Primary Central Nervous System Lymphoma

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TABLE OF CONTENTS

[CLINICAL=20 FEATURES] [RARE=20 PRIMARY...] [CONCLUSION]=20 [REFERENCES]=20 [FIGURES]

=A9=20 Copyright by College of American Pathologists 2008=20

Archives of Pathology and Laboratory = Medicine:=20 Vol. 132, No. 11, pp. 1830=961834.

Primary Central Nervous System Lymphoma

Sharathkumar Bhagavathi, MD; Jon D. Wilson, MD

From the Department of Anatomic Pathology, William Beaumont=20 Hospital, Royal Oak, = Mich

Accepted April 23, 2008

Primary=20 central nervous system lymphoma (PCNSL) is an uncommon extranodal=20 non-Hodgkin lymphoma. Its incidence has increased during the last 3 = decades=20 and has been reported in both immunocompromised and immunocompetent=20 patients. Immunocompromised patients are affected at a younger age = compared=20 with immunocompetent patients. It presents with raised intracranial = pressure=20 and focal neurologic and neuropsychiatric symptoms. The lesions are=20 typically solitary. The majority of the lesions are located in the=20 periventricular area, whereas in a few cases they are located in the = supratentorial area. Diffuse large B-cell lymphomas constitute most = PCNSLs,=20 whereas T-cell, low-grade, anaplastic, and Hodgkin lymphomas are = rarely=20 encountered. The morphology of PCNSL shows a characteristic = angiocentric=20 pattern and is positive for B-cell markers by immunohistochemistry. = The=20 differential diagnosis of PCNSL includes central nervous system = gliomas,=20 metastatic tumors, demyelinating disorders, subacute infarcts, and=20 space-occupying lesions due to an infectious etiology. The = understanding of=20 the molecular mechanisms involved in the pathogenesis of PCNSL and = the=20 identification of molecular biomarkers have lagged behind that of = systemic=20 nodal lymphomas. Primary central nervous system lymphomas are = treated with=20 combined radiotherapies and chemotherapies. The prognosis for PCNSL = is worse=20 than for other extranodal = lymphomas.

3D"" Primary central nervous system lymphoma (PCNSL) = is an=20 uncommon variant of extranodal non-Hodgkin lymphoma that involves the = brain,=20 leptomeninges, eyes, or spinal cord without evidence of systemic = disease. It=20 does not include systemic lymphomas spreading to the central nervous = system=20 (CNS). This entity was first described by Bailey in 1929 (Intracranial=20 sarcomatous tumours of leptomeningeal origin. Arch Surg.=20 1929;18:1359=961402) as =93perithelial sarcoma=94 of the CNS until its = lymphoid=20 lineage was clarified. In most patients, PCNSL presents as an = intracerebral=20 mass, but occasionally it may present in the orbit, the leptomeningies, = or the=20 spinal cord.^{1<=
/SUP>=20
According to the World Health Organization classification, most PCNSLs =
are=20
diffuse large B-cell lymphomas (DLBCLs),^{2<=
/SUP>=20
whereas T-cell, low-grade, anaplastic, and Hodgkin lymphomas are rarely=20
encountered.^3,=^{4<=
/SUP>=20
It has been reported in both immunocompromised and immunocompetent =
patients, and=20
it accounts for 2.7% of all malignant diseases of the CNS. The incidence =
of=20
PCNSL has increased during the last 3 decades and occurs at a younger =
age in=20
immunocompromised patients. In human immunodeficiency virus=96infected =
patients,=20
PCNSL occurs at a rate that is 3600-fold higher than the general =
population. The=20
lifetime risk of developing CNS lymphoma approaches 20% in patients with =
human=20
immunodeficiency virus infection.^{5<=
/SUP>=20
The PCNSL in human immunodeficiency virus=96positive patients is often =
associated=20
with Epstein-Barr virus (EBV), whereas its association with EBV is rare =
in=20
immunocompetent patients.^{6<=
/SUP>=20
The present article will focus on clinical features, gross and =
microscopic=20
findings, ancillary studies, pathogenesis, differential diagnosis, =
prognostic=20
markers, and treatment of PCNS DLBCL. Rare variants of PCNSL are =
described=20
briefly.}}}}}

CLINICAL FEATURES Return=20 to TOC

Age and Sex

3D"" The median age of occurrence of PCNSL in = immunocompetent=20 patients is 53 to 57 years,^5,=^{6<=
/SUP>=20
whereas in immunocompromised patients it is 31 to 35 years.^{7<=
/SUP>=20
The sex distribution of this disease is almost equal in immunocompetent =
patients=20
(male-female ratio, 1.2:1.0), whereas there is a clear male predominance =
in=20
AIDS-associated PCNSL (male-female ratio, 7.38:1).}}

Predisposing Conditions

3D"" Immunodeficiency is an important risk factor for = the=20 development of PCNSL. Apart from AIDS, iatrogenic immune suppression for = transplant procedures, congenital immune deficiency, and autoimmune = conditions=20 are risk factors for the development of PCNSL. Congenital = immunodeficiency=20 syndromes that predispose to lymphoma include ataxia-telangiectasia,=20 Wiskott-Aldrich syndrome, and severe combined and common variable=20 immunodeficiency. Autoimmune diseases that predispose to lymphoma = include=20 rheumatoid arthritis, systemic lupus erythematotosis, Sj=F6gren = syndrome,=20 myasthenia gravis, sarcoidosis, and vasculitis.

Symptoms

3D"" The location of the lymphoma in the CNS = determines the=20 clinical presentation. In a large series with immunocompetent patients = with=20 PCNSL, focal neurologic deficits were the most common presentation in = 70% of=20 patients, followed by neuropsychiatric symptoms in 43%, signs of raised=20 intracranial pressure like headache/nausea/vomiting in 33%, seizures in = 14%, and=20 ocular symptoms in 4%.^8<=
/SUP>

3D"" Immunocompromised patients with PCNSL present = with raised=20 intracranial pressure, personality changes, and neurologic and = neuropsychiatric=20 symptoms.

Anatomical Location

3D"" Primary CNS lymphoma may present either as an = isolated lesion=20 or as a combination of the following features: (1) discrete or diffuse=20 intracranial lesions that are either solitary or multiple, (2) ocular = lymphomas=20 with or without other lesions, and (3) leptomeningeal surface and spinal = cord=20 lesions. Immunocompetent patients tend to present predominantly with = solitary=20 lesions in 70% of cases, compared with 50% in AIDS patients.^{8<=
/SUP>=20
The majority of the discrete lesions are supratentorial (85%), and a =
minority=20
are infratentorial (15%).^6,=^{8<=
/SUP>=20
In 60% of cases, the lesions of PCNSL are primarily located in =
periventricular=20
areas involving the thalamus, basal ganglia, and corpus callosum. The =
lobes of=20
the cerebral cortex are involved with following frequency: frontal lobe =
is=20
involved in 20%, parietal lobe in 18%, temporal lobe in 15%, and =
occipital lobe=20
in 4%.^8<=
/SUP>}}

Macroscopic Features

3D"" The gross appearance of PCNSL in immunocompetent = and=20 immunodeficient patients is similar. The size may vary, but most of the = lesions=20 are well circumscribed and are greater than 2 cm in diameter. Grossly, = the=20 lesions could be firm, homogenous, centrally necrotic, brownish, = gray-tan, and=20 yellow with areas of hemorrhage. Their demarcation of the lesions from = the=20 surrounding brain is variable. They may resemble gliomas due to the=20 architectural effacement and diffuse borders. Diffuse infiltrating = tumors are=20 referred to as lymphomatosis cerebri. In AIDS patients, necrotic = areas=20 simulating those of cerebral toxoplasmosis are observed. Meningeal = lymphoma may=20 mimic meningioma or meningitis or appear microscopically normal.^2<=
/SUP>

Microscopic Features

3D"" The PCNSL shows a characteristic angiocentric = pattern,=20 forming cuffs of tumor cells within and around cerebral blood vessels. = Reticulin=20 preparation shows concentric reticulin fibers around blood vessels. The = tumor=20 infiltrates the brain parenchyma as small clusters and as individual = cells. The=20 tumor may show areas of necrosis, with viable cells found mainly around = blood=20 vessels. The cells lack a cohesive appearance. Most of the PCNSLs show a = diffuse=20 growth pattern, whereas a follicular growth pattern has not been = observed. A=20 focally prominent reactive astrocytic and microglial response, as well = as=20 reactive lymphocytic infiltrates with a predominance of small = CD4-positive T=20 cells are common.^{2<=
/SUP>=20
The malignant lymphoid cells may be centroblasts or immunoblasts with =
scant=20
cytoplasm and a variable number of mitotic figures (Figure=
=20
1 ).}

Immunohistochemical Profile

3D"" Immunohistochemical stains for the diagnostic = workup include=20 CD45 (leukocyte common antigen), CD20, CD79a, and CD3. In PCNSL, the = large=20 atypical cells are positive for CD20 (B-cell marker), and small benign = admixed=20 cells are positive for CD3 (T-cell marker). Glial fibrillary acidic = protein=20 staining shows gliosis of the infiltrated brain parenchyma by tumor = cells. Most=20 tumors are BCL2 positive (Figure= =20 2 ). The=20 PCNS DLBCL is further subcategorized into germinal center B-cell and = activated=20 B-cell type based on CD10, BCL6, and MUM-1 staining patterns. The BCL6 = protein=20 is a zinc-finger transcriptional repressor required for the formation of = the=20 germinal center.^{9<=
/SUP>=20
A number of studies have shown the expression of BCL6 in PCNS DLBCL (Figure=
=20
3 ).^1=
0,^1=
1=20
Most PCNSLs (96%) are positive for MUM-1 (a marker of germinal center/ =
early=20
post=96germinal center B cells), indicating a late germinal center/early =

post=96germinal center stage of differentiation (Figure=
=20
4 ).^1=
2=20
A far greater number of PCNSLs express the pattern of an activated =
B-cell=20
phenotype when compared with systemic DLBCL, and are associated with =
poor=20
prognosis.^1=
2}

Pathogenesis and Molecular Studies

3D"" Since the CNS is devoid of B cells, the = understanding of the=20 molecular mechanisms involved in the pathogenesis of PCNSL is quite = limited. Due=20 to its association with EBV in immunodeficient individuals, the proposed = mechanisms for the development of PCNSL are focused on the body's = immunologic=20 response to EBV infection. In immunodeficient patients, EBV is = associated with=20 PCNSL, and latent EBV infection of B cells leads to their = immortalization and to=20 CNS tropism. In healthy individuals, the EBV-infected B cells are held = in check=20 by T cells, and as the immunodeficiency becomes severe, a gradual fall = in T=20 cells leads to the proliferation and dissemination of B cells. Another = proposed=20 mechanism for the development of PCNSL is the expression of specific = adhesion=20 molecules by systemic malignant B cells that could facilitate their = homing to=20 the CNS. A B-cell chemokine, BCA-1, has been shown to be expressed at a = higher=20 level in PCNSL. A study by Rubenstein et al^1=
3=20 showed that certain factors are required for the retention of = peripherally=20 derived lymphoma cells in the CNS as well as for the angiocentric = pattern in=20 PCNSL. This group has shown that interleukin 4 and STAT6 molecules are = involved=20 in the pathogenesis of PCNSL. They also showed that the expression of = STAT6 is=20 associated with tumor progression and a shortened survival.

3D"" Cytogenetic analyses show gains of chromosomes = 12, 1, 18, and=20 7 by comparative genomic hybridization. A study by Kady et al^1=
4=20 suggests distinct differences between genetic pathways of PCNSL and = systemic=20 lymphomas. Their study showed less frequent translocations of = immunoglobulin H=20 (IgH), BCL6, and MYC in PCNSL compared with systemic lymphomas. In = contrast to=20 systemic lymphomas, homozygous deletion and promoter hypermethylation of = CDKN2A, which produces p14ARF, have been identified in PCNSL.^1=
5,^1=
6=20 Unlike systemic lymphomas, mutations of TP53 are extremely rare = in=20 PCNSL.^1=
5,^1=
6

Differential Diagnosis

3D"" Since PCNSL predominantly presents as a single = homogenous=20 lesion surrounded by edema on radiologic studies, the differential = diagnosis=20 includes a wide range of benign and malignant lesions, which present = with a=20 similar radiologic pattern. Malignant lesions include glioblastoma = multiforme=20 and metastatic lesions to the CNS from other malignancies, like prostate = cancer,=20 small blue cell tumors, or adenocarcinoma of the lung. Benign lesions in = the=20 differential diagnosis include subacute infarction, lesions due to = demyelinating=20 diseases, or space-occupying lesions due to infectious or parasitic = etiologies.=20 Histopathology and immunohistochemical staining of the lesion is crucial = to=20 differentiate PCNSL from other lesions.

3D"" Malignant gliomas tend to have a greater degree = of cellular=20 and nuclear pleomorphism, infiltrative borders, vascular proliferation, = and=20 necrosis with pseudopalisading by tumor cells. Anaplastic carcinomas = tend to be=20 cohesive and lack perivascular reticulin deposition. A macrophage-rich = lesion=20 may be due to an infarction or a demyelinating disorder. Axons are = destroyed in=20 infarctions compared with their preservation in demyelinating disorders. = Small=20 cell carcinomas show nuclear molding, a feature not seen in PCNSL.=20 Immunohistochemical stains, glial fibrillary acidic protein, and = phosphotungstic=20 acid hematoxylin accentuate the fibrillary pattern in gliomas. Leukocyte = common=20 antigen (CD45) confirms the diagnosis of lymphoma. Cytokeratin may be = useful in=20 detecting undifferentiated carcinomas. In immunodeficient patients, a = parasitic=20 infestation due to toxoplasmosis needs to be ruled out.

Treatment and Prognosis

3D"" The favorable prognostic factors described to = date include a=20 single, well-circumscribed intracranial lesion, the absence of meningeal = or=20 periventricular tumor, the absence of immunodeficiency, and age younger = than 60=20 years.^{2<=
/SUP>=20
Patients with diffuse mixed and small noncleaved cell lymphomas do =
better than=20
those with large immunoblastic and large noncleaved or cleaved =
lymphomas.^1=
7}

3D"" The primary treatment for PCNSL includes a = combination of=20 chemotherapy containing high-dose methotrexate followed by radiotherapy. = With=20 the combined radiotherapy and chemotherapy approach, immunocompetent = patients=20 show a response rate of 85%, with a median survival of 17 to 45 = months.^{2<=
/SUP>=20
Patients with AIDS have a poorer prognosis, with median survival of 13.5 =
months,=20
even when treated with multimodal therapy.^1=
8=20
The dramatic response to corticosteroids is usually temporary.}

RARE PRIMARY CNS LYMPHOMAS Return=20 to TOC

T-Cell Lymphomas

3D"" T-cell PCNSL is occasionally seen, and case = reports have been=20 described in the literature. The reported incidence of T-cell PCNSL in = Western=20 countries is 2%.^1=
9=20 The largest series of T-cell PCNSL included 45 patients from 7 countries = (The=20 International Primary CNS Lymphoma Corroborative Group).^2=
0=20 In this study, a supratentorial lesion was most commonly seen. T-cell = origin was=20 ascertained by immunophenotyping and T-cell receptor gene rearrangement = studies.=20 The morphology showed an =93angiocentric=94 pattern in 28% of the cases. = The cell=20 size ranged from small to medium in 50% of the cases and either = =93pleomorphic=94 or=20 =93medium to large=94 cells in the other 50% of the cases.^2=
0

Anaplastic Large Cell Lymphoma

3D"" Primary or secondary CNS anaplastic large cell = lymphomas=20 (ALCLs) are extremely rare, and only 20 cases have been reported in the=20 literature.^2=
1=20 There is no association between ALCL and immunodeficiency disorders or=20 immunosuppression. Most cases occurred in patients younger than 22 = years, and a=20 minority of cases after 50 years.^2=
2=20 Primary CNS ALCL is notable for dural or leptomengeal involvement.

3D"" The morphology of ALCL shows large cells with = pleomorphic=20 nuclei and multiple prominent nucleoli. The majority of the lymphomas = are=20 positive T-cell markers, and staining for CD45, CD30, and epithelial = membrane=20 antigen is variable. The majority (60%=9685%) of ALCLs show t(2;5) that = fuses ALK=20 (anaplastic large cell kinase) on chromosome 2, with the nucleophosmin = on=20 chromosome 5. This can be detected immunohistochemically by reactivity = with=20 ALK-1 antibody. The morphologic variants include lymphohistocytic and = small cell=20 types. The morphologic and immunohistochemical variability makes its = diagnosis a=20 challenge.^2=
2=20 Metastatic carcinoma, sarcoma, and melanoma are in the differential = diagnosis.=20 Epithelial membrane antigen, cytokeratin, S100, and lymphoid markers are = used to=20 differentiate ALCL from other tumors. Multifocal disease, ALK-1 = negativity,=20 tumor necrosis, and elderly patients are associated with a bad = prognosis.

Low-Grade Lymphoma

3D"" Low-grade lymphomas are extremely rare and = constitute 3% of=20 PCNSLs. Supratentorial localization is common. The International Primary = CNS=20 Lymphoma Study Group recently published a series of low-grade PCNSLs.^2=
3=20 Of the 40 patients with low-grade PCNSL, 32 (80%) were of B-cell = lymphoma type,=20 and 8 (20%) were of the T-cell type.^2=
3=20 T-cell lymphomas showed a similar angiocentricity compared with DLBCL, = and they=20 were diagnosed by the presence of T-cell markers and the absence of = B-cell=20 markers. The low-grade lymphomas showed an indolent behavior compared = with the=20 high-grade DLBCLs. There was no difference in the prognosis between = B-cell and=20 T-cell low-grade lymphomas. A low-grade PCNSL should be differentiated = from=20 inflammatory processes, like viral encephalitis and multiple sclerosis.=20 Nonneoplastic processes are composed mainly of reactive T cells, whereas = most=20 lymphomas are composed predominantly of B cells. T-cell receptor and IgH = gene=20 rearrangement studies are helpful in diagnosis.

Primary Hodgkin Lymphoma

3D"" This entity is rare in the CNS. Secondary = involvement of the=20 brain or meninges is an uncommon complication of systemic Hodgkin = lymphoma. The=20 lesions are dura based in most cases. Identification of Reed-Sternberg = cells or=20 their variants in the appropriate nonneoplastic background and = immunoreactivity=20 of Reed-Sternberg cells for CD30 and CD15 confirms the diagnosis. = Epstein-Barr=20 virus genes and proteins may occur even in immunocompetent patients.^2=
4

Primary Intraocular Lymphoma

3D"" Primary intraocular lymphoma involves the retina, = the=20 vitreous, and the optic nerve. The majority of the cases present = bilaterally and=20 develop intracerebral disease during the course of progression. Most of = the=20 primary intraocular lymphomas are DLBCLs and show positive B-cell = markers.=20 Vitreous cytology and chorioretinal biopsy are necessary for the = diagnosis and=20 show a malignant lymphoid infiltrate between the retinal pigment = epithelium and=20 the Bruch membrane.

CONCLUSION Return=20 to TOC

3D"" The incidence of PCNSL is increasing. Diffuse = large B-cell=20 lymphoma is the most common type of PCNSL, the majority of which are = activated=20 B-cell type. The molecular mechanisms involved in pathogenesis of PCNSL = are not=20 yet understood fully. There is an urgent need to discover new = therapeutic=20 targets and drugs to improve the clinical outcome of patients with=20 PCNSL.

References Return=20 to TOC

1. Central Brain = Tumor=20 Registry of the United States. Primary Brain Tumors in The United = States=20 1995=961999: Statistical Report. Chicago, Ill: Central Brain Tumor = Registry of=20 the United States; 2002=962003.

2. Kleihues P, Cavenee WK. = Pathology=20 and Genetics of Tumours of the Nervous System. Lyon, France: IARC = Press;=20 2000. World Health Organization Classification of Tumors. =

3. Aubrey LE, Batchelor TT, = Ferreri AJ.=20 et al. Report of an international workshop to standardize baseline = evaluation=20 and response criteria for primary CNS lymphoma. J Clin Oncol=20 2005;23:5034=965043.

4. Aubrey=20 LE, Ben-Porat L, Panageas KS. et al. Primary central nervous system = lymphoma:=20 the Memorial Sloan-Kettering cancer center prognostic model. J Clin = Oncol=20 2006;24:5711=965715.

5. Schabet=20 M. Epidemiology of primary CNS lymphoma. J Neurooncol = 1999;43:199=96201.=20

6. Camilleri-Broet = S, Martin=20 A, Moreau A. et al. Primary central nervous system lymphomas in 72=20 immunocompetent patients: pathologic findings and clinical correlations. = Am J=20 Clin Pathol 1998;110:607=96611.

7. Fine HA, Mayer RJ. Primary = central=20 nervous system lymphoma. Ann Intern Med 1993;119:1093=961104. =

8. Bataille B, Delwail V, = Menet E. et=20 al. Primary intracerebral malignant lymphoma: report of 248 cases. J=20 Neurosurg 2000;92:261=96266.

9. Dent AL, Shaffer AL, Yu X, = Allman D,=20 Staudt LM. Control of inflammation, cytokine expression and germinal = center=20 formation by BCL-6. Science 1997;276:589=96592.

10. Braaten KM, Betensky RA, = de Level=20 L. et al. BCL-6 expression predicts improved survival in patients with = primary=20 central nervous system lymphoma. Clin Cancer Res = 2003;9:1063=961069.=20

11. Lin CH, Kuo = KT, Chuang=20 SS. et al. Comparison of the expression and prognostic significance of=20 differentiation markers between diffuse large B-cell lymphoma of central = nervous=20 origin and peripheral nodal origin. Clin Cancer Res = 2006;12:1152=961156.=20

12. Camilleri-Broet S,=20 Criniere E, Broet P. et al. A uniform activated B-cell-like = immunophenotype=20 might explain the poor prognosis of primary central nervous system = lymphomas:=20 analysis of 83 cases. Blood 2005;1007:190=96196.

13. Rubenstein JL, Fridlyand = J, Shen A.=20 et al. Gene expression and angiotropism in primary CNS lymphoma. = Blood=20 2006;1007:3716=963723.

14. Kady FM, Law ME, = Porter-Umphrey AB.=20 et al. The frequency of specific chromosomal abnormalities in primary = central=20 system lymphomas (PCNSL) differs from systemic diffuse large B-cell = lymphoma=20 (DLBCL), suggesting a distinct pathogenesis. Poster presented at: United = States=20 and Canadian Academy of Pathology; March 24=9630, 2007; San Diego, = Calif.=20

15. Nakamura M, = Shimada K,=20 Konishi N. Histopathology, pathogenesis and molecular genetics in = primary=20 central nervous system lymphomas. Histol Histopathol = 2004;19:211=96219.=20

16. Rubenstein JL, = Treseler=20 P, O'Brien JM. Pathology and genetics of primary central nervous system = and=20 intraocular lymphoma. Hematol Oncol Clin North Am = 2005;19:705=96717.=20

17. Miller DC, = Hochberg FH,=20 Harris NL. et al. Pathology with clinical correlations of primary = central=20 nervous system non-Hodgkin's lymphoma: the Massachusetts General = Hospital=20 experience 1958=961989. Cancer 1994;74:1383=961397.

18. Chamberlain MC. Long = survival in=20 patients with acquired immune deficiency syndrome related primary = central=20 nervous system lymphoma. Cancer 1994;73:1728=961730.

19. Ferreri AJ, Reni M, = Pasini F. et=20 al. A multicenter study of treatment of primary CNS lymphoma. = Neurology=20 2002;58:1513=961520.

20. Shenkier TN, Blay JY, = O'Neill BP.=20 et al. Primary CNS lymphoma of T cell origin: a descriptive analysis = from the=20 international Primary CNS Lymphoma Collaborative Group. J Clin = Oncol=20 2005;23:2233=962239.

21. Rupani A, Modi C, Desai = S, Rege J.=20 Primary large cell anaplastic cell lymphoma of central nervous system-a = case=20 report. J Postgrad Med 2006;51:326=96327.

22. George DH, Scheithauer = BW, Aker FV.=20 et al. Primary anaplastic large cell lymphoma of the central nervous = system:=20 Prognostic effect of ALK-1 expression. Am J Surg Pathol = 2003;27:487=96493.=20

23. Jahnke K, = Korfel A,=20 O'Neill BP. et al. International study on low-grade primary central = nervous=20 system lymphoma. Ann Neurol 2006;59:755=96762.

24. Klein R, Mullges W, = Bendszus M,=20 Woydt M, Kreipe H, Roggendorf W. Primary intracerebral Hodgkin's = disease: report=20 of a case with Epstein-Barr virus association and review of literature. = Am J=20 Surg Pathol 1999;23:477=96481.

Figures Return=20 to TOC

Click on thumbnail for full-sized = image.

3D""=20 Figure 1. 3D""=20 Primary=20 central nervous system diffuse large B-cell lymphomas showing a = characteristic=20 angiocentric pattern, forming cuffs of tumor cells within and around = cerebral=20 blood vessels and consisting of centroblasts (hematoxylin-eosin, = original=20 magnification =D7100). Figure 2. 3D""=20 A=20 case of primary central nervous system diffuse large B-cell lymphoma.=20 Immunohistochemical staining for BCL2. Tumor cells show strong staining = for BCL2=20 (original magnification =D7100). Figure 3. 3D""=20 Primary=20 central nervous system diffuse large B-cell lymphoma. = Immunohistochemical=20 staining for BCL6. Lymphoma cells are positive for BCL6 (original = magnification=20 =D7100). Figure 4. 3D""=20 A=20 case of primary central nervous system diffuse large B-cell lymphoma.=20 Immunohistochemical staining for MUM-1. Tumor cells show strong nuclear = staining=20 for MUM-1 (original magnification = =D7100)

The authors have no relevant financial interest in the = products or=20 companies described in this article.

Reprints: Sharathkumar = Bhagavathi, MD,=20 Department of Anatomic Pathology, William Beaumont Hospital, 3601 W 13th = Mile=20 Rd, Royal Oak, MI 48076 (E-mail: vmsharathkumar@yahoo.com)

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