Primary CNS Lymphoma

Slide 1 · Primary CNS lymphoma

Pathogenesis • morphology • diagnostic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Define primary CNS lymphoma and distinguish secondary CNS lymphoma.

Explain the host-related EBV and PD-L1 immune-evasion contexts.

Recognize the characteristic distribution, histology and CD20 phenotype.

Integrate morphology, lineage and anatomic context in diagnosis.

Slide 3 · The entity is an extranodal lymphoid neoplasm

Primary CNS lymphoma is a lymphoma arising within the CNS compartment.

The designation “primary” distinguishes it from spread of a lymphoma originating outside the CNS.

The predominant histologic type is diffuse large B-cell lymphoma (DLBCL).

Brain parenchyma is a major site; Ocular involvement may accompany CNS disease.

Slide 4 · Why this tumor is not a glioma

Primary CNS lymphoma

Diffuse glioma

Malignancy of lymphoid (usually B-cell) lineage

Infiltrates brain parenchyma

Typically expresses B-cell antigens

Glial lineage rather than lymphoid lineage

May infiltrate brain parenchyma

Classification depends on glial and molecular features

Slide 5 · The word “primary” is an anatomic statement

Primary CNS lymphoma

Secondary CNS lymphoma

Initial tumor arises in CNS compartment

Extracranial involvement is rare and generally late

Can affect brain and eye

Systemic lymphoma precedes or accompanies CNS involvement

Usually involves meninges or CSF rather than brain parenchyma

May yield lymphoma cells on CSF cytology

Slide 6 · Relative frequency: Uncommon, clinically consequential

2%

Of extranodal lymphomas

1%

Of intracranial tumors

These are Robbins 11e textbook frequencies; Denominators are different.

Slide 7 · Two host contexts frame the disease

Immunosuppressed host

Host without known immunosuppression

AIDS and post-transplant immunosuppression are classic settings

Primary CNS lymphoma is a prominent CNS neoplasm in this population

Tumor B cells are usually EBV infected

Occurs over a wide adult age range

Frequency increases after age 60

PDL1 amplification/overexpression is described in many tumors

Slide 8 · AIDS is an established high-risk setting

Primary CNS lymphoma as the most common CNS neoplasm in immunosuppressed individuals.

Advanced HIV-associated immunodeficiency is a major example.

Many AIDS-associated lesions as EBV-positive B-cell tumors.

Effective antiretroviral therapy has reduced secondary neurologic effects of HIV.

Slide 9 · Post-transplant immunosuppression

Transplant recipient

Immunosuppressive treatment

Impaired T-cell immune control

Reduced surveillance

EBV-associated B-cell proliferation

Relevant pathobiologic setting

Primary CNS lymphoma

Possible CNS presentation

Slide 10 · Older age matters without immunosuppression

The age range in non-immunosuppressed patients is relatively broad.

Disease frequency rises after 60 years of age.

Age is epidemiologic context—not a stand-alone diagnostic criterion.

The characteristic pathology remains that of an aggressive B-cell lymphoma.

Slide 11 · Host context changes mechanistic expectations

Characteristic

Immunosuppressed

Not immunosuppressed

Risk setting

AIDS or transplant therapy

Frequency increases after age 60

Commonly emphasized mechanism

Latent EBV infection in B cells

PDL1 amplification/overexpression in many tumors

Morphologic clue

Necrosis often prominent

No specific necrosis rule stated

Slide 12 · T-cell surveillance is central to the story

Host T-cell immunity

Controls virally infected or abnormal B cells

Immune deficiency

Weakens control of susceptible B-cell clones

B-cell tumor growth

Can emerge within CNS

Conceptual synthesis immunodeficiency-associated DLBCL.

Slide 13 · EBV latency in malignant B cells

In immunosuppression-associated primary CNS lymphoma, malignant B cells are usually latently infected by Epstein–Barr virus.

The virus is a biologic association of the malignant B-cell population, not a histologic stain itself.

The textbook supports EBER in situ hybridization as the tissue assay for detecting EBV.

The strength of the EBV association depends on host context.

Slide 14 · EBV detection is a tissue-level observation

Tumor section

Malignant lymphoid infiltrate

EBER in situ hybridization

Viral RNA signal

Interpretation

EBV within tumor population

Slide 15 · What a positive EBER signal supports

EBERs are small RNAs encoded by the Epstein–Barr virus genome.

EBER in situ hybridization identifies viral RNA within cells.

Detection in the malignant population supports an EBV-associated lymphoma context.

EBER detection must be interpreted together with cell morphology and lineage.

Slide 16 · Do not equate all CNS lymphomas with EBV

EBV especially strongly to immunosuppressed hosts.

A CNS lymphoma in an immunocompetent patient need not follow that EBV-associated pattern.

The immunocompetent setting has a separate PD-L1 immune-evasion association.

A universal “EBER-positive” expectation would misrepresent the textbook.

Slide 17 · DLBCL provides the cellular identity

Most primary CNS lymphomas are diffuse large B-cell lymphomas.

DLBCL is a mature B-cell malignancy.

“Diffuse” describes a non-follicular tissue growth pattern; “large B-cell” describes cell size and lineage.

Primary CNS presentation does not make the cells a glial neoplasm.

Slide 18 · DLBCL cytology: Large atypical lymphoid cells

Typical cells are several times larger than resting small lymphocytes.

Nuclei can be round or oval, sometimes irregular.

Open/vesicular chromatin and prominent nucleoli are common.

Cytologic variation within DLBCL is substantial.

Slide 19 · DLBCL cytology: Nucleoli and cytoplasm

Nuclear details

Cytoplasm and growth

Vesicular chromatin

One prominent central or several peripheral nucleoli

Occasionally irregular or lobated forms

Moderately abundant cytoplasm; Pale or basophilic

Diffuse sheets of malignant cells

Microscopic phenotype requires B-cell marker confirmation

Slide 20 · The B-cell phenotype has diagnostic value

The primary CNS lymphoma excerpt explicitly identifies CD20 expression.

The general DLBCL section also describes CD19/CD20 positivity.

CD10 and BCL6 can vary among systemic DLBCLs.

CD20 provides lineage support, but must be interpreted in a tissue context.

Slide 21 · CD20 is a lineage marker, not an anatomic marker

What CD20 addresses

What CD20 cannot answer alone

Is the malignant population B-cell lineage?

Does lymphoma belong in the diagnostic frame?

Does the immunophenotype support a B-cell neoplasm?

Whether CNS involvement is primary or secondary

Whether tumor B cells harbor EBV

Whether a lesion is multifocal or periventricular

Slide 22 · PDL1 amplification is a different route

Amplification and overexpression of the PDL1 gene in many primary CNS large B-cell lymphomas without immunosuppression.

The encoded protein PD-L1 acts as an immune checkpoint ligand.

Increased checkpoint signaling suppresses anti-tumor T-cell responses.

This mechanism is distinct from EBV latency in immunodeficiency.

Slide 23 · PD-1–PD-L1 checkpoint signaling

Tumor B cell

PD-L1 ligand

Host T cell

PD-1 receptor

Inhibitory signaling

Reduced T-cell activation

Slide 24 · How PD-L1 overexpression favors escape

PDL1 alteration

Amplification/overexpression

Tumor-cell PD-L1

More inhibitory ligand

PD-1 on T cell

Inhibitory signaling

Dampened T-cell response

Immune evasion

Slide 25 · Checkpoint blockade is an investigational context

Immune-checkpoint inhibition is designed to interrupt PD-1/PD-L1 mediated T-cell suppression.

The Robbins primary CNS lymphoma section reports ongoing trials of checkpoint inhibitors.

It does not provide response rates, approved regimens or outcomes for those trials.

No efficacy estimate is asserted on this slide.

Slide 26 · Two biologic settings—do not collapse them

Dimension

EBV-associated context

PD-L1 context

Host emphasis

Immunosuppression

Without immunosuppression

Key finding

Latent EBV infection

PDL1 gene amplification/overexpression

Relevant detection

EBER in situ hybridization

PD-L1 pathway analysis (conceptual)

Textbook distinction

Association is usually present

Described in many tumors

Slide 27 · Macroscopic location: Deep subcortical brain

Simplified anatomy

Masses often occupy deep subcortical tissue.

A solitary or multifocal pattern is possible.

Diagram is schematic.

Slide 28 · Periventricular spread is common

Simplified anatomy

Lesions can border ventricular spaces.

Periventricular extension is common.

Diagram is schematic.

Slide 29 · One mass or multiple masses

Single lesion

Multiple lesions

A solitary CNS lymphoma mass is possible

Can still infiltrate the surrounding parenchyma

Macroscopy alone does not determine lineage

Multiple masses are frequent

Multifocality is compatible with primary origin

Distribution does not by itself demonstrate systemic disease

Slide 30 · Ocular involvement belongs to CNS lymphoma biology

Primary brain lymphoma may also involve the eye.

The retina has tissue layers derived developmentally from the brain.

Primary retinal lymphoma as predominantly DLBCL.

Ocular disease does not automatically establish lymphoma outside the CNS category.

Slide 31 · Primary retinal lymphoma: The eye–brain link

Neurosensory retina / RPE

CNS-derived retinal tissue

Primary retinal lymphoma

Usually DLBCL

Optic nerve pathway

Brain spread may occur

Slide 32 · Vitreous aspiration can establish retinal disease

Primary retinal lymphoma may mimic uveitis clinically.

Robbins specifies demonstration of lymphoma cells in vitreous aspirates for diagnosis.

Ocular sampling evaluates an intraocular population; It is not identical to CSF cytology.

Interpret ocular involvement in the context of the CNS lymphoma distribution.

Slide 33 · Extracranial disease is unusual in primary CNS lymphoma

Lymph-node or bone-marrow involvement outside the CNS is rare.

When it occurs, it as a late complication.

The “primary” designation requires attention to the initial distribution.

This differs from a systemic lymphoma extending into CNS structures.

Slide 34 · The site of secondary CNS involvement differs

Primary CNS lymphoma

Secondary CNS lymphoma

Typically affects brain parenchyma

Often deep/periventricular and sometimes multifocal

May affect the eye

Systemic lymphoma may involve the CNS

Meningeal and CSF compartments are characteristic

Parenchymal brain involvement is relatively rare

Slide 35 · CSF cytology can reveal secondary lymphoma

Systemic lymphoma

CNS involvement suspected

CSF compartment

Malignant lymphoid cells may enter

Lumbar puncture sample

Cells can be recognized cytologically

Slide 36 · Map the CNS compartments before assigning origin

Brain parenchyma

Usual primary CNS pattern

Eye / retina

Can participate in CNS lymphoma

Meninges + CSF

Common secondary CNS route

Lymph nodes / marrow

Rare and late in primary CNS lymphoma

Slide 37 · Gross appearance: Soft gray-white masses

A soft consistency and gray-white appearance.

The disease can form one or more masses.

Masses often occupy deep subcortical parenchyma.

Their superficial color does not establish a specific lymphoma subtype.

Slide 38 · Tumor invades the brain rather than merely compressing it

Malignant lymphoid cells infiltrate the surrounding brain parenchyma.

This microscopic infiltration is a defining relationship to host tissue.

The tumor can coexist with a grossly visible mass.

Anatomic infiltration should be conveyed in both low-power and high-power interpretation.

Slide 39 · Perivascular accumulation is characteristic

Schematic

Dark ovals: Malignant B cells

Central pale area: Vessel lumen

Tumor cells cluster around vessel and infiltrate surrounding parenchyma.

Slide 40 · Interpreting perivascular lymphoma on a section

Identify the vessel lumen and its wall first.

Determine whether malignant lymphoid cells accumulate around the vessel.

Assess adjacent parenchyma for diffuse infiltration by the same cells.

Link the pattern to CD20 expression and cytologic malignancy.

Slide 41 · Angiocentric distribution ≠ intravascular growth

Primary CNS lymphoma

Intravascular large B-cell lymphoma

Malignant cells infiltrate brain tissue

Perivascular accumulation is common

Tumor cells are described outside vessel walls

Preferential proliferation within small venules

May produce neurologic symptoms due to brain vessels

Often does not form conventional tissue masses

Slide 42 · A high proliferative index supports aggressiveness

High proliferative indices in primary CNS lymphoma.

A proliferation-associated stain assesses cell cycling, not B-cell lineage.

No numeric Ki-67 threshold is provided in the primary CNS lymphoma section.

The finding complements—but cannot substitute for—morphology.

Slide 43 · Necrosis has a host-related pattern

With immunosuppression

Without immunosuppression

Necrosis is often prominent

EBV is usually detectable in malignant B cells

EBER in situ hybridization is explicitly described

PD-L1 pathway alterations

A distinct necrosis percentage or threshold is not given

Necrosis alone cannot assign the biologic context

Slide 44 · Gross and microscopic observations connect

Level

Observation

Interpretive relevance

Gross

Soft gray-white mass(es)

Macroscopic neoplasm

Distribution

Deep subcortical/periventricular

Characteristic CNS topography

Histology

Infiltrative/perivascular lymphoid cells

Parenchymal growth pattern

Immunophenotype

CD20 positive B cells

Lymphoid lineage

Host context

EBER in immunosuppression

EBV-associated biology

Slide 45 · Three distinct tissue questions

H&E morphology

Are atypical lymphoid cells present?

CD20 immunophenotype

Is there B-cell lineage support?

EBER in situ hybridization

Is EBV detectable in tumor cells?

Slide 46 · Do not confuse diagnostic and biologic tests

Observation

What it tests

What it does not establish

CD20

B-cell lineage

Primary rather than secondary origin

EBER ISH

Latent EBV in examined cells

Every possible EBV-negative PCNSL excluded

Proliferation marker

Cell-cycle activity

Specific lineage

PD-L1 pathway

Immune evasion biology

Tissue-of-origin on its own

Slide 47 · The diagnostic synthesis needs four axes

Anatomic context

CNS-centered vs systemic

Morphology

Large malignant lymphoid cells

Pattern

Parenchymal + perivascular infiltration

Phenotype / virus

CD20 ± EBER evidence

Slide 48 · Differential diagnosis: Diffuse glioma

CNS lymphoma

Diffuse glioma

Malignant lymphoid-cell morphology

CD20 supports B-cell origin

Characteristic perivascular tumor accumulation

Glial neoplastic lineage

Molecular and histologic glial classification

Infiltration may be present, but lineage differs

Slide 49 · Differential diagnosis: Metastasis

Primary CNS lymphoma

Metastatic tumor

Primary lymphoid neoplasm in CNS

B-cell lineage is expected

Systemic spread is rare and generally late

Originates outside CNS

Carcinomas comprise the commonest metastases

CNS involvement follows dissemination from primary elsewhere

Slide 50 · Differential diagnosis: Meningioma

Primary CNS lymphoma

Meningioma

Usually intraparenchymal, often deep

Infiltrative malignant lymphoid cells

CD20 B-cell phenotype

Usually attached to dura

Arises from meningothelial/arachnoid cells

Often compresses brain rather than diffusely infiltrating it

Slide 51 · The highest-impact differential is secondary lymphoma

Dimension

Primary CNS lymphoma

Secondary CNS lymphoma

Initial disease

Within CNS

Elsewhere in body

Typical CNS site

Parenchyma (often deep)

Meninges/CSF

Eye

May be involved

Not the defining distinction

Systemic spread

Rare, late

Present by definition of systemic origin

CSF cells

Not specified as required

May establish involvement

Slide 52 · Clinical effects depend on site as well as cell type

That location strongly modifies outcomes for any CNS mass.

Brain infiltration can disrupt neurologic function even without extracranial spread.

Deep/periventricular involvement places tumor within functionally important tissue.

Do not infer a particular symptom complex without patient-specific evidence.

Slide 53 · Biologic behavior is aggressive

Most primary CNS lymphomas are DLBCL.

The textbook characterizes them as aggressive tumors.

Outcomes are generally worse than comparable histologic lymphomas at non-CNS sites.

The excerpt does not quantify survival or specify a therapeutic regimen.

Slide 54 · Why systemic DLBCL data cannot simply be transferred

What Robbins establishes

What differs in CNS

Shared DLBCL histologic identity

CD20-positive B-cell malignant population

Aggressive biology at both sites

CNS anatomic compartment and tissue interaction

Often different host/immune context

Textbook states poorer outcomes at CNS site

Slide 55 · Application case: Immunosuppressed host

Hypothetical teaching scenario

An immunosuppressed adult has several deep cerebral masses. A biopsy shows a CD20-positive infiltrative large B-cell lymphoma with prominent necrosis.

Which additional tissue assay is especially informative in this setting?

Slide 56 · Case reasoning: Immunosuppression and EBV

EBER in situ hybridization

Immunosuppressed PCNSL with latent EBV infection.

Prominent necrosis is a compatible host-associated morphologic feature.

EBER positivity in tumor cells supports EBV-associated pathobiology.

Slide 57 · Application case: Ocular involvement

Hypothetical teaching scenario

An older adult has ocular inflammation clinically resembling uveitis. Vitreous sampling reveals malignant large B lymphocytes.

What CNS association should enter the anatomic interpretation?

Slide 58 · Case reasoning: Retina and CNS

Primary retinal lymphoma may accompany or spread to brain lymphoma.

Primary retinal lymphoma as usually DLBCL.

It can mimic uveitis and is evaluated with vitreous aspirates.

Brain spread via the optic nerve is recognized in the retinal lymphoma section.

Slide 59 · Application case: Systemic lymphoma

Hypothetical teaching scenario

A patient already has systemic B-cell lymphoma. Malignant lymphoid cells are identified in cerebrospinal fluid; No parenchymal tumor is demonstrated.

Does this presentation favor primary or secondary CNS involvement?

Slide 60 · Case reasoning: Secondary involvement

Secondary CNS lymphoma

The lymphoma originated outside the CNS.

CNS extension from systemic lymphoma commonly involves meninges or CSF.

CSF malignant cells can establish CNS involvement in that setting.

Slide 61 · Morphology exercise: Locate the tumor cells

Schematic

Identify the vessel, tumor-cell distribution, and supporting immunophenotype.

Slide 62 · Morphology exercise: Interpret the pattern

Perivascular accumulation within an infiltrative B-cell lymphoma

Cells concentrate around the blood vessel rather than only inside its lumen.

The pattern supports the PCNSL morphologic constellation.

CD20 confirmation is needed to establish the B-cell phenotype.

Slide 63 · Five features to retain

Axis

Primary CNS lymphoma

Identity

Usually DLBCL

Host

Immunosuppression; Or older adults without it

Distribution

Deep subcortical, often multifocal/periventricular

Histology

Parenchymal infiltration with perivascular accumulation

Phenotype/virus

CD20; EBER commonly detectable in immunosuppressed hosts

Slide 64 · Integrating mechanism, phenotype and anatomy

Susceptible host / immune evasion

EBV or PD-L1 context

Aggressive B-cell lymphoma

Usually DLBCL / CD20

CNS tissue pattern

Deep, periventricular, angiocentric

Primary vs secondary assessment

Interpret anatomic distribution

Slide 65 · Source-specific boundaries of this lecture

Textbook focus: Host, lineage, gross/microscopic morphology and CNS distribution.

Mechanistic context drawn from the same Robbins edition (Chapters 6, 7 and 13).

Eye–brain relationship drawn from the same edition (Chapter 29).

Current clinical guidelines, drug protocols and molecular taxonomies were not independently reviewed for this deck.

Slide 66 · Primary references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Ch. 28, p. 1182 — Primary CNS Lymphoma.

Robbins, Cotran & Kumar. 11th ed. Ch. 13, pp. 546–547 — Diffuse Large B-Cell Lymphoma.

Robbins, Cotran & Kumar. 11th ed. Chs. 6–7 — PD-1/PD-L1 and tumor immune evasion.

Robbins, Cotran & Kumar. 11th ed. Ch. 29, p. 1207 — Retinal Lymphoma.