Primary CNS lymphoma is an aggressive extranodal non-Hodgkin lymphoma, usually diffuse large B-cell type, arising within the brain, spinal cord, leptomeninges, or eyes without systemic involvement.

Primary CNS Lymphoma (PCNSL)

Primary CNS lymphoma (PCNSL) is a rare, aggressive extranodal non-Hodgkin lymphoma (NHL) that arises within and is confined to the central nervous system — that is, the brain parenchyma, leptomeninges, spinal cord, and/or eyes (vitreoretinal compartment) — without evidence of systemic lymphoma at the time of diagnosis. ^[1]^[2]

Let's break the name down:

"Primary" = the tumour originates in the CNS, not metastasised from elsewhere (i.e. it is not secondary CNS involvement by a systemic lymphoma).
"CNS" = confined to the brain, spinal cord, leptomeninges, and eyes (the eye is considered an extension of the CNS embryologically because the retina derives from the diencephalon).
"Lymphoma" = a clonal neoplasm of lymphoid cells — here, almost always diffuse large B-cell lymphoma (DLBCL), the non-germinal-centre (activated B-cell / ABC) subtype.

Key distinction: If a patient has known systemic (nodal or extranodal) lymphoma that subsequently involves the CNS, that is called secondary CNS lymphoma — a completely different entity with different epidemiology, biology, and management. PCNSL by definition requires exclusion of disease outside the CNS (including bone marrow and testes). ^[1]^[2]

Parameter	Detail
Incidence	~0.5 per 100,000 person-years in the general population; ~3–4% of all primary brain tumours ^[1]^[2]
Proportion of NHL	~1–2% of all NHLs; ~2–3% of all extranodal NHLs ^[2]
Age at diagnosis	Bimodal: immunocompromised patients present younger (30–40 y); immunocompetent patients present older (median 60–65 years, peak 55–75 y)
Sex	Male predominance ~1.5–2:1
Trend over time	Incidence in immunocompetent elderly has been rising steadily over recent decades (reason incompletely understood); incidence in HIV patients has declined dramatically since widespread ART
Geography / Hong Kong relevance	Rare overall. Hong Kong's relatively high hepatitis B seroprevalence and immunosuppressive therapy use (e.g. post-renal or liver transplant — HK has an active transplant programme) contribute a small pool of at-risk patients

EBV, immunosuppression → primary CNS lymphoma — this association is highlighted as a brain tumour risk factor. ^[1]

Epidemiology Pearl

In the immunocompromised population (HIV/AIDS, post-transplant), nearly 100% of PCNSL is EBV-driven. In the immunocompetent population, EBV is found in fewer than 10–15% of cases. This has major implications for diagnosis (EBV PCR in CSF) and pathogenesis.

3. Risk Factors

Risk Factor	Mechanism / Detail
HIV/AIDS	The single strongest risk factor. Before ART, ~2–6% of AIDS patients developed PCNSL. Risk rises dramatically when CD4 < 50 cells/μL. HIV itself does not directly transform B cells; rather, profound T-cell immunodeficiency allows unchecked EBV-driven B-cell proliferation within the immune-privileged CNS. Since widespread ART, incidence has dropped > 50%. ^[3]
Post-transplant immunosuppression	Solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) recipients on long-term immunosuppression (e.g. calcineurin inhibitors, anti-thymocyte globulin, mycophenolate) are at risk of post-transplant lymphoproliferative disorder (PTLD), which can manifest as cerebral lymphoma — a type of PTLD. ^[4] The risk correlates with cumulative immunosuppressive dose and is highest in the first year post-transplant.
Congenital immunodeficiency	Rare congenital cell-mediated immunodeficiencies (e.g. Wiskott-Aldrich syndrome, ataxia-telangiectasia, common variable immunodeficiency, severe combined immunodeficiency) carry increased lymphoma risk, including PCNSL
Iatrogenic immunosuppression for autoimmune disease	Long-term methotrexate, azathioprine, or biologic agents (e.g. anti-TNF) for RA, SLE, IBD etc. → EBV-associated lymphoproliferative disease including PCNSL

EBV infection is directly implicated in PCNSL pathogenesis in immunocompromised patients. ^[1]^[5]
EBV latent membrane proteins (LMP1, LMP2A) mimic constitutive CD40 and BCR signalling respectively, driving B-cell survival and proliferation.
In immunocompetent PCNSL, EBV is usually absent — other pathogenic mechanisms dominate (see §5 Pathophysiology).

Independent risk factor in immunocompetent patients (incidence peaks 55–75 y).
Age-related decline in immune surveillance ("immunosenescence") may partially explain this.

No consistent association with ionising radiation (unlike gliomas and meningiomas).
No proven dietary, occupational, or genetic predisposition in immunocompetent PCNSL (unlike systemic DLBCL, where certain HLA subtypes and SNPs are implicated).

High Yield — Risk Factors

Risk factors for primary brain tumours as taught in the brain tumours lecture:

High-dose ionising radiation → meningioma & gliomas (the only proven environmental factor!)
EBV, immunosuppression → primary CNS lymphoma
Familial syndromes e.g. NF1, NF2, VHL, TSC, MEN1, Turcot syndrome, Li-Fraumeni syndrome

Note: radiation and familial syndromes are not risk factors for PCNSL specifically — they apply to other primary brain tumours. For PCNSL, think immunosuppression + EBV. ^[1]

4. Anatomy and Function — The Immunological Privilege of the CNS

Understanding why lymphoma develops in the brain requires understanding the unique immunological environment of the CNS.

The BBB is formed by tight junctions between brain capillary endothelial cells, reinforced by astrocyte foot processes and pericytes.
It restricts passage of large molecules, most drugs, and immune cells from the systemic circulation into the brain parenchyma.
Why this matters for PCNSL:
1. The CNS is relatively "immune-privileged" — there is limited T-cell surveillance. This means an EBV-infected B cell that enters the CNS may proliferate without the cytotoxic T-cell control that would normally destroy it systemically.
2. The BBB limits drug delivery — many standard chemotherapy agents (e.g. CHOP drugs like doxorubicin and vincristine) penetrate the BBB poorly, which is why R-CHOP does not work for PCNSL and high-dose methotrexate (HD-MTX) is used instead (MTX achieves cytotoxic CSF concentrations at high doses).

The leptomeninges (pia + arachnoid) are bathed in CSF, which circulates from the choroid plexus through the ventricular system to the subarachnoid space.
PCNSL has a propensity for leptomeningeal dissemination (10–25% at diagnosis), spreading via CSF pathways — similar to other CNS malignancies like medulloblastoma.
This is why CSF cytology is part of the diagnostic work-up.

PCNSL has a strong predilection for deep periventricular white matter structures — the corpus callosum, basal ganglia, thalamus, and periventricular regions.
These areas are rich in small penetrating vessels and are thought to be where circulating B cells enter the brain parenchyma via the Virchow-Robin perivascular spaces.
The angiocentric (perivascular) growth pattern is a histological hallmark of PCNSL.

The retina is an embryological extension of the diencephalon.
Vitreoretinal lymphoma (intraocular lymphoma) occurs in ~15–25% of PCNSL patients and is considered a manifestation of the same disease. Conversely, ~50–80% of patients with primary vitreoretinal lymphoma eventually develop brain involvement.

5. Etiology and Pathophysiology

Almost all PCNSL (~95%) is diffuse large B-cell lymphoma (DLBCL), specifically the activated B-cell (ABC) / non-germinal centre subtype.
Rare subtypes: T-cell PCNSL (~2–5%), Burkitt lymphoma, low-grade (indolent) B-cell lymphoma, lymphoblastic lymphoma — all extremely rare.
DLBCL is the most common aggressive NHL ^[2], and when it arises primarily in the CNS, it is biologically distinct from systemic DLBCL.

5.2 Pathogenesis — Why Do B Cells Proliferate in the Brain?

The brain normally lacks lymphoid tissue and resident B cells. So how does a B-cell lymphoma arise here? There are two leading models:

EBV infects B cells systemically (EBV has tropism for B cells via the CD21 receptor).
In a healthy host, EBV-infected B cells are kept in check by cytotoxic CD8+ T cells.
In profound immunosuppression (HIV with CD4 < 50, post-transplant), T-cell surveillance fails.
EBV-infected B cells that traffic through the CNS (via the Virchow-Robin perivascular spaces) proliferate unchecked in this immune-privileged site.
EBV latent proteins (LMP1 mimics CD40 → NF-κB activation; LMP2A mimics BCR signalling) provide constitutive survival signals → clonal expansion → lymphoma.

A pre-malignant or fully transformed B cell (likely a post-germinal centre, ABC-type cell) acquires genetic alterations systemically.
This cell expresses chemokine receptors (e.g. CXCR4, CXCR5) and adhesion molecules that allow it to cross the BBB and home to the brain.
Once inside the CNS, the cell receives survival signals from the brain microenvironment (e.g. IL-4, BAFF from astrocytes and microglia) and loses the ability to egress.
Accumulation of oncogenic hits → clonal proliferation.

PCNSL has a distinct molecular profile compared to systemic DLBCL:

Pathway	Aberration	Frequency	Significance
NF-κB pathway	Gain-of-function mutations in MYD88 (esp. MYD88 L265P)	50–80%	MYD88 is an adaptor protein in Toll-like receptor signalling → constitutive NF-κB activation → survival. This is the most common mutation in PCNSL and is far more frequent than in systemic DLBCL.
BCR signalling	Gain-of-function mutations in CD79B	20–40%	Constitutive BCR signalling → NF-κB + PI3K/AKT activation
Immune evasion	Homozygous deletion or mutation of HLA class I/II genes; B2M loss	Very common	Loss of MHC → tumour cannot be recognised by T cells → explains immune evasion even in immunocompetent hosts
Immune evasion	PD-L1/PD-L2 copy number gains (9p24.1)	~30%	Upregulated PD-L1 on tumour cells → T-cell exhaustion
Cell cycle	CDKN2A (p16) homozygous deletion	~40–60%	Loss of cell cycle checkpoint → unchecked proliferation
Epigenetic	TBL1XR1, KMT2D mutations	Variable	Epigenetic dysregulation

MYD88 L265P — The PCNSL Signature Mutation

The MYD88 L265P point mutation is the single most common and characteristic genetic event in PCNSL. It activates the NF-κB survival pathway, is also found in Waldenström's macroglobulinaemia and testicular DLBCL (which shares biology with PCNSL), and is a potential therapeutic target (e.g. BTK inhibitors like ibrutinib block downstream signalling from MYD88/BCR). It can also be detected in CSF cell-free DNA as a diagnostic biomarker.

Pathophysiological Process	Clinical Consequence
Mass effect in deep cerebral structures (periventricular, corpus callosum, basal ganglia)	Focal neurological deficits (hemiparesis, aphasia, visual field defects), personality/cognitive change
Raised intracranial pressure (↑ICP) from tumour bulk ± peritumoral oedema ± obstructive hydrocephalus	Headache (worse in morning), vomiting, papilloedema, ↓consciousness
Periventricular and multifocal involvement → disruption of white matter tracts	Cognitive/behavioural change (often prominent and early), psychomotor slowing
Leptomeningeal seeding via CSF dissemination	Cranial nerve palsies, radiculopathy, cauda equina syndrome
Vitreoretinal infiltration	Floaters, blurred vision, painless visual loss
Diffuse cerebral infiltration → cortical irritation	Seizures (~10–15%)
Tumour necrosis and BBB disruption → vasogenic oedema	Worsening mass effect and neurological deficits
Steroid sensitivity of lymphoma cells (glucocorticoid receptor-mediated apoptosis) → rapid tumour lysis with corticosteroids	The "ghost tumour" / "vanishing tumour" phenomenon — dramatic radiological improvement after corticosteroids, which can mask the diagnosis and delay definitive biopsy. This is why steroids should be avoided before biopsy whenever clinically safe.

6. Classification

PCNSL is classified under "Lymphomas of the CNS" in the WHO Classification of Tumours of the Central Nervous System:

Diffuse large B-cell lymphoma of the CNS — the overwhelming majority (~95%)
Rare subtypes:
- T-cell and NK/T-cell lymphoma of the CNS
- MALT lymphoma of the dura (indolent, excellent prognosis)
- Intravascular large B-cell lymphoma (may present with CNS symptoms)
- Low-grade B-cell lymphoma of the CNS (very rare)
- Lymphomatoid granulomatosis (EBV-associated, angiocentric)

PCNSL (DLBCL type) is considered a high-grade (aggressive) neoplasm. There is no formal WHO grade I–IV applied as with gliomas, but behaviourally it is analogous to WHO Grade IV in aggressiveness.

Compartment	Frequency	Notes
Brain parenchyma	~90%	Most common; deep periventricular structures favoured
Leptomeninges	~10–25% (at diagnosis)	May be sole site in ~5%
Eyes (vitreoretinal)	~15–25% (at diagnosis)	May precede brain disease by months–years
Spinal cord (intramedullary)	< 1%	Extremely rare

Setting	Pathology	EBV Association	Prognosis
Immunocompetent	DLBCL (ABC type)	~10–15%	Median OS 3–5 y with optimal therapy
HIV/AIDS-associated	DLBCL, often with immunoblastic or plasmablastic features	~100%	Historically very poor; improved with ART + chemotherapy
Post-transplant (PTLD)	Monomorphic PTLD (DLBCL type)	~90–100%	Variable; reduction of immunosuppression ± rituximab may induce remission
Iatrogenic immunosuppression	DLBCL	Variable	May remit with withdrawal of immunosuppressive agent

7. Clinical Features

The concept of malignancy is different in primary intracranial tumours — a histologically benign-looking tumour can display aggressive clinical behaviour, and a histologically malignant-looking tumour rarely shows extracranial metastasis. Extracranial metastasis rare in brain tumours (∵ no lymphatic drainage) → TNM staging not useful. ^[1]

Onset: Subacute (days to weeks), occasionally more insidious.
Median symptom duration before diagnosis: ~2–3 months in immunocompetent; can be shorter in immunocompromised.
PCNSL typically presents like any other intracranial mass — but certain features are more suggestive.

7.2 Symptoms (with Pathophysiological Basis)

Why: PCNSL preferentially involves deep periventricular white matter, corpus callosum, and basal ganglia — structures critical for executive function, processing speed, and personality. Unlike metastases which tend to be cortical, PCNSL disrupts white matter tracts connecting frontal-subcortical circuits.
What the patient reports:
- Personality change (apathy, disinhibition, emotional blunting)
- Memory loss, confusion, difficulty with concentration
- Psychomotor slowing — "the patient seems slow"
- Frank dementia in advanced cases

PCNSL Mimicking Dementia

In elderly patients, PCNSL is a treatable cause of "a short course of dementia" — rapidly progressive dementia over weeks to months. Always consider PCNSL (and other intracranial SOLs) in the differential of subacute/rapidly progressive cognitive decline, especially if there are accompanying focal signs, headache, or personality change. A contrast-enhanced MRI will reveal the lesion. ^[6]

Why: Mass effect and direct infiltration of eloquent brain regions.
What the patient reports: Depends on location:

Tumour Location	Expected Deficit	Pathophysiological Basis
Frontal lobe	Personality change, motor weakness (contralateral), expressive dysphasia (dominant hemisphere), abulia	Disruption of prefrontal circuits and primary motor cortex
Corpus callosum	Disconnection syndromes, bilateral signs, cognitive impairment	PCNSL has a predilection for crossing the corpus callosum (similar to GBM — "butterfly lesion")
Basal ganglia / thalamus	Contralateral hemiparesis, hemisensory loss, movement disorders	Involvement of deep grey matter nuclei and internal capsule
Parieto-occipital region	Homonymous hemianopia, visuospatial neglect, sensory deficits	Disruption of optic radiations and parietal association cortex
Cerebellum (uncommon in PCNSL)	Ataxia, nystagmus, dysmetria	Involvement of cerebellar hemispheres or vermis
Brainstem (uncommon)	Cranial nerve palsies, long tract signs, ataxia	Direct infiltration

Why: Raised ICP — due to tumour bulk, peritumoral vasogenic oedema, or obstruction of CSF pathways (especially if periventricular tumour obstructs the foramen of Monro or aqueduct → obstructive hydrocephalus). ^[1]
Character: Generalised, dull, constant headache (worse in morning), vomiting, ↓consciousness ^[1]
Morning worsening occurs because ICP is highest during sleep (supine position → ↑ venous return to head + ↓ CSF reabsorption due to ↓ upright hydrostatic gradient).

Why: Cortical irritation from tumour infiltration or peritumoral oedema. PCNSL causes seizures less frequently than cortically-based tumours (e.g. meningiomas, gliomas, metastases) because it preferentially involves deep white matter rather than cortex.
Can be focal (with or without secondary generalisation) or generalised.

Two distinct mechanisms:
1. Vitreoretinal (intraocular) lymphoma: Floaters, blurred vision, painless progressive visual loss. Often bilateral. May precede brain involvement by months to years. Slit-lamp examination shows vitritis with characteristic "leopard skin" or "aurora borealis" sub-RPE deposits.
2. Compressive/infiltrative: Homonymous hemianopia (optic radiations), visual field cuts, or rarely optic nerve involvement.

Why: CSF dissemination of lymphoma cells along the leptomeninges.
What the patient reports:
- Multiple cranial nerve palsies (especially VI → diplopia; V → facial numbness; VII → facial weakness)
- Radiculopathy (shooting limb pain)
- Cauda equina syndrome (leg weakness, saddle anaesthesia, sphincter disturbance)

Unlike systemic lymphoma, B symptoms (fever, night sweats, weight loss) are uncommon in PCNSL — found in < 10% of immunocompetent patients.
However, in HIV/AIDS-associated PCNSL, systemic symptoms are more common due to the underlying immunosuppression and coinfections.

CNS involvement [in NHL]: headache, lethargy, focal neurological symptoms, seizures, paralysis, cord compression, lymphomatous meningitis ^[2]^[7]

7.3 Signs (with Pathophysiological Basis)

Sign	Basis
Focal motor deficit (UMN pattern — increased tone, hyperreflexia, upgoing plantar, weakness)	Corticospinal tract involvement by mass or oedema
Aphasia (expressive or receptive)	Involvement of Broca's or Wernicke's area (dominant hemisphere)
Cognitive impairment (impaired MMSE/MoCA, executive dysfunction, psychomotor slowing)	White matter tract disruption, especially frontal-subcortical circuits
Cranial nerve palsies (most commonly CN VI, also III, V, VII)	Direct infiltration (e.g. brainstem), leptomeningeal disease, or raised ICP (false localising CN VI palsy)
Papilloedema	Raised ICP transmitted along the optic nerve sheath → axonal swelling at the optic disc
Visual field defects (homonymous hemianopia, bitemporal hemianopia if rare chiasmal involvement)	Optic radiation or chiasm involvement
Ataxia (rare)	Cerebellar or brainstem involvement
Altered level of consciousness	Diffuse cerebral infiltration, raised ICP, or brainstem compression (late)

Sign	Basis
Vitritis (vitreous cells/haze)	Lymphoma cell infiltration of the vitreous
Sub-RPE deposits ("leopard skin" pattern)	Lymphoma cell aggregates beneath the retinal pigment epithelium
Retinal or sub-retinal infiltrates	Direct tumour infiltration
Anterior uveitis (less common)	Anterior chamber involvement

Clinical Pearl — The Slit Lamp Exam

Every patient with suspected or confirmed PCNSL requires a slit-lamp examination by an ophthalmologist to assess for intraocular (vitreoretinal) involvement. This is because ~15–25% have ocular disease at diagnosis, and it changes staging and management.

Cushing's triad: hypertension + bradycardia + irregular respiration (a late, pre-terminal sign of brainstem compression from transtentorial herniation). ^[1]
Brain herniation patterns (subfalcine, transtentorial, tonsillar) — life-threatening. ^[1]

In HIV/AIDS patients: look for concurrent signs of other AIDS-defining conditions (oral candidiasis, Kaposi sarcoma, wasting, etc.)
CD4 count typically < 50 cells/μL in HIV-associated PCNSL ^[3]

Feature	PCNSL	GBM	Metastases	Meningioma
Location	Deep periventricular, corpus callosum, basal ganglia	White matter (can be anywhere)	Grey-white junction, cortical	Extra-axial (dura-based)
Number	Multifocal in 25–50%	Usually single	Often multiple	Usually single
Enhancement	Homogeneous (immunocompetent); ring-enhancing (HIV)	Ring-enhancing with central necrosis	Ring or homogeneous	Homogeneous with dural tail
Oedema	Moderate	Extensive	Variable	Variable
Steroid response	Dramatic ("ghost tumour")	Partial	Partial	Minimal
Restricted diffusion on MRI (DWI)	Yes (high cellularity)	Variable	Variable	No

The 'Ghost Tumour' Phenomenon

Corticosteroids cause rapid apoptosis of lymphoma cells (via glucocorticoid receptor-mediated cell death). This can produce dramatic radiological and clinical improvement within days — the tumour may completely "vanish" on imaging. This is dangerous because it prevents histological diagnosis. If PCNSL is suspected, withhold steroids until after biopsy unless the patient's life is in immediate danger from raised ICP or herniation.

High Yield Summary

Definition: PCNSL is an aggressive extranodal NHL (almost always DLBCL, ABC subtype) confined to the CNS (brain, spinal cord, leptomeninges, eyes) without systemic disease.
Epidemiology: Rare (~3–4% of brain tumours); bimodal — young immunocompromised, elderly immunocompetent. Male predominance.
Risk factors: Immunosuppression (HIV with CD4 < 50, post-transplant, congenital immunodeficiency) + EBV are the key risk factors. ^[1]
Pathophysiology: In immunocompromised → EBV-driven B-cell proliferation escaping T-cell control in the immune-privileged CNS. In immunocompetent → acquired somatic mutations (especially MYD88 L265P in 50–80%) driving constitutive NF-κB activation.
Clinical features:
- Most common presentation: Subacute cognitive/behavioural change + focal neurological deficits (deep white matter predilection)
- Headache (raised ICP), seizures (less common than cortical tumours)
- Ocular involvement in 15–25% (floaters, visual loss)
- Leptomeningeal disease in 10–25% (CN palsies, radiculopathy)
- B symptoms are uncommon (unlike systemic NHL)
- "Ghost tumour" — dramatic steroid response → avoid steroids before biopsy
Key imaging clue: Homogeneously enhancing periventricular lesion(s) with restricted diffusion on DWI-MRI in an immunocompetent patient; ring-enhancing lesion in HIV/AIDS.
Classification: WHO CNS tumours classification; not staged by Ann Arbor/TNM. Always confined to CNS by definition.

Active Recall - Primary CNS Lymphoma (Overview, Epidemiology, Risk Factors, Pathophysiology, Clinical Features)

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf (risk factors for brain tumours, clinical presentation of brain tumours, concept of malignancy in brain tumours) ^[2] Senior notes: Maksim Medicine Notes.pdf p.178 (lymphoma classification, investigations including MRI brain/LP for CNS lymphoma, DLBCL) ^[3] Senior notes: Block A - HIV positive_ HIV related diseases, accidental needle prick injury.pdf p.3 (CD4 < 200, opportunistic infections, AIDS-defining malignancies) ^[4] Senior notes: Block A - Renal Replacement Therapies.pdf p.39 (PTLD including cerebral lymphoma post-transplant) ^[5] Senior notes: Maksim Surgery Notes.pdf p.361 (brain tumour epidemiology, risk factors including EBV and immunosuppression for PCNSL) ^[6] Lecture slides: GC 241. A short course of dementia.pdf (rapidly progressive dementia differential including CNS lymphoma) ^[7] Senior notes: Ryan Ho Haemtology.pdf p.97-100 (NHL clinical presentation including CNS involvement, DLBCL subtypes and management)

Differential Diagnosis of Primary CNS Lymphoma

A patient presents with subacute onset of cognitive/behavioural change, focal neurological deficits, and/or headache. MRI shows one or more enhancing deep cerebral lesions. What else could this be besides PCNSL?

The differential diagnosis essentially asks: what other pathologies can produce an enhancing intracranial mass (or masses) in this clinical context? The answer depends critically on the patient's immune status, age, tempo of illness, and imaging characteristics.

The DDx of an enhancing intracranial mass lesion can be organised by the mnemonic VITAMIN-C (Vascular, Infectious/Inflammatory, Traumatic, Autoimmune, Metabolic/toxic, Idiopathic, Neoplastic, Congenital), but for a brain mass the most practical approach is to think in three categories:

Other neoplasms (primary and secondary)
Infections (especially in immunocompromised patients)
Non-infectious inflammatory/demyelinating conditions

The lecture slides emphasise the broad headache red flag framework: Systemic upset (constitutional symptoms, fever, cancer) → CNS infections, Neoplastic (lymphoma or metastasis), Vasculitis and Neurological symptoms (confusion, focal symptoms, LOC, seizures, meningism) → Intracranial pathologies (vascular, neoplastic, infection). ^[8]^[9]

A. Differential Diagnosis in the Immunocompetent Patient

Feature	PCNSL	GBM
Age	60–65 y (peak)	55–70 y (peak)
Location	Deep periventricular, basal ganglia, corpus callosum	White matter, can be anywhere; also crosses corpus callosum ("butterfly GBM")
Number	Multifocal in 25–50%	Usually solitary
MRI enhancement	Homogeneous enhancement (immunocompetent)	Ring-enhancing with central necrosis and surrounding vasogenic oedema ^[10]
DWI (diffusion)	Prominent diffusion restriction (high cellularity → restricted water movement) ^[10]	Variable, often less restricted
Steroid response	Dramatic ("ghost tumour")	Partial (reduces oedema but tumour persists)
Key distinguishing point	No necrosis on imaging (immunocompetent); homogeneous; may resolve with steroids	Central necrosis, irregular enhancing rim, extensive oedema disproportionate to tumour size

Why GBM is the top differential: Both GBM and PCNSL are the most common primary malignant brain tumours in adults and both can involve the corpus callosum. However, high-grade glioma shows heterogeneous enhancement with surrounding vasogenic oedema ± central necrosis ^[10], while PCNSL shows homogeneous, dense enhancement with relatively less oedema and no central necrosis in the immunocompetent host.

Adults: 80-85% supratentorial, commonly metastases, glioma, meningioma ^[1]

Feature	PCNSL	Brain Metastases
History	No known primary malignancy	Pre-existing cancer (lung, breast, RCC, colorectal, melanoma) ^[11]
Location	Deep periventricular white matter	Grey-white junction, watershed areas (where tumour cell clumps get trapped in narrowing vessels) ^[11]
Number	Multifocal possible but deep-seated	Often multiple, scattered across both hemispheres
MRI	Homogeneous enhancement	Round, well-circumscribed contrast-enhancing lesion with variable signal ± large surrounding oedema ^[10]^[11]
Key distinguishing point	No known systemic cancer; periventricular predilection	Known primary; cortical/subcortical; large oedema relative to lesion size

Why metastases must always be considered: Secondary tumours are 6–10× more common than primary brain tumours ^[1]. However, PCNSL should be suspected when there is no known primary, the lesion is deep/periventricular, and it shows homogeneous enhancement with restricted diffusion.

High Yield — GC Lecture Point

10–15% of solitary cerebral mass lesions in patients with pre-existing cancer are NOT metastases — always consider PCNSL, high-grade glioma, or even brain abscess. ^[11]

Feature	PCNSL	Meningioma
Origin	Intra-axial (within brain parenchyma)	Extra-axial (dura-based)
MRI	Homogeneous intra-axial enhancement	Extra-axial, dura-based lesion with strong homogeneous enhancement and "dural tail" sign ^[10]
Clinical tempo	Subacute (weeks)	Chronic (months–years), often incidental
Key distinguishing point	Intra-axial, deep periventricular	Extra-axial, displaces brain rather than infiltrating it

Meningioma is usually straightforward to distinguish because it is extra-axial (outside the brain parenchyma, arising from the meninges). PCNSL is intra-axial. The dural tail sign and broad dural base are classic for meningioma. ^[10]

Feature	PCNSL	Tumefactive MS
Age/Sex	Older male	Younger female (typical MS demographics)
MRI	Homogeneous enhancement, restricted diffusion	"Open ring" enhancement (incomplete rim enhancement, open edge faces grey matter), less diffusion restriction
Steroid response	Dramatic shrinkage	Also improves with steroids (both are steroid-responsive, which can confuse!)
Key distinguishing point	Dense homogeneous enhancement, no prior MS history	Open ring enhancement, leading edge of demyelination, may have prior demyelinating episodes, CSF OCBs positive

Why this is a critical mimic: Both PCNSL and tumefactive MS can present as a large enhancing white matter lesion in a young-to-middle-aged patient, and both respond to steroids. The "open ring" enhancement pattern (where the open side faces cortical grey matter) is characteristic of demyelination and helps distinguish it from PCNSL. Brain biopsy may ultimately be needed.

Feature	PCNSL	Brain Abscess
Clinical context	No fever (usually); subacute	Fever, recent infection/surgery, endocarditis, dental infection, immunocompromised
MRI	Homogeneous enhancement, restricted diffusion (solid mass)	Ring-enhancing lesion with restricted diffusion of the cavity contents (pus restricts diffusion) on DWI
Key distinguishing point	Solid enhancing mass; restricted diffusion within the tumour itself	Ring enhancement with central restricted diffusion (pus), surrounding oedema, smooth thin enhancing wall

Both PCNSL and abscess show restricted diffusion, but in abscess the restriction is within the liquefied centre (pus is viscous → restricted water movement), whereas in PCNSL the restriction is within the solid tumour mass itself (due to extreme cellularity, tumour cells are tightly packed with very little extracellular water).

Pituitary macroadenoma / craniopharyngioma: If the PCNSL is in the sellar/suprasellar region, these enter the DDx. Differential diagnosis of sellar mass includes CNS lymphoma along with pituitary adenoma, craniopharyngioma, meningioma, germ cell tumours, chordomas, and metastases. ^[12] Craniopharyngiomas classically show calcifications in ~50% and cause bitemporal hemianopia, diabetes insipidus, or hydrocephalus. ^[13]
Ependymoma: Intraventricular, seen more in children/young adults.
Medulloblastoma: Posterior fossa, children (2–12 y); children: 70% infra-tentorial ^[1].
Germinoma: Pineal or suprasellar region, young males.

When PCNSL presents primarily with subacute cognitive decline, the differential includes causes of rapidly progressive dementia:

Creutzfeldt-Jakob disease (CJD): Rapidly progressive dementia (in months), myoclonic jerks, seizures, cerebellar ataxia. MRI shows cortical ribboning on DWI/FLAIR. ^[14] CJD is the key differential for PCNSL presenting as rapid dementia.
Autoimmune encephalitis (e.g. anti-LGI1): Limbic encephalitis with memory deficit, confusion, seizures (early seizures may be facio-brachial dystonic or tonic seizures), SIADH common (60%). Good response to steroid. Differential diagnosis includes CJD. ^[15]
Normal pressure hydrocephalus (NPH): Classical triad of frontal dementia, apraxic gait, and urinary incontinence. ALL ventricles enlarged disproportionate to sulcal effacement. ^[14]
Cerebral vasculitis
Chronic subdural haematoma in the elderly

B. Differential Diagnosis in the Immunocompromised Patient (HIV/AIDS)

In HIV/AIDS patients (especially CD4 < 50 cells/μL), the DDx of an enhancing brain lesion is narrower but critically important because treatment differs dramatically:

Feature	PCNSL (HIV)	Cerebral Toxoplasmosis
CD4 count	Typically < 50	Typically < 100
Number of lesions	Often solitary (or 2–3)	Usually multiple
Location	Periventricular, corpus callosum, basal ganglia	Basal ganglia, grey-white junction
MRI	Ring-enhancing (unlike immunocompetent PCNSL)	Ring-enhancing (similar!)
DWI	Restricted diffusion	Less restricted
Toxoplasma serology	Usually negative (IgG−)	Usually positive (IgG+)
CSF EBV PCR	Positive (~80–90% sensitivity)	Negative
Thallium-201 SPECT / FDG-PET	Increased uptake (metabolically active tumour)	Decreased uptake (infection, not tumour)
Clinical trial of anti-toxoplasma therapy	No response at 2 weeks	Response at 2 weeks (clinical + radiological)

The Empirical Anti-Toxoplasma Trial

In HIV/AIDS patients with ring-enhancing brain lesions and positive Toxoplasma IgG serology, the standard approach is an empirical 2-week trial of anti-toxoplasma therapy (pyrimethamine + sulfadiazine + leucovorin). If there is no clinical or radiological improvement at 2 weeks, PCNSL is strongly suspected and brain biopsy is indicated. This avoids unnecessary biopsy in toxoplasmosis (which is far more common than PCNSL in AIDS).

Caused by JC virus reactivation in severe immunosuppression.
MRI: Non-enhancing (or minimally enhancing) white matter lesions — no mass effect (unlike PCNSL, which enhances strongly and has mass effect).
Clinical: Progressive focal deficits without headache or seizures.
Distinguished from PCNSL by lack of enhancement and lack of mass effect.

Chronic meningitis causes include TB and Cryptococcus ^[16]. Both can produce mass lesions (tuberculoma, cryptococcoma) that mimic PCNSL on imaging.
TB: The most common cause of meningitis in this locality (Hong Kong) ^[16]. May cause tuberculoma (ring-enhancing), basal meningeal enhancement, hydrocephalus. Triphasic illness: prodrome → meningitic → paralytic. ^[16]
Cryptococcus: Gelatinous pseudocysts in basal ganglia; India ink + / Cryptococcal Ag + in CSF.

Kaposi sarcoma (rare in brain)
High-grade glioma (not specifically AIDS-related but occurs)

Post-transplant lymphoproliferative disorder (PTLD) can manifest as cerebral lymphoma ^[4].
The DDx in transplant recipients also includes opportunistic infections (toxoplasmosis, aspergillosis, CMV encephalitis).
Key: check EBV viral load (elevated in PTLD) and consider reduction of immunosuppression.

Feature	PCNSL	GBM	Metastasis	Toxoplasmosis	Abscess	Tumefactive MS
Enhancement	Homogeneous	Ring + necrosis	Ring or solid	Ring	Ring	Open ring
DWI restriction	Yes (solid mass)	Variable	Variable	Mild	Yes (pus cavity)	Leading edge
Location	Periventricular, deep	Any white matter	Grey-white junction	Basal ganglia	Variable	White matter
Multifocal	25–50%	Rarely	Often	Often	May be	Rarely
Steroid response	Dramatic	Partial	Partial	None	None	Yes
Immune status	Any	Immunocompetent	Any	HIV/AIDS	Any	Young, MS demographics
Systemic cancer	No	No	Yes	No	No	No

High Yield Summary — DDx of PCNSL

Immunocompetent patient with a deep, homogeneously enhancing periventricular mass with restricted diffusion:

Top DDx: GBM (but ring-enhancing with necrosis), metastasis (but cortical, known primary), tumefactive MS (open ring enhancement), abscess (ring, pus restricts on DWI)
If rapidly progressive dementia: consider CJD, autoimmune encephalitis

Immunocompromised (HIV, CD4 < 50) with ring-enhancing lesion(s):

Top DDx: Cerebral toxoplasmosis — start empirical anti-toxoplasma Rx; biopsy if no response at 2 weeks
Also consider PML (non-enhancing), TB/Crypto granuloma

Post-transplant: Think PTLD (cerebral lymphoma) — check EBV viral load

Key distinguishing features of PCNSL:

Homogeneous enhancement (immunocompetent) / ring-enhancing (HIV)
Deep periventricular location
Restricted diffusion (high cellularity)
Dramatic steroid response ("ghost tumour" — avoid steroids before biopsy!)
No systemic malignancy (by definition)

Active Recall - Differential Diagnosis of PCNSL

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf (risk factors for brain tumours, tumour locations and types by age, secondary vs primary tumours) ^[4] Senior notes: Block A - Renal Replacement Therapies.pdf p.39 (PTLD including cerebral lymphoma post-transplant) ^[8] Senior notes: Ryan Ho Neurology.pdf p.58 (headache red flags — systemic upset, neurological symptoms) ^[9] Senior notes: Ryan Ho Fundamentals.pdf p.313 (headache red flags framework) ^[10] Senior notes: Adrian Lui Pediatrics Notes.pdf p.431 (MRI appearance of brain tumours: PCNSL, GBM, metastases, meningioma) ^[11] Senior notes: Ryan Ho Neurology.pdf p.164 (brain metastases — commonest intracranial tumour, origins, sites, suggestive features) ^[12] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf p.1029 (differential diagnosis of sellar mass including CNS lymphoma) ^[13] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf p.6 (craniopharyngioma: calcifications, bitemporal hemianopia, DI, hydrocephalus) ^[14] Senior notes: Ryan Ho Psychiatry.pdf p.82 (CJD, NPH, dementia approach) ^[15] Lecture slides: GC 225. Neuroimmunological disorders of the central nervous system.pdf p.42 (anti-LGI1 autoimmune encephalitis features, DDx with CJD) ^[16] Senior notes: Ryan Ho Neurology.pdf p.144 (chronic meningitis — TB, Cryptococcus, malignant meningitis including lymphoma)

Diagnostic Criteria, Diagnostic Algorithm & Investigation Modalities for PCNSL

1. Diagnostic Criteria

Unlike many systemic cancers that have formal "diagnostic criteria" (e.g. Bethesda criteria, RECIST), PCNSL diagnosis is based on a constellation of mandatory requirements rather than a single points-based system. The International PCNSL Collaborative Group (IPCG) and NCCN guidelines define the diagnosis as follows:

Requirement	Rationale
1. Histopathological confirmation of lymphoma in CNS tissue	The gold standard — you MUST have tissue. A stereotactic brain biopsy showing DLBCL is definitive.
2. Tumour confined to the CNS	By definition, PCNSL requires no systemic lymphoma. You must exclude disease elsewhere (body CT, PET-CT, bone marrow biopsy).
3. Exclusion of immunodeficiency-associated lymphoma (when relevant)	If the patient is HIV+ or post-transplant, the diagnosis is classified separately as "HIV-associated PCNSL" or "PTLD" — same treatment principles but distinct biology. Requires HIV testing.

The Non-Negotiable Rule

You cannot diagnose PCNSL without tissue. An enhancing brain lesion on MRI, even with classic features, is insufficient. The one exception is in HIV/AIDS patients where CSF EBV PCR positivity + compatible imaging + failure to respond to empirical anti-toxoplasma therapy may constitute a presumptive diagnosis when biopsy is too risky.

Accurate diagnosis of lymphoma requires integration of: clinical features, morphologic features, immunophenotypic features, and genetic features. ^[17]

The brain biopsy specimen is processed identically to any lymphoma specimen, following the MCICM framework (Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics) ^[18]^[19]:

Component	Finding in PCNSL (DLBCL type)	Why This Matters
Morphology (Histology)	Diffuse growth pattern with sheets of large transformed B cells effacing normal architecture. Angiocentric (perivascular) growth pattern — lymphoma cells cuff blood vessels. ^[2]	The perivascular pattern is highly characteristic of PCNSL and helps distinguish it from metastasis or glioma
Immunophenotyping	Pan-B cell antigen positive: CD19, CD20, CD22, CD79a ^[20]. Typically BCL6+ (~60–80%), MUM1/IRF4+ (~90%), BCL2+ (~50–80%). CD10 usually negative (i.e. non-GCB / ABC subtype by Hans algorithm). Ki-67 proliferation index typically high (> 70%).	CD20 positivity is critical because it determines eligibility for rituximab (anti-CD20 monoclonal antibody). The ABC/non-GCB profile distinguishes PCNSL from systemic GCB-DLBCL.
Cytogenetics	No single pathognomonic translocation (unlike follicular lymphoma with t(14;18) or Burkitt with t(8;14)). May show gains of 9p24.1 (PD-L1/PD-L2 locus), deletions of 6q, 6p21 (HLA). ^[2]	Cytogenetics are non-diagnostic but inform prognosis and potential targeted therapy
Molecular genetics	IgH gene rearrangement by PCR → clonal = single sharp band on electrophoresis (vs smear pattern in non-lymphoma tissue) ^[21]^[22]. MYD88 L265P mutation in 50–80%. CD79B mutation in 20–40%.	Every cell from the lymphoma is derived from one neoplastic cell and only ONE single rearrangement pattern can be seen ^[20]. Clonality by IgH rearrangement PCR confirms the B-cell population is neoplastic, not reactive.

Lymphoma classification requires ALL 3 features: histological appearance, immunophenotyping, and cytogenetics/molecular genetics ^[23]

These are not sufficient alone for diagnosis but raise suspicion and may guide management when biopsy is impossible:

Finding	Sensitivity	Specificity	Role
Characteristic MRI features (see §3.2)	High	Moderate	Raises suspicion; guides biopsy targeting
CSF cytology positive for malignant lymphocytes	15–30% (low)	~100% (if positive, diagnostic)	If positive, may obviate brain biopsy in some centres
CSF flow cytometry showing monoclonal B-cell population	30–50%	Very high	More sensitive than cytology; demonstrates clonality
CSF EBV PCR positive (HIV/AIDS setting)	80–90%	~95%	In HIV patients, high positive predictive value
CSF MYD88 L265P (cell-free DNA)	~50–80%	Very high	Emerging liquid biopsy tool
Vitreous biopsy showing lymphoma cells	Definitive if positive	100%	For vitreoretinal lymphoma

2. Diagnostic Algorithm

The diagnostic pathway must achieve three goals simultaneously:

Confirm the histological diagnosis (tissue)
Exclude systemic lymphoma (staging)
Assess disease extent within the CNS (ocular, leptomeningeal)

A. Why hold steroids before biopsy? Glucocorticoids induce apoptosis of lymphoma cells (they express glucocorticoid receptors). Within 48–72 hours, the tumour may shrink dramatically or disappear entirely on imaging ("ghost tumour"). If the biopsy is then performed, the pathologist may find only necrotic debris, reactive gliosis, and perivascular inflammation — yielding a non-diagnostic or misleading sample. Therefore: avoid steroids before biopsy unless life-threatening raised ICP or herniation. If steroids have already been given and the lesion has shrunk, you may need to wait weeks for it to regrow before attempting biopsy again.

B. Why is biopsy (not resection) the standard approach? Unlike gliomas or metastases, gross total resection does NOT improve outcomes in PCNSL. PCNSL is a diffusely infiltrating disease — the visible tumour on MRI is just the "tip of the iceberg," with microscopic disease throughout the brain. Chemotherapy and/or radiotherapy are the definitive treatments. Therefore, stereotactic biopsy (minimally invasive, frameless or frame-based) is preferred over craniotomy and resection. ^[1]

C. Why must systemic disease be excluded? By definition, PCNSL is confined to the CNS. If PET-CT or CT reveals nodal or extranodal disease outside the CNS, the diagnosis becomes "systemic DLBCL with secondary CNS involvement," which has different staging, prognosis, and management. MRI brain / LP with cytospin (if suspect CNS lymphoma) and PET-CT (preferred esp. DLBCL & HL) are standard lymphoma investigations. ^[2]

D. Why check testes in older males? Testicular DLBCL is the one extranodal DLBCL subtype that shares the same biology as PCNSL (ABC subtype, MYD88 L265P mutation, high rate of CNS relapse). It may be occult on examination but visible on ultrasound. If found, the diagnosis changes.

3. Investigation Modalities — Detailed Breakdown

Investigation	Expected Finding	Why / Interpretation
CBC with differential	Usually normal. May show mild lymphopaenia. Rarely cytopaenias from leptomeningeal involvement.	CBC, clotting, RFT/LFT, CaPO4, ESR & LDH (prognostic), urate (TLS) are standard lymphoma bloods. ^[2] If there are unexplained cytopaenias, think of bone marrow involvement or an alternative diagnosis.
LDH	May be elevated (non-specific marker of cell turnover)	Elevated LDH correlates with tumour bulk and is an adverse prognostic factor in PCNSL (included in IELSG scoring).
β2-microglobulin	Often elevated	A component of MHC class I. Shed from the surface of lymphoma cells. Elevated levels correlate with tumour burden and poorer prognosis.
Serum protein electrophoresis (SPE)	Usually normal in PCNSL (no systemic M-protein)	Helps exclude myeloma or Waldenström's macroglobulinaemia, which can have CNS manifestations (Bing-Neel syndrome).
HIV serology	Must be checked in ALL patients	EBV, immunosuppression → primary CNS lymphoma ^[1]. HIV status fundamentally changes the diagnostic and management pathway.
HBV, HCV serology	Pre-treatment screen	Pre-treatment: HBV, HCV, HIV ^[2]. Rituximab (anti-CD20) can reactivate hepatitis B → fatal fulminant hepatitis. HBsAg and anti-HBc must be checked. If positive, antiviral prophylaxis (e.g. entecavir) is mandatory.
RFT, LFT, electrolytes, calcium	Baseline	Methotrexate is renally excreted → baseline renal function critical. Hypercalcaemia may suggest alternative diagnosis.
Urate	Baseline	Risk of tumour lysis syndrome (TLS), especially after initial chemotherapy for bulky disease.
G6PD	Pre-treatment	If rasburicase is needed for TLS prophylaxis, G6PD deficiency is a contraindication.
Coagulation profile	Before biopsy	Essential to ensure safe stereotactic biopsy; correct any coagulopathy beforehand.

3.2 Neuroimaging

Role: Usually the first imaging obtained in the emergency setting. Raises suspicion but is NOT definitive.
Findings: Normal brain tissue does not enhance (due to BBB). Enhancement indicates structures outside the BBB (e.g. meningioma) or disruption of BBB (e.g. high-grade tumours, inflammation). ^[24]
- Non-contrast CT: Iso- to hyperdense mass (due to high cellularity — packed tumour cells are denser than normal brain) in a periventricular location. Usually minimal surrounding hypodensity (oedema) compared to GBM.
- Contrast CT: Homogeneous enhancement in immunocompetent patients; ring-enhancement in HIV patients.
- Site and multiplicity, mass effect, contrast enhancement pattern should all be noted. ^[24]

MRI with contrast: generally preferred over CT for brain tumours because it allows better soft tissue delineation and is especially useful at skull base, craniocervical junction, brainstem. ^[10]

MRI Sequence	PCNSL Finding	Pathophysiological Basis
T1-weighted	Iso- to hypointense mass	Solid cellular tumour without fat or haemorrhage
T1 + gadolinium	Homogeneous enhancement (immunocompetent); ring-enhancing (immunocompromised)	BBB disruption by tumour → gadolinium leaks into tumour. The uniformity of enhancement reflects the homogeneous cellularity of lymphoma (unlike GBM which has necrotic centre → ring pattern)
T2-weighted / FLAIR	Iso- to hypointense (iso or even LOW signal relative to grey matter)	High nuclear-to-cytoplasmic ratio → densely packed cells with very little extracellular water → LOW T2 signal. This is a key distinguishing feature — most brain tumours are T2-hyperintense, but PCNSL is characteristically T2-iso/hypointense. ^[10]
DWI (Diffusion-Weighted Imaging)	Prominent diffusion restriction (bright on DWI, dark on ADC map) ^[10]	Extreme cellularity restricts extracellular water movement → restricted diffusion. This is one of the most helpful distinguishing features from other brain tumours.
SWI / GRE	Usually no haemorrhage or calcification	Lymphoma does not induce neovascularisation to the same extent as GBM → less prone to haemorrhage
MR Spectroscopy	Elevated lipid and choline peaks; reduced NAA	High cell turnover (↑choline) with membrane breakdown (↑lipid) and neuronal loss (↓NAA). Not specific but supportive.
Perfusion MRI (DSC-MRI)	Lower relative cerebral blood volume (rCBV) than GBM	PCNSL is less vascular than GBM. Helps distinguish when imaging features overlap.

1° CNS lymphoma: solitary/multifocal T2W-iso/hypointense, contrast-enhancing lesions in subcortical regions, classically associated with prominent diffusion restriction on DWI ^[10]

High Yield — MRI Pattern Recognition for PCNSL

The classic MRI triad of PCNSL in an immunocompetent patient:

Homogeneously enhancing periventricular mass
T2-iso/hypointense (unlike most brain tumours which are T2-bright)
Restricted diffusion on DWI (bright DWI, dark ADC)

If you see this triad → think PCNSL → hold steroids → biopsy

If there are symptoms suggestive of spinal cord or leptomeningeal disease (e.g. radiculopathy, back pain, sphincter disturbance).
Gadolinium-enhanced MRI of the whole spine to evaluate for leptomeningeal enhancement or intramedullary lesions.

Whole-body FDG PET-CT is now the preferred staging modality because:
- PCNSL is FDG-avid (high metabolic activity → high glucose uptake → lights up)
- It detects occult systemic lymphoma that would reclassify the diagnosis
- It detects occult testicular disease
PET-CT preferred especially for DLBCL & HL ^[2]
If PET-CT is unavailable, contrast-enhanced CT of chest, abdomen, and pelvis is an acceptable alternative.

Used to distinguish PCNSL from cerebral toxoplasmosis when both present as ring-enhancing lesions:
- PCNSL: Increased uptake (metabolically active tumour)
- Toxoplasmosis: Decreased uptake (infectious/inflammatory, not tumour)
This investigation is most useful in the HIV population where biopsy may be high-risk.

LP is a critical investigation in PCNSL — it serves both diagnostic and staging purposes. Must be performed unless contraindicated by raised ICP or coagulopathy (CT brain first to rule out imminent herniation risk).

CSF Parameter	Expected Finding	Interpretation
Opening pressure	May be elevated	Raised ICP from mass effect
Protein	Elevated (usually 0.5–2.0 g/L)	BBB disruption and tumour protein secretion
Glucose	Usually normal or mildly low	Consumed by high-metabolic-rate tumour cells (but not as dramatically low as in bacterial meningitis)
Cell count	Mild lymphocytic pleocytosis	Tumour cells + reactive lymphocytes
Cytology	Malignant lymphoid cells in 15–30% (low sensitivity)	If positive → diagnostic. Must send adequate volume (≥ 5–10 mL) and process promptly (lymphoma cells are fragile and degenerate quickly)
CSF flow cytometry	Monoclonal B-cell population (light chain restriction) in 30–50%	Detection of surface immunoglobulin light chains is very helpful in determining clonality of B cell proliferation ^[20]. Flow cytometry is more sensitive than cytology because it can detect small numbers of clonal cells.
CSF EBV PCR	Positive in ~80–90% of HIV-associated PCNSL; usually negative in immunocompetent	In HIV patients, a positive CSF EBV PCR combined with compatible imaging has high predictive value
CSF MYD88 L265P (cell-free DNA)	Positive in ~50–80% of immunocompetent PCNSL	Emerging biomarker — may allow "liquid biopsy" diagnosis in the future
CSF IL-10	Markedly elevated (often > 10 pg/mL)	IL-10 is an autocrine growth factor for DLBCL cells. CSF IL-10:IL-6 ratio > 1 is suggestive of PCNSL

MRI brain / LP with cytospin (if suspect CNS lymphoma) — cytospin is essential to concentrate cells for cytological examination ^[2]

CSF Interpretation Pearls

Lymphoma vs bacterial vs TB vs viral CSF:

Bacterial: cloudy, ↑↑polymorphs, ↑protein, ↓↓glucose
TB/Crypto: opalescent, ↑lymphocytes, ↑↑↑protein, ↓glucose
Viral: clear, ↑lymphocytes, mildly ↑protein, normal glucose
PCNSL: clear to mildly turbid, ↑lymphocytes (some malignant), ↑protein, normal/mildly ↓glucose. The key is finding monoclonal B cells on flow cytometry or malignant cells on cytology.

Reference CSF table from lecture: ^[25]

Aspect	Detail
Technique	Frame-based or frameless (neuronavigation-guided) stereotactic biopsy under local or general anaesthesia. A small burr hole is made and a biopsy needle advanced to the lesion under image guidance.
Diagnostic yield	~90–95% for a single attempt
Complications	~5% risk of clinically significant haemorrhage; < 1% mortality
Why not excisional biopsy?	Excisional biopsy / core biopsy for histology, cytogenetics & immunophenotyping (FNA not adequate!) ^[2]. For systemic lymphoma, excisional LN biopsy is preferred. For PCNSL, the "excision" equivalent would be craniotomy and resection — but resection does NOT improve survival in PCNSL because the disease is diffusely infiltrating. Stereotactic biopsy provides sufficient tissue for all necessary analyses.
Specimen handling	Fresh tissue for flow cytometry; fixed tissue for H&E, immunohistochemistry; frozen tissue for molecular studies

FNA Is Not Adequate for Lymphoma Diagnosis

FNA is not adequate for lymphoma diagnosis in any setting — it provides cytological information only and cannot assess tissue architecture, which is essential for lymphoma subtyping (e.g. diffuse vs follicular pattern). For PCNSL, stereotactic core/needle biopsy is the minimum acceptable tissue sample. ^[2]

BM aspiration and trephine biopsy: for staging ^[2]
In PCNSL work-up: performed to exclude systemic lymphoma involving the marrow.
For systemic NHL, bilateral biopsies are recommended (NHL: bilateral, ∵non-contiguous spread) ^[2]. For PCNSL staging, a unilateral biopsy is generally sufficient.
Expected finding in true PCNSL: normal or uninvolved marrow.

Primary CNS lymphoma commonly involves the eyes ^[26]
Slit-lamp examination by an ophthalmologist is mandatory in ALL patients with suspected or confirmed PCNSL.
Findings suggestive of vitreoretinal lymphoma: vitritis (vitreous cells/haze), sub-RPE deposits ("leopard skin" pattern), retinal/sub-retinal infiltrates.
If vitreoretinal involvement is suspected: diagnostic vitrectomy with cytology, flow cytometry, and IL-10/IL-6 ratio of vitreous fluid.
~15–25% of PCNSL patients have ocular involvement at diagnosis.

Indicated in males ≥ 60 years (or any male with testicular symptoms).
Testicular DLBCL shares biological features with PCNSL and can be occult. Finding testicular involvement would change the diagnosis and staging.

Purpose	Investigations
Confirm diagnosis	Stereotactic brain biopsy → histology, IHC, flow cytometry, cytogenetics, molecular genetics. OR CSF cytology/flow cytometry (if positive). OR vitreous biopsy (if ocular involvement).
Exclude systemic disease	Whole-body PET-CT (or CT CAP), bone marrow biopsy, testicular USS (males), LDH, HIV serology
Assess CNS disease extent	MRI brain + spine with gadolinium, LP with CSF analysis (cytology, flow cytometry, protein, glucose), slit-lamp ophthalmological examination
Pre-treatment baseline	CBC, RFT, LFT, electrolytes, coagulation, HBV/HCV/HIV serology, G6PD, pregnancy test (if applicable)
Prognostic	Age, ECOG performance status, serum LDH, CSF protein, involvement of deep brain structures → IELSG prognostic score

The International Extranodal Lymphoma Study Group (IELSG) score is the standard prognostic tool for PCNSL (analogous to IPI for systemic DLBCL):

Factor (1 point each)	Threshold
Age	> 60 years
ECOG performance status	> 1
Serum LDH	Elevated above ULN
CSF protein	Elevated above ULN
Deep brain structure involvement	Periventricular, basal ganglia, brainstem, cerebellum

Score	Risk Group	2-year OS
0–1	Low	~80%
2–3	Intermediate	~50%
4–5	High	~15%

High Yield Summary — Diagnosis of PCNSL

Gold standard diagnosis: Stereotactic brain biopsy with histology (DLBCL), immunophenotyping (CD20+, BCL6+, MUM1+, CD10−), and molecular studies (IgH clonality, MYD88 L265P).
Accurate diagnosis of lymphoma requires: clinical + morphologic + immunophenotypic + genetic features ^[17]
FNA is not adequate for lymphoma — need core/excisional biopsy for architecture ^[2]
HOLD STEROIDS before biopsy — ghost tumour phenomenon renders biopsy non-diagnostic.
Must exclude systemic disease: PET-CT (or CT CAP) + bone marrow biopsy + testicular USS (males) + HIV test.
Must assess CNS extent: MRI brain + spine + LP with cytology/flow cytometry + slit-lamp eye exam.
Classic MRI triad: Homogeneous enhancement + T2-iso/hypointense + restricted diffusion on DWI, in periventricular location.
CSF: Malignant lymphoid cells on cytology (low sensitivity ~15–30%); monoclonal B cells on flow cytometry (higher sensitivity ~30–50%); EBV PCR useful in HIV setting.
HIV/AIDS pathway: CSF EBV PCR + Toxoplasma IgG + empirical anti-toxoplasma trial → biopsy if no response.
IELSG score: 5 factors (age > 60, ECOG > 1, ↑LDH, ↑CSF protein, deep brain structures) → risk stratification.

Active Recall - Diagnosis of PCNSL

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf (risk factors, clinical presentation, investigation approach, concept of malignancy in brain tumours) ^[2] Senior notes: Maksim Medicine Notes.pdf p.178 (lymphoma investigations including bloods, pathology, imaging, pre-treatment screen; FNA not adequate; PET-CT; MRI brain/LP with cytospin) ^[10] Senior notes: Adrian Lui Pediatrics Notes.pdf p.431 (MRI appearance of PCNSL: T2-iso/hypointense, contrast-enhancing, diffusion restriction on DWI; CT enhancement principles) ^[17] Lecture slides: GC 055. Generalized lympadenopathy.pdf p.30 (accurate diagnosis of lymphoma requires clinical + morphologic + immunophenotypic + genetic features) ^[18] Senior notes: Ryan Ho Fundamentals.pdf p.390–391 (MCICM framework: Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics; marrow examination) ^[19] Senior notes: Ryan Ho Haemtology.pdf p.47 (MCICM workup for haematological malignancies) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.1426 (histological examination, immunophenotyping markers table, flow cytometry, IHC, cytogenetics, molecular genetics — IgH rearrangement clonality) ^[21] Lecture slides: Molecular Pathology Seminar 4_MALIGNANT LYMPHOMA.pdf p.44 (PCR interpretation — non-lymphoma tissue gives smear pattern) ^[22] Lecture slides: Molecular Pathology Seminar 4_MALIGNANT LYMPHOMA.pdf p.45 (PCR interpretation — lymphoma gives single sharp band confirming clonality) ^[23] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf p.751 (lymphoma classification requires histology + immunophenotyping + cytogenetics/molecular genetics) ^[24] Senior notes: Ryan Ho Neurology.pdf p.162 (CT brain principles — normal brain does not enhance due to BBB; enhancement = outside BBB or BBB disruption) ^[25] Senior notes: Maksim Medicine Notes.pdf p.197 (CSF analysis table for bacterial, TB, viral, autoimmune meningitis) ^[26] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf p.1423 (Primary CNS lymphoma commonly involves the eyes; physical examination in lymphoma)

Management of Primary CNS Lymphoma

Before diving into regimens, let's understand from first principles why PCNSL cannot be treated like systemic DLBCL:

The Blood–Brain Barrier (BBB): Most conventional chemotherapy agents (doxorubicin, vincristine, cyclophosphamide) cannot cross the intact BBB at therapeutic concentrations. This is why R-CHOP — the backbone of systemic DLBCL treatment — does not work for PCNSL. Instead, drugs that penetrate the CNS must be used: high-dose methotrexate (HD-MTX), high-dose cytarabine (HD-AraC), thiotepa, and temozolomide.
Surgery is NOT therapeutic: Stereotactic biopsy for pathological diagnosis — usually for non-resectable tumours (e.g. pontine) or lymphoma (not treated by surgery) ^[27]. Gross total resection does not improve survival because PCNSL is a diffusely infiltrating disease — what you see on MRI is only a fraction of the microscopic disease.
Steroids can mask the disease: C/I: suspect CNS lymphoma → steroid causes acute lysis of lymphocyte → ↓ diagnostic yield in biopsy ^[27]. However, once the diagnosis is histologically confirmed, corticosteroids (dexamethasone) are used liberally for oedema control during treatment.
Whole-brain radiotherapy (WBRT) has a neurotoxicity problem: WBRT was historically the standard, but it causes devastating delayed neurotoxicity (leukoencephalopathy, dementia), especially in patients > 60 years. Modern protocols aim to avoid or defer WBRT, using consolidation chemotherapy or reduced-dose WBRT instead.
CD20 expression → Rituximab: Since PCNSL is CD20+ DLBCL, rituximab (anti-CD20) is incorporated into regimens. However, rituximab is a large monoclonal antibody (~145 kDa) with very limited BBB penetration. Its benefit in PCNSL likely comes from activity against circulating or leptomeningeal disease and from BBB disruption by the tumour itself allowing some drug penetration.

Treatment Phases — Detailed Breakdown

Before starting chemotherapy, several critical steps must be completed:

Action	Rationale
Confirm histology	Never treat empirically (except in HIV setting with presumptive diagnosis)
Complete staging	Exclude systemic disease (PET-CT, BM biopsy, testicular USS)
Slit-lamp eye examination	Detect vitreoretinal involvement (changes management — may need intravitreal chemotherapy or ocular RT)
LP with CSF analysis	Stage leptomeningeal involvement; intrathecal chemotherapy if positive
Baseline bloods	CBC, clotting, RFT/LFT, CaPO4, ESR & LDH (prognostic), urate (TLS) ^[2]
Pre-treatment: HBV, HCV, HIV ^[2]	Rituximab can reactivate HBV → screen HBsAg, anti-HBc. If HBsAg +ve or HBcAb +ve, check baseline HBV DNA + LFT → start prophylactic antiviral therapy (entecavir) irrespective of baseline HBV DNA levels ^[28]. Continue for 12 months if using anti-CD20 ^[28].
G6PD	If rasburicase may be needed for TLS
Creatinine clearance	Methotrexate is renally excreted — dose must be adjusted for renal function; CrCl < 30–40 mL/min is a relative contraindication to HD-MTX
IELSG prognostic score	Determines risk group and informs treatment intensity
Ommaya reservoir consideration	If leptomeningeal disease is present and intrathecal therapy planned, an Ommaya reservoir (subcutaneous intraventricular access device) provides reliable CSF drug delivery

HBV Reactivation with Rituximab — High Yield

Planning to start anti-CD20 / anti-CD52 for a patient → check HBsAg, anti-HBs, anti-HBc. If any HBV marker +ve, check baseline HBV DNA + LFT. ^[28]

For HBsAg +ve patients: start prophylactic antiviral therapy irrespective of baseline HBV DNA levels. Choice: entecavir or TDF/TAF (low resistance profiles). Continue for 12 months after completion of anti-CD20 therapy. ^[28]

This is especially relevant in Hong Kong with its high HBV seroprevalence (~8% carrier rate).

Phase 2: Induction Chemotherapy

The goal of induction is to achieve complete response (CR) — complete disappearance of enhancing disease on MRI. This is critical because achieving CR after induction is the single strongest predictor of long-term survival.

Aspect	Detail
Drug	Methotrexate (MTX) — "metho" = methyl, "trex" = folic acid analogue. It is a dihydrofolate reductase (DHFR) inhibitor that blocks de novo nucleotide synthesis, preventing DNA replication in rapidly dividing cells.
Why high-dose?	At standard doses (e.g. 15–25 mg weekly for RA), MTX does not cross the BBB. At high doses (≥ 3 g/m²), the sheer concentration gradient forces MTX across the BBB, achieving cytotoxic levels in the CSF and brain parenchyma. Typical PCNSL dosing: 3.5 g/m² IV over 2–4 hours.
Leucovorin rescue	HD-MTX is toxic to all rapidly dividing cells. Leucovorin (folinic acid) is given 24 hours after MTX infusion to "rescue" normal cells by providing reduced folate that bypasses the DHFR block. Tumour cells cannot utilise leucovorin as efficiently because they have impaired folate transport.
Hydration and alkalinisation	MTX crystallises in acidic urine → renal tubular obstruction → acute kidney injury. Prevention: aggressive IV hydration (3 L/m²/day) + urine alkalinisation (target pH > 7) with IV sodium bicarbonate.
MTX level monitoring	Serum MTX levels are measured at 24h, 48h, and 72h post-infusion. Leucovorin rescue continues until MTX level < 0.05 μmol/L. Delayed clearance (e.g. renal impairment, third-space fluid) requires extended leucovorin and potentially glucarpidase (carboxypeptidase G2), an enzyme that cleaves MTX.
Renal function requirement	CrCl must be > 40–50 mL/min before each cycle. Methotrexate is 90% renally excreted. Dose reduction or omission if renal impairment.

Regimen	Components	Notes
MATRix (current preferred in fit patients < 65–70)	HD-MTX 3.5 g/m² + HD-AraC (cytarabine) 2 g/m² BD + thiotepa 30 mg/m² + rituximab 375 mg/m²	IELSG32 trial showed this 4-drug combination had highest CR rate (~49%) and best OS. Thiotepa is an alkylating agent with excellent CNS penetration.
R-MPV	Rituximab + HD-MTX 3.5 g/m² + procarbazine + vincristine	Alternative induction regimen; widely used in North America.
R-MTX + HD-AraC	Rituximab + HD-MTX + HD-cytarabine	Two-drug CNS-penetrant backbone + rituximab
HD-MTX monotherapy	HD-MTX 3.5–8 g/m² Q2–3 weeks × 6–8 cycles	For older or less fit patients who cannot tolerate multi-agent chemotherapy

Multi-agent cytotoxic chemotherapy ± monoclonal antibodies (e.g. anti-CD20 in CD20+ B-cell lymphomas) ^[29]

Multiple cycles of chemotherapy with interim and end-of-treatment assessment by imaging ± biomarkers ^[29]

Aspect	Detail
Indication	Documented leptomeningeal disease on CSF cytology/flow cytometry; some protocols include prophylactic intrathecal therapy
Agents	Intrathecal can only give methotrexate, cytarabine and steroid → medicolegal implications, nothing else ^[30]. Typically intrathecal MTX 12–15 mg or liposomal cytarabine (DepoCyt).
Route	Via lumbar puncture or Ommaya reservoir (preferred for repeated dosing — subcutaneous device connected to a ventricular catheter for direct intraventricular drug delivery)
Rationale	Systemic HD-MTX achieves good CSF levels, so intrathecal therapy is less critical than in ALL. However, if leptomeningeal disease is documented, direct intrathecal delivery ensures drug reaches all CSF compartments.

Important Safety Point

Vincristine must NEVER be given intrathecally. This is a well-known fatal medication error. Intrathecal vincristine causes ascending myeloencephalopathy and death. Intrathecal can only give methotrexate, cytarabine and steroid ^[30]. This medicolegal point is critical for clinical practice.

Aspect	Detail
Mechanism	Monoclonal antibody against CD20 ^[31] — binds CD20 on B-cell surface → complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and direct apoptosis
BBB penetration	Very poor (~0.1% of serum concentration reaches CSF). However, in PCNSL the BBB is disrupted by the tumour itself, allowing some penetration. Benefit is modest but additive.
HBV screening	Mandatory before rituximab. Start entecavir when HBV DNA becomes detectable. Continue for at least 12 months after last cycle of rituximab — profound B-cell depletion takes ~1 year to recover, and reconstituting B cells can prime T cells which then damage the liver ^[28].
Infusion reactions	Fever, rigors, hypotension — usually with first infusion. Pre-medicate with paracetamol, antihistamine, and steroid.

Timepoint	Modality	Criteria
After 2–4 cycles of induction	Gadolinium-enhanced MRI brain	IPCG response criteria: CR (complete disappearance of enhancement), PR (≥ 50% reduction), PD (≥ 25% increase or new lesions)
After induction completion	MRI brain + LP with CSF cytology/flow cytometry + slit-lamp eye exam	Must assess all three CNS compartments (brain, CSF, eyes)
Additional	PET-CT is less established for CNS assessment than for systemic DLBCL because PET-CT is not good for brain as the background activity is too hypermetabolic ^[32] — normal brain has very high FDG uptake, making interpretation difficult

Phase 4: Consolidation Therapy

Consolidation aims to eradicate residual microscopic disease after achieving CR with induction. Without consolidation, relapse is almost inevitable.

Aspect	Detail
Rationale	Thiotepa is an alkylating agent with excellent CNS penetration (CSF:plasma ratio ~1:1). Myeloablative doses of thiotepa + carmustine (BCNU) ± busulfan can eradicate residual CNS lymphoma but cause lethal bone marrow aplasia → requires autologous stem cell rescue.
Procedure	(1) Peripheral blood stem cell harvest after induction; (2) Conditioning with thiotepa ± BCNU; (3) Autologous stem cell re-infusion to rescue marrow
Evidence	IELSG32 trial: Consolidation with thiotepa-BCNU + ASCT was superior to WBRT in PFS and had less neurotoxicity
Candidacy	Age typically < 65 (some centres up to 70 if very fit), adequate organ function, achieved CR or PR after induction

Autologous HSCT is reserved for selected relapsed patients who are chemo-sensitive ^[29]. In PCNSL, autologous HSCT is also used as first-line consolidation (unlike most other lymphomas where it is reserved for relapse).

Aspect	Detail
Mechanism	Ionising radiation damages DNA in rapidly dividing tumour cells. WBRT treats the entire brain because PCNSL is a diffuse disease — focal RT would miss microscopic disease elsewhere.
Traditional dose	36–45 Gy in 20–25 fractions
Reduced dose	23.4 Gy in 13 fractions — used after achieving CR with chemotherapy. Lower dose → less neurotoxicity while maintaining efficacy.
Neurotoxicity	The major limitation. Delayed (months–years) leukoencephalopathy with progressive cognitive decline, gait ataxia, urinary incontinence (mimics NPH). Risk increases with age > 60 and higher dose. This is why modern protocols increasingly defer or omit WBRT.
Current role	(1) Reduced-dose WBRT for patients who achieve CR but are not candidates for ASCT; (2) Full-dose WBRT as consolidation in patients who did not achieve CR; (3) Palliative WBRT in patients unfit for chemotherapy

High-dose cytarabine or etoposide-based regimens for patients who are not ASCT candidates.
Less evidence than ASCT but avoids WBRT neurotoxicity.

Approach	Detail
Re-induction with HD-MTX	If relapse occurs > 12 months after initial CR, re-induction with HD-MTX-based regimen is reasonable (suggests chemo-sensitivity preserved)
Ibrutinib (BTK inhibitor)	Targeted therapy (BTK or BCL-2 inhibitors) ^[29]. Ibrutinib ("ibru" = Bruton's) inhibits Bruton's tyrosine kinase, which is downstream of both the BCR and MYD88 signalling pathways — both constitutively activated in PCNSL. Ibrutinib crosses the BBB well. Response rates ~50–70% as single agent.
Temozolomide	Oral alkylating agent with good BBB penetration (the same drug used for GBM). Used as salvage in relapsed PCNSL.
Lenalidomide + rituximab (R²)	Immunomodulatory agent + anti-CD20; emerging evidence for relapsed PCNSL.
CAR-T cell therapy	Chimeric antigen receptor T (CART) cell therapy for specific subtypes of B lymphomas (e.g. R/R DLBCL) ^[29]. CAR-T targeting CD19 (e.g. axicabtagene ciloleucel, tisagenlecleucel) is FDA-approved for relapsed/refractory systemic DLBCL and is under investigation for PCNSL. Early trials show promising responses. Key toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
Checkpoint inhibitors	The use of immuno-conjugates, checkpoint inhibitors, bi-specific antibodies for certain subtypes of lymphoma ^[29]. PD-L1/PD-L2 gains are common in PCNSL (9p24.1 amplification) → rationale for anti-PD-1 therapy (nivolumab, pembrolizumab). Case series show responses but formal trials are ongoing.
Salvage WBRT	For patients who have not received prior RT and are unfit for further chemotherapy.

Special Populations

Aspect	Detail
First priority	Start antiretroviral therapy (ART) — immune reconstitution alone can induce partial or complete tumour regression in some patients
Chemotherapy	HD-MTX-based regimens can be used if the patient's performance status and immune function allow. Concurrent ART is essential. Drug interactions between ART and chemotherapy must be monitored.
Prognosis	Historically very poor (median survival 2–3 months without ART). With ART + chemotherapy, outcomes are improving but remain worse than immunocompetent PCNSL.

Aspect	Detail
First step	Reduction of immunosuppression (RI) — this alone may induce regression of EBV-driven PTLD. Must balance risk of graft rejection.
If RI fails	Rituximab monotherapy → if fails → chemotherapy (R-CHOP or HD-MTX-based depending on CNS involvement)

Approach	Detail
Reduced-dose HD-MTX	1–3 g/m² (lower than standard 3.5 g/m²) with careful renal monitoring
Temozolomide-based regimens	Oral, well-tolerated, good BBB penetration
Palliative WBRT	If unfit for any chemotherapy; provides temporary disease control but neurotoxicity is high in the elderly
Best supportive care	For patients with very poor performance status; includes dexamethasone for oedema control, anticonvulsants, palliative care

Issue	Management
Cerebral oedema	High-dose glucocorticoids: PO (or IV if severe) dexamethasone 10 mg then 4 mg Q4h or 8 mg BD ^[27]. Reduce and wean once chemotherapy takes effect. Gastric protection (PPI) during steroid use.
Seizures	Anticonvulsants: treatment or secondary prophylaxis of seizures, usually levetiracetam (Keppra). NOT for infratentorial lesions, usually not for primary prophylaxis ^[27]
Tumour lysis syndrome (TLS) prophylaxis	Supportive care with the prevention of tumour lysis syndrome ^[29]. Adequate hydration + allopurinol (check HLA-B*5801 first) ± rasburicase if high risk ^[2]
Neutropenic fever	HD-MTX and multi-agent regimens cause myelosuppression. Standard febrile neutropenia management: blood cultures → empirical broad-spectrum antibiotics (e.g. piperacillin-tazobactam)
MTX toxicity monitoring	Serum MTX levels, renal function, mucositis assessment. Glucarpidase for dangerously delayed clearance.
PJP prophylaxis	Co-trimoxazole during and after chemotherapy (lymphocyte depletion → risk of Pneumocystis jirovecii)
Thromboprophylaxis	Immobilised patients with brain tumours are at high VTE risk. LMWH unless contraindicated.

Modality	Indication	Key Contraindications
HD-MTX (≥ 3 g/m²)	First-line induction in ALL fit patients	CrCl < 30–40 mL/min; severe hepatic impairment; significant third-space fluid; pregnancy
Rituximab	Added to HD-MTX in CD20+ PCNSL	HBV without antiviral cover; severe previous infusion reaction
HD-Cytarabine	Combined with HD-MTX in MATRix regimen	Severe renal/hepatic impairment; cerebellar toxicity risk in elderly
Thiotepa	Myeloablative consolidation with ASCT	Age > 65–70 (relative); significant cardiac/hepatic/renal comorbidity
Autologous HSCT	First-line consolidation in fit patients achieving CR/PR	Age > 65–70 (relative); inadequate stem cell harvest; active infection; poor organ function
WBRT (reduced dose 23.4 Gy)	Consolidation if ASCT not feasible; achieved CR	Prior WBRT; severe pre-existing cognitive impairment (relative)
WBRT (full dose 36–45 Gy)	Palliative; primary therapy if unfit for chemo	As above
Ibrutinib	Relapsed/refractory PCNSL	Concomitant strong CYP3A4 inhibitors; severe bleeding risk; atrial fibrillation (relative)
Temozolomide	Salvage therapy; elderly patients	Severe myelosuppression; hypersensitivity to dacarbazine
Intrathecal MTX/AraC	Documented leptomeningeal disease	NEVER give vincristine intrathecally
CAR-T cell therapy	R/R DLBCL including PCNSL (emerging)	Active infection; severe organ dysfunction; prior severe neurotoxicity

High Yield Summary — Management of PCNSL

Surgery is NOT therapeutic — stereotactic biopsy for diagnosis only. Lymphoma is not treated by surgery ^[27].
Induction: HD-MTX-based multi-agent chemotherapy (MATRix = MTX + AraC + thiotepa + rituximab is current gold standard for fit patients). Multi-agent cytotoxic chemotherapy ± monoclonal antibodies (anti-CD20 in CD20+ B-cell lymphomas) ^[29].
Consolidation: Thiotepa-based myeloablative chemo + autologous HSCT (fit, < 65) > reduced-dose WBRT (23.4 Gy) > non-myeloablative chemo.
Avoid full-dose WBRT in elderly (devastating neurotoxicity).
R-CHOP does NOT work for PCNSL — CHOP drugs don't cross the BBB.
HBV screening mandatory before rituximab — start entecavir prophylaxis if any HBV marker positive, continue ≥ 12 months post-rituximab ^[28].
Relapsed PCNSL: Re-induction with HD-MTX (if late relapse), ibrutinib (BTK inhibitor — crosses BBB, targets MYD88/BCR pathway), temozolomide, lenalidomide, CAR-T, or checkpoint inhibitors ^[29].
HIV-associated PCNSL: ART first → then HD-MTX-based chemo if fit.
Supportive care: Dexamethasone for oedema (once diagnosis confirmed), levetiracetam for seizures, TLS prophylaxis, HBV prophylaxis, PJP prophylaxis.
Intrathecal drugs: Only methotrexate, cytarabine, and steroid can be given intrathecally — never vincristine ^[30].

Active Recall - Management of PCNSL

References

^[2] Senior notes: Maksim Medicine Notes.pdf p.178 (lymphoma investigations, pre-treatment screen including HBV/HCV/HIV, PET-CT, LDH, urate for TLS) ^[27] Senior notes: Ryan Ho Neurology.pdf p.163 (brain tumour management — steroids C/I in suspected lymphoma, stereotactic biopsy for lymphoma, anticonvulsants, dexamethasone dosing) ^[28] Senior notes: Block A - I am a hepatitis B carrier.pdf p.69–70 (rituximab and HBV: screening, prophylaxis with entecavir, duration 12 months post-anti-CD20, monitoring) ^[29] Lecture slides: GC 055. Generalized lympadenopathy.pdf p.40 (principles of management of lymphomas: multi-agent chemo ± anti-CD20, targeted therapy, checkpoint inhibitors, HSCT, CAR-T, TLS prevention) ^[30] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf p.20 (intrathecal can only give MTX, cytarabine, steroid; CNS prophylaxis with intrathecal MTX) ^[31] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf p.18 (monoclonal antibody against CD20) ^[32] Senior notes: Ryan Ho Respiratory.pdf p.144 (PET-CT not good for brain as background activity is too hypermetabolic)

Complications of Primary CNS Lymphoma

Complications of PCNSL can be organised into three broad categories: (1) complications of the disease itself, (2) complications of treatment, and (3) complications of relapse. Understanding the "why" behind each complication is essential — each one can be traced back to a pathophysiological mechanism.

A. Complications of the Disease Itself

These are the complications that arise from the tumour's direct effects on the CNS and from systemic consequences of malignancy.

Complication	Mechanism	Clinical Features
Obstructive hydrocephalus	Large periventricular tumour mass compresses the ventricular system (especially the third ventricle, aqueduct of Sylvius, or fourth ventricle) → blocks CSF outflow → CSF accumulates proximal to the obstruction → ↑ICP	Progressive headache (worse in morning), nausea/vomiting, ↓consciousness, papilloedema. Requires CSF shunting for hydrocephalus (e.g. in posterior fossa lesions, leptomeningeal meningitis, CSF mets) ^[10]
Brain herniation	Progressive ↑ICP → brain tissue displaced across fixed dural partitions (falx cerebri, tentorium cerebelli, foramen magnum)	Uncal herniation: ipsilateral CN III palsy (fixed dilated pupil) → contralateral hemiparesis → ↓GCS → death. Tonsillar herniation: cerebellar tonsils through foramen magnum → brainstem compression → Cushing's triad → cardiorespiratory arrest
Cerebral oedema	Tumour disrupts the BBB → vasogenic oedema (plasma leaks into extracellular space of white matter) → increases brain volume → ↑ICP	Worsening focal deficits, headache, ↓consciousness. Responsive to dexamethasone (which stabilises BBB and reduces oedema — but recall the steroid caution pre-biopsy)

Why does vasogenic oedema respond to dexamethasone? Dexamethasone reduces BBB permeability by stabilising endothelial tight junctions and reducing expression of vascular endothelial growth factor (VEGF) and other permeability factors. In PCNSL specifically, steroids ALSO directly lyse lymphoma cells (an additional mechanism beyond oedema reduction), which is why the response can be so dramatic.

Complication	Mechanism	Management Considerations
Focal or secondarily generalised seizures (~10-20%)	Tumour infiltration or oedema irritates cortical neurons → abnormal paroxysmal electrical discharges. Less common in PCNSL than in cortical tumours (e.g. meningioma, GBM) because PCNSL preferentially involves deep white matter	Levetiracetam (Keppra) preferred for treatment/secondary prophylaxis; usually NOT for primary prophylaxis in infratentorial lesions ^[10]. Avoid enzyme-inducing AEDs (phenytoin, carbamazepine) because they accelerate hepatic metabolism of chemotherapy agents
Status epilepticus	Sustained or recurrent seizures without recovery → medical emergency → can cause permanent neuronal damage	IV benzodiazepines (lorazepam) → IV levetiracetam or phenytoin → if refractory, ICU for propofol/midazolam infusion

Present in 10–20% at diagnosis; can also develop during disease course.

Feature	Detail
Mechanism	Lymphoma cells disseminate through CSF pathways → coat the leptomeninges (pia and arachnoid) → compress cranial nerves as they traverse the subarachnoid space and infiltrate spinal nerve roots
Clinical features	Multiple cranial nerve palsies (especially CN III, VI, VII), radiculopathy, cauda equina syndrome, headache, meningism, communicating hydrocephalus (CSF protein and cells clog arachnoid granulations → impaired CSF reabsorption)
Diagnosis	CSF cytology and flow cytometry (may need repeated LPs — sensitivity improves with each tap); MRI with gadolinium showing leptomeningeal enhancement
Treatment	Intrathecal methotrexate (± cytarabine) via LP or Ommaya reservoir; systemic HD-MTX also contributes
Prognosis	Carries a worse prognosis than parenchymal-only disease

Complication	Mechanism	Clinical Impact
Vitreoretinal lymphoma	Lymphoma cells infiltrate vitreous humour and retina (embryologically CNS-derived tissue)	Progressive painless visual loss, floaters; often misdiagnosed as "chronic uveitis" for months (masquerade syndrome)
Secondary glaucoma	Tumour cells or inflammatory debris block aqueous outflow through trabecular meshwork	Raised intraocular pressure → optic nerve damage if untreated
Retinal detachment	Subretinal lymphoma infiltrates → fluid accumulates between retinal pigment epithelium and neurosensory retina	Sudden visual field loss, photopsia

Primary CNS lymphoma commonly involves the eyes ^[28] — always perform slit-lamp examination and dilated fundoscopy at diagnosis and during follow-up. ~50-80% of patients with primary vitreoretinal lymphoma eventually develop brain disease.

Feature	Detail
Mechanism	CNS pathology (tumour mass, ↑ICP, or leptomeningeal disease) disrupts hypothalamic osmoreceptor function → inappropriate secretion of ADH → excessive free water retention → dilutional hyponatraemia
Why this matters	CNS causes of SIADH include meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP ^[36]. PCNSL, as a CNS mass causing ↑ICP or infiltrating the hypothalamus, falls into this category
Clinical features	Malaise, lethargy, headache (mild); confusion, convulsions, coma (severe) — symptoms vary based on level and acuity; more severe if acute hyponatraemia ^[36]
Management	Fluid restriction; treat underlying cause (tumour); if severe (Na⁺ < 120 with seizures), cautious hypertonic saline. Rate of correction must be slow for chronic hyponatraemia — < 0.5 mmol/L/hour or < 12 mmol/L/day — to avoid central pontine myelinolysis ^[36]

Important Exam Point

Central pontine myelinolysis (osmotic demyelination syndrome) is a complication of too rapid correction of chronic hyponatraemia ^[36]. Patients become tetraplegic with pseudobulbar features. In a PCNSL patient who is already neurologically compromised, this would be devastating. Always correct chronic hyponatraemia slowly.

Feature	Detail
Mechanism	Lymphoma cells can produce calcitriol (1,25-dihydroxyvitamin D₃) — via ectopic expression of 1α-hydroxylase in tumour cells → increased intestinal calcium absorption and bone resorption. Less commonly, direct bony involvement or PTHrP secretion
Relevance to PCNSL	Less common than in systemic lymphoma (PCNSL is confined to CNS), but hypercalcaemia and tumour lysis syndrome are listed as complications of NHL ^[2]
Management	IV saline hydration → IV bisphosphonates (zoledronic acid) once eGFR adequate → glucocorticoids are indicated for hypercalcaemia due to endogenous overproduction of calcitriol (chronic granulomatous disease, lymphoma) ^[37] → denosumab if refractory or eGFR < 35

Feature	Detail
Mechanism	Virchow's triad: (1) Stasis — immobility from neurological deficits, hospitalisation; (2) Hypercoagulability — malignancy-associated procoagulant state (tissue factor, cancer procoagulant, inflammatory cytokines); (3) Endothelial injury — from chemotherapy, central venous catheters
Manifestations	Deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral venous sinus thrombosis (rare but devastating in a patient already with CNS disease)
Prevention	LMWH prophylaxis during hospitalisation; compression stockings; early mobilisation

B. Complications of Treatment

HD-MTX is the backbone of PCNSL therapy but carries significant toxicity. Understanding the "why" behind each side effect comes from its mechanism — MTX inhibits DHFR, blocking DNA synthesis in ALL rapidly dividing cells, not just tumour cells.

Complication	Mechanism	Prevention / Management
Acute kidney injury (AKI)	Methotrexate causes direct toxicity to renal tubular cells ^[29]. At high doses, MTX and its metabolites crystallise in renal tubules (especially in acidic urine) → obstructive tubular nephropathy	Aggressive IV hydration; urinary alkalinisation (NaHCO₃ to pH ≥ 7.0); monitor serum MTX levels; avoid concomitant NSAIDs, penicillins, PPIs (compete for tubular secretion)
Mucositis	Rapidly dividing mucosal epithelial cells are damaged by folate depletion → oral ulceration, oesophagitis, diarrhoea	Leucovorin rescue (folinic acid) — must be started 24h post-MTX and continued until serum MTX level < 0.05 μmol/L. Ice cubes during infusion may reduce oral mucositis
Myelosuppression	Bone marrow progenitor cells are rapidly dividing → suppressed by MTX → pancytopenia (nadir at 7-14 days)	CBC monitoring; leucovorin rescue; G-CSF support if severe neutropenia; platelet/RBC transfusion as needed
Hepatotoxicity	MTX causes hepatocyte injury → transaminitis; chronic use can cause hepatic fibrosis	Monitor LFT before each cycle; hold or dose-reduce if transaminases significantly elevated
Delayed MTX clearance	Third-space fluid collections (pleural effusion, ascites) act as reservoirs → MTX slowly leaches out → prolonged systemic exposure → ↑all toxicities	Drain significant effusions BEFORE starting HD-MTX; monitor serum MTX levels at 24h, 48h, 72h

Complication	Mechanism	Prevention / Management
Infusion reactions	First-dose effect: rituximab binding to CD20 on circulating B cells triggers cytokine release (TNF-α, IL-6) → fever, rigors, hypotension, bronchospasm	Pre-medicate with paracetamol + antihistamine + IV hydrocortisone; slow initial infusion rate; subsequent infusions are usually better tolerated
HBV reactivation	Rituximab causes profound B-cell depletion → loss of anti-HBs-producing B cells → HBV reactivation can occur even in patients with resolved infection (anti-HBc +ve, HBsAg -ve) ^[31]. Reactivation can occur over 11 months after the last cycle of rituximab → profound depletion of B cells will take 1 year to recover ^[31]	Start prophylactic entecavir/TDF; continue ≥12 months after last rituximab cycle ^[31]; presence of anti-HBs appears to have some protective benefit ^[31]
Hypogammaglobulinaemia	Depletion of B cells → reduced immunoglobulin production → ↑susceptibility to encapsulated organisms (S. pneumoniae, H. influenzae)	Monitor serum Ig levels; IVIG replacement if severe hypogammaglobulinaemia with recurrent infections
Progressive multifocal leukoencephalopathy (PML)	JC virus reactivation in the setting of profound immunosuppression from rituximab	Very rare but devastating; no effective treatment; monitor for new white matter lesions on MRI
Reactivation of other infections	Anti-CD20 is capable of reactivating CMV, Parvovirus B19, Adenovirus, PCP/PJP ^[38]	PCP prophylaxis (co-trimoxazole); vigilance for atypical infections

High Yield — HBV Reactivation with Rituximab

Fatal HBV reactivation has been reported even 11 months after stopping rituximab, because B-cell reconstitution takes approximately 1 year. Once B cells recover, they prime T cells, which then mount an immune response against HBV-infected hepatocytes → potentially dangerous and fatal, especially in decompensated liver disease or lymphoma patients ^[38]. This is why antiviral prophylaxis must continue for ≥12 months post-last rituximab.

This is arguably the most feared long-term complication in PCNSL management and the main reason WBRT has been largely replaced by ASCT consolidation.

Complication	Mechanism	Clinical Features	Time Course
Radiation-induced leukoencephalopathy	Ionising radiation damages oligodendrocytes (myelin-producing cells) and small vessel endothelium → progressive demyelination + microvascular ischaemia → confluent white matter damage	Progressive subcortical dementia (memory loss, psychomotor slowing, personality change, apathy), gait ataxia, urinary incontinence — a triad resembling normal pressure hydrocephalus (NPH)	Months to years after WBRT (typically 6 months to 5 years); irreversible and progressive
Cerebral atrophy	Loss of neural tissue from radiation damage	Progressive cognitive decline, ventriculomegaly on imaging	Gradual, cumulative
Radiation necrosis	Focal vascular damage → ischaemic necrosis of brain tissue	Can mimic tumour recurrence on imaging (ring-enhancing lesion); may require biopsy to distinguish from relapse	Typically 6-18 months post-RT
Endocrine dysfunction	Radiation to hypothalamic-pituitary axis → hypopituitarism	Fatigue, hypothyroidism, adrenal insufficiency, hypogonadism	Months to years
Second malignancies	Radiation-induced DNA damage in normal brain tissue → meningioma (most common radiation-induced brain tumour), glioma	New mass lesion years after treatment	Typically > 5-10 years

Risk of second malignancies from RT: 1.5-4.5× solid tumours ^[39]. Sites include breast, lung, colon for body RT; for cranial RT, meningioma and glioma are the main concerns.

Why is neurotoxicity worse in elderly patients? The ageing brain has reduced capacity for oligodendrocyte regeneration and has pre-existing white matter disease (small vessel disease). Radiation damage is additive on top of age-related changes, so the threshold for clinically apparent leukoencephalopathy is lower. This is why current guidelines recommend avoiding WBRT in patients > 60 years whenever possible.

Complications of HSCT include ^[39]:

Phase	Complication	Mechanism
Early (< 1 year)	Mucositis (oral and non-oral)	Conditioning regimen (thiotepa, BCNU) damages rapidly dividing mucosal epithelium. Oral mucositis: ice cubes, pre-treatment by laser, IV palifermin ± TPN ^[39]
	Neutropenic infections (bacterial and fungal)	Myeloablative conditioning → profound neutropenia (nadir day 7-14) until engraftment (day 10-21). Most dangerous period; requires empirical broad-spectrum antibiotics if febrile
	Haemorrhagic complications	Thrombocytopenia from conditioning → bleeding sites: lung (16%), GI (14%), CNS (12%) ^[39] — CNS haemorrhage is particularly catastrophic in a patient with pre-existing brain disease
	Veno-occlusive disease (VOD) of the liver	Conditioning damages hepatic venous endothelium → S/S: painful hepatomegaly, ascites, jaundice ± fulminant failure; Mx: ursodeoxycholic acid/heparin for prophylaxis, defibrotide + supportive Tx ^[39]
	Engraftment syndrome	Cytokine storm during neutrophil recovery → fever, rash, pulmonary infiltrates
Late (> 1 year)	Second malignancies	DNA damage from conditioning; post-transplant lymphoproliferative disease (PTLD), post-treatment MDS and acute leukaemia, solid organ tumours ^[39]
	Endocrine dysfunction	T2DM, hypothyroidism, hypogonadism, infertility, osteoporosis from conditioning agents ^[39]
	Cardiovascular disease	5% at 5 years, 9% at 15 years; most common cause of morbidity/non-relapse mortality ^[39]

Note: Autologous HSCT does NOT carry risk of graft-versus-host disease (GvHD) — GvHD only occurs in allogeneic HSCT where donor immune cells attack recipient tissues.

Agent	Key Toxicity	Mechanism
Cytarabine (high-dose Ara-C)	Cerebellar toxicity → irreversible ataxia, dysarthria	Direct neurotoxicity to cerebellar Purkinje cells at high doses; risk ↑ with age > 50 and renal impairment
Thiotepa	Skin toxicity (erythroderma), mucositis, myelosuppression	Alkylating agent; skin toxicity is characteristic of thiotepa specifically
Procarbazine	Myelosuppression, nausea, MAO inhibitor-like reactions (tyramine-containing foods → hypertensive crisis)	Procarbazine has weak MAO inhibitor activity → dietary tyramine must be restricted

S/E of high-dose glucocorticoids: peptic ulcer (need prophylaxis), immunosuppression, diabetes mellitus ^[10].

Complication	Mechanism	Prevention
Peptic ulcer / GI bleeding	Steroids inhibit prostaglandin synthesis → reduced mucosal protection; also potentiate acid secretion	PPI prophylaxis (omeprazole)
Hyperglycaemia / steroid-induced DM	Steroids promote gluconeogenesis, insulin resistance	Blood glucose monitoring; insulin sliding scale if needed
Immunosuppression	Steroids suppress both innate and adaptive immunity	Monitor for opportunistic infections; PCP prophylaxis if prolonged steroid use
Proximal myopathy	Steroid-induced protein catabolism in proximal muscles	Minimise duration; physiotherapy
Osteoporosis	Steroids inhibit osteoblast function + promote osteoclast activity	Calcium, vitamin D supplementation; consider bisphosphonates if prolonged use
Adrenal suppression	Exogenous steroids suppress hypothalamic-pituitary-adrenal (HPA) axis via negative feedback → adrenal atrophy	Never abruptly stop prolonged steroids — taper gradually

Feature	Detail
Relapse rate	~50% of PCNSL patients relapse, most within 2 years of completing treatment
Pattern of relapse	Usually within the CNS (same or new brain location); systemic relapse is rare (< 10%) — the disease remains "trapped" in the CNS
Intraocular relapse	May occur as isolated vitreoretinal recurrence even when brain disease is controlled — reinforces need for ongoing ophthalmological surveillance
Leptomeningeal relapse	CSF dissemination at relapse carries very poor prognosis
Prognosis at relapse	Generally poor, especially if relapse is within 1 year of initial treatment (early relapse → chemorefractory). Late relapse ( > 2 years) may respond to HD-MTX re-induction
Salvage options	HD-MTX re-challenge (if late relapse); BTK inhibitors (ibrutinib); lenalidomide-rituximab; WBRT if not previously given; CAR-T cell therapy for R/R DLBCL ^[30]; clinical trials

Category	Complication	Key Mechanism	Key Management Point
Disease	↑ICP / herniation	Mass effect + oedema + hydrocephalus	Dexamethasone (post-biopsy); CSF shunting
Disease	Seizures	Cortical irritation	Levetiracetam; avoid enzyme-inducing AEDs
Disease	Leptomeningeal disease	CSF dissemination	Intrathecal MTX
Disease	Intraocular involvement	Vitreoretinal infiltration	Slit-lamp exam; intravitreal MTX
Disease	SIADH / hyponatraemia	Hypothalamic dysfunction / ↑ICP	Fluid restriction; correct slowly
Disease	VTE	Virchow's triad (stasis + hypercoagulability + endothelial injury)	LMWH prophylaxis
Treatment	MTX nephrotoxicity	Tubular crystallisation	Hydration + alkalinisation + leucovorin
Treatment	HBV reactivation	Rituximab depletes B cells	Antiviral prophylaxis ≥12 months post-rituximab
Treatment	WBRT leukoencephalopathy	Oligodendrocyte + vascular damage	Avoid WBRT if possible (prefer ASCT)
Treatment	ASCT complications	Conditioning-related myelosuppression	Supportive care; infection prophylaxis
Treatment	Steroid side effects	Systemic metabolic effects	PPI, glucose monitoring, taper gradually
Relapse	CNS relapse (~50%)	Residual clonal disease	Re-induction or novel agents

High Yield — GC Lecture Slide

Investigations for lymphomas have seven aims ^[20]:

Accurate diagnosis
Staging
Detect complications of lymphoma
Determine prognosis
Determine suitability or fitness for treatment
Detecting complications of treatment
Assessing response to treatment

Points 3, 6, and 7 are directly relevant to this complications section — always monitor for both disease-related and treatment-related complications throughout the patient's journey.

High Yield Summary — Complications of PCNSL

Disease complications: ↑ICP/herniation (mass effect + oedema + hydrocephalus), seizures, leptomeningeal disease, intraocular involvement, SIADH, VTE
HD-MTX toxicity: AKI (renal tubular crystallisation — prevent with hydration + alkalinisation), mucositis, myelosuppression, hepatotoxicity — all rescued by leucovorin
Rituximab toxicity: Infusion reactions, HBV reactivation (can be fatal; cover ≥12 months post-last cycle), hypogammaglobulinaemia, PML
WBRT: Delayed leukoencephalopathy (dementia + ataxia + incontinence — resembles NPH) — the main reason WBRT is now avoided in favour of ASCT consolidation
ASCT: Early — mucositis, neutropenic sepsis, VOD; Late — second malignancies, endocrine dysfunction, cardiovascular disease
Steroids: PUD, DM, immunosuppression, myopathy, osteoporosis — always PPI cover and glucose monitoring
Relapse occurs in ~50%, almost always within the CNS; salvage options include HD-MTX re-challenge, BTK inhibitors, CAR-T, and WBRT if not previously given
Chronic hyponatraemia must be corrected slowly (< 12 mmol/L/day) to avoid central pontine myelinolysis

Active Recall - Complications of PCNSL

References

^[2] Senior notes: Ryan Ho Haemtology, Ch 3.5 — NHL complications including hypercalcaemia and TLS (pp. 97–98) ^[10] Senior notes: Ryan Ho Neurology, Section 8.3 — Brain tumour management, steroids CI, anticonvulsants, CSF shunting (pp. 163, 165) ^[20] Lecture slides: GC 055. Generalized lympadenopathy.pdf — Investigations for lymphomas: aims (p. 36) ^[28] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai) — Primary CNS lymphoma commonly involves the eyes (p. 1423) ^[29] Senior notes: Block A - Drugs and the Kidney — MTX direct tubular toxicity, checkpoint inhibitor nephrotoxicity (p. 9) ^[30] Lecture slides: GC 055. Generalized lympadenopathy.pdf — Principles of management of lymphomas including CAR-T (p. 40) ^[31] Senior notes: Block A - I am a hepatitis B carrier — Rituximab and HBV reactivation, antiviral prophylaxis, anti-HBs protective (pp. 68–69) ^[36] Senior notes: Block A - Electrolyte and Acid-Base Disorders — SIADH causes (CNS), hyponatraemia management, central pontine myelinolysis (pp. 21–22) ^[37] Senior notes: Block A - Confused and dehydrated — Hypercalcaemia management, glucocorticoids in lymphoma-related hypercalcaemia (pp. 11–12) ^[38] Senior notes: Block A - I am a hepatitis B carrier — Anti-CD20 reactivating CMV, Parvovirus B19, PCP (p. 68) ^[39] Senior notes: Ryan Ho Haemtology — HSCT complications: early and late, treatment-related complications of HL/NHL therapy including second malignancies, cardiovascular disease (pp. 96, 156)

High Yield Summary

Definition: PCNSL is an aggressive extranodal NHL (almost always DLBCL, ABC subtype) confined to the CNS (brain, spinal cord, leptomeninges, eyes) without systemic disease.
Epidemiology: Rare (~3–4% of brain tumours); bimodal — young immunocompromised, elderly immunocompetent. Male predominance.
Risk factors: Immunosuppression (HIV with CD4 < 50, post-transplant, congenital immunodeficiency) + EBV are the key risk factors. ^[1]
Pathophysiology: In immunocompromised → EBV-driven B-cell proliferation escaping T-cell control in the immune-privileged CNS. In immunocompetent → acquired somatic mutations (especially MYD88 L265P in 50–80%) driving constitutive NF-κB activation.
Clinical features:
- Most common presentation: Subacute cognitive/behavioural change + focal neurological deficits (deep white matter predilection)
- Headache (raised ICP), seizures (less common than cortical tumours)
- Ocular involvement in 15–25% (floaters, visual loss)
- Leptomeningeal disease in 10–25% (CN palsies, radiculopathy)
- B symptoms are uncommon (unlike systemic NHL)
- "Ghost tumour" — dramatic steroid response → avoid steroids before biopsy
Key imaging clue: Homogeneously enhancing periventricular lesion(s) with restricted diffusion on DWI-MRI in an immunocompetent patient; ring-enhancing lesion in HIV/AIDS.
Classification: WHO CNS tumours classification; not staged by Ann Arbor/TNM. Always confined to CNS by definition.

High Yield Summary — DDx of PCNSL

Immunocompetent patient with a deep, homogeneously enhancing periventricular mass with restricted diffusion:

Top DDx: GBM (but ring-enhancing with necrosis), metastasis (but cortical, known primary), tumefactive MS (open ring enhancement), abscess (ring, pus restricts on DWI)
If rapidly progressive dementia: consider CJD, autoimmune encephalitis

Immunocompromised (HIV, CD4 < 50) with ring-enhancing lesion(s):

Top DDx: Cerebral toxoplasmosis — start empirical anti-toxoplasma Rx; biopsy if no response at 2 weeks
Also consider PML (non-enhancing), TB/Crypto granuloma

Post-transplant: Think PTLD (cerebral lymphoma) — check EBV viral load

Key distinguishing features of PCNSL:

Homogeneous enhancement (immunocompetent) / ring-enhancing (HIV)
Deep periventricular location
Restricted diffusion (high cellularity)
Dramatic steroid response ("ghost tumour" — avoid steroids before biopsy!)
No systemic malignancy (by definition)

High Yield Summary — Diagnosis of PCNSL

Gold standard diagnosis: Stereotactic brain biopsy with histology (DLBCL), immunophenotyping (CD20+, BCL6+, MUM1+, CD10−), and molecular studies (IgH clonality, MYD88 L265P).
Accurate diagnosis of lymphoma requires: clinical + morphologic + immunophenotypic + genetic features ^[17]
FNA is not adequate for lymphoma — need core/excisional biopsy for architecture ^[2]
HOLD STEROIDS before biopsy — ghost tumour phenomenon renders biopsy non-diagnostic.
Must exclude systemic disease: PET-CT (or CT CAP) + bone marrow biopsy + testicular USS (males) + HIV test.
Must assess CNS extent: MRI brain + spine + LP with cytology/flow cytometry + slit-lamp eye exam.
Classic MRI triad: Homogeneous enhancement + T2-iso/hypointense + restricted diffusion on DWI, in periventricular location.
CSF: Malignant lymphoid cells on cytology (low sensitivity ~15–30%); monoclonal B cells on flow cytometry (higher sensitivity ~30–50%); EBV PCR useful in HIV setting.
HIV/AIDS pathway: CSF EBV PCR + Toxoplasma IgG + empirical anti-toxoplasma trial → biopsy if no response.
IELSG score: 5 factors (age > 60, ECOG > 1, ↑LDH, ↑CSF protein, deep brain structures) → risk stratification.

High Yield Summary — Management of PCNSL

Surgery is NOT therapeutic — stereotactic biopsy for diagnosis only. Lymphoma is not treated by surgery ^[27].
Induction: HD-MTX-based multi-agent chemotherapy (MATRix = MTX + AraC + thiotepa + rituximab is current gold standard for fit patients). Multi-agent cytotoxic chemotherapy ± monoclonal antibodies (anti-CD20 in CD20+ B-cell lymphomas) ^[29].
Consolidation: Thiotepa-based myeloablative chemo + autologous HSCT (fit, < 65) > reduced-dose WBRT (23.4 Gy) > non-myeloablative chemo.
Avoid full-dose WBRT in elderly (devastating neurotoxicity).
R-CHOP does NOT work for PCNSL — CHOP drugs don't cross the BBB.
HBV screening mandatory before rituximab — start entecavir prophylaxis if any HBV marker positive, continue ≥ 12 months post-rituximab ^[28].
Relapsed PCNSL: Re-induction with HD-MTX (if late relapse), ibrutinib (BTK inhibitor — crosses BBB, targets MYD88/BCR pathway), temozolomide, lenalidomide, CAR-T, or checkpoint inhibitors ^[29].
HIV-associated PCNSL: ART first → then HD-MTX-based chemo if fit.
Supportive care: Dexamethasone for oedema (once diagnosis confirmed), levetiracetam for seizures, TLS prophylaxis, HBV prophylaxis, PJP prophylaxis.
Intrathecal drugs: Only methotrexate, cytarabine, and steroid can be given intrathecally — never vincristine ^[30].

High Yield Summary — Complications of PCNSL

Disease complications: ↑ICP/herniation (mass effect + oedema + hydrocephalus), seizures, leptomeningeal disease, intraocular involvement, SIADH, VTE
HD-MTX toxicity: AKI (renal tubular crystallisation — prevent with hydration + alkalinisation), mucositis, myelosuppression, hepatotoxicity — all rescued by leucovorin
Rituximab toxicity: Infusion reactions, HBV reactivation (can be fatal; cover ≥12 months post-last cycle), hypogammaglobulinaemia, PML
WBRT: Delayed leukoencephalopathy (dementia + ataxia + incontinence — resembles NPH) — the main reason WBRT is now avoided in favour of ASCT consolidation
ASCT: Early — mucositis, neutropenic sepsis, VOD; Late — second malignancies, endocrine dysfunction, cardiovascular disease
Steroids: PUD, DM, immunosuppression, myopathy, osteoporosis — always PPI cover and glucose monitoring
Relapse occurs in ~50%, almost always within the CNS; salvage options include HD-MTX re-challenge, BTK inhibitors, CAR-T, and WBRT if not previously given
Chronic hyponatraemia must be corrected slowly (< 12 mmol/L/day) to avoid central pontine myelinolysis

Primary CNS Lymphoma

1. Definition

2. Epidemiology

3. Risk Factors

3.1 Immunosuppression (the dominant risk factor)

3.2 EBV Infection

3.3 Increasing Age

3.4 Other / Unproven

4. Anatomy and Function — The Immunological Privilege of the CNS

4.1 The Blood–Brain Barrier (BBB)

4.2 CSF and Leptomeninges

4.3 Periventricular White Matter

4.4 The Eye as Part of the CNS

5. Etiology and Pathophysiology

5.1 Cell of Origin

5.2 Pathogenesis — Why Do B Cells Proliferate in the Brain?

Model 1: The "Immune Privileged Sanctuary" Model (Immunocompromised PCNSL)

Model 2: The "Homing and Trapping" Model (Immunocompetent PCNSL)

5.3 Key Molecular / Genetic Aberrations (Immunocompetent PCNSL)

5.4 Pathophysiology → Clinical Consequences

6. Classification

6.1 WHO Classification of CNS Tumours (5th Edition, 2021)

6.2 WHO Grading

6.3 Classification by Anatomical Compartment

6.4 Clinical Classification by Immune Status

7. Clinical Features

7.1 General Clinical Profile

7.2 Symptoms (with Pathophysiological Basis)

A. Cognitive and Behavioural Changes (~30–50%) — The Most Common Presenting Feature

B. Focal Neurological Deficits (~50–70%)

C. Headache (~30–50%)

D. Seizures (~10–15%)

E. Visual Symptoms (~15–25%)

F. Symptoms of Leptomeningeal Disease (~10–25%)

G. Constitutional / B Symptoms

7.3 Signs (with Pathophysiological Basis)

A. Neurological Examination Findings

B. Ophthalmological Signs (Slit-Lamp and Fundoscopy)

C. Signs of Raised ICP (Late Features)

D. Signs Specific to the Immunocompromised Host

7.4 Unique Features That Help Distinguish PCNSL From Other Brain Tumours

8. Summary of Key Pathophysiological Connections

Active Recall - Primary CNS Lymphoma (Overview, Epidemiology, Risk Factors, Pathophysiology, Clinical Features)

References

The Clinical Problem

Framework for the Differential Diagnosis

A. Differential Diagnosis in the Immunocompetent Patient

1. High-Grade Glioma (Glioblastoma Multiforme / GBM)

2. Brain Metastases — The Commonest Intracranial Tumour in Adults [11]

3. Meningioma

4. Tumefactive Demyelination (Tumefactive MS / ADEM)

5. Brain Abscess

6. Other Primary Brain Tumours

7. Rapidly Progressive Dementia DDx (When Cognitive Decline Dominates)

B. Differential Diagnosis in the Immunocompromised Patient (HIV/AIDS)

1. Cerebral Toxoplasmosis — The Main DDx in HIV/AIDS

2. Progressive Multifocal Leukoencephalopathy (PML)

3. Cryptococcal / Tuberculous CNS Infection

4. Other AIDS-Defining Malignancies

C. Post-Transplant Setting

Differential Diagnosis Summary — Mermaid Diagram

Key Discriminating Features — Summary Table

Active Recall - Differential Diagnosis of PCNSL

1. Diagnostic Criteria

1.1 Essential Diagnostic Requirements

1.2 Histopathological Diagnostic Features

1.3 Supportive (Non-Tissue) Criteria

2. Diagnostic Algorithm

2.1 Step-by-Step Algorithm

2.2 Critical Decision Points Explained

3. Investigation Modalities — Detailed Breakdown

3.1 Blood Investigations

3.2 Neuroimaging

A. CT Brain ± Contrast (First-Line / Emergency)

B. MRI Brain with Gadolinium Contrast (Investigation of Choice)

C. MRI Spine (When Indicated)

D. PET-CT or CT Chest/Abdomen/Pelvis (Staging — Exclude Systemic Disease)

E. Thallium-201 SPECT or FDG-PET Brain (HIV/AIDS Setting)

3.3 Lumbar Puncture and CSF Analysis

3.4 Stereotactic Brain Biopsy — The Gold Standard