Surgical Pathology Criteria–

Angioimmunoblastic T Cell Lymphoma

Differential Diagnosis

Angioimmunoblastic T Cell Lymphoma Peripheral T Cell Lymphoma Unspecified
Characteristic morphology with vascular proliferation, follicular dendritic cell proliferation, and polymorphic infiltrate including immunoblasts Morphology varies widely but does onot show all of the features of AITL
Germinal center T cell phenotype (CD10+, CXCL13+) ini 60-90% Usually not germinal center phenotype (only in 10-30% of cases)
Infrequent T cell antigen loss Frequent T cell antigen loss (CD5, CD7)
Characteristic clinical presentation with pruritic rash, immune dysregulation Rash and immune dysregulation uncommon
Both are clinically aggressive nodal T cell lymphomas arising in similar patient populations

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.

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