Primary CNS lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma confined to the brain and spinal cord. It most commonly affects immunocompetent elderly patients and presents with neurological symptoms. Diagnosis requires biopsy and imaging shows contrast-enhancing lesions. Standard treatment is high-dose methotrexate-based chemotherapy with consolidation radiotherapy, though radiotherapy is being used less due to neurotoxicity risks, especially in older patients. The prognosis remains poor with median survival around 2 years despite treatment.

1. Primary CNS
Lymphoma
Presented by-Dr. Rashmi Yadav
JR-II
Moderator- Dr. Piyush Kumar

2. For JR’s
•Approach to case of PCNSL
For SR’s
•Role of CSI
•Role after failure of case
•Role of any targeted therapy

3. OVERVIEW
• Introduction
• Anatomy
• Epidemiology
• Pathology
• Molecular markers
• Clinical presentation
• Diagnostic workup
• Treatment

4. INTRODUCTION
• Primary central nervous system lymphoma
(PCNSL) is a Non-Hodgkin lymphoma (NHL)
confined to the brain, leptomeninges, eyes, or
spinal cord.
• PCNSL accounts for <3% of all primary central
nervous system (CNS) tumors, with a median
age of 65 years at diagnosis.

5. Occur in distinct patient population.
• 1. Immunocompetent- in 6th and 7th decade
One or multifocal mass lesion.
• 2. Immunocompromised- in 3rd and 4th decade
• Majority are B-cell lymphomas

6. ANATOMY

8. EPIDEMIOLOGY
• 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.

9. PATHOLOGY
• Approximately 90% of PCNSL cases are diffuse large B-cell
lymphomas (DLBCL), other 10% are T-cell lymphomas.
• 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

10. Pathologic features of PCNSL. (A) Diffuse, large B-cell lymphoma (DLBCL)
involving the left parietal lobe and basal ganglia exhibits marked mass effect (B)
DLBCL cells exhibiting an angiotropic growth pattern in a diagnostic specimen
of PCNSL .(C) Invasive growth of DLBCL cells along the cerebral vasculature in
PCNSL. (D) High expression of MYC by DLBCL cells in a diagnostic specimen of
PCNSL.

13. MOLECULAR MARKERS
• Most tumors express pan–B-cell markers, including CD19, CD20,
CD22, and CD79a.
• The molecular mechanisms underlying transformation and
localization to the CNS are poorly understood.(Limitations-rarity of
the disease and the limited availability of tissue because the
diagnosis is most often made with stereotactic needle biopsy.)
• PCNSL harbors chromosomal translocations of the BCL6 gene,
deletions in 6q, and aberrant somatic hypermutation in proto-
oncogenes including MYC and PAX5.

15. 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.

16. • Usually present with –
1. cognitive dysfunction,
2. personality change,
3. headache,
4. focal neurological deficit..i.e.,hemiparesis,hemisensory loss
5. Seizures
6. symptoms of ocular involvement include eye pain, blurred vision,
and floaters.
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.

17. DIAGNOSTIC WORKUP
• History & clinical examination(nodal,testicular exa)
• Opthalmic examination
(slit lamp examination, indirect opthalmoscopy)
• Complete neurological examination
• Laboratory examination-
1. Complete blood counts
2. Liver function Tests,
3. Kidney Function Tests,
4. Electrolytes
5. Serum LDH
6. HIV serology,EBV and viral markers
• CSF cytology

18. WORKUP

19. Imaging
• Contrast enhanced MRI brain
• CECT neck+ chest+ abdomen
• PCNSL is hypointense on T1 & hypointense to isointense on T2/FLAIR
with variable surrounding odema.
• The appearences of T2 sequences & lack of necrosis differentiates from
glioma.

21. • Biopsy for confirmation of diagnosis(stereotactic brain
biopsy/ Surgery)
• CSF and ocular involvement occurs in approximately 15%
to 20% and 5% to 20% respectively.
• Corticosteroids should be held at presentation because of
their lytic effect on lymphoma may lead to false-negative
biopsy.

22. 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.
• 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.

24. TREATMENT OPTIONS
•Surgery
•Chemotherapy
•Radiotherapy

25. 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.

28. 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.
• Adequate levels of drug are produce by high dose rapid infusion so
intrathecal instillation is not necessary unless CSF is positive.

29. • 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.

30. • 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.

31. 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

32. • WBRT is more beneficial than focal radiotherapy due to extensive
infiltration of lymphoma throught the brain.
• 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%.

33. Indication of radiotherapy
1. post-chemo therapy in younger pts <60yrs
2. As salvage for recurrence
3. Upfront therapy with poor KPS pts
4. Renal failure

35. RADIOTHERAPY-TECHNIQUES
German Helmet technique

36. • 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, cribriform
plate, posterior aspect of eyes
included.
• 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

37. TOXICITY
• 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

38. • The most frequent complication in long-term PCNSL survivors is
delayed neurotoxicity.
• The elderly are at highest risk for this complication, with nearly all
patients over the age of 60 developing clinical neurotoxicity
following combined modality therapy.
• Treatment with WBRT has been identified as the major risk factor
for the development of late neurotoxicity.

39. • Common symptoms and signs include deficits in attention,
memory, executive function, gait ataxia, and incontinence. These
deficits have a detrimental impact on quality of life.
• Radiographic findings -include periventricular white matter
changes, ventricular enlargement, and cortical atrophy.
• Pathologic studies- reveal demyelination, hippocampus
neuronal loss, and large-vessel atherosclerosis. Currently, there
are no treatments to reverse these delayed neurotoxic effects.

40. ROLE OF CSI
•In case of CSF involvement

41. NCCN GUIDELINES

45. EVIDENCE-BASED
TREATMENT SUMMARY
• Surgical resection is not necessary.
• Avoiding or deferring WBRT results in inferior progression-
free survival but without significantly affecting overall sur- vival.
Because of the toxicities associated with WBRT, its role is being
evaluated in a risk-adapted approach by the RTOG.
• High-dose systemic methotrexate is the only agent that has demonstrated
improved survival over WBRT alone. High-dose methotrexate–based
chemotherapy followed by whole-brain radiotherapy is the standard
treatment for patients younger than 60 years of age with a good perfor-
mance status.
• High-dose methotrexate–based chemotherapy alone with deferred
radiotherapy may be preferred in elderly patients because of substantial
risk of neurotoxicity associated with combined chemotherapy–
radiotherapy regimens.

46. TARGETED THERAPY

47. TREATMENT OF RELAPSE
• Retreatment with MTX 3-8GM/M2 or MTX based combination
therapy
• Alternative chemotherapy regimens(topotecan,
cytarabine,temozolomide, thiotepa, pemetrexed
• WBRT in previously non irradiated patient
• Steriotactic radiotherapy for previously radiated patient

49. IN LEPTOMENINGEAL DISEASE
• MTX 12mg weekly intrathecal or through ommaya reservoir.

50. IN HIV POSITIVE
•MTX based chemotherapy with anti retro viral
therapy with or without radiation

51. IN 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.

52. IN INTRAOCULAR
•Systemic high dose MTX + local therapy
•Local therapy :
Intravitreal chemotherapy with MTX or Rituximab or
Ocular radiation upto 4oGy

54. SURVIVAL

56. THANK YOU