General
- Rare form of extra-nodal non-Hodgkin lymphoma
- A diffuse large B-cell lymphoma (DLBCL) confined to the CNS at presentation (i.e. Without systemic involvement)
- Made up of
- 90% Diffuse large B-cell lymphoma of the CNS (DLBCL)
- Rarely: Burkitt, low-grade, or T-cell lymphoma
Definition
- Essential
- Biopsy-proven mature large B-cell lymphoma confined to the CNS at presentation AND
- Expression of one or more B-cell markers (CD20, CD19, CD22, CD79a, PAX5).
- Desirable
- Immunohistochemical phenotype of late germinal-centre exit B cells (IRF4 [MUM1]+, BCL6+/-, CD10-). Note that CD10 expression does not preclude the diagnosis, but it is uncommon and suggests the possibility of systemic DLBCL.
- Immunohistochemical positivity for BCL2 and MYC.
- Absence of EBV-associated markers (in >97% of cases).
- Molecular detection of a clonal B-cell population in cases where histology is not definitive, such as corticoid-mitigated CNS-DLBCL
Numbers
- 2-3% of all brain tumours
- 2% of all cases of NHL
- 4-6% of all extra-nodal lymphomas
- Annual incidence rate: 0.47/100 000 population
- Past >20 yrs, an increased incidence has been reported in patients aged > 60 years
- Age
- Can affect patients of any age
- Peak incidence 50-70yrs
- Median age: 56 years
- Male-to-female ratio is 3:2
Localisation
- Mainly deep and periventricular
- 60% supratentorial space
- Frontal lobe (15%)
- Basal ganglia and periventricular brain parenchyma (10%)
- Temporal lobe (8%)
- Parietal lobe (7%)
- Corpus callosum (5%)
- Occipital lobe (3%)
- 40% infra-tentorial
- Posterior fossa (13%)
- Spinal cord (1%)
- Leptomeninges may be involved (15– 20% )
- But exclusive meningeal manifestation is unusual
- May present with multiple cranial nerve palsies.
- Ocular manifestation (20%)
- (i.e. in the vitreous, retina, or optic nerve)
- May indicate intracranial disease
- Extraneural dissemination is very rare.
- In cases with systemic spread, PCNSL has a propensity to home to the testis, another immunoprivileged organ
Aetiology
- In immunocompetent individuals: unknown.
- Virus that play a role
- EBV: EBV is detected in over
- 95% of HIV-related PCNSL cases
- 5% of immunocompetent cases
- Viruses below do not play a role
- HHV6
- HHV8
- Polyomaviruses SV40
- BK virus
Genetics
- PCNSLs are mature B-cell lymphomas
- B cells have undergone hypersomatic mutation (mainly substitution) of genes because tumour cells are formed from late germinal centre exit B cells with blocked terminal B-cell differentiation:
- Immunoglobulin (IG) genes
- The fixed IgM/lgD phenotype is due to impaired IG class switching
- Smu region deletion → miscarried IG class switching
- PRDM1 mutations also contribute to impaired IG class switch recombination
- BCL6 gene → persistent BCL6 activity
- Other genes that have been implicated in tumorigenesis
Genetic changes
Translocations
- Affect the
- IG genes (38%)
- BCL6 gene (17-47%)
- Doe not affect
- MYC gene
- BCL2 gene
Gains of genetic material
- Chr 18q21.33-q23 (in 43% of cases)
- BCL2
- MALT1 genes
- Chr 12 (in 26%)
- Chr 10q23.21 (in 21%)
Losses of genetic material
- Chr 6q21 (in 52% of cases)
- Chr 6p21 (in 37%)
- Chr 8q12.1-q12.2 (in 32%)
- Chr 10q23.21.
- Heterozygous or homozygous loss or partial uniparental disomies of chromosomal region 6p21.32 (73%)
- This region harbours the HLA class ll-encoding genes
- HLA-DRB
- HLA-DQA
- HLA-DQB
- Lost of expression of
- HLA class I (55%)
- HLA class II (46%)
Several important pathways (the B cell receptor, the toll-like receptor, and the NF-kappaB pathway) are frequently activated due to genetic alterations affecting the genes (which may foster proliferation and prevent apoptosis)
- CD79B (20% of cases),
- INPP5D (in 25%),
- CBL (in 4%),
- BLNK (in 4%),
- CARD11 (in 16%),
- MALT1 (in 43%)
- BCL2 (in 43%)
- MYD88 (in > 50%)
Epigenetic changes
- Epigenetic silencing by DNA hypermethylation of the following genes
- DAPK1 (84%)
- CDKN2A (75%)
- MGMT (52%)
- RFC (30%)
Genetic susceptibility
- Immunocompetent individuals, genetic predispositions to PCNSL have not been described.
- 8% of patients with PCNSL have had a prior extracranial tumour
- Haematopoietic malignancy
- Most are due to this
- Use common clonality to distinguish CNS relapse from an unrelated secondary cerebral lymphoma
- Other tumours (e.g. carcinoma, meningioma, and glioma) or hereditary tumour syndromes (e.g. neurofibromatosis type 1) are likely to be coincidental
- Folate and methionine metabolism
- The G allele of the methyltetrahydrofolate homocysteine S-methyltransferase c.2756A → G (D919G) missense polymorphism has protective function
Histology
Macroscopy
- Number of lesion
- 60-70% single
- 30-40% multiple
- Cerebral hemispheres
- Deep-seated
- Adjacent to the ventricular system
- Variable characteristics
- Firm, friable, granular, haemorrhagic, and greyish tan or yellow, with central necrosis
- Virtually indistinguishable from the adjacent neuropil.
- Lymphomatosis cerebri
- Like malignant gliomas, these tumours may diffusely infiltrate large areas of the hemispheres without forming any distinct mass
(B) Primary malignant CNS lymphomas of the basal ganglia. Note the additional foci in the left insular region (arrowheads).
Microscopy
- Highly cellular, diffusely growing, patternless tumours
- Centrally
- Large areas necrosis are common
- May harbour viable perivascular lymphoma islands
- Periphery
- Angiocentric infiltration pattern is frequent.
- Infiltration of cerebral blood vessels causes fragmentation of the argyrophilic (reticular) fibre network → these form perivascular cuffs (perivascular spaces filled with leukocyte) → from these leukocyte they invade neural parenchyma in two ways
- A well-delineated invasion front with small clusters
- Diffuse invasion with a prominent astrocytic and microglial activation and harbours reactive inflammatory infiltrates consisting of mature T and B cells
- Ki-67 proliferation index > 70% or even 90%
Immunophenotype
- The tumour cells are mature B cells
- Positive
- PAX5
- CD19 positive in all B cells
- CD20 positive in all B cells
- CD22 positive in all B cells
- CD79a
- IgM and IgD
- kappa or lambda light chain restriction
- BCL6 (60-80%)
- MUM1/IRF4 (90%)
- Negative
- IgG
- Plasma cell markers
- CD38
- CD138
- CD10
- <10% of all PCNSLs express CD10
- CD10 expression is more frequent in systemic DLBCL
- Therefore, CD10 positivity in a CNS lymphoma with DLBCL characteristics should prompt a thorough investigation for systemic DLBCL that might have metastasized to the CNS.
- EBV infection
- Immunocompetent no evidence of EBV infection,
- Immunocompromised common to find. So if you find EBV infection check for poor immunity
- HLA-A/B/C and HLA-DR
- Variably expressed,
- 50% of PCNSLs having lost HLA class I and/or II expression
- 82% of PCNSLs have a BCL2-high, MYC-high phenotype
Clinical features
- More common
- Cognitive dysfunction
- Psychomotor slowing
- Focal neurological symptoms
- Less common
- Headache
- Seizures (20%)
- Cranial nerve palsies (Leptomeningeal involvement)
- Ocular involvement
- Often affecting both eyes
- Reduced visual acuity
- Eye floaters
- Pain
- Redness
- Photophobic
- Timeline
- Can be acute
- Can take years
- Immuno-incompetent
- Low CD4 counts
- EBV infection
- More likely to present with encephalopathy
- History of other concurrent infections.
Investigation
- All patients suspected of having PCNSL must undergo the following investigations
Ophthalmic examination
- Gündüz et al., 2003
- 25% PCNSL develop ocular involvement
- 90% primary intraocular lymphoma (PIOL) go on to develop PCNSL
- Abnormalities consistent with PCNSL on the slit- lamp examination would prompt a biopsy
- A fine- needle aspiration to obtain a vitreous sample
- A diagnostic vitrectomy
- Done in the eye where vision or disease is worse.
- Vitrectomy can also improve vision by removing the cellular debris that is responsible for the blurred vision and floaters.
- This procedure is less invasive than a brain biopsy and could potentially clinch the diagnosis in about 25% of patients without having to subject them to the hazards of a stereotactic brain biopsy.
CSF analysis
- Test for
- CSF chemokines (Rubenstein et al., 2013: 99.3% specific for PCNSL).
- CXCL13
- IL-10
- Cytology
- Positive CSF cytology nearly always represents leptomeningeal involvement but has limited sensitivity in specimens with low cellularity.
- Flow cytometry
- CSF flow cytometry on the other hand, does not suffer from this limitation of low cellularity and has demonstrated good sensitivity and specificity in the detection of PNCSL (Craig et al., 2011).
- PCR
- Demonstration of monoclonality of lymphocytes in the CSF by PCR can establish the diagnosis,
- PCR can be used in vitrectomy specimens to diagnose PIOL.
- CSF examination is particularly useful and important in the setting of AIDS associated PCNSL by
- Demonstrating EBV DNA
- Obviating the need for a stereotactic brain biopsy.
Stereotactic biopsy
- Is the gold standard for establishing the diagnosis and classification of CNS lymphoma.
- Important to withhold corticosteroids before biopsy, because they induce rapid tumour waning.
- Corticosteroids prevent diagnosis in 50% of cases
- The option of performing the procedure under local anaesthetic exists,
- A theoretical reduction in the risk of tumour seeding along the path of the biopsy.
- Target the centre of the suspected PCNSL lesion to reduce the chances of a negative biopsy
Grading
Low grade vs high grade
Feature | Low-Grade PCNSL | High-Grade PCNSL (DLBCL) |
Frequency | Very rare subset; minority of PCNSL cases | Vast majority of PCNSL cases |
Typical morphology | More heterogeneous, sometimes ill-defined | Typically solid, homogeneous masses |
Usual location | Deeper locations; spinal/dural more common | Periventricular and superficial CNS |
Contrast enhancement | Absent, irregular, or mild; patchy | Intense, usually homogeneous |
Edema/mass effect | Often mild to moderate | Often marked |
DWI/ADC | Variable restriction; less pronounced | Strong diffusion restriction, very low ADC |
Perfusion (rCBV) | Lower relative CBV overall | Higher relative CBV than low-grade |
Treatment approach | May allow more conservative or tailored systemic therapy | High-dose methotrexate–based chemoimmunotherapy ± radiotherapy |
Overall prognosis | Often relatively better long-term outlook | Generally poorer prognosis despite intensive treatment |
Imaging
General
- Sentinel lesions
- Rare cases, PCNSL has been reported to be preceded (by as long as 2 years) by demyelinating and inflammatory lesions similar to multiple sclerosis
Depending on immunocompetency
Immuno-competent
CT
- Hyperdense avidly enhancing mass
- Calcification, haemorrhage, and necrosis
- Rarely see, except post treatment
MRI
- T1 hypointense
- T2 variable majority are iso to hypointense to grey matter
- Isointense: 33%
- Hypointense: 20%
- Hyperintense: 15-47% more common in tumours with necrosis
- Tracking along Virchow- Robinson perivascular spaces
- T1+C
- High grade Enhancing lesion
- Low grade poor enhancing lesion.
- 10% of immunocompetent patients will harbour nonenhancing lesions
- Particularly seen at recurrence
- DWI: restricted diffusion
- ADC values are lower than the brain
- Lower the ADC value, poorer the response to Tx and higher the recurrence
- Higher ADC value after chemo predictive of complete response
- MR Spectroscopy
- Large choline peak
- High cell turnover
- Reversed choline/creatinine ratio
- Creatinine is a baseline marker
- Markedly decreased NAA
- Dec in healthy cell
- Lactate peak may also be seen
- Ischaemia
- Large lipid peaks
- Special features
- Exhibiting subependymal extension
- Crossing of the corpus callosum
Images
Nuclear medicine
- Thallium 201 scintigraphy: Inc uptake
PET
- Fluorine 18 FDG PET: Inc uptake
- Carbon 11 methionine PET inc. Uptake
Immuno-incompetent
- More heterogeneous tumours, featuring central non-enhancement/necrosis and haemorrhage
CT
- Multiple lesions (70%)
MRI
- T1 same
- T2 same
- T1+C
- Peripheral ring enhancement
Pathophysiology
Normal B cell development
flowchart TD A[B cells arise from<br>Haematopoietic stem cells] --> B[B cells emerge from bone<br>marrow as mature but<br>naïve B cells] B --> C[B cells encounter antigen in<br>peripheral lymphoid tissue] C --> D[B cells undergo somatic<br>hypermutation and affinity<br>maturation] D --> F[Terminally differentiate into] F --> E[Plasma cells] F --> G[Memory B cells]
Abnormal
- Changes of the normal B- cell development pathway to cause Diffuse large B cell lymphoma is due to alterations to the genes critical to B- cell development or physiology.
- The role of genes and regulators in PCNSL
- CD, cluster of differentiation; CDKN, cyclin-dependent kinase inhibitor; HLA, human leucocyte antigen; IL, interleukin; JAK, janus kinase; PRDM, positive regulatory domain; PTPRK, protein tyrosine phosphatase receptor type K; MALT, mucosa-associated lymphoid tissue lymphoma translocation; MYC, myelocytomatosis; MYD, myeloid differentiation; NFKB, nuclear factor kappaB; STAT, signal transducer and activator of transcription; TBL1XR1, transducin (beta)-like 1 X-linked receptor 1; TNFAIP3, tumour necrosis factor alpha-induced protein 3.
Gene/Mediator | Role | Authors |
HLA (6p21) | Antigen processing, signalling pathway | Cady et al., 2008 |
PRDM1 (6q21) | Regulate B-cell differentiation into plasma cell | Courts et al., 2008 |
PTPRK | Cell adhesion | Cady et al., 2008 |
TNFAIP3 | Regulator of nuclear factor NFKB signalling | Paik et al., 2013 |
MALT1 | Activation of NFKB pathway | Schwindt et al., 2009 |
TBL1XR1 | Transcriptional regulation of NFKB pathway | Nakamura et al., 2004 |
MYD88 | Activation of NFKB pathway and JAK/STATb pathways | Nakamura et al., 2016 |
CD79B | B-cell receptor signalling pathway | Nakamura et al., 2016 |
CDKN2A | Cell cycle regulator | Schwindt et al., 2009 |
MYC | Transcription regulation | Rubenstein et al., 2006; Cady et al., 2008 |
IL4 | Up-regulation promotes cell survival via JAK/STAT pathway | Rubenstein et al., 2006 |
Abbreviations
- PCNSL is a distinct mature B- cell lymphoma that corresponds to late germinal- centre exit B cells with blocked terminal B- cell differentiation
- Evidence of B cells are on the verge of exiting the germinal centre.
- 10% of tumours express CD10,
- 50– 90% express BCL2 and BCL6 (Braaten et al., 2003),
- > 95% stain positive for MUM1 (Camilleri- Broët et al., 2006),
- However, as the brain is devoid of germinal centres, it is not known whether the malignant transformation of B cells in PCNSL occurs prior to migration into the CNS.
- The microenvironment contains chemokines act as neurotropic or survival factors.
- CSF chemokines can be used as biomarkers of PCNSL
- For
- Aiding diagnosis
- esp for
- High- risk patients
- Patient with potentially low- yield biopsy.
- Monitoring treatment response
- Elevated levels of CXCL13 and IL-10 in CSF were found to be 99.3% specific for PCNSL, with good sensitivity (Rubenstein et al., 2013).
- The benefits of testing for these biomarkers may be more pronounced for
Spread
- The diagnostic value of cerebrospinal fluid (CSF) analysis is limited
- Pleocytosis (many WBC in CSF)
- Found in 35-60% of PCNSL cases
- Correlates with meningeal dissemination
- But only a minority of patients with leptomeningeal involvement have Lymphoma cells in their CSF
- To improve detection of CSF lymphoma cells
- The combination of cytological and immunohistochemical analysis with multiparameter flow cytometry
- Repeated Lumbar puncture
- Meningeal dissemination found in 15.7% of cases
- 12.2% by CSF cytomorphology
- 10.5% by PCR
- 4.1% by MRI
Treatment
Reference
- https://ascopubs.org/doi/full/10.1200/EDBK_242547 (Good detail summary of treatment)
Steroid therapy
- Corticoid-mitigated lymphoma
- Mechanism
- Cytotoxic to PCNSL cells
- Reduces vasogenic oedema by stabilizing the BBB
- Reduces the permeability of the BBB to chemotherapy
- May impair the therapeutic benefit of chemotherapy
- Effects are invariably short-lived
- Can cause
- Negative biopsies
- Post dex biopsy will show
- Microscopically
- Neoplastic B cells may be present in only small numbers or may even be absent.
- Samples may show non-specific inflammatory and reactive changes and/or necrosis;
- Foamy macrophages (macrophages with a lot of lipid) are frequent
- PCR analysis of the CDR3 region of the IGH gene may reveal a monoclonal B-cell population.
- But due to low numbers of B cells a fake pseudoclonality has a higher chances of occurring
- Dramatic decrease in enhancement and size of the lesions
Surgery debulking/excision
- Not for surgery
- Bierman, 2014: Anything more invasive than a biopsy is thought to risk neurological deficits while failing to improve overall survival
- The patient with a rapidly deteriorating neurological status secondary to mass effect by PCNSL
- High- dose dexamethasone + mannitol is usually adequate very rarely require surgery
- Weller et al., 2012: German PCNSL Study Group- 1 (G- PCNSL- SG- 1):
- Patients who underwent gross- total or subtotal resection were more likely to be in complete remission six months after surgery.
- The study was flawed as Biopsy patients more often had
- Multifocal disease
- Large lesions
- Deeply seated CNS lesions
Chemotherapy
- Treatment of choice: High-dose methotrexate-based polychemotherapy
- No more WBRT or HD- MTX monotherapy
- This current standard of care has been accompanied by improved overall survival rates (OS), compared to results obtained by treatment with WBRT alone, or single- agent HD- MTX chemotherapy (Table 9.4)
- Treatment is divided into two phases:
- Aim
- At controlling the disease
- Inducing remission
- Vincristine
- PCB
- Cytarabine (ARA-C)
- Ferreri 2009 n79 HD MTX vs HD MTX + ARA-C
- 18–75 years
- Thiopeta
- Alkylating agent that is active against aggressive lymphomas, and can cross the blood–brain barrier with a plasma-to-cerebrospinal fluid (CSF) ratio of 100%
- Rituximab
- An anti- CD20 monoclonal antibody
- Trials are assessing the role of concurrent immunotherapy using rituximab (IELSG- 32 and HOVON105 PCNSL/ ALLG NHL24 trials)
- Ferreri 2016 :
- HD-MTX–cytarabine vs HD-MTX–cytarabine +thiotepa + rituximab to an combination
- Combinations of high doses of MTX and cytarabine with or without rituximab, with an
- Overall response rate (ORR) of 87%
- A 2-year PFS 62%
- Overall survival (OS) 67%
- Methods of infusing chemo
- IV
- Most studies uses this route
- Therapeutic concentrations of MTX are readily achieved via the IV route.
- Intrathecal chemotherapy, often including rituximab
- Preferably by intraventricular route via an Ommaya reservoir
- Indication
- Patients with CSF disease with insufficient response to intravenous HD-MTX–based chemotherapy
- Intraocular and CSF disease is a poor prognostic sign and HD MTX tx regiments have not been proven to be fully successful.
- Patients who are not able to receive a dose of MTX 3 g/m2 or greater
- No clear evidence for it
- BBB disruption followed by chemotherapy
- A novel approach developed with the hope of improving effects of chemotherapy
- Has been limited to research centres equipped with appropriate facilities and technical capabilities (see International Blood- Brain Barrier Disruption Consortium).
- Using this technique, McAllister et al. (2000) showed comparable results to that of other studies utilizing HD- MTX- based regimens
- But reported four deaths, and increased seizure, TIAs, and stroke rates.
- While this treatment approach appears promising by potentially enhancing chemotherapy effectiveness and reducing chemotherapy doses, it requires further evaluation.
- Aim to eradicate residual disease following induction chemotherapy.
- Takes the form of
- Option 1
- WBRT ANB/OR
- Chemotherapy.
- Options 2: In the younger and fitter patients (Schorb et al., 2013).
- High- dose chemotherapy AND
- Autologous stem cell transplantation (HDT- ASCT)
Induction phase
HD- MTX (MTX delivered at doses of 1 g/m2 or more) based chemotherapy regimens
Asd | HD MTX | HD MTX + ARA-C |
Complete remission rate | 18% | 46% |
Partial response rate | 40% | 69% |
Grade 3–4 haematological toxicity | 15% | 92% |
3-year overall survival | 32% | 46% |
Consolidation phase
- Outcome
- The current treatment options have not proven to be robust in producing durable results by producing sustained complete remission or cure.
- Evidence
- Various combined modality regimens and survival rates
- ARA-C, cytarabine; ASCT, autologous stem cell transplantation; IT, intrathecal; NA, not available; NR, not reached; OS, overall survival; MTX, methotrexate; PCB, procarbazine; PFS, progression-free survival; TMZ, temozolomide.
- ARAC, cytarabine; ASCT, autologous stem cell transplantation; MTX, methotrexate; ORR, overall response rate; PCZ, procarbazine; PFS, progression-free survival; TMZ, temozolomide; VCR, vincristine; VP-16, etoposide; WBRT, whole-brain radiotherapy.
Year | Reference | Regimen | No. of patients | Median follow-up (months) | OS (%) | Median OS (months) | 2-year PFS (%) | Median PFS (months) |
2002 | DeAngelis et al. (2002) | MTX, PCB, Vincristine, IT-MTX, WBRT | 98 | 56 | NA | 37 | NA | 24 |
2006 | Illerhaus et al. (2006) | MTX, ASCT, WBRT | 30 | 63 | (3 y OS) 68.5 | NA | NA | NA |
2007 | Montemurro et al. (2007) | MTX, thiotepa, ASCT, WBRT | 28 | 15 | (2 y OS) 48 | 48 | 45 | 45 |
2009 | Ferreri et al. (2009) | MTX, ARA-C, WBRT | 79 | 30 | (3 y OS) 46 | NA | NA | NA |
2012 | Wieruwilt et al. (2012) | MTX, TMZ, rituximab, etoposide, ARA-C | 31 | 79 | NA | 66 | 79 | 24 |
2013 | Morris et al. (2013) | MTX, rituximab, vincristine, PCB, ARA-C, rd-WBRT | 52 | 70 | (5 y OS) 80 | 79 | 77 | 39 |
2015 | Omuro et al. (2015) | MTX, rituximab, vincristine, PCB, ASCT | 33 | 45 | (2 y OS) 81 | NR | 79 | NR |
Induction Regimen | Consolidation Therapy | No. of Patients | ORR (%) | 2-Year PFS (%) | Study |
MTX, PCZ, VCR, rituximab | Low-dose WBRT | 52 | 79 | 57 | Morris et al |
MTX, PCZ, VCR, rituximab | ASCT (age < 65) | 33 | 94 | 79 | Omuro et al |
MTX, TMZ, rituximab | ARAC VP-16 | 44 | 77 | 59 | Rubenstein et al |
MTX, TMZ, rituximab | WBRT + TMZ | 53 | 57 | 64 | Glass et al |
MTX, ARAC thiotepa, rituximab | WBRT or ASCT | 67 | 87 | 62 | Ferreri et al |
Radiotherapy
The case against radiotherapy
- Wang et al. (2014) summarized three important limitations with WBRT:
- Inadequate local control
- Dissemination of radiologically occult lymphoma cells outside of the radiation field
- Deleterious effects of radiation on brain function.
- Nelson et al. (1992)
- Profound initial immediate response
- >60% of patients receiving WBRT as the sole form of treatment had progression within the radiation field.
- The median overall survival was only 11.6 months
- With the introduction of HDMTX, more encouraging outcomes were demonstrated when used in combination with WBRT.
- G- PCNSLSG- 1 (Thiel et al., 2010)
- Demonstrated that overall survival did not change when WBRT was omitted
- Doolittle et al., 2013
- Patients with a sustained complete response to treatment suffered from significant delayed neurotoxicity with increased mortality and morbidity ().
- Patients more than 60 years of age were particularly susceptible, and survivors often required custodial care.
- In an attempt to reduce this complication, the concept of rdWBRT as consolidation treatment was trialled but was met with mixed results.
- Bessell et al. (2002) reported inferior results for rdWBRT (at 30.6Gy) following combination chemotherapy.
- Morris et al. (2013),
- Demonstrated encouraging results using combination chemotherapy followed by 23.4Gy radiotherapy
- But the subgroup older than 60 years had a significantly inferior outcome.
The case for radiotherapy
- The rationale for consolidation radiotherapy following combination chemotherapy regimens lies in the fact that PCNSL is a diffuse disease, and consolidation WBRT has been associated with increased PFS and OS.
- The G- PCNSL- SG- 1 trial
- Modest improvement in PFS with inclusion of WBRT
- But failed to demonstrate any significant improvement in OS.
- Criticisms
- Flaws in its execution:
- Failure in meeting its primary endpoint,
- Protocol violations,
- A high risk of bias.
- Cochrane Collaboration
- Found insufficient data to draw any definitive conclusion that combination chemo- radiotherapy compared to chemotherapy alone have similar effects on OS.
- Evidence for the outcome of PFS to be low (Zacher et al., 2014).
- Ferreri et al. (2009) compared chemotherapeutic modalities (HDMTX vs. HD- MTX in combination with cytarabine) followed by WBRT.
- The effects of WBRT were not studied as a primary outcome but
- WBRT following either regime was accompanied by complete remission rates of
- 64% in the intervention arm VS 30% in the control arm.
- Prica et al. (2012) published results from a decision analysis study that suggested improvements in survival and quality adjusted life years for patients less than 60 years old who had received chemotherapy followed by consolidation WBRT.
Treatment for recurrence (relapse following complete response to initial therapy)
- Disease recurrence
- Is almost inevitable
- A particularly challenging area as no standard treatment approach exists.
- Options available
- Radiotherapy, if not already utilised as part of consolidation treatment
- Second- line chemotherapy regimens.
- Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide
- Enting 2004.pdf
- Median overall survival is 14 months
- Median progression free survival of responding patients is 7.7 months.
Prognosis
- PCNSL has a considerably worse outcome than does systemic DLBCL.
- Prognosis without treatment is dismal for this rare tumour, perhaps in the range of weeks to months.
- Henry 1973: 3.3 months with supportive care alone
- SEER database: median survival was 7.5 months
- Prognosis with treatment
- SEER: 14 months
- Negative prognostic factors
- Older patient age (> 65 years)
- Major negative prognostic factor
- Reduced survival
- Increased risk of neurotoxicity
- The missense variant Tc2c.776C → G mutation of transcobalamin C is associated with shorter survival and neurotoxicity
- Positive prognostic factors
- Presence of reactive perivascular CD3 T-cell infiltrates on biopsy
- LM02 protein expression by the tumour cells has been associated with prolonged overall survival
- Median progression-free survival: 12 months
- Overall survival: 3 years
Elderly
- 50% of patients with newly diagnosed PCNSL are age 60 or older
- Highest incidence > 75.
- Over the past years, numerous studies have demonstrated that treatment of PCNSL in older and even very old patients can lead to clinically meaningful outcomes.
- An option for patients who are unable to tolerate HD-MTX is WBRT; however, as a result of significant neurotoxicity, especially in patients at advanced age, and limited duration of response to WBRT alone, this is not considered preferred first-line treatment for these patients.
- Evidence
- A recent multi-institutional meta-analysis with data from 783 patients assessed, the outcomes of immunocompetent patients with newly diagnosed PCNSL age 60 or older who received a number of different first-line regimens.
- OS in these patients has improved over the past 4 decades, likely because of more aggressive and effective treatment
- Younger age and Karnofsky PS of 70 or less was associated with significantly improved survival.
- HD-MTX–based therapy is associated with improved survival compared with regimens without HD-MTX.
- No evidence that, overall, the addition of other chemotherapy agents to HD-MTX improved survival.
- ARAC, cytarabine; CCNU, lomustine; CR, complete response; IDA, idarubicin; mOS, median overall survival; MTX, methotrexate; ORR, overall response rate; PCNSL, primary central nervous system lymphoma; PCZ, procarbazine; PFS, progression-free survival; TMZ, temozolomide; VCR, vincristine; VIND, vindesin.
Year | Median OS (months) |
1987–1997 | 14 |
1997–2007 | 19 |
after 2007 | 35 |
Induction Regimen | MTX Dose (g/m²) | No. of Patients | Age Cutoff (Years) | Median Age (Years) | CR (%) | ORR (%) | mOS (Months) | PFS (Months) | Study |
MTX, CCNU, PCZ | 3 | 27 | >65 | 70 | 44 | 70 | 15.4 | 5.9 | Illerhaus et al |
MTX, CCNU, PCZ, rituximab | 3 | 28 | ≥66 | 75 | 64 | 86 | 17.5 | 16 | Fritsch et al |
MTX, VIND, IDA, prednisolone | 3 | 35 | 60–70 | 65 | 17 | 51 | 19 | 13 | Olivier et al |
MTX, ARAC, TMZ, VIND, rituximab, dexamethasone | 5 | 27 | 66–75 | 70 | 69 | 89 | Not reached | 13 | Pulczynski et al |
MTX, PCZ, VCR, ARAC | 3.5 | 47 | ≥60 | 72 | 62 | 82 | 31 | 9.5 | Omuro et al |
MTX, TMZ | 3.5 | 48 | ≥60 | 73 | 45 | 71 | 14 | 6.1 | Omuro et al |
Immunocompetent vs. Immunocompromised primary diffuse large B cell lymphoma of the CNS
PCNSL | Immunocompetent | Immunocompromised |
Age (years) | 60s (median 56) | 30s (median 35) |
Time to diagnosis | 3 months | 2 months |
Symptoms | - Neurological deficits (extent dictated by location of tumour) - Seizures and cranial nerve palsies less common | - Neurological deficits (extent dictated by location of tumour) - Commonly presents with seizures, encephalopathy, and cranial nerve palsies |
Location in CNS | - Adults: Solitary (70%), supratentorial (85%), periventricular (60%), corpus callosum (12%) - Paediatrics: Solitary, Parietal and frontal lobes, cerebellum, pituitary stalk, hypothalamus, Leptomeningeal spread commoner (18%) | - Adults: Multiple (50%), supratentorial - Paediatrics: Solitary, Parietal and frontal lobes, cerebellum, pituitary stalk, hypothalamus, Leptomeningeal spread commoner (18%) |
Differential diagnosis | - High-grade gliomas - Multiple sclerosis - Metastasis - Neurosarcoidosis | - Toxoplasmosis - Abscess - Progressive multifocal leukoencephalopathy |
Radiological features | CT: - Hyperdense to grey matter - Enhances homogeneously with contrast MRI: -Hypointense on T1WI, hyperintense on T2WI, homogeneously enhancing | CT: -Heterogenous, ring enhancing MRI: -Heterogenous, ring enhancing (also commonly seen in paediatric population) |
Subtyping | - Ranges from low grade to high grade - 95% DLBCL - Association with EBV: rare | - Almost always EBV-positive - Mostly high-grade, DLBCL, immunoblastic type (features similar in both AIDS and transplant patients) |
- AIDS, acquired immunodeficiency disease; BCL-6, B-cell lymphoma 6 protein; CNS, central nervous system; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; DWI/ADC, diffusion-weighted imaging/apparent diffusion coefficient map; EBV, Epstein–Barr virus; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PCNSL, primary central nervous system lymphoma; T1WI, T1-weighted imaging; T2WI: T2-weighted imaging.
- Increase in frequency of PCNSL immunocompetent patients from the 1990s onwards, especially in those above 65 years old. Dec in fq of PCNSL HIV-associated PCNSL
- Due to the widespread availability and access to highly effective antiretroviral treatment
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