Laboratory Studies
Almost any laboratory value can be abnormal in angioimmunoblastic T-cell lymphoma (AITL). As is true with its clinical symptoms, the presence of incongruous laboratory values, especially pancytopenia, should prompt a consideration of AITL as a diagnosis.
Patients with AITL may exhibit laboratory findings characteristic of autoimmune disease, such as the following:
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Circulating immune complexes
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Anti–smooth muscle antibodies
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Rheumatoid factor
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Autoimmune hemolysis
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Cold agglutinins
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Paraproteinemia
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Anticardiolipin antibodies
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Rheumatoid factor (less common)
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Cryoglobulins (less common)
Other blood chemistry values that can be abnormal include the following:
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Erythrocyte sedimentation rate (almost all cases)
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Lactate dehydrogenase (LDH) level (commonly increased)
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Polyclonal gamma globulins (common)
Anemia with hemoglobin with values below 10 g/dL can be present, and a direct Coombs test can be positive. Often, thrombocytopenia with platelet counts below 100 × 109/L is present. Platelet-associated immunoglobulin G can be present. In many patients, whole complement activity (CH50) is reduced. Pancytopenia can also be present. These changes are related to compromised bone marrow function.
In some cases, trisomies 3, 5, and X in AITL can be detected with fluorescence in situ hybridization (FISH). Cells with +5, +15, +19, +21, and +22 trisomies have been seen as well.
AITL shows a high proportion of tumor necrosis factor alpha–positive T-lymphocytes. In addition, the percentages of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-13, and interferon-gamma–positive T-lymphocyte counts are relatively higher than in other diseases. These data underlie the state of multiple hypercytokinemia typically observed in AITL.
Flow cytometry has potential utility for the diagnosis of AITL. [40, 41, 42] Chen et al reported that multiparameter flow cytometry identified a distinct population of immunophenotypically aberrant T cells in 15 of 16 cases. [40] Yuan et al suggested that finding coexpression of CD10 on flow cytometry can help discriminate AITL from other peripheral T-cell lymphomas (PTCLs). [42]
Tumor cells in AITL express T-cell–associated antigens and are usually CD4 positive. The clonality of cells can be detected, with T-cell clonality eventually detected in 75% of cases. After treatment, residual disease can be detected by polymerase chain reaction (PCR) by analyzing the rearrangement of TCR genes. Polymerase chain reaction amplification and sequencing of immunoglobulin H (IgH) genes is advisable because a gene rearrangement is detected in 10% of cases.
Yamane et al reported AITL with polyclonal proliferation of plasma cells in peripheral blood and marrow. [43] Cho et al found that 70% of cases of AITL involve bone marrow and that CD5, bcl-6, and CD10 were useful markers of bone marrow infiltration. [44]
Imaging Studies
Radiographs and CT scans can demonstrate lymphadenopathy. They may also demonstrate pulmonary abnormalities, such as pleural effusions and multiple opacities, predominantly basal, of variable size. Radiographic findings include bilateral mediastinal and hilar lymphadenopathy, pleural effusion, interstitial shadow, alveolar shadow, and atelectasis. Diffuse CT contrast enhancement of cervical lymph nodes can aid in diagnosing angioimmunoblastic lymphadenopathy.
Magnetic resonance imaging of bone marrow can demonstrate angioimmunoblastic lymphadenopathy. MRI scans show lymphadenopathy, but this finding is not diagnostic.
Gallium scans and radiographic appearances may assist in diagnosing AITL, but lymph node biopsy is necessary to distinguish AITL from lymphoma.
Biopsy
Biopsies of the bone marrow, lymph node, and skin are key in diagnosing AITL. AITL is diagnosed by a positive biopsy result obtained from an affected lymph node, although sometimes, biopsy results are only suggestive of AITL, not diagnostic. In patients with ascites (25% of cases), paracentesis with cytologic examination of ascitic fluid is indicated.
Histologic Findings
Skin biopsy samples in AITL demonstrate a perivascular dermal infiltrate with eosinophils, histiocytes, plasma cells, and lymphoid cells. The infiltrate can be patchy. The number of blood vessels can be increased. The endothelial cells, which are often cuboidal, are prominent.
In some cases, skin histologic analysis shows extensive perivascular and periadnexal mixed lymphoid infiltrates, including centroblasts and immunoblasts, with a high proliferative index and with focal erythrocyte extravasation.
In skin lesions, T-cell and B-cell blasts predominate, together with endothelial cell proliferation. T-cell receptor gene rearrangement analysis reveals a monoclonality T cell; however, B-cell proliferations are usually polyclonal.
Histologic examination of the lymph nodes can show nearly complete effacement of the follicular architecture, a mixed lymphoid infiltrate, and numerous high endothelial venules in an expanded T-cell zone. In some cases, the lymph nodes show diffuse obliteration of their architecture by lymphoid infiltrates consisting of lymphocytes, immunoblasts, plasma cells, and histiocytes, together with numerous high endothelial venules surrounded by an expanded network of follicular dendritic cells.
Immunohistochemical analysis can demonstrate preservation of at least some follicular structures.
Attygalle et al reported that clear cells and Epstein-Barr virus (EBV) infection (when present) are useful distinguishing features and that CD10 is a sensitive and specific marker of AITL. [45] Hyperplastic follicles are present in a significant minority of AITL patients.
Sakai et al described an AITL patient initially presenting with replacement of bone marrow with polymorphic cellular infiltrates containing aggregates of CD10-positive T cells, along with peripheral plasmacytosis. [46] Karube et al reported on 11 cases of adult T-cell lymphoma/leukemia in which morphologic features were suggestive of AITL, but the immunohistochemical features of the disease—CD10 and CXCL13 expression in lymphoma cells and proliferation of CD21-positive follicular dendritic cells—were not detected. [47]
Dorfman et al reported that programmed death–1 (PD-1), a member of the CD28 costimulatory receptor family, is expressed by germinal center-associated T cells in reactive lymphoid tissue. These researchers suggest PD-1 as a useful marker for AITL. [48]
Bone marrow infiltration by AITL demonstrates variable patterns that correlate with prognosis. PD-1 and BCL6 can be used to identify lymphoma infiltrates. [49]
Staging
The standard staging system used for angioimmunoblastic T-cell lymphoma (AITL) is the Ann Arbor system which was developed for Hodgkin disease but is also used in non-Hodgkin lymphoma. Unfortunately, the Ann Arbor system does not provide a completely reliable match for prognosis in patients with AITL, but it is the only system available.
The Ann Arbor staging system uses both the number of sites of involvement and the presence of disease above or below the diaphragm. It defines the following 4 stages of disease:
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Stage I - Involvement of a single lymph node region (I) or a single extranodal site (IE)
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Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE)
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Stage III - Involvement of lymph node regions on both sides of the diaphragm (III) and localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs)
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Stage IV - Diffuse or disseminated involvement of 1 or more extralymphatic organs with or without associated lymph node involvement; localized involvement of liver or bone marrow is also considered stage IV
Patients are divided into 2 subsets according to the absence (subset A) or presence (B) of systemic symptoms. Fever of no evident cause, night sweats, and weight loss of more than 10% of the patient's body weight are considered systemic symptoms. Even though itching is frequently present, it should not be considered a systemic symptom.
Bulky disease (eg, a lesion of 10 cm or more in the longest diameter) is designated by appending "X" to the stage designation. Extranodal involvement is identified by the following modifiers:
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O – Bone
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L – Lung
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D – Skin
