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 Photomicrographs of cases of diffuse large B-cell lymphoma, demonstrating infiltrating sheets of large ovoid cells, which may be associated with other features such as sclerosis (retroperitoneal sclerosing type).

image

Fig 8.18 Photomicrograph of a case of diffuse large B-cell lymphoma infiltrating the liver, demonstrating strong expression of CD20.

ANAPLASTIC LARGE CELL LYMPHOMA (ALCL)

Epidemiology

• 10–30% of childhood lymphoma
• M > F

Genetics

• Most show TCR rearrangements
• t(2;5)(p23;35) NPM-ALK is classical ALK translocation

image associated with nuclear and cytoplasmic ALK expression on immunostaining

• Other ALK variants also reported

image caution in interpretation of RT-PCR for NPM-ALK

Clinical features

• Nodal and extranodal disease common
• B symptoms common

image fever

• 30% show marrow involvement

Histopathological features (Figs 8.19–8.22)

• Infiltration by ALCL hallmark cells

image large cells

– eccentric pleomorphic reniform nuclei
– plentiful cytoplasm

• Extent highly variable
• Nodal architecture effaced

image sinusoidal infiltration

• Variants:

image common

– 70% of cases
– mainly composed of hallmark cells

image lymphohistiocytic

– 10% of cases

· numerous admixed histiocytes

image small cell

– 10% of cases

· mainly smaller T-cells
· scattered hallmark cells (often in perivascular location)

image

Fig. 8.19

image

Fig. 8.20

image

Figs 8.19–8.21 Photomicrographs of cases of anaplastic large cell lymphoma, demonstrating infiltration by ‘hallmark’ cells with eccentric pleomorphic reniform nuclei.

image

Fig 8.22 Photomicrograph of a case of anaplastic large cell lymphoma, demonstrating immunoexpression of CD30 (inset) and ALK1.

Immunohistochemical staining

• Membrane and Golgi CD30+
• Nuclear and/or cytoplasmic ALK expression in 80–90% pediatric cases

image more frequent than in adults

• Most also show:

image EMA+
image T cell marker+

– TIA-1, granzyme B, perforin+

LYMPHOMATOID GRANULOMATOSIS

Epidemiology

• Immunodeficient children

Clinical features

• Lung, skin and other extranodal sites

image local symptoms

• Generalized malaise, fever
• Multiple nodular lesions

Histopathological features

• Extranodal angiocentric / angiodestructive EBV+ B-cell proliferation with recruitment of T-cells
• Infiltrate of lymphocytes, plasma cells, histiocytes and immunoblasts
• No true granulomas
• Spectrum of morphology

image grading according to proportion of large B-cells

– I: Polymorphous infiltrate with scattered EBV+ B-cells
– II: Mixed infiltrate with numerous large EBV+ B-cells
– III: DLBCL phenotype

Immunohistochemical staining

• Large cells CD20 / CD79a +
• EBV-ISH+ B-cells
• Background CD3/5+ T-cells

Differential diagnoses and pitfalls

• Main differential is T-cell lymphoma

image search for scattered EBV+ large B-cells

PRIMARY CUTANEOUS CD30-POSITIVE T-CELL LYMPHOPROLIFERATIVE DISORDERS

• Includes:

image Primary cutaneous ALCL
image Lymphomatoid papulosis
image Borderline lesions

Primary cutaneous ALCL

• Rare in childhood

image although well reported

• No other features of systemic ALCL

image systemic ALCL is much more common in childhood
image limited to skin at diagnosis

• Diffuse infiltrate dermis and subcutis
• Cells morphologically similar to systemic ALCL

image CD4+
image CD30+ >75% of cells

• Most are ALK negative

image cf systemic ALCL

Lymphomatoid papulosis

• Chronic recurrent benign disease
• May transform to lymphoma
• Mainly affects elderly

image rarely reported in childhood

• Dermis and subcutis with infiltrate as above

PERIPHERAL T-CELL LYMPHOMA (UNSPECIFIED)

• Rare in children
• Diffuse infiltrate of large, irregular, pleomorphic T-cells
• Nodal or extranodal
• T-cell markers and TCR gene rearrangements
• CD30 may also be expressed

JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML)

Epidemiology

• Rare

image <5% pediatric leukemia

• 75% <3 years

image can affect all ages from birth to teens

• M > F
• 10% associated with NF1

Genetics

• Monosomy 7 in <40%

image not specific for JMML

Clinical features

• Marrow, liver, spleen mainly affected

image raised white count

– mainly neutrophils
– <20% blasts

image anemia
image thrombocytopenia

• Skin rash 50%
• Systemic upset

image may present as an infectious mononucleosis-like illness

– infections should be excluded

• Poor prognosis

Histopathological features

• Hypercellular marrow with granulocyte predominance
• Monocytes prominent
• <20% blasts
• With or without dysplastic features
• Leukemic infiltrates in other tissues

Immunohistochemical staining

• Lysozyme+
• MPO+

image weak

• Chloracetate esterase+
• Variable CD68 and CD15+

Differential diagnoses and pitfalls

• Blood film and other tests required for diagnosis

image eg GM-CSF sensitivity

HODGKIN LYMPHOMA

• Predominantly nodal disease

image young adults

• Main subtypes

image nodular lymphocyte predominant HL (NLPHL)
image classical HL

– nodular sclerosis
– mixed cellularity
– lymphocyte deplete
– lymphocyte predominant CHL

Epidemiology

• Mainly young adults and older children
• Some cases are EBV related
• Preadolescent children

image more likely to show mixed cellularity and nodular lymphocyte predominant HD

• Adolescents

image predominance of nodular sclerosing HD (Schwartz 2005)

Clinical features

• Usually lymphadenopathy
• With or without systemic ‘B’ features

Histopathological features of specific subtypes (Figs 8.23–8.33)

Nodular lymphocyte predominant Hodgkin lymphoma

• 5% of HL

image usually older males

• Actually a monoclonal B-cell lymphoma

image with immunoglobulin gene rearrangement

• EBV negative
• Nodular and/or diffuse morphologies
• May be associated with progressive transformation of germinal centers (PTGC)
• Nodular and/or diffuse nodal infiltrate

image predominant small lymphocytes and histiocytes
image scattered B-cells

• Expanded nodular follicles highlighted with CD21
• Characteristic B-cell Hodgkin cell variants

image popcorn / L&H cells

– folded / multilobated nuclei
– multiple nucleoli
– CD20, CD79a+
– EMA+ in 50%
– CD15 / CD30−
– Oct2+
– surrounded by CD3+, CD57+ T cells

image

Fig. 8.23

image

Fig. 8.24

image

Figs 8.23–8.25 Photomicrographs of cases of classical Hodgkin disease, demonstrating variable effacement of the normal lymph node architecture by neoplastic cells.

image

Fig. 8.26

image

Fig. 8.27

image

Fig. 8.28

image

Fig. 8.29

image

Fig. 8.30

image

Fig. 8.31

image

Figs 8.26–8.32 Photomicrographs of cases of classical Hodgkin disease, demonstrating variable numbers of Hodgkin cells with prominent eosinophilic nucleoli (binucleate and mononuclear forms) in a background of small lymphocytes and variable numbers of eosinophils.

image

Fig 8.33 Photomicrograph of a case of classical Hodgkin disease, demonstrating strong expression of CD30 by Hodgkin cells.

Classical HL (CHL)

• Monoclonal Hodgkin cells in a variable reactive background
• Monoclonal immunoglobulin gene rearrangements
• 95% of HL
• 15–35 years and elderly
• Effaced nodal architecture
• Variable inflammatory background

image TGFb

– fibrosis

image IL-6

– eosinophil recruitment

• Variable numbers of Hodgkin cells
• Variable types of Hodgkin cells

image classical Reed–Sternberg (RS) cells

– large
– two or more nuclei/lobes
– prominent eosinophilic cytoplasm

image mononuclear Hodgkin cells

– mononuclear RS cells
– mummified cells
– lacunar cells

image CD30+ in all cases
image CD15+ in 85%
image CD45−
image CD20+ in 40%

– scattered cells

image Usually Ki67+

• EBV+ in 75% of mixed cellularity
• EBV+ in 10–40% nodular sclerosing subtype
• EBV+ in 100% of immunodeficiency associated cases

Nodular sclerosis CHL

• 70% of CHL
• 80% have mediastinal involvement
• Mononuclear HCs (lacunar cells)

image syncytial variant if predominant HCs

• Collagen bands surrounding nodules
• Thickened capsule

image Grade I

– standard type

· 75% of nodules have only scattered HCs

image Grade II

– less common

· >25% of nodules show increased numbers of RS cells (to fill a ×40 objective hpf)

Mixed cellularity CHL

• 25% of CHL
• Increased in immunodeficiency
• Scattered RS cells
• Mixed inflammatory background

image macrophages, eosinophils and neutrophils

• Classical RS cells

Lymphocyte rich CHL

• 5% of CHL
• Older patients mainly
• Background mainly composed of small lymphocytes
• Scattered RS cells
• Nodular or diffuse pattern
• Main differential is NLPHD

image immunophenotyping required

Lymphocyte deplete CHD

• Rare in childhood
• Many HCs

image relatively few lymphocytes

• May be pleomorphic
• Also associated with HIV infection

PRIMARY IMMUNODEFICIENCY ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS (LPDs)

Epidemiology

• Many underlying disorders
• Variable phenotype of LPDs
• Mainly present in childhood
• Most are EBV related

Clinical features

• Often present as extranodal disease
• May be the initial presentation of an immunodeficiency disorder
• Worse outcome than PTLD
• Outcome related to underlying degree of immunosuppression and T-lymphocyte number and function (Canioni et al 2001)

Histopathological features

• Underlying features of the underlying immune disorder
• Superimposed variable phenotypes of LPD

image DLBCL
image HL-like
image PTLD-like
image LyG (especially Wiskott–Aldrich syndrome)
image T cell LPD (ataxia telangiectasia and ALPS)

X-linked lymphoproliferative disorder (Duncan syndrome)

• Fatal infectious mononucleosis
• Polymorphous proliferation of lymphoid cells

image plasmacytoid
image immunoblastic
image RS-like cells

HIV-associated lymphoproliferative disorders

• Mainly B-cell lymphomas

image especially Burkitt and DLBCL, and HL
image also PTLD like

• Mainly extranodal
• More specific types:

image primary effusion lymphoma

– HHV-8 associated
– originates in body cavities

image plasmablastic lymphoma of the oral cavity

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD)

Epidemiology

• Immunosuppressed patients post-transplantation
• Variable phenotype of lymphoproliferative disorders
• Majority are EBV-related

image EBV-negative cases increasingly reported (Pinkerton et al 2002, Koch et al 2007)

• Prevalence related to degree of immunosuppression and organ type

image <1% post renal transplant
image 5% post cardiac transplant
image 10% post lung transplant (Webber et al 2006)

Clinical features

• Often present as extranodal disease

image especially GIT and respiratory tract

• Average interval from transplant 2 years overall

image may occur early

– even within weeks (Webber et al 2006)

• Overall about 70% survive

image death due to

– PTLD
– graft loss

Histopathological features (Figs 8.34, 8.35)

• Hyperplastic subtype

image architecture conserved
image numerous plasma cells admixed with lymphocytes

• Polymorphic subtype

image architecturally destructive
image infiltrating cells demonstrate full spectrum of differentiation

– immunoblasts to mature B cells / plasma cells

• Monomorphic subtype

image architecturally destructive
image indistinguishable morphologically from lymphoma
image monomorphic does not mean all cells identical in size and shape

– refers to absence of full spectrum of differentiation from immunoblasts to mature B cells / plasma cells

image phenotype may be identical to wide range of lymphomas

– usually DLBCL

• Hodgkin-like PTLD

image well reported

image

Fig. 8.34

image

Figs 8.34–8.35 Photomicrographs of a case of post-transplant lymphoproliferative disorder, demonstrating infiltration of normal tissue by sheets of lymphoid cells, in this case with the morphology of diffuse large B-cell lymphoma (monomorphic type), the majority of the neoplastic cells showing strong EBV-ISH expression.

Immunohistochemical staining

• Lymphoid markers expressed

image usually B cell

• Often EBV / EBER-ISH positive

image pattern depends on exact subtype

• Clonality determination

image limited importance

– both polymorphic and monomorphic may be monoclonal
– polyclonal types may behave aggressively

REACTIVE LYMPHADENOPATHIES

NON-SPECIFIC REACTIVE LYMPHOID HYPERPLASIA (Figs 8.36, 8.37)

Follicular pattern

• Indicates humoral response / B-cell stimulation
• Follicles enlarged

image multiple cortical rows
image vary in size and shape

– may be enlarged and coalesce

• Prominent germinal centers

image tingible body macrophages
image peripheral rim of small lymphocytes

image

Fig. 8.36

image

Figs 8.36–8.37 Photomicrographs of cases of non-specific reactive lymphoid hyperplasia, enlarged, variably sized follicles and paracortical expansion.

Sinus pattern (draining lymph nodes)

• Numerous histiocytes expanding sinuses

Diffuse pattern

• Mainly viral infection-related
• Effaced architecture
• Paracortical expansion

image lymphocytes
image immunoblasts
image macrophages

Mixed pattern

• Many causes

image especially EBV and toxoplasma infection

Progressive transformation of germinal centers (Fig 8.38)

• Enlarged lymphoid follicles
• Germinal centers contain aggregates of small mature lymphocytes
• Obscured mantle zone
• May be non-specific reactive pattern or associated with NLPHD
image

Fig 8.38 Photomicrograph of a lymph node with progressive transformation of the germinal center, demonstrating an enlarged follicle with an obscured mantle zone and central aggregates of small lymphocytes.

VIRAL LYMPHADENOPATHIES

• Many show similar features

image non-specific follicular hyperplasia
image paracortical expansion

EBV-related lymphadenitis

• Partially distorted architecture

image non-specific reactive follicles
image expanded paracortex with mottled appearance due to

– numerous immunoblasts

· larger than normal
· vesicular nuclei with prominent nucleoli
· sometimes Hodgkin cell-like

image infiltrate may extend outside node

• Focal necrosis may be present
• EBV-ISH+

image interfollicular areas

CMV-lymphadenitis

• Partially distorted architecture

image non-specific reactive follicles
image expanded paracortex with mottled appearance due to

– numerous immunoblasts and macrophages

· immunoblasts sometimes Hodgkin cell-like

• Focal intranuclear inclusions
• CMV immunostaining+

HSV-lymphadenitis

• Partially distorted architecture

image expanded paracortex

– immunoblasts and macrophages
– scattered multinucleate cells

• Focal intranuclear inclusions
• HSV immunostaining+

Measles-lymphadenitis

• Partially distorted architecture

image expanded paracortex

– immunoblasts and macrophages
– scattered multinucleate giant cells

· Warthin–Finkeldey

HIV-associated lymphadenitis

• Secondary-infection-related
• HIV-associated persistent generalized lymphadenopathy (PGL)
• Acute

image hyperplastic, coalescing lymphoid follicles
image infiltration by monocytoid cells
image scattered multinucleate giant cells

• Chronic

image lymphoid depleted nodes
image atrophic follicles

– prominent vascular proliferation
– hyalinization

OTHER INFECTIVE LYMPHADENOPATHIES

Cat-scratch lymphadenitis (Figs 8.39, 8.40)

• Skin lesion and regional lymphadenopathy

image due to Bartonella henselae

– may be seen with silver stains

• May be contracted from other domestic animals in addition to cats
• Histological features:

image follicular hyperplasia
image monocytoid cell infiltration
image multiple microabscess formation

– necrosis and neutrophils

image abscesses become surrounded by pallisading macrophages

– form ‘stellate necrotizing granulomas’

image

Fig. 8.39

image

Figs 8.39–8.40 Photomicrographs of a biopsy from a lymph node with cat-scratch disease, demonstrating multiple microabscesses with surrounding pallisading macrophages.

Toxoplasma lymphadenitis

• Follicular hyperplasia
• Diffuse nests of epithelioid cells

image in paracortex
image within germinal centers

• Monocytoid B-cell proliferation

Mycobacterial lymphadenitis (and other granulomatous lymphadenopathy)

Tuberculous

• Caseating granulomatous lymphadenopathy (Fig 8.41)

image central caseation
image peripheral epithelioid histiocytes
image giant cells

– peripheral nuclei

• Caseation not always present
• AFBs may be visible
image

Fig 8.41 Photomicrograph of a lymph node showing caseating granulomatous inflammation due to tuberculosis.

BCG-lymphadenopathy (Fig 8.42)

• Clusters of epithelioid histiocytes
• Necrosis
• Numerous organisms
• Few well-formed granulomata or giant cells
image

Fig 8.42 Photomicrograph showing multiple non-caseating granulomata due to BCG-osis.

Atypical mycobacteria (Fig 8.43)

• Usually immunocompromised patients
• Poorly formed clusters of histiocytes

image often necrotizing / suppurative

• Numerous organisms
image

Fig 8.43 Photomicrograph of a lymph node showing granulomatous inflammation due to atypical mycobacterial infection.

Fungal / histoplasma infection

• Necrotizing granulomata
• Silver stains shows organisms

Sarcoid lymphadenopathy

• Numerous small non-caseating granulomata
• Schaumann and asteroid bodies may be present

KIMURA LYMPHADENOPATHY

• Follicular hyperplasia
• Reactive germinal centers
• Peripheral mantle
• Diffuse marked eosinophilia

image eosinophilic microabscesses

• Vascular proliferation

SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY (ROSAI–DORFMAN DISEASE) (Figs 8.44, 8.45)

• Cervical adenopathy
• Usually children

image especially black races

• Enlarged nodes
• Capsular fibrosis
• Sinus dilation
• Mixed cellular population
• Many histiocytes

image some large with vacuoles containing lymphocytes (emperipolesis), erythrocytes or neutrophils
image S100+

• No atypia
• No granulomata
image

Fig. 8.44

image

Figs 8.44–8.45 Photomicrographs of a cervical lymph node from a child with Rosai–Dorfman disease (sinus histiocytosis with massive lymphadenopathy), demonstrating massive sinus expansion by histiocytes, some showing obvious emperipolesis.

KIKUCHI–FUJIMOTO LYMPHADENOPATHY (Figs 8.46–8.48)

• Usually young adults
• Cervical lymphadenopathy
• Overall architecture preserved

image reactive follicles

• Patchy areas of irregularly shaped necrosis

image fibrinoid material
image nuclear fragmentation / nuclear dust
image histiocytes
image no neutrophils / eosinophils

image

Fig. 8.46

image

Fig. 8.47

image

Figs 8.46–8.48 Photomicrographs of a cervical lymph node from a child with Kikuchi–Fujimoto lymphadenopathy, demonstrating irregular areas of necrosis with marked nuclear fragmentation but no neutrophilic infiltration.

LUPUS LYMPHADENOPATHY

• Architecture effaced
• Edema
• Sinus dilation
• Patchy necrosis

image abruptly demarcated
image no neutrophils

• Hematoxylin bodies
• Immunoblasts prominent

CASTLEMAN DISEASE (ANGIOFOLLICULAR LYMPH NODE HYPERPLASIA) (Figs 8.49–8.51)

• Two main types
image

Fig. 8.49

image

Fig. 8.50

image

Figs 8.49–8.51 Photomicrographs of lymph nodes from cases of Castleman disease, demonstrating interfollicular areas containing sheets of plasma cells and germinal centers with a central vessel surrounded by hyaline cuffing and small lymphocytes.

Hyaline-vascular type

• Numerous lymphoid follicles throughout entire node

image abnormal

– small central germinal centers

· contain vessels surrounded by hyaline cuffing
· surrounding concentric layers of small lymphocytes (onion-skin pattern)

– intervening prominent postcapillary venules

Plasma cell type

• Prominent follicles

image large / normal rather than small

– cf hyaline vascular type

• Active germinal centers
• Interfollicular areas contain sheets of numerous plasma cells

HISTOPATHOLOGY OF IMMUNODEFICIENCIES

INTRODUCTION

• Relatively common immunodeficiences include (but are not limited to):

image common variable immunodeficiency (CVID)
image CD40 ligand deficiency
image Wiskott–Aldrich syndrome
image X-linked agammaglobulinemia
image chronic mucocutaneous candidiasis
image ataxia telangiectasia
image X-linked lymphoproliferative disease
image Chediak–Higashi syndrome
image leukocyte adhesion defects
image Di George syndrome
image chronic granulomatous disease
image hyper IgE syndrome
image severe combined immunodeficiency
image Omenn syndrome
image MHC class II deficiency

• There is little systematic published data regarding histopathological features of most specific immunodeficiencies
• In general, immunodeficiencies present with non-specific features:

image recurrent bacterial (and other) infections

– histological findings usually reflect this secondary pathology

image other non-specific features according to the underlying condition

– paucity of the normal lymphocyte subpopulations

• Rarely, more specific clinical or pathological features may also be present:

image chronic mucocutaneous candidiasis

– candidal infection

image leukocyte adhesion defects

– delayed cord separation

image hyper IgE syndrome

– recurrent Staphylococcal infection

image chronic granulomatous disease (Figs 8.52, 8.53)

– multiple infections

· including fungal

– abscess formation and granulomata
– characteristic lightly pigmented macrophages (Levine et al 2006)
image X-linked lymphoproliferative disease

– EBV infection

image Chediak–Higashi syndrome

– abnormal hair pigmentation (see hair section)

image

Fig. 8.52

image

Figs 8.52–8.53 Photomicrographs of a lymph node and colonic mucosal biopsy from cases of chronic granulomatous disease, demonstrating granulomatous inflammation and scattered characteristic lightly pigmented macrophages.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS)

• Due to inherited mutations in genes that mediate lymphocyte apoptosis

image most have Fas (CD95, Apo1) mutations (Sneller et al 2003)
image somatic heterozygous mutations of Fas can also cause sporadic ALPS (Holzelova et al 2004)

• Expanded population of CD4-CD8-negative T cells

Clinical features

• Chronic, nonmalignant lymphadenopathy and splenomegaly
• Development of autoimmune disease
• 10–50-fold increased risk of HL and NHL (Straus et al 2001)
• Major determinants of morbidity and mortality are

image autoimmune disease
image hypersplenism
image asplenia-related sepsis
image lymphoma development (Rao et al 2006)

Histopathology (Figs 8.54, 8.55)

• Marked paracortical expansion of CD3+, CD4-CD8-negative (double negative) T-cells

image paracortical lymphocytes may express cytotoxic markers

– perforin, TIA-1, CD57

• Associated florid follicular hyperplasia

image with or without progressive transformation of germinal centers (Lim et al 1998)

• 40% have sinus histiocytosis with massive lymphadenopathy-like features (SHML; Rosai–Dorfman disease; Maric et al 2005)
• Double-negative T cell infiltration of spleen and portal tracts
image

Fig. 8.54

image

Figs 8.54–8.55 Photomicrographs of a lymph node from a case of autoimmune lymphoproliferative disorder (ALPS), demonstrating marked paracortical expansion by CD3+, CD4-CD8 negative (double negative) T-cells.

LANGERHANS CELL HISTIOCYTOSIS

• LCH may involve lymph nodes
• Features identical to LCH at other sites (see skin section) (Figs 8.56–8.58)
image

Fig. 8.56

image

Fig. 8.57

image

Figs 8.56–8.58 Photomicrographs of a lymph node involved by Langerhans cell histiocytosis, showing interfollicular infiltration by LCH cells, confirmed on Langerin immunostaining.

REFERENCES

Al-Adnani M, Williams S, Anderson J, Ashworth M, Malone M, Sebire NJ. Immunohistochemical nuclear positivity for WT1 in childhood acute myeloid leukemia. Fetal Pediatr Pathol. 2007;26:193-197.

Canioni D, Jabado N, MacIntyre E, Patey N, Emile JF, Brousse N. Lymphoproliferative disorders in children with primary immunodeficiencies: immunological status may be more predictive of the outcome than other criteria. Histopathol. 2001;38:146-159.

Holzelova E, Vonarbourg C, Stolzenberg MC, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004;351:1409-1418.

Koch DG, Christiansen L, Lazarchick J, Stuart R, Willner IR, Reuben A. Post-transplantation lymphoproliferative disorder – the great mimic in liver transplantation: appraisal of the clinicopathologic spectrum and the role of Epstein–Barr virus. Liver Transpl. 2007;13:904-912.

Levine S, Smith VV, Malone M, Sebire NJ. Histopathological features of chronic granulomatous disease (CGD) in childhood. Histopathol. 2005;47:508-516.

Lim MS, Straus SE, Dale JK, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998;153:1541-1550.

Maric I, Pittaluga S, Dale JK, et al. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol. 2005;29:903-911.

Pinkerton CR, Hann I, Weston CL, et al. Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children’s Cancer Study Group Registry. Br J Hematol. 2002;118:456-461.

Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematol. 2006;11:15-23.

Sneller MC, Dale JK, Straus SE. Autoimmune lymphoproliferative syndrome. Curr Opin Rheumatol. 2003;15:417-421.

Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001;98:194-200.

Webber SA, Naftel DC, Fricker FJ, et al. Lymphoproliferative disorders after pediatric heart transplantation: a multi-institutional study. Lancet. 2006;367:233-239.

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