Peripheral B Cell Neoplasms

Slide 1 · Peripheral B-Cell Neoplasms

Pathogenesis • morphology • immunophenotype • clinical behavior

CLL/SLL Follicular lymphoma DLBCL Burkitt lymphoma Mantle cell lymphoma

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Relate tumor biology to B-cell maturation and lymphoid tissue architecture.

Identify morphologic and immunophenotypic hallmarks of five major neoplasms.

Explain oncogenic consequences of BCL2, BCL6, MYC, and cyclin D1 alterations.

Integrate growth tempo, site of disease, and transformation with diagnosis.

Slide 3 · Normal B-cell differentiation provides the diagnostic framework

Naive B cell

Mantle zone

Germinal center

Proliferation and selection

Memory / mature B cell

Antigen-experienced states

Different neoplasms preserve features of B-cell developmental stages; Lineage markers alone do not establish a specific diagnosis.

Schematic

Slide 4 · Clinical tempo is a first diagnostic clue

CLL/SLL and follicular lymphoma commonly show indolent clinical courses.

Mantle cell lymphoma is often disseminated and typically more aggressive than indolent lymphomas.

DLBCL usually enlarges rapidly; Burkitt lymphoma is among the fastest-growing human tumors.

An indolent lymphoma can acquire new lesions and transform into a high-grade neoplasm.

Slide 5 · Five disease entities: A first-pass map

Entity

Growth / architecture

Defining molecular association

CLL/SLL

Small-cell, diffuse; proliferation centers

13q14 deletion / BCL2 overexpression

Follicular lymphoma

Nodular / follicular

IGH–BCL2, t(14;18)

DLBCL

Diffuse large B cells

BCL6 / BCL2 / MYC lesions; heterogeneous

Burkitt lymphoma

Intermediate cells; very rapid growth

Immunoglobulin–MYC rearrangement

Mantle cell lymphoma

Small to medium cells; mantle / diffuse

IGH–CCND1, t(11;14)

Slide 6 · A diagnosis requires concordant evidence

Growth pattern and cytology establish the morphologic differential.

Immunophenotyping confirms mature B-cell lineage and narrows lineage subtype.

Characteristic genetic lesions strengthen diagnosis and inform tumor biology.

Anatomic distribution and clinical history reveal important exceptions and transformations.

Slide 7 · CLL/SLL: Two manifestations of one neoplasm

Chronic lymphocytic leukemia and small lymphocytic lymphoma share the same cellular disease.

The leukemia designation reflects sufficient circulating clonal lymphocytes.

Predominantly tissue-based presentation with less blood lymphocytosis is termed SLL.

CLL is a common adult leukemia in Western populations.

Slide 8 · CLL and SLL differ in distribution, not core biology

CLL

Persistent circulating small lymphocytes are prominent.

Peripheral blood smear often reveals fragile lymphocytes / smudge cells.

Marrow, nodes, spleen, and liver may also be infiltrated.

SLL

Lymphadenopathy and tissue involvement may dominate.

Peripheral blood lymphocytosis may be below the leukemia threshold.

Tissue morphology and marker profile match CLL.

Slide 9 · CLL/SLL cytology: Predominance of small mature lymphocytes

Recognize the pattern

Condensed chromatin

Scant cytoplasm

Small round or slightly irregular nuclei

Smudge cells in blood smears

Cell diagrams are schematic—not photomicrographs

Slide 10 · CLL/SLL: Diffuse nodal effacement with proliferation centers

Simplified nodal architecture

Diffuse small cells

Most of the node is replaced.

Proliferation centers

Loose larger-cell aggregates with mitoses.

Diagnostic context

Characteristic for CLL/SLL in this setting.

Schematic nodal architecture; Not a histologic section.

Slide 11 · CLL/SLL: Proliferation centers reflect local growth

Most neoplastic lymphocytes are small and relatively inactive in tissue.

Scattered larger activated cells form pale aggregates termed proliferation centers.

Proliferation centers concentrate mitotically active tumor cells.

Microenvironment-derived signals help sustain neoplastic cell growth.

Slide 12 · CLL/SLL immunophenotype: The diagnostic combination

Marker

Usual pattern

Interpretive value

CD19; CD20

B-lineage; CD20 present

Supports mature B-cell neoplasm

CD5

Positive

Aberrant coexpression with B lineage

CD23

Positive

Favors CLL/SLL over typical mantle cell lymphoma

Surface IgM ± IgD

Relatively dim

Characteristic weak surface immunoglobulin

BCL2

Strong

Supports apoptosis resistance

Slide 13 · 13q14 loss provides a route to apoptosis resistance

13q14 deletion

MiR-15a / miR-16-1 loss

BCL2 rises

Reduced apoptotic cell death

Cell survival

Accumulation of mature B cells

BCL2 overexpression favors prolonged survival; It is not simply a marker of increased mitotic rate.

Schematic

Slide 14 · CLL/SLL: Additional recurrent genetic lesions

Common cytogenetic findings include deletions of 11q and 17p and trisomy 12.

Deletion of 17p may involve TP53 and is associated with worse outcome.

NOTCH1 gain-of-function mutations are associated with less favorable prognosis.

Mutations affecting RNA splicing are also documented.

Slide 15 · IGHV somatic hypermutation stratifies biologic behavior

Hypermutated IGH genes

Suggest antigen-experienced / post–germinal center history.

Associated with comparatively more favorable clinical behavior.

Unmutated IGH genes

May reflect naive B-cell derivation.

Associated with more aggressive clinical behavior in the source.

Slide 16 · CLL/SLL infiltrates multiple hematolymphoid organs

Peripheral blood involvement varies from modest to marked lymphocytosis.

Marrow involvement is common and may contribute to cytopenias.

Splenic and hepatic infiltration can accompany lymphadenopathy.

Liver involvement may be visible as periportal lymphocytic infiltrates.

Slide 17 · CLL-associated hypogammaglobulinemia produces infection risk

CLL/SLL

Abnormal immune regulation

Low immunoglobulins

Impaired humoral defense

Clinical consequence

Greater bacterial infection susceptibility

Immunodeficiency is clinically important even when the lymphoma burden appears indolent.

Schematic

Slide 18 · CLL/SLL can cause autoimmune cytopenias

Autoantibodies produced by nonneoplastic B cells can damage circulating blood cells.

Autoimmune hemolytic anemia and immune thrombocytopenia are recognized complications.

Anemia may therefore reflect immune destruction, marrow replacement, or both.

A peripheral smear and appropriate laboratory correlation are essential.

Slide 19 · CLL/SLL: Clinical heterogeneity is substantial

Many patients have minimal symptoms at presentation.

Fatigue, weight loss, lymphadenopathy, and hepatosplenomegaly may develop.

Some patients remain stable for long periods while others progress rapidly.

Clinical stage and selected molecular features correlate with prognosis.

Slide 20 · Richter transformation changes the disease tempo

Underlying CLL/SLL

Often indolent

Clonal evolution

Additional lesions may involve TP53 / MYC

Aggressive lymphoma

Usually DLBCL morphology

A newly rapidly enlarging nodal or splenic mass should prompt assessment for Richter transformation.

Schematic

Slide 21 · CLL/SLL: Therapeutically relevant biology

BCL2 inhibitors target the survival program common in CLL/SLL.

BTK inhibitors interfere with B-cell receptor–associated survival signaling.

Anti-CD20 antibodies target the surface B-cell antigen.

Specific regimen selection is evolving and lies beyond the morphologic diagnosis.

Slide 22 · Follicular lymphoma: A germinal center B-cell neoplasm

An important indolent non-Hodgkin lymphoma, generally presenting in middle age.

The tumor commonly shows nodular / follicular nodal growth.

Neoplastic cells resemble germinal center centrocytes and centroblasts.

The neoplasm commonly expresses BCL2 despite its germinal center phenotype.

Slide 23 · T(14;18) connects immunoglobulin regulation to BCL2

IGH–BCL2 fusion

T(14;18) rearrangement

Enhancer effect

IGH regulation drives BCL2

BCL2 protein rises

Apoptosis is inhibited

The translocation favors persistence of germinal center-derived cells that would normally be deleted by apoptosis.

Schematic

Slide 24 · Normal vs neoplastic germinal center: BCL2 is the discriminator

Reactive germinal center

Germinal center B cells are usually BCL2-negative.

Apoptosis helps eliminate cells failing selection.

Mantle zone B cells retain BCL2 expression.

Follicular lymphoma

Neoplastic follicle cells usually express BCL2.

Reduced apoptosis permits persistence of altered cells.

The pattern is interpreted alongside follicular architecture.

Slide 25 · Histone-modifying enzymes contribute to FL pathogenesis

KMT2D encodes a histone-modifying enzyme and is frequently mutated.

EZH2 encodes a different chromatin-modifying enzyme and may carry activating lesions.

Abnormal epigenetic programs complement BCL2-driven survival.

The source links EZH2-mutated tumors to sensitivity to EZH2 inhibition.

Slide 26 · Follicular lymphoma depends on its microenvironment

Neoplastic follicles contain a follicular dendritic-cell network.

Macrophages and reactive T cells coexist with lymphoma B cells.

Gene-expression features of surrounding stromal cells relate to outcome.

This illustrates that clinical behavior is not determined solely by tumor-cell mutations.

Slide 27 · Follicular lymphoma: Repeated neoplastic follicles

Simplified nodal architecture

Nodular pattern

Follicles replace the nodal architecture.

Mixed cytology

Centrocytes with variable centroblasts.

Diagnostic principle

Morphology needs IHC corroboration.

Schematic lymph node; Do not interpret as actual H&E.

Slide 28 · Follicular lymphoma: Centrocytes and centroblasts

Recognize the pattern

Centrocytes: Irregular cleaved nuclei

Centroblasts: Larger cells with nucleoli

Proportions vary among tumors

Both populations contribute to grading considerations

Cell diagrams are schematic—not photomicrographs

Slide 29 · FL commonly infiltrates marrow paratrabecularly

Bone marrow involvement is frequent description.

Neoplastic lymphoid aggregates preferentially track along bony trabeculae.

Spleen white-pulp nodules and hepatic portal triads may also be involved.

Anatomic patterns support—but never independently prove—the diagnosis.

Slide 30 · Follicular lymphoma: Germinal center marker profile

Feature

Expected profile

Why it matters

CD19 / CD20

Positive

Mature B-cell lineage

CD10 / BCL6

Positive

Germinal center differentiation

CD5

Negative

Distinguishes from typical CLL/SLL and MCL

BCL2

Often positive in follicles

Distinguishes most FL from reactive germinal centers

Slide 31 · Follicular lymphoma versus reactive follicular hyperplasia

Reactive germinal centers typically lack BCL2 in center B cells.

Lymphoma follicles commonly contain BCL2-positive neoplastic cells.

Distribution and cytologic uniformity add evidence beyond BCL2 staining.

Interpret immunostaining by cellular compartment rather than global tissue positivity.

Slide 32 · FL: The typical clinical presentation is widespread lymphadenopathy

Painless generalized adenopathy is characteristic.

Extranodal sites including gut, central nervous system, and testis are less common.

The natural history is often relapsing and remitting.

Indolent clinical tempo does not exclude extensive marrow or splenic involvement.

Slide 33 · Histologic transformation: FL may evolve into DLBCL

Follicular lymphoma

Indolent BCL2-driven clone

Additional genetic events

May include MYC activation

Transformed tumor

Diffuse large B-cell lymphoma

Accelerated enlargement or new aggressive clinical findings warrant reassessment of histology.

Schematic

Slide 34 · FL clinical biology guides therapeutic concepts

Anti-CD20 therapy exploits retained B-cell lineage antigen expression.

EZH2 inhibition is biologically relevant to tumors with activating EZH2 mutations.

Choice and intensity of treatment depend on clinical circumstances.

High-grade transformation requires a different clinicopathologic approach.

Slide 35 · DLBCL: A common aggressive mature B-cell lymphoma

Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma.

It affects adults frequently but also occurs in younger patients.

It typically presents with a rapidly enlarging mass.

DLBCL is a heterogeneous family of tumors, not a single molecular lesion.

Slide 36 · DLBCL: Diffuse effacement by large lymphoid cells

Simplified nodal architecture

Diffuse growth

Native architecture is replaced.

Large tumor cells

Size greatly exceeds a small lymphocyte.

Cytologic diversity

Nuclear shape and nucleoli vary.

Schematic; Actual tumor morphology requires an authentic slide.

Slide 37 · DLBCL cell morphology: Large nuclei and active nucleoli

Recognize the pattern

Large lymphoid cell size

Vesicular / open nuclear chromatin

Prominent nucleoli

Variable cytoplasm and nuclear contour

Cell diagrams are schematic—not photomicrographs

Slide 38 · BCL6 controls the germinal center transcriptional state

BCL6 is a transcriptional repressor needed in normal germinal center development.

It restrains programs promoting growth arrest, apoptosis, and differentiation.

Persistent inappropriate BCL6 expression can favor neoplastic survival and expansion.

Several DLBCL molecular lesions converge on BCL6 dysregulation.

Slide 39 · BCL6 dysregulation can arise by more than one route

BCL6 rearrangement

Chromosome 3q27 locus

BCL6 promoter mutations

Impaired autoregulation

Sustained BCL6

Reduced normal GC exit programs

Rearrangements and promoter lesions are distinct routes to abnormal BCL6 activity.

Schematic

Slide 40 · Aberrant somatic hypermutation may target oncogenes

Germinal center DNA-modifying processes can inadvertently affect non-Ig genes.

The source describes BCL6 promoter mutations as a prominent example.

Similar acquired changes may involve MYC and other oncogenes.

Off-target mutation helps explain the genetic diversity of DLBCL.

Slide 41 · BCL2-associated DLBCL represents another survival route

A subset contains t(14;18), causing BCL2 overexpression.

Some cases may arise through transformation of follicular lymphoma.

BCL2 and BCL6 rearrangements can occur in different molecular contexts.

An antiapoptotic phenotype alone does not establish a follicular lymphoma origin.

Slide 42 · MYC plus BCL2 couples growth with survival

MYC activation

Accelerated growth / biosynthesis

BCL2 activation

Apoptosis resistance

Combined lesions

Highly aggressive lymphoma biology

This combination is distinct from protein coexpression alone; Genetic rearrangements must be established by molecular testing.

Schematic

Slide 43 · DLBCL has multiple genetic backgrounds

BCL6, BCL2, and MYC rearrangements account for some—not all—tumors.

The text also implicates CD79B, MYD88, EZH2, NOTCH1, and NOTCH2 alterations.

Different combinations of abnormalities underlie molecular subgroups.

Do not equate a morphologic DLBCL diagnosis with one uniform genotype.

Slide 44 · DLBCL: Immunophenotype and Key diagnostic consideration: S

Marker / testing

Textbook expectation

Caveat

CD19, CD20

Expressed by most cases

Confirms mature B-cell lineage

CD10, BCL6

Variable

May reflect germinal-center phenotype

Surface immunoglobulin

Often present

Expression may vary

MYC and BCL2 protein

High in some cases

Protein coexpression ≠ proven gene rearrangement

Slide 45 · DLBCL: The mass can arise at almost any site

Most cases present as rapidly growing nodal or extranodal masses.

Waldeyer ring, gastrointestinal tract, skin, bone, and brain are possible sites.

Liver and splenic tumors may form large destructive masses.

Marrow disease is less conspicuous early than in several indolent B-cell lymphomas.

Slide 46 · Splenic involvement: Indolent lymphoma versus DLBCL

Indolent B-cell lymphoma

Often expands multiple white-pulp nodules.

May produce generalized splenic enlargement.

DLBCL

Can produce a solitary dominant destructive splenic mass.

Aggressive growth may efface normal architecture.

Slide 47 · Immunodeficiency-associated DLBCL: EBV is important

Some large B-cell proliferations occur with impaired T-cell surveillance.

Advanced HIV infection and organ or stem-cell transplantation are contexts in the text.

Tumor B cells are often Epstein–Barr virus-associated.

Restoration of immune surveillance can lead to regression in selected settings.

Slide 48 · Primary effusion lymphoma: Fluid-space disease

May present as malignant pleural or ascitic effusion rather than a solid mass.

Classically associated with severe immune compromise but also seen in older adults.

Tumor cells can lack conventional surface B- and T-cell markers.

HHV8 infection and clonal immunoglobulin gene rearrangement identify its lineage.

Slide 49 · Primary mediastinal large B-cell lymphoma: Immune escape

Mediastinal tumor

Often bulky localized mass

PD-L1 gene amplification

Checkpoint protein overexpression

Immune evasion

Reduced antitumor response

Mass effect may cause superior vena cava obstruction and swelling of face or neck.

Schematic

Slide 50 · Intravascular large B-cell lymphoma: A deceptive presentation

Tumor cells preferentially proliferate inside small vessels.

A conventional enlarged nodal mass may be absent.

Neurologic symptoms may result from cerebral small-vessel involvement.

Skin biopsy can reveal the diagnosis when the entity is suspected.

Slide 51 · Large B-cell lymphoma with MYC and BCL2 rearrangements

Combined oncogenic drivers create rapid proliferation and enhanced survival.

May arise de novo or evolve from follicular lymphoma.

Genetic documentation matters: Rearranged genes are distinct from IHC protein positivity.

The source describes these lesions as exceptionally aggressive.

Slide 52 · DLBCL: Clinically relevant treatment principles

Untreated DLBCL has an aggressive natural history.

Combination immunochemotherapy can cure a substantial subset of patients.

Anti-CD20 therapy targets the surface B-cell antigen.

CD19-targeted CAR-T cells provide an option in relapsed/refractory disease.

Slide 53 · Burkitt lymphoma: One histology, three epidemiologic settings

Endemic, sporadic, and immunodeficiency-associated cases share characteristic morphology.

An immunoglobulin–MYC rearrangement is a central feature of classic Burkitt lymphoma.

Clinical distribution and EBV association differ by setting.

The tumor exhibits extraordinarily rapid proliferative behavior.

Slide 54 · Burkitt lymphoma: Clinical settings

Setting

Typical distribution

EBV association in source

Endemic

Often jaw; can involve abdominal viscera

Essentially all cases

Sporadic

Often ileocecal / peritoneal mass

Minority of cases

HIV-associated

Aggressive lymphoma in immune compromise

Subset of cases

Slide 55 · Immunoglobulin–MYC rearrangement drives Burkitt lymphoma

IGH or Ig light chain

Strong immunoglobulin enhancer

MYC deregulation

High MYC expression

Growth program

Rapid synthesis and division

MYC is a transcriptional regulator of biosynthesis, cellular metabolism, and proliferation.

Schematic

Slide 56 · Canonical Burkitt lymphoma rearrangements

Translocation

Partner genes

Consequence

t(8;14)

MYC / IGH

Most common immunoglobulin enhancer juxtaposition

t(2;8)

IGK / MYC

Alternative immunoglobulin light-chain partner

t(8;22)

MYC / IGL

Alternative immunoglobulin light-chain partner

Slide 57 · AID links germinal-center biology to MYC rearrangements

Activation-induced cytidine deaminase participates in class switching and somatic hypermutation.

DNA breaks created during normal antibody diversification can be misrepaired.

The source implicates AID in MYC–immunoglobulin translocations.

Breakpoint patterns vary between endemic and sporadic Burkitt lymphoma.

Slide 58 · MYC promotes biosynthesis through Warburg-type metabolism

MYC overexpression

Reprogrammed gene expression

Aerobic glycolysis

Nutrient assimilation and biosynthesis

Tumor proliferation

Rapid cell accumulation

Enhanced synthesis of nucleotides, lipids, and proteins supports the extraordinary growth rate.

Schematic

Slide 59 · TCF3 signaling cooperates with MYC

Many tumors harbor lesions increasing TCF3 transcription-factor activity.

The source describes TCF3 as a regulator of germinal center gene expression.

Its downstream program includes genes promoting cell-cycle progression.

Burkitt biology therefore cannot be explained by MYC deregulation alone.

Slide 60 · EBV association differs among Burkitt settings

EBV is present in essentially all endemic cases in the source.

A smaller fraction of sporadic and HIV-associated tumors harbor EBV.

Clonally uniform viral genomes suggest infection precedes malignant expansion.

The specific causal contribution of EBV remains incompletely resolved.

Slide 61 · Burkitt lymphoma: Macrophages create a “starry sky”

Simplified nodal architecture

Monomorphic tumor

Intermediate-sized lymphoid cells.

Numerous apoptotic bodies

High cellular turnover.

Pale macrophages

Phagocytosis produces starry-sky spaces.

Conceptual architecture only; The starry-sky pattern is not exclusive to Burkitt lymphoma.

Slide 62 · Burkitt lymphoma: Intermediate cells with intense turnover

Recognize the pattern

Intermediate-sized, relatively monotonous cells

Coarse chromatin and multiple nucleoli

Cytoplasmic vacuoles may be seen in aspirates

High mitotic and apoptotic activity

Cell diagrams are schematic—not photomicrographs

Slide 63 · Starry-sky morphology reflects cellular death and clearance

Numerous tumor cells undergo apoptosis in this rapidly proliferating neoplasm.

Benign tingible-body macrophages ingest apoptotic debris.

Pale macrophage cytoplasm interrupts the dense basophilic tumor field.

The resulting “starry sky” is a pattern, not a standalone diagnosis.

Slide 64 · Burkitt lymphoma: Immunophenotypic profile

Marker

Usual pattern

Interpretive value

CD19 / CD20

Positive

Mature B-cell differentiation

CD10 / BCL6

Positive

Germinal center phenotype

Surface IgM

Positive

Surface immunoglobulin expression

BCL2

Typically negative

Consistent with abundant apoptotic cells

Slide 65 · Burkitt presentation depends on epidemiologic context

Endemic presentation

Often a jaw / mandibular mass.

May involve kidneys, ovaries, or adrenal glands.

Predominantly children or young adults.

Sporadic presentation

Ileocecal and peritoneal masses are characteristic.

May present with abdominal symptoms.

Also predominantly younger patients.

Slide 66 · Burkitt lymphoma: Aggressive but potentially curable

The natural growth rate is extremely high.

Intensive multidrug chemotherapy can be highly effective.

Most children and young adults in the text can be cured.

Outcome is more guarded in older adults.

Slide 67 · Mantle cell lymphoma: Usually a naive B-cell phenotype

Tumor cells resemble B lymphocytes normally surrounding germinal centers.

Often presents in the fifth or sixth decade with male predominance.

Dissemination is frequent and may include extranodal gastrointestinal sites.

The common genetic hallmark is IGH–CCND1 rearrangement.

Slide 68 · T(11;14) causes cyclin D1 overexpression

IGH–CCND1 fusion

T(11;14) rearrangement

Enhancer effect

Cyclin D1 expression rises

Cell-cycle effect

G1 to S progression promoted

Cyclin D1 is a cell-cycle regulator; Its dysregulation promotes inappropriate proliferation.

Schematic

Slide 69 · Cyclin D1 connects the genotype to the cell cycle

Cyclin D1 promotes transition from G1 into S phase.

IGH–CCND1 rearrangement induces inappropriate cyclin D1 overexpression.

The lesion therefore enhances cell-cycle entry rather than primarily blocking apoptosis.

Cyclin D1 IHC is a high-value diagnostic adjunct in an appropriate B-cell phenotype.

Slide 70 · Mantle cell lymphoma: Expanded mantle zones or diffuse growth

Simplified nodal architecture

Mantle-zone pattern

Tumor surrounds small residual germinal centers.

Diffuse pattern

Architecture may become completely effaced.

Characteristic clue

Lacks CLL/SLL proliferation centers.

Schematic; Actual tissue section not provided.

Slide 71 · Mantle cell lymphoma: Relatively uniform irregular small cells

Recognize the pattern

Small cells, sometimes clefted nuclei

Condensed chromatin

Inconspicuous nucleoli

No typical centroblast-rich follicles

Cell diagrams are schematic—not photomicrographs

Slide 72 · Mantle cell lymphoma: B-cell markers plus cyclin D1

Marker

Typical profile

Differential utility

CD19 / CD20

Positive

Confirms mature B-cell lineage

Surface IgM / IgD

Usually appreciable

Often stronger than in CLL/SLL

CD5

Usually positive

Shared with CLL/SLL

CD23

Usually negative

Contrasts with typical CLL/SLL

Cyclin D1

Strong overexpression

Supports IGH–CCND1 biology

Slide 73 · CLL/SLL versus mantle cell lymphoma: CD5 is not enough

CLL/SLL

CD5+, CD23+ usually.

Surface immunoglobulin often weak.

Pseudofollicular proliferation centers may be present.

Mantle cell lymphoma

CD5+, CD23− typically.

Cyclin D1 strongly expressed.

Mantle-zone growth or uniform small-cell infiltrate.

Slide 74 · Mantle cell lymphoma: Gastrointestinal dissemination

Gut involvement can be prominent and sometimes produces multiple mucosal polyps.

The pattern is termed lymphomatoid polyposis.

Marrow, spleen, and liver are other common extranodal sites.

Systemic spread is therefore common even when the diagnosis is made in a lymph node.

Slide 75 · The blastoid variant is a diagnostic and prognostic challenge

Some tumors show larger cells with open chromatin and brisk mitotic activity.

Such blastoid cases may resemble lymphoblastic leukemia/lymphoma morphologically.

B-lineage markers and cyclin D1 help establish the correct differentiation state.

Blastoid morphology correlates with less favorable clinical behavior.

Slide 76 · MCL: Clinical behavior and prognostic modifiers

Painless lymphadenopathy is a common initial finding.

Splenic and intestinal involvement can produce organ-related symptoms.

The disease is typically moderately aggressive with variable survival.

Blastoid morphology, high proliferation, and TP53 lesions are adverse.

Slide 77 · Genetic driver comparison across the five neoplasms

Neoplasm

Selected molecular driver

Biological effect

CLL/SLL

miR-15a/16-1 loss; BCL2 expression

Enhanced survival

Follicular lymphoma

IGH–BCL2; epigenetic regulators

Antiapoptotic survival / chromatin change

DLBCL

BCL6, BCL2, MYC; diverse pathways

Variable survival / differentiation / growth

Burkitt lymphoma

Immunoglobulin–MYC

Accelerated metabolism and proliferation

Mantle cell lymphoma

IGH–CCND1 (cyclin D1)

G1–S cell-cycle progression

Slide 78 · Comparative immunophenotype: Interpret the full panel

Disease

CD5

CD23

CD10 / BCL6

Cyclin D1 / BCL2

CLL/SLL

+

+

Usually −

BCL2 high

Follicular

−

Not defining

CD10+, BCL6+

BCL2 in neoplastic follicles

DLBCL

Variable

Variable

Variable

May express BCL2

Burkitt

Usually −

Not defining

CD10+, BCL6+

Usually BCL2−

Mantle cell

Usually +

Usually −

Usually −

Cyclin D1 high

Slide 79 · Architectural recognition across mature B-cell neoplasms

CLL/SLL

Small diffuse cells± pale centers

Follicular

Repetitive nodules

DLBCL

Large diffuse cells

Burkitt

Diffuse + starry sky

Mantle cell

Expanded mantle zones

These labels are schematic diagnostic abstractions—not substitutes for examining H&E sections.

Slide 80 · Clinical tempo directs the differential diagnosis

Slow, waxing-and-waning adenopathy suggests an indolent lymphoma but is not definitive.

Rapidly enlarging masses support aggressive entities such as DLBCL or Burkitt.

New rapid growth in known CLL or follicular lymphoma raises concern for transformation.

Morphology, markers, and genetics must resolve the clinical impression.

Slide 81 · A practical workup: From architecture to molecular interpretation

Tissue / blood

Site and cytology

B-cell panel

CD19/CD20 + focused markers

Genetic testing

IGH–BCL2 / CCND1 / MYC as indicated

The most informative test set is dictated by the morphologic differential, not a single positive marker.

Schematic

Slide 82 · Diagnostic pitfall: One marker rarely defines a disease

CD5 is shared by CLL/SLL and most mantle cell lymphomas.

CD10 and BCL6 are seen in both follicular and Burkitt lymphomas and some DLBCLs.

BCL2 IHC expression is not equivalent to a BCL2 gene rearrangement.

MYC and BCL2 protein coexpression is not synonymous with rearrangements of both genes.

Slide 83 · Indolent lymphomas can evolve through clonal progression

Indolent B-cell clone

CLL/SLL or follicular lymphoma

Additional genetic lesions

Tumor evolution / selection

Aggressive phenotype

Often large B-cell transformation

Abrupt clinical change creates a new biopsy question: Has the histology transformed?

Schematic

Slide 84 · Application 1: Small lymphocytes with CD5 and CD23

Hypothetical case: Blood lymphocytosis with mature small lymphocytes.

Flow cytometry: CD19+, CD5+, CD23+, relatively dim surface Ig.

Question: Which lymphoma is favored, and what blood-film artifact may be seen?

Interpretation: CLL/SLL; Smudge cells may be present.

Slide 85 · Application 2: BCL2-positive follicles

Hypothetical case: Persistent painless generalized lymphadenopathy.

Biopsy: Nodular population of centrocytes and centroblasts.

Immunophenotype: CD10+, BCL6+, BCL2+ within the follicles.

Interpretation: Follicular lymphoma; Correlate with IGH–BCL2 rearrangement.

Slide 86 · Application 3: Rapidly progressive extranodal B-cell mass

Hypothetical case: A rapidly enlarging extranodal destructive mass.

Biopsy: Diffuse sheets of large lymphocytes with prominent nucleoli.

Immunophenotype establishes a mature B-cell neoplasm.

Interpretation: DLBCL is a major consideration; Molecular characterization follows.

Slide 87 · Application 4: Starry sky with a MYC lesion

Hypothetical case: Young patient with an ileocecal mass.

Biopsy: Monomorphic intermediate cells and many tingible-body macrophages.

Profile: CD10+, BCL6+, BCL2−; MYC–immunoglobulin rearrangement.

Interpretation: Classic Burkitt lymphoma.

Slide 88 · Application 5: CD5-positive lymphoma with cyclin D1

Hypothetical case: Generalized adenopathy with intestinal polyposis.

Biopsy: Relatively uniform small lymphocytes with irregular nuclei.

Markers: CD20+, CD5+, usually CD23−, cyclin D1 high.

Interpretation: Mantle cell lymphoma with gastrointestinal involvement.

Slide 89 · Final diagnostic discriminators

CLL/SLL: CD5+CD23+, weak surface immunoglobulin, proliferation centers.

Follicular: Follicular growth, CD10/BCL6+, abnormal follicular BCL2 expression.

DLBCL: Diffuse large B cells and genetically heterogeneous aggressive disease.

Burkitt: MYC rearrangement, germinal-center phenotype, extreme turnover.

Mantle cell: CD5+, cyclin D1+, t(11;14), frequent extranodal spread.

Slide 90 · Primary reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 13: Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus.

Section: Peripheral B-Cell Neoplasms.

Morphologic schematics in this lecture are instructional drawings, not photomicrographs.