Dr Tai Al Akawy

Senior Pediatrician at

Alexandria University Children’s Hospital

LYMPHOPROLIFERATIVE DISORDERS

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BASED ON

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LYMPHOPROLIFERATIVE DISORDERS

Mean

Uncontrolled hyperplasia of lymphoid tissues

An abnormal overgrowth of the lymphatic system that is similar in many ways to lymphomas

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THEY ARE

• Heterogenous group of diseases that range from reactive polyclonal hyperplasia ( immunologic disorders )

To

• True monoclonal ( malignant ) diseases

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Lymphoproliferative diseases associated with immune deficiency in children

• The immunodeficient state predisposes a patient not only to infectious diseases but also to cancer, in particular cancer of the immune system

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• Patients with various forms of immune deficiency have an increased risk , especially , for malignant lymphomas

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LYMPHOPROLIFERATION IN IMMUNODEFICIENT PATIENTS

• forms a spectrum from benign-appearing polymorphic, polyclonal processes

to

• monomorphic, monoclonal processes with morphologic features of large cell or Burkitt lymphoma

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These lymphoproliferations are, in most cases, driven by the Epstein-Barr virus (EBV)

• Epstein-Barr virus (EBV) is a γ herpesvirus that is able to establish a long-term, latent infection in human B cells.

• EBV was discovered in the 1960s by electron microscopy of cells cultured from a Burkitt lymphoma

IMPORTANCE OF EPSTEIN BARR VIRUS

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EBV

10

• Once infected, a lifelong carrier state develops.

• Low grade virus replication and shedding can be demonstrated in the epithelial cells of the pharynx of all seropositive individuals.

• EBV is able to immortalize B-lymphocytes in vitro and in vivo

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EBV in B CellInfectious mononucleosisX-Linked Lymphoproliferative DiseaseChronic active EBVHodgkin Disease Burkitt LymphomaLymphoproliferative diseases

 EBV in Other Cells

Nasopharyngeal carcinomaGastric carcinomaNasal T/NK cell lymphomasPeripheral T cell lymphomasOral hairy leukoplakiaSmooth muscle tumors in transplant patients

 

Diseases Associated with EBV

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MOLECULAR CONFIGURATION OF EPSTEIN BARR VIRUS

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EBV genome is enclosed in a nuclear capsid surrounded by a glycoprotein envelope

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MOLECULAR BIOLOGY • Viral capsid antigens (VCAs) are found in replicating cells.• EBV early antigens (EAs) consist of >15 proteins coded by genes

distributed throughout the genome.• EBV nuclear antigen (EBNA) corresponds to six proteins found in

the nucleus of an EBV-infected cell.

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ANTIBODIES IN EBV INFECTIONInfection VCA IgG VCA

IgMEA(D) EBNA

No previous infection

- - - -

Acute infectionRecent infection

+

+

+

+/-

+/-

+/-

-

+/-

Past infection

+ - +/- +

AAP. Red book2010;286-288.03/05/2023 14

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LATENCY• Latently infected B cells are the primary reservoir of EBV in the body

• >100 gene may be expressed during active viral replication, only 11 are expressed during viral latency.

• Latency ( the virus limits cytotoxic T-cell recognition of EBV-infected cells) .

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EBV Latency Proteins

Cohen NEJM 200003/05/2023 16

LMP: latent membrane protein EBNA: EBV nuclear antigens

1- Oncogene

Expression in transgenic mice leads to B cell lymphoma; expression

in fibroblasts leads to tumors in nude mice

2- B Cell Proliferation Upregulates adhesion molecules, CD23, CD40, IL-6, IL-10, etc.

Activates NF-B

3- Inhibits apoptosis Upregulates Bcl-2, A20, Mcl-1

LMP-1 is the EBV Oncogene

(Kulwichit et al. Science 1998)03/05/2023 17

EBV

• EBV is widely disseminated. It is estimated that 95% of world’s population is exposed to the virus, which makes it the most ubiquitous virus known to man

• EBV is only a minor problem for immuno-competent persons, but it can become a major one for immunologically compromised patients

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Ubiquitous : present everywhere

LYMPHOPROLIFERATIVE DISORDERS

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• X-linked lymphoproliferative disorder• The autoimmune lymphoproliferative syndrome ( ALPS)

• Castleman disease (CD)

• Posttransplant lymphoproliferative disease (PTLD)

X-linked lymphoproliferative disorder (DUNCAN DISEASE)

1 in 100,0000 Age of onset: 2.5 yrs old, older reported

Unique predisposition to uncontrolled infection with Epstein Barr virus

EBV induces:- fatal/severe infectious mononucleosis- Secondary agammaglobulinemia- Lymphoma- Bone marrow failure

DUNCAN DISEASE

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• Defect in SAP- interferes with NK and CD8+ CTL function

• The prognosis is poor

• The nature of the lymphoproliferation might change from a polyclonal to a monoclonal process (more aggressive )

CLONALITY ASSESSMENT

• Clonality can be detected by immunohistochemical analysis of immunoglobulins

• The most reliable method for clonality assessment is by using polymerase chain reaction to detect the complete spectrum of possible rearrangements

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Autoimmune lymphoproliferative syndrome

(ALPS)

Canale-Smith syndrome

HISTORY

• Canale and Smith reported five cases with lymphadenopathy, splenomegaly, and autoimmune cytopenias in 1967.

• In 1995, Rieux-Laucat et al. and Fisher et al. documented that this novel disorder was associated with inherited mutations in the Fas gene.

• FAS : cell surface death receptor

(TNF receptor superfamily, member 6; apoptosis stimulating fragment)

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2004,

• New mutations in other intermediates , in the Fas signaling pathway, such as Fas ligand (FasL) gene mutation and caspase gene mutations ( 8 or 10)

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ALPS ETIOLOGY

• ALPS , is the first human disease in which the etiology has been attributed to a primary defect in apoptosis

• The etiology has been attributed to dysregulation of lymphocyte homeostasis due to a primary defect in Fas-induced apoptosis

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APOPTOSIS DYSREGULATION• Dramatically illustrated in the autoimmune lymphoproliferative

syndrome (ALPS) of childhood

• ALPS is the result of dominant inheritance of a mutated gene, TNFRSF6, which encodes the transmembrane protein Fas (also known as CD95), a major mediator of lymphocyte apoptosis

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Caspase-activated deoxyribonuclease (CAD) and its inhibitor (I-CAD)

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Structure of the FAS gene with mutations associated with ALPS-FAS

GENOTYPE-BASED ALPS CLASSIFICATION

• Type Ia : Mutation on TNFRSF6 (Fas) gene

• Type Ib : Mutation on TNFSF6 (FasL) gene

• Type II : Mutation on caspase 8 or 10 genes

• Type III : No known mutation

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ALPS

• FAS mutations are either somatic or germ-line

• Patients with germline mutation of the intracellular domain of Fas have the highest risk of developing lymphoma

14 times greater for non-Hodgkin’s lymphoma and

51 times greater for Hodgkin’s lymphoma

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ALPS IS DEFINED BY THE TRIAD OF

1- Chronic , non-malignant enlargement of lymph nodes and spleen;

2- Increased number of double negative T cells (DNTs) ,

that lack both the CD4 and CD8 surface molecules but , express the α/β T cell receptors (α/β+ DNTs);

3- Impaired lymphocyte apoptosis in vitro

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ALPS, CLINICAL FEATURES

• The median age at presentation is 24 months

• Prominent non-malignant lymphadenopathy often accompanied by splenomegaly (in some cases with hepatomegaly)

And

• Autoimmune cytopenias of one or more lineages

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ALPS

• Non-hematological autoimmune diseases can also occur in association with ALPS, including ,

glomerulonephritis, uveitis, Guillain- Barré syndrome, autoimmune liver disease, urticaria and arthritis

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ALPS

• Several cytokine abnormalities have been found in patients with ALPS, the most striking of which is a significantly elevated IL-10

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OVEREXPRESSION OF IL-10

• May be involved in the proliferation of autoimmune B cells

and

• May cause the persistence and activation of malignant and autoimmune cell clones.

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DIFFERENTIAL DIAGNOSIS

Children with

• Generalized lymphadenopathy,

• Splenomegaly,

and

• Autoimmune multilineage cytopenias represents

a diagnostic challenge

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Clinical and laboratory features overlap with and may manifest as

other childhood diseases

ALPS

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AS

• Systemic infections,

• collagen vascular diseases,

• lymphoma,

• Evans syndrome

• 1ry immunological disorders:

Common variable immunodeficiency, Wiskott-Aldrich syndrome, IL-2 receptor α-chain deficiency

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(Oliveira JB et al., Blood 2010, 116(14) :e35-e40)

REVISED DIAGNOSTIC CRITERIA FOR THE AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS)

(CANALE-SMITH SYNDROME)

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(Oliveira JB et al., Blood 2010, 116(14) :e35-e40 )

REQUIRED

1. Chronic (> 6 months), nonmalignant, noninfectious lymphadenopathy or splenomegaly or both

2. Elevated CD3+TCRαβ+ CD4−CD8− DNT cells in the setting of normal or elevated lymphocyte counts

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ACCESSORY• Primary 1. Defective lymphocyte apoptosis (in 2 separate assays)

2. Somatic or germline mutation in FAS, FASL, or CASP10

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ACCESSORY

Secondary 1. Elevated plasma sFASL levels (>200 pg/mL) OR elevated plasma interleukin-10 levels (>20 pg/mL) OR elevated serum vitamin B12 levels (> 1500 ng/L) OR elevated plasma interleukin-18 levels > 500 pg/mL

2. Typical immunohistological findings as reviewed by an experienced hematopathologist

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ACCESSORY 2RY

3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia)

4. Family history of a nonmalignant / noninfectious lymphoproliferation with or without autoimmunity

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ALPS

• A definitive diagnosis is based on the presence of both required criteria plus one primary accessory criterion.

• A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion

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ALPSTreatment modalities for ALPS are directed at

• The chronic and persistent lymphoproliferation

• Autoimmunity, and

• Malignancies

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ALPS• Lymphoproliferation does respond to corticosteroids and other

immunosuppressants like azathioprine , cyclosporine or mycophenolate mofetil

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ALPSThe treatment of all autoimmune manifestations is the same as in

patients without ALPS

• Autoimmune cytopathies respond well to corticosteroids• Immune thrombocytopenia is less sensitive to intravenous

immunoglobulin (IVIG) therapy than conventional ITP

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ALPS• Some ALPS patients with chronic neutropenia and recurrent

infections benefit from thrice weekly, low dose (1-2 μg/kg/d) recombinant granulocyte colony stimulating factor

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FOR CHRONIC, REFRACTORY IMMUNE CYTOPENIAS

• use of mycophenolate mofetil (MMF; 600 mg/ m2/dose twice daily

• Rituximab (375 mg/ m2/ wk x 4)

• Recombinant α-interferon therapy

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ALPS , PROGNOSIS

• Despite the often impressive lymphadenopathy and splenomegaly, the prognosis with regard to lymphoproliferation is good

• Most patients demonstrate regression of lymphoproliferation

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THE MAJOR DETERMINANTS OF MORBIDITY AND MORTALITY IN ALPS ARE

• The severity of the autoimmune disease

• Hypersplenism

• Postsplenectomy-related sepsis

• Development of lymphoma

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Careful long-term surveillance in patients with mutations of the Fas

protein is especially required

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REFERENCES• *Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP.

Mutations in Fas associated

with human lymphoproliferative syndrome and autoimmunity. Science 2005;268:1347-9.

• *Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 2006;335:1643-9.

• *Straus SE, Sneller M, Lenardo MJ, Puck JM, Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 2009;130:591-601.

• *Rieux-Laucat F, Fischer A, Deist FL. Cell-death signaling and human disease. Curr Opin Immunol 2003;15:325-31.

• *Alvarado CS, Straus SE, Li S, Dale JK, Mann K, Le A, Lauer SJ. Autoimmune lymphoproliferative syndrome: a cause of chronic splenomegaly, lymphadenopathy, and cytopenias in children-report on diagnosis and management of five patients. Pediatr Blood Cancer 2014;43:164-9.

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REFERENCES• *Bleesing JJ, Brown MR, Novicio C, Guarraia D, Dale JK, Straus SE, Fleisher TA. A composite

picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta- DNTCs) in humans with autoimmune lymphoproliferative syndrome. Clin Immunol 2012;104:21-30.

• *Clementi R, Dagna L, Dianzani U, Dupre L, Dianzani I, Ponzoni M, Cometa A, Chiocchetti A, Sabbadini MG, Rugarli C, Ciceri F, Maccario R, Locatelli F, Danesino C, Ferrarini M, Bregni M. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. N Engl J Med 2004;351:1419-24.

• *Ceretelli S, Petrini M, Galimberti S, Testi C, Frizzera G. Interferon-alpha activity in a case of severe autoimmune lymphoproliferative disease. Ann Hematol 2011;80:49-52

• *Heelan BT, Tormey V, Amlot P, Payne E, Mehta A, Webster AD. Effect of anti-CD20 (rituximab) on resistant thrombocytopenia in autoimmune lymphoproliferative syndrome. Br J Haematol 2012;118:1078-81.

• *Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK, Fleisher T, Puck J, Straus SE. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol 2005;129:534-8.

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REFERENCES

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• *Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81(6):935-946.

• *Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995;268(5215):1347-1349.

• *Oliveira JB, Fleisher T. Autoimmune lymphoproliferative syndrome. Curr Opin Allergy Clin Immunol 2004;4:497-503.

• *Rieux-Laucat F, Deist FL, Fischer A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differentiation 2013;10:124-33.

• *Carter LB, Procter JL, Dale JK, Straus SE, Cantilena CC. Description of serologic features in autoimmune lymphoproliferative syndrome. Transfusion 2006;40:943-48

• *Rao VK, Carrasquillo JA, Dale JK, Bacharach SL, Whatley M, Dugan F, Tretler J, Fleisher T, Puck JM, Wilson W, Jaffe ES, Avila N, Chen CC, Straus SE. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS). Am J Hematol 2010 ;8:81-85.

• *Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol 2006;133:124-40.

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a rare disease of lymph nodes and other lymphatic tissues

CASTLEMAN DISEASE (CD)

CASTLEMAN DISEASE (CD)

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• It is also known as giant lymph node hyperplasia, and angiofollicular lymph node hyperplasia

• It was first described by Dr. Benjamin Castleman in the 1950s.

• CD is not a cancer. Instead, it is a lymphoproliferative disorder.

TYPES OF CASTLEMAN DISEASE

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There are 2 main forms of CD.

1.Localized or Unicentric (UCD)

2. Multicentric (MCD)

Localized (Unicentric) Castleman disease affects a single group of lymph nodes. Mainly thoracic or abdominal LN

MULTICENTRIC CD

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• affects more than a single group of lymph nodes

• It can also affect other lymphoid tissue

• It is more serious than the localized type, particularly in people with HIV infection.

MICROSCOPIC SUBTYPES OF CASTLEMAN DISEASE

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• The hyaline vascular type – It is most common. It tends to be localized, but in rare cases it is multicentric

• The plasma cell type – It is slightly more likely to be multicentric, but it is sometimes localized

• The mixed subtype -- It shows areas of both types. It occurs less often.

• In choosing treatments, the microscopic type is less important than whether the disease is localized or multicentric .

Effaced architecture of the LN , increased angiogenesis in castlemans disease , HE stain 4 X

Normal architecture of LN

RISK FACTOR

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• Infection with HIV virus

• Infection with HHV-8

• Age : Younger patients are more likely to have the localized form . Adults and those with HIV and HHSV-8 infection are more likely to have the multicentric form.

PATHOGENESIS

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• Dysregulated and overproduced IL-6, particularly in patients with MCD, stimulates the production of acute phase reactants in the liver,

• resulting in constitutional symptoms, including fever, sweats, and fatigue, and

• laboratory abnormalities, such as anemia, elevated inflammatory markers, hypergammaglobulinemia, and hypoalbuminemia.

CASTLEMAN DISEASE

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• IL-6 also stimulates B-cell proliferation and induces the expression of vascular endothelial growth factor and increased angiogenesis.

• The activation of the IL-6 receptor further results in the activation of the Janus kinase–signal transducers and the activation of transcription pathway and the mitogen-activated protein kinase cascade, which enhances B-cell proliferation and survival

CASTLEMAN DISEASE

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• HIV-associated MCD, is usually associated with HHV-8 infection

• Patients with HHV-8-positive MCD,

infected cells express a viral analog of IL-6 (vIL-6), which likely contributes to the pathogenesis of this significant subset of

Castleman disease

PATHOLOGICAL DIAGNOSIS

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• Castleman disease is a pathological diagnosis made by excisional biopsy of affected lymph node.

• In cases of deeper or less accessible disease, core needle biopsy is preferred to fine needle aspiration, because fine needle aspirations are insensitive for both UCD and MCD.

Atrophic germinal centers , HE stain

40X

Normal germinal center, containing larger

lymphocytes undergoing activation

Vascular proliferation ,20 X, increased angiogenesis

Vascular proliferation 40 X

STAGING

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The goals of the staging and pretreatment evaluation in Castleman disease are to

• (1) determine whether the patient has unicentric or multicentric disease

• (2) identify patients with systemic inflammatory manifestations of Castleman disease,

• (3) assess for the presence of HIV, as well as associated conditions and malignancies.

THE INITIAL LABORATORY EVALUATION

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• Complete blood count

• Inflammatory markers (erythrocyte sedimentation rate and C-reactive protein)

• Complete metabolic panel, and albumin

• HIV testing should be performed in all patients

• Plasma HHV-8 DNA levels (a helpful biomarker, both to support the diagnosis of MCD and to monitor disease activity and response to therapy)

CASTLEMAN DISEASE

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• Levels of cytokines, most notably IL-6 and IL-10 are not recommended to be routinely measured.

• Computed tomography of the chest, abdomen, and pelvis should be obtained at the time of diagnosis to assess for adenopathy and splenomegaly and to assess resectability in patients with UCD

MANAGEMENT

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• The optimal therapy for UCD is surgical resection

• Radiation therapy in patients who are not candidate for surgical excision.

The natural history of MCD is variable

Some patients may present with indolent disease and very slow progression over months to years,

while others will experience an acute and fulminant disease that can be fatal within weeks

TREATMENT OPTIONS FOR MCD

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• Antiretroviral Therapy : for HIV-associated MCD

• Glucocorticoids

• Cytotoxic Chemotherapy : single-agent chemotherapy in the treatment of MCD,

etoposide, vinblastine, cyclophosphamide, chlorambucil

Single-agent chemotherapies are often administered at doses and schedules routinely used to treat patients with lymphoma

TREATMENT OPTIONS FOR MCD

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• Rituximab: (the current mainstay therapy), is highly active as monotherapy in MCD.

• Anti-Interleukin 6 Therapy: Siltuximab and tocilizumab are monoclonal antibodies targeting IL-6 and its receptor (IL-6R), respectively, (new additions to the treatment)

• Antiherpesvirus Therapy: have been explored as therapy for HIV-associated MCD , given the pathogenetic link with HHV-8

POEMS SYNDROME

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(Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin changes)

• MCD is present in 15% to 25% of patients with POEMS syndrome (Castle-POEMS)

• MCD is included as a major criterion for the diagnosis of POEMS syndrome

POEMS SYNDROME

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• Clinical features include

hepatosplenomegaly, lymphadenopathy, endocrinopathy, skin changes, osteosclerotic bone lesions, elevated levels of vascular endothelial growth factor and elevated protein in the cerebrospinal fluid.

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REFERENCES

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• *Stebbing J, Adams C, Sanitt A, et al. Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease. Blood. 2011;118(2):271-275

• * . Newsom-Davis T, Bower M, Wildfire A, et al. Resolution of AIDS-related Castleman’s disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels. Leuk Lymphoma. 2004;45(9):1939-1941.

• * Bower M, Veraitch O, Szydlo R, et al. Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease. Blood. 2009;113(19):4521-4524.

• * Carbone A, De Paoli P, Gloghini A, et al. KSHV-associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies. Int J Cancer. 2014.

• * . Matthiesen C, Ramgopol R, Seavey J, et al. Intensity modulated radiation therapy (IMRT) for the treatment of unicentric Castlemans disease: a case report and review of the use of radiotherapy in the literature. Radiol Oncol. 2012;46(3):265-270

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POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD)

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD)

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• is a well-recognized complication of both solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT).

PTLD

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• In most cases, PTLD is associated with (EBV) infection of B cells, either as a consequence of reactivation of the virus post-transplantation or from primary EBV infection

PTLD

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• In cases of primary infection,

EBV may be acquired from the donor graft or, less commonly, from environmental exposure.

PTLD

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• While T-cell lymphoproliferative disorders can also occur after SOT and HSCT, the vast majority are B-cell proliferations.

• PTLD is identified by having a high index of suspicion in the appropriate clinical setting

PTLD

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• The diagnosis is made by histopathological evidence of lymphoproliferation, commonly with the presence of EBV DNA, RNA, detected in tissues

• Most cases of PTLD occur within the first post-transplant year.

FREQUENCY A.Parker etal, BJH 149; 675 (2010)

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The more intense the immunosuppression used, the greater the risk of PTLD and the earlier it tends to

occur

PTLD

THE 2008 (WHO) CLASSIFICATION SYSTEM

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• 4 major histopathologic subtypes of PTLD:

(1) early hyperplastic lesions,

(2) polymorphic lesions

(3) monomorphic lesions, and

(4) classic Hodgkin-type lymphomas

Jaffe et al -2001

A

BC

D

PATHOGENESIS - PTLD • B cell proliferation induced by EBV infection• Cytotoxic T cells keep EBV-infected B cells in check

Anti T cell Rx or T cell depletion is therefore a risk factor for PTLD

• EBV-driven polyclonal proliferations leading to EBV(+) or EBV(-) lymphomas of predominantly B-cell or less often T-cell type

D.A.Thoreley-Lawson, NEJM: 350;1328 (2004)

EBV-negative PTLD

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- Present much later

(median 50-60mo vs 6-10 mo)

- Monomorphic

- Poor outcomes , poor response to therapy

- Increasing in frequency

PTLD DIAGNOSIS

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• EBV viral load

• Imaging

• Tissue biopsy (excisional node biopsy) -Confirm EBV positivity by immunostaining LMP1 – latent membrane protein 1

EBER- EBV-encoded RNA

-Histological grade

-Immunophenotyping (CD 20)

-Cytogenetics

PTLD DIAGNOSTIC CRITERIA

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2 out of three features 1- Disruption of underlying tissue architecture by a

lymphoproliferative process

2- Presence of mono- or oligoclonal cell population

3- EBV infection of many cells

PTLD MANAGEMENT

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1) REDUCTION OF IMMUNOSUPPRESSION2) Antiviral agents (Ganciclovir, Acyclovir,Maribavir)

3) Surgery and Radiotherapy (localized)

4) Rituximab

5) Rituximab + Chemotherapy

6) EBV Directed cytotoxic T lymphocytes (CTL) – in clinical trials

PTLD

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• The cornerstone of initial management of PTLD is reduction or withdrawal of immunosuppression, which may reverse the lymphoproliferative process

• This potential for reversibility with reduction of immunosuppression distinguishes PTLD from neoplastic lymphoproliferative disorders

BUT,

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• Reduction of immunosuppression also carries the risk of inducing allograft dysfunction or loss and is not always feasible

PTLD CNS RIS LOCALISED

RADIO MULTIFOCAL RADIOOR CHEMO OR LOCAL EXCN LOW HIGH RISK RISK

RITUX RITUX + CHEMORIS: reduce immuno-suppression

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POST-TRANSPLANT EBV – MONITORING

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AT LEAST WEEKLY FOR 3 MONTHS

• LONGER MONITORING FOR:

- GVHD

- PREVIOUS EBV REACTIVATION

J.Styczynski etal, BMT 43; 757 (2009)

PTLD PREVENTION

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1) IV ganciclovir to high-risk pts for at least 100 days

2) Oral acyclovir in low risk patients

MEDICOLEGAL ISSUES

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Transplantation and the accompanying immunosuppression, put patients at risk for potentially

fatal infection and malignancy. Transplant candidates must be fully informed of these risks as part of the

consent process pre-transplantation.

REFERENCES

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• Green M, Webber S. Posttransplantation lymphoproliferative disorders. Pediatr Clin North Am. 2003 Dec. 50(6):1471-91.

• Swerdlow SH, Webber SA, Chadburn A, Ferry JA. Posttransplant lymphoproliferative disorders. Swerdlow SH, Campo E, Harris NL, Jaffe ES. WHO classification of tumors of haemotopoietic and lymphoid tissue. IARC, Lyon; 2008. 343-350.

• Glotz D, Chapman JR, Dharnidharka VR, Hanto DW, Castro MC, Hirsch HH, et al. The Seville Expert Workshop for Progress in Posttransplant Lymphoproliferative Disorders. Transplantation. 2012 Sep 18.

• Shaknovich R, Basso K, Bhagat G, et al. Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling. Haematologica. 2006 Oct. 91(10):1313-20.

• D'Antiga L, Del Rizzo M, Mengoli C, Cillo U, Guariso G, Zancan L. Sustained Epstein-Barr virus detection in paediatric liver transplantation. Insights into the occurrence of late PTLD. Liver Transpl. 2007 Mar. 13(3):343-8.

REFERENCES

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