2. ILOS
 Discuss pathogenesis of PCNSL
 Discuss the epidemiological data of PCNSL
 Describe the microscopic, macroscopic and
immunohistochemical characters of PCNSL
 Discuss presentation, D.D., and investigations of PCNSL
 Tabulate management protocol for a patent with PCNS

3. Introduction

4. Introduction
 Classification of CNS lymphoma:
Primary CNS lymphoma (PCNSL)
 Secondary CNS lymphoma
 Definition of PCNSL:
Brain
 Spinal cord
 Ocular structure
 Synonyms of PCNSL:
Reticulum cell sarcoma,
 Perivascular sarcoma,
 Immunoblastic sarcoma,
 Microgliomatosis
 Malignant reticulosis.

6. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

7. Pathology: Cell of origin & Pathogenesis
 Theories of PCNSL
CNS infection → inflammatory process → Neoplastic
process
Systemic lymphoma cells eradicated by the immune system
but CNS is an immunologically protected
Systemic lymphoma ceils but have special receptors to CNS
vessels

8. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

9. Pathology: Epidemiology
 Incidence:
1-2% of intracranial tumors
 10 % of systemic lymphomas will have CNS mets.
A similar percentage develop systemic disease after brain
involvement.
 10 % of AIDS patients will have PCNSL
 Sex:
 Immunocompetent: : = 1.5:1
 Immunocompromised: even more
 Race:
 Age:
 Immunocompetent: 6th decade
 Immunocompromised: 4th decade
 Risk factors:
 Immune compromise

10. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

11. Pathology: Macroscopic features
 Site:
 PCNS: Supratentorial, periventricular
 Mets: Leptomeningeal
 Size:
 Number: mostly solitary
 Characters:
 Well circumscribed, irregularly margined or diffuse infiltrate
 Yellow-brown
 Areas of focal hemorrhage or necrosis
 Cut surface firm, soft, friable or granular

12. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

13. Pathology: Microscopic Features
 Mostly diffuse large B-cell lymphomas (DLBCLs)
 Other cells found are
- Histocytes - Plasma cells - reactive astroytes
- Microglia
 Diffuse infiltrate rather than nodular
 At the periphery, the neoplastic infiltrate tends to be
perivascular
 Deposition of reticulin fibers arranged in concentric layers

14. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

15. Pathology: Immunohistochemistry
 Stain positive to the leukocyte marker CD45
CD45 immunological markers

16. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

17. Pathology: Genetic & Ultra structures
Features
 EBV genomic material is identified in over 90% of PCNSL
tissue from immunocompromised patients

18. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

19. Pathology: Radiological Features
 CT:
 MRI:
 MRS:
 PET:

20. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

21. Pathology: Growth Pattern & Spread
 Spread along fibers of C.C
 Spread along ependymal surface.
 The eye, however, is an important site for tumor
spread, with intraorbital involvement occurring in
approximately 5% of patients at presentation.

22. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

23. Pathology: Grading & Behavior
 Most CNS NHMLs are high-grade lesions corresponding to
large B cells.
 MIB-l, proliferation index, usually high, 50%

24. Pathology
 1) Cell of origin & pathogenesis
 2) Epidemiology
 3) Macroscopic features
 4) Microscopic features
 5) Immunohistochemistry
 6) Genetic features
 7) Radiological features
 8) Growth pattern & spread
 9) Grading & behavior
 10) Prognosis

25. Pathology: Prognosis
• Immunocompetent patients is 17-45
 Median survival in Older
months • Immunocompromise
Patient’s
• Lower Karnofsky less than 3
Factors: in Immunocompromiseperformancemonths
 Median survival
 Despite a high initial response rate, radiotherapy alone
rarely leads to long-term survival; only 7% of patients are
• Deeper regions of the brain
alive 5Tumor’s treatment
years after
• Multiplicity of lesions
 Radio Factors: = ↑ the 5-year survival rate from 7 to 20-
+ Chemo
30%.
• No chemotherapy
TTT’ Factors:

27.  Cranial or spinal masse
Increase intracranial pressure:
Seizure:
Neurological deficits
 Hormonal disturbance mainly DI or SIDH
 lymphomatous meningitis: 5–65%
 Radicular or plexus invasion by lymphoma
(neurolymphomatosis) in the absence of brain or spinal fluid
involvement
 Infarcts
 Primary intraocular lymphoma (Lymphoma invading the
vitreous, retina, and optic nerves ): 10–15%

29.  To diagnose CNS lymphoma:
Radiological features: Increase suspicious
 CSF examination !!!
No steroid test
 Tissue diagnosis
 To differentiate systemic lymphoma from PCNSL (esp.
in Immunocompromised patient):
General examination esp. to L.Ns. & testicle
CT chest, abdomen & pelvis
 Bone marrow biopsy
 To diagnose extent of PCNSL
 Cranial:
 Spinal:
 Orbital: Slit lamp examination
 To define the competence of the immune system:
 HIV testing

31. Hypometabolism PET in Toxoplasmosis Hypermetabolism PET in PCNSL

33. Surgery
 Stereotactic biopsy:
 Relief of hydrocephalus
 Excision:

34. Radiotherapy
 Highly radiosensitive
 Recurrence
 Lesion radiation # whole brain radiation
 40-50 Gy to the primary tumor

35. Chemotherapy
 Radio + Chemo = ↑ mean survival from 16 to 44.5 months
 Radio + Chemo = ↑ the 5-year survival rate from 7 to 20-
30%.

36. Management Protocol in
Immunocompromised Patients
 Immunocompromised patient presented with intracranial
mass
 MRI ? PCNSL # Toxoplasmosis
 PET if available or
 Test therapy with
 Pyrimethamine and sulfadiazine: or
Trimethoprim-sulfamethoxazole (Septrin D.S tab 160/800mg
): Dose 5 mg/kg TMP and 25 mg/kg SMX PO

37. References
 Joachim M. Baehring, Uwe Schlegel, and Fred H. Hochberg (2010): Primary CNS Lymphoma in Oncology of CNS Tumors Jörg-Christian
Tonn, Manfred Westphal and James T. Rutka (Eds.) Second edition part I cranial neuro-oncology Springer Heidelberg Dordrecht London
New York chapter 19 pp 331-341
 Alderson L, Fetell MR, Sisti M, Hochberg F, Cohen M, Louis DN. (1996) Sentinel lesions of primary CNS lymphoma. J Neurol Neurosurg
Psychiatry 60:102–105
 Drillenburg P, Pals ST. (2000) Cell adhesion receptors in lymphoma dissemination. Blood 95:1900–1910
 Smith JR, Braziel RM, Paoletti S, Lipp M, Uguccioni M, Rosenbaum JT. (2003) Expression of B-cell-attracting chemokine 1 (CXCL13)
by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 101:815–821
 Springer TA. (1994) Traffi c signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314
 CBTRUS Supplement Report: Primary Brain Tumors in the United States, 2004. (2008) CBTRUS, Central Brain Tumor Registry of the
United States, Hinsdale, IL
 Joachim M. Baehring, Uwe Schlegel, and Fred H. Hochberg (2010): Primary CNS Lymphoma in Oncology of CNS Tumors Jörg-Christian
Tonn, Manfred Westphal and James T. Rutka (Eds.) Second edition part I cranial neuro-oncology Springer Heidelberg Dordrecht London
New York chapter 19 pp 331-341
 71. Olson JE, Janney CA, Rao RD, Cerhan JR, Kurtin PJ, Schiff D, et al (2002) The continuing increase in the incidence of primary central
nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 95:1504–1510
 Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. (2004) Primary central nervous system posttransplant lymphoproliferative
disorders. Am J Clin Pathol 121: 246–253
 Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular
pathogenesis and treatment. J Neurol Sci 181:1–12
 Catherine Haberland (2007): Clinical Neuropathology: TEXT AND COLOR ATLAS. DEMOS MEDICAL PUBLISHING, LLC. Chapte 11
pp 245-246.
 Gijtenbeek JM, Rosenblum MK, DeAngelis LM. (2001) Primary central nervous system T-cell lymphoma. Neurology 57:716–718
 Shenkier TN, Blay JY, O’Neill BP, Poortmans P, Thiel E, Jahnke K, et al (2005) Primary CNS lymphoma of T-cell origin: a descriptive
analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 23: 2233–2239
 Hochberg FH, Miller G, Schooley RT, Hirsch MS, Feorino P, Henle W. (1983) Central-nervous-system lymphoma related to Epstein-Barr
virus. N Engl J Med 309:745–748
 Nakamura M, Kishi M, Sakaki T, Hashimoto H, Nakase H, Shimada K, et al (2003) Novel tumor suppressor loci on 6q22–23 in primary
central nervous system lymphomas. Cancer Res 63:737–741

38. References
 Harder H, Holtel H, Bromberg JE, Poortmans P, Haaxma- Reiche H, Kluin-Nelemans HC, et al (2004) Cognitive status and quality of life
after treatment for primary CNS lymphoma. Neurology 62:544–547
 Grimm SA, Pulido JS, Jahnke K, Schiff D, Hall AJ, Shenkier TN, et al (2007) Primary intraocular lymphoma: an International Primary
Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18:1851–1855
 Ferreri AJ, Blay JY, Reni M, Pasini F, Gubkin A, Tirelli U, et al (2002) Relevance of intraocular involvement in the management of
primary central nervous system lymphomas. Ann Oncol 13:531–538
 Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. (2003) Neurolymphomatosis. Neuro Oncol 5:104–115
 Glass J, Hochberg FH, Miller DC. (1993) Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer
71:3156–3164
 Hochberg FH, Miller DC. (1988) Primary central nervous system lymphoma. J Neurosurg 68:835–853
 Joachim M. Baehring, Uwe Schlegel, and Fred H. Hochberg (2010): Primary CNS Lymphoma in Oncology of CNS Tumors Jörg-Christian
Tonn, Manfred Westphal and James T. Rutka (Eds.) Second edition part I cranial neuro-oncology Springer Heidelberg Dordrecht London
New York chapter 19 pp 331-341
 Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, et al (2005) Report of an international workshop to
standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034–5043
 Diagnostic imaging. Brain / Anne 0. Osborn ... let al.]. Amirsys Inc 2004
 Charito Love, Maria B. Tomas, Gene G. Tronco, Christopher J. Palestro: FDG PET of Infection and Inflammation. RG Volume
25, Number 5 September-October 2005 pp 1357-1368
 Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al (2000) Primary intracerebral malignant lymphoma:report of
248 cases. J Neurosurg 92:261–266
 Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular
pathogenesis and treatment. J Neurol Sci 181:1–12