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

2. Lymphocytic origin established
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.

3. Hypothetical scheme of lymphocyte differentiation
Extranodal Lymphomas
1. Mucosa associated Lymphoma (MALT)
2. Cutaneous Lymphoma T-Cell-Lymphoma (CD 30 + or -)
3. Intravascular large B-Cell-Lymphoma
4. Orbital Lymphoma
5. Primary Effusion Lymphoma
CNS-Lymphoma a) Brain b) Meningeal c) Ocular d) Spinal
7. Burkitt‘s Lymphoma

4. Primary CNS-Lymphoma:. Brain-Manifestation. Ocular-Lymphoma
Primary CNS-Lymphoma: Brain-Manifestation Ocular-Lymphoma Leptomeningeal-Lymphoma Spinal-Cord-Lymphoma
Secondary CNS-Lymphoma: Metastatic involvement of Brain
Subarachnoidal Cavity Ocular Compartments

5. Entities associated with CNS-Lymphoma as secondary manifestation
Centroblastic Lymphoma Immunoblastic Lymphoma

6. Main entities associated with CNS-Lymphoma as secondary manifestation Lymphoblastic Leukemia
Type I - L1
Type II – L2
Type III – L3

7. Entities associated with CNS-Lymphoma as secondary manifestation
Burkitt-Lymphoma

8. Entities associated with CNS-Lymphoma as secondary manifestation
Diffuse Large B Cell Lymphoma

9. Different Locations of CNS-Lymphoma
Brain-Lymphoma
Ocular-Lymphoma
Leptomeningeal-Lymphoma
Spinal-Cord-Lymphoma

10. Diagnostic Procedures in PCNS-Lymphoma
Clinical-neurological Investigation
MRT of Brain without and with Gadolinium
Cerebrospinal Fluid examination associated with Cytophotometric
Ophthalmologic Investigation, Slit-Lamp
Systemic staging • CT, Thorax + Abdomen • Bone marrow • Testicle • HIV-virology
Histologic Confirmation

11. MRT-Investigation in Primary CNS-Lymphoma
T1-without Contrast
Single occipital lesion with hyperintensity right
T2 FLAIR
Transversal and sagittal-Investigation after Gadolinium.
Gadolinium revealing remarkable enhancing.

12. Primary Brain-Lymphoma
Sagittal MRT
T  Contrast
Transversal
+ Contrast
Sagittal
+ Contrast

13. MRT in Primary CNS-Lymphoma
a – c: T2-MRT-Investigation revealing multiple lesions within both hemisphere
e: FLAIR-Sequence revealing remarkable enhancement
f – g: Remarkable decreased enhancement after Administration of Gadolinium

14. MRT-Investigation of Primary CNS-Lymphoma in Patients with AIDS
T1-MRT after Administration of Gadolinium
T2-MRT after Gadolinium

15. CNS-Lymphoma
a) Brain-Lymphoma
b) Leptomeningeal-Lymphoma a) b)

16. Leptomenigeal-Lymphoma
Cytology of CSF in Patient with Leptomeningeal Lymphoma as secondary Involvement in Connection with ALL

17. 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

18. Chronology of different therapeutic modalities
Corticosteroid
‹ 12 months but initially excellent Effect
Cranial Radiotherapy
12 – 18 months
WBRT + Corticosteroids Ocular Neuraxis
(5-year survival 3-4%)
Surgery Resection
3 – 5 months
Chemotherapy as Preradiation Modality:
Assessment of response in intact Blood-Brain barrier before RT reduce late neurologic toxicity

19. Chemotherapy of CNS-Lymphoma
Systemic Non-Hodgkin-Lymphoma
Regimens CHOP
Short-lasting remission
‹ 12 months quickly development of leptomennigeal or multifocal brain recurrence
RTOG-Study
CHOP + WBRT
Median Survival
12,8 months
High-dose Methotrexate with potential to penetrate BBB and known Activity against Lymphoma
1g/m² g/m²
actual 3 g/m²
Median Survival (Mo)
40 – 60
MTX, WBRT + HDAC
Radiation-Dosis Gy
5 Y. survival %
Patient ‹ 60 Y.
Median Survival (Mo) › 70
3 Y. survival % vs 60%
MTX, Procarbazine, VCR, HDAC + WBRT
Median Survival 60 months
Unable to penetrate an intakt Blood-Brain-Barrier

20. 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.

21. Intensification of Chemotherapy Sloan-Kettering Cancer Center
Methotrexate Week 1 3 5
Vincristine Week 1 3 5
Procarbazine Week 1 5
WBR Week …..11
High-Dose Cytarabine
Week …..16, 20
Median Survival 40 Months
Chemotherapy for BBB-Disruption McAllister
Cyclophosphamide 1, 2
Intraarterial Methotrexate 1, 2
Leucovorin
Procarbazine 3 – 7
Duxamethason
WBR 
Median Survival 40,7 Months
No difference in Comparison to HD – MTX
HD – Cytarabine

22. New Developments in Therapy of CNS-Lymphoma
High-dose MTX
High-dose ARAC + Thiotepa
HCT (Thiotepe + BCNU)
Autolog. Bone-marrow Transplantation
30 Pat.
Complete Therapy
21 / 30
CR / 30

23. 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.

24. 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

25. Therapy of PCNSL in Immunocompromised Patients
Systemic Therapy more toxic in immunodeficient Patients
EBV-DNA-Identification in CSF by PCR
AIDS-related PCNSL occurs in Patients with CD4  25 x 106 cell/L
Most important Component of PCNSL-Therapy in immunodeficient Patient: Reduction of Immunosupressiva, HAART
HAART + Ganciclovir
HAART + Corticosteroid + cranial Radiotherapy
HD MTX 3 g/m²
Monitoring of CSF-EBV-Level

26. Question for Auditorium
Case-Report
Question for Auditorium

27. Case-Report
MRT-Transversal

28. combined-modality-Treatment
Case-Report
Plan-Radiology
after
combined-modality-Treatment

29. Clinic: Severe Headace, Fever, vomitus and opistotonus
Case-Report
Clinic: Severe Headace, Fever, vomitus and opistotonus
CSF-Cytology

30. CSF-Report
Magnification

31. CSF-Cytology

32. MRT-Investigation of Neurocranium
Case-Report
MRT-Investigation of Neurocranium

33. Case-Report
MRT-Investigation

34. Conclusion
Precise histologic or cytologic Investigations are essential for Treatment of CNS-Lymphoma
HD-MTX is for time being unique therapeutic options for Patients with PCNS-Lymphoma
Additional Components (ARA-C, Procarbazine) important for younger Patients
WBR should be considered in Connection with recurrent disease
In Patients with immunodeficiency induced by Post-Transplantation immunosuppressive or AIDS: Tapering of immunosuppressive Medication, HAART and EBV-Monitoring