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%