27 lymphoma
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PEDIATRIC LYMPHOMASJULY,2012Haileyesus Adam
INTRODUCTION LYMPHOMAS Account for 10% to 15% of malignancies in pediatric
patients(third most frequent ) 3% for children younger than 5 years old 24% for 15- to 19-year-olds
The most common subtypes are Hodgkin lymphoma (HL)and non-Hodgkin Lymphoma (NHL)
Younger children NHL more frequent Adolescents HL more common NHL = most common malignancy in children with HIV (before age 4)
The most “curable” forms of pediatric cancer More than 70% NHL will survive at least 5 y with CT (nr of factors)
HODGKIN LYMPHOMA
is rare in children under 5 years of age
Sex predilection under age 10,more common in boys Equally affected among adolescents and young adults
BIOLOGY
• Inflammatory milieu with rare multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (Hodgkin’s or lacunar cells)
• R-S cell appears to arise from preapoptotic germinal center B cells (no Ig production), although rarely may arise from T cells
RS CELLS
LACUNAR CELLS
CLINICAL PRESENTATIONIndolent, painless lymphadenopathy (80%) the lower cervical and supraclavicular regions in majority the size of these nodes may appear to fluctuate over time mediastinal involvement in 60% of patients inguinal lymph nodes in less than 5%
B symptoms (25-30%) fever >380C x 3 days wt loss >10% of body wt. over 6 mo drenching night sweats associated with more aggressive disease
Bulky disease (20%) med mass >1/3 of internal thoracic diameter node/nodal aggregate >6 cm
CLINICAL PRESENTATION
15% to 20% of patients will have noncontiguous extranodal involvement
• most common sites of extranodal involvement are the lung, liver, bones, and bone marrow
Bone marrow involvement at diagnosis is rare (2% of patients) confined exclusively to those with advanced disease
AUTOIMMUNE DISORDERS
Nephrotic syndrome
Autoimmune hemolytic anemia
Autoimmune neutropenia
Immune thrombocytopenia (ITP)
IMMUNOLOGIC STATUS
generalized cellular immune deficiency
ineffective host antitumor response
CELLULAR CLASSIFICATION
Classical HL (CD15, CD30 +, B cell markers ) nodular sclerosis (50-60%) mixed-cellularity (20-30%) lymphocyte rich (<5%) lymphocyte depleted (5-15%)
Nodular Lymphocyte Predominant HL (5%) (CD15 -, CD30 +/-, B cell markers +)
CLASSICAL HODGKIN LYMPHOMA
A pre-requisite for diagnosis:Reed-Sternberg cells
derived from B lymphocytes positive for CD15 and CD30
NODULAR LYMPHOCYTE-PREDOMINANT VARIANT
very rareLocalizedexhibits a slowly progressive course Lymphocytic and histiocytic cells are
foundexpress CD20 and other B-cell antigens are negative for CD15 andCD30 Late relapses are more common may progress to large B-cell NHL
HODGKIN VS TB
Most common differential especially if limited to cervical
Often put on ATT without definitive diagnosis
Biopsy is essential
DIAGNOSIS
Excision Biopsy of Node
Needle Biopsy of mass if excision not possible
FNAC is not recommended in children
STAGING
Ann Arbor staging system I-IV
“A” vs “B”
“E”- extralymphatic disease resulting from direct extension of involved LN region
“S”- splenic disease
ideally want pathologic confirmation of noncontiguous extralymphatic involvement (Stage IV disease)
ANN ARBOR STAGING
Stage I: Involvement of single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)
Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single extralymphatic organ or site and its regional lymph node(s) with involvement of one or more lymph regions on the same side of the diaphragm (IIE)
Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIS), or both (III E+S)
Stage IV: Disseminated (multifocal) involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement.
STAGING WORKUPImagingCXRU/SoundCT scan of neck, chest, abdomen and pelvisGalliumPET ScanOther TestsBone marrow aspirate and trephine only in Patients with stage II B or more
Bone scan only in stage III or moreBlood tests CBC LDH Urea, Cr, electrolytes, Ca, Mg, LFTs Hepatitis screening
Therapy
XRT alone cured early stage disease 1960s- MOPP 1970s- ABVD Combined modality therapy (CMT)
Chemotherapy and radiation
NON-HODGKIN LYMPHOMA
• Originating in cells and organs of immune system
• Usually restricted to lymphoid tissue such as lymphnode, spleen ,Peyers patches (could involve BM)
• Overlap with ALL pathologically and clinically
EPIDEMIOLOGY NHL
Incidence varies by age-peaks at ages15-19 years Sex: male: female 2.5:1 histological subtype geographically
Etiology unknown (except Burkitt)
Risks factors:
• viral (EBV and HIV)
• radiation,
• immunosuppression related to development of NHL, eg. HIV,Wiskott-Aldrich, SCID
WHO classification- Lymphoid neoplasmsDLBCL Mycosis fungoides/Sezary
Marginal zone lymphoma Peripheral T-cell lymphoma
Follicular lymphoma -Anaplastic large cell lymphoma
CLL/SLL -peripheral T lymphoma NOS
Mantle cell lymphoma -T/NK cell lymphoma
Burkitt lymphoma/leukemia -γδ lymphomas
Plasma cell neoplasms Lymphoblastic lymphomas
Multiple myeloma -T-precursor leukemia/lymphoma
Plasma cell leukemia -B-precursor Leukemia/lymphoma
Plasmacytoma Angioimmunoblastic lymphoma
Hairy cell leukemia
Lymphoplasmacytic lymphoma
Waldenstrom macroglobulinemia
B-cell lymphoid neoplasms, NOS
WHO CLASSIFICATION
Precursor B-cell neoplasms (leukemia/lymphoma)
Mature(peripheral) B cell neoplasms
Precursor T-cell neoplasms (leukemia/lymphoma)
Mature (peripheral)Tcell neoplasms
PEDIATRIC NHL-WHAT CELL LINE ARE THEY?
Burkitts Lymphoblastic Large cell
52% 23% 25%
B-cell large cell (DBCLC) 11%
Anaplastic(ALCL) 14%
Mature B-cell immature -T cell 85% Mature T
cell immature -B-cell 15% Non-ALCL peripheral
T-cell
CLASSIFICATION NHL
Almost all are high grade-4 groups1)lymphoblastic lymphoma2)Burkitt’s and Burkitt’s like
lymphoma/small non cleaved B-cell lymphoma
3)diffuse large cell lymphoma4)anaplastic large cell lymphoma
CHILDHOOD NHL
The results of lymphoma therapy depend on giving the correct type of therapy for that type of lymphoma
Use clinical features • Can usually distinguish Burkitts from lymphoblastic
• Depend on location
BURKITT’S AND NON-BURKITT’S (SMALL NONCLEAVED CELL LYMPHOMA)
• 40-50% of NHL• 90% intra-abdominal• Other sites( CNS,peripheral
lymphnodes,skin,BM,bone,testis)• B cell origin• 25% contain Epstein Barr virus genomes• TdT enzyme(terminal deoxynucleotidyl transferase)-
negative• CALLA (CD10) positive• Characteristic chromosomal translocations
CLINICAL FEATURES-BL
• Abdomen- 35 % BL ileocecal region
• Lymphoma-most common anatomic lesion causing intussusception in children >6 years
• Head and neck -13%
• Mediastinum 26% svc syndrome
• Other sites: peripheral nodes, skin, etc
AFRICAN BURKITT LYMPHOMA
First tumour associated with an oncogenic virus
First tumour successfully treated with combination chemotherapy
Introduced oncology to “tumour lysis syndrome”
Classical chromosomal translocations
Different to Burkitt-type tumours in the west
BURKITT LYMPHOMA
Types:Immunodeficiency-associated (HIV)Sporadic Lymphoid tissues of GIT tract, especially abdomen Bone marrow (20%)
Endemic Maxilla, orbit, other facial bones CNS (30%)
BURKITTS LYMPHOMA TYPES
Endemic Sporadic HIV-assocAge 2-9 yrs any age 10-19(any)
Area Malaria none Africa
EBV 100% 30% Africa yes other no Cure poor 90% good if HIV low and CD4
OK
BURKITTS LYMPHOMA
Sporadic Endemic
0.2/10,000 10/100,000
Abd mass Abd mass
Jaw occ Jaw 70%
Leptomeningeal Extradural- paraplegia
t(8;14) t(8;14) diff
breakpoint in the Ig gene
BURKITT’S LYMPHOMA
• Extranodal masses, especially lymphoid tissues of GIT tract and upper respiratory tract
• Often boys 5-10 years
• >95% cells in cycle • Doubling time 17-72 hours• High tumour burden
• High spontaneous cell death rate –up to 70% in big tumors
N.B. tumor lysis syndrome!!
Early and rapid diagnosis and therapy
WHERE DOES BURKITTS LYMPHOMA ARISE?Arise in relatively mature B lymphocytes
80% Peyers patches ie Abdominal mass
20% Waldeyer’s ring (tonsil and adenoid)
Endemic -jaw --often localized
BURKITTS LYMPHOMA
ADVANCED DISEASE: abdominal in
endemic and sporadic forms
Abdominal pain
Abdominal Distention
Ascites Right pleural effusion (but not lung)
Commonly involves kidney
Commonly spreads to CNS and bone marrow --less in endemic
Endemic more paraspinal (epidural) --paraplegia
BURKITTS LESSONS
Early diagnosis --- keep high index suspicion –highly treatable condition
Intussusception in a child >2 years of age
think about lymphoma
BURKITT’S- LESSONSBack pain Back tenderness ---In a patient with possible
malignancy spinal cord SPINAL CORD! SPINAL CORD!!!
MRI or contrast CT same day!!No spinal tap until MRI spine reported
BURKITT”S
Most nuclei have 1-nucleoli; macrophage at left with debris in cytoplasm
LYMPHOBLASTIC LYMPHOMA ~25% OF NHL
How does it present? 90% advanced stage - 10% localized to lymph nodes
T-cell 85% -thymus
• 75% anterior mediastinal mass-• dyspnea, wheezing,stridor,dysphagia, swelling of the head and neck +_
involvement lymph node and pleural effusion
• Infrequently only with neck/axillary nodes
• Involvement of BM-confusion(25%)
B-cell 15% --anywhere -Rx like ALL
ALCL
14% of childhood NHL
Any site
Lymphoma in unusual sites –skin, bone, lung -usually large cell
ALCL
Adenopathy may be tender
Nodes may fluctuate for a while before increasing
May present with systemic symptoms---fever, night sweats, weight loss, neutrophilia
In differential diagnosis of fever and tender adenopathy
Often involves skin, nodes and bone
May produce diffuse pulmonary disease
ALCL
Diagnosis made on immunostains
CD30 pos
t(2;5) NPM-ALK
ALK pos
If not available --? Suggested at least on morphology?
DIAGNOSIS
2 potentially life threatening situations
Superior vena cava sd (mediastinal tumor with airway obstruction)-lymphoblastic lymphoma
Tumor lysis sd (small noncleaved cell NHL)
LIFE-THREATENING PRESENTATIONS
Airway compression (careful with sedation)
Pericardial tamponade
Renal failure
Acute abdomen
STAGING
Baseline bloods + EBVHIVCXR, CT chestAbdominal sonar, CT abdomenLPBone marrow biopsyEcho Histology: FNA, flow cytometry on
ascites, biopsy, pleural fluid Cytogenetics and
immunohistochemistryBone scan (ALCL,DLBCL)
NHL STAGING (ST JUDE)
I single tumour/nodal mass (not in mediastinum/abdomen)
II single tumour with regional nodes two/more nodes or extranodal masses
same side of diaphragm primary GIT tumour
III disease opposite sides of diaphragm all intra-thoracic tumours all extensive abdominal disease
paraspinal or epidural tumours IV + CNS or BM involvement
CHARACTERISTICS OF PEDIATRIC NHL Burkitt Lymphoblastic DLBCL
ALCL
52% 25% 11% 14%
mature B immature T (80%) mature B mature T
Abd chest any any
t(8;14) Notch1, t(2;5)(ALK)
others
Rx 3-6mo 24mo 3-6mo 4-12mo
EFS 90% 85% 90% 76%