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AUTHOR AND EDITOR INFORMATION

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Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld is a member of the following medical societies: American Academy of Dermatology

Editors: Evan R Farmer, MD, Professor of Dermatology, Johns Hopkins University School of Medicine, Clinical Professor of Pathology, Virginia Commonwealth University School of Medicine; Consulting Staff, Department of Dermatology, Johns Hopkins Hospital, VCU Health Services; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Daniel S Loo, MD, Associate Professor, Residency Program Director, Department of Dermatology, Boston University School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author and Editor Disclosure

Synonyms and related keywords: AILD, angioimmunoblastic T-cell lymphoma, diffuse plasmacytic sarcomatosis, immunoblastic lymphadenopathy, lymphogranulomatosis X, immunologic aberrations in idiopathic reticulosis, angioimmunoblastic lymphadenopathy, AIL

INTRODUCTION

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Background

In 1974, Frizzera et al1 described angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). In some classifications, similar atypical lymphoproliferative disorders were later grouped as lymphogranulomatosis X or immunoblastic lymphadenopathy.

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

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, subclassification has been introduced and comprises 3 subsets of the disease: AILD with no evidence of clonal lymphoid proliferation; AILD-type dysplasia with inconsistent findings regarding the clonality of the proliferating cells; and AILD-type lymphoma with strong evidence of clonality by immunohistochemical tests, rearrangement analysis, and cytogenetic studies. However, AILD-type dysplasia with an oligoclonal T-cell pattern has frequently been shown to progress into AILD-type lymphoma. Thus, subclassification may reflect the existence of stages in the development of the disease rather than independent disease entities.

Krenacs et al2 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.

Pathophysiology

Evidence exists that 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. Moreover, latent infections with Epstein-Barr virus (EBV) or human cytomegalovirus (CMV) as evidenced by data from in situ hybridization and polymerase chain reaction tests, may also be involved.

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.

A deletion mutant of the LMP1 oncogene of EBV is associated with the evolution of angioimmunoblastic lymphadenopathy into B immunoblastic lymphoma.

Dunleavy et al3 noted that over expression 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.
 
Using immunohistochemistry, Grogg et al4 noted CD10 and CXCL13 staining in bone marrow samples in a subset of patients with AILD. 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 al5 noted that, similarly to multiple myeloma, c-Maf expression occurs in persons with angioimmunoblastic T-cell lymphoma.

Frequency

United States

The exact incidence is not known. However, it is well reported. Approximately 1-2% of non-Hodgkin lymphomas are associated with AILD.

International

The exact incidence is not known. 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.

Mortality/Morbidity

Treatment of AILD is suboptimal, with approximately 25% of patients achieving complete and sustained remission when combined chemotherapy agents are used. However, in most patients, the condition eventually evolves into AILD-type lymphoma.

Race

This disease has been reported in Asia, the United States, and Europe. Few reports in the literature describe this disease in African American and Hispanic persons.

Sex

In 2000, in a series of 10 patients, Martel et al6 reported 7 women and 3 men. In 1995, Siegert et al7 reported a female-to-male ratio of 1:1.4 in a series of 62 patients.

Age

Most patients are middle aged or elderly. AILD has been reported in children. In 1995, Siegert et al7 reported a median patient age of 64 years (range, 21-87 y) in a series of 62 patients.


CLINICAL

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History

  • AILD usually starts in a nonspecific fashion with maculopapular rashes (that can resemble a viral rash), seropositive polyarthritis, fever, pruritus, lymphadenopathy, night sweats, and weight loss. Bone pain can occur in AILD. Such symptoms are also generally the presenting signs of lymphoma. Initially, AILD has a waxing and waning course; however, as it progresses, symptoms persist. Patients can also have edema, ascites, and hepatosplenomegaly.
  • Patients can manifest with odd infections. For example, immunoblastic lymphadenopathy presented as an acute abdomen and mixed bacteremia with Eikenella corrodens and group C streptococci 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, a case of AILD manifested with sick sinus syndrome, and others have the appearance of collagen vascular diseases. Some patients have a history of collagen-vascular diseases, such as rheumatoid arthritis and dermatomyositis.
  • In 2004, Singh et al8 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. The case was subsequently diagnosed as AILD based on lymph node biopsy results.
  • Also in 2004, De Samblanx et al9 described a 67-year-old man with a nephrotic syndrome secondary to a proliferative glomerulonephritis, which was coincident with angioimmunoblastic T-cell lymphoma.
  • Batinac et al10 reported a case of AILD that resulted in death following the administration of doxycycline.
  • In 2007, Hosoki et al11 described angioimmunoblastic T-cell lymphoma developing with lymphocytic pleural effusion.
  • Renner et al12 described eosinophilic cellulitis (Wells' syndrome) in association with angioimmunoblastic lymphadenopathy.
  • Karube et al13  reported on 11 cases of adult T-cell lymphoma/leukemia with angioimmunoblastic T-cell lymphomalike features.

Physical

All organ systems can be affected by AILD. At diagnosis, patients present with a skin rash (50%), pruritus (30%), edema (40%), pleural effusion (40%), arthritis (20%), and ascites (25%).

  • Skin findings often include a morbilliform rash. It is 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 al14 suggested the “deck-chair sign” is specific for cutaneous involvement by angioimmunoblastic T cell lymphoma. AILD with scleromyxedemalike lesions and serum monoclonal protein has been reported.15
  • Gastrointestinal findings include ascites, gastrointestinal lymphomatous polyposis, and sclerosing cholangitis.
  • Lymph node and glandular findings include adenopathy and lacrimal and salivary gland and systemic lymphadenopathy.
  • Hepatic and splenic findings include hepatosplenomegaly.
  • Renal findings include renal amyloidosis, proliferative glomerulonephritis, and acute interstitial nephritis.
  • Pulmonary findings are varied and include hypoxemia. Some patients have interstitial pneumonia or bronchopneumonia. Patients with bronchopneumonia can have opportunistic infections, such as Pneumocystis carinii, and 1 patient had CMV.
  • Neurologic, rheumatologic, and related findings include retrobulbar neuritis, neuropathy, polyneuropathy, arthritis, papilledema, myelofibrosis, and inflammatory myopathy.

Causes

  • AILD has been linked to a variety of viral infections, such as EBV, CMV, and herpesvirus type 6. It has also been linked with a variety of genetic mutations. 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.
  • Medications linked to the induction of AILD include salazosulfapyridine, azithromycin, and doxycycline.


DIFFERENTIALS

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Other Problems to be Considered

  • Multicentric giant lymph node hyperplasia
  • Acute viral lymphadenitis
  • Lymphoma
  • Leukemia
  • Viral exanthem
  • Crohn disease: Kang et al16 described angioimmunoblastic T-cell lymphoma mimicking Crohn disease.


WORKUP

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Lab Studies

  • Almost any laboratory value can be abnormal in AILD. As is true with its clinical symptoms, incongruous laboratory values, especially pancytopenia, should prompt a consideration of AILD as a diagnosis. Patients also exhibit autoimmune laboratory findings, such as circulating immune complexes, a positive Coombs test result, smooth muscle antibodies, rheumatoid factors, autoimmune hemolysis, cold agglutinins, paraproteinemia, antinuclear antibodies, and cryoglobulins.
  • In AILD, a variety of hematologic anomalies are present; anticardiolipin antibodies and anemia with hemoglobin with values below 10 g/dL can be present, and a direct Coombs test result can be positive. Often, thrombocytopenia with platelet counts below 100 X 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. Cells with +5, +15, +19, +21, +22 trisomies have been seen as well.
  • Blood chemistry values that can be abnormal include erythrocyte sedimentation rate (almost all cases), lactate dehydrogenase (LDH) level (commonly increased), polyclonal gammaglobulins (common), autoantibodies, antinuclear antibodies, antismooth muscle antibodies, anticardiolipin antibodies, rheumatoid factor (less common), and cryoglobulins (less common).
  • AILD shows a high proportion of tumor necrosis factor-alpha–positive T lymphocytes, and, in addition, the percentages of interleukin (IL)–2, IL-4, IL-5, IL-6, IL-13, and interferon-gamma–positive T lymphocytes were relatively higher than in other diseases. These data underlie the state of multiple hypercytokinemia typically observed in AILD.
  • The role of EBV infection in skin lesions is not clear.
  • 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. PCR amplification and sequencing of immunoglobulin H (IgH) genes is advisable because a gene rearrangement is detected in 10% of cases.
  • Yamane et al17 reported angioimmunoblastic T-cell lymphoma with polyclonal proliferation of plasma cells in peripheral blood and marrow.

Imaging Studies

  • Radiography and CT scanning can demonstrate lymphadenopathy. They can 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. They show lymphadenopathy, ie, enlargement of the lymph nodes; 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.

Procedures

  • 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.
    • A tap of ascites fluid is useful as well. Ascites is present in 25% of cases and requires cytologic examination.

Histologic Findings

On examination of the skin biopsy sample, a perivascular dermal infiltrate with eosinophils, histiocytes, plasma cells, and lymphoid cells is observed. 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- 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 al18 reported in 2007 that clear cells and EBV infection (when present) are useful distinguishing features and that CD10 is a sensitive and specific marker of AILD. Hyperplastic follicles are present in a significant minority of AILD patients.

Sakai et al19 described an angioimmunoblastic T-cell lymphoma patient initially presenting with replacement of bone marrow and peripheral plasmacytosis.

Staging

The standard staging system used for angioimmunoblastic T-cell lymphoma is the same as that proposed for Hodgkin disease at the Ann Arbor Conference in 1971. Its use is not certain because its staging does not seem to match the prognosis, but it is the only system available and is used nevertheless.

The Ann Arbor staging system uses both the number of sites of involvement and the presence of disease above or below the diaphragm. The Ann Arbor staging system defines 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 presence (A) or absence (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 it is a frequently accompanying symptom, itching should not be considered a systemic symptom. The presence of a bulky mass, such as a lesion of 10 cm or more in the longest diameter, is signaled as "X," whereas the extranodal involvement should be identified by a symbol such as the following: O for bone, L for lung, and D for skin.

Miura et al20 reported acute renal failure resulting from immunoglobulin M–lambda glomerular thrombi and membranoproliferative glomerulonephritis–like lesions in a patient with angioimmunoblastic T-cell lymphoma.


TREATMENT

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Medical Care

Polychemotherapy is often used. Prednisone is a first-line agent in the treatment of AILD. Regimens include prednisone alone or cyclophosphamide and prednisone, cyclophosphamide with vincristine, and prednisone. Cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone (CHOP)–like regimens used as first-line therapy before or after steroids administration, with or without interferon alfa as consolidation, in retrospective analyses have produced complete remission rates of about 60%.

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.

Radiation therapy has been used as well. Cyclosporine and 2-chlorodeoxyadenosine and cyclophosphamide have also been used. The treatment regimen of cyclophosphamide, Oncovin (vincristine), prednisone, bleomycin, Adriamycin (doxorubicin), and Matulane (procarbazine) (COP-BLAM) and ifosfamide, mesna uroprotection, methotrexate, and etoposide (IMVP-16) has been used. Methotrexate has not been found to be effective.

High-dose chemotherapy (HDCT) followed by autologous bone marrow transplantation (ABMT) represents a promising new treatment modality for patients with advanced lymphoma, conceivably including AILD.

A 5-month-old girl with AILD was treated with interferon alfa, cyclosporine 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.

Halene et al21 reported sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab.

Rodríguez et al22 described prolonged survival for patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.

Dunleavy et al3 have suggested that novel therapeutic strategies including immunomodulation with agents such as cyclosporine and angiogenesis inhibition with drugs such as bevacizumab might be helpful in the future.

Shinohara et al23 reported durable remission after the administration of rituximab for EBV-negative, diffuse large B-cell lymphoma following autologous peripheral blood stem cell transplantation for angioimmunoblastic T-cell lymphoma.

Surgical Care

In a few cases, the removal of the spleen has improved the symptoms of AILD or induced remission. In addition, Nakashima et al24 reported successful coil embolization of a ruptured hepatic aneurysm in a patient with polyarteritis nodosa accompanied by angioimmunoblastic T cell lymphoma.

Consultations

This disease requires consultations from all specialists who can deal with specific manifestations of AILD. The primary doctor that should supervise care is an oncologist/hematologist. Because most patients die from infectious complications, an infectious disease specialist should also be involved.


MEDICATION

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The first-line agent in the treatment of AILD is prednisone. Interferon alfa is a promising agent in the treatment of AILD. Many agents have been used to treat AILD, but none is universally or consistently effective. The dosing regimens of these treatments have not been definitively set and hence are not included.


FOLLOW-UP

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Further Inpatient Care

  • In patients with AILD, possible infections must be assessed and proper treatment for the infections that AILD sets the stage for with its accompanying immunosuppression must be treated.

Further Outpatient Care

  • Patients must be monitored for infections and informed that they must be evaluated for infections if they have a fever or other constitutional symptoms.

In/Out Patient Meds

  • Patients who are treated with chemotherapy must maintain their regimens and take proper medications for infections that can accompany AILD and chemotherapy.

Complications

  • Most patients die of infections due to immunologic compromise.

Prognosis

  • With treatment, remission occurs in about 25% of patients. However, most patients die from AILD. Overall, 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, EBV-positive B-cell lymphomas, and chronic lymphatic leukemia (CLL) among other kinds of lymphoma and leukemia.
    • In 1995, in a univariate analysis, Siegert et al found that survival was significantly related to the following: age (P = .032), stage (P = .037), rash/pruritus (P = .038), edema (P = .030), ascites (P = .013), number of clinical symptoms (P = .004), LDH level (P = .007), and hemoglobin (P = .020).
    • In 1996, Schlegelberger et al25 found that certain cytogenetic findings were associated with a significantly lower incidence of therapy-induced remissions and a significantly shorter survival duration. Specifically, these cytogenetic findings included the presence of aberrant metaphases in unstimulated cultures; clones with an additional X chromosome; structural aberrations of the short arm of chromosome 1, preferentially involving 1p31-32; and complex aberrant clones with more than 4 aberrations.

Patient Education

  • Patients and their families must understand that AILD is usually a fatal disease and is accompanied by many potentially serious infections.
  • For excellent patient education resources, see eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Lymphoma.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • AILD must be distinguished from reactive processes that mimic it.
  • 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.

Special Concerns

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


REFERENCES

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  1. Frizzera G, Moran EM, Rappaport H. Angio-immunoblastic lymphadenopathy with dysproteinaemia. Lancet. Jun 1 1974;1(7866):1070-3. [Medline].
  2. Krenacs L, Schaerli P, Kis G, Bagdi E. Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells. Blood. Aug 1 2006;108(3):1110-1. [Medline].
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  6. Martel P, Laroche L, Courville P, Larroche C, Wechsler J, Lenormand B, et al. Cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia: a clinical, immunohistological, and molecular analysis. Arch Dermatol. Jul 2000;136(7):881-6. [Medline].
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  22. Rodríguez J, Conde E, Gutiérrez A, Arranz R, Gandarillas M, Leon A, et al. Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience. Eur J Haematol. Apr 2007;78(4):290-6. [Medline].
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  24. Nakashima M, Suzuki K, Okada M, Takada K, Kobayashi H, Hama Y. Successful coil embolization of a ruptured hepatic aneurysm in a patient with polyarteritis nodosa accompanied by angioimmunoblastic T cell lymphoma. Clin Rheumatol. Aug 2007;26(8):1362-4. [Medline].
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Angioimmunoblastic Lymphadenopathy With Dysproteinemia excerpt

Article Last Updated: Feb 11, 2008