4. THEY ARE
• Heterogenous group of diseases that range from reactive
polyclonal hyperplasia ( immunologic disorders )
To
• True monoclonal ( malignant ) diseases
02-12-2016 4
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
02-12-2016 5
6. • Patients with various forms of immune deficiency have an
increased risk , especially , for malignant lymphomas
02-12-2016 6
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
02-12-2016 7
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
902-12-2016
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
02-12-2016
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
02-12-2016 11
12. MOLECULAR CONFIGURATION OF
EPSTEIN BARR VIRUS
1202-12-2016
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.
02-12-2016
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) .
02-12-2016
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)
02-12-2016 17
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
02-12-2016 18
Ubiquitous : present everywhere
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
02-12-2016 21
• 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
02-12-2016 22
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)
02-12-2016 24
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)
02-12-2016 25
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
02-12-2016 26
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
02-12-2016 27
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
02-12-2016 31
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
02-12-2016 32
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
02-12-2016 33
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
02-12-2016 34
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
02-12-2016 35
36. ALPS
• Several cytokine abnormalities have been found in patients with
ALPS, the most striking of which is a significantly elevated
IL-10
02-12-2016 36
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.
02-12-2016 37
38. DIFFERENTIAL DIAGNOSIS
Children with
• Generalized lymphadenopathy,
• Splenomegaly,
and
• Autoimmune multilineage cytopenias represents
a diagnostic challenge
02-12-2016 38
39. Clinical and laboratory features
overlap with and may manifest as
other childhood diseases
ALPS
02-12-2016 39
41. (Oliveira JB et al., Blood 2010, 116(14) :e35-e40)
REVISED DIAGNOSTIC CRITERIA FOR THE
AUTOIMMUNE LYMPHOPROLIFERATIVE
SYNDROME (ALPS)
(CANALE-SMITH SYNDROME)
02-12-2016 41
(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
02-12-2016 42
43. ACCESSORY
• Primary
1. Defective lymphocyte apoptosis (in 2 separate assays)
2. Somatic or germline mutation in FAS, FASL, or CASP10
02-12-2016 43
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
02-12-2016 44
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
02-12-2016 45
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
02-12-2016 46
50. ALPS
Treatment modalities for ALPS are directed at
• The chronic and persistent lymphoproliferation
• Autoimmunity, and
• Malignancies
02-12-2016 50
51. ALPS
• Lymphoproliferation does respond to corticosteroids and other
immunosuppressants like azathioprine , cyclosporine or
mycophenolate mofetil
02-12-2016 51
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
02-12-2016 52
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
02-12-2016 53
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
02-12-2016 54
55. ALPS , PROGNOSIS
• Despite the often impressive lymphadenopathy and
splenomegaly, the prognosis with regard to lymphoproliferation
is good
• Most patients demonstrate regression of lymphoproliferation
02-12-2016 55
56. THE MAJOR DETERMINANTS OF MORBIDITY
AND MORTALITY IN ALPS ARE
• The severity of the autoimmune disease
• Hypersplenism
• Postsplenectomy-related sepsis
• Development of lymphoma
02-12-2016 56
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.
02-12-2016 58
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.
02-12-2016 59
60. REFERENCES
02-12-2016 60
• *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. 02-12-2016 61
a rare disease of lymph nodes and other lymphatic
tissues
CASTLEMAN DISEASE (CD)
62. CASTLEMAN DISEASE (CD)
02-12-2016 62
• 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
02-12-2016 63
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
02-12-2016 64
• 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
02-12-2016 65
• 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
02-12-2016 67
• 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
02-12-2016 68
• 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
02-12-2016 69
• 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
02-12-2016 70
• 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
02-12-2016 71
• 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
75. STAGING
02-12-2016 75
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
02-12-2016 76
• 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
02-12-2016 77
• 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
02-12-2016 78
• 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
02-12-2016 79
• 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
02-12-2016 80
• 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
02-12-2016 81
(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
02-12-2016 82
• 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.
84. REFERENCES
02-12-2016 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
87. PTLD
02-12-2016 87
• 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
02-12-2016 88
• In cases of primary infection,
EBV may be acquired from the donor graft or, less commonly, from
environmental exposure.
89. PTLD
02-12-2016 89
• 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
02-12-2016 90
• 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.
92. 02-12-2016 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
02-12-2016 93
• 4 major histopathologic subtypes of PTLD:
(1) early hyperplastic lesions,
(2) polymorphic lesions
(3) monomorphic lesions, and
(4) classic Hodgkin-type lymphomas
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
98. EBV-negative PTLD
02-12-2016 98
- Present much later
(median 50-60mo vs 6-10 mo)
- Monomorphic
- Poor outcomes , poor response to therapy
- Increasing in frequency
100. PTLD DIAGNOSTIC CRITERIA
02-12-2016 100
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
02-12-2016 101
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
02-12-2016 102
• 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,
02-12-2016 103
• 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
108. MEDICOLEGAL ISSUES
02-12-2016 108
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
02-12-2016 109
• 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
02-12-2016 110
• 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
02-12-2016 111
• 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.