1. Felice Giangaspero BIOPATOLOGIA DEI LINFOMI PRIMITIVI CEREBRALI Mediterranean School of Oncology Burning questions on lymphoproliferative diseases Rieti 27-29 ottobre 2006

2. Primary CNS Lymphoma (PCNSL) Epidemiology Incidence has risen dramatically in past few decades, as PCNSL now accounts for 4-7% of all newly diagnosed primary brain tumors Incidence has decreased in the HIV/immunocompromised (HAART) Median age of onset 55 years in immunocompetent, incidence rises with age Greatest rise has occurred among the elderly

3. Sites of Disease Involvement Brain parenchyma is usual location (>90%) Usually solitary lesion (75%), can be multifocal Mainly occur in supratentorial sites (75%), but may also be infratentorial Tend to be periventricular in location

4. Imaging: Other considerations Features of mass lesion in brain that are suggestive of CNS lymphoma: Periventricular distribution Multiple lesions Less edema than expected for brain met or glioma Steroids can significantly alter appearance on imaging by decreasing tumor size, edema, and enhancement – and preferably should be held prior to Dx if CNS lymphoma suspected

5. Sites of Disease Involvement Ocular only involvement in ~10% Leptomeningeal disease may occur, but usually not without brain involvement Primary spinal disease is rare (<1% PCNSL)

6. Clinical History Focal neurologic deficit (i.e. hemiparesis, aphasia) present in >50% of all patients with PCNSL Altered mental status (memory loss, confusion, etc.) found in ~33% - may be insidious onset Headache, nausea (from increased ICP) in ~33% May present with new-onset seizure in <10% Blurred vision if ocular lymphoma is present

7. PCNSL: Tissue diagnosis Stereotactic biopsy is usually preferred Goal of surgery is to obtain a tissue diagnosis with minimal morbidity, without formal attempt at surgical resection Steroids can cause false negative biopsy results due to cytolytic effects, and should be held if suspected PCNSL on imaging

8. PCNSL: Pathology More than 95% of primary CNS lymphomas are diffuse large B cell (DLBCL). CD20 angiotropism DLBCL Mutations Ig Variable gene region Expression BCL-6 Germinal center origin

9. Are DLCBL of CNS a distinct entity? Short duration of response to combined therapy Growth limited to CNS Angiotropism High responsiveness to methotrexate

10. Rubenstein, J. L. et al. Blood 2006;107:3716-3723

11. Target gene IL-4

12. Rubenstein, J. L. et al. Blood 2006;107:3716-3723 IL-4 EXPRESSION IN PCNSL

13. Are DLCBL of CNS a distinct entity?

14. Primary CNS Lymphoma Pathology DIFFUSE LARGE B CELL LYMPHOMA T-CELL LYMPHOMAS INTRAVASCULAR LYMPHOMA MALT/MARGINAL ZONE B CELL LYMPHOMA LYMPHOPLASMACYTIC LYMPHOMA PLASMOCYTOMA BURKITT LYMPHOMA PRECURSOR B-CELL LYMPHOBLASTIC LYMPHOMA ANAPLASTIC LARGE-CELL LYMPHOMA NK/T CELL LYMPHOMA HODGKIN DISEASE

15. ACCUMULATIONS OF LARGE B- CELLS, WITHIN SMALL AND MEDIUM VESSELS EXCEPTIONALLY T-CELLS, NK CELLS OR HISTIOCYTIC CELLS, AFFECTS MULTIPLE ORGAN SYSTEMS. THE CNS, INCLUDING THE ENTIRE NEURAXIS, IS INVOLVED IN MORE THAN 30% OF CASES. ALTERED MENTAL STATUS (MEMORY LOSS, CONFUSION) INTRAVASCULAR LYMPHOMA

16. ACCUMULATIONS OF LARGE B- CELLS, WITHIN SMALL AND MEDIUM VESSELS LEAD TO VASCULAR OCCLUSION AND DISSEMINATED SMALL INFARCTS INTRAVASCULAR LYMPHOMA

17. Baehring, J M et al. J Neurol Neurosurg Psychiatry 2005;76:540-544 Diffusion weighted image: Areas of ischemia INTRAVASCULAR LYMPHOMA

18. THE MOST COMMON PRIMARY LOW-GRADE INTRACRANIAL LYMPHOMA INTRACRANIAL MALT TYPE LYMPHOMA PRESENTS AS A DURAL-BASED MASS MIMICKING MENINGIOMA

19. N=1512 F(80%)F:M = 4:1 Age 55 yrs, 29-70 yrs (mean, range) All but 1 presented with a dural based masses mimicking meningioma All tumor resection ± Radiation (6) and/or chemo (3) Follow-up available in 10 patients Complete remission FU length 11 mo to 7.9 yrs Tu et al. J Clin Oncol 2005; 23:5718 INTRACRANIAL MALT TYPE LYMPHOMA

20. DIFFUSE THICKENING OF DURA

22. CD20 CD3

23. kappa lambda

25. MALT of the Dura genetic alterations (FISH) J Clin Oncol 2005; 23:5718 No traslocations Trisomy chr 3 in 50% of cases

26. CNS ANAPLASTIC LARGE CELL LYMPHOMA CD30ALK-1 From George et al. Am J Surg Pathol 2003; 27:487-93

28. Primary CNS Lymphoma (PCNSL) Histogenesis B-CELLS MAY BE TRANSFORMED AT A SITE ELSEWHERE IN THE BODY AND THEN DEVELOP ADHESION MOLECULES SPECIFIC FOR CEREBRAL ENDOTHELIA. LYMPHOMA CELLS MAY BE SYSTEMATICALLY ERADICATED BY AN INTACT IMMUNE SYSTEM BUT MAY ESCAPE THE IMMUNE SYSTEM WITHIN THE CNS. A POLYCLONAL INTRACEREBRAL INFLAMMATORY LESION MAY EXPAND CLONALLY WITHIN THE BRAIN AND PROGRESS TO THE MONOCLONAL NEOPLASTIC STATE.