Primary and secondary CNS-Lymphoma Prof. Nossrat Firusian, Recklinghausen, Germany.

Primary and secondary

CNS-Lymphoma

Prof. Nossrat Firusian,

Recklinghausen, Germany

Primary CNS-Lymphoma:

Non Hodgkin-Lymphoma arising in and confined to CNS.

a) Microglioma

b) Reticulum Cell Sarcoma

c) Perivascular Lymphoma

Lymphocytic origin established

How a Lymphoma develops within the CNS,

which lacks Lymph Nodes and Lymphatics.

However Lymphocytes do traffic in and out of

CNS normaly ans these Lymphocytes are

probably the source of PCNSL.

Hypothetical scheme of lymphocyte differentiation

Extranodal Lymphomas

1. Mucosa associated Lymphoma(MALT)

2. Cutaneous LymphomaT-Cell-Lymphoma (CD 30 + or -)

3. Intravascular large B-Cell-Lymphoma

4. Orbital Lymphoma

5. Primary Effusion Lymphoma

CNS-Lymphoma6. a) Brain b) Meningeal c) Ocular d) Spinal

7. Burkitt‘s Lymphoma

Primary CNS-Lymphoma:

Brain-Manifestation

Ocular-Lymphoma

Leptomeningeal-Lymphoma

Spinal-Cord-Lymphoma

Secondary CNS-Lymphoma:

Metastatic involvement of

Brain

Subarachnoidal Cavity

Ocular Compartments

Entities associated with CNS-Lymphoma as secondary manifestation

Centroblastic Lymphoma Immunoblastic Lymphoma

Main entities associated with CNS-Lymphoma as secondary manifestation Lymphoblastic Leukemia

Type I - L1

Type II – L2

Type III – L3

Entities associated with CNS-Lymphomaas secondary manifestation

Burkitt-Lymphoma

Entities associated with CNS-Lymphoma as

secondary manifestation

Diffuse Large B Cell Lymphoma

Different Locations of CNS-Lymphoma

1. Brain-Lymphoma

2. Ocular-Lymphoma

3. Leptomeningeal-Lymphoma

4. Spinal-Cord-Lymphoma

Diagnostic Procedures in PCNS-Lymphoma

1. Clinical-neurological Investigation

2. MRT of Brain without and with Gadolinium

3. Cerebrospinal Fluid examination associated with Cytophotometric

4. Ophthalmologic Investigation, Slit-Lamp

5. Systemic staging• CT, Thorax + Abdomen• Bone marrow• Testicle• HIV-virology

6. Histologic Confirmation

MRT-Investigation in Primary CNS-Lymphoma

T1-without ContrastSingle occipital lesion with

hyperintensity right

T2 FLAIR

Transversal and sagittal-Investigation after Gadolinium.Gadolinium revealing remarkable enhancing.

Primary Brain-Lymphoma

Sagittal MRTT Contrast

Transversal+ Contrast

Sagittal+ Contrast

MRT in Primary CNS-Lymphoma

a – c: T2-MRT-Investigation revealing multiple lesions within both hemisphere

e: FLAIR-Sequence revealing

remarkable enhancementf – g: Remarkable decreased enhancement after Administration of Gadolinium

MRT-Investigation of Primary CNS-Lymphoma in Patients with AIDS

T1-MRT after Administration of

Gadolinium

T2-MRT after Gadolinium

CNS-Lymphoma

a) Brain-Lymphomab) Leptomeningeal-Lymphoma

a) b)

Leptomenigeal-Lymphoma

Cytology of CSF in Patient with Leptomeningeal Lymphoma as secondary Involvement in Connection with ALL

Principles of Management

Surgery: Avoid Corticosteroids before diagnostic Biopsy for diagnosis

Chemotherapy: Should be considered at diagnosis for every Patient.

Must penetrate the blood-brain barrier.

High-dose MTX (1,5 - 8 g/m²) with excellent penetration of CNS.

Lipophilic (Procarbazine)

Must have anti-lymphoma activity should be given before Radiotherapy

Radiotherapy:Must be whole brain 3600 – 4500 cGy Avoid boost

3600 cGy Ocular-Lymphoma

May be deferred in Patients age 60 years or older, who have a complete response to Chemotherapy

Chronology of different therapeutic modalities

Corticosteroid ‹ 12 months but initially excellent Effect

Cranial Radiotherapy 12 – 18 months

WBRT + CorticosteroidsOcular

Neuraxis

(5-year survival 3-4%)

SurgeryResection 3 – 5 months

Chemotherapyas Preradiation Modality:

Assessment of response in intact Blood-Brain barrier before RT reduce

late neurologic toxicity

Chemotherapy of CNS-Lymphoma

Systemic Non-Hodgkin-Lymphoma

Regimens CHOP

Short-lasting remission‹ 12 months quickly development of leptomennigeal or multifocal brain recurrence

RTOG-StudyCHOP + WBRT

Median Survival12,8 months

High-dose Methotrexate with potential to penetrate BBB and known Activity against Lymphoma

1g/m² - 8 g/m²actual 3 g/m²

Median Survival (Mo)40 – 60

MTX, WBRT + HDACRadiation-Dosis 30.000 Gy

Median Survival 5 Y. survival 50%

MTX, WBRT + HDACPatient ‹ 60 Y.

Median Survival (Mo) › 70 3 Y. survival 92% vs 60%

MTX, Procarbazine, VCR, HDAC + WBRT Median Survival 60 months

Unable to penetrate an intakt Blood-Brain-Barrier

Follow Up under Therapy with remarkable improvement under comb. CT

Gadolinium enhanced magnetic resonance imaging scans demonstrating a complete response of primary central nervous system lymphoma to high-dose methotrexate, procarbazine and vincristine. Note the prominent and diffuse enhancment pattern and periventricular location so characteristic of primary central nervous system lymphoma.

Intensification of Chemotherapy

Sloan-Kettering Cancer Center

Methotrexate Week 1 35

Vincristine Week 1 35

Procarbazine Week 15

WBR Week …..11

High-Dose Cytarabine

Week …..16, 20

Median Survival 40 Months

Chemotherapy for BBB-Disruption

McAllister

Cyclophosphamide1, 2

Intraarterial Methotrexate 1, 2

Leucovorin 2

Procarbazine3 – 7

Duxamethason 3 - 7

WBR

Median Survival 40,7 Months

No difference in Comparison toHD – MTX

HD – Cytarabine

New Developments in Therapy of CNS-Lymphoma

1. High-dose MTX

2. High-dose ARAC + Thiotepa

3. HCT (Thiotepe + BCNU)4. Autolog. Bone-marrow

Transplantation

30 Pat.

Complete Therapy 21 / 30

CR 21 / 30

Kaplan-Meier curve

A Kaplan-Meier curve demonstrating overall (•) and disease-free (hatch marks) survival 52 patients treated with methotrexate, procarbazine, vincristine, cranial irradiation and high-dose cytarabine. Median survival is 60 months.

Recurrent Disease of PCNS

• No established second line Therapy

• WBRT If Patients did not receive as part of initial Therapy

• Ocular Radiotherapy in Patient with ocular Relapse (Bilateral)

• HD MTX In Patient with long disease-free interval

HD Cytarabine Tenrozolomide High-dose with Thiotepa, Busulfan and Cyclophosphamide followed by autologous Stem-Cell-Rescue - 3 year Survival

• Leptomeningeal Relapse: Intrathecal or intraventricular MTX + Radiotherapy

Therapy of PCNSL in Immunocompromised Patients

1. Systemic Therapy more toxic in immunodeficient Patients

2. EBV-DNA-Identification in CSF by PCR

3. AIDS-related PCNSL occurs in Patients with CD4 25 x 106 cell/L

4. Most important Component of PCNSL-Therapy in immunodeficient Patient: Reduction of Immunosupressiva, HAART

5. HAART + Ganciclovir

6. HAART + Corticosteroid + cranial Radiotherapy

7. HD MTX 3 g/m²

8. Monitoring of CSF-EBV-Level

Case-ReportQuestion for Auditorium

Case-ReportMRT-Transversal

Case-Report

Plan-Radiologyafter

combined-modality-Treatment

Case-ReportClinic: Severe Headace, Fever, vomitus and opistotonus

CSF-Cytology

CSF-Report

Magnification

CSF-Cytology

Case-Report MRT-Investigation of Neurocranium

Case-Report MRT-Investigation

Conclusion

1) Precise histologic or cytologic Investigations are essential for Treatment of CNS-Lymphoma

2) HD-MTX is for time being unique therapeutic options for Patients with PCNS-Lymphoma

3) Additional Components (ARA-C, Procarbazine) important for younger Patients

4) WBR should be considered in Connection with recurrent disease

5) In Patients with immunodeficiency induced by Post-Transplantation immunosuppressive or AIDS: Tapering of immunosuppressive Medication, HAART and EBV-Monitoring