HEMATOLYMPHOID PATHOLOGY

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CHAPTER 8 HEMATOLYMPHOID PATHOLOGY

Pediatric leukemia / lymphoma

Introduction
Acute myeloid leukemia (AML)
Myeloid sarcoma
Acute leukemia of ambiguous lineage
Precursor b acute lymphoblastic leukemia / lymphoma
Precursor t acute lymphoblastic leukemia / lymphoma
Mature b cell leukemia / lymphoma
Burkitt lymphoma
Diffuse large b-cell lymphoma (DLBCL)
Anaplastic large cell lymphoma (ALCL)
Lymphomatoid granulomatosis
Primary cutaneous cd30-positive t-cell lymphoproliferative disorders
Peripheral t-cell lymphoma (UNSPECIFIED)
Juvenile myelomonocytic leukemia (JMML)
Hodgkin lymphoma
Primary immunodeficiency associated lymphoproliferative disorders (LPDs)
Post-transplant lymphoproliferative disorders (PTLD)

Reactive lymphadenopathies

Non-specific reactive lymphoid hyperplasia
Viral lymphadenopathies
Other infective lymphadenopathies
Kimura lymphadenopathy
Sinus histiocytosis with massive lymphadenopathy (rosai–dorfman disease)
Kikuchi–fujimoto lymphadenopathy
Lupus lymphadenopathy
Castleman disease (angiofollicular lymph node hyperplasia)

Histopathology of immunodeficiencies

Introduction
Autoimmune lymphoproliferative syndrome (alps)

Langerhans cell histiocytosis

PEDIATRIC LEUKEMIA / LYMPHOMA

INTRODUCTION

• Diagnostic features are generally same as adults but different distribution of entities, mainly:

image acute myeloid leukemia
image acute lymphoblastic leukemia / lymphoma (ALL)
image Burkitt lymphoma
image diffuse large B cell lymphoma
image anaplastic large cell lymphoma
image Hodgkin lymphoma
image juvenile myelomonocytic leukemia

ACUTE MYELOID LEUKEMIA (AML)

• Clonal expansion of myeloid blasts
• Classified according to categories and subtypes (WHO)

image AML with recurrent genetic abnormalities
image AML with multilineage dysplasia
image therapy related AML
image AML not otherwise categorized

– minimally differentiated through to lineage differentiation subtypes

Epidemiology

• Most AML occurs in adults

image represents around one-third of pediatric leukemia

Histopathological features (Figs 8.1, 8.2)

• Diagnosis requires blood and marrow aspirate with or without trephine
• Increased myeloblasts
• Trephine shows:

image increased cellularity

– usually! – see pitfalls

image fibrosis
image specific features

– see subtypes

image

Fig. 8.1

image

Figs 8.1–8.2 Photomicrographs of bone marrow trephine biopsies from a child with acute myeloid leukemia, demonstrating marked infiltration of the marrow by sheets of myeloblasts.

Immunohistochemical staining

• Glycophorin for erythroid
• CD61 for megakaryocytes
• CD34 for immature precursors

image useful in hypocellular AML

• TdT for blasts

image usually ALL

• MPO, CD15, CD117 for myeloid differentiation
• Nuclear WT1+ in a proportion of AML

image caution in interpretation of such staining in soft tissue lesions

• Flow cytometry from aspirate is usually better for immunophenotyping than immunostaining of tissue sections

Differential diagnoses and pitfalls

• A minority of AML may present with hypocellular marrow
• AML may present as granulocytic sarcoma

image always consider this possibility in an unusual soft tissue lesion

AML with recurrent genetic abnormalities

• Better prognosis as a group
• Histopathological samples rarely allow such specific diagnosis

image requires genetic testing

t(8;21)(q22;q22)(AML1/ETO)

• 5–10% of AML

image mainly childhood cases

• May present as granulocytic sarcoma
• Myeloid markers +
• Coexpression of CD19
• CD34+
• Variable TdT+
• CD56 expression associated with adverse prognosis

Inv(16)(p13q22) or t(16;16)(p13;q22)(CBFb;MYH11)

• 10% of AML

image mainly childhood cases

• May present as granulocytic sarcoma
• Eosinophilic granulocytes in marrow
• Myeloid markers + lysozyme
• FISH / RT-PCR required for diagnosis

t(15;17)(q22;q12)(PML/RARa)

• Acute promyelocytic leukemia

image 5% of AML

– mainly adults

• May present with DIC
• Hypercellular marrow
• Promyelocytes with granular cytoplasm
• CD33, CD13, MPO+
• CD15−
• Nuclear PML+
• Responds to transretinoic acid

AML with 11q23 (MLL) abnormalities

• 5% of AML

image more common in children

– especially AML in infants

• DIC with soft tissue infiltration
• Monocytic / myelomonocytic phenotype
• No specific immunohistochemical features

AML NOS

• >20% myeloblasts
• Without specific molecular genetic features

AML minimally differentiated

• FAB M0
• 5% of AML

image mainly adults

• Marrow failure
• Medium sized blasts
• Hypercellular marrow

image poorly differentiated blasts

• CD117+
• CD34+

image one-third

• Sometimes lymphoid markers may also be focally positive
• MPO, CD15 usually negative

AML without maturation

• FAB M1
• Extensive blasts without morphological differentiation
• Marrow failure
• Hypercellular marrow
• MPO, CD34, CD117, lysozyme+

AML with maturation

• FAB M2

image 30–40% of AML

• AML with maturation to neutrophils
• Marrow failure
• Hypercellular marrow
• Blasts and granulocyte differentiation
• MPO, lysozyme, CD15, CD117, CD34+
• Some are translocation associated

Acute myelomonocytic leukemia

• FAB M4
• 15–25% of AML

image mainly adults

• AML with neutrophil and monocyte differentiation
• >20% marrow blasts
• >20% monocyte differentiation
• Marrow failure
• MPO, CD36, CD64, lysozyme +
• Subpopulation of CD34+ cells

Acute monoblastic / monocytic leukemia

• FAB M5
• >80% monocytic differentiation
• 5% of AML

image mainly adults

• Marrow failure with or without extramedullary masses
• Hypercellular marrow with large blasts
• Monoblasts

image lysozyme+
image variable CD68+
image MPO−

• Other blasts

image MPO, CD117, lysozyme+

Acute erythroid leukemia

• FAB M6
• 5% of AML

image mainly adults

• Acute leukemia with >50% erythroid precursors

image if >80% then classify as pure erythroid

• >20% of non-erythroid cells are myeloblasts
• Hypercellular marrow
• Erythroblasts

image MPO−
image glycophorin+

• Other blasts

image MPO, CD117, lysozyme +

Acute megakaryoblastic leukemia

• AML M7
• <5% of AML

image adults and children

• Association with preceding mediastinal germ cell tumors in males
• Poorly differentiated blasts and megakaryoblasts in marrow with variable fibrosis
• May be associated with t(1;22) in infants
• MPO−
• CD41+, CD61+, Factor VIII RA+

image variant is AML / transient myeloproliferative disorder in Trisomy 21

– neonates with T21
– increased blasts

Acute basophilic leukemia

• Rare

image <1% AML

• Marrow blasts are CD34+
• Granular cytoplasm

Acute panmyelosis with myelofibrosis

• Rare
• Variable increased marrow reticulin fibrosis with blasts
• Variable expression of myeloid markers

image MPO, CD117, CD13, CD33

• Overlap with other AML with marrow fibrosis

image especially megakaryoblastic

MYELOID SARCOMA (Figs 8.3–8.5)

• Extramedullary mass of immature myeloid cells
• Always consider the possibility in ‘odd’ sarcoma biopsies in children
• May demonstrate nuclear WT1+ (Al Adnani et al 2007)
• MPO, lysozyme, CD117, CD13, CD33, CD43 variably +
• May be associated with concurrent AML or be apparently isolated
image

Fig. 8.3

image

Figs 8.3–8.4 Photomicrographs of a granulocytic sarcoma presenting as an apparently primary soft tissue mass, demonstrating sheets of myeloblasts.

image

Fig 8.5 Photomicrograph of a granulocytic sarcoma presenting as an apparently primary soft tissue mass, demonstrating sheets of myeloblasts, expressing myeloid markers, in this case lysozyme.

ACUTE LEUKEMIA OF AMBIGUOUS LINEAGE

• Some leukemias show neither diagnostic lymphoid nor myeloid features or mixtures of both
• <5% acute leukemia
• May express CD34 and/or TdT but no other specific diagnostic markers, or multiple markers of more than one lineage

PRECURSOR B ACUTE LYMPHOBLASTIC LEUKEMIA / LYMPHOMA (Figs 8.6, 8.7)

• Small to medium uniform B-lymphoblasts
• Arbitrary definition of extramedullary sites with <25% blasts in marrow classified as lymphoma
• 75% of ALL affects patients <6 years of age

image of these >80% are pre-B ALL

• Diffuse uniform infiltration of marrow or extramedullary sites

image focal ‘starry sky pattern’ may also be seen

• Nuclear TdT+

image most useful marker, especially in extramedullary sites

• CD19, CD79a+
• CD10 and CD20+ in most

image note that hematogones in marrow are also TdT and CD10+

• Ki67 index high but lower than Burkitt lymphoma

image usually 50–90%

• Cytogenetic abnormalities in some cases

image may be related to prognosis

• >70% overall survival
image

Fig. 8.6

image

Figs 8.6–8.7 Photomicrographs of a case of acute pre B / common lymphoblastic leukemia, demonstrating extensive marrow involvement by sheets of bland, uniform lymphoblasts, which express nuclear TdT and membranous CD10 (shown in Fig 8.7) on immunostaining.

PRECURSOR T ACUTE LYMPHOBLASTIC LEUKEMIA / LYMPHOMA

• Small to medium sized uniform T-lymphoblasts
• Arbitrary definition of extramedullary sites with <25% blasts in marrow classified as lymphoma
• 15% of childhood ALL

image more common in adolescent males

• Often with mediastinal or other tissue mass
• Diffuse uniform infiltration of marrow or extramedullary sites
• Focal ‘starry sky pattern’ may also be seen
• Nuclear TdT+
• CD3/5+
• CD10, CD79a, CD13, CD33 may also be positive

MATURE B CELL LEUKEMIA / LYMPHOMA

• Clonal proliferations of B-cells in varying stages of maturity
• May be associated with immunodeficiency or autoimmune disease in childhood
• Some types are infection related

image EBV – Burkitt lymphoma
image HHV8 – primary effusion lymphoma
image H. pylori – mucosa associated lymphoid tissue

• Many types are reported but in childhood almost all are:

image Burkitt lymphoma
image Diffuse large B-cell lymphoma (DLBCL)

BURKITT LYMPHOMA

Epidemiology

• Endemic type

image Africa
image children 4–7 years
image almost all are EBV-related

• Sporadic type

image all countries
image mainly children

– <50% of childhood lymphoma

image <30% are EBV+

• Immunodeficiency-associated cases

image EBV+ in around 40%

Genetics

• Clonal immunoglobulin gene rearrangements
• Classical translocation is t(8;14)

image results in MYC deregulation

Clinical features

• Often affects extranodal sites

image especially:

– bone
– jaw
– ileum / cecum
– ovaries
– kidney
– breast

• Sporadic cases mainly present as abdominal masses
• Risk of tumor lysis syndrome on treatment

Histopathological features (Figs 8.8–8.14)

• Monomorphic B-cell infiltration

image sheets of B-lymphocytes

– round / ovoid nuclei
– clumped chromatin
– basophilic cytoplasm with lipid vacuoles

image numerous macrophages

– starry sky pattern

image high proliferation rate

– >95% with Ki67 staining

• Variants:

image plasmacytoid
image atypical / Burkitt-like

– increased pleomorphism

image

Fig. 8.8

image

Fig. 8.9

image

Fig. 8.10

image

Figs 8.8–8.11 Photomicrographs of cases of Burkitt lymphoma, demonstrating sheets of uniform small ovoid B-lymphocytes, infiltrating surrounding tissue, with areas showing prominent tingible body macrophages (’starry sky pattern’).

image

Fig. 8.12

image

Fig. 8.13

image

Figs 8.12–8.14 Photomicrographs of a case of Burkitt lymphoma, demonstrating immunoexpression of CD20, CD10 and almost 100% proliferation rate with Ki67 staining.

Immunohistochemical staining

• CD20 / CD79a+
• Usually CD10 + and bcl6+
• Ki67 >95%
• TdT−

DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (Figs 8.15–8.18)

• Large neoplastic B-cells

image more than twice normal size

• Nodal or extranodal involvement
• In childhood cases consider an underlying immunodeficiency
• Diffuse infiltration by large B-cells

image often with centroblastic or immunoblastic differentiation

• Variants:

image T-cell rich
image anaplastic
image plasmacytic
image ALK+ (CD30−) variants

• CD19, CD20, CD79a+
• Variable Bcl2 and bcl6+
• Ki67 30–90%
image

Fig. 8.15

image

Fig. 8.16

image

Figs 8.15–8.17

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