal plasma cells
  • Molecular evidence of B cell clonality is not sufficient for diagnosis of B cell lymphoma or plasmacytoma
• May produce a Hodgkin-like proliferation with Reed-Sternberg-like cells
• Constitutional symptoms and laboratory abnormalities common

Dita Gratzinger MD PhD
Yasodha Natkunam MD PhD

Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Initial posting : October 7, 2007

Supplemental studies

Immunohistology and Flow Cytometry

• Neoplastic T cell population:
  • T lineage markers
    • CD2+
    • CD3+
    • CD4 ~90% +
    • CD5+
    • CD7 often lost (~1/3+)
  • Germinal center T cell markers
    • CD10 60-90%+
      • Native germinal center B cells are larger and weakly CD10+
      • Granulocytes are strongly CD10+
    • CXCL13+
    • Bcl6 70-80%+
• Proliferation of follicular dendritic cells outside follicle centers/around high endothelial venules is characteristic
• CD21+ (more sensitive marker)
• CD23+

Genetic analysis

• Molecular clonality studies
• 80-90% of cases show clonal T cell receptor gene rearrangement
• ~1/4 of T cell gene rearrangements are oligoclonal
• ~ 1/3 show immunoglobulin gene rearrangement
• rare cases show immunoglobulin gene rearrangement in the absence of a T cell receptor gene rearrangement
• Cytogenetic abnormalities often present
• help establish clonality
• not specific for this diagnosis
• In situ hybridization for EBV early region RNA (EBER):
• ~50% of cases positive, including 70% of cases with accompanying B cell proliferation
• EBV+ cells correspond to CD20+ B immunoblasts

Clinical laboratory

• A variety of abnormalities may be found
  • Cold agglutinins
  • Positive Coombs test
  • Circulating immune complexes
  • Anti-smooth muscle antibodies
  • Rheumatoid factor
  • Anti-nuclear antibodies
  • Paraproteins
  • Cryoglobulins

Differential Diagnosis

• Other lymphomas
  • Peripheral T cell lymphoma, unspecified
  • Nodal marginal zone lymphoma
  • T cell / histiocyte rich diffuse large B cell lymphoma
  • Nodular lymphocyte predominance Hodgkin lymphoma
  • Classical Hodgkin lymphoma
• Non-neoplastic lymphadenopathies
  • Paracortical (T zone) lymphoid hyperplasia
    • Viral lymphadenitis, especially infectious mononucleosis
    • Anticonvulsant-associated lymphadenopathy
    • Dermatopathic lymphadenopathy
    • Toxoplasmosis lymphadenitis
• Angiofollicular lymphoid hyperplasia (Castleman disease), plasma cell type

Nodal Marginal Zone B Cell Lymphoma	Angioimmunoblastic T Cell Lymphoma
B cell immunophenotype	T cell immunophenotype although many cases show accompanying B cell proliferation
Marginal zone distribution, sometimes with colonization of germinal centers	Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation, and polymorphic infiltrate including immunoblasts
Clinically indolent	Clinically aggressive, frequently presents with constitutional symptoms

T Cell / Histiocyte Rich B Cell Lymphoma	Angioimmunoblastic T Cell Lymphoma
<10% scattered large B lymphocytes; morphology varies but is generally unifiorm within a case	May show monomorphous or polymorphous B cell proliferation, scattered or in sheets
Monoclonal immunoglobulin gene rearrangement usually present	Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3 of cases)
T cells polyclonal	T cells usually monoclonal or oligoclonal
Background of small T lymphocytes, sometimes with numerous epithelioid histiocytes	Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation, and polymorphic infiltrate including immunoblasts
No cytologically malignant T cell population present	Malignant T cell population with clear cytoplasm and irregular nuclear contour sometimes morphologically discernible
T cells not germinal center phenotype	Germinal center T cell phenotype (CD10+, CXCL13+) in 60-90%
Often presents with mass lesion	Often presents with generalized lymphadenopathy, pruritic rash, immune dysregulation

Both may show large B cell population in a background of small T cells and may be clinically aggressive

Angioimmunoblastic T Cell Lymphoma	Nodular Lymphocyte Predominance Hodgkin Lymphoma
Spectrum of B cells usually present including immunoblasts and Reed-Sternberg-like cells	Scattered L&H cells with “popcorn” nuclei, nodules of smaller B cells
Germinal centers usually atretic or absent; early phase may have hyperplastic germinal centers	Large nodules and sometimes diffuse areas efface the lymph node
Follicular dendritic cell proliferation sprouts and arborizes outside germinal centers	Large nodules may show expanded /disrupted follicular dendritic cell network but confined to large follicle
Malignant T cell population with clear cytoplasm and irregular nuclear contour sometimes morphologically discernible	No cytologically malignant T cell population present
Germinal center T cell phenotype (CD10+, CXCL13+) in 60-90%	T cells not germinal center phenotype
T cells usually monoclonal or oligoclonal	T cells polyclonal
Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3)	Monoclonal immunoglobulin gene rearrangement may be detectable
Aggressive clinical course with generalized lymphadenopathy, pruritic rash, immune dysregulation.	Generally indolent with localized lymphadenopathy; but may coexist with or recur as diffuse large B cell lymphoma.

Both may show scattered large atypical B cells in a T cell rich background, expanded follicular dendritic cell networks and may show monoclonal immunoglobulin gene rearrangements

Angioimmunoblastic T Cell Lymphoma	Classical Hodgkin Lymphoma
Spectrum of B cells usually present including immunoblasts and Reed-Sternberg-like cells.	B cells are predominantly large mononuclear and multinucleated Reed-Sternberg variants
Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation outside of germinal centers	Broad bands of fibrosis present in the most common (nodular sclerosis) variant
Malignant T cell population with clear cytoplasm and irregular nuclear contour sometimes morphologically discernible	No cytologically malignant T cell population present
Germinal center T cell phenotype (CD10+, CXCL13+) in 60-90%	T cells not germinal center phenotype
T cells usually monoclonal or oligoclonal	T cells polyclonal
Monoclonal immunoglobulin gene rearrangement sometimes present (~1/3)	Monoclonal immunoglobulin gene rearrangement rarely detectable

Both may show CD30+, CD15+, EBV+, CD20+ large cells with Reed-Sternberg morphology and polymorphic background infiltrate including plasma cells, histiocytes, and eosinophils; and present with generalized lymphadenopathy and constitutional symptoms

Angioimmunoblastic T Cell Lymphoma	Reactive T Zone Hyperplasia: Viral (e.g. Infectious Mononucleosis)
Follicular dendritic cell proliferation outside germinal centers	No follicular dendritic cell proliferation outside germinal centers
Necrosis generally absent	Necrosis may be present
EBV often positive in B cells	EBV positive in T cells in infectious mononucleosis
Immunoblasts/Reed-Sternberg-like cells B lineage	Immunoblasts/Reed-Sternberg-like cells T lineage
T cells usually monoclonal or oligoclonal	T cells polyclonal
1/3 also show B cell clonality	EBV-associated monoclonal B-cell proliferations rarely develop (especially with immunodeficiency/immunosuppression).
Aggressive clinical course with generalized lymphadenopathy, pruritic rash, immune dysregulation (viral serologies may be positive in the setting of immunodeficiency).	Localized lymphadenopathy, viral syndrome, viral serologies.

Both may show paracortical expansion with numerous immunoblasts and sometimes Reed-Sternberg-like cells, residual germinal centers, increased vascularity

Angioimmunoblastic T Cell Lymphoma	Reactive T Zone Hyperplasia: Anticonvulsant-associated
Follicular dendritic cell proliferation outside germinal centers	No follicular dendritic cell proliferation outside germinal centers
Necrosis generally absent	Necrosis may be present
EBV often positive in B cells	EBV negative
Immunoblasts/Reed-Sternberg-like cells B lineage	Immunoblasts/Reed-Sternberg-like cells T lineage
T cells usually monoclonal or oligoclonal	T cells polyclonal
1/3 also show B cell clonality	B cells polyclonal.
Aggressive clinical course despite chemotherapy	History of anticonvulsant exposure; symptoms usually resolve with drug withdrawal

Both may show paracortical expansion with numerous immunoblasts, sometimes Reed-Sternberg-like cells, residual germinal centers, increased vascularity and present with fever, rash, lymphadenopathy and immune dysregulation (anticonvulsant hypersensitivity syndrome)

Angioimmunoblastic T Cell Lymphoma	Reactive T Zone Hyperplasia: Dermatopathic Lymphadenopathy
Pale-staining cells, if present, are CD3+/CD10+/CXCL13+ T cells	Pale-staining cells are S100+/CD1a positive interdigitating reticulum cells, Langerhans histiocytes
Numerous immunoblasts present	Hemosiderin and pigment-laden histiocytes
1/3 may show B cell clonality in addition to T cell clonality	No B cell clonality
Follicular dendritic cell proliferation outside germinal centers	No follicular dendritic cell proliferation outside germinal centers
Aggressive clinical features with systemic lymphadenopathy, constitutional symptoms, immune dysregulation	Usually clinically indolent unless associated with advanced cutaneous T cell lymphoma

Both may show paracortical expansion with patches of pale-staining cells, admixed histiocytes, plasma cells, and eosinophils, increased vascularity, reactive or atretic follicles, accompanying pruritic rash. Both may have clonal T cell populations (in dermatopathic lymphadenopathy if there is an associated cutaneous T cell lymphoma).

Angioimmunoblastic T Cell Lymphoma	Reactive T Zone Hyperplasia: Toxoplasma Lymphadenitis
Pale-staining cells, if present, are CD3+/CD10+/CXCL13+ T cells	Pale-staining cells are monocytoid B cells.
Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation, and polymorphic infiltrate including immunoblasts	Characteristic triad of reactive germinal centers, perifollicular clusters of epithelioid histiocytes, and islands of monocytoid cells
T cells usually monoclonal or oligoclonal; 1/3 also show B cell clonality	B and T cells polyclonal
Aggressive clinical features with systemic lymphadenopathy, constitutional symptoms, immune dysregulation	Localized lymphadenopathy, positive Toxoplasma serology

Both may show paracortical expansion with patches of pale-staining cells, admixed histiocytes

Angioimmunoblastic T Cell Lymphoma	Angiofollicular Lymphoid Hyperplasia (Castleman Disease), Plasma Cell Type
B cell proliferation: immunoblasts usually predominate	B cell proliferation: plasma cells usually predominate
Vascular proliferation: arborizing network of plump vessels in paracortex	Vascular proliferation: hyalinized vessels penetrate atretic follicles
Follicular dendritic cells: arborizing proliferation away from germinal centers	Follicular dendritic cells: concentric layers of hyperplastic follicular dendritic cells within atretic follicles
Malignant T cell population with clear cytoplasm and irregular nuclear contour sometimes morphologically discernible	No cytologically malignant T cell population present
T cells usually monoclonal or oligoclonal	T cells polyclonal
B cell or plasma cell proliferation monoclonal in ~1/3 of cases	Plasma cell proliferation is sometimes lambda-monoclonal
HHV8 negative	Lambda-monoclonal plasmablasts HHV8+
B cell proliferation may progress to diffuse large B cell lymphoma, less commonly other lymphomas	May progress to plasmablastic lymphoma
Not associated with HIV	Highly associated with HIV

Both may show reactive and atretic follicles, vascular proliferation, and proliferation of immunoblasts and plasma cells.  Clinically both may have systemic lymphadenopathy, constitutional symptoms, and polyclonal hypergammaglobulinemia.

Clinical

• Aggressive T cell lymphoma of middle-aged/older adults
• ~20% of peripheral T cell lymphomas
• Usually presents at advanced stage with constitutional symptoms, systemic lymphadenopathy+/- hepatosplenomegaly, and bone marrow involvement
• Occasionally involves extranodal sites, such as skin
• Constitutional symptoms and findings may include fever, pruritic skin rash, edema
• Polyclonal hypergammaglobulinemia
• Inflammatory disorders (arthritis, vasculitis, pleuritis)
• Autoimmune disorders (hemolytic anemia)
  • Laboratory abnormalities common
• Results in immunocompromised with susceptibility to infection
• Secondary lymphomas may develop
• usually diffuse large B cell lymphoma, often EBV+
• Prognosis poor
  • Death frequently due to infection

Staging / Report

Grading not applicable

Staging

• 70% present in stage III or IV

Ann Arbor Staging System

• Stage I
  • I if involvement of a single lymph node region
  • IE if involvement of a single extralymphatic organ or site
• Stage II
  • II if two or more lymph node regions on same side of diaphragm
  • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
• Stage III
  • III if Involvement of lymph node regions on both sides of the diphragm
  • IIIS if spleen involved
  • IIIE if extralymphatic site involved
• Stage IV
  • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
• Systemic Symptoms in 6 months preceding admission
  • Fever, night sweats, 10% weight loss
  • A = absent
  • B = present
• Extranodal sites are also designated
  • M+ = marrow
  • L+ = lung
  • H+ = liver
  • P+ = pleura
  • O+ = bone
  • D+ = skin and subcutaneous tissue
• Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

• Diagnosis in the World Health Organization (WHO) classification
  • Equivalent diagnosis in other classifications used by relevant clinicians
• Results of supplementary studies if performed
• Relationship to other specimens from the same patient
• Information relevant to staging if available

Lists

Mature T and NK cell neoplasms (WHO classification)

• Leukemic
  • T cell prolymphocytic leukemia
  • T cell large granular lymphocytic leukemia
  • Aggressive NK cell leukemia
  • Adult T cell leukemia/lymphoma
• Predominantly cutaneous
  • Mycosis fungoides
  • Anaplastic large cell lymphoma, primary cutaneous
  • Lymphomatoid papulosis
  • CD4+/CD56+ hematodermic neoplasm (Blastic NK cell lymphoma)
• Predominantly extranodal, noncutaneous
  • Extranodal NK/T cell lymphoma, nasal type
  • Enteropathy type T cell lymphoma
  • Hepatosplenic T cell lymphoma
  • Subcutaneous panniculitis-like T cell lymphoma
• Predominantly nodal
  • Peripheral T cell lymphoma unspecified
  • Angioimmunoblastic T cell lymphoma
  • Anaplastic large cell lymphoma, primary systemic

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