Lymphomas of the central nervous system
- Biogen Australia Pty Ltd, Investigator-Initiated Research Grant for CAD software in multiple sclerosis: finished Oct 2021 (past)
Updates to Article Attributes
Primary CNS lymphomas (PCNSL)Lymphomas of the central nervous system are relatively uncommon tumours, accounting for 2.5% of all brain tumours, but the second most common primary brain tumour after gliomas 17. By definition, there is no co-existing systemic disease at the time of diagnosis, distinguishing it from CNS involvement from systemic lymphoma (secondary CNS lymphoma).
On imaging, primary CNSdiffuse large B-cell lymphoma characteristicallyof the CNS is characteristically identified as a CT hyperdense enhancing supratentorial mass, with MRI T1 hypointense, T2 iso- to hypointense, vivid homogeneous enhancement and restricted diffusion. Usually, there is relatively little associated vasogenic oedema and no central necrosis, although it is important to note that in immunocompromised individuals appearances tend to be more heterogeneous.
Terminology
The current (2016) WHO classification of CNS tumours divides CNS lymphomas into a number of subtypes, based on the cell of origin, and molecular and histological features. Generally, imaging features are similar and as such this article does not distinguish between these explicitly, grouping them together under
-
CNS lymphomas
primary diffuse large B-cell lymphoma of the
umbrella term primaryCNSlymphoma.-
A number of subtypes are, however, worth discussing in more detail and these have earned their own articles: -
miscellaneous rare lymphomas in the CNS
other low-grade B-cell lymphomas of the CNS
anaplastic large cell lymphoma (ALK+/ALK−)
T-cell and NK/T-cell lymphomas
It is worth noting that the WHO classification of hematolymphoid tumours (5th edition, 2022) overlaps the CNS classification and groups primary diffuse large B-cell lymphoma of the CNS in with tumours of the vitreous and testes under the primary DLBCL of immune-privileged sites17.
The remainder of this article presents a general discussion of primary
CNSdiffuse large B-cell lymphoma of the CNS.Epidemiology
Typically patients diagnosed with primary CNS lymphoma are over the age of 50 years with a short duration of symptoms (at most a few months) 4. There is a male predominance of approximately 2:1 4.
Historically there has been a strong association with HIV/AIDS and other immunocompromised states and demographics in these patients reflect the underlying condition – see immunodeficiency-associated CNS lymphomas.
More recently, there has been an increase in the incidence of sporadic, non-EBV-associated primary CNS lymphomas in immunocompetent individuals, which is particularly seen in older patients (50-80 years of age) 14.
Clinical presentation
Patients with primary CNS lymphoma present similarly to patients with other central nervous system masses; symptoms and signs of raised intracranial pressure, focal neurological disorders and seizures.
Pathology
The vast majority (>90%) of primary CNS lymphomas are B-cell in origin: diffuse large B-cell lymphoma and high-grade Burkitt-like B-cell lymphoma 1. Malignant cells tend to accumulate around and within blood vessels. Low-grade tumours are more frequently T-cell in origin 1.
Effects of steroids
An important factor to be aware of is the transient but profound response of CNS lymphoma to the use of glucocorticoids (e.g. dexamethasone and prednisolone) which are routinely administered in patients with intracranial mass effect from a tumour and oedema. Within a few days of administration of steroids, CNS lymphoma can shrink dramatically due to the combined effect of steroid as a cytotoxic agent (reducing the neoplastic B-cell population) and anti-oedema agent (resulting in decreased permeability of capillaries via a variety of mechanisms) 12,16. Whatever the underlying mechanism, the result is that administration of steroid prior to biopsy prevents a diagnosis in as many as 50% of cases 14, although some more recent studies have suggested that this effect is perhaps not as profound as initially suspected 16.
Nonetheless, if the diagnosis is suspected and the patient does not require steroids emergently to treat mass effect, then they are best avoided prior to biopsy to maximise the diagnostic yield 16.
Location
Primary CNS lymphomas present as solitary (60-70%) or multiple (30-40%) lesions with a predilection for the periventricular white matter, although they can also arise in the cortex or deep grey matter; the latter being more common in low-grade lesions 1,14. They are most frequently found in the supratentorial brain (~70%) 14.
Macroscopic appearance
Macroscopic appearance is variable, ranging from almost indistinguishable from the normal brain to well-circumscribed masses to heterogeneous ill-defined haemorrhagic or necrotic masses 14.
Microscopic appearance
Primary CNS lymphomas are composed of large quantities of lymphocytes without a particular growth pattern, although there is a predilection for a perivascular distribution, and in many instances infiltration within blood vessels 14. They may demonstrate areas of necrosis, especially in immunodeficient patients.
Immunophenotype
The exact immunophenotype depends on the tumour type.
Diffuse large B-cell lymphoma, which is the most common, is characterised by immunohistochemical reactivity for CD19, CD20, CD22, CD79a and PAX-5 14.
CSF
CSF examination demonstrates elevated protein and decreased glucose. Positive cytology is uncommon (~25%). Positive EBV DNA in CSF is helpful for the diagnosis of lymphoma, particularly in immunocompromised individuals.
Radiographic features
Classic imaging appearance for primary CNS lymphoma is of a CT hyperdense avidly enhancing mass, with T1 hypointense, T2 iso- to hypointense, vivid homogeneous gadolinium-enhancing lesion(s) with restricted diffusion on MRI, and exhibiting subependymal extension and crossing of the corpus callosum.
While this typical pattern is helpful in diagnosis, it is predominantly observed in untreated non-immunocompromised patients; diffuse large B-cell lymoboma, EBV negative 17.
Primary CNS lymphomas in immunocompromised patients (typically HIV/AIDS or post-transplant), or other types of lymphoma may be more heterogeneous
tumours, featuringin appearance. For example in immunocompromised individuals central non-enhancement/necrosis and haemorrhage is smore common, although the latter is still uncommon – see immunodeficiency-associated CNS lymphomas 8.Typically primary CNS lymphomas are supratentorial (75-85%) 5 and appear as a mass/multiple masses (11-50% 3) that are usually in contact with the subarachnoid/ependymal surfaces. Crossing the corpus callosum is not infrequently seen. Enhancement on both CT and MRI is pronounced and usually homogeneous. Even with larger lesions, there is a little mass effect for size and limited surrounding vasogenic oedema.
Low-grade tumours differ from the more common high-grade primary CNS lymphomas in several ways 1:
deep locations and spinal involvement is more common
contrast enhancement is absent, irregular or only mild
Disseminated meningeal or intraventricular disease is uncommon. It is seen in ~5% (range 1-7%) of cases at presentation and usually in high-grade cases 8.
CT
most primary CNS lymphomas are hyperattenuating (70%) 3
show enhancement
haemorrhage is distinctly uncommon 8
often multiple lesions in patients with HIV/AIDS
MRI
Reported signal characteristics of primary CNS lymphoma include:
T1: typically hypointense to grey matter 9
-
T1 C+ (Gd)
typical high-grade tumours show intense homogeneous enhancement while low-grade tumours have absent to moderate enhancement 1
peripheral ring enhancement may be seen in immunocompromised patients (HIV/AIDS)
notch sign 15
-
T2: variable
-
majority are iso to hypointense to grey matter
isointense: 33% 9
hypointense: 20% 9 - when present this is a helpful distinguishing feature
hyperintense: 15-47%, more common in tumours with necrosis 1,9
-
-
DWI/ADC
restricted diffusion with ADC values lower than a normal brain, typically between 400 and 600 x 10-6 mm2/s (lower than high-grade gliomas and metastases 8,13)
a number of studies have suggested that the lower the ADC values of a tumour the poorer the response to a tumour and higher likelihood of recurrence 13
ADC is particularly useful in assessing response to chemotherapy, with increases in ADC values to above those of normal brain predictive of complete response 13
-
MR spectroscopy
large choline peak
reversed choline/creatinine ratio
markedly decreased NAA
lactate peak may also be seen 7
-
MR perfusion
only modest, if any, increase in rCBV (much less marked than in high-grade gliomas, where angiogenesis is a prominent feature 11)
Nuclear medicine
Thallium-201scintigraphy
primary CNS lymphoma shows increased uptake
PET
fluorine-18FDG PET
primary CNS lymphoma shows increased uptake
carbon-11methionine PET
primary CNS lymphoma shows increased uptake
Treatment and prognosis
Treatment of primary CNS lymphoma is predominantly with steroids (which can dramatically shrink a tumour due to combined anti-oedema and cytotoxic effects) and methotrexate-based chemotherapy 4,13. Whole-brain irradiation can also be added, particularly in patients with high-grade tumours, or recurrence 4,13.
If a tumour is a low grade (uncommon: see above), then the local treatment with surgical resection and radiotherapy may be effective 1 and long-term survival is possible.
The tumours are often high grade and despite treatment have a poor prognosis. If only surgical resection is performed, then death occurs within a few months. With high dose chemotherapy, the tumour can be significantly reduced in size; however, recurrence is common, with a median survival of around 30 months 1. Those who are immunocompromised (e.g. HIV positive) have worse outcomes.
Differential diagnosis
For general imaging appearances on CT and MRI consider:
secondary CNS lymphoma: indistinguishable on imaging, however, it tends to involve more leptomeninges (~2/3 of cases) 8
-
cerebral toxoplasmosis: see toxoplasmosis vs lymphoma
toxoplasmosis does not exhibit subependymal spread
more likely to lie in basal ganglia, corticomedullary junction
CNS lymphoma is thallium/PET avid, whereas toxoplasmosis is not
-
more commonly centrally necrotic
more commonly demonstrates evidence of haemorrhage
-
peripheral enhancement of primary CNS lymphoma is thicker 3
central restricted diffusion
-<p><strong>Primary CNS lymphomas (PCNSL)</strong> are relatively uncommon tumours, accounting for 2.5% of all <a href="/articles/brain-tumours">brain tumours</a>. By definition, there is no co-existing systemic disease at the time of diagnosis, distinguishing it from CNS involvement from systemic <a href="/articles/lymphoma">lymphoma</a> (<a href="/articles/secondary-cns-lymphoma">secondary CNS lymphoma</a>).</p><p>On imaging, primary CNS lymphoma characteristically is identified as a CT hyperdense enhancing supratentorial mass, with MRI T1 hypointense, T2 iso- to hypointense, vivid homogeneous enhancement and restricted diffusion. Usually, there is relatively little associated vasogenic oedema and no central necrosis, although it is important to note that in immunocompromised individuals appearances tend to be more heterogeneous.</p><h4>Terminology</h4><p>The current (2016) <a href="/articles/who-classification-of-cns-tumours-1">WHO classification of CNS tumours</a> divides CNS lymphomas into a number of subtypes, based on the cell of origin and histological features. Generally, imaging features are similar and as such this article does not distinguish between these explicitly, grouping them together under the umbrella term primary CNS lymphoma. </p><p>A number of subtypes are, however, worth discussing in more detail and these have earned their own articles:</p><ul>-<li>-<a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a><ul>-<li><a href="/articles/aids-related-diffuse-large-b-cell-lymphoma">AIDS-related diffuse large B-cell lymphoma</a></li>-<li><a href="/articles/ebv-positive-diffuse-large-b-cell-lymphoma-nos">EBV-positive diffuse large B-cell lymphoma, NOS</a></li>-<li>-<a href="/articles/lymphomatoid-granulomatosis-cns-manifestations">lymphomatoid</a><a href="/articles/lymphomatoid-granulomatosis-cns-manifestations"> granulomatosis</a>-</li>-<li><a href="/articles/primary-central-nervous-system-posttransplant-lymphoproliferative-disorder">primary CNS posttransplant lymphoproliferative disorder</a></li>-</ul>-</li>-<li><a href="/articles/intravascular-lymphoma">intravascular lymphoma</a></li>-<li><a href="/articles/malt-lymphoma-dura">MALT lymphoma of the dura</a></li>-</ul><p>The remainder of this article presents a general discussion of primary CNS lymphoma. </p><h4>Epidemiology</h4><p>Typically patients diagnosed with primary CNS lymphoma are over the age of 50 years with a short duration of symptoms (at most a few months) <sup>4</sup>. There is a male predominance of approximately 2:1 <sup>4</sup>.</p><p>Historically there has been a strong association with <a href="/articles/hiv-aids">HIV/AIDS</a> and other immunocompromised states and demographics in these patients reflect the underlying condition – see <a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a>. </p><p>More recently, there has been an increase in the incidence of sporadic, non-EBV-associated primary CNS lymphomas in immunocompetent individuals, which is particularly seen in older patients (50-80 years of age) <sup>14</sup>.</p><h4>Clinical presentation</h4><p>Patients with primary CNS lymphoma present similarly to patients with other central nervous system masses; symptoms and signs of <a href="/articles/raised-intracranial-pressure">raised intracranial pressure</a>, focal neurological disorders and seizures.</p><h4>Pathology</h4><p>The vast majority (>90%) of primary CNS lymphomas are B-cell in origin: diffuse large B-cell lymphoma and high-grade Burkitt-like B-cell lymphoma <sup>1</sup>. Malignant cells tend to accumulate around and within blood vessels. Low-grade tumours are more frequently T-cell in origin <sup>1</sup>. </p><h5>Effects of steroids</h5><p>An important factor to be aware of is the transient but profound response of CNS lymphoma to the use of glucocorticoids (e.g. dexamethasone and prednisolone) which are routinely administered in patients with intracranial mass effect from a tumour and oedema. Within a few days of administration of steroids, CNS lymphoma can shrink dramatically due to the combined effect of steroid as a cytotoxic agent (reducing the neoplastic B-cell population) and anti-oedema agent (resulting in decreased permeability of capillaries via a variety of mechanisms) <sup>12,16</sup>. Whatever the underlying mechanism, the result is that administration of steroid prior to biopsy prevents a diagnosis in as many as 50% of cases <sup>14</sup>, although some more recent studies have suggested that this effect is perhaps not as profound as initially suspected <sup>16</sup>. </p><p>Nonetheless, if the diagnosis is suspected and the patient does not require steroids emergently to treat mass effect, then they are best avoided prior to biopsy to maximise the diagnostic yield <sup>16</sup>. </p><h5>Location</h5><p>Primary CNS lymphomas present as solitary (60-70%) or multiple (30-40%) lesions with a predilection for the periventricular white matter, although they can also arise in the cortex or deep grey matter; the latter being more common in low-grade lesions <sup>1,14</sup>. They are most frequently found in the supratentorial brain (~70%) <sup>14</sup>. </p><h5>Macroscopic appearance</h5><p>Macroscopic appearance is variable, ranging from almost indistinguishable from the normal brain to well-circumscribed masses to heterogeneous ill-defined haemorrhagic or necrotic masses <sup>14</sup>. </p><h5>Microscopic appearance</h5><p>Primary CNS lymphomas are composed of large quantities of lymphocytes without a particular growth pattern, although there is a predilection for a perivascular distribution, and in many instances infiltration within blood vessels <sup>14</sup>. They may demonstrate areas of necrosis, especially in immunodeficient patients.</p><h5>Immunophenotype</h5><p>The exact immunophenotype depends on the tumour type. </p><p><a href="/articles/diffuse-large-b-cell-lymphoma">Diffuse large B-cell lymphoma</a>, which is the most common, is characterised by <a href="/articles/immunohistochemistry">immunohistochemical</a> reactivity for CD19, CD20, CD22, CD79a and PAX-5 <sup>14</sup>. </p><h5>CSF</h5><p><a href="/articles/cerebrospinal-fluid-1">CSF</a> examination demonstrates elevated protein and decreased glucose. Positive cytology is uncommon (~25%). Positive EBV DNA in CSF is helpful for the diagnosis of lymphoma, particularly in immunocompromised individuals. </p><h4>Radiographic features</h4><p>Classic imaging appearance for primary CNS lymphoma is of a CT hyperdense avidly enhancing mass, with T1 hypointense, T2 iso- to hypointense, vivid homogeneous gadolinium-enhancing lesion(s) with restricted diffusion on MRI, and exhibiting subependymal extension and crossing of the corpus callosum.</p><p>While this typical pattern is helpful in diagnosis, it is predominantly observed in untreated non-immunocompromised patients. Primary CNS lymphomas in immunocompromised patients (typically HIV/AIDS or post-transplant) may be more heterogeneous tumours, featuring central non-enhancement/necrosis and haemorrhage, although the latter is still uncommon – see <a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a> <sup>8</sup>.</p><p>Typically primary CNS lymphomas are supratentorial (75-85%) <sup>5</sup> and appear as a mass/multiple masses (11-50% <sup>3</sup>) that are usually in contact with the subarachnoid/ependymal surfaces. Crossing the <a href="/articles/corpus-callosum">corpus callosum</a> is not infrequently seen. Enhancement on both CT and MRI is pronounced and usually homogeneous. Even with larger lesions, there is a little mass effect for size and limited surrounding vasogenic oedema. </p><p>Low-grade tumours differ from the more common high-grade primary CNS lymphomas in several ways <sup>1</sup>:</p><ul>-<li>deep locations and spinal involvement is more common</li>-<li>contrast enhancement is absent, irregular or only mild</li>-</ul><p>Disseminated meningeal or intraventricular disease is uncommon. It is seen in ~5% (range 1-7%) of cases at presentation and usually in high-grade cases<sup> 8</sup>.</p><h5>CT</h5><ul>-<li>most primary CNS lymphomas are hyperattenuating (70%) <sup>3</sup>-</li>-<li>show enhancement</li>-<li>haemorrhage is distinctly uncommon <sup>8</sup>-</li>-<li>often multiple lesions in patients with HIV/AIDS</li>-</ul><h5>MRI</h5><p>Reported signal characteristics of primary CNS lymphoma include:</p><ul>-<li>-<strong>T1:</strong> typically hypointense to grey matter <sup>9</sup>-</li>-<li>-<strong>T1 C+ (Gd)</strong><ul>-<li>typical high-grade tumours show intense homogeneous enhancement while low-grade tumours have absent to moderate enhancement <sup>1</sup>-</li>-<li>peripheral <a href="/articles/cerebral-ring-enhancing-lesions">ring enhancement</a> may be seen in immunocompromised patients (HIV/AIDS)</li>-<li>-<a href="/articles/notch-sign-primary-cns-lymphoma-1">notch sign</a> <sup>15</sup>-</li>-</ul>-</li>-<li>-<strong>T2:</strong> variable<ul>-<li>majority are iso to hypointense to grey matter<ul>-<li>isointense: 33% <sup>9</sup>-</li>-<li>hypointense: 20% <sup>9</sup> - when present this is a helpful distinguishing feature</li>-</ul>-</li>-<li>hyperintense: 15-47%, more common in tumours with necrosis <sup>1,9</sup>-</li>-</ul>-</li>-<li>-<strong>DWI/ADC</strong><ul>-<li>restricted diffusion with ADC values lower than a normal brain, typically between 400 and 600 x 10<sup>-6</sup> mm<sup>2</sup>/s (lower than high-grade gliomas and metastases <sup>8,13</sup>)</li>-<li>a number of studies have suggested that the lower the ADC values of a tumour the poorer the response to a tumour and higher likelihood of recurrence <sup>13</sup>-</li>-<li>ADC is particularly useful in assessing response to chemotherapy, with increases in ADC values to above those of normal brain predictive of complete response <sup>13</sup>-</li>-</ul>-</li>-<li>-<strong>MR spectroscopy</strong><ul>-<li>large choline peak</li>-<li>reversed choline/creatinine ratio</li>-<li>markedly decreased NAA</li>-<li>lactate peak may also be seen <sup>7</sup>-</li>-</ul>-</li>-<li>-<strong>MR perfusion</strong><ul><li>only modest, if any, increase in <a href="/articles/cerebral-blood-volume-cbv">rCBV</a> (much less marked than in high-grade gliomas, where angiogenesis is a prominent feature <sup>11</sup>) </li></ul>-</li>-</ul><h5>Nuclear medicine</h5><h6>Thallium-201<sup> </sup>scintigraphy</h6><ul><li>primary CNS lymphoma shows increased uptake</li></ul><h6>PET</h6><h6>fluorine-18<sup> </sup>FDG PET</h6><ul><li>primary CNS lymphoma shows increased uptake</li></ul><h6>carbon-11<sup> </sup>methionine PET</h6><ul><li>primary CNS lymphoma shows increased uptake</li></ul><h4>Treatment and prognosis</h4><p>Treatment of primary CNS lymphoma is predominantly with steroids (which can dramatically shrink a tumour due to combined anti-oedema and cytotoxic effects) and methotrexate-based chemotherapy <sup>4,13</sup>. Whole-brain irradiation can also be added, particularly in patients with high-grade tumours, or recurrence <sup>4,13</sup>.</p><p>If a tumour is a low grade (uncommon: see above), then the local treatment with surgical resection and radiotherapy may be effective <sup>1</sup> and long-term survival is possible.</p><p>The tumours are often high grade and despite treatment have a poor prognosis. If only surgical resection is performed, then death occurs within a few months. With high dose chemotherapy, the tumour can be significantly reduced in size; however, recurrence is common, with a median survival of around 30 months <sup>1</sup>. Those who are immunocompromised (e.g. HIV positive) have worse outcomes.</p><h4>Differential diagnosis</h4><p>For general imaging appearances on CT and MRI consider:</p><ul>-<li>-<a href="/articles/secondary-cns-lymphoma">secondary CNS lymphoma</a>: indistinguishable on imaging, however, it tends to involve more leptomeninges (~2/3 of cases) <sup>8</sup>-</li>-<li>-<a href="/articles/neurotoxoplasmosis">cerebral toxoplasmosis</a>: see <a href="/articles/toxoplasmosis-vs-lymphoma">toxoplasmosis vs lymphoma</a><ul>-<li>toxoplasmosis does not exhibit subependymal spread</li>-<li>more likely to lie in basal ganglia, corticomedullary junction</li>-<li>CNS lymphoma is thallium/PET avid, whereas toxoplasmosis is not</li>-</ul>-</li>-<li>-<a href="/articles/butterfly-glioma">butterfly glioma/</a><a href="/articles/glioblastoma-idh-wildtype">GBM</a><ul>-<li>more commonly centrally necrotic</li>-<li>more commonly demonstrates evidence of haemorrhage</li>-</ul>-</li>-<li>-<a href="/articles/tumefactive-demyelinating-lesion">tumefactive MS</a>/<a href="/articles/acute-disseminated-encephalomyelitis-adem-1">ADEM</a>-</li>-<li>-<a href="/articles/brain-abscess-1">cerebral abscess</a><ul>-<li>peripheral enhancement of primary CNS lymphoma is thicker <sup>3</sup>-</li>-<li>central restricted diffusion</li>-</ul>-</li>-<li>-<a href="/articles/neurosarcoidosis">neurosarcoidosis</a> <sup>4</sup>-</li>- +<p><strong>Lymphomas of the central nervous system </strong>are relatively uncommon tumours, accounting for 2.5% of all <a href="/articles/brain-tumours">brain tumours</a>, but the second most common primary brain tumour after gliomas <sup>17</sup>. By definition, there is no co-existing systemic disease at the time of diagnosis, distinguishing it from CNS involvement from systemic <a href="/articles/lymphoma">lymphoma</a> (<a href="/articles/secondary-cns-lymphoma">secondary CNS lymphoma</a>).</p><p>On imaging, primary diffuse large B-cell lymphoma of the CNS is characteristically identified as a CT hyperdense enhancing supratentorial mass, with MRI T1 hypointense, T2 iso- to hypointense, vivid homogeneous enhancement and restricted diffusion. Usually, there is relatively little associated vasogenic oedema and no central necrosis, although it is important to note that in immunocompromised individuals appearances tend to be more heterogeneous.</p><h4>Terminology</h4><p>The <a href="/articles/who-classification-of-cns-tumours-1">WHO classification of CNS tumours</a> divides CNS lymphomas into a number of subtypes, based on the cell of origin, and molecular and histological features.</p><ul>
- +<li>
- +<p>CNS lymphomas</p>
- +<ul>
- +<li><p>primary diffuse large B-cell lymphoma of the CNS</p></li>
- +<li>
- +<p><a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a></p>
- +<ul>
- +<li><p><a href="/articles/aids-related-diffuse-large-b-cell-lymphoma">AIDS-related diffuse large B-cell lymphoma</a></p></li>
- +<li><p><a href="/articles/ebv-positive-diffuse-large-b-cell-lymphoma-nos">EBV-positive diffuse large B-cell lymphoma, NOS</a></p></li>
- +<li><p><a href="/articles/primary-central-nervous-system-posttransplant-lymphoproliferative-disorder">primary CNS posttransplant lymphoproliferative disorder</a></p></li>
- +</ul>
- +</li>
- +<li><p><a href="/articles/lymphomatoid-granulomatosis-cns-manifestations">lymphomatoid granulomatosis</a></p></li>
- +<li><p><a href="/articles/intravascular-lymphoma">intravascular large B-cell lymphoma</a></p></li>
- +</ul>
- +</li>
- +<li>
- +<p>miscellaneous rare lymphomas in the CNS</p>
- +<ul>
- +<li><p><a href="/articles/malt-lymphoma-dura">MALT lymphoma of the dura</a></p></li>
- +<li><p>other low-grade B-cell lymphomas of the CNS</p></li>
- +<li><p>anaplastic large cell lymphoma (ALK+/ALK−)</p></li>
- +<li><p>T-cell and NK/T-cell lymphomas</p></li>
- +</ul>
- +</li>
- +</ul><p>It is worth noting that the <a href="/articles/who-classification-of-tumours-of-haematopoietic-and-lymphoid-tissues-1" title="WHO classification of tumours of haematopoietic and lymphoid tissues">WHO classification of hematolymphoid tumours</a> (5th edition, 2022) overlaps the CNS classification and groups primary diffuse large B-cell lymphoma of the CNS in with tumours of the vitreous and testes under the <a href="/articles/primary-dlbcl-of-immune-privileged-sites" title="primary DLBCL of immune-privileged sites">primary DLBCL of immune-privileged sites</a> <sup>17</sup>. </p><p>The remainder of this article presents a general discussion of primary diffuse large B-cell lymphoma of the CNS.</p><h4>Epidemiology</h4><p>Typically patients diagnosed with primary CNS lymphoma are over the age of 50 years with a short duration of symptoms (at most a few months) <sup>4</sup>. There is a male predominance of approximately 2:1 <sup>4</sup>.</p><p>Historically there has been a strong association with <a href="/articles/hiv-aids">HIV/AIDS</a> and other immunocompromised states and demographics in these patients reflect the underlying condition – see <a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a>. </p><p>More recently, there has been an increase in the incidence of sporadic, non-EBV-associated primary CNS lymphomas in immunocompetent individuals, which is particularly seen in older patients (50-80 years of age) <sup>14</sup>.</p><h4>Clinical presentation</h4><p>Patients with primary CNS lymphoma present similarly to patients with other central nervous system masses; symptoms and signs of <a href="/articles/raised-intracranial-pressure">raised intracranial pressure</a>, focal neurological disorders and seizures.</p><h4>Pathology</h4><p>The vast majority (>90%) of primary CNS lymphomas are B-cell in origin: diffuse large B-cell lymphoma and high-grade Burkitt-like B-cell lymphoma <sup>1</sup>. Malignant cells tend to accumulate around and within blood vessels. Low-grade tumours are more frequently T-cell in origin <sup>1</sup>. </p><h5>Effects of steroids</h5><p>An important factor to be aware of is the transient but profound response of CNS lymphoma to the use of glucocorticoids (e.g. dexamethasone and prednisolone) which are routinely administered in patients with intracranial mass effect from a tumour and oedema. Within a few days of administration of steroids, CNS lymphoma can shrink dramatically due to the combined effect of steroid as a cytotoxic agent (reducing the neoplastic B-cell population) and anti-oedema agent (resulting in decreased permeability of capillaries via a variety of mechanisms) <sup>12,16</sup>. Whatever the underlying mechanism, the result is that administration of steroid prior to biopsy prevents a diagnosis in as many as 50% of cases <sup>14</sup>, although some more recent studies have suggested that this effect is perhaps not as profound as initially suspected <sup>16</sup>. </p><p>Nonetheless, if the diagnosis is suspected and the patient does not require steroids emergently to treat mass effect, then they are best avoided prior to biopsy to maximise the diagnostic yield <sup>16</sup>. </p><h5>Location</h5><p>Primary CNS lymphomas present as solitary (60-70%) or multiple (30-40%) lesions with a predilection for the periventricular white matter, although they can also arise in the cortex or deep grey matter; the latter being more common in low-grade lesions <sup>1,14</sup>. They are most frequently found in the supratentorial brain (~70%) <sup>14</sup>. </p><h5>Macroscopic appearance</h5><p>Macroscopic appearance is variable, ranging from almost indistinguishable from the normal brain to well-circumscribed masses to heterogeneous ill-defined haemorrhagic or necrotic masses <sup>14</sup>. </p><h5>Microscopic appearance</h5><p>Primary CNS lymphomas are composed of large quantities of lymphocytes without a particular growth pattern, although there is a predilection for a perivascular distribution, and in many instances infiltration within blood vessels <sup>14</sup>. They may demonstrate areas of necrosis, especially in immunodeficient patients.</p><h5>Immunophenotype</h5><p>The exact immunophenotype depends on the tumour type. </p><p><a href="/articles/diffuse-large-b-cell-lymphoma-1">Diffuse large B-cell lymphoma</a>, which is the most common, is characterised by <a href="/articles/immunohistochemistry">immunohistochemical</a> reactivity for CD19, CD20, CD22, CD79a and PAX-5 <sup>14</sup>. </p><h5>CSF</h5><p><a href="/articles/cerebrospinal-fluid-1">CSF</a> examination demonstrates elevated protein and decreased glucose. Positive cytology is uncommon (~25%). Positive EBV DNA in CSF is helpful for the diagnosis of lymphoma, particularly in immunocompromised individuals. </p><h4>Radiographic features</h4><p>Classic imaging appearance for primary CNS lymphoma is of a CT hyperdense avidly enhancing mass, with T1 hypointense, T2 iso- to hypointense, vivid homogeneous gadolinium-enhancing lesion(s) with restricted diffusion on MRI, and exhibiting subependymal extension and crossing of the corpus callosum.</p><p>While this typical pattern is helpful in diagnosis, it is predominantly observed in untreated non-immunocompromised patients; diffuse large B-cell lymoboma, EBV negative <sup>17</sup>.</p><p>Primary CNS lymphomas in immunocompromised patients (typically HIV/AIDS or post-transplant), or other types of lymphoma may be more heterogeneous in appearance. For example in immunocompromised individuals central non-enhancement/necrosis and haemorrhage is smore common, although the latter is still uncommon – see <a href="/articles/immunodeficiency-associated-cns-lymphomas">immunodeficiency-associated CNS lymphomas</a> <sup>8</sup>.</p><p>Typically primary CNS lymphomas are supratentorial (75-85%) <sup>5</sup> and appear as a mass/multiple masses (11-50% <sup>3</sup>) that are usually in contact with the subarachnoid/ependymal surfaces. Crossing the <a href="/articles/corpus-callosum">corpus callosum</a> is not infrequently seen. Enhancement on both CT and MRI is pronounced and usually homogeneous. Even with larger lesions, there is a little mass effect for size and limited surrounding vasogenic oedema. </p><p>Low-grade tumours differ from the more common high-grade primary CNS lymphomas in several ways <sup>1</sup>:</p><ul>
- +<li><p>deep locations and spinal involvement is more common</p></li>
- +<li><p>contrast enhancement is absent, irregular or only mild</p></li>
- +</ul><p>Disseminated meningeal or intraventricular disease is uncommon. It is seen in ~5% (range 1-7%) of cases at presentation and usually in high-grade cases<sup> 8</sup>.</p><h5>CT</h5><ul>
- +<li><p>most primary CNS lymphomas are hyperattenuating (70%) <sup>3</sup></p></li>
- +<li><p>show enhancement</p></li>
- +<li><p>haemorrhage is distinctly uncommon <sup>8</sup></p></li>
- +<li><p>often multiple lesions in patients with HIV/AIDS</p></li>
- +</ul><h5>MRI</h5><p>Reported signal characteristics of primary CNS lymphoma include:</p><ul>
- +<li><p><strong>T1:</strong> typically hypointense to grey matter <sup>9</sup></p></li>
- +<li>
- +<p><strong>T1 C+ (Gd)</strong></p>
- +<ul>
- +<li><p>typical high-grade tumours show intense homogeneous enhancement while low-grade tumours have absent to moderate enhancement <sup>1</sup></p></li>
- +<li><p>peripheral <a href="/articles/cerebral-ring-enhancing-lesions">ring enhancement</a> may be seen in immunocompromised patients (HIV/AIDS)</p></li>
- +<li><p><a href="/articles/notch-sign-primary-cns-lymphoma-1">notch sign</a> <sup>15</sup></p></li>
- +</ul>
- +</li>
- +<li>
- +<p><strong>T2:</strong> variable</p>
- +<ul>
- +<li>
- +<p>majority are iso to hypointense to grey matter</p>
- +<ul>
- +<li><p>isointense: 33% <sup>9</sup></p></li>
- +<li><p>hypointense: 20% <sup>9</sup> - when present this is a helpful distinguishing feature</p></li>
- +</ul>
- +</li>
- +<li><p>hyperintense: 15-47%, more common in tumours with necrosis <sup>1,9</sup></p></li>
- +</ul>
- +</li>
- +<li>
- +<p><strong>DWI/ADC</strong></p>
- +<ul>
- +<li><p>restricted diffusion with ADC values lower than a normal brain, typically between 400 and 600 x 10<sup>-6</sup> mm<sup>2</sup>/s (lower than high-grade gliomas and metastases <sup>8,13</sup>)</p></li>
- +<li><p>a number of studies have suggested that the lower the ADC values of a tumour the poorer the response to a tumour and higher likelihood of recurrence <sup>13</sup></p></li>
- +<li><p>ADC is particularly useful in assessing response to chemotherapy, with increases in ADC values to above those of normal brain predictive of complete response <sup>13</sup></p></li>
- +</ul>
- +</li>
- +<li>
- +<p><strong>MR spectroscopy</strong></p>
- +<ul>
- +<li><p>large choline peak</p></li>
- +<li><p>reversed choline/creatinine ratio</p></li>
- +<li><p>markedly decreased NAA</p></li>
- +<li><p>lactate peak may also be seen <sup>7</sup></p></li>
- +</ul>
- +</li>
- +<li>
- +<p><strong>MR perfusion</strong></p>
- +<ul><li><p>only modest, if any, increase in <a href="/articles/cerebral-blood-volume-cbv">rCBV</a> (much less marked than in high-grade gliomas, where angiogenesis is a prominent feature <sup>11</sup>) </p></li></ul>
- +</li>
- +</ul><h5>Nuclear medicine</h5><h6>Thallium-201<sup> </sup>scintigraphy</h6><ul><li><p>primary CNS lymphoma shows increased uptake</p></li></ul><h6>PET</h6><h6>fluorine-18<sup> </sup>FDG PET</h6><ul><li><p>primary CNS lymphoma shows increased uptake</p></li></ul><h6>carbon-11<sup> </sup>methionine PET</h6><ul><li><p>primary CNS lymphoma shows increased uptake</p></li></ul><h4>Treatment and prognosis</h4><p>Treatment of primary CNS lymphoma is predominantly with steroids (which can dramatically shrink a tumour due to combined anti-oedema and cytotoxic effects) and methotrexate-based chemotherapy <sup>4,13</sup>. Whole-brain irradiation can also be added, particularly in patients with high-grade tumours, or recurrence <sup>4,13</sup>.</p><p>If a tumour is a low grade (uncommon: see above), then the local treatment with surgical resection and radiotherapy may be effective <sup>1</sup> and long-term survival is possible.</p><p>The tumours are often high grade and despite treatment have a poor prognosis. If only surgical resection is performed, then death occurs within a few months. With high dose chemotherapy, the tumour can be significantly reduced in size; however, recurrence is common, with a median survival of around 30 months <sup>1</sup>. Those who are immunocompromised (e.g. HIV positive) have worse outcomes.</p><h4>Differential diagnosis</h4><p>For general imaging appearances on CT and MRI consider:</p><ul>
- +<li><p><a href="/articles/secondary-cns-lymphoma">secondary CNS lymphoma</a>: indistinguishable on imaging, however, it tends to involve more leptomeninges (~2/3 of cases) <sup>8</sup></p></li>
- +<li>
- +<p><a href="/articles/neurotoxoplasmosis">cerebral toxoplasmosis</a>: see <a href="/articles/toxoplasmosis-vs-lymphoma">toxoplasmosis vs lymphoma</a></p>
- +<ul>
- +<li><p>toxoplasmosis does not exhibit subependymal spread</p></li>
- +<li><p>more likely to lie in basal ganglia, corticomedullary junction</p></li>
- +<li><p>CNS lymphoma is thallium/PET avid, whereas toxoplasmosis is not</p></li>
- +</ul>
- +</li>
- +<li>
- +<p><a href="/articles/butterfly-glioma">butterfly glioma/</a><a href="/articles/glioblastoma-idh-wildtype">GBM</a></p>
- +<ul>
- +<li><p>more commonly centrally necrotic</p></li>
- +<li><p>more commonly demonstrates evidence of haemorrhage</p></li>
- +</ul>
- +</li>
- +<li><p><a href="/articles/tumefactive-demyelinating-lesion">tumefactive MS</a>/<a href="/articles/acute-disseminated-encephalomyelitis-adem-1">ADEM</a></p></li>
- +<li>
- +<p><a href="/articles/cerebral-abscess-1">cerebral abscess</a></p>
- +<ul>
- +<li><p>peripheral enhancement of primary CNS lymphoma is thicker <sup>3</sup></p></li>
- +<li><p>central restricted diffusion</p></li>
- +</ul>
- +</li>
- +<li><p><a href="/articles/neurosarcoidosis">neurosarcoidosis</a> <sup>4</sup></p></li>
References changed:
- 17. Pons-Escoda A, Naval-Baudin P, Velasco R, Vidal N, Majós C. Imaging of Lymphomas Involving the CNS: An Update-Review of the Full Spectrum of Disease with an Emphasis on the World Health Organization Classifications of CNS Tumors 2021 and Hematolymphoid Tumors 2022. AJNR Am J Neuroradiol. 2023. <a href="https://doi.org/10.3174/ajnr.a7795">doi:10.3174/ajnr.a7795</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/36822829">Pubmed</a>
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