2. • Anatomy
• Epidemiology
• Pathology
• Clinical Presentation
• Work Up
• Management
• Review Of Literature
• Treatment in various condition
• Conclusion
7. DEFINITION
• Primary central nervous system lymphoma
(PCNSL) is a Non-Hodgkin lymphoma (NHL)
confined to the brain, leptomeninges, eyes, or
spinal cord
8. EPIDEMIOLOGY
1% of all intracranial
tumours
4% of all intracranial tumours
Sarkar C, Sharma MC, Deb P, Singh R, Santosh V, Shankar SK.
Primary central nervous system lymphoma--a hospital based study of
incidence and clinicopathological features from India (1980-2003). J
Neurooncol. 2005;71(2):199-204
9. • The annual incidence rate is 0.47 cases per 100,000
person-years.
• Since 2000, there has been an increase in the overall
incidence of PCNSL, especially in the elderly.
• Immunodeficiency is the only known risk factor.
10. PATHOLOGY
• Stereotactic biopsy followed by histopathological examination
• Primary CNS DLBCL is composed of immunoblasts clustered in the
perivascular space, with reactive lymphocytes, macrophages, and
activated microglial cells intermixed with the tumor cells
• 95% DLBCL
• Molecular subtypes Germinal center, Activated
• B cell and Type 3
. Overlapping state of differentiation
• EBV associated in immunocompromised
11.
12. CLINICAL PRESENTATION
• Presents with one or multifocal(30%) mass
lesions
• Common sites-frontal lobes, corpus
callosum, deep ventricular brain structures.
• Although appear focal ,diffuse involvement
of parenchyma is invariably present
13. CLINICAL FEATURES
• Usually present with –
1.1.cognitive dysfunction,
2.2.personality change,
3.3.headache,
4.4.focal neurological deficit..i.e.,hemiparesis,hemisensory loss
5.5.Seizures
6.6.symptoms of ocular involvement include eye pain, blurred vision, and floaters.
7.7.B symptoms such as weight loss, fevers, and night sweats are infrequent in
PCNSL.
• Symptoms often progress over weeks –months before a diagnosis is made.
14. WORK UP
Central review of
pathology
Immunophenotypi
ng EBV-LMP-1
Bone Marrow
Biopsy+ Aspirate
CSF cytology+
Biochemistry
History and Clinical
examination
Ophthalmic
examination (Slit
lamp and indirect
ophthalmoscopy)
Neuropsychological
evaluation
Complete blood
counts
Liver function
Tests, Kidney
Function Tests,
Electrolytes
Serum LDH
HIV serology and
viral markers
Contrast enhanced
MRI brain
CECT neck+
chest+ abdomen
15. NEURO-IMAGING
Sites of Disease
Brain hemispheres (38%)
Thalamus/basal ganglia
(16%)
Corpus Callosum (14%)
Periventricular region(12%)
Cerebellum (9%)
Eyes (5-20%)
Meninges (16%)
Spinal cord (1%)
Cranial and Spinal nerves
(<1%)
Kuker W, et al: Primary central
nervous system lymphomas
(PCNSL): MRI features at
presentation in 100 patients. J
Neurooncol 72:169-177, 2005
16. TREATMENT
1•Surgery
2•Chemotherapy
3•Radiotherapy
• High dose methotrexate based poly-chemotherapy is the
mainstay of treatment
• Role of radiation has been argued upon but it is recommended
in young patients
• The role of rituximab is investigational
17. SURGERY
• The role of surgery is limited to establish
tissue diagnosis.
• Best achieved by stereotactic biopsy.
• Extensive resection of tumor has no
survival benefit.
• Lymphoma often responds dramatically to
corticosteroids , so should be avoided until
tissue diagnosis is established.
18. CHEMOTHERAPY
• PCNSL is a exquisitely sensitive to radiotherapy &
chemotherapy.
• High dose systemic methotrexate is mainstay choice.
• High dose methotrexate administered at dose of 1-8mg/m2 at
rapid rate of infusion to overcome the blood brain barrier.
• Only agent that has demonstrated improved survival over
WBRT alone.
• intrathecal instillation is not necessary unless CSF is positive
19. • Doses of methotrexate ≥3 g/m2 result in therapeutic concentrations in the brain
parenchyma and CSF, and when combined with WBRT, lead to more durable
treatment responses.
• In a phase II trial, 79 PCNSL patients were randomized to receive either HD-MTX
(3.5 g/m2, day 1 or HD-MTX (3.5 g/m2, day 1) + cytarabine (2 g/m2 twice per
day, days 2 to 3).
• Each chemotherapy cycle was 21 days. All patients underwent consolidative
WBRT after induction chemotherapy. The HD-MTX + cytarabine arm had a
higher proportion of complete radiographic responses and a superior 3-year OS.
20. • However, it is now widely recognized that there is a high incidence of
neurotoxicity with combined modality treatment that includes WBRT.
The latter observation prompted studies utilizing lower doses of
WBRT.
• In a multicenter, phase II study, no significant neurocognitive decline
was observed after consolidative reduced dose WBRT (23.4 Gy) and
cytarabine in patients who had achieved a complete response to
induction chemotherapy including HD-MTX.
• Rituximab can be added to methotrexate in CD20 positive cases.
21. DEANGELIS PROTOCOL
• Inj Methotrexate 2.5 gm/m 2
IV on weeks 1, 3, 5, 7 and 9
• Inj Vincristine 1.4 mg/m 2
IV on weeks 1, 3, 5, 7, 9
• Cap Procarbazine 100 mg/m 2
/day per oral for 7 days on
weeks 1, 5, 9
• Inj Methotrexate 12 mg intrathecal on weeks 2, 4, 6, 8, 10
• Tab Leucovorin 20 mg per oral every 6 h for 12 doses on
weeks 1, 3, 5, 7 and 9 following high dose methotrexate
• Tab Dexamethasone per oral tapering dose for 7 days (16,
12, 8, 6, 4, 2 mg on weeks 1-6)
• Whole brain radiotherapy (WBRT) 45 Gray in 25 fractions
over 5 weeks (weeks 11-15)
• Inj Cytarabine 3 gm/m 2
/day IV for 2 days on weeks 16 and
19
22. RADIOTHERAPY
• Historically, PCNSL was treated only with whole brain radiation
(WBRT) at doses ranging from 36 to 45 Gy, which resulted not
only in a high proportion of radiographic responses, but also in
rapid relapse.
• In a multicenter, phase II trial, 41 patients were treated with
WBRT to 40 Gy plus a 20 Gy tumor boost and achieved a
median overall survival (OS) of only 12 months.
• Given the lack of durable responses to radiation and the risk of
neurotoxicity associated with this modality of therapy, WBRT
alone is no longer a recommended treatment for most patients
with PCNSL. Moreover, because PCNSL is an infiltrative,
multifocal disease, focal radiation or radiosurgery is not
recommended
23. •
•Optimal dose of 45-50 Gy & there is no benefit of
boost to the tumor site. With WBRT alone overall
survival is 12-18 months, 5- year survival is only
4%.
•WBRT is more beneficial than focal
radiotherapy due to extensive infiltration of
lymphoma throught the brain.
25. • Whole Brain is treated due to multifocal
and infiltrative nature of tumour
• Left and right opposed lateral fields with
6-10mv photons
• Anterior temporal lobe, cribiform plate,
posterior aspect of eyes included
• Divergence beam to lens reduced by
placing isocenter anteriorly between the
lateral canthi or if anterior fields are
made coplanar
• Inferior field edge in lower border of C2
vertebrae
• If ocular involvement both globes
included for a portion of treatment to
receive a dose of 30-36 Gy
• No role of CSI except for palliation in
case of spinal involvement
26. TOXICITIES
• Acute Adverse Effects- alopecia, erythema and dry
desquamation of the scalp. Some experience fatigue,
headache and inflammation of the external auditory canal
or middle ear
• Patients requiring treatment of the eye are likely to
experience conjunctival irritation and dry eye.
• These acute effects typically resolve within 6 – 8 weeks
of completion of WBRT
27. • Late adverse effects: neurocognitive
decline, sensorineural hearing loss,
permanent alopecia
• Those whose eyes are treated- cataracts,
chronic dry eye
• The risk of neurocognitive dysfunction
increases with age, total RT dose and co-
administration of chemotherapy
29. PCNSL: RT alone
• RTOG 8315
• Phase II study of WBRT 40Gy + 20Gyboost N =
41
• Overall median survival 12.2 months
• Benefit of boost doubtful: disease recurrence
frequently occurred in the boosted field, survival
no better than previous study without use of boost
• Ocular involvement: 36Gy to both eyes (or
Rx with high dose MTX)
Nelson DF et al. IJROBP Volume 23,
Issue 1, 1992, Pages 9–17
30. PCNSL: CHEMO+RADIOTHERAPY
CR 58%, PR 36% (Overall RR 94%)
Overall survival 37 months
15% ( 12 patients) developed severe delayed neurologic toxicity
8 out of 12 died ( 5/8 from the group > 60 years of age and 3/8 from < 60 years of
age)
32. EKEVtER
International Journal ofRadiation
Oncology*BioIogy*Physics
Volume 51. Issue 2, 1October 2001, Pages 41%425
Clinical relevance of consolidation radiotherapy and other
main therapeutic issues in primary central nervous system
lymphomas treated with upfront high—dose methotrexate
Michele Reni,M.D.•• * ^, Andrés J.MFerreri, M.D.*, Nandita Guha-Thakurta,
M.D.!, Jean-Yves Blay, M.D.!, Stefania DeII’Oro, M.D.*, Pierre Biron, M.D.!,
Fred HHochberg, M.D.*
+ Show more
33. • 280 receiving HDMTX (>1gm/m2) from 19 prospective series
• No difference in OS between mono CHT and combination CHT (p=0.38)
• MTX ≥3gm/m2 (p=0.04), thiotepa (p=0.03) and intrathecal CHT (p=0.03)
improved survival and nitrosoureas (p=0.01) correlated with worse survival
• In multivariate analysis, limited to patient receiving ≥ 3
• gm/m2 MTX, only the addition of cytarabine improved OS
• A RT dose ≥ 40 Gy to the whole brain or tumor bed did not improve OS
• RT delay had no negative impact on survival
• Similar findings were reported in another restrospective analysis by Ferrari et
al on 370 patients
35. Home Current Issue All Issues Ahead of Print Topics WriteClick CME Aboutthe Journal
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High-dose methotrexate with or without
rituximab in newly diagnosed primary CNS
lymphoma
Mafthias Holdhoff, MD, PhD, Prakash Ambady, MD, Ahmed Abdelaziz, MD, Guneet Sarai, MD, David
Bonekamp, MD, PhD, Jaishri BlaKeley, MD, Stuart A. Grossman, MD and Xiaobu Ye, MD, MS
* SH0^”J AFFILATIONS + SH0*”J FULL DISCLOSURES
Correspondence to Dr. Holdhoff: mhoIdho1@jhmi.edu
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36. • 81 patients analysed, 54 HDMTX only, 27 HDMTX+R
• • CR- 36% vs 73% (p=0.0145)
• Median PFS 4.5 months vs 26.7 months (p=0.003)
• Median OS 16.3 months vs not reached (p=0.01)
• A retrospective study by Gregory et al in 120 patients
published in Neuro Oncol showed addition of rituximab is
associated with increased OS.
• Care must be given to chances of Hepatitis B reactivation in
HBsAg positive patients when given Rituximab
37. PRIMARY INTRAOCULAR
• Systemic high dose
methotrexate based
chemotherapy + Local
therapy
• Local therapy either
intravitreal
chemotherapy with
methotrexate or
rituximab or ocular
radiation upto 40 Gy
39. HIV POSITIVE
• MTX based chemotherapy with anti retro
viral therapy with or without radiation
40. ELDERLY
• Patients 6oyrs of age or older are at high
risk of developing treatment-related
neurotoxicity following treatment with
methotrexate and WBRT.
• WBRT is often deferred in elderly except
for recurrence
41. Treatment of refractory or relapsed
disease
• Retreatment with methotrexate (ie, 3 to 8 g/m2 ) or
methotrexate based combination chemotherapy if there has
been a prior complete remission with this agent
• Alternative chemotherapy regimens (eg, topotecan,
cytarabine, temozolomide, thiotepa, pemetrexed including
high dose chemotherapy followed by autologous
hematopoietic cell transplantation (HCT)
• Whole brain radiation therapy in previously nonirradiated
patients, stereotactic radiotherapy may be an option for
patients who have received whole brain radiation
43. PROGNOSTIC FACTORS
• Age >60 years,
• Karnofsky performance status ,
• Elevated serum lactate dehydrogenase (LDH)
level,
• Elevated CSF protein concentration, and
• Involvement of deep regions of the brain.
44. •In patients with 0 to 1 factors, 2 to 3 factors, and 4 to 5
factors, the 2-year survival proportions were 80%,
48%, and 15%, respectively
45. THE ROLE OF NEW TECHNOLOGY
Neuro Oncol (August 2009) 11 (4): 423-429
46. CONCLUSION
• High dose methotrexate based chemotherapy with
consolidation cytarabine is the mainstay of treatment
• WBRT should be included in the treatment especially in young
patients (<60 years), response adapted approach may be
beneficial
• Rituximab may be tried in upfront management or can be
reserved for recurrence
• Local therapy is recommended for Intraocular lymphoma, or
leptomeningeal involvement along with systemic therapy
• Targeted therapies are investigational
