Basics
Description
- Lymphoproliferative disorders are a class of nonmalignant diseases characterized by uncontrolled growth of lymphoid tissues (spleen, bone marrow, liver, lymph nodes).
- Can be congenital or acquired
- Most common in children include
- Autoimmune lymphoproliferative syndrome (ALPS)
- Castleman disease (CD)
- Rosai " �Dorfman disease (RDD)
- EBV-associated lymphoproliferative disorder (ELD)
- X-linked lymphoproliferative syndrome (XLP)
- Rarer disorders (not discussed in detail)
- Angioimmunoblastic lymphadenopathy
- Caspase-8 deficiency syndrome
- Dianzani autoimmune lymphoproliferative disease
- Kikuchi-Fujimoto syndrome
- Lymphomatoid granulomatosis
- Lymphomatoid papulosis
- Ocular adnexal lymphoid proliferation
- RAS-associated leukoproliferative disorder
Epidemiology
All uncommon � �
Risk Factors
Often multifactorial with inherited genetic defect and acquired infection � �
Genetics
- ALPS (80% of patients have identifiable mutation)
- 60 " �70% germline mutation in FAS (TNFRSF6)
- 10% somatic mutation in FAS
- 2% germline mutation in CASP10
- <1% germline mutation in FASL
- XLP
- Majority of cases mutation in SH2DIA
- XLP-like syndrome caused by X-linked inhibitor of apoptosis protein (XIAP) mutations
Pathophysiology
- ALPS
- Defective FAS-mediated apoptosis leads to abnormal lymphocyte survival with subsequent lymphoproliferation, autoimmunity, and cancer.
- CD
- Largely unknown but can be triggered by HHV-8 infection, especially in immunocompromised patients
- ELD
- EBV triggered lymphoproliferative disorder found in patients on chronic immune suppression typically after organ or bone marrow transplant (PTLD) or with inherited immune deficiency
- XLP
- Mutation in SH2D1A leads to abnormal production of SAP protein in NK and T cells, leading to defective SAP-SLAM signaling and inability to appropriately respond to EBV infection.
Diagnosis
History
- ALPS
- Typically presents at young age (average 18 months) with massive lymphadenopathy and splenomegaly
- Many patients develop secondary autoimmune disease.
- Most often, autoimmune destruction of blood cells (80% of patients); can be mild to severe
- Destruction of platelets: See chapter on "Idiopathic Thrombocytopenic Purpura. " �
- Destruction of erythrocytes: See chapter on "Autoimmune Hemolytic Anemia. " �
- Destruction of neutrophils: See chapter on "Neutropenia. " �
- Can have autoimmune involvement of any organ system, similar to systemic lupus erythematosus
- In young adult years, 10 " �20% develop lymphoma.
- Lymphoproliferation can improve or worsen with infection. Often progresses through teenage years and improves in adulthood.
- Autoimmune disease is less likely to improve with older age.
- CD
- Two variants
- Hyaline vascular: presents with enlarged single lymph node or chain of nodes; >90% with no other symptoms; rarely can have fever, weight loss, fatigue
- Plasma cell: presents with enlarged single lymph node or chain (unicentric) or diffuse adenopathy (multicentric); often with constitutional symptoms (fever, sweats, lethargy, rashes, neuropathy, arthritis)
- RDD
- Massive, painless bilateral cervical lymphadenopathy with or without other involved nodal groups
- Fever
- Snoring common
- Can have extranodal invasion of almost any organ (25% of patients have extranodal disease) and signs and symptoms depend on involved organ
- ELD/PTLD
- Can be mild, with lymphadenopathy, fever, and/or diarrhea, or severe, with massive lymphadenopathy, high fever, night sweats, rash, and pruritus, and organ compression from involved nodes
- XLP
- Can present as fulminant infectious mononucleosis or aplastic anemia or lymphoma or hematophagocytic syndrome
- Often critically ill in the setting of EBV infection
Physical Exam
- ALPS
- Massive lymphadenopathy (90% of patients): Can compress vital organs including trachea (rare). Most common site of adenopathy is anterior cervical. Nodes are hard but mobile.
- Splenomegaly (90% of patients)
- Hepatomegaly (50% of patients)
- Other physical exam findings as expected with autoimmune destruction of blood cells and/or end-organ autoimmune disease
- CD
- Hyaline vascular: single enlarged lymph node or chain; most often cervical or mediastinal; may have shotty diffuse nonpathologic adenopathy
- Plasma cell: single or multiple pathologically enlarged lymph nodes; abdominal nodes most common; hepatosplenomegaly common. Peripheral edema, ascites, and pleural effusions may be present.
- RDD
- Massive bilateral anterior cervical lymphadenopathy (90% of patients). Other physical exam findings can vary based on extranodal disease.
- Hepatosplenomegaly (10% of patients)
- ELD/PTLD
- Similar to other lymphoproliferative disorders (See "Epstein-Barr virus " � chapter.)
- XLP
- Similar to other lymphoproliferative disorders, however, far more acutely ill (see also "Epstein " �Barr virus " � chapter and Aplastic Anemia " � chapter)
Diagnostic Tests & Interpretation
Lab
General
- Complete blood and reticulocyte count for anemia, thrombocytopenia, and neutropenia
- Direct antiglobin test (DAT) to check for autoimmune destruction of red blood cells
- Serum chemistries, uric acid, phosphorus to look for cell turnover (usually normal in lymphoproliferative disorders)
- Liver function tests, PT, PTT, and fibrinogen to measure liver function and for coagulopathy
- EBV, PCR and titers, CMV-PCR
- If acutely ill, consider ESR or CRP and ferritin.
- Quantitative immunoglobulins: often elevated in lymphoproliferative disorders
Diagnostic tests for ALPS
- Mandatory criteria
- (1) Chronic (>6 months) nonmalignant lymphoproliferation (lymphadenopathy) and/or splenomegaly
- (2) Elevated peripheral blood double-negative T cells (DNTs): T cells that are CD3+, TCR alpha/beta+, CD4 � � �, and CD8 � � �. DNTs are usually rare in peripheral blood (<1% of total lymphocytes or <2.5% of total T cells). DNTs are elevated and often markedly elevated in ALPS. Slight elevation in DNTs can be found in other autoimmune disorders.
- Major (primary) criteria
- (1) Genetic mutation in ALPS causative gene (germline or somatic) in FAS, FASL, or CASP10
- (2) In vitro evidence of defective FAS-mediated apoptosis. This assay requires growing blood cells from patient in culture for weeks and exposing to anti-Fas monoclonal antibody to see if T cells are resistant to death. Only performed in a few labs.
- Minor (secondary) criteria
- (1) Elevated vitamin B12 (>1,500 ng/L)
- (2) Elevated IL-10 (>20 pg/mL)
- (3) Elevated IL-18 (>500 pg/mL)
- (4) Elevated sFASL (>200 pg/mL)
- (5) Classic histopathologic findings on lymph nodes or spleen biopsy
- (6) Autoimmune cytopenias AND elevated serum IgG
- (7) Positive family history
- Diagnosis
- Definitive: both mandatory and one major criteria
- Probable: both mandatory and one minor criteria (Probable ALPS should be treated the same as definitive ALPS.)
Diagnostic tests for CD
- Castleman syndrome diagnosed by histopathology
- Hypergammaglobulinemia, anemia, high ESR, high IL-6, HHV-8, PCR+
Diagnostic tests for RDD
- RDD diagnosed by histopathology
- Hypergammaglobulinemia, anemia, high ESR, leukocytosis with neutropenia, hematologic autoantibodies
Diagnostic tests for ELD/PTLD
- PTLD after bone marrow graft
- Persistent EBV infection (positive EBV PCR or abnormal seroconversion by titers) in setting of immune suppression or immune compromise
- Diagnosis confirmed with imaging and/or histopathology
Diagnostic tests for XLP
- Persistent EBV infection (positive EBV PCR or abnormal seroconversion on titers)
- Inverted CD4/CD8 ratio
- High IgM and IgA, low IgG
- Defective NK activity
- Secondary hematophagocytic syndrome (elevated ferritin, high triglycerides, low fibrinogen, cytopenias, high fever, splenomegaly, poor NK function, elevated s-IL-2R-alpha, and hematophagocytosis on marrow or node biopsy)
- Diagnosis confirmed by genetic testing for mutations in SH2D1A and XIAP genes, and/or SAP protein quantification
Imaging
- CT scans of head, neck, chest, abdomen, and pelvis with IV contrast is important for all lymphoproliferative disorders at initial diagnosis to define extent of disease.
- It is IMPORTANT to obtain plain chest x-ray on initial presentation in patient with diffuse lymphadenopathy before CT scan to ensure a large mediastinal mass is not present. If present, it may be unsafe to lie patient flat and/or sedate for CT scan.
- Most lymphoproliferative disorders are very PET-avid.
Diagnostic Procedures/Other
- ALPS and PTLD can be diagnosed without histopathology; however, most patients have a lymph node biopsy.
- Other lymphoproliferative disorders typically require tissue for diagnosis (biopsy, not fine needle aspirate).
- Consider bone marrow aspirate and/or biopsy to rule out marrow disease or other disease processes.
Pathological Findings
- ALPS: DNTs in lymph node and spleen
- CD: hyaline vascular (shrunken germinal centers with eosinophilic expansion of mantle zones with and vessel hyalinization); plasma cell (extensive plasma cell infiltrate in interfollicular regions)
- RD: emperipoiesis (lymphophagocytosis) " �hallmark of disease on biopsy; presence of histiocytes
- XLP/PTLD/ELD: EBER+
Differential Diagnosis
- Other lymphoproliferative disorders
- Lymphoma
- Infection: EBV, CMV, toxoplasmosis, HIV, TB
- Evans syndrome
- Rheumatologic disease
Treatment
Medication
First Line
- For ALPS: Corticosteroids or IVIG for acute flares
- For CD localized disease
- Surgical resection or focal radiation. Steroids may be used to shrink lesions prior to surgery.
- For CD multicentric disease
- Multiagent therapy (vincristine, prednisone, rituximab, cyclophosphamide, doxorubicin)
- For RD
- May self-resolve (20% of patients)
- If not, consider prednisone, or vinblastine plus prednisone, or mercaptopurine plus methotrexate, or 2CdA.
- For ELD/PTLD
- Reduce immune suppression or convert immune suppression to sirolimus if possible
- Consider rituximab, adoptive transfer of EBV-specific cytotoxic T cells
- If fails or generalized disease, consider multiagent chemotherapy similar to RDD
- For XLP
- If hematophagocytosis or aplasia: rituximab, etoposide, steroids, and cyclosporine
- Hematopoietic stem cell transplant is the only cure.
Second Line
- For ALPS
- Sirolimus or mycophenolate mofetil for chronic disease
- Sirolimus (rapamycin): pros: improves autoimmune disease and lymphoproliferation and eliminates DNTs. Cons: drug " �drug interactions; requires therapeutic drug monitoring; 10% of patients develop mouth sores (most common in first month).
- Mycophenolate mofetil (CellCept): pros: No drug " �drug interactions, no mouth sores, no therapeutic drug monitoring. Cons: not as effective; does not help lymphoproliferation or lower DNTs; GI upset
- Recommended treatment: Mild to moderate autoimmune disease start with mycophenolate and transition to sirolimus if poor response or side effects. More severe autoimmune disease or clinically significant lymphoproliferation start with sirolimus.
Third Line
- For ALPS
- Combination therapy: stem cell transplant
- Relative contraindications (AVOID, if possible)
- Splenectomy: high incidence of pneumococcal sepsis even with antibiotic prophylaxis and immunization
- Rituximab: can lead to lifelong hypogammaglobulinemia (5 " �10% of patients)
Ongoing Care
Follow-up Recommendations
- Recommended follow-up imaging varies among institutions. Most physicians will repeat imaging if patient 's history changes OR to determine response to therapy.
Prognosis
- Prognosis is good to fair for most lymphoproliferative disorders.
- Prognosis is poor in XLP and advanced CD.
Additional Reading
- Blaes � �AH, Morrison � �VA. Post-transplant lymphoproliferative disorders following solid-organ transplantation. Expert Rev Hematol. 2010;3(1):35 " �44. � �[View Abstract]
- Oliveira � �JB, Bleesing � �JJ, Dianzani � �U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35 " �e40. � �[View Abstract]
- Rezaei � �N, Mahmoudi � �E, Aghamohammadi � �A, et al. X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. Br J Haematol. 2011;152(1):13 " �30. � �[View Abstract]
- Schulte � �KM, Talat � �N. Castleman 's disease " �a two compartment model of HHV8 infection. Nat Rev Clin Oncol. 2010;7(9):533 " �543. � �[View Abstract]
- Teachey � �DT, Seif � �AE, Grupp � �SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010;148(2):205 " �216.
Codes
ICD09
- 238.79 Other lymphatic and hematopoietic tissues
- 279.41 Autoimmune lymphoproliferative syndrome
- 238.77 Post-transplant lymphoproliferative disorder (PTLD)
- 759.89 Other specified congenital anomalies
ICD10
- D47.9 Neoplasm of uncertain behavior of lymphoid, hematopoietic and related tissue, unspecified
- D89.82 Autoimmune lymphoproliferative syndrome [ALPS]
- D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
- D82.3 Immunodef fol heredit defctv response to Epstein-Barr virus
- D47.Z9 Oth neoplm of uncrt behav of lymphoid, hematpoetc & rel tiss
SNOMED
- 277466009 Lymphoproliferative disorder (disorder)
- 702444009 Autoimmune lymphoproliferative syndrome (disorder)
- 254290004 Post-transplant lymphoproliferative disorder (disorder)
- 77121009 X-linked lymphoproliferative syndrome (disorder)