Angioimmunoblastic Lymphoma 

In 1974, Frizzera et al^[1] described angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). In some classifications, similar atypical lymphoproliferative disorders were later grouped as lymphogranulomatosis X or immunoblastic lymphadenopathy. The disorder is now classified as angioimmunoblastic lymphoma. As both terms are in common use, they will be used interchangeably in this article.

AILD is a type of peripheral T-cell lymphoma that is clinically characterized by high fever and generalized lymphadenopathy. Approximately 40-50% of patients also have cutaneous involvement. As the disorder progresses, hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia may develop. In one series, other symptoms included weight loss (58%), hepatomegaly (60%), polyclonal hyperglobulinemia (65%), and generalized adenopathy (87%). Patients are usually aged 40-90 years.

AILD may represent a spectrum of disease ranging from a hyperplastic but still benign immune reaction to frank malignant lymphoma. Because clonal expansion of T cells has been demonstrated in most but not all cases of AILD, the following 3 subclassifications have been introduced:

• AILD with no evidence of clonal lymphoid proliferation
• AILD-type dysplasia with inconsistent findings regarding the clonality of the proliferating cells
• AILD-type lymphoma with strong evidence of clonality by immunohistochemical tests, rearrangement analysis, and cytogenetic studies

AILD-type dysplasia with an oligoclonal T-cell pattern has frequently been shown to progress into AILD-type lymphoma. Thus, this subclassification may reflect the existence of stages in the development of the disease rather than independent disease entities.

Krenacs et al have suggested that the phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma appears consistent with the phenotype of activated follicular B-helper T cells.^[2] It has become clear that AILD is a clonal T-cell disorder involving deregulation of B-cells and endothelial cells against a background involving a unique malignant microenvironment.

Biopsies of the bone marrow, lymph node, and skin are key in diagnosing AILD (see Workup). Many agents have been used to treat AILD, but none has proved universally or consistently effective (see Treatment and Management).

For other discussions on lymphoma, see the overview topic Non-Hodgkin Lymphoma.

Evidence exists that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) develops in a serial fashion. The initial reaction may be an unbalanced immune response to an unknown antigen. This stage is followed by an oligoclonal phase that is driven by persistence and ineffective handling of the primary and initial stimulus. Further events, assumed to take place on a molecular level, may then evolve into malignant monoclonal disease.

In AILD, the factors that result in the serial evolution into malignant lymphoma have yet to be defined. Patients frequently pass through a phase of atypical immune reactions, such as an allergic drug reaction or an allergic reaction to an arthropod bite. Latent viral infection may also be involved (see Etiology).

AILD, specifically angioimmunoblastic T-cell lymphoma, is mainly derived from CD2⁺ CD3⁺ CD4⁺ CD5⁺ CD7^- mature T-helper cells with varying expression and partial loss of detectable CD4. A significant number of non-neoplastic T cells (resting CD4⁺ T cells and activated small- or medium-sized CD8⁺ lymphocytes) may coexist with a minor neoplastic T-cell population.

Dunleavy et al noted that overexpression of the chemokine CXCL13 and vascular endothelial growth factor–A in angioimmunoblastic T cell lymphoma suggests that it may be derived from follicular helper T cells.^[3]

Using immunohistochemistry, Grogg et al noted CD10 and CXCL13 staining in bone marrow samples in a subset of patients with AILD.^[4] The lymphomatous infiltrate in some bone marrow specimens from these AILD patients contained numerous small or scattered large B cells, and these cells resembled either benign lymphoid aggregates or T-cell–rich large B-cell lymphoma, respectively. Trilineage hematopoietic hyperplasia and plasmacytosis were other changes noted by Grogg et al.

Murakami et al reported that the oncogene c-Maf was expressed in the majority of angioimmunoblastic T-cell lymphomas studied.^[5]c-Maf is also overexpressed in approximately half of multiple myelomas.

Tripodo et al have suggested that mast cells have a role in the proinflammatory microenvironment of AILD.^[6] They observed that mast cells, which preferentially occurred in AILD cases, directly synthesized interleukin 6 and correlated with the presence of interleukin 17–producing T cells.

Data from in situ hybridization and polymerase chain reaction tests suggest that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) may be linked to latent infection with a variety of viruses, such as Epstein-Barr virus (EBV),^[7] cytomegalovirus (CMV), and herpesvirus type 6. A deletion mutant of the LMP1 oncogene of EBV is associated with the evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.

The body's immune system is also thought to misapprehend some antigens, resulting in the cascade of cytokines and gene expression that underlies AILD. The actual proximate cause is not known. The role of EBV infection in skin lesions is not clear.

Patients with Sjögren syndrome are at increased risk for developing lymphoma. Although most lymphomas in these patients are of the B-cell variety, AILD constitutes the majority of T-cell lymphomas associated with Sjögren syndrome.^[8]

Medications linked to the induction of AILD include salazosulfapyridine, azithromycin, and doxycycline.

The exact incidence of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is not known. In the United States, approximately 1-2% of non-Hodgkin lymphomas are associated with AILD. In one case series in Korea, 1 of 78 cases of lymphoma was diagnosed as AILD. In a series of 3194 cases of lymphoma in Japan, 2.35% were diagnosed as AILD.

The female-to-male ratio in AILD remains uncertain. In 2000, in a series of 10 patients, Martel et al reported 7 women and 3 men.^[9] In 1995, Siegert et al reported a female-to-male ratio of 1:1.4 in a series of 62 patients.^[10]

Although AILD has been reported in children, most patients are middle aged or elderly. Siegert et al reported a median patient age of 64 years (range, 21-87 y) in a series of 62 patients.^[10]

History

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) usually starts in a nonspecific fashion. Clinical manifestations are typical of lymphoma and may include the following:

• Maculopapular rashes (these can resemble a viral rash)
• Seropositive polyarthritis
• Fever
• Pruritus
• Lymphadenopathy
• Night sweats
• Weight loss
• Edema

As the disease progresses, patients may experience bone pain, ascites, and hepatosplenomegaly. Initially, AILD has a waxing and waning course; however, as it progresses, symptoms persist.

Patients can present with unusual infections. For example, Mönkemüller and Bronze reported a case of immunoblastic lymphadenopathy that presented as an acute abdomen and mixed bacteremia with Eikenella corrodens and group C Streptococcus infection. Some patients have had disseminated infections with herpesvirus type 6 and other viral infections.

Incongruous clinical symptoms raise the possibility of AILD. For example, one reported case of AILD manifested as sick sinus syndrome, and others have had the appearance of collagen vascular diseases. Some patients have a history of collagen-vascular diseases, such as rheumatoid arthritis and dermatomyositis.

AILD can mimic tuberculosis. Singh et al reported a case of AILD with pulmonary involvement that was initially mistaken for tuberculosis based on fine-needle aspiration cytology and was treated with antituberculous therapy for 3 months.^[11] The case was subsequently diagnosed as AILD based on lymph node biopsy results.

Hosoki et al described angioimmunoblastic T-cell lymphoma developing with lymphocytic pleural effusion.^[12]

Rare cases of AILD associated with proliferative glomerulonephritis have been reported. De Samblanx et al described a 67-year-old man with a nephrotic syndrome secondary to a proliferative glomerulonephritis, which was coincident with angioimmunoblastic T-cell lymphoma.^[13]

Batinac et alreported a case of AILD in an elderly patient who presented with generalized pruritic maculopapular eruption and fever after taking doxycycline.^[14] Renner et al described eosinophilic cellulitis (Wells syndrome) in association with angioimmunoblastic lymphadenopathy.^[15]

Physical examination

All organ systems can be affected by AILD. Typical findings at presentation include the following:

• Skin rash (50% of cases)
• Pruritus (30%)
• Edema (40%)
• Pleural effusion (40%)
• Arthritis (20%)
• Ascites (25%)

Skin involvement in AILD manifests as a vascular reaction pattern rash that can resemble a viral exanthem, a toxic-mediated erythema, or a drug reaction. It can manifest as erythroderma or with pruritus that is intense and dermatitis herpetiformis–like lesions. Ferran et al suggested that the "deck-chair sign" (ie, rash with sparing of skin creases) is specific for cutaneous involvement by angioimmunoblastic T cell lymphoma.^[16] AILD with scleromyxedema-like lesions and serum monoclonal protein has been reported,^[17] as have subcorneal pustules and deep dermal-hypodermal nodules^[18] and toxic epidermal necrolysis.^[19]

Other possible findings include systemic lymphadenopathy, lacrimal and salivary gland involvement, and hepatosplenomegaly. Renal findings include renal amyloidosis, proliferative glomerulonephritis, and acute interstitial nephritis. Miura et al reported acute renal failure resulting from immunoglobulin M–lambda glomerular thrombi and membranoproliferative glomerulonephritis–like lesions in a patient with angioimmunoblastic T-cell lymphoma.^[20]

Pulmonary findings are varied and include hypoxemia. Some patients have interstitial pneumonia or bronchopneumonia. Patients with bronchopneumonia can have opportunistic infections, such as Pneumocystis jiroveci pneumonia; a case of cytomegalovirus infection has also been reported. Jarrett et al reported a case of shortness of breath and peripheral edema.^[21]

Neurologic, rheumatologic, and related findings include retrobulbar neuritis, neuropathy, polyneuropathy, arthritis, papilledema, myelofibrosis, and inflammatory myopathy.

Goenka et al described a case of angioimmunoblastic lymphadenopathy with multiple polyps of the gastrointestinal tract. The patient presented with fever, abdominal mass, ascites, diarrhea, generalized lymphadenopathy, anemia, and marked peripheral eosinophilia.^[22]

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) must be distinguished from reactive processes that mimic it.^[23] AILD is usually diagnosed at advanced stages because its symptoms are nonspecific; thus, in older people, so-called B symptoms (ie, fever, weight loss, lymphadenopathy) should prompt investigation for AILD, leukemia, and lymphoma.

Reactive processes can mimic AILD; moreover, infections can occur with AILD, and AILD can evolve into high-grade lymphoma. These situations should be considered when assessing and treating AILD.

Other problems to be considered in patients with possible angioimmunoblastic lymphoma include the following:

• Multicentric giant lymph node hyperplasia
• Acute viral lymphadenitis
• Lymphoma
• Leukemia
• Viral exanthema
• Crohn disease^[24]
• Atypical linear immunoglobulin A dermatosis^[25]

Almost any laboratory value can be abnormal in angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). As is true with its clinical symptoms, the presence of incongruous laboratory values, especially pancytopenia, should prompt a consideration of AILD as a diagnosis.

Patients with AILD may exhibit laboratory findings characteristic of autoimmune disease, such as the following:

• Circulating immune complexes
• Anti –smooth muscle antibodies
• Rheumatoid factor
• Autoimmune hemolysis
• Cold agglutinins
• Paraproteinemia
• Anticardiolipin antibodies
• Rheumatoid factor (less common)
• Cryoglobulins (less common)

Other blood chemistry values that can be abnormal include the following:

• Erythrocyte sedimentation rate (almost all cases)
• Lactate dehydrogenase (LDH) level (commonly increased)
• 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 AILD can be detected with fluorescence in situ hybridization (FISH). Cells with +5, +15, +19, +21, and +22 trisomies have been seen as well.

AILD 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 AILD.

Flow cytometry has potential utility for the diagnosis of AILD.^{[26, 27, 28]} Chen et al reported that multiparameter flow cytometry identifed a distinct population of immunophenotypically aberrant T cells in 15 of 16 cases.^[26] Yuan et al suggested that finding coexpression of CD10 on flow cytometry can help discriminate AILD from other peripheral T-cell lymphomas.^[28]

Tumor cells in AILD 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 angioimmunoblastic T-cell lymphoma with polyclonal proliferation of plasma cells in peripheral blood and marrow.^[29] Cho et al found that 70% of cases of AILD involve bone marrow and that CD5, bcl-6, and CD10 were useful markers of bone marrow infiltration.^[30]

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 AILD, but lymph node biopsy is necessary to distinguish AILD from lymphoma.

Biopsies

Biopsies of the bone marrow, lymph node, and skin are key in diagnosing AILD. AILD is diagnosed by a positive biopsy result obtained from an affected lymph node, although sometimes, biopsy results are only suggestive of AILD, not diagnostic. In patients with ascites (25% of cases), paracentesis with cytologic examination of ascitic fluid is indicated.

Histologic findings

Skin biopsy samples in AILD 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 infection (when present) are useful distinguishing features and that CD10 is a sensitive and specific marker of AILD.^[31] Hyperplastic follicles are present in a significant minority of AILD patients.

Sakai et al described an angioimmunoblastic T-cell lymphoma patient initially presenting with replacement of bone marrow with polymorphic cellular infiltrates containing aggregates of CD10-positive T cells, along with peripheral plasmacytosis.^[32] Karube et al reported on 11 cases of adult T-cell lymphoma/leukemia in which morphologic features were suggestive of angioimmunoblastic T-cell lymphoma, 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.^[33]

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 angioimmunoblastic lymphoma.^[34]

The standard staging system used for angioimmunoblastic T-cell lymphoma 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 angioimmunoblastic T-cell lymphoma, 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:

• Stage I - Involvement of a single lymph node region (I) or a single extranodal site (IE)
• 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)
• 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)
• 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:

• O – Bone
• L – Lung
• D – Skin

Many agents have been used to treat angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), but none has proved universally or consistently effective. The dosing regimens of these treatments have not been definitively set.

Corticosteroids are first-line agents for angioimmunoblastic lymphoma.^[35] Prednisone may be used alone or in combination with cyclophosphamide, vincristine, or both. The combination of cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone (CHOP) has been used before or after prednisone and with or without interferon alfa as consolidation. In retrospective analyses, CHOP and CHOP-based regimens have produced complete remission rates of about 60%.^{[36, 37]}

Two thirds of patients treated with low doses of recombinant interferon alfa-2a (used as a single agent) achieved an objective remission, while, in the remaining one third of patients, no change or progressive disease was observed. The median remission duration was 3.5 months. Thus, interferon seems a promising agent in the treatment of AILD, but its role must be further defined.

Other therapeutic approaches that have been tried include the following:

• Radiation therapy
• Cyclosporine, 2-chlorodeoxyadenosine, and cyclophosphamide
• Cyclophosphamide, Oncovin (vincristine), prednisone, bleomycin, Adriamycin (doxorubicin), and Matulane (procarbazine) (COP-BLAM)
• Ifosfamide, mesna uroprotection, methotrexate, and etoposide (IMVP-16)

Methotrexate has not been found to be effective.

High-dose chemotherapy followed by autologous bone marrow transplantation represents a promising new treatment modality for patients with advanced lymphoma and may conceivably be useful in AILD. Rodríguez et al described prolonged survival for patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.^[38] Shinohara et al reported durable remission after the administration of rituximab for EBV-negative, diffuse large B-cell lymphoma that developed after autologous peripheral blood stem cell transplantation for angioimmunoblastic T-cell lymphoma.^[39]

Dunleavy et al have suggested that novel therapeutic strategies that include immunomodulation with agents such as cyclosporine and angiogenesis inhibition with drugs such as bevacizumab may prove helpfu.^[3] There are reports of sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab.^{[40, 41]}

In a few cases, the removal of the spleen has improved the symptoms of AILD or induced remission. A 5-month-old girl with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) was treated with interferon alfa, cyclosporin A, deoxyspagarine, and azathioprine, alternating regimens of low-dose 6-mercaptopurine, cyclophosphamide, and methotrexate, and results were inconsistent. At age 58 months, a splenectomy was performed, which induced a prolonged complete remission of the AILD, without any medication.

Nakashima et alreported successful coil embolization of a ruptured hepatic aneurysm in a patient with polyarteritis nodosa accompanied by angioimmunoblastic T cell lymphoma.^[42]

Management of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) requires consultations with all specialists who can deal with its myriad specific manifestations. An oncologist/hematologist should supervise the care of these patients. Because most patients die of infectious complications, an infectious disease specialist should also be involved.

Patients must be monitored for infections and must be educated about the importance of seeking medical care if they develop a fever or other constitutional symptoms. In most patients, angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) eventually progresses to immunocopmromise, and the assessment and treatment of infection becomes a critical aspect of care.

Overall, angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) has a moderately aggressive course, with occasional spontaneous remissions or protracted responses to therapy. The median survival is 24 months. AILD can evolve into high-grade lymphomas of T- or B-cell type, Epstein-Barr virus (EBV)-positive B-cell lymphomas, and chronic lymphatic leukemia (CLL), among other kinds of lymphoma and leukemia. Most patients eventually die of infections due to immunologic compromise.

A univariate analysis by Siegert et al showed that survival was significantly related to the following^[10] :

• Age
• Stage
• Rash/pruritus
• Edema
• Ascites
• Number of clinical symptoms
• LDH level
• Hemoglobin level

Schlegelberger et al found that certain cytogenetic findings were associated with a significantly lower incidence of therapy-induced remissions and a significantly shorter survival duration.^[43] These cytogenetic findings included the following:

• Aberrant metaphases in unstimulated cultures
• Clones with an additional X chromosome
• Structural aberrations of the short arm of chromosome 1, preferentially involving 1p31-32
• Complex aberrant clones with more than 4 aberrations

Patient Education

Patients and their families must understand that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is usually a fatal disease and is accompanied by many potentially serious infections.

For patient education information, see the Cancer and Tumors Center, as well as Lymphoma.