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Lymphoproliferative disorders
Lymphoproliferative disorders (LPDs) manifest with uncontrolled hyperplasia of lymphoid tissues (lymph nodes, spleen, bone marrow, liver). They are a heterogeneous group of diseases that range from reactive polyclonal hyperplasia (immunologic disorders) to true monoclonal (malignant) diseases.
Angioimmunoblastic lymphadenopathy with dysproteinemia
This monoclonal disorder is now recognized as a form of peripheral T-cell lymphoma.
Manifestations of this clinicopathological syndrome include:
- 1.
generalized lymphadenopathy (80%);
- 2.
hepatosplenomegaly (70%);
- 3.
fever (70%), malaise, weight loss, polyarthralgia;
- 4.
quantitative changes in serum proteins (polyclonal hypergammaglobulinemia, 70%), hypocomplementemia;
- 5.
autoantibodies; circulating immune complexes, antismooth muscle antibody;
- 6.
rashes;
- 7.
pulmonary infiltrates, pleural effusions;
- 8.
thrombocytopenia; and
- 9.
hemolytic anemia [often direct antiglobulin test (Coombs’) positive].
Diagnosis
The lymph node shows architectural effacement, absence of germinal center, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts and plasma cells. Immunoblasts are CD4-positive. Lymph node cytogenetic studies have shown nonrandom abnormalities, including +3, 14q+, and del(8) (p21). Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) was previously considered to be a benign LPD with the potential to transform into lymphoma. Since it is a monoclonal disorder, it is recognized as a type of angioimmunoblastic peripheral T-cell lymphoma.
Prognosis
The prognosis is poor. The median overall survival is 1.5 years; however, one in five patients is a long-term survivor.
Treatment of AILD-type lymphoma
Chemotherapy: T-cell acute lymphoblastic leukemia (ALL) therapy or peripheral T-cell lymphoma regimens are often used as initial therapy and patients with favorable disease response are often consolidated with autologous or allogeneic stem cell transplant. Second-line therapies include fludarabine, lenalidomide, pralatrexate, romidepsin, and bortezomib.
Small lymphocytic infiltrates of the orbit and conjunctiva (ocular adnexal lymphoid proliferation, pseudolymphoma, benign lymphoma, atypical lymphocytic infiltrates)
Lymphocytic infiltrates of the orbit and conjunctiva may be divided into three histologic groups:
- 1.
monomorphous infiltrates of clearly atypical lymphocytes,
- 2.
infiltrates composed of small lymphocytes with minimal or no cytologic atypia, and
- 3.
benign inflammatory pseudotumor or reactive follicular hyperplasia.
On the basis of immunophenotypic criteria, they can be divided into two classes:
- 1.
infiltrates with monotypic immunoglobulin expression and
- 2.
infiltrates with polytypic immunoglobulin expression.
For the localized small lymphocytic infiltrates, monotypic (monoclonal) immunoglobulin expression confers a 50% risk of dissemination. The initial immunophenotypic (monoclonal or polyclonal) and molecular studies of various histologic groups fail to correlate with the eventual outcome of these cases because the initial polyclonal tumors may become monoclonal.
All patients presenting with small lymphocyte infiltrates of the orbit and conjunctiva should have a systemic evaluation with serum chemistries, blood counts, and appropriate imaging studies at initial diagnosis and every 6 months for 5 years thereafter. Immunoglobulin G (IgG)4-related disease should be considered in the differential diagnosis.
For localized disease, local radiotherapy is commonly used, regardless of histologic grading. DNA from Chlamydia psittaci has been isolated in a large percentage of biopsies and treatment with doxycycline may be efficacious.
Angiocentric immunolymphoproliferative disorders
These are a collection of entities classified as peripheral T-cell disorders and include lymphomatoid granulomatosis, midline granuloma, and postmalignancy angiocentric immunolymphoproliferative (AIL) lymphoma.
There are three grades of AIL disorders:
- 1.
Grade I : polymorphic infiltrates with minimal necrosis, few large atypical lymphoid cells, and small lymphocytes lacking nuclear irregularities
- 2.
Grade II : cytologic atypia of small lymphocytes, scattered large atypical lymphoid cells, and intermediate amount of necrosis
- 3.
Grade III : lymphoma, either diffuse, mixed, large cell, or immunoblastic, with prominent necrosis
The cellular origin of AIL lymphoma remains uncertain because of the following findings:
- 1.
Immunophenotype of T cells (CD2+, CD3+, CD4±, CD5±, CD7±)
- 2.
Absence of clonal rearrangements of T-cell receptors (TCRs)
- 3.
Expression of natural killer (NK) cell antigens (CD16+, CD56+, CD57+)
AIL lymphoma has been postulated to be a clonal process induced by Epstein–Barr virus (EBV) infection of T lymphocytes.
Clinical features
Lymphomatoid granulomatosis
This is a systemic disease in which the lungs are typically involved. Patients may present with cough, dyspnea, and chest pain, or they may be asymptomatic and discovered incidentally on a chest radiograph. Chest radiographs may show bilateral nodules, consolidation, diffuse bilateral reticulonodular infiltrates, lymphadenopathy (mediastinal and/or hilar), and/or pleural effusion. Purplish skin nodules occur and may undergo spontaneous central necrosis and ulceration. The kidneys, central nervous system (CNS), skeletal muscles, nasopharynx, or peripheral nerves may also be involved.
Midline lethal granuloma
This presents with a progressive necrotizing and destructive process involving the upper airways. There may or may not be a tumor mass. The most common sites of the disease are the nasal fossa, nasal septum, nasopharynx, palate, and adjacent soft tissue or bony structures. There is often a history of long-standing sinusitis with purulent and foul-smelling nasal discharge.
Postmalignancy angiocentric immunolymphoproliferative lymphoma
This rarely occurs in children and most commonly occurs after a history of ALL. The interval between the remission of ALL to the diagnosis of AIL lymphoma ranges from 1 month to 4–5 years. The prognosis is poor.
Treatment
There is no standard treatment; the majority of patients are treated with chemotherapy based on adult non-Hodgkin lymphoma protocols and rituximab. The most commonly used agents are cyclophosphamide, prednisone, adriamycin, and vincristine.
Castleman disease (angiofollicular lymph node hyperplasia, benign giant lymph node hyperplasia, angiomatous lymphoid hamartoma)
Castleman disease is characterized by an accumulation of nonmalignant lymphoid tissue interspersed with plasma cells and blood vessels.
Vascular hyperplasia has been attributed to a humoral vasoproliferative factor.
Table 16.1 shows the relationship between histologic types and clinical features in Castleman disease.
Table 16.1
Relationship between histologic types and clinical features in Castleman disease.
| Histologic type (frequency) | Disease sites | Symptoms |
|---|---|---|
| Hyaline vascular type (80%) | Solitary lymph node 1.5–16 cm or chain of lymph nodes; two-thirds in mediastinum; sometimes other sites such as peripheral lymph nodes, abdomen, and pelvis | >90% Asymptomatic; pressure effects referable to the location of the mass may be present; 5–10% patients have constitutional symptoms |
| Plasma cell variety (20%) |
|
|
Abbreviation: ESR, Erythrocyte sedimentation rate .
The production of interleukin-6 (IL-6) by B cells in the germinal centers of hyperplastic lymph nodes in Castleman disease plays a central role in inducing the variety of symptoms in this disease. In localized disease, human herpesvirus 8 (HHV8) DNA sequences have been detected in CD19 B cells. In multicentric disease, HHV8 sequences have been detected in CD19 B cells and CD2 T cells.
Clinical features
Unicentric hyaline vascular variant
- 1.
Single lymph node or chain: cervical and mediastinal nodes most common.
- 2.
About 5–10% of patients have constitutional symptoms, but most are asymptomatic.
- 3.
May have reactive diffuse shotty nonpathologic lymphadenopathy.
- 4.
Rarely associated with thrombotic thrombocytopenic purpura.
Unicentric plasma cell variant
- 1.
Single lymph node or chain: abdominal nodes most common.
- 2.
Associated with increased IL-6.
- 3.
May have reactive diffuse shotty nonpathologic lymphadenopathy and splenomegaly.
- 4.
More frequently has constitutional symptoms, hematologic abnormalities (anemia, thrombocytopenia, lymphocytosis), hypoalbuminemia, and hypergammaglobulinemia.
Multicentric plasma cell variant
- 1.
Similar clinical presentation as unicentric plasma cell variant; however, it involves multiple lymph nodes and chains and more likely to have systemic symptoms. Hepatosplenomegaly is more common.
- 2.
May have neurologic manifestations, anasarca with peripheral edema, ascites, and pleural effusions, constitutional symptoms, including fever, weight loss, and night sweats, pruritus, and Raynaud symptoms.
- 3.
Multicentric Castleman disease (MCD) is typically divided into HHV8-positive and HHV8-negative subgroups. HHV8-positive MCD is usually associated with immune compromise, most commonly with HIV. MCD is more common in adults. If children present with MCD, it is often HHV8 negative. Patients with multicentric disease often have cytopenias, hypergammaglobulinemia, hypoalbuminemia, elevated erythrocyte sedimentation rate, CRP, ALT, AST, LDH, IL-6, and ferritin.
TAFRO variant
Recently described variant of HHV8-negative MCD that has T hrombocytopenia, A nasarca, F ever, R eticulin myelofibrosis, and O rganomegaly, TAFRO variant typically has normal gammaglobulin levels.
Prognosis
Localized disease
excellent.
Multicentric disease
Multicentric disease: poor in adults but the prognosis in children is good. A minority with multicentric disease progress rapidly and develop hemolytic anemia and fatal intercurrent infection. Some develop secondary malignancies, including non-Hodgkin lymphoma or Kaposi sarcoma.
Treatment
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