This document discusses lymphoproliferative disorders in children, highlighting their association with immune deficiencies and the role of Epstein-Barr virus (EBV) in driving these diseases. It details the spectrum of disorders, including Autoimmune Lymphoproliferative Syndrome (ALPS) characterized by mutations affecting lymphocyte apoptosis and the resultant clinical manifestations. The document outlines diagnostic criteria, treatment strategies, and prognosis for affected individuals.

1. Dr Tai Al Akawy
Senior Pediatrician at
Alexandria University Children’s Hospital
LYMPHOPROLIFERATIVE DISORDERS
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2. BASED ON
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3. 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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4. THEY ARE
• Heterogenous group of diseases that range from reactive
polyclonal hyperplasia ( immunologic disorders )
To
• True monoclonal ( malignant ) diseases
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5. 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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6. • Patients with various forms of immune deficiency have an
increased risk , especially , for malignant lymphomas
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7. 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)

9. • 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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10. 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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11. EBV in B Cell
Infectious mononucleosis
X-Linked Lymphoproliferative Disease
Chronic active EBV
Hodgkin Disease
Burkitt Lymphoma
Lymphoproliferative diseases
EBV in Other Cells
Nasopharyngeal carcinoma
Gastric carcinoma
Nasal T/NK cell lymphomas
Peripheral T cell lymphomas
Oral hairy leukoplakia
Smooth muscle tumors in transplant patients
Diseases Associated with EBV
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12. MOLECULAR CONFIGURATION OF
EPSTEIN BARR VIRUS
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EBV genome is enclosed in a nuclear capsid surrounded by a glycoprotein envelope

13. MOLECULAR BIOLOGY
13
• 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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14. ANTIBODIES IN EBV INFECTION
Infection VCA
IgG
VCA
IgM
EA(D) EBNA
No previous
infection
- - - -
Acute
infection
Recent
infection
+
+
+
+/-
+/-
+/-
-
+/-
Past
infection
+ - +/- +
AAP. Red book2010;286-288.29-11-2016 14

15. LATENCY
15
• 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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16. EBV Latency Proteins
Cohen NEJM 2000
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LMP: latent membrane protein
EBNA: EBV nuclear antigens

17. 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)
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18. 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

19. LYMPHOPROLIFERATIVE DISORDERS
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• X-linked lymphoproliferative disorder
• The autoimmune lymphoproliferative syndrome ( ALPS)
• Castleman disease (CD)
• Posttransplant lymphoproliferative disease (PTLD)

20. 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

21. 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 )

22. 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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23. 29-11-2016 23
Autoimmune lymphoproliferative
syndrome
(ALPS)
Canale-Smith syndrome

24. 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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25. 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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26. 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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27. 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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28. 29-11-2016 28
Caspase-activated
deoxyribonuclease (CAD)
and its inhibitor (I-CAD)

29. 29-11-2016 29

30. 29-11-2016 30
Structure of the FAS
gene with mutations
associated with ALPS-
FAS

31. 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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32. 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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33. 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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34. 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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35. 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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36. 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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37. 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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38. DIFFERENTIAL DIAGNOSIS
Children with
• Generalized lymphadenopathy,
• Splenomegaly,
and
• Autoimmune multilineage cytopenias represents
a diagnostic challenge
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39. Clinical and laboratory features
overlap with and may manifest as
other childhood diseases
ALPS
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40. 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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41. (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)

42. 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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43. ACCESSORY
• Primary
1. Defective lymphocyte apoptosis (in 2 separate assays)
2. Somatic or germline mutation in FAS, FASL, or CASP10
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44. 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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45. 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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46. 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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47. 29-11-2016 47

48. 29-11-2016 48

49. 29-11-2016 49

50. ALPS
Treatment modalities for ALPS are directed at
• The chronic and persistent lymphoproliferation
• Autoimmunity, and
• Malignancies
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51. ALPS
• Lymphoproliferation does respond to corticosteroids and other
immunosuppressants like azathioprine , cyclosporine or
mycophenolate mofetil
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52. ALPS
The 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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53. 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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54. 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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55. 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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56. 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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57. Careful long-term surveillance in
patients with mutations of the Fas
protein is especially required
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58. 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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59. 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.
29-11-2016 59

60. 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.

61. 29-11-2016 61
a rare disease of lymph nodes and other lymphatic
tissues
CASTLEMAN DISEASE (CD)

62. 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.

63. 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

64. 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.

65. 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.

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

67. 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.

68. 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.

69. 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

70. 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

71. 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.

72. Atrophic germinal centers
, HE stain 40X
Normal germinal center, containing
larger lymphocytes undergoing
activation

73. Vascular proliferation ,20 X, increased angiogenesis

74. Vascular proliferation 40 X

75. 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.

76. 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)

77. 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

78. 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

79. 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

80. 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

81. 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

82. 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.

83. 29-11-2016 83

84. REFERENCES
29-11-2016 84
• *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

85. 29-11-2016 85
POSTTRANSPLANT LYMPHOPROLIFERATIVE
DISEASE (PTLD)

86. POSTTRANSPLANT LYMPHOPROLIFERATIVE
DISEASE (PTLD)
29-11-2016 86
• is a well-recognized complication of both solid organ
transplantation (SOT) and allogeneic hematopoietic stem cell
transplantation (HSCT).

87. 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

88. PTLD
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• In cases of primary infection,
EBV may be acquired from the donor graft or, less commonly, from
environmental exposure.

89. 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

90. 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.

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

92. 29-11-2016 92
The more intense the immunosuppression used, the
greater the risk of PTLD and the earlier it tends to
occur
PTLD

93. 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

94. Jaffe et al -2001
A
B
C
D

95. 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

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

98. 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

99. 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

100. 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

101. PTLD MANAGEMENT
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1) REDUCTION OF IMMUNOSUPPRESSION
2) 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

102. 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

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

104. PTLD
CNS RIS LOCALISED
RADIO MULTIFOCAL RADIO
OR CHEMO OR LOCAL EXCN
LOW HIGH
RISK RISK
RITUX RITUX + CHEMO
RIS: reduce immuno-suppression

105. 29-11-2016 105

106. 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)

107. 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

108. 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.

109. 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.

110. REFERENCES
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• Swinnen LJ, LeBlanc M, Grogan TM, Gordon LI, Stiff PJ, Miller AM. Prospective study of
sequential reduction in immunosuppression, interferon alpha-2B, and chemotherapy for
posttransplantation lymphoproliferative disorder. Transplantation. 2008 Jul 27. 86(2):215-
22.
• Schubert S, Renner C, Hammer M, Abdul-Khaliq H, Lehmkuhl HB, Berger F. Relationship
of immunosuppression to Epstein-Barr viral load and lymphoproliferative disease in
pediatric heart transplant patients. J Heart Lung Transplant. 2008 Jan. 27(1):100-5.
• Dharnidharka VR, Lamb KE, Gregg JA, Meier-Kriesche HU. Associations between EBV
serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National
Registry Data in the United States. Am J Transplant. 2012 Apr. 12(4):976-83.
• Jamali FR, Otrock ZK, Soweid AM, Al-Awar GN, Mahfouz RA, Haidar GR. An overview of
the pathogenesis and natural history of post-transplant T-cell lymphoma. Leuk Lymphoma.
2007 Jun. 48(6):1237-41.

111. REFERENCES
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• Cruz RJ Jr, Ramachandra S, Sasatomi E, Dimartini A, de Vera M, Fontes P, et al. Surgical
management of gastrointestinal posttransplant lymphoproliferative disorders in liver
transplant recipients. Transplantation. 2012 Aug 27. 94(4):417-23.
• Becker YT, Samaniego-Picota M, Sollinger HW. The emerging role of rituximab in organ
transplantation. Transpl Int. 2006 Aug. 19(8):621-8.
• Taj MM, Messahel B, Mycroft J, Pritchard-Jones K, Baker A, Height S. Efficacy and
tolerability of high-dose methotrexate in central nervous system positive or relapsed
lymphoproliferative disease following liver transplant in children. Br J Haematol. 2008 Jan.
140(2):191-6.
• Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant
lymphoproliferative disease. Nat Rev Clin Oncol. 2012 Sep. 9(9):510-9.
• Gross TG, Bucuvalas JC, Park JR, Greiner TC, Hinrich SH, Kaufman SS. Low-dose
chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative
disease in children after solid organ transplantation. J Clin Oncol. 2005 Sep 20.
23(27):6481-8.

112. THANK YOU
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