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

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.

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 6. a) Brain b) Meningeal c) Ocular d) Spinal 7. Burkitt‘s Lymphoma

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

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-Lymphoma as secondary manifestation Burkitt-Lymphoma

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

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

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

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.

Primary Brain-Lymphoma Sagittal MRT T  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 enhancement f – 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-Lymphoma b) 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 + 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

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 - 8 g/m² actual 3 g/m² Median Survival (Mo) 40 – 60 MTX, WBRT + HDAC Radiation-Dosis 30.000 Gy 5 Y. survival 50% Patient ‹ 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 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 2 Procarbazine 3 – 7 Duxamethason 3 - 7 WBR  Median Survival 40,7 Months No difference in Comparison to HD – MTX HD – Cytarabine

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 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 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

Question for Auditorium Case-Report Question for Auditorium

Case-Report MRT-Transversal

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

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

CSF-Report Magnification

CSF-Cytology

MRT-Investigation of Neurocranium Case-Report MRT-Investigation of Neurocranium

Case-Report MRT-Investigation

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