Acute Lymphoblastic Leukemia Lymphoma

Slide 1 · Acute Lymphoblastic Leukemia / Lymphoma

Precursor B- and T-lineage lymphoid neoplasms

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how arrested lymphoid maturation produces B-ALL and T-ALL.

Recognize marrow and blood morphology and lineage-defining immunophenotypes.

Connect infiltration sites to clinical manifestations and complications.

Interpret genetic, age-related and post-treatment prognostic findings.

Slide 3 · ALL is a malignancy of lymphoblasts

Immature B- or T-lineage precursor

Clonal genetic lesions and maturation arrest

Expanding population of nonfunctional lymphoblasts

The defining cell is an immature lymphoid precursor—not a mature lymphocyte.

Slide 4 · Leukemia and lymphoma describe a disease spectrum

Predominant form

Leukemic disease

Lymphomatous disease

Principal burden

Marrow and often peripheral blood

Discrete tissue mass

Shared biology

Immature lymphoid blasts

Immature lymphoid blasts

Possible evolution

Extramedullary lesions may occur

Marrow/blood dissemination may occur

Lineage and blast biology—not the initial site—establish the entity.

Slide 5 · Two major precursor lineages

Precursor lymphoid cell

B-lineage lymphoblast (B-ALL)

T-lineage lymphoblast (T-ALL)

Similar blast morphology can conceal profoundly different lineage-specific genetics.

Slide 6 · ALL predominates in childhood

ALL is as the most common cancer of childhood.

Most cases occur before age 15; Both B- and T-lineage disease can also affect adults.

Incidence varies with age and shows a modest male predominance.

Age at onset helps frame probability but cannot assign lineage.

Slide 7 · B-ALL usually presents as childhood leukemia

Precursor B-cell neoplasms constitute the majority of ALL.

Marrow-based disease is the usual presentation in children.

Less commonly, B-ALL produces a localized skin or bone mass.

B-cell precursor

Marrow predominance

Possible extranodal mass

Slide 8 · T-ALL frequently presents as a thymic mass

T-ALL is less common than B-ALL.

Adolescent males often present with a mediastinal/thymic mass.

A leukemic phase can be present initially or develop later.

T-cell precursor

Thymic involvement

Variable marrow disease

Slide 9 · Typical presentations differ without being exclusive

Feature

B-ALL

T-ALL

Peak pattern

Early childhood

Adolescence

Common initial form

Acute leukemia

Thymic or mediastinal tumor

Site overlap

Occasional soft-tissue masses

Frequent marrow/blood involvement

Microscopic appearance

Lymphoblasts

Lymphoblasts

Clinical pattern suggests lineage; Immunophenotyping establishes it.

Slide 10 · B-ALL peaks early in childhood

The incidence peak at approximately age 3 years.

The peak may reflect abundant normal pre-B precursors in early life.

The putative link between precursor abundance and incidence is an explanatory hypothesis—not a deterministic rule.

Slide 11 · T-ALL tracks thymic precursor biology

Thymus expands through childhood

Pre-T-cell populations are abundant in adolescence

T-ALL incidence peaks during adolescence

This age distribution is consistent with an origin in thymic precursors.

Slide 12 · Normal differentiation supplies the cellular context

Common lymphoid precursor

Bone marrow: Pre-B maturation

Thymus: Pre-T maturation

ALL arises at an immature stage along either of these lineages.

Slide 13 · Maturation arrest is the central pathogenic lesion

Altered developmental regulators

Differentiation program stalls

Immature self-renewing blasts accumulate

Tumor cells retain a stem-cell-like phenotype instead of becoming functional lymphocytes.

Slide 14 · A second class of alterations favors proliferation

Impaired differentiation

Cooperating growth/survival mutations

Aggressive clonal expansion

A developmental block alone is generally insufficient for overt ALL.

Slide 15 · ALL follows a multistep oncogenic model

One lesion perturbs differentiation or precursor-cell identity.

Additional driver alterations promote proliferation, survival, or altered signaling.

Sequencing evidence that relatively few driver mutations may suffice for overt ALL.

Slide 16 · Chromosomal abnormalities are very common

Approximately 90% of cases show numerical or structural changes.

Aneuploidy and balanced translocations are recognized patterns.

Their causal importance varies; Many also stratify immunophenotype or prognosis.

Numerical change

Structural rearrangement

Clinical correlation

Slide 17 · Hyperdiploidy and hypodiploidy are not equivalent

Feature

Hyperdiploidy

Hypodiploidy

Chromosome content

Increased number

Reduced number

Lineage

B-ALL

B-ALL

Prognostic direction

Generally favorable

Generally adverse

Interpretation

Correlate with context

Correlate with context

Aneuploid categories are prognostic descriptors, not morphologic diagnoses.

Slide 18 · B-ALL disrupts early B-lineage regulation

PAX5 / TCF3 / ETV6 / RUNX1 and related lesions

Disturbed precursor B-cell differentiation

Arrested B-lineage lymphoblast

The source groups many B-ALL lesions around altered hematopoietic regulation.

Slide 19 · T-ALL frequently involves NOTCH1

NOTCH1 is crucial to normal T-cell development.

Mutations in NOTCH1 are common in T-ALL.

The molecular profile is distinct from the typical genetic lesions of B-ALL.

NOTCH1 perturbation

Abnormal pre-T program

Clonal T lymphoblasts

Slide 20 · Growth pathways cooperate with lineage defects

Precursor maturation defect

Abnormal tyrosine kinase or RAS signaling

Expanded lymphoblast clone

The same clone can combine arrested differentiation with enhanced growth.

Slide 21 · BCR::ABL1 creates a constitutively active kinase

T(9;22) chromosomal rearrangement

BCR::ABL1 fusion oncoprotein

Persistent tyrosine kinase signaling

This alteration has direct therapeutic relevance in a subset of B-ALL.

Slide 22 · Genetic identity separates morphologic look-alikes

Level

B-ALL

T-ALL

Precursor

Bone marrow pre-B cell

Often thymic pre-T cell

Frequent genetic theme

B-lineage developmental regulators

NOTCH1 and T-lineage lesions

Morphology

Immature lymphoblast

Immature lymphoblast

Required resolution

Lineage markers ± genetics

Lineage markers ± genetics

Slide 23 · Marrow replacement explains the leukemic picture

Normal marrow

Blast-filled marrow

Original schematic — no microscopy image

Leukemic marrow becomes hypercellular and densely infiltrated by lymphoblasts.

Normal erythroid, myeloid and megakaryocytic production is suppressed.

Morphologic burden and hematopoietic failure are causally linked.

Slide 24 · Lymphoblast cytology: Small cytoplasm, large nucleus

Schematic lymphoblast (not a specimen)

Scant, usually basophilic cytoplasm with absent conspicuous granules.

Finely stippled chromatin with small, sharply outlined nucleoli.

Nuclear contour may be deeply indented or convoluted.

The schematic emphasizes classic features; Actual smears show a range of appearances.

Slide 25 · Nuclear chromatin helps—but does not decide

Lymphoblast nuclei commonly show more condensed chromatin than myeloblasts.

Nucleoli tend to be less conspicuous and cytoplasm less abundant.

There is important morphologic overlap between ALL and AML.

Do not make a definitive lineage call from H&E or cytology alone.

Slide 26 · High mitotic activity reflects aggressive growth

Rapid blast proliferation

Frequent apoptosis and cell turnover

Macrophage clearance of apoptotic debris

Macrophage–blast admixture can create a “starry-sky” appearance.

Slide 27 · A “starry sky” pattern is not lineage specific

Pale macrophages contain ingested apoptotic tumor-cell debris.

The surrounding field consists of numerous proliferating tumor cells.

The pattern can occur in other high-turnover lymphoid tumors.

Dark blast-rich background

Pale scavenger macrophages

High cell turnover

This is a growth pattern, not an ALL-specific diagnostic criterion.

Slide 28 · AML and ALL can be clinically indistinguishable

Feature

ALL

AML

Neoplastic cell

Lymphoblast

Myeloblast

Symptoms

Marrow failure ± infiltration

Marrow failure ± infiltration

Typical cytoplasm

Scant; Usually agranular

Often more abundant; Sometimes granular

Myeloperoxidase

Usually negative

Commonly positive in myeloid blasts

Final decision

Lineage immunophenotype

Lineage immunophenotype

Slide 29 · Cytochemical clues complement antibody studies

Stain

Lymphoblasts

Myeloblasts

Myeloperoxidase

Negative

Often positive

Periodic acid–Schiff

May show positive cytoplasmic material

Not the defining lineage test

Interpretation

Supportive only

Supportive only

Cytochemistry cannot replace a coherent antigen-based diagnosis.

Slide 30 · The diagnostic strategy integrates three data types

Morphology: Verify immature blast proliferation

Antigen expression: Determine B vs T lineage

Genetics: Define subtype and therapeutic markers

Every domain answers a different diagnostic question.

Slide 31 · TdT is a major immaturity marker

Terminal deoxynucleotidyl transferase is a DNA polymerase characteristic of precursor lymphoblasts.

TdT staining in more than 95% of ALL cases.

TdT positivity supports immaturity but does not alone establish B or T lineage.

Nuclear TdT

Precursor phenotype

Add lineage panel

Slide 32 · B-ALL: CD19 and PAX5 support B lineage

B lymphoblasts commonly express CD19 and the transcription factor PAX5.

CD10 is often present but may be absent in very immature cases.

Marker patterns reflect developmental stage and may vary among tumors.

Slide 33 · CD10 absence does not rule out B-ALL

Very immature precursor B-cell clone

CD19 / PAX5 expression may persist

CD10 may be negative

Lineage assignment requires the full immunophenotype, not a single antigen.

Slide 34 · Late pre-B tumors acquire additional markers

Early B precursor: CD19 ± CD10

Later pre-B maturation

CD20 and cytoplasmic IgM μ chain may appear

An ALL immunophenotype can be read as a snapshot of developmental arrest.

Slide 35 · T-ALL: Characteristic precursor T-cell antigens

Robbins commonly describes expression of CD1, CD2, CD5, and CD7.

Expression varies with the stage at which maturation is interrupted.

No single marker should be interpreted without the rest of the panel.

Slide 36 · Surface markers change along T-cell maturation

Phenotype

Earlier precursor T-ALL

Later precursor T-ALL

Surface CD3

Usually absent

Can be positive

CD4 and CD8

Usually absent

May become positive

Precursor antigens

Commonly retained

Variable with maturation

Distinguish surface CD3 from any assay of cytoplasmic CD3.

Slide 37 · B-ALL versus T-ALL: Practical marker map

Question

B-lineage evidence

T-lineage evidence

Immaturity

TdT often positive

TdT often positive

Lineage

CD19 / PAX5

CD2 / CD5 / CD7; CD3 stage-dependent

Maturation

CD10, CD20, cytoplasmic μ

CD1, CD4, CD8 variable

Interpretation

Pattern, not isolated stain

Pattern, not isolated stain

Slide 38 · Do not infer lineage from one positive stain

Identify blasts morphologically

Establish immaturity (e.g., TdT)

Integrate several lineage markers

The phenotype is interpreted as a coordinated profile.

Slide 39 · ALL often begins abruptly

Clinical illness may evolve over days to a few weeks.

The presenting syndrome may resemble AML despite different lineage genetics.

A rapidly developing constellation of cytopenias and infiltration signs should raise concern for acute leukemia.

Slide 40 · Marrow failure results from blast accumulation

Expanding intramedullary blasts

Crowding, growth-factor competition and other effects

Suppression of normal blood-cell formation

The hematologic phenotype is produced by loss of normal marrow function.

Slide 41 · Anemia explains fatigue and reduced exercise capacity

Reduced erythropoiesis

Lower red-cell mass

Fatigue, pallor and exercise intolerance

The marrow lesion has systemic physiologic consequences.

Slide 42 · Neutropenia predisposes to febrile infection

Suppressed normal granulopoiesis

Reduced effective neutrophil defense

Fever and bacterial or fungal infection risk

Fever may reflect infection in a cytopenic patient rather than tumor fever.

Slide 43 · Thrombocytopenia explains mucocutaneous bleeding

Blast replacement of megakaryocytic compartment

Reduced platelet output

Easy bruising, petechiae and bleeding

Blood-count abnormalities are mechanistically connected to marrow occupancy.

Slide 44 · Bone pain signals marrow expansion and periosteal spread

ALL frequently produces painful skeletal symptoms.

Mechanism: Expanding blast population in marrow and infiltration beneath periosteum.

This can be a prominent presenting clue in childhood disease.

Marrow expansion

Subperiosteal infiltration

Pain

Slide 45 · Nodal and visceral enlargement signal infiltration

Circulating/infiltrating blasts

Lymph nodes

Spleen and liver

Generalized lymphadenopathy, splenomegaly and hepatomegaly may accompany ALL.

Slide 46 · Mediastinal T-ALL creates compression risk

Thymic/mediastinal blast mass

Compression of airways and major veins

Respiratory distress or venous obstruction

A mediastinal syndrome in an adolescent strongly raises concern for T-ALL.

Slide 47 · CNS involvement results from meningeal spread

Lymphoblast infiltration of meninges

Raised pressure or neurologic dysfunction

Headache, vomiting or cranial nerve palsies

Neurologic symptoms have an anatomic basis in meningeal disease.

Slide 48 · Testicular enlargement is another infiltration clue

Testicular involvement can produce clinically apparent enlargement.

It is an extramedullary manifestation of the same precursor-cell malignancy.

Its presence reinforces the importance of examining sites outside marrow.

Slide 49 · Symptoms can be classified by anatomic mechanism

Dominant site

Mechanism

Typical manifestation

Bone marrow

Hematopoietic suppression

Anemia, infections, bleeding

Bones

Expansion/subperiosteal disease

Bone pain

Mediastinum

Tumor mass, compression

Airway/vascular syndrome

Meninges

Lymphoblast infiltration

Headache, vomiting, palsies

Slide 50 · ALL treatment outcomes differ strongly by age

Major improvements with pediatric chemotherapy.

Complete remission and cure are not synonymous.

Outcomes remain substantially less favorable in adults in the cited source.

Pediatric: Frequent remission

Many children cured

Adults: More guarded

Slide 51 · Pediatric remission and cure: Distinct endpoints

Outcome

Robbins 11th ed. Description

Interpretation

Complete remission

Approximately 95% of children

No clinically demonstrable disease by conventional criteria

Cure

Approximately 75–85% of children

Durable disease control

Adult cure

Fewer than half

Marked age-related difference

These are textbook-described values, not independently updated population estimates.

Slide 52 · Age is a powerful prognostic variable

Age grouping

Source-described association

Context

Under 2 years

Adverse

KMT2A rearrangements and CNS disease enriched

2–10 years

Favorable

Better average prognosis

Adolescence or adulthood

Adverse

Higher-risk presentation and treatment challenges

Slide 53 · High circulating blast count reflects burden

Large disseminated blast population

Elevated peripheral blast count

Worse prognosis at presentation

Counts >100,000 as an adverse feature; Verify units and laboratory context before clinical use.

Slide 54 · Several B-ALL cytogenetic findings are favorable

Hyperdiploidy is described as favorable compared with hypodiploidy.

Trisomy of chromosomes 4, 7 and 10 is a favorable constellation.

ETV6::RUNX1 fusion is another favorable marker account.

Slide 55 · ETV6::RUNX1 results from t(12;21)

T(12;21) rearrangement

ETV6::RUNX1 gene fusion

Favorable prognostic association in B-ALL

The molecular subtype has significance beyond its appearance on a blood smear.

Slide 56 · Infantile disease often carries KMT2A lesions

Presentation before age 2

Enrichment of KMT2A rearrangements / CNS involvement

Adverse average prognosis

The source frames age-related risk partly through distinct molecular biology.

Slide 57 · Minimal residual disease adds post-therapy prognosis

Therapy administered

Sensitive detection of persistent leukemia

Greater subsequent relapse risk

Molecular residual-disease assessment informs treatment decisions in both lineages.

Slide 58 · BCR::ABL1 is both a lesion and a drug target

B-ALL with BCR::ABL1

Constitutive tyrosine kinase activity

Kinase inhibitor + chemotherapy

The molecular alteration supplies a mechanistic rationale for targeted treatment.

Slide 59 · Other kinase rearrangements may be actionable

Cryptic rearrangements of kinase-encoding genes beyond ABL.

These are particularly relevant in adult B-ALL in the source text.

Molecular characterization can therefore affect therapy, not only diagnosis.

Slide 60 · CD19-directed CAR T-cell treatment

B-ALL expresses CD19

Engineered T cells recognize CD19

Anti-leukemic responses

Robbins also emphasizes potential severe toxicities and high financial cost.

Slide 61 · Why adult ALL remains challenging

Adults differ from children in the molecular spectrum of ALL.

Older patients may not tolerate intensive pediatric-type regimens.

Absence of targetable lesions can limit therapeutic options.

Slide 62 · Integrated case: Acute marrow failure

A child presents with rapidly progressive fatigue, fever, petechiae and severe cytopenias.

Marrow evaluation reveals an extensive population of immature blasts.

Which mechanism links the presenting symptoms to the marrow lesion?

Blast replacement suppresses erythropoiesis, granulopoiesis and platelet production.

Slide 63 · Integrated case: A mediastinal syndrome

An adolescent male develops respiratory symptoms and a large anterior mediastinal mass.

Biopsy shows lymphoblasts; Marrow examination also reveals blasts.

What lineage should be investigated first, and how is it confirmed?

T-ALL is an important possibility; Confirm with an integrated precursor T-lineage antigen panel.

Slide 64 · Integrated case: Uncertain blast lineage

Marrow aspirate shows small agranular blasts with fine chromatin.

TdT is positive; Myeloperoxidase is negative.

Can B-ALL versus T-ALL be established from these results?

No. Add B- and T-lineage markers (e.g., CD19/PAX5 and T-cell antigens).

Slide 65 · The diagnostic and prognostic questions differ

Question

Main evidence

Clinical significance

Is this an acute blast neoplasm?

Marrow/blood morphology

Recognize disease process

B or T lineage?

Antigen-expression profile

Classify ALL

What genetic subtype?

Cytogenetics/molecular testing

Prognosis and treatment options

Is leukemia persisting?

Residual disease testing

Refine post-treatment risk

Slide 66 · Core principles to retain

ALL is an aggressive malignancy of immature B- or T-lineage lymphoblasts.

Developmental blockade plus cooperating growth lesions creates an expanding blast clone.

Marrow replacement causes cytopenias; Infiltration explains mass effects and CNS findings.

Immunophenotyping resolves lineage; Genetics and residual-disease assays refine risk.

Slide 67 · Primary reference and image provenance

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. Chapter 13, “Acute Lymphoblastic Leukemia/Lymphoma,” pp. 539–543.

All illustrations in this lecture are original, editable educational schematics—not histologic or clinical specimens.

Quantitative treatment/prognostic values are reported as described in the textbook and were not independently updated.