Clinical Presentation, Pathologic Features, and Diagnosis of Primary Central Nervous System Lymphoma - UpToDate

5/11/2019 Clinical presentation, pathologic features, and diagnosis of primary central nervous system lymphoma - UpToDate
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Clinical presentation, pathologic features, and diagnosis of

primary central nervous system lymphoma
Authors: Tracy Batchelor, MD, MPH, Jay S Loeffler, MD
Section Editor: Arnold S Freedman, MD
Deputy Editor: April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Dec 04, 2018.
INTRODUCTION
Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin
lymphoma (NHL) that involves the brain, leptomeninges, eyes, or spinal cord without evidence of
systemic disease.
The epidemiology and clinical presentation vary depending upon the immunocompetence of the patient.
This topic will discuss the clinical presentation, pathologic features, and diagnosis of PCNSL in
immunocompetent patients. AIDS-related PCNSL is discussed separately. (See "AIDS-related
lymphomas: Primary central nervous system lymphoma".)
Lymphomatous involvement of the central nervous system (CNS) in patients with widespread systemic
nodal or extra-nodal lymphoma is also reviewed separately. (See "Treatment and prognosis of primary
central nervous system lymphoma" and "Clinical presentation and diagnosis of secondary central
nervous system lymphoma".)
EPIDEMIOLOGY
PCNSL represents approximately 4 percent of newly diagnosed primary central nervous system (CNS)
tumors, with an age-adjusted incidence rate of four cases per million persons per year [1,2]. The
incidence in the general population rose from the 1960s to the 1990s, peaked in the mid-1990s, and
then declined [1,3-13]. Such changes were largely driven by PCNSL cases in men between the ages of
20 and 64 years [14]. Thus, the trend has been attributed in large part to changes in HIV/AIDS incidence
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and management over the same time period. By contrast, the incidence rate in adults >65 years of age
has steadily risen, even in the last decade [14].
Most cases of non-AIDS-related PCNSL are diagnosed in patients between 45 and 65 years of age,
with a median age at diagnosis in the fifth decade [3,15-17]. Rare cases have been described in children
with a median age of 14 years [4,18]. Men and women are equally affected.
PREDISPOSING FACTORS
The most notable risk factor for the development of PCNSL is immunodeficiency [7,19]. This includes
HIV infection, iatrogenic immune suppression, and congenital immune deficiency including ataxia-
telangiectasia, Wiskott-Aldrich syndrome, severe combined and common variable immunodeficiencies,
and X-linked lymphoproliferative disease.
Sporadic PCNSL, in apparently immunocompetent individuals, has been reported in association with
other diseases. Antecedent flu-like or gastrointestinal illnesses have been seen in up to 15 percent of
patients and many patients with PCNSL [4]. In addition, patients with autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, myasthenia gravis, sarcoidosis,
and vasculitis may be predisposed to develop either disease- or therapy-related PCNSL [19]. Following
organ transplants, PCNSL occurs in proportion to the extent of therapeutic immunosuppression. Rarely,
patients have experienced a demyelinating disease, either sporadic or Lyme disease related, that
anteceded PCNSL [20].
PATHOGENESIS
The cellular and molecular events leading to neoplastic lymphocytic infiltration of the central nervous
system (CNS) seen in PCNSL remain to be clarified [21]. The CNS normally lacks lymphoid aggregates
and it remains speculative whether malignant transformation develops locally within normally trafficking
CNS lymphocytes, or systemically in a subpopulation of lymphocytes with specific tropism for the CNS
[22,23]. Such tropism may be facilitated through the expression of specific cell-surface adhesion
molecules, such as CD44 and CD18, and various chemokine receptors (eg, CXCL). Spreading of
malignant lymphoid cells within the CNS is believed to involve a complex interaction of selectin and
cadherin molecules, such as adhesion molecule CD44 and transmembrane protein receptor Fas (CD95)
[24-26].
Characterization of the genomic landscape of PCNSL is in progress. Alterations that occur with high
frequency in PCNSL include biallelic cyclin dependent kinase inhibitor 2A (CDKN2A) loss and somatic
mutations in myeloid differentiation primary response gene 88 (MYD88), CD79B, and TBL1XR1 [27-
30]. The B cell receptor/Toll-like receptor/NF-kappa B pathways are altered in the majority of tumors [28].
The observation that systemic dissemination of PCNSL is rare suggests that the cells of origin in PCNSL
may be derived from neoplastic lymphocytes that are eradicated from the periphery by an intact immune
system, but which are able to survive in an immunologically aberrant CNS [15]. The high incidence of
PCNSL in immunodeficient states strongly implicates the immune system in the pathogenesis of
PCNSL.
In addition, Epstein-Barr virus (EBV) may have a causal link to the development of PCNSL and the virus
may be oncogenic when detected. Genomic material from EBV has been detected within PCNSL cells in
both immunocompromised and nonimmunocompromised individuals [3,31]. However, the majority of
nonimmunosuppressed patients do not appear to have EBV genomic DNA within their tumors [32]. In
addition, not all patients with EBV DNA in spinal fluid have PCNSL [33]. PCNSL may be a consequence
of EBV-mediated clonal expansion and malignant transformation of B-lymphocytes, a process that may
be regulated by immune mechanisms [15,32]. (See "AIDS-related lymphomas: Primary central nervous
system lymphoma", section on 'Pathogenesis'.)
Immunoglobulin variable heavy (IgHV) gene analysis has offered some insight into cell origin in PCNSL.
Almost all PCNSL cells demonstrate IgHV genes that have high levels of somatic mutations and show
intraclonal heterogeneity pointing towards their derivation from mutated germinal center B cells [34].
However, immunohistochemical evaluation suggests that PCNSL are derived from postgerminal center B
cells [35,36].
CLINICAL PRESENTATION
PCNSL can manifest in the brain, its coverings, the eye, or spinal cord. Five distinct clinicopathologic
entities have been described [4,15,16,37-39]:
● Intracranial lesion (solitary or multiple)

● Diffuse leptomeningeal or periventricular lesions
● Vitreous/uveal deposits
● Intradural spinal cord lesion
● Nerve-seeking lymphoma (Neurolymphomatosis [NL])
A sixth entity, intravascular large cell lymphoma, commonly involves the central nervous system (CNS) but
is categorized as a variant of systemic large cell lymphoma. (See "Intravascular large cell lymphoma".)
Presenting symptoms and signs vary, depending on the site of involvement. Although much less common,
the clinical presentation of T cell PCNSL appears to be similar to that of B cell PCNSL [40], possibly with
less common eye involvement.
Primary cerebral lymphoma — Most cases of PCNSL present as symptoms related to periventricular
lesions in the brain. As an example, a retrospective series of 248 immunocompetent patients with
primary intracerebral lymphoma reported the following symptoms at presentation [41]:
● Focal neurologic deficits – 70 percent

● Neuropsychiatric symptoms – 43 percent
● Signs of raised intracranial pressure – 33 percent
● Seizures – 14 percent
● Ocular symptoms – 4 percent
Presenting symptoms may include headaches, blurred vision, motor difficulties, and personality changes.
The latter may manifest as depression, apathy, psychosis, confusion, memory impairment, slowness of
thought, or visual hallucinations. Personality changes are most often associated with lesions of the frontal
lobes, periventricular white matter, or corpus callosum. Although a frequent symptom, personality
changes tend to develop slowly and remain unnoticed for long periods.
Visual hallucinations may result from infiltration of visual pathways or the brainstem, or may result from
ocular or leptomeningeal involvement. This may result in delayed diagnosis, as it is the later development
of motor difficulties, such as hemiparesis or speech disturbances, that usually prompts neurologic
evaluation.
Cranial neuropathies, in particular facial nerve palsies, can occur as a result of either meningeal
involvement, infiltration of the brainstem, or invasion of isolated cranial nerves or their roots. Headache,
especially late in the course of the disease, may be indicative of increased intracranial pressure or
involvement of the leptomeninges.
While most cases of PCNSL are composed of aggressive lymphoma subtypes such as diffuse large B
cell lymphoma (DLBCL), a small number of patients with indolent CNS lymphoma (eg, mantle cell
lymphoma, neurologic chronic lymphocytic leukemia, or Waldenström macroglobulinemia) have been
reported in the literature [42-44]. These may mimic meningioma, sometimes involving the dura rather
than the brain parenchyma.
Primary leptomeningeal lymphoma — Up to 40 percent of patients with cerebral PCNSL may have
evidence of meningeal involvement at the time of diagnosis based on cerebrospinal fluid (CSF) analysis
and neuroimaging [45,46]; involvement of the leptomeninges by high-risk systemic lymphoma is also a
common relapse pattern. On the other hand, primary leptomeningeal lymphoma without synchronous
cerebral/spine or systemic disease is very rare, making up less than 10 percent of all cases of PCNSL.
Given the rarity of primary leptomeningeal lymphoma, symptomatic leptomeningeal involvement at
presentation should prompt serious consideration of an underlying systemic lymphoma. (See "Clinical
presentation and diagnosis of secondary central nervous system lymphoma".)
Patients with primary leptomeningeal lymphoma present with symptoms and signs of multilevel
involvement of the neuraxis, which may include worsening headaches, cranial nerve palsies,
meningismus, cervical/lumbar radiculopathies, and hydrocephalus. In an international multicenter
retrospective study that identified 48 patients with primary leptomeningeal lymphoma diagnosed over a
30-year period, the most common presenting features were cranial neuropathies (58 percent; especially
of the eye and facial movements), spinal symptoms (48 percent), headache (44 percent), leg weakness
(35 percent), ataxia (25 percent), and encephalopathy (25 percent) [47].
In the same series, the CSF profile was abnormal in all cases, and CSF cytology detected malignant
lymphocytes in two-thirds of patients [47]. A monoclonal population was detected by flow cytometry and
receptor rearrangement studies in 80 and 71 percent of cases, respectively. Multiple CSF samples or
meningeal biopsy were commonly required for diagnosis. While the majority of cases were B cell
lymphoma, there was a relatively high representation of T cell lymphoma (19 percent), which has been
described in other reports as well [48,49]. (See 'Cerebrospinal fluid analysis' below.)
Primary intraocular lymphoma — Primary intraocular lymphoma (PIOL) refers to a PCNSL that initially
presents in the eye, with or without concurrent CNS involvement. It is estimated that 15 to 25 percent of
patients with PCNSL will have involvement of the eye. Diagnosis can be made by biopsy of the involved
vitreous, choroid, or retina [50]. PIOL should be differentiated from retro-orbital lymphoma, which is
frequently associated with systemic extranodal disease.
Ocular involvement, either unilateral or bilateral, can be the initial presentation of PCNSL [51]. In almost
half of patients, it precedes the development of clinically evident deposits within the brain parenchyma or
CSF [39]. Alternatively, the vitreous and uvea may be a site of relapse in patients with established
cerebral lymphoma, or more rarely as a relapse of systemic lymphoma [52,53].
PIOL tends to involve the posterior segment of the eye, including the vitreous, choroid, or retina, with
subsequent development of uveitis (usually chronic and bilateral and occasionally atypical), exudative
retinal detachment, and retinal/vitreous hemorrhages (picture 1) [51,54]. Occasionally, visual symptoms
may follow occlusion of the retinal artery as a result of lymphomatous infiltration. Fluorescein angiography
may help to confirm retinal involvement. If ocular involvement is noted, color photography of the posterior
pole of the eye should be obtained (picture 2).
The ocular symptoms and findings are frequently subtle and nonspecific and not easily distinguished from
those due to sarcoidosis, viral infections, or collagen-vascular diseases. They manifest as
obscured/blurred vision, altered visual acuity, floaters, or visual hallucinations [38,51,55]. Typically
symptoms are unilateral initially, but then usually progress to involve both eyes [56].
A retrospective analysis of 221 patients with PCNSL with ocular involvement at diagnosis reported the
following symptoms at diagnosis [50]:
● Ocular symptoms – 62 percent (isolated in 3 percent)

● Behavioral or cognitive change – 27 percent
● Hemiparesis – 14 percent
● Headache – 14 percent
● Aphasia – 11 percent
● Seizure – 5 percent
● Ataxia – 4 percent
● Visual field defect – 2 percent
Note that up to 38 percent of patients with ocular involvement will not have ocular symptoms [50].
Diagnosis, therefore, requires a high degree of suspicion [57], referral for slit lamp examination, and
careful cytologic and molecular analysis of vitrectomy specimens. Patients diagnosed with ocular
involvement should undergo cranial imaging with magnetic resonance imaging (MRI) and lumbar
puncture with cytologic examination of the CSF. In one study, positive CSF cytology was found in 35 of
151 patients (23 percent) with ocular involvement [50].
Primary spinal lymphoma — Primary spinal involvement occurs in less than 1 percent of patients with
PCNSL. The lesions are almost always discrete intramedullary nodules. This is in contrast to spinal
involvement in systemic lymphoma, where there is usually diffuse leptomeningeal involvement or
extradural nodules.
In either case, spinal cord involvement manifests as a myelopathy. The pattern of weakness and sensory
level (if present) will depend on the localization and extent of the lesion. The majority of reported cases of
primary spinal lymphoma have involved the lower cervical or upper thoracic regions.
A single-institution retrospective analysis of 14 patients with primary intramedullary spinal cord lymphoma
reported that all patients initially presented with a progressive myelopathy, which was subacute (<8
weeks) in nine patients and insidious (>8 weeks) in five patients [58]. The diagnosis was often delayed,
with a median time to diagnosis of eight months (range 1 to 22 months). Presenting signs and symptoms
included:
● Progressive myelopathy – 100 percent

● Systemic B symptoms (fever/chills, night sweats, weight loss, malaise) – 64 percent
● Back pain – 64 percent
● Evidence of lower motor neuron involvement on examination (areflexia or flaccid paralysis) – 43
percent
Of importance, this study demonstrated that the clinical presentation and findings on MRI were
nonspecific and the CSF was nondiagnostic. Most patients had a concomitant lesion in the brain, a
biopsy of which confirmed the diagnosis. Three patients had associated comorbidities: one with HIV, one
with post-transplant lymphoproliferative disorder, and one with intravascular lymphoma. The lower motor
neuron findings are not easily explained.
Neurolymphomatosis — NL refers to the lymphomatous invasion of nerve roots of the cranial or spinal
nerves. Symptoms include loss of facial sensation or motor function, such as asymmetric weakness of
the extremities [48,59-61]. Rare cases of optic nerve infiltration presenting with rapid and severe visual
loss have been described [62].
The hallmark of NL is poorly localized severe pain in the absence of parenchymal lesions of the brain or
spinal cord or obvious lymphoma in the CSF. The process frequently spares the meninges; thus, CSF
cytologic studies may not be revealing.
The largest detailed series was a retrospective study performed by the International Primary CNS
Lymphoma Collaborative Group that analyzed the presentation and outcomes of 50 patients with NL [63].
The majority of cases were due to B cell non-Hodgkin lymphoma (NHL). NL was the initial presenting
feature in 26 percent of cases and secondary to relapse of systemic or primary CNS lymphoma in the
remaining cases. Over half of cases involved multiple neural structures with the following distribution:
● Peripheral nerves (60 percent)

● Spinal nerve roots (48 percent)
● Cranial nerves (46 percent)
● Plexus (40 percent)
Most patients had both sensory and motor dysfunction on examination [63]. Approximately 50 to 75
percent complained of painful neuropathy.
EVALUATION OF SUSPECTED DISEASE
In addition to a detailed history and physical examination, the evaluation of persons suspected of having
PCNSL should include:
● Imaging of the central nervous system (CNS), ideally with contrast-enhanced magnetic resonance
imaging (MRI)
● Cerebrospinal fluid (CSF) analysis, unless contraindicated due to elevated intracranial pressure
● Slit lamp examination of both eyes
● Testicular examination and ultrasound in males, particularly in older patients, to exclude the
possibility of an occult primary testicular lymphoma (see 'Differential diagnosis' below)
Pathologic evaluation of material from the eyes or CSF may provide sufficient diagnostic material in
some patients, thereby avoiding brain biopsy. For patients who do not have evidence of CSF or ocular
involvement, a stereotactic needle biopsy is the diagnostic procedure of choice [64]. Nerve biopsy is
necessary if isolated neurolymphomatosis (NL) is suspected. (See 'Diagnosis' below.)
Radiographic features — Patients with symptoms suggesting the diagnosis of PCNSL should have a
radiographic evaluation of the CNS. Contrast-enhanced MRI of the brain is the preferred imaging
modality. Contrast-enhanced computed tomography (CT) may be used for patients with contraindications
to MRI. Approximately 10 percent of PCNSL are missed on CT scans. MRI may detect lesions missed by
CT, although both CT and MRI commonly fail to detect leptomeningeal or vitreal disease. Spinal disease
can be detected by MRI.
Several distinctive radiographic features suggest the diagnosis of PCNSL in immunocompetent

individuals. Approximately 50 to 70 percent of immunocompetent patients with PCNSL develop solitary
lesions [32], with the remainder (approximately 25 percent) developing multifocal disease. Periventricular
lesions (eg, thalamus, basal ganglia, and corpus callosum) are most common (60 percent) followed by
lesions in the frontal, parietal, temporal, and occipital lobes in 20, 18, 15, and 4 percent of patients,
respectively [41].
The radiographic lesion tends to be a solitary nonhemorrhagic mass, situated in the deep white matter
adjacent to the ventricular surface [65]. The borders are sharply circumscribed in the majority of lesions
(87 percent), but may be ill defined (15 percent) [41]. Although mild surrounding edema is present in the
majority of cases, it is usually less profound than that which accompanies metastatic foci of carcinoma.
Mass effect and tumor edema are seen in over half of the cases.
Lesions appear isodense to hyperdense on CT images, isointense to hypointense on T2-weighted MRI

images, and enhance homogeneously after contrast administration (image 1). Diffusion-weighted MRI
images, sensitive to the intracellular water of masses of lymphoma cells, are frequently abnormal, but
similar changes may be seen in stroke, other malignant brain tumors, and acute demyelinating diseases.
Enhancement of the perivascular component surrounding small blood vessels as they course from the
subarachnoid space and penetrate the brain parenchyma (eg, Virchow-Robin space) may be seen.
Calcification, necrosis, cystic appearance, and ring enhancement are uncommon [65]. However, cystic
appearance may characterize PCNSL in immunocompromised patients. The role of positron emission
tomography (PET) scans in diagnosis is unclear. 18-F fluorodeoxyglucose PET (FDG-PET) scans of
brain may reveal uptake in three-quarters of patients [66] and be used to distinguish glucose-absorbing
neoplastic lesions from areas of radiation necrosis, infection, or inflammation, which may also enhance
on conventional CT/MRI [67]. Body FDG-PET may also be of value. In a study of 49 patients who had a
body PET for staging of PCNSL, systemic lymphoma was identified in 7 percent of newly diagnosed
patients and 27 percent of patients with relapsed PCNSL [68].
In cases of NL, conventional brain and spine MRI may be normal. MRI of the involved region of the spine
with coronal images through the exiting nerve roots may be required to show characteristic thickening
and enhancement of the nerve roots. MRI of the brachial plexus or lumbosacral plexus can also be
sensitive to disease in these locations. In most series, FDG-PET is slightly more sensitive than MRI in the
evaluation of suspected NL [61,63,69].
Cerebrospinal fluid analysis — Evaluation of the CSF may reveal the presence of malignant lymphoid
cells in up to 40 percent of patients with PCNSL. If no mass effect exists, lumbar puncture should be
performed on patients with suspected PCNSL. This examination should be performed either before or at
least one week after surgical biopsy to avoid false-positive results.
The CSF analysis should include cell counts, protein and glucose measurements, cytology, flow
cytometry, and immunoglobulin heavy-chain (IgH) gene rearrangement studies by polymerase chain
reaction (PCR). The last study is particularly suited to the evaluation of pauci-cellular samples. (See
"Lumbar puncture: Technique, indications, contraindications, and complications in adults".)
The CSF often reveals a nonspecific elevated protein concentration and a lymphocytic predominant
pleocytosis [4,38,58]. Glucose concentration is usually normal, but may be lowered in the presence of
leptomeningeal disease [4,38]. There may be difficulty distinguishing between reactive and malignant
cells or distinguishing reactive cells in the CSF from small cells of medulloblastoma as distinct from
malignant B cells. In such cases, immunophenotypic analysis using antibodies against lymphocytic
antigens is particularly helpful in establishing the lymphoid origin and clonality of the malignant cells, when
present, and to differentiate between B and T cell subtypes.
The sensitivity and specificity of cytomorphologic analysis and PCR analysis of the CSF have not been
fully evaluated; each may have false-negative or false-positive results. There is no agreement on a gold-
standard test, although most centers favor PCR analysis of rearranged IgH genes. This was best
demonstrated in a prospective randomized trial that included 282 immunocompetent patients with
PCNSL. Meningeal dissemination was evaluated using CSF cytomorphology, PCR of the rearranged IgH
genes, and MRI in conjunction with cell count and protein concentration [70]. It is not clear if
immunophenotypic analysis was performed. PCR and morphologic analysis produced discordant results.
Lymphoma cells were confirmed by PCR in only 32 percent of cytomorphologically positive samples
while only 35 percent of samples with a monoclonal result on PCR demonstrated lymphoma cells on
cytology. These results suggest that both PCR for rearranged IgH genes and cytologic examination of the
CSF may provide complimentary information regarding meningeal dissemination. It also suggests that
serial CSF samples may increase the sensitivity of this analysis.
Studies are ongoing to evaluate and optimize other methods of CSF analysis, including detection of
MYD88 and other genomic alterations by sequencing or droplet digital polymerase chain reaction
(ddPCR), to improve the sensitivity and specificity of CSF testing [71].
Measurement of microRNA levels (either specific for PCNSL or others, such as miR-21, that are
overexpressed in brain tumors), nucleotide metabolites such as neopterin, and interleukin-10 (IL-10)
levels are also under investigation [72,73].
The demonstration of neoplastic lymphocytes in the CSF is sufficient to confirm the diagnosis of PCNSL
and obviates the need for a brain biopsy. However, while a positive CSF analysis can provide valuable
diagnostic information, negative results do not exclude PCNSL or the infiltration of the leptomeninges by
PCNSL.
The diagnosis of leptomeningeal involvement can be made by:
● Demonstration of immunoglobulin gene rearrangement of B cells in the CSF
● Immunocytologic identification of clonal B cells in the CSF
● Identification of lymphoma nodules on lumbar nerve roots via scanning procedures such as CT or
MRI in patients with pathologically diagnosed PCNSL
Slit lamp exam and intraocular biopsy — Slit lamp examination is the diagnostic procedure of choice
for evaluation of possible ocular disease in patients with suspected or confirmed PCNSL. Initial signs of
primary ocular lymphoma include yellowish-white infiltrates at the subretinal pigment epithelium and/or
vitreous opacity (picture 3) [74]. Ophthalmic ultrasonography may be a useful adjunctive technique for
detecting ocular or retro-bulbar involvement in PCNSL [75]; additional adjunctive studies that may be
used by retinal specialists include fluorescence studies of the ocular fundus and retinal vessels and
optical coherence tomography.
Suspected ocular involvement can be evaluated with biopsy of the vitreous fluid, choroid, or retina [76].
Multiple biopsy attempts may be necessary to confirm the diagnosis; as with other sites of disease,
exposure to glucocorticoids can reduce the yield of biopsy. Vitrectomy, when combined with
cytopathology, flow cytometry, and analysis of IgH gene arrangement, can facilitate diagnosis of vitreous
involvement with a sensitivity and specificity of 64 and 100 percent in one study [77]. In some cases, a
chorioretinal biopsy will establish the diagnosis even when prior or concomitant vitrectomy fluid is
negative [76].
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Detection of genomic alterations such as MYD88 mutations in vitreous fluid or aqueous humor by
sequencing has been reported in multiple cases of intraocular lymphoma and, if validated, may further
enhance the sensitivity and specificity of ocular biopsies [78-80]. In small series, the prevalence of
MYD88 mutations in vitreous fluid of patients with intraocular lymphoma ranges from 75 to 85 percent
[79,80].
Biopsy — Stereotactic needle biopsy of involved tissue is the diagnostic procedure of choice for
PCNSL if there is no evidence of ocular or CSF involvement. The reason for this is twofold: patients do
not benefit clinically from the surgical resection of PCNSL and their frequent periventricular location
increases the risk of surgical complications.
The pathologic evaluation and classification of PCNSL tumors is similar to that of tumors of systemic
non-Hodgkin lymphoma (NHL). Tumors are evaluated based upon their morphology and
immunophenotype. The vast majority of PCNSL tumors (80 to 85 percent) are of the aggressive or highly
aggressive, diffuse large cell subtypes, and almost all are of B cell phenotypic origin [3,4,11,15,81-83].
However, the relative frequency of different lymphoma subtypes may differ by geography. As an example,
an analysis from Korea reported 7 of 42 patients were found to have PCNSL of T cell origin [84]. Primary
CNS Hodgkin lymphoma and low-grade PCNSL are extremely rare [85]. The latter has a better long-term
outcome than aggressive histology PCNSL [86].
The most common histopathologic subtype of PCNSL is diffuse large B cell lymphoma (DLBCL). As
examples, a series of 33 patients with PCNSL reported that all of these tumors were DLBCL, with the
vast majority being of the centroblastic subtype [17]. The majority was positive for BCL6, MUM1, and
BCL2; all were negative for CD138. Similar results were seen in a series of 51 patients with HIV-
unrelated PCNSL and a histologic diagnosis of DLBCL [87]. Positivity for MUM1, BCL6, BCL2, CD10,
or CD138 was seen in 84, 61, 49, 18, and 0 percent, respectively. The diagnosis of DLBCL is discussed
in detail separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of
diffuse large B cell lymphoma".)
Tumors tend to infiltrate along the perivascular spaces and surrounding parenchyma, occasionally
invading the blood vessel wall. The vast majority of these tumors are composed of large immunoblastic
and centroblastic cells [3,10,11]. Endothelial proliferation and cyst formation are uncommon.
The edges of the infiltrating growth often contain mixtures of tumor cells, reactive astrocytes, and T
lymphocytes. T cells appear within the spinal fluid. In one study, reactive perivascular T cell infiltrates
(RPVIs) were found in 36 percent of 73 assessable cases [88]. RPVIs were associated with significantly
better overall survival than RPVI-negative cases, particularly among those treated with high-dose
methotrexate-based chemotherapy.
DIAGNOSIS
Early diagnosis of PCNSL often requires a high degree of suspicion, as symptoms can evade diagnosis
for many months.
Tissue diagnosis should not be delayed in patients with suspected PCNSL. Definitive diagnosis requires
histopathologic evaluation of tissue obtained from masses suspected to be PCNSL. Some patients may
be diagnosed based upon the pathologic evaluation of vitreal biopsies or cerebrospinal fluid (CSF)
analysis. (See 'Cerebrospinal fluid analysis' above and 'Slit lamp exam and intraocular biopsy' above.)
For patients without ocular or CSF involvement, stereotactic brain biopsy is usually the method of choice,
providing a high rate of positive tissue diagnosis, with a low rate (<2 percent) of morbidity and mortality.
Extensive resection of the lesion(s) is impractical in the majority of cases, given the deep location of the
lesions and predisposition of the disease to involve multiple areas of the brain. Moreover, resection
results in high rates of complication and does not improve prognosis.
In general, we avoid the use of corticosteroids prior to biopsy, as these agents are lymphocytotoxic; a
single injection is known to alter proper histopathologic evaluation, and a short course of treatment may
cause the tumor to disappear temporarily [89-92]. (See "Treatment and prognosis of primary central
nervous system lymphoma", section on 'Initial treatment'.)
Pathologic evaluation of the tissue specimen should include both light microscopy and
immunohistochemistry. Occasionally, the initial specimen fails to confirm the pathologic diagnosis of
PCNSL. The pathology may be suggestive of "inflammation," "demyelination," or "viral encephalitis."
These may represent sentinel lesions eventually progressing into lymphoma, since some patients with
these findings have returned with new lesions that are pathologically proven to be PCNSL [3,4,38].
Similarly uncertain diagnoses may accompany partially treated PCNSL or biopsies performed on the
edge of the tumor.
Occasional cases can be diagnosed using polymerase chain reaction (PCR) techniques on tissue
biopsies or cells from the CSF by showing clonal rearrangements of the T cell receptor or
immunoglobulin heavy-chain (IgH) genes [84]. As the PCR primers employed do not include the entire
range of possible rearranged sites, and as some PCNSL may be initially polyclonal in nature, the IgH
analyses, at present, have a sensitivity of approximately 70 percent. T cell receptor gene rearrangements
are occasionally identified in pathologically confirmed B cell PCNSL.
Once a diagnosis of PCNSL is made, a thorough evaluation of the central nervous system (CNS),
systemic organs, and bone marrow is critical in order to determine the full extent of disease and guide
appropriate therapy [64]. (See "Treatment and prognosis of primary central nervous system lymphoma",
section on 'Pretreatment evaluation'.)
Prompt initiation of therapy is important in patients with PCNSL. In one study, treatment delay (>30 days
after diagnosis) was the most important clinical variable associated with decreased survival,
independent of baseline performance status or risk score [93].
DIFFERENTIAL DIAGNOSIS
Other primary or secondary central nervous system (CNS) tumors are frequently considered in the
radiologic differential diagnosis of PCNSL. The peritumoral edema surrounding most glial tumors and
metastatic lesions is uncommonly encountered in PCNSL. Calcification, hemorrhage, necrosis, cystic
appearance, and ring enhancement pattern are uncommon in PCNSL in immunocompetent individuals.
Their presence should raise the possibility of PCNSL in the setting of immunosuppression or a diagnosis
other than PCNSL. In the setting of immunosuppression, PCNSL may coexist with brain abscess,
tuberculoma, or other infectious complications.
Occasionally, dural-based lymphomas may mimic a meningioma. These tumors may also be mistaken
for inflammatory pseudotumors of the dura, plasma cell granulomas, Castleman disease, Rosai-Dorfman
disease, and non-Hodgkin lymphoma (NHL) of the skull extending into the dura [4,38].
Pathologically, diseases of small "blue cells" similar to lymphoma include primitive neuroectodermal
tumors (PNET), undifferentiated carcinoma, anaplastic oligodendroglioma, metastatic amelanotic
melanoma, and toxoplasmosis [3,4]. Immunohistochemical studies are invaluable in this regard. In
particular, leukocyte common antigen (CD45) can help to confirm the diagnosis of lymphoma [19].
Patients with initial tissue pathology suggestive of demyelination or nonspecific inflammation should be
followed carefully, as these findings may be precursors of frank lymphomatous pathology later in the
course of the disease.
Several variants of systemic NHL with predilection for CNS involvement have been described [38]. These
include:
● Intravascular lymphoma (angioendotheliomatosis) is a rare form of systemic lymphoma in which

neoplastic lymphocytes can be seen within the lumen of cerebral blood vessels without extravasation
into the brain parenchyma. These patients often develop acute neurologic deficits or rapidly
progressive encephalopathy as a result of multifocal ischemic strokes, secondary to occlusion of
small arteries with lymphoma cells. Unlike PCNSL, skin and adrenals are often involved. (See
"Intravascular large cell lymphoma".)
● Testicular lymphoma has an increased propensity for CNS involvement, especially in the
parenchymal compartment [94]. Although CNS disease is usually seen in the setting of relapse,
synchronous presentations of primary testicular NHL with secondary CNS involvement can occur
and are the reason why the evaluation of suspected PCNSL in men includes testicular examination
and ultrasound. (See 'Evaluation of suspected disease' above and "Clinical presentation and
diagnosis of secondary central nervous system lymphoma", section on 'Primary site'.)
● Systemic T cell lymphomas not uncommonly disseminate to the leptomeninges, presenting with a
mass lesion or meningeal signs.
Occasionally, solitary masses of benign lymphocytes are seen in the CNS. They are thought to represent
low-grade lymphoma. Similarly, lymphocytic infiltrates that do not have a malignant phenotype are said to
be pseudolymphomas.
SUMMARY
Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin
lymphoma (NHL) that involves the brain, leptomeninges, eyes, or spinal cord without evidence of
systemic lymphoma. (See 'Introduction' above.)
● The most notable risk factor for the development of PCNSL is immunodeficiency, and this may play
a role in the pathogenesis of disease. (See 'Epidemiology' above and 'Predisposing factors' above
and 'Pathogenesis' above.)
● PCNSL can manifest in the brain, its coverings, the eye, or spinal cord. Presenting symptoms and
signs vary, depending on the site of involvement. Symptoms may include focal neurologic deficits,
neuropsychiatric symptoms, signs of raised intracranial pressure, seizures, and ocular symptoms.
(See 'Clinical presentation' above.)
● In addition to a detailed history and physical examination, the evaluation of persons suspected of
having PCNSL should include:
• Imaging of the central nervous system (CNS), ideally with contrast-enhanced magnetic
resonance imaging (MRI). (See 'Radiographic features' above.)
• Cerebrospinal fluid (CSF) analysis, unless contraindicated due to elevated intracranial

pressure. (See 'Cerebrospinal fluid analysis' above.)
• Testicular examination and ultrasound in males, particularly in older patients.
• Slit lamp examination of both eyes. (See 'Slit lamp exam and intraocular biopsy' above.)
● Pathologic evaluation of material from the eyes or CSF may provide sufficient diagnostic material in
some patients, thereby avoiding brain biopsy. For patients who do not have evidence of CSF or
ocular involvement, a stereotactic needle biopsy is the diagnostic procedure of choice. Nerve biopsy
is necessary if isolated neurolymphomatosis (NL) is suspected. (See 'Diagnosis' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Fred Hochberg, MD, who contributed to an
earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4693 Version 23.0
GRAPHICS
Characteristic fundus findings of intraocular-central

nervous system lymphomalymphomatous subretinal
pigment epithelial (subRPE) infiltrates, retinochoroiditis,
and vasculitis
Fundus photograph of the right eye show s characteristic subretinal

pigment epithelium yellow infiltrates.
Reproduced from: Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-central

nervous system lymphoma: clinical features, diagnosis, and outcomes.
Ophthalmology 1999; 106:1805. Illustration used with the permission of Elsevier
Inc. All rights reserved.
Graphic 85793 Version 2.0
Vitreous cells in intraocular-central nervous system

lymphoma
Fundus photograph of the right eye show s large clumps of vitreous cells.
Reproduced from: Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-central

nervous system lymphoma: clinical features, diagnosis, and outcomes.
Ophthalmology 1999; 106:1805. Illustration used with the permission of Elsevier
Inc. All rights reserved.
MRI of primary central nervous system (CNS) lymphoma
The MRI examination in the transverse plane is from a 63-year-old female w ith
primary CNS lymphoma. The T1 w eighted sequence (A) reveals a single mass that
infiltrates the splenium of corpus callosum [a relatively common location for primary
CNS lymphoma] (arrow ), abutting the third ventricle anteriorly. The mass enhances
homogeneously follow ing gadolinium administration (B), is relatively dark on T2
w eighted images (C), and reveals restricted diffusion on the diffusion w eighted
sequence (bright, D). The reader should note the relative lack of edema on flair
studies. These features are consistent w ith the diagnosis of primary lymphoma of the
brain.
MRI: magnetic resonance imaging; C NS: central nervous system.
Fundoscopy of a patient with primary vitreoretinal lymphoma
There are many small, round, yellow -orange lesions (arrow s) at the retinal
pigment epithelium level in the deep retina.
Reproduced with permission from: Chan CC, Rubenstein JL, Coupland, SE, et al. Primary
vitreoretinal lymphoma: a report from an international primary central nervous system
lymphoma collaborative group symposium. Oncologist 2011; 16:1589. Copyright © 2011
AlphaMed Press. All rights reserved.
Contributor Disclosures
Tracy Batchelor, MD, MPH Grant/Research Support: Pfizer [Glioblastoma]; Oncoceutics [Gliomas (ONC201)].
Consultant/Advisory Boards: Merck [Glioblastoma (Temozolomide)]; NXDC [Malignant glioma (5-ALA)]; Amgen
[Glioblastoma]; Genomicare [Brain tumors (diagnostic testing)]. Other financial interest: Champions Oncology. Jay
S Loeffler, MD Nothing to disclose Arnold S Freedman, MD Other Financial Interest: Bayer [DMB (Bayer
17833)]. April F Eichler, MD, MPH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

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Clinical presentation, pathologic features, and diagnosis of

● Intracranial lesion (solitary or multiple)

less common eye involvement.

● Focal neurologic deficits – 70 percent

● Ocular symptoms – 62 percent (isolated in 3 percent)

● Progressive myelopathy – 100 percent

● Peripheral nerves (60 percent)

EVALUATION OF SUSPECTED DISEASE

● Slit lamp examination of both eyes

Several distinctive radiographic features suggest the diagnosis of PCNSL in immunocompetent

Lesions appear isodense to hyperdense on CT images, isointense to hypointense on T2-weighted MRI

The diagnosis of leptomeningeal involvement can be made by:

● Demonstration of immunoglobulin gene rearrangement of B cells in the CSF

● Immunocytologic identification of clonal B cells in the CSF

● Intravascular lymphoma (angioendotheliomatosis) is a rare form of systemic lymphoma in which

• Cerebrospinal fluid (CSF) analysis, unless contraindicated due to elevated intracranial

• Testicular examination and ultrasound in males, particularly in older patients.

Use of UpToDate is subject to the Subscription and License Agreement.

7. Schabet M. Epidemiology of primary CNS lymphoma. J Neurooncol 1999; 43:199.

36. Camilleri-Broët S, Crinière E, Broët P, et al. A uniform activated B-cell-like immunophenotype

61. Tomita M, Koike H, Kawagashira Y, et al. Clinicopathological features of neuropathy associated

Topic 4693 Version 23.0

Characteristic fundus findings of intraocular-central

Fundus photograph of the right eye show s characteristic subretinal

Reproduced from: Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-central

Graphic 85793 Version 2.0

Vitreous cells in intraocular-central nervous system

Reproduced from: Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-central

Graphic 85794 Version 2.0

MRI of primary central nervous system (CNS) lymphoma

MRI: magnetic resonance imaging; C NS: central nervous system.

Graphic 83271 Version 3.0

Fundoscopy of a patient with primary vitreoretinal lymphoma

Graphic 69592 Version 1.0

Conflict of interest policy

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