Doctor123.org

Lymphoproliferative Disorders, Pediatric

Basics

Description

- 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

- XLP - Majority of cases mutation in SH2DIA - XLP-like syndrome caused by X-linked inhibitor of apoptosis protein (XIAP) mutations

- 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. " пїЅ - Destruction of erythrocytes: See chapter on "Autoimmune Hemolytic Anemia. " пїЅ - Destruction of neutrophils: See chapter on "Neutropenia. " пїЅ - Can have autoimmune involvement of any organ system, similar to systemic lupus erythematosus - In young adult years, 10 " пїЅ20% 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

- 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 " пїЅ10% of patients)

  • 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 includeAutoimmune lymphoproliferative syndrome (ALPS)Castleman disease (CD)Rosai " пїЅDorfman disease (RDD)EBV-associated lymphoproliferative disorder (ELD)X-linked lymphoproliferative syndrome (XLP)
  • Rarer disorders (not discussed in detail)Angioimmunoblastic lymphadenopathyCaspase-8 deficiency syndromeDianzani autoimmune lymphoproliferative diseaseKikuchi-Fujimoto syndromeLymphomatoid granulomatosisLymphomatoid papulosisOcular adnexal lymphoid proliferationRAS-associated leukoproliferative disorder

Epidemiology

All uncommon пїЅ пїЅ

Risk Factors

Often multifactorial with inherited genetic defect and acquired infection пїЅ пїЅ

Genetics

  • ALPS (80% of patients have identifiable mutation)60 " пїЅ70% germline mutation in FAS (TNFRSF6)10% somatic mutation in FAS2% germline mutation in CASP10<1% germline mutation in FASL
  • XLPMajority of cases mutation in SH2DIAXLP-like syndrome caused by X-linked inhibitor of apoptosis protein (XIAP) mutations

Pathophysiology

  • ALPSDefective FAS-mediated apoptosis leads to abnormal lymphocyte survival with subsequent lymphoproliferation, autoimmunity, and cancer.
  • CDLargely unknown but can be triggered by HHV-8 infection, especially in immunocompromised patients
  • ELDEBV triggered lymphoproliferative disorder found in patients on chronic immune suppression typically after organ or bone marrow transplant (PTLD) or with inherited immune deficiency
  • XLPMutation 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

  • ALPSTypically presents at young age (average 18 months) with massive lymphadenopathy and splenomegalyMany patients develop secondary autoimmune disease.Most often, autoimmune destruction of blood cells (80% of patients); can be mild to severeDestruction of platelets: See chapter on "Idiopathic Thrombocytopenic Purpura. " пїЅDestruction of erythrocytes: See chapter on "Autoimmune Hemolytic Anemia. " пїЅDestruction of neutrophils: See chapter on "Neutropenia. " пїЅCan have autoimmune involvement of any organ system, similar to systemic lupus erythematosusIn young adult years, 10 " пїЅ20% 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.
  • CDTwo variantsHyaline vascular: presents with enlarged single lymph node or chain of nodes; >90% with no other symptoms; rarely can have fever, weight loss, fatiguePlasma cell: presents with enlarged single lymph node or chain (unicentric) or diffuse adenopathy (multicentric); often with constitutional symptoms (fever, sweats, lethargy, rashes, neuropathy, arthritis)
  • RDDMassive, painless bilateral cervical lymphadenopathy with or without other involved nodal groupsFeverSnoring commonCan have extranodal invasion of almost any organ (25% of patients have extranodal disease) and signs and symptoms depend on involved organ
  • ELD/PTLDCan 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
  • XLPCan present as fulminant infectious mononucleosis or aplastic anemia or lymphoma or hematophagocytic syndromeOften critically ill in the setting of EBV infection

Physical Exam

  • ALPSMassive 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
  • CDHyaline vascular: single enlarged lymph node or chain; most often cervical or mediastinal; may have shotty diffuse nonpathologic adenopathyPlasma cell: single or multiple pathologically enlarged lymph nodes; abdominal nodes most common; hepatosplenomegaly common. Peripheral edema, ascites, and pleural effusions may be present.
  • RDDMassive bilateral anterior cervical lymphadenopathy (90% of patients). Other physical exam findings can vary based on extranodal disease.Hepatosplenomegaly (10% of patients)
  • ELD/PTLDSimilar to other lymphoproliferative disorders (See "Epstein-Barr virus " пїЅ chapter.)
  • XLPSimilar to other lymphoproliferative disorders, however, far more acutely ill (see also "Epstein " пїЅBarr virus " пїЅ chapter and Aplastic Anemia " пїЅ 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 пїЅ пїЅ пїЅ, and CD8 пїЅ пїЅ пїЅ. 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
  • DiagnosisDefinitive: both mandatory and one major criteriaProbable: 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) " пїЅhallmark 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 diseaseSurgical resection or focal radiation. Steroids may be used to shrink lesions prior to surgery.
  • For CD multicentric diseaseMultiagent therapy (vincristine, prednisone, rituximab, cyclophosphamide, doxorubicin)
  • For RDMay self-resolve (20% of patients)If not, consider prednisone, or vinblastine plus prednisone, or mercaptopurine plus methotrexate, or 2CdA.
  • For ELD/PTLDReduce immune suppression or convert immune suppression to sirolimus if possibleConsider rituximab, adoptive transfer of EBV-specific cytotoxic T cellsIf fails or generalized disease, consider multiagent chemotherapy similar to RDD
  • For XLPIf hematophagocytosis or aplasia: rituximab, etoposide, steroids, and cyclosporineHematopoietic stem cell transplant is the only cure.

Second Line

  • For ALPSSirolimus or mycophenolate mofetil for chronic diseaseSirolimus (rapamycin): pros: improves autoimmune disease and lymphoproliferation and eliminates DNTs. Cons: drug " пїЅdrug interactions; requires therapeutic drug monitoring; 10% of patients develop mouth sores (most common in first month).Mycophenolate mofetil (CellCept): pros: No drug " пїЅdrug interactions, no mouth sores, no therapeutic drug monitoring. Cons: not as effective; does not help lymphoproliferation or lower DNTs; GI upsetRecommended 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 ALPSCombination therapy: stem cell transplantRelative contraindications (AVOID, if possible)Splenectomy: high incidence of pneumococcal sepsis even with antibiotic prophylaxis and immunizationRituximab: can lead to lifelong hypogammaglobulinemia (5 " пїЅ10% 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 пїЅ пїЅAH, Morrison пїЅ пїЅVA. Post-transplant lymphoproliferative disorders following solid-organ transplantation. Expert Rev Hematol. 2010;3(1):35 " пїЅ44. пїЅ пїЅ[View Abstract]
  • Oliveira пїЅ пїЅJB, Bleesing пїЅ пїЅJJ, Dianzani пїЅ пїЅU, 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 " пїЅe40. пїЅ пїЅ[View Abstract]
  • Rezaei пїЅ пїЅN, Mahmoudi пїЅ пїЅE, Aghamohammadi пїЅ пїЅA, 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 " пїЅ30. пїЅ пїЅ[View Abstract]
  • Schulte пїЅ пїЅKM, Talat пїЅ пїЅN. Castleman 's disease " пїЅa two compartment model of HHV8 infection. Nat Rev Clin Oncol. 2010;7(9):533 " пїЅ543. пїЅ пїЅ[View Abstract]
  • Teachey пїЅ пїЅDT, Seif пїЅ пїЅAE, Grupp пїЅ пїЅSA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010;148(2):205 " пїЅ216.

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)