ILOS Discuss pathogenesis of PCNSL Discuss the epidemiological data of PCNSL Describe     the      microscopic,     mac...
Introduction
Introduction Classification of CNS lymphoma:  Primary CNS lymphoma (PCNSL)   Secondary CNS lymphoma Definition of PCNS...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Cell of origin & Pathogenesis Theories of PCNSL  CNS infection → inflammatory process → Neoplastic   process ...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Epidemiology Incidence:  1-2% of intracranial tumors   10 % of systemic lymphomas will have CNS mets.  A si...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Macroscopic features Site:   PCNS: Supratentorial, periventricular   Mets: Leptomeningeal Size: Number: mo...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Microscopic Features Mostly diffuse large B-cell lymphomas (DLBCLs) Other cells found are   - Histocytes   - ...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Immunohistochemistry Stain positive to the leukocyte marker CD45                  CD45 immunological markers
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Genetic & Ultra structures                 Features EBV genomic material is identified in over 90% of PCNSL  t...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Radiological Features CT: MRI: MRS: PET:
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Growth Pattern & Spread Spread along fibers of C.C Spread along ependymal surface. The eye, however, is an i...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Grading & Behavior Most CNS NHMLs are high-grade lesions corresponding to  large B cells. MIB-l, proliferatio...
Pathology 1) Cell of origin & pathogenesis 2) Epidemiology 3) Macroscopic features 4) Microscopic features 5) Immunoh...
Pathology: Prognosis                      • Immunocompetent patients is 17-45 Median survival in Older  months           ...
 Cranial or spinal masse   Increase intracranial pressure:   Seizure:   Neurological deficits    Hormonal disturbance...
 To diagnose CNS lymphoma:  Radiological features: Increase suspicious   CSF examination !!!  No steroid test   Tissu...
Hypometabolism PET in Toxoplasmosis   Hypermetabolism PET in PCNSL
Surgery Stereotactic biopsy: Relief of hydrocephalus Excision:
Radiotherapy Highly radiosensitive Recurrence Lesion radiation # whole brain radiation 40-50 Gy to the primary tumor
Chemotherapy Radio + Chemo = ↑ mean survival from 16 to 44.5 months Radio + Chemo = ↑ the 5-year survival rate from 7 to...
Management Protocol in        Immunocompromised Patients Immunocompromised patient presented with intracranial mass MRI ...
References    Joachim M. Baehring, Uwe Schlegel, and Fred H. Hochberg (2010): Primary CNS Lymphoma in Oncology of CNS Tum...
References    Harder H, Holtel H, Bromberg JE, Poortmans P, Haaxma- Reiche H, Kluin-Nelemans HC, et al (2004) Cognitive s...
Primary CNS lymphoma
Primary CNS lymphoma
Primary CNS lymphoma
Primary CNS lymphoma
Primary CNS lymphoma
Primary CNS lymphoma
Primary CNS lymphoma
Upcoming SlideShare
Loading in...5
×

Primary CNS lymphoma

1,517

Published on

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,517
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
55
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • There are two types of lymphoma: Hodgkin lymphoma (HL, also called Hodgkin's disease) and non-Hodgkin lymphoma (NHL). Both HL and NHL can occur in the same places and have similar symptoms. Their differences are visible at a microscopic level. Hodgkin lymphoma develops from a specific abnormal lineage of B cells. There are five subtypes of HL. NHL may derive from either abnormal B or T cells, and its 30 subtypes are distinguished by unique genetic markers. The large number of lymphoma subtypes has led to a complicated classification scheme that involves microscopic appearance and well-defined genetic and molecular configurations. PCNSL is an extranodal non-Hodgkin lymphoma
  • Lymphoma of the brain or spinal cord not involving other areas, except for ocular structures, is termed "primary CNS lymphoma" (PCNSL).PCNSL has been referred to within the literature as reticulum cell sarcoma, perivascular sarcoma, immunoblastic sarcoma, microgliomatosis and malignant reticulosis. - Lymphoma is a malignant lymphocytic neoplasm that can occur in the central nervous system (CNS), either primarily or as a secondary manifestation of systemic disease.
  • Primary CNS lymphoma, like systemic lymphoma, arises from lymphocytes. The source of the pre-malignant lymphocytes is controversial as the CNS lacks lymphoid tissue and lymphatics. The exact pathogenesis of PCNSLs in the immunocompetent is still not clear. Various theories of origin have been put forward.1) A polyclonal intracerebral inflammatory lesion may expand clonally in the brain and progress to a monoclonal neoplastic state. However, infection or inflammatory diseases have only exceptionally been described to antedate the development of PCNSL. Studies have shown a consistent association of tumors occurring in immunocompromised individuals with Ebstein Barr virus (EBV), suggesting an important role for the virus in the pathogenesis of these tumors. (Paul TR, 2008)2) Lymphoma cells may be systematically eradicated by an intact immune system, but may be protected in an immunologically protected site like the brain. However, there is no evidence of concomitant lymphoma at other immunologically privileged sites like the testis. (Paul TR, 2008)3) The perivascular distribution of cerebral tumor suggests that it may originate from systemic neoplastic lymphocytes that selectively infiltrate CNS tissue. This selectivity may depend on adhesion molecules within the CNS vasculature and parenchyma specific for the malignant cells. However, a study by Pauluset al, (Paulus W J. K., 1993) showed that the expression pattern of a number of integrins and immunoglobulin adhesion molecules by tumor cells did not differ between cytologically similar PCNSLs and nodal lymphomas. It is possible that the responsible adhesion molecules were missed in the study or were down regulated by lymphoma cells, once they entered the brain. (25, 90, 94)6. 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 25. Drillenburg P, Pals ST. (2000) Cell adhesion receptors in lymphoma dissemination. Blood 95:1900–1910 90. 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 94. Springer TA. (1994) Traffi c signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314
  • Incidence: Primary CNS lymphoma represents about 1% of intracranial tumors. The incidence of PCNSL has increased significantly over the last two decades. 1 Systemic lymphoma spreads to the CNS in about 10% of cases, most commonly in the setting of advanced or relapsing disease (85) .A similar percentage develop systemic disease after brain involvement. (2) The incidence is as high as 5% to 10% in patients with AIDS. The incidence of lymphomas in AIDS patients increases with the duration of antiretroviral therapy and the decline of CD4 countsSex: In the immunocompetent population with primary CNS lymphoma, 60% of patients are male and 40% are female (Hochberg PH, 1988). This is similar to the gender distribution of patients with systemic lymphoma. The immunocompromised population with PCNSL is even more disproportionately male because of the male predominance in the AIDS epidemic. Race:Age: For immunocompetent patients, the sixth decade of life is the most common age of diagnosis of PCNSL (Hochberg PH, 1988) (Miller DC H. P., 1994). In general, PCNSL patients with AIDS are younger than those with an intact immune system (within the fourth decade). (3)Childhood disease is rare and is usually associated with congenital or acquired immunodeficiency. Risk factors: Several risk factors for developing PCNSL have been identified . Given its etiologic role in other lymphoproliferative disorders among immunosuppressed patients This increase is partially attributable to an increased prevalence of immunodeficient patients secondary to acquired immune deficiency syndrome (AIDS) and immunosuppressive treatment after organ transplantation. However, the incidence of the disease among immunocompetent persons has also increased.The rise in solid organ transplantation has increased the incidence of posttransplantlymphoproliferative disorder (PTLD), although this lymphoma still arises in fewer than 2% of organ transplant recipients. PTLD tends to involve the donor organ and multiple extranodal sites, and is rarely confined to the nervous system [18].1. CBTRUS Supplement Report: Primary Brain Tumors in the United States, 2004. (2008) CBTRUS, Central Brain Tumor Registry of the United States, Hinsdale, IL 2) 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 331-3413) 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 95:1504–151018. Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. (2004) Primary central nervous system posttransplantlymphoproliferative disorders. Am J ClinPathol 121: 246–25385. Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment. J NeurolSci 181:1–12
  • Site:- Deposits of PCNSL within the brain vary may be leptomeningeal, parenchymal, subependymal or a combination of these. Murray et al. found the majority of lesions to be solitary and supratentorial (52.1%), with the most frequent sites of involvement being frontal (26%), temporal (15%) and parietal (14%) (Miller DC H. P., 1994). Diencephalic and infra tentorial lesions, particularly in the cerebellum (11%), were also seen.- CNS involvement by secondary lymphoma is usually leptomeningeal; the parenchyma is rarely involved.Size:Number: Primary CNS lymphoma may be unifocal or multicentric. The tumor is solitary almost twice as often as it is multi focal.Shape: It can be a diffuse microscopic infiltrate that to the unassisted eye leaves the areas involved intact. It can be identified as an area of tissue expansion in which the architecture is well preserved and may be associated with narrowing of cortical gyri and ventricles. The differential diagnosis with a glioblastomamultiforme should be entertained when the lymphoma diffusely infiltrates the parenchyma and reveals a variegated cut surface with hemorrhage and necrosis; the latter is a feature of AIDS associated lymphoma Discrete parenchymal nodules of PCNSL may be seen with yellow-brown discoloration. There may be areas of focal hemorrhage or necrosis. The cut surfaces are gray or brown, firm or soft, friable or granular.Catherine Haberland (2007): Clinical Neuropathology: TEXT AND COLOR ATLAS. DEMOS MEDICAL PUBLISHING, LLC. Chapte 11 pp 245-246.
  • - On microscopic examination, CNS NHMLs exhibit a diffuse histologic pattern; nodular lymphomas are rare (Hochberg et al., 1988; O’Neill et al., 1989; Russell et al., 1989; Burger et al., 1991). The infiltrate is polymorphous and includes histiocytes, plasma cells, reactive and neoplastic lymphoid elements, microglial cells, and a variable number of reactive astrocytes; mitoses and nuclear atypia are common. The great majority of PCNSLs are monoclonal B cell lymphomas. T cell lymphomas of the CNS are exceptionally rare. Most PCNSLs (about 90%) are diffuse large B-cell lymphomas (DLBCLs); the remaining 10% are poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas (37 & 89) T-cell lymphomas constitute only 2% of all PCNSLs, occur mainly in the immunocompetent, have a higher male to female ratio, are more frequent in the posterior fossa, mainly cerebellum, with a propensity to arise in the meninges. Microscopically, diffuse infiltration of tumor into brain parenchyma well beyond the macroscopic borders of the tumor is common. At the periphery, the neoplastic infiltrate tends to be perivascular and is associated with deposition of reticulin fibers arranged in concentric layers that separate individual cells and cellular groups. (Fig.). An astrocytic reaction can be prominent, especially in the peripheral parts of the tumor. An infiltrate of T lymphocytes is typically present at the tumor margins and occasionally within the tumor itself. 37. Gijtenbeek JM, Rosenblum MK, DeAngelis LM. (2001) Primary central nervous system T-cell lymphoma. Neurology 57:716–718 89. 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 ClinOncol 23: 2233–2239
  • Immunological markers help to distinguish B cell lymphomas from other tumors such, as gliomas and small cell carcinomas (antibody against CD45,a leukocyte marker), and from T cell lymphomas (antibodies against CD20 and CD79a, both B cell markers).
  • EBV genomic material is identified in over 90% of PCNSL tissue from immunocompromised patients [47]. EBV episomes are not found in PCNSL occurring in immunocompetent patients. The mechanism of viral oncogenesis might involve virally induced activation of human oncogenes or expression of oncogenes encoded by the virus that alters cell growth and prolongs cell survival. According to one report two thirds of specimens of PCNSL exhibit deletions on 6q22–23, and three quarters have reduced expression of the associated RPTRK gene [65]. 47. 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 65. Nakamura M, Kishi M, Sakaki T, Hashimoto H, Nakase H, Shimada K, et al (2003) Noveltumorsuppressorloci on 6q22–23 in primary central nervous system lymphomas. Cancer Res 63:737–741
  • General Features: Best diagnostic clue: Enhancing lesion(s) within basal ganglia, periventricular WM 90% supratentorial Frontal and parietal lobes most common Deep gray nuclei commonly affected Lesions cluster around ventricles, GM-WM junction Often involve, cross corpus callosum Frequently abut, extend along ependymal surfacesInfratentorial, sellar, pineal region uncommon May involve leptomeninges or dura, more commonly in secondary lymphoma Solitary mass (65–80%) or multiple lesions May be circumscribed or infiltrative- CT: NECT:Hyperdense classically - May be isodense +/- Hemorrhage, necrosis (immunocompromised) CECT: Common: Moderate, uniform (immunocompetent) Less common: Ring (immunocompromised) Rare: Nonenhancing (infiltrative, mimics white matter disease). MRI:- TlWI: Homogeneous isointense/hypointense to cortex in both Immunocompetent and Immunocompromised. May be heterogeneous from hemorrhage, necrosis T2WI: Homogeneous isointense/hypointense to cortex (hypointensity related to high nuclear to cytoplasmic ratio) May be heterogeneous from hemorrhage, necrosis Ca++ may rarely be seen, usually after therapy Mild surrounding edema is typical (Perifocal edema tends to be less prominent than in malignant glioma or metastases). DWI: Restricted diffusion (hyperintense lesions on diffusion-weighted imaging (DWI),. T1 C+: Immunocompetent: Strong homogeneous enhancement Immunocompromised: Peripheral enhancement with central necrosis or homogeneous enhancementNonenhancement extremely rareLymphomatous meningitis is typically related to systemic disease MRS: MRS: NAA decreased, Cho elevated. Lipid and lactate peaks reported Nuclear Medicine Findings: FDG PET: Hypermetabolic. 20l-Thallium SPECT: Hypermetabolic.
  • The eye, however, is an important site for tumor spread, with intraorbital involvement occurring in approximately 5% of patients at presentation. As many as 15% to 20% of patients are at risk for ocular relapse, since most systemically administered chemotherapeutic agents do not achieve cytotoxic concentrations within the eye and standard whole-brain radiation fields (C2) do not involve the orbits. (Fine, 2002:)
  • According to the WHO classification [43], the majority of PCNSL are classified as diffuse large-cell lymphomas (DLCL) of the B-cell type. 42. 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
  • Despite a high initial response rate, radiotherapy alone rarely leads to long-term survival; only 7% of patients are alive 5 years after treatment (Leibel SA, 1987). Symptomatic therapy alone resulting in a median survival of 2–3 months may be improved to 5 months by the provision of steroids. Rare patients experience prolonged remissions from steroid therapy, but cure is unlikely. A dramatic shrinkage of tumor volume after as little as 1 week of steroid treatment is present in 15–25% of cases (84)84. Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment. J NeurolSci 181:1–12
  • A proclivity to invade the walls of the third ventricle and the medial nuclei of the thalamus may result in organic psychoses and endocrine dysfunction, such as diabetes insipidus. Although PCNSL presents most commonly as diffuse and multifocal supratentorial brain masses, the clinician should be aware of four other initial appearances. These include [40]. lymphomatous infiltration of the leptomeninges or ependymal surfaces to produce lymphomatous meningitis: Involvement of the subependymal space or spinal fl uid has been reported in 5–65% [46] of patients. Leptomeningeal lymphoma presents with confusion, psychomotor slowing, cranial neuropathies, and caudaequina syndrome.Radicular or plexus invasion by lymphoma (neurolymphomatosis) in the absence of brain or spinal fluid involvement: When lymphoma invades the cranial or peripheral nerve roots, migratory pain syndromes, isolated cranial neuropathies, painless polyneuropathies, or involvement of a single peripheral nerve emerge [9] Infarcts produced by aggregates of intraluminalclonal B-cells within the brain (angiocentric or intravascular lymphoma): The multivessel involvement in intravascular lymphoma produces “lacunar strokes” with subcortical dementia or myelopathies as well as peripheral neurologic syndromes [38]. Lymphoma invading the vitreous, retina, and optic nerves (primary intraocular lymphoma). Some 10–15% of PCNSL patients experience eye involvement at presentation or during their treatment [28] 40. 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 18:1851–185528. 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 9. Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. (2003) Neurolymphomatosis. NeuroOncol 5:104–115 38. Glass J, Hochberg FH, Miller DC. (1993) Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer 71:3156–3164 46. Hochberg FH, Miller DC. (1988) Primary central nervous system lymphoma. J Neurosurg 68:835–853
  • Is it lymphoma? Radiological featuresAs many types of brain infiltrates improve with steroid therapy, the steroid response is not diagnostic of PCNSL. Similar responses have been seen in lesions of acute disseminated encephalomyelitis, multiple sclerosis, the granulomas of sarcoidosis, and granulomatousangiitis. (1) CSF examination:Some authors claim that the combination of increased uptake on thallium SPECT and EBV DNA in CSF has 100% sensitivity and specificity for CNS lymphoma and obviates the need for biopsy (Antoniri A, 1999).The typical CSF profile with primary CNS lymphoma is elevated protein, low glucose and pleocytosis. CSF cytology showing a monomorphic population of abnormal lymphocytes is diagnostic, but only 10% (reported range 5–25%) of patients undergoing CSF analysis at the time of presentation have positive cytologic findings. Furthermore, lumbar puncture may be contraindicated by increased intracranial pressure in many patients. (1)Is it systemic or PCNSL? Once a diagnosis of CNS lymphoma is established, the need for investigations to exclude systemic lymphoma with secondary cerebral involvement is controversial. (Batchelor T, 2006) (Fitzsimmons A, 2005) (Abrey LE, 2005) There are those who advocate that it is sufficient to perform a thorough clinical examination, complete blood counts, routine biochemical tests, serum LDH levels and chest radiographs; but there are others who recommend that the patients have contrast-enhanced CT scans of the chest, abdomen, pelvis as well as a bone marrow biopsy, given that 3.9-12.5% of patients with PCNSLs are found to have occult extra neural disease on additional evaluation. In immunocompetent patients, spread of systemic lymphoma to the CNS is uncommon. When it does occur, it is usually late in the course of the disease and the leptomeninges are predominantly affected so only screening tests (clinical examination, complete blood counts, routine biochemical tests, serum LDH levels and chest radiographs) will be enough. While for patients with AIDS, systemic lymphoma has a greater propensity to involve the CNS secondarily. In these patients staging evaluations in patients with primary CNS lymphoma is advised and it include General physical examination with evaluation of lymph nodes and testicles, Ophthalmologic evaluation including a slit-lamp examination of the eye, Cerebrospinal fluid evaluation, CT of chest, abdomen, and pelvis, and An international collaborative group has recommended bone marrow biopsy [2], although its yield is low in the absence of clinical and radiographic signs of systemic dissemination.. To diagnose extent of PCNSLIn general, investigations should be limited to determining the extent of disease within the CNS (LM., 1995): cranial MRI with contrast, ophthalmologic examination, spinal MRI with contrast (for patients with neck or back pain or myelopathy) and lumbar puncture (if not contraindicated). 1) 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 331-3412. 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 ClinOncol 23:5034–5043
  • D.D. (1)Toxoplasmosis Involves basal ganglia, corti co medullary junction Enhancing lesions, "eccentric target sign“ No ependymal spread Often indistinguishable on standard MRI SPECT, PET helpful (iso/hypometabolic)Glioblastomamultiforme (GBM)• "Butterfly glioma" involving corpus callosum• Hemorrhage common• Enhancement typically heterogeneous• Necrosis with ring enhancement in 95%Abscess• T2 hypointenserim, diffusion restriction typical• Peripheral enhancement with central necrosis• Enhancement often thinner on ventricular side• MRS: Elevated amino acids in cystic cavity (low TE)Progressive multifocalleukoencephalopathy (PML)• White matter T2 hyperintensity, involves subcorticalU-fibers• May involve corpus callosum• Typically nonenhancingDemyelination• May involve corpus callosum• Often incomplete, "horseshoe-shaped" enhancement,open towards cortex• Other lesions in characteristic locations• Younger patientsMetastases• Multiple lesions common• Significant associated vasogenic edema• Primary tumor often known• Lacy leptomeningeal enhancement typical• Dural, leptomeningeal> > parenchymal disease• Most patients have systemic diseaseSecondary involvement from systemic lymphoma• Intravascular pattern, lymphomatous meningitis or dural disease common• Can have single/multiple deep, periventricular lesions• Often affects brain and spineFigure 3. (a, b) Toxoplasmosis in an AIDS patient. (a) Contrast material–enhanced T1-weighted MR image shows an enhancing lesion in the right frontal operculum. (b) On an FDG PET scan, the lesion is hypometabolic. The final diagnosis was toxoplasmosis. (c, d) CNS lymphoma in a different AIDS patient. (c) Contrast- enhanced T1-weighted MR image reveals an enhancing mass in the splenium of the corpus callosum. (d) On an FDG PET scan, the lesion is hypermetabolic. The lesion subsequently proved to be lymphoma. (2) 1) Diagnostic imaging. Brain / Anne 0. Osborn ... let al.]. Amirsys Inc 2004 2) 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
  • The “routine” provision of glucocorticoids should be withheld in favor of osmotic therapy with mannitol. Often, steroid-treated lesions will disappear within hours, and “non-diagnostic” biopsies will result [84].Surgeons are reluctant to perform craniectomy for tumor resection; indeed, partial resection is associated with worse survival [11]. 11. 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 92:261–26684. Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment. J NeurolSci 181:1–12
  • Primary CNS lymphoma is highly radiosensitive. Early reports indicated an increase in median survival from 3.3 to 15.2 months for patients receiving radiotherapy. Subsequent reports confirmed this benefit to survival. Despite a high initial response rate, radiotherapy alone rarely leads to long-term survival; only 7% of patients are alive 5 years after treatment (Leibel SA, 1987). The optimal dose of radiation is controversial. Retrospective data suggest that total doses of 40-50 Gy to the primary tumor improve survival (Murray K, 1987). Protocol of radiotherapy is lesion radiation and no need for the whole brain or the entire cranio-spinal axis radiation. Spinal irradiation is reserved for patients with spinal disease, demonstrated radiographically or by CSF cytology.
  • Patients receiving chemotherapy and radiotherapy live longer than those receiving radiotherapy alone (Rosenthal MA, 1993;) (Pollack IF, 1989) (DeAngelis LM, 1992).The most effective treatment of PCNSL is systemic high-dose methotrexate (MTX)-based chemotherapyThe use of chemotherapy for PCNSL is expanding (Liang BC, 1993) (Pollack IF, 1989) (Table 16.7). Patients receiving chemotherapy and radiotherapy live longer than those receiving radiotherapy alone (Rosenthal MA, 1993;) (Pollack IF, 1989) (DeAngelis LM, 1992). The median survival following combinations of radiation and chemotherapy has ranged from 16 to 44.5 months; the 5-year survival rate is 20-30%. The rationale for administering chemotherapy before radiotherapy is twofold: (1) since radiotherapy often results in complete radiographic remission, administering it first prevents assessment of the effect of chemotherapy on measurable disease, and (2) the neurologic toxicity of some chemotherapeutic agents, including methotrexate, is less frequent and less severe when the drug is given prior to, rather than after, radiation.
  • As a general rule, the treating physician who is uncertain as to the contribution of toxoplasmosis and PCNSL should provide 2–3 weeks of therapy (with pyrimethamine and sulfadiazine) for toxoplasmosis prior to the performance of a stereotactic biopsy.When the availability of other regimens is limited or when patients need IV therapy the alternative regimen is: Trimethoprim-sulfamethoxazole (Septrin D.S tab 160/800mg ): Dose 5 mg/kg TMP and 25 mg/kg SMX PO or IV Q12H. Average 2 tab Q12H. Should show radiologic response in 2 weeks. If response is good then continue dose for 6-12 weeks then reduce by 50% and continue for life. Imaging studies are performed every 4-6 weeks until complete resolution of the lesion or stabilization after partial resolution. If no response within 2 weeks tissue biopsy should be done.
  • 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 NeurolNeurosurg Psychiatry 60:102–105Drillenburg 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 95:1504–1510Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. (2004) Primary central nervous system posttransplantlymphoproliferative disorders. Am J ClinPathol 121: 246–253 Schlegel U, Schmidt-Wolf IG, Deckert M. (2000) Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment. J NeurolSci 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 57:716–718Shenkier 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 ClinOncol 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 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 18:1851–1855Ferreri 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 13:531–538Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. (2003) Neurolymphomatosis. NeuroOncol 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 331-341Abrey 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 ClinOncol 23:5034–5043 Diagnostic imaging. Brain / Anne 0. Osborn ... let al.]. Amirsys Inc 2004Charito 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 1357-1368Bataille 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 NeurolSci 181:1–12
  • Primary CNS lymphoma

    1. 1. 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
    2. 2. Introduction
    3. 3. 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.
    4. 4. 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
    5. 5. 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
    6. 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. 7. 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
    8. 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. 9. 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
    10. 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. 11. 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
    12. 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. 13. Pathology: Immunohistochemistry Stain positive to the leukocyte marker CD45 CD45 immunological markers
    14. 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. 15. Pathology: Genetic & Ultra structures Features EBV genomic material is identified in over 90% of PCNSL tissue from immunocompromised patients
    16. 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. 17. Pathology: Radiological Features CT: MRI: MRS: PET:
    18. 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. 19. 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.
    20. 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. 21. Pathology: Grading & Behavior Most CNS NHMLs are high-grade lesions corresponding to large B cells. MIB-l, proliferation index, usually high, 50%
    22. 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. 23. 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:
    24. 24.  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%
    25. 25.  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
    26. 26. Hypometabolism PET in Toxoplasmosis Hypermetabolism PET in PCNSL
    27. 27. Surgery Stereotactic biopsy: Relief of hydrocephalus Excision:
    28. 28. Radiotherapy Highly radiosensitive Recurrence Lesion radiation # whole brain radiation 40-50 Gy to the primary tumor
    29. 29. Chemotherapy Radio + Chemo = ↑ mean survival from 16 to 44.5 months Radio + Chemo = ↑ the 5-year survival rate from 7 to 20- 30%.
    30. 30. 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
    31. 31. 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
    32. 32. 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
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×