cns lymphoma: a practical diagnostic...

REVIEW ARTICLE

CNS Lymphoma: A Practical Diagnostic Approach

Caterina Giannini, MD, PhD, Ahmet Dogan, MD, PhD, and Diva R. Salomao, MD

AbstractThe concept and understanding of central nervous system (CNS)

lymphoma have greatly evolved in the past few years. Better char-acterization of a number of lymphoproliferative neoplasms throughclinical, immunophenotyping, and molecular studies is reflected in amuch more complexWHO Classification of Tumours of Hematopoieticand Lymphoid Tissue. The term primary CNS lymphoma is nowrestricted to primary diffuse large B-cell lymphoma confined tothe CNS (and/or to the eye) that occurs in immunocompetentpatients. Many other lymphoma subtypes, some of which are pri-mary or exclusive to the CNS, such as lymphomas of the dura andimmunodeficiency-associated lymphomas, are excluded from thisdefinition. We describe the clinical and morphologic features of a di-verse group of lymphomas occurring in the CNS, including primaryCNS lymphoma, primary vitreoretinal lymphoma, lymphomatosiscerebri, Epstein-Barr virusYassociated lymphoproliferative disorders,low-grade B-cell lymphoma, T-cell lymphoma, anaplastic large celllymphoma, intravascular large B-cell lymphoma, and Hodgkin lym-phoma. The purpose of this review is to provide a practical approach tothe diagnosis of an often-challenging entity, focusing on how to max-imize the use of small tissue biopsies and prevent diagnostic traps,which we have encountered with similar cases. Clinical, radiologic, andhistologic examples are presented.

Key Words: CNS, Large B-cell lymphoma, Primary CNS lympho-ma, Retina, Vitreous.

INTRODUCTIONMalignant lymphoma can occur in the central nervous

system (CNS) in the absence of involvement elsewhere at thetime of diagnosis or as secondary involvement in the settingof systemic lymphoma. The most commonmorphology in bothprimary and secondary CNS lymphomas is that of a diffuselarge B-cell lymphoma (DLBCL), but a variety of lymphomas,including low-grade B-cell lymphomas and T-cell lymphoma,can affect the CNS. According to the most recent WHO Clas-sification of Tumours of Hematopoietic and Lymphoid Tissue(1), the term primary CNS lymphoma (PCNSL) should be

reserved for primary DLBCL of the CNS, a rare parenchymalbrain lymphoma confined to the CNS (and/or to the eye)occuring in immunocompetent patients (2). A variety ofother lymphomas, which may also manifest primarily or ex-clusively in the CNS, such as lymphomas of the dura andimmunodeficiency-associated lymphomas, are excluded fromthis definition. Intravascular large B-cell lymphoma (IVLBCL),also a rare form of disseminated B-cell lymphoma characterizedby selective growth of lymphoma cells within small vessels/capillary lumina, can also present clinically with a predominantneurologic variant secondary to CNS involvement (1).

With rare exceptions, histopathologic diagnosis is man-datory in planning appropriate treatment, which typically con-sists of systemic chemotherapy with or without whole brainradiotherapy. Diagnosis is most often obtained using stereo-tactic needle biopsy. Because most lesions are located deep intothe brain, stereotactic needle biopsy is the standard diagnosticprocedure for patients with suspected CNS lymphoma. In con-trast to other brain tumors, virtually all review articles and na-tional or international guidelines recommend that efforts atPCNSL resection not be undertaken (3). The US NationalComprehensive Cancer Network guidelines suggest biopsy usingthe least invasive approach (recommending referral to a special-ized center if stereotactic biopsy is not available) when cerebro-spinal fluid (CSF) examination (if safe) and eye examinationfail to yield the diagnosis (http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf). This traditional view that the extentof resection has no prognostic impact and may even be detri-mental is based on a small number of retrospective studies (4Y7)and has only recently been challenged (3).

In our experience, biopsy has been highly successful indiagnosing CNS lymphoma, but obtaining a definitive di-agnosis may be challenging for a variety of reasons. Theprimary goal of this review is not to present an in-depthdiscussion of all types of lymphoma that may affect the CNS.Rather, we share our practical diagnostic approach, largelythrough a series of cases that we have encountered in ourclinical in-house and consultation practice and that illus-trate the difficulties and potential pitfalls in diagnosing CNSlymphoma, and offer suggestions as to how to handle thosedifficult cases. We will largely concentrate on lymphomasthat primarily involve the neuraxis rather than the leptome-ninges or dura.

PRIMARY CNS LYMPHOMAPrimary CNS lymphoma is rare, representing less than

1% of all non-Hodgkin lymphomas (NHLs) and approximately2% of all primary brain tumors (8). Primary CNS lymphoma

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J Neuropathol Exp NeurolCopyright 2014 by the American Association of Neuropathologists, Inc.

Vol. 73, No. 6June 2014

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From the Division of Anatomic Pathology, Department of Laboratory Medi-cine and Pathology, Mayo Clinic, Rochester, Minnesota (CG, DRS); andDivision of Hematopathology, Department of Pathology, Memorial SloanKettering Cancer Center, New York, New York (AD).

Send correspondence and reprint requests to: Caterina Giannini, MD, PhD,Division of Anatomic Pathology, Department of Laboratory Medicine andPathology, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; E-mail:[email protected]

Copyright 2014 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.

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occurs at all ages, with a predominance of patients in their 60sor 70s and with a slight male predominance, with a male-to-female ratio of 3:2. Most patients (50%Y80%) present with focalneurologic deficits that are related to the location of the lesions.Approximately 60% of patients with PCNSL present with sin-gle or multiple intraparenchymal supratentorial lesions, whereas13% of PCNSLs primarily involve the posterior fossa, and onlya minority of cases present primarily with diffuse leptomeningealinvolvement. Indeed, leptomeningeal presentation shouldpromptworkup for a systemic lymphoma. Imaging characteristics are of-ten suggestive of the diagnosis. Lesions are typically symmetric,located in the deep periventricular white matter with occasionalsubependymal extension, many times involving the corpus cal-losum. Signal characteristics on magnetic resonance imaging(MRI) are also quite typical, with isohyperintense T2 signalsand associated restricted diffusion due to their cellular nature.They avidly and homogenously enhance after the administrationof contrast, with variable perilesional edema (Fig. 1a). PrimaryCNS lymphoma is a highly aggressive lymphoma associatedwith poor prognosis (median survival, 9 months).

Primary CNS lymphoma is a DLBCL with large blasticcells, pleomorphic nuclei, and single or multiple distinct nu-cleoli (immunoblasts and centroblasts) (Figs. 1b, c). Tumorcells show a differentiation state corresponding to late germinalcenter exit B-cells (9) and, as such, express specific proteinsthat can be exploited as diagnostic markers (Figs. 1dYf, 2). Inaddition to the expression of pan-B cell markers, includingCD19, CD20, and CD79a, lymphoma cells express BCL6 (al-though often only focally) and MUM1 (990%) in most cases(Figs. 2aYf). Expression of proteins associated with plasma celldifferentiation (CD38, CD138) is absent. Tumor cells may alsoexpress CD10 (10) and BCL2, which is not related to thet(14;18)(q32;q21) translocation (1).

In most cases, the diagnosis of CNS lymphoma, evenwith the limited tissue sample often provided by stereotacticneedle biopsy, is straightforward. In our practice, we find re-liable and cost-effective method for providing a definitivediagnosis, a first-line diagnostic approach based on hematox-ylin and eosin (H&E) findings, in conjunction with CD3 andCD20 immunostains. We reserve additional studies only forselected cases depending on morphologic, clinical, and imagingfeatures. Immunohistochemical classifiers, including the origi-nal Hans classifier, based on CD10, BCL6, and MUM1 (11)and the more recent ones, which include a larger number ofmarkers especially of germinal center B-cells (12), have longbeen used in nodal DLBCL as surrogates of gene expressionprofiling to distinguish 2 basic subgroups: the activated B-celland the germinal center B-cell type, which have signifi-cantly different clinical courses and prognoses (13, 14). Therationale for this distinction in PCNSL, based on nodal DLBCLprofile, has been doubted given the fact that gene expressionprofiling has shown PCNSL to be segregated over the entirespectrum of DLBCL (10), and no evidence of distinctive sub-groups in PCNSL has been found in accordance with clinicalobservations (15). In addition, classifying PCNSL as a germinalcenter B-cell type does not have treatment implications. BCL6protein expression, the marker that has been most extensivelystudied as a possible stratification factor for PCNSL, alsoseems to be very problematic given the fact that it is frequently

expressed in PCNSL, with most cases showing more than 50%to 60% BCL6-positive cells (15). Flow cytometry, a techniquethat has become essential for the diagnosis of many hemato-logic malignancies in routine clinical practice, has a very lim-ited role in PCNSL, largely restricted to the analysis ofCSF and mostly for staging and long-term follow-up ofPCNSL patients rather than for primary diagnosis (15, 16). Avariable number of reactive small T lymphocytes accompanyPCNSL, with some cases showing only scattered T lympho-cytes and others showing a large number of lymphocytes,nearly obscuring lymphoma cells. In a recent study, the pres-ence of reactive perivascular T-cell infiltrates has been shownto be associated with significantly better overall survival, par-ticularly among patients treated with high-dose methotrexatechemotherapy (17).

Although primary CNS presentation of systemic NHLis very rare, staging of all patients first diagnosed as havinglymphoma in the CNS is mandatory to exclude this possibility.In our practice, slit-lamp eye examination, positron emissiontomography scan, bilateral bone marrow aspirate and biopsy,CSF examination (if safe to perform), lactic dehydrogenase, andhuman immunodeficiency virus tests are routinely performedin patients presenting with CNS lymphoma, whereas spinalMRI, testis ultrasound, and chest/abdomen/pelvis computedtomography may be performed in selected patients (Dr B.P.ONeill, personal communication). Primary CNS lymphoma andsecondary CNS involvement by systemic DLBCL cannot bedistinguished simply on the basis of their morphology andimmunophenotype, although CD10 expression, particularly inassociation with a relatively low Ki67 labeling index (G50%),should prompt an intense search of primary extracerebralDLBCL or follicular lymphoma (15). Central nervous systeminvolvement in systemic NHL occurs infrequently (approxi-mately 4% of cases) and may occur either at the time of pri-mary treatment or at relapse. The risk of CNS relapse is low(2%Y3%) or high (915%), depending on lymphoma histology(low vs high grade), primary site (e.g. testis is high risk), andtreatment (CNS prophylaxis) (18).

PRIMARY VITREORETINAL LYMPHOMAIntraocular lymphoma is also rare, accounting for less

than 1% of all NHLs (19). It represents a diverse group ofhematologic malignancies involving different tissues withinthe eye (e.g. iris, ciliary body, choroid, vitreous, and retina),each with different morphologic, immunophenotypic, genetic,and clinical features (20, 21) on the basis of which it should beclassified (22). Among these, primary vitreoretinal lymphoma(PVRL), characterized by vitreous and/or retinal lymphoma-tous infiltration, is considered a subset of PCNSL (1). Similarto PCNSL, PVRL is an aggressive lymphoma. Treatment ofPVRL can induce remission, but disease relapses are commonand cure is rare. Approximately 15% to 25% of patients withPCNSL develop vitreoretinal involvement in the course of theirdisease (23), and brain involvement is present and/or developsin 56% to 90% of patients with PVRL (24), ultimately causingan unfavorable outcome. The largest reported series of primaryintraocular lymphoma cases included 83 immunocompetent pa-tients assembled from 16 centers in 7 countries as a result of a

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FIGURE 1. Primary CNS lymphoma. A 71-year-old woman presented with cognitive decline. (A) Magnetic resonance images,including T1 (left), FLAIR (middle), and T1 postcontrast (right) sequences, demonstrated an avidly enhancing mass with moderatesurrounding edema involving the deep white matter of the left parietal lobe and the splenium of the corpus callosum. (B, C)Primary CNS lymphoma cells diffusely infiltrate the parenchyma (B) and show a characteristic angiocentric pattern (C). (D, E)Anti-CD20 immunohistochemistry highlighted the large lymphoma cells (D) in comparison with the small infiltrating CD3-positivereactive T lymphocytes (E). (F) Variable numbers of KP1-positive macrophages. Original magnification: (B, DYF) 200; (C) 400.

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multi-institutional international collaboration (24). In these pa-tients, the disease was confined to the eyes at diagnosis, withno evidence of brain, systemic, or spinal cord lymphoma; theirsymptoms were typical of vitreoretinal involvement (i.e. blurredvision, decreased visual acuity, and floaters). The median age ofthese patients at diagnosis was 63 years (range, 24Y85 years);women represented 57% of patients. Similar to PCNSL pa-tients, patients with PVRL have a limited life expectancy, withthe median progression-free and overall survival at 29.6 and58 months, respectively, regardless of treatment type (24). Inthis study, the diagnosis was made via vitrectomy in 74 (89%)cases, via choroidal/retinal biopsy in 6 (7%) cases, and via oph-thalmic slit-lamp examination in 3 (4%) cases. Of these last3 patients, 1 was subsequently diagnosed via positive CSF cy-tology, and 2 underwent brain biopsy at the time of tumorprogression.

Primary vitreoretinal lymphoma is also typically a DLBCLcharacterized by large atypical lymphocytes with high nuclear-cytoplasmic ratio, irregular nuclear membrane, coarse chro-matin, and scant cytoplasm (Fig. 3). In view of its rarity, very

few studies describing the immunophenotype of intraocularlymphoma are available (25, 26). In the study by Raparia et al(26), which included 16 patients, 11 of which were diagnosedas having DLBCL, only a limited panel of antigens (CD19,CD20, CD5, CD10, and J/L light chains) was examined byflow cytometry. The study by Coupland et al (25) included8 intraocular lymphoma cases (and 42 cases of PCNSL), in-cluding 2 enucleated eyes and 6 chorioretinal biopsies exam-ined with a wider panel of antibodies, including antibodiesto CD3, CD20, CD10, PAX5, MUM1, BCL6, IgL, and IgH,among others. Similar to PCNSL, intraocular lymphoma dem-onstrates an immunophenotype consistent with mature B-cellsthat have undergone germinal center reaction (25).

Vitreous aspiration biopsy is the preferred diagnosticmethod for PVRL; however, its sensitivity has varied greatlyin different studies (26, 27). Multiple diagnostic proceduresmay be necessary before a definitive diagnosis is achieved,particularly in cases with few neoplastic cells intermixed withreactive cells (28) or in cases where neoplastic cells aremarkedly degenerated (26). The presence of vitreous cells on

FIGURE 2. Primary CNS lymphoma immunophenotype. (AYF) Primary CNS lymphoma cells are positive for B-cell markers, in-cluding CD79a and CD20 (A); they express BCL6 (B) variably in 60% to 80% of cases and strong MUM1 (C) in approximately 90%of cases. BCL2 (D) is frequently expressed. CD10 (E) is generally not expressed (i.e. expressed in 10%Y20% of cases). A variablenumber of CD3-positive small T lymphocytes are present in association with lymphoma cells (F). Original magnification: (AYF) 200.




slit-lamp examination (Fig. 3a) in an older patient with per-sistent symptoms of uveitis, associated with the finding ofretinal and subretinal infiltrates on optical coherence tomog-raphy, is virtually diagnostic of PVRL (19). In patients withassociated CNS lesions, a diagnostic vitrectomy and/or retinalbiopsy, in addition to CSF cytology, may prevent further needfor a stereotactic brain biopsy prior to treatment.

Secondary involvement of the eye by a systemicDLBCL is rare and usually presents with choroidal infiltratesin the late stages of the disease. In a recent study, ocular in-volvement in systemic lymphomas was found in some cases tobe limited to vitreoretinal involvement, therefore mimickingPVRL (29). Similar to what occurs in the CNS, rare intraocularT-cell lymphomas with exclusive vitreoretinal involvementhave been reported, most likely representing secondary intra-ocular involvement (26, 30).

DIAGNOSTIC CHALLENGES IN PCNSLDiagnostic challenges in reaching a diagnosis of PCNSL

may arise in a variety of situations. By far, the most commondiagnostic challenge is the ability to reach a definitive diagnosiswhen corticosteroids have been administered prior to the bi-opsy; however, other challenges, including limited biopsy sam-ple size and occurrence of unusual growth patterns such aslymphomatosis, are not uncommon.

CORTICOSTEROID EFFECTSCorticosteroids can have a profound apoptotic effect

on lymphoma cells, causing them to disappear in a very shorttime interval (31), a phenomenon referred to as vanishing lym-phoma (32). Steroid effect can be quite variable, with somecases showing scattered apoptotic bodies among tumor cells

FIGURE 3. Primary vitreoretinal lymphoma. (A) A 67-year-old woman with complaints of blurred vision and floaters underwent slit-lamp examination, which revealed the presence of vitreous aggregates. (B, C) This was followed by a vitreous aspiration biopsythat demonstrated a cellular specimen with few preserved large atypical lymphocytes (B), which were CD20-positive (C). (D) A79-year-old woman with a history of progressive visual loss evolving to severe ocular pain and blindness underwent eye enucle-ation. This revealed extensive retinal and subretinal infiltrates with large atypical lymphocytes totally effacing the retinal architec-ture. The asterisk demarcates the subretinal space, indicating the retinal pigment epithelium superiorly and the Bruch membraneinferiorly. (E) The neoplastic cells are CD20-immunopositive; the choroid is not immunostained. Original magnification: (B) 400;(C) 600; (D, E) 200.




and with other cases showing numerous apoptotic bodies withno remaining intact diagnostic cells (Figs. 4a, eYf). In our expe-rience, some of these cases, especially those demonstratingflorid apoptosis, can be rescued from a diagnostic point ofview by obtaining multiple levels from tissue blocks and pre-serving a few unstained sections at each level for confirmatoryimmunostains. One example is illustrated in Figures 4a to d.Once lymphoma cell debris has disappeared, only an extensivemacrophage infiltrate, which closely mimics primary demye-lination, remains (Fig. 5). Despite the similarities between thehistopathologic features of treated lymphoma and demyelin-ation, there are, in our experience, subtle differences that canprovide clues to the correct interpretation of the biopsy. Attimes, a definitive diagnosis may have to be postponed until anadditional biopsy has been obtained, as in the illustrated case(Figs. 5aYf vs hYj). Myelin loss is often marked but is typicallynot as sharply demarcated from the surrounding intact whitematter as in classic active demyelination (Fig. 5a). Axons arealso somewhat less preserved and not simply spread apart byinfiltrating foamy macrophages, as in active demyelination(Figs. 5b, d). Their density is often decreased to some extentand, not infrequently, a number of axonal spheroids are pres-ent, consistent with axonal damage, a finding that is mostunusual in primary demyelination. Although large atypical neo-plastic B-cells disappear from the lesion, infiltrating small Tlymphocytes are often moderately to highly numerous, and theirdistribution is often more diffuse than in demyelination, inwhich they are typically concentrated around perivascularspaces (Fig. 5f).

Despite the marked apoptotic effect, the impact of ste-roids on the diagnosis of PCNSL is highly variable; in manycases, a diagnosis can still be made even when steroids havebeen used (32Y34). In our series of 109 PCNSL patients, 64%had received corticosteroids before biopsy, and most did notexperience significant radiographic change or require a sec-ond biopsy for diagnosis. We had 13 patients (14%) in whicha repeat biopsy was performed to reach the diagnosis; theyincluded 8 patients who had received steroids and 5 patientswho had not, a difference that was not statistically significant(34). Similar to our study, in a review of 58 PCNSL cases inimmunocompetent patients, Haldorsen et al (33) found the firstbiopsy to be nondiagnostic in one third of patients youngerthan 65 years and in 4% of patients older than 65 years, with amedian time of 100 days (range, 9Y290 days) from the firstbiopsy to the final diagnosis in their series. Because only 22%of these patients had received corticosteroids before biopsy,they concluded that the unfavorable effect of steroids onthe yield of biopsy was not statistically significant in oursmall series (33). In our series, we identified only 3 PCNSLpatients with lesion regression, one of which was considered avanishing tumor, supporting the view that true vanishinglymphoma is a rare phenomenon. We recommend that, whenpossible, corticosteroids be postponed until the biopsy has beenobtained, but ultimately, the use of corticosteroids should bedetermined by the clinical circumstances and by necessity,rather than by the concern of obscuring PCNSL diagnosis. Incases in which contrast enhancement persists after administra-tion of corticosteroids, a biopsy can still be performed with highdiagnostic yield. Lastly, it is also important to recognize that the

vanishing phenomenon is not necessarily pathognomonicfor PCNSL. In their retrospective study evaluating the rela-tionship of PCNSL and vanishing tumors, Bromberg et al

FIGURE 4. Primary CNS lymphoma with steroid effect:vanishing lymphoma. (AYF) An 81-year-old man presentedwith confusion and a large right frontal lobe mass with en-hancement, marked surrounding edema, and mass effect withmidline shift, prompting administration of corticosteroids. Astereotactic biopsy was performed less than 48 hours afteradministration of corticosteroids, at which time the imagingshowed persistence of enhancement. The first set of sectionsobtained (A) demonstrated extensive macrophage infiltrationwith abundant apoptotic debris, particularly in the perivascularspaces, but no intact diagnostic lymphoma cells. After multiplelevels from the block had been obtained, a small focus ofviable-appearing lymphoma was identified (in order; B, C). (D)The lymphoma cells showed distinct CD20 immunoreactiv-ity. Interestingly, granular CD20 stain was present in thebackground because of the cell lysis of some lymphoma cells.(E, F) This 63-year-old man presented with multiple enhanc-ing, mostly periventricular solid lesions but had received corti-costeroids for approximately 8 days before biopsy; there wereno obvious lymphoma cells (E), and only granular CD20stain (F) remained because of tumor cell lysis. Original mag-nification: (AYE) 400; (F) 200.




FIGURE 5. Primary CNS lymphoma with steroid effect. A 62-year-old man presented with progressive memory decline and in-creasing headache, prompting MRI, which demonstrated a large enhancing temporal lobe mass suspected to represent a glio-blastoma. He received a 3-week course of Decadron to reduce swelling in anticipation of surgery. While on steroids, his headacheand cognitive symptoms significantly improved. On the day of surgery, a repeat MRI demonstrated that the tumor had shrunkdramatically, prompting modification of the surgical plan to stereotactic biopsy. (AYG) The biopsy was not diagnostic. The biopsycore (A) demonstrated an area of pallor on H&E stain (left core), corresponding to an area of myelin loss (LFB/PAS stain, secondcore from left) and, to a lesser extent, axonal loss (neurofilament stain, second core from right. In this area, macrophages werenumerous (H&E; B, C, and KP1 immunostain; A, right core; and G). Axon density was decreased, and there were scattered axonalspheroids (D). No large B-cells were observed on CD20 immunostain (E), whereas CD3 immunostain highlighted the presence of amoderate number of T lymphocytes (f). A descriptive diagnosis was made, and the possibility of treated/vanishing lymphomawas raised. The patient did well for approximately 3 months; his memory started declining again at that time. Magnetic resonanceimaging demonstrated recurrence of the temporal lobemass, prompting a new stereotactic biopsy. (HYJ) The new stereotactic biopsywas diagnostic of PCNSL (H, H&E; I, CD20; J, CD3). Original magnification: (A) 1.25; (B, D, EYG, I, J) 200; (C, H) 400.




(32) identified 12 patients, 5 of whom subsequently received adiagnosis of PCNSL, whereas the remaining had a number ofdiagnoses, including demyelinating disease, infarct, sarcoido-sis, and renal cell carcinoma.

STEREOTACTIC BIOPSY SAMPLESWhen lymphoma is suspected clinically, the preferred

diagnostic approach is stereotactic biopsy, generally MRI-guided. It is the least invasive biopsy with a low complicationrate. Typically, neurosurgeons in our practice quote the patientsthe following: temporary worsening, 5%; permanent worsen-ing, 1%; 30-day mortality largely caused by hemorrhagic com-plications, less than 1% (35Y37). Stereotactic biopsy allowssurgeons to reach deep-seated lesions, which are challenging toapproach otherwise, making it the ideal diagnostic techniquefor lymphoma. The size of the sample obtained with this tech-nique is usually limited, and all efforts should be made to pre-serve material for diagnosis. An optimal and tissue-sparingtechnique for intraoperative examination of stereotactic biopsiesis the preparation of cytologic smears. This allows a thoroughevaluation of each core while preserving its integrity for per-manent section evaluation. We use this proactive careful ap-proach in all stereotactic biopsies because many factors (e.g.location of the lesion or unexpected bleeding) may limit thenumber of obtainable cores, often in an unpredictable manner,as in the case illustrated in Figures 6a, c.

The cytologic features of lymphoma are distinctive. Ty-pically, lymphoma has a noncohesive, relatively monomorphousappearance, with cells showing large generally naked nuclei,round to notched, and often prominent nucleoli (Fig. 6d). Al-though markedly reactive astrocytes, with their characteristicstellate appearance, are often present in the background, thefibrillarity typical of glial neoplasms is absent. Macrophagescan be present in the background, usually as a few scatteredcells. Marked macrophage infiltrates are observed in steroid-treated cases in which only rare viable tumor cells may remain.Although, in most cases, intraoperative diagnosis can be rea-sonably certain in previously treated cases, intraoperative as-sessment may be limited simply to extensive macrophageinfiltrate with scattered atypical cells. Similar to glial tumors,CNS lymphoma can also be very heterogeneous, and assess-ment of the permanent paraffin-embedded sections may be verychallenging, depending on the extent of involvement of tissuecores. In cases clinically suspicious for lymphoma in which thefirst level is nondiagnostic, similar to what we recommend forcorticosteroid-treated cases demonstrating extensive apoptosis,we also routinely obtain multiple levels from tissue blocks,maintaining a few unstained sections at each level for confir-matory immunostains. This practice has been very rewarding inmore than 1 case (Fig. 6e). A special intraoperative challenge ispresented by the involvement of the cerebellum, where recog-nizing tumor cells, especially when scant in number, amongcerebellar granular cells may be nearly impossible (Fig. 6f).

LYMPHOMATOSIS CEREBRI(A PATTERN OF PCNSL)

Primary CNS lymphoma can present with widespreadand diffuse infiltration of the cerebral white matter by indi-

vidual lymphoma cells without the formation of a discretetumor mass, an unusual PCNSL pattern often referred to aslymphomatosis cerebri. The term was coined by Bakshiet al (38) in analogy to what is observed in classic examplesof gliomatosis cerebri, a rare diffusely infiltrative glioma thatalso presents with extensive involvement of the brain in the ab-sence of a mass lesion. Although less than 20 cases of PCNSLwith features of lymphomatosis cerebri in immunocompetentpatients have been reported, mostly as single case reports(39Y51) or small series of 2 to 3 cases (38, 52), this pattern isnot rare in clinical practice. Personality change and subacutecognitive impairment/dementia are the most common present-ing symptoms, in association with imaging of diffuse leuko-encephalopathy in both hemispheres and a lack of enhancementon postcontrast images. This pattern is very unusual comparedwith the most common imaging pattern, which raises a highsuspicion for a PCNSL diagnosis even before a tissue diagnosisis obtained. It is, however, a very important pattern to recognizebecause the diagnosis of PCNSL may not be entertained bythe pathologist in these cases. Figure 7 illustrates a challengingexample of an 80-year-old woman who presented with anxiety,spells of perioral numbness, left hand tingling, aphasia, anddiffuse symmetric hyperreflexia. Preoperative MRI showed ex-tensive confluent T1 hypointense and T2 hyperintense lesionsin the white matter of the parieto-occipital lobes with minimalenhancement, raising a wide differential diagnosis, includinggliomatosis cerebri and, less likely, lymphoma (Fig. 7a).Despite the H&E appearance showing mild hypercellularitywith a number of cells with nuclei, which, at first, may suggestan infiltrating glioma, scant large atypical lymphoma cellsdiffusely infiltrated the biopsy sample (Figs. 7b, c). The largelymphomatous cells were highlighted by the CD20 immu-nostain (Fig. 7d), whereas a low number of small reactiveCD3-positive T lymphocytes were present in the underlyingparenchyma (Fig. 7e).

EPSTEIN-BARR VIRUSYASSOCIATEDLYMPHOPROLIFERATIVE DISORDERSEpstein-Barr virus (EBV)Yassociated lymphoid prolif-

erations are a well-recognized complication of both congenitaland acquired systemic immunosuppression and vary frompolymorphic lymphoplasmacytic proliferation to frank lym-phoma (53). Although they can occur in any anatomic site, theyseem to have a predilection for extranodal locations, particu-larly for immune-privileged sites such as the CNS (54). Centralnervous system lymphomas developing in immunocompro-mised individuals are typically B-cell neoplasms, mostlyDLBCL, and are EBV-positive (995% vs 0%Y20% in im-munocompetent patients). The frequency of CNS DLBCL,originally the most common primary brain tumor in AIDSpatients and largely responsible for the increase in CNS lym-phoma in the immunocompromised population, has decreaseddramatically with highly active antiretroviral therapy (HAART)and is now stable. Iatrogenic immunosuppression is todaya well-recognized and important risk factor for DLBCL, al-though its frequency is not well known and is difficult todetermine. Clinically, the most common association is withorgan transplantation (i.e. posttransplant lymphoproliferative




FIGURE 6. Primary CNS lymphoma and stereotactic biopsy. (AYC) A 20-year-old immunocompetent man presented with fatigue,double vision, intermittent headache, and gait unsteadiness. He was found to have an enhancing third ventricular mass thatmarkedly decreased in size with 5 days of dexamethasone (initially given intravenously then orally). His symptoms virtuallydisappeared. After 3 weeks off steroids, despite remaining asymptomatic, the mass started growing again, (A, right) and a newlesion appeared in the cerebellum, abutting the ventricle (A, left). The cerebellar lesion was chosen as a biopsy target because it wasa new lesion and was in a less critical location. After a few nondiagnostic biopsy cores had been taken, the biopsy was abortedbecause of bleeding (B). A single diagnostic cluster of lymphoma cells was found on permanent sections in the last core taken,largely blood (C). The cells were positive for CD20 (inset) and PAX5 (not shown), consistent with a DLBCL. The immunostains wereobtained on unstained slides (which had been ordered up front), whereas no residual tumor remained on recuts of the blocks. Thisspared the patient the need for a second biopsy, avoiding the chance of another bleed at a more critical site. He received aggressivetreatment of PCNSL, including chemotherapy, salvage radiotherapy, and autologous stem cell transplant, and was free of thedisease 4 years and 2 months from the biopsy. (D) Cytology of CNS lymphoma. (E) In a patient with a history of systemic DLBCLpresenting with a brain lesion suspicious for CNS recurrence, this small focus of DLBCL was identified in the deep levels of an atfirst nondiagnostic biopsy (CD20 stain is illustrated in the inset). (F) Diffuse infiltration of cerebellar folia, including molecular andgranular cell layer, highlighted by CD20 stain (inset). Original magnification: (CYF) 400.




FIGURE 7. Primary CNS lymphoma presenting as lymphomatosis cerebri. (A) Preoperative MRI (T1, left; T2, middle; T1postgadolinium, right) with extensive confluent T1 hypointense and T2 hyperintense lesions in the white matter of the parieto-occipital lobes and with minimal enhancement raised a wide differential diagnosis, including gliomatosis cerebri and, less likely,lymphoma. (B, C) Hematoxylin and eosin stain with mild hypercellularity and a number of cells with elongated nuclei suspicious atfirst for an infiltrating glioma. (D, E) Large atypical lymphoma cells were highlighted by CD20 immunostain (D), whereas a lownumber of small reactive CD3-positive T lymphocytes were present in the underlying parenchyma (E). Original magnification:(B, D, E) 200; (C) 400.




disorders), but there is a growing population of patients re-ceiving immunosuppressive therapy for a variety of immune-related disorders (18). Although a significant proportion ofthese lymphoproliferative disorders may show at least partialregression in response to drug withdrawal, response seemsto decrease as severity increases, and aggressive treatment isoften needed in DLBCL cases. Occasionally, EBV-positiveDLBCLs can develop in patients without any known primaryand secondary immunodeficiency. When this occurs in patientsolder than 50 years, it is termed EBV-positive DLBCL ofthe elderly, based on the WHO Classification of Tumours ofHematopoietic and Lymphoid Tissue (1). In rare instances,similar cases can occur in younger individuals. Although im-munocompromised patients are generally younger than immu-nocompetent patients developing PCNSL, clinical presentationmay be quite similar in both settings. On imaging, single ormultiple brain lesions with a ring-enhancing appearance arerelatively common in immunocompromised patients because ofthe presence of extensive necrosis, a feature that is very un-common in PCNSL and may be difficult to distinguish fromnon-neoplastic infectious processes such as toxoplasmosisand/or other primary high-grade CNS neoplasms. Surprisingly,but not infrequently, critical information regarding immunosup-pressive treatment may be withheld at the time of biopsy. It isvery important for the pathologist to probe the clinician appro-priately with direct questions. Morphologically, EBV-associatedDLBCL tends to be a more prominently angiocentric and angio-destructiveprocess than the typicalPCNSLand frequentlyshowsextensive necrosis (Figs. 8aYc). Accompanying reactive Tlymphocytes can vary markedly and, in some cases, may pre-dominate in a morphologic pattern typical of lymphomatoidgranulomatosis (55), a large EBV-driven B-cell lymphomaassociated with a florid T-cell reaction (56). Morphologicfeatures, immunohistochemical markers, and EBV in situhybridization are critical for reaching a definitive diagnosis.Because of the extensive necrosis often present in these biopsysamples, a definitive diagnosis may be quite difficult. In thesecases, one can take advantage of the fact that some protein an-tigens may persist for some time even in necrotic cells. Ghostsof necrotic cells are often outlined by anti-CD20 antibodies(Figs. 8f, h) to such an extent that a confident diagnosis canoften be made even in subtotally necrotic biopsies. At times, asimilar phenomenon can be observed with EBV latent mem-brane protein 1 immunostain compared with EBV-encodedsmall RNA in situ hybridization, with RNA being more sensi-tive to degradation than proteins (Fig. 8i).

RARE LYMPHOMAS IN THE CNSThe CNS can be primarily affected by a variety of

lymphoid tumors. Although we are only briefly describing thelymphoid tumors that affect the CNS with some frequency,we recognize that many histologic types, including follicularlymphoma (57, 58), Burkitt lymphoma (59, 60), precursor B-cell lymphoblastic lymphoma (61), and the recently describedB-cell lymphoma with features intermediate between DLBCLand Burkitt lymphoma (62), have been reported in the CNS,often as single cases. Even when present in the CNS withoutsystemic involvement, these lymphomas are not consideredPCNSL.

LOW-GRADE B-CELL LYMPHOMAMarginal zone B-cell lymphoma or low-grade mucosa-

associated lymphoid tissue (MALT lymphoma) is likely themost common low-grade B-cell lymphoma involving the CNS.It most frequently presents as a dura-associated process mim-icking meningioma; at times, the dural involvement is verydiffuse, mimicking a diffuse pachymeningitis (63). Tumor cellsare small to medium, with slightly irregular nuclei and incon-spicuous nucleoli resembling centrocytes. They have relativelyabundant clear pale cytoplasm and frequently show plasma-cytoid differentiation. Extensive amyloid deposition may bepresent in MALT lymphoma of the dura. Immunopheno-typically, tumor cells express B-cell markers, including CD19,CD20, and CD79a, occasionally express CD5, and do not ex-press CD3, CD10, and CD23. Intraparenchymal involvement oflow-grade B-cell lymphoma is extremely rare. The largest seriesof low-grade PCNSL reported is the 2006 study by Jahnke etal (64). In this series of 32 patients retrospectively collectedfrom 18 cancer centers over a wide period (1979Y2004), mosttumors (80%) were B-cell lymphomas, with the most commonsubtype being lymphoplasmacytic lymphoma. Althoughthe diagnosis was originally made and/or confirmed by anexperienced hematopathologist at each institution, nosystematic central review of cases was possible because oflogistic and regulatory issues. This, together with the paucity ofmaterial available and the application of older classificationschemes, largely limited the ability to subclassify many of thecases. Despite the limitations that Jahnke et al (64) openly ac-knowledged, overall clinical and radiologic presentation inthese patients seem to differ from that observed in PCNSL, andlong-term outcome seems to be better.

T-CELL LYMPHOMASPrimary peripheral T-cell lymphoma (PTCL) of the

CNS is rare, accounting for 2% to 9% of all CNS lymphomas,depending on the patient population (4, 65). The largest serieswas published by the International Primary CNS LymphomaCollaborative Group (66). In this series, the median age ofpresentation was 60 years, but with a wide age distribution.The most common site of involvement was the cerebral he-misphere, followed by the basal ganglia, corpus callosum,brainstem, and, rarely, the cerebellum. Although a pathologicdiagnosis of PTCL was established in each case, detailed mor-phologic features, immunophenotype, or genetics were notavailable. A review of the literature and our experience suggestthat the pathology of PTCL of the CNS is heterogenous. Ar-chitecturally, neoplastic cells may have a perivascular distribu-tion but often spill into the surrounding parenchyma in a diffusepattern (Fig. 9a). The diffuse parenchymal component may bedifficult to observe in H&E sections due to marked reactivechanges accompanying the neoplastic infiltrate. Most cases arecomposed of intermediate-size T-cells with cytologic atypia,including nuclear membrane abnormalities, which can be bestappreciated by immunohistochemistry (Figs. 9bYd). A subsetof the cases, in particular in young patients, may show smallcell morphology with minimal cytologic atypia and may posea major diagnostic challenge, particularly in the absence of




FIGURE 8. Epstein-Barr virusYassociated lymphoma. Examples of DLBCLs associated with EBV. (AYC) A 62-year-old woman, whohad received a kidney transplant 3 years earlier for IgA nephropathy, presented with recent-onset confusion and weakness. A leftparietal rim-enhancing lesion was noted in the subcortical white matter. The lymphomatous infiltrate showed angiodestructive fea-tures, as demonstrated by the presence of fibrinoid necrosis in the vascular wall (A). Many of the large CD20-positive (B) lympho-matous cells were positive for EBV (C). (DYF) A 78-year-old woman with a history of Parkinson disease and extensively necroticthalamic lymphoma (D, E). (F) CD20 stain corresponding to the same area illustrated in (E). CD20 immunoreactivity is maintainedon the surface of anucleated necrotic cells. (GYI) A 59-year-old woman presenting with a right frontal lobe centrally necrotic massand with no known history of immunosuppression. The biopsy showed a subtotally necrotic lymphoma. An area of complete necrosisis illustrated (G), with corresponding CD20 stain (H) and EBV latent membrane protein 1 (I) both showing partial preservation ofsurface stain despite the necrotic appearance of the tissue. Epstein-Barr virus in situ hybridization (inset) yielded negative resultsbecause RNA is more sensitive to degradation than proteins, which may persist for a somewhat longer period. Original magnification:(AYC, E, F) 400; (D, GYI) 200.




aberrant phenotype and/or clonality. Immunohistochemistryreflects the heterogenous nature of the biology. Neoplastic T-cellsmay show loss of some of the pan T-cell antigens, in particularCD5 and/or CD7. They may be of helper (CD4-positive) orcytotoxic (CD8-positive) T-cell origin and may express T-cellreceptor >/A chains (most cases) or F/C chains (rare) (Fig. 9e).Demonstration of the clonal rearrangement of T-cell receptorgenes, which are present in most T-cell lymphomas, is oftencritical for reaching a definitive diagnosis. T-cell receptorclonal rearrangement, however, should always be interpretedin conjunction with pathologic and clinical findings becausemany chronic immunostimulatory disorders may also be asso-ciated with the development of T-cell clones. The clinicalcourse of PTCL in the CNS seems to be aggressive; however,a small number of cases with lower-grade cytology may havea more indolent behavior with a protracted disease course.

ANAPLASTIC LARGE CELL LYMPHOMAAnaplastic large cell lymphoma occurs very rarely in the

CNS. It is an uncommon, generally T-cell lymphoma composedof large pleomorphic CD30-positive cells. It most frequentlyoccurs at nodal sites, primary involvement or secondary spreadto extranodal sites may occur. Most cases arising in the CNShave been reported as single case reports, with the largest seriesdescribing 9 cases, 5 of which had been previously reported(67). Six (of 9) cases occurred in women across a wide agerange (4Y66 years), and the majority (7 of 9) of cases involvedthe dura or leptomeninges rather than the CNS parenchyma.Most tumors were T-cellYpositive (n = 7), 2 were null cellpositive and 5 were ALK1-positive. Althoughmortality was high(n = 6), 3 patients were alive at 4.8- to 6.1-year follow-up. These3 patients were young (4Y18 years), and their anaplastic large celllymphoma was ALK1-positive, supporting the view that young

FIGURE 9. Primary peripheral T-cell lymphoma. A 79-year-old man presented with a left frontal lobe mass. (AYE) On biopsy, adense lymphoid infiltrate was present, accumulating around vessels (A, left) and diffusely infiltrating the adjacent parenchyma(A, middle), which shows marked reactive gliosis (A, right). Intermediate-size tumor cells with cytologic atypia (B) show phenotypicfeatures of T-cell, expressing CD3 (C, D), CD2, CD4, CD5 (not shown), and T-cell receptor F/C (E), a very uncommon finding in CNSPTCL. CD10, CD20, CD30, CD7, CD8, TCR AF1, TdT, TIA-1, and granzyme B were not expressed in tumor cells (not shown). Originalmagnification: (A, C) 100; (B, D, E) 400.




FIGURE 10. Intravascular large B-cell lymphoma. (AYD) A 69-year-old woman presented with a left temporal lesion with substantialhemosiderin deposition following the distribution of a left middle cerebral artery branch. Extensive changes of subacute hemor-rhagic infarct were present in the biopsy, with no evidence of amyloid angiopathy. Very focally, a small leptomeningeal vesselappeared to be filled by large lymphoma cells (A), which were CD20-positive (B), MUM1-positive (C), and PAX5-positive (D),consistent with a B-cell phenotype. The cells also expressed BCL6 but did not express CD10 (not shown). (E, F) A 62-year-oldwoman presented with a right temporal hemorrhagic lesion, submitted in consultation with a suspicion of cerebral amyloidangiopathy. Intravascular large B-cell lymphoma was instead present in 2 of the biopsy fragments. Intravascular large B-cell lym-phoma cells with large prominent nucleoli and a central mitotic figure (E); the large lymphoma cells were CD20-positive, con-sistent with a B-cell phenotype (F). Original magnification: (AYF) 400.




age and ALK1 positivity are associated with a better outcome,similar to systemic anaplastic large cell lymphoma.

INTRAVASCULAR LARGE B-CELL LYMPHOMAIntravascular large B-cell lymphoma, also called angio-

tropic large cell lymphoma, is a rare type of large B-cell lym-phoma in which atypical lymphocytes selectively grow withinblood vessel lumens, particularly in small vessels and capil-laries. This is likely caused by a defect in homing receptors inneoplastic cells (68, 69). Extravascular extension of neoplasticcells, if present, is minimal. This lymphoma occurs predomi-nantly in adults (median age, 67 years), with nearly equal fre-quency in men and women (70). It is usually a widelydisseminated lymphoma in extranodal sites and may be virtu-ally present in any organ. Two main patterns of presentationoccur: one pattern is characterized by symptoms related to theorgans involved, primarily cutaneous or neurologic (so-calledWestern form); the other in which multiorgan failure, hepa-tosplenomegaly, pancytopenia, and hemophagocytic syndromepredominate (so-called Asian form), in reference to the patientpopulation in which they are more frequently, but not exclu-sively, seen. Involvement of the CNS is common, with intra-luminal lymphoma cell accumulation causing small vesselocclusion and disseminated infarcts that are, at times, associatedwith fibrin microthrombi and hemorrhage. Clinical presentationseems to result from ischemia, which can be widespread withinvolvement of the entire neuraxis, resulting in a wide range ofsymptoms from acute or chronic encephalopathy to progressivedementia, spinal cord symptoms, cranial neuropathy, or caudaequina syndrome. Rarely, IVLBCL can present with a mass-like lesion (71). Although the diagnosis of IVLBCL used to bepredominantly postmortem, awareness of this rare lymphomatype and of its variable presentation has made diagnosis bysurgical biopsies more common. Signs of acute or subacuteischemia can be seen in the cerebral parenchyma, raising awide differential diagnosis, including primary CNS vasculitis,thromboembolic conditions, and amyloid angiopathy. Vascularchanges in IVLBCL can be very focal and subtle. It is importantfor the neuropathologist to systematically examine the lumensof the small and medium leptomeningeal and parenchymalvessels to identify the diagnostic cells. Two cases are illustratedin Figure 10.

Rare examples of intravascular T-cell or natural killercell lymphoma have been reported (72), which, according toWorld Health Organization classification, should be consid-ered a different entity (70). Intravascular large B-cell lym-phoma is an aggressive lymphoma and is generally poorlyresponsive to chemotherapy (70). However, poor prognosismay, in part, be a reflection of the fact that many of these casesare diagnosed late in the course of the disease, with early di-agnosis potentially leading to successful treatment (73).

HODGKIN LYMPHOMA AND THE CNSAlthough neurologic manifestations in Hodgkin lym-

phoma (HL) are rare, several unique disorders may occur in HL,with which the pathologist should be familiar. Complications ofHL can be categorized as direct and indirect, resulting eitherimmediately from the lymphoma, including direct/metastatic

involvement of the CNS (intraparenchymal, dural, leptomen-ingeal, and epidural at the spinal cord level) or from itstreatment (secondary to radiotherapy and chemotherapy) and/orinfection (74). Direct/metastatic involvement of the CNS by HLis rare and typically occurs in advanced-stage disease. Centralnervous system involvement has been reported in rates varyingfrom 0.5% to 3% (75, 76). As in secondary CNS involvementby systemic lymphoma, dura-based lesions are more commonthan parenchymal involvement. Primary CNS presentation ofHL is exceedingly rare (77Y85), with less than 10 cases reported.Interestingly, most cases primarily involving the CNS had pa-renchymal (77Y85) rather than dural localization (86Y88).Diagnosis of HL requires identification of Hodgkin and Reed-Stenberg cells, with the appropriate immunophenotype occur-ring in a typical non-neoplastic background with lymphocytes,plasma cells, macrophages, and eosinophils.

In addition, HL may occur in association with severalparaneoplastic syndromes, including cerebellar degenerationand limbic encephalitis, which are typically associated withonconeural autoantibodies, including anti-Tr antibodies (89,90) directed against cerebellar Purkinje cells, and anti-Hu (91)and anti-NMDA (92) antibodies in cases of limbic encephalitis.Of particular interest to the neuropathologist is the associationwith CNS granulomatous angiitis (93Y96), a unique, oftennecrotizing granulomatous vasculitis. The pathogenesis of thissecondary CNS granulomatous angiitis remains unclear,although varicella zoster virus reactivation has been implicatedby some (97). In most cases, the diagnoses of granulomatousangiitis and HL are made simultaneously or closely correlatedin time, with either the diagnosis of HL or the diagnosis ofgranulomatous angiitis preceding the other (96, 98Y100).Morphologically, this CNS granulomatous vasculitis is similarto the granulomatous pattern of primary CNS vasculitis, whichis, however, frequently associated with amyloid angiopathy(101). Accurate clinical history and examination may be theonly key to the correct diagnosis. Although full recovery isuncommon, early diagnosis is critical since the disease is re-sponsive to steroids and/or immunosuppression in associationwith specific HL chemotherapy (93, 95).

In summary, PCNSL, morphologically a DLBCL con-fined to the CNS (and/or to the eye) that occurs in immuno-competent patients, is the most common lymphoma occurringin the CNS. In addition, many other lymphoma subtypes,someprimaryorexclusive to theCNS,suchas immunodeficiency-associated lymphomas, intravascular large cell lymphoma, andlymphomas of the dura, can occur in the CNS. Although, inmany cases, the biopsy diagnosis of CNS lymphoma is straight-forward, a variety of reasons may make it quite challenging attimes. Maintaining a high index of suspicion (clinically anddiagnostically) and optimizing use of the tissue at hand willgenerally allow the pathologist to achieve a definitive diagnosisof CNS lymphoma in most cases.

ACKNOWLEDGMENTThe authors would like to thank Dr Fausto J. Rodriguez

for his critical review of the manuscript and his invaluableadvice.




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