Lymphoma & related disorders
Extranodal organ specific lymphoma
Primary CNS lymphoma
Authors: Lena Young, D.O., Elizabeth Courville, M.D.
Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Last author update: 8 December 2020
Last staff update: 31 January 2024
Copyright: 2002-2024, PathologyOutlines.com, Inc.
PubMed Search: Primary CNS lymphoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Intraoperative frozen / smear cytology images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Young L, Courville E. Primary CNS lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaprimaryCNSlymphoma.html. Accessed April 19th, 2024.
Definition / general
- Primary central nervous system (CNS) lymphoma occurs first in the brain, eye, spinal cord or leptomeninges, without systemic involvement and not arising in the setting of immunodeficiency
- Majority are high grade diffuse large B cell lymphomas, with only rare cases representing T cell lymphomas, low grade B cell lymphomas or Burkitt lymphoma
- This topic addresses primary diffuse large B cell lymphoma of the CNS and does not include cases that are associated with immunodeficiency (see separate category of immunodeficiency associated lymphoproliferative disorders)
Essential features
- Rare aggressive large B cell lymphoma occurs predominantly in elderly individuals, with an overall worse prognosis than systemic diffuse large B cell lymphoma
- Composed of large, atypical basophilic lymphocytes with perivascular cuffing and frequent necrosis
- Positive for CD45 and B cell markers and typically positive for BCL6, MUM1 and BCL2
- Unlike CNS lymphomas associated with HIV infection, primary CNS lymphoma is not associated with Epstein-Barr virus infection
Terminology
- Previously known as reticulum cell sarcoma, diffuse histiocytic lymphoma or lymphomatosis cerebri (no longer recommended)
- Primary CNS lymphoma is used interchangeably with primary diffuse large B cell lymphoma of the CNS
- Excluded from this category are immunodeficiency associated lymphomas (see separate immunodeficiency associated topic)
ICD coding
Epidemiology
- Accounts for < 1% of all non-Hodgkin lymphoma cases and 2 - 3% of all CNS tumors (Cancer 2017;123:4314)
- Overall incidence rate is < 1 cases per 100,000 population
- Rates among men and women aged 65+ years have increased in recent decades (1992 - 2011), although the reason for the increase is unclear
- Among immunocompetent individuals (HIV uninfected, nontransplant recipients), the median age at diagnosis among a U.S. population is 67 (range 52 - 77 years) with a similar male to female ratio (Br J Haematol 2016;174:417)
Sites
- Majority involve the supratentorial space, with the posterior fossa and spinal cord less frequently involved (Leukemia 2011;25:1797)
- Most patients present with a single tumor but can present with multiple (Isr J Med Sci 1992;28:268)
- 10 - 20% show concurrent intraocular involvement (Cancer 2017;123:4314)
- Extraneural dissemination is very rare but shows a propensity for the testis (J Neurooncol 2006;80:159)
Pathophysiology
- Not definitively understood
- Central nervous system is an immune privileged site and the lymphoma itself may have genetic and phenotypic features that protect the tumor from ongoing immune surveillance (Virchows Arch 2020;476:647)
- Neoplastic cells may arise from lymphocytes normally residing in the immune privileged milieu of the CNS or from lymphocytes that transform to a malignant clone outside the CNS and then home to the CNS and escape normal immune regulation in the immune privileged site (Virchows Arch 2020;476:647, Curr Oncol Rep 2015;17:60)
Etiology
- Unknown in immunocompetent patients
- Viruses, including Epstein-Barr virus, do not play a role
- Rising rates in elderly individuals (HIV uninfected, nontransplant recipients) may be related to increasing use of immunosuppressive medications to treat autoimmune conditions in the elderly (Br J Cancer 2011;105:1414)
Clinical features
- Symptoms vary depending on the CNS site involved and commonly include cognitive or behavioral changes, focal neurologic deficits and symptoms of increased intracranial pressure (Cancer 2017;123:4314)
- Seizures are relatively uncommon and patients typically do not present with B symptoms (fever, night sweats, weight loss)
- Ocular manifestations may present as decreased acuity, blurry vision or floaters (Hematol Oncol Clin North Am 2019;33:597)
Diagnosis
- Contrast enhanced MRI of the brain is the neuroimaging modality of choice for diagnosis; however, the diagnosis must be confirmed by review of sampled tumor tissue or fluid (Br J Haematol 2019;184:348)
- Stereotactic needle biopsy is the gold standard for diagnosis and classification of CNS lymphoma (Neurooncol Pract 2019;6:415)
- Cerebrospinal fluid (CSF) cytology and flow cytometry may be used when biopsy is not possible or to evaluate for leptomeningeal involvement
Radiology description
- On MRI, there is an isointense to hypointense lesion on T1 weighted images with homogenous gadolinium contrast enhancement
- Lesions are usually solitary, involving the deep white matter and periventricular in location
- In immunocompetent individuals, the lesions typically do not show hemorrhage, calcifications, necrosis or ring enhancement (Hematol Oncol Clin North Am 2019;33:597)
Radiology images
Images hosted on other servers:
Brain MRI with contrast enhancing lesion
Solid and enhancing nodules on MRI
Prognostic factors
- Overall poor prognosis with considerably worse prognosis than systemic diffuse large B cell lymphoma
- Age and performance status are the most important prognostic factors
- In the Memorial Sloan Kettering Cancer Center prognostic model, only age and performance status were independent prognostic factors
- The prognostic model from the International Extranodal Lymphoma Study Group includes age and performance status as well as serum lactate dehydrogenase level, CSF protein concentration and involvement of deep structures of the brain (Cancer 2017;123:4314)
- In patients treated with methotrexate based regimens, BCL6 expression may be a predictor of improved progression free survival (Br J Haematol 2014;165:640)
Case reports
- 25 year old man with 1 week history of severe headaches and changes in vision (Can J Ophthalmol 2019;54:e134)
- 54 year old woman with symptoms of numbness and weakness in the right leg (BMC Neurol 2019;19:90)
- 71 year old man presented with cerebellar symptoms (dizziness, nausea, vomiting and gait imbalance) (J Med Case Rep 2018;12:341)
- 75 year old woman presented with subacute progressive confusion and unusual behavior (Neurooncol Pract 2017;4:46)
- 3 patients presenting with primary CNS diffuse large B cell lymphoma with anaplastic morphology (Diagn Pathol 2019;14:45)
Treatment
- High dose intravenous methotrexate based regimen is the first line induction therapy
- Consolidation therapy may include conventional chemotherapy, radiotherapy, high dose chemotherapy with autologous stem cell transplantation or their combinations (Transl Oncol 2019;12:523)
Gross description
- From postmortem examination, tumors have a variable macroscopic appearance, including variable demarcation from the surrounding parenchyma
- Lesions may be firm, homogenous, centrally necrotic, brownish, gray-tan or yellow with areas of hemorrhage (Clin Neuropathol 2008;27:13)
Gross images
Images hosted on other servers:
Cerebral lymphoma
spreading across
the corpus callosum
Frozen section description
- Histologic features seen on frozen section are similar to those seen on permanent
- Intraoperative cytology is an important component of intraoperative evaluation (Neuropathology 2016;36:313)
Intraoperative frozen / smear cytology images
Contributed by Genevieve M. Crane, M.D., Ph.D. and Lena Young, D.O.
Squash preparation
Frozen section
Frozen section control
Touch prep of
monomorphic
basophilic cells with
crush artifact
Touch prep
Intraoperative squash preparation
Microscopic (histologic) description
- Characteristic angiocentric growth pattern with cuffs of neoplastic lymphocytes within and around blood vessels (Clin Neuropathol 2008;27:13)
- Diffuse infiltration of brain parenchyma by small clusters or individual cells; necrosis is common
- Accompanied by astrocytic and microglial activation and may be accompanied by a reactive inflammatory infiltrate
- Neoplastic B cells are intermediate to large and frequently have vesicular chromatin and prominent nucleoli
- Corticosteroid administration prior to biopsy may induce dramatic tumor shrinkage with increased macrophages and cellular debris
Microscopic (histologic) images
Contributed by Elizabeth Courville, M.D. and Lena Young, D.O.
Perivascular infiltrate of atypical lymphoid cells
Diffuse infiltrate
of intermediate
to large
mononuclear cells
Cytology of mononuclear cells
Perivascular cuffing by neoplastic lymphocytes
Infiltrate of neoplastic intermediate to large lymphocytes with background inflammation and necrosis
Pleomorphic lymphocytes infiltrating brain
Immunohisto-
chemistry for B and T cells
ISH shows lambda restriction
Cytology description
- Neoplastic lymphocytes in the cerebrospinal fluid are dispersed cells, increased in size compared to background reactive lymphocytes and frequently show irregular nuclear contours, abnormal chromatin and prominent nucleoli
- Mostly discohesive groups of monomorphic, medium to large basophilic lymphoid cells with prominent smearing artifact and background reactive glial cells
- Touch preparations show discohesive, large, atypical basophilic cells with a high nucleus to cytoplasm ratio and open chromatin with immature (lymphoblast) features; in post treatment tumors, only necrotic cells or reactive T cells may remain
- Reference: Asian J Neurosurg 2013;8:195
Positive stains
- PAX5, CD19, CD20, CD22, CD79a (B cell markers)
- BCL6 (60 - 80%)
- MUM1 / IRF4 (90%) (Cibas: Cytology: Diagnostic Principles and Clinical Correlates, 2nd Edition, 2003)
- BCL2 (90%)
- MYC (92%) (Acta Neuropathol 2013;126:603)
Negative stains
- CD38, CD138 (plasma cell markers)
- CD10 (< 10% are positive); CD10 positivity is seen more commonly in systemic diffuse large B cell lymphoma so should prompt careful search for systemic disease (Hematol Oncol 2014;32:57)
- EBV positivity suggests underlying immunodeficiency
- Pertinent negative stains include CD30, ALK1, HHV8, as they are helpful in the evaluation of mimicker neoplasms including systemic large B cell lymphoma, anaplastic large cell lymphoma and HHV8 associated lymphoproliferative disorders respectively
Flow cytometry description
- Specimen is not always sent for flow cytometry from stereotactic needle core biopsies due to limited material; flow cytometry of cerebrospinal fluid can aid in the diagnosis when needle core biopsy is not possible or to evaluate for leptomeningeal involvement
- Flow cytometric immunophenotyping can identify abnormal B cell populations showing light chain restriction
- References: J Exp Clin Cancer Res 2016;35:128, Cytometry B Clin Cytom 2018;94:928
Molecular / cytogenetics description
- MYC or BCL2 gene rearrangements are rare; BCL6 gene rearrangements are frequent (Blood Adv 2019;3:3953)
- Oncogenic gain of function mutations in MYD88 (MYD88 L265P) are frequent (Blood 2016;127:869)
Sample pathology report
- Brain, biopsy:
- Diffuse large B cell lymphoma (see comment)
- Comment: In the absence of systemic disease, the morphologic and immunophenotypic findings are consistent with a diagnosis of primary diffuse large B cell lymphoma of the central nervous system. Clinical correlation is required, such as excluding an immunodeficiency associated lymphoproliferative disorder.
Differential diagnosis
- Systemic malignant lymphoma (diffuse large B cell lymphoma or other) involving the CNS:
- CD10 expression by the lymphoma should strongly raise the possibility
- Prior history and clinical workup is required to exclude systemic lymphoma involving the CNS
- Lymphoma associated with HIV infection:
- EBV positivity suggests this
- Clinical workup is required
- Posttransplant lymphoproliferative disorder (PTLD):
- EBV positive
- History of immunosuppression after allograft
- High grade glioma:
- Lacks the diffuse monomorphic lymphocyte infiltrate, neuronal morphology and IHC staining
- CD45 negative
- Infection including toxoplasma or cerebral abscess:
- Occasionally multiloculate enhancement, generally encapsulated
- Suppurative with mixed acute and chronic inflammation
- Metastatic melanoma or carcinoma:
- Demyelinating lesions:
- May not enhance on imaging
- Generally demarcated
- Histiocytic as opposed to lymphoid infiltrate
- Cerebral infarct:
- Ischemic, "red dead" neurons
- Slight to no lymphoid infiltrate
- Histiocytes predominate
Additional references
Board review style question #1
A 73 year old woman presents with progressive confusion and lethargy. Imaging shows a solitary lesion in the parietal lobe. A brain biopsy is performed and intraoperative touch preparations show discohesive, monomorphic, basophilic cells with crush artifact. Permanent sections show perivascular cuffing by intermediate to large mononuclear cells with scant cytoplasm, vesicular chromatin and prominent nucleoli. By immunohistochemical stains, the mononuclear cells are positive for CD20, BCL6 and MUM1 and negative for CD10 and EBV. What is the most likely diagnosis?
- Glioblastoma multiforme (GBM)
- Metastatic melanoma
- Metastatic neuroendocrine carcinoma
- Primary central nervous system lymphoma
Board review style answer #1
D. Primary central nervous system lymphoma. Based on the provided description, primary CNS lymphoma is the most likely diagnosis. This entity stains with B cells markers and is typically positive for MUM1 and negative for CD10. The entity primary CNS lymphoma excludes lymphomas associated with HIV infection or lymphomas arising after transplant. In contrast to the CNS lymphomas in those clinical scenarios, primary CNS lymphoma is almost always EBV negative.
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Reference: Primary CNS lymphoma
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Board review style question #2
Which of the following immunohistochemical stains is typically negative in the neoplastic lymphocytes in primary central nervous system (CNS) lymphoma?
- BCL6
- CD10
- CD20
- IRF4 / MUM1
Board review style answer #2
B. CD10. Less than 10% of cases of primary CNS lymphoma are positive for CD10. CD10 positivity is seen more commonly in systemic diffuse large B cell lymphoma so should prompt careful search for systemic disease. The other stains listed are typically positive in primary CNS lymphoma.
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Reference: Primary CNS lymphoma
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