This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 75-year-old woman with a history of hypertension presented with approximately five weeks of progressive dysarthria, gait instability, left facial weakness, and fatigue. MRI of the brain showed several enhancing lesions throughout the right frontal and parietal lobes with associated surrounding T2/FLAIR signal abnormality and moderate mass effect. A biopsy was performed.
Brain, right parietal lobe
Whole Slide Image
The whole slide image provided is an H&E of stereotactic biopsy, right parietal lobe lesion.
What is the most likely diagnosis?
CNS embryonal neoplasm
Metastatic small cell carcinoma
Primary CNS lymphoma
Progressive multifocal leukoencephalopathy (PML)
What IHC stain is most likely to be diffusely positive and confirm the diagnosis?
Which of the following markers is almost always absent in this entity and, if positive, should prompt an investigation for a systemic primary?
Discussion and Diagnosis
Primary lymphoma of the central nervous system (PCNSL) is an extranodal malignant lymphoid neoplasm arising in the CNS in the absence of systemic lymphoma at the time of diagnosis. Historically, it was first described as “perithelial sarcoma” and then known by other names such as “microglioma.” Subsequent identification of similarities with non-Hodgkin lymphomas led to its identification as a malignancy of lymphoid origin. Classifications have changed over time, but in broad terms according to the latest WHO classification, there are two categories of CNS lymphoma: primary diffuse large B-cell lymphoma (DLBCL) of the CNS, which is the most common, and others, including immunodeficiency-associated lymphomas and rare entities such as intravascular large B-cell lymphoma.
Many cases of immunodeficiency-associated lymphomas involving the CNS were identified in the immunosuppressed population during the AIDS epidemic, but after widespread use of effective antiretroviral therapy most cases are now seen in immunocompetent patients. While immunodeficiency-associated lymphoma is largely driven by the Epstein-Barr virus (EBV), there is no known etiology in the immunocompetent population. Overall, PCNSL represents ~3% of all brain neoplasms and <1% of all non-Hodgkin lymphomas. An increased incidence in both the immunosuppressed and the immunocompetent groups has been documented in the past two decades, with the greatest increase noticed in immunocompetent adults over 65 years of age. The male to female ratio is 3:2.
The cerebral hemispheres (frontal, temporal, and parietal lobes) are the most common sites of involvement, with the basal ganglia, ventricular system, and corpus callosum being frequently involved. The most common presenting symptoms include focal neurological signs, neuropsychiatric deficits, signs of increased intracranial pressure, seizures, and ocular symptoms. Multifocal involvement is common (30% to 40%), and leptomeningeal spread can occur. Ocular extension may be seen in up to 20% of cases.
The typical appearance on MRI is that of T1-hypointense homogeneously enhancing lesion(s) (Image A) with associated edema (although with relatively limited mass effect when compared to other primary tumors such as high-grade gliomas). Lymphomatosis cerebri describes an extensive infiltrative involvement of the brain parenchyma, while neurolymphomatosis refers to the infiltration of peripheral nerves, spinal roots, or cranial nerves. Imaging of the chest, abdomen, and pelvis and examination of the testicles in elderly men are necessary to rule out the possibility of a systemic lymphoma secondarily involving the CNS. Additionally, CSF analysis and eye examination may be indicated. Pleocytosis is common, although cytological examination of CSF only results in a definitive diagnosis in up to one-third of cases. Ancillary studies such as flow cytometry and PCR testing for IgH rearrangement analysis can provide evidence of a clonal population, however the utility of these tests is determined by the number of cells available in the sample, and the possibility of pseudoclonality in a low-cellularity specimen should always be considered.
The typical histological appearance in this case is that of a diffuse large B-cell lymphoma, with sheets of large neoplastic cells with scant cytoplasm and frequent prominent nucleoli (Image B), occasionally involving the cerebral parenchyma in an “infiltrating” single cell fashion. Abundant mitoses and apoptotic bodies are frequently found, and geographic necrosis can be seen (Image C), particularly in EBV-driven cases. An angiocentric architecture with tumor cells found within concentric layers of reticulin fibers is characteristic (Image D), although not uniquely specific. This pattern can be seen in nonneoplastic inflammatory processes, as well. The large atypical neoplastic cells are usually associated with variable numbers of reactive small mature lymphocytes and macrophages. The diagnosis may be challenging after the patient has been exposed to steroids, since the tumor cells are exquisitely vulnerable to these drugs, and their numbers may be largely reduced, being replaced by frequent foamy macrophages and reactive lymphocytes.
By IHC, the neoplastic cells are positive for B-cell markers such as CD19, CD20 (Image E), PAX5, and CD79a. A known pitfall, however, is that CD20 may be nonreactive following anti-CD20 therapies, such as rituximab. PCNSL tumor cells are positive for MUM1 in most cases (Image F). CD3 and CD5 frequently highlight numerous reactive mature T-cells (Image G), while CD68 and CD163 may highlight variable numbers of macrophages and microglia. In most cases of PCNSL, tumor cells demonstrate a nongerminal center B-cell-like phenotype with positive BCL6 and lack of CD10 immunoreactivity, as per the Hans algorithm. The presence of CD10 positivity indicates a germinal center B-cell-like classification and should raise the possibility of secondary involvement of the CNS by a systemic diffuse large B-cell lymphoma rather than PCNSL. The Ki-67 proliferation index is usually greater than 70% (Image H). The utility of flow cytometry in biopsy material can be limited given the abundance of reactive lymphocytes frequently present in the sample. As such, small biopsies should be prioritized for IHC.
Several signaling pathways may be altered in the pathogenesis of PCNSL. In the B-cell receptor pathway, translocations involving the immunoglobulin genes (IG) and BCL6 are described in some cases, while MYC translocations are rare, and BCL2 translocations are absent. PCNSLs that express higher levels of MYC and BCL2 by IHC are referred to as “double-expressor” lymphomas and carry a poor prognosis; such cases should undergo molecular testing for MYC/BCL2/BCL6 rearrangements in order to identify “double-hit” lymphomas. Hypermethylation of DAPK1, CDKN2A, and MGMT may lead to loss of expression of these proteins. The MYD88 L265P mutation, involved in nuclear factor-kappa-beta signaling, is highly recurrent and present in more than half of cases.
An essential consideration at the time of intraoperative consultation is the differentiation between lymphoma and high-grade glioma as the surgical approach is entirely different: a diagnostic biopsy is sufficient in the management of lymphoma, while a resection is usually indicated for high-grade glioma. Intraoperative smear preparations may show relatively scant-to-numerous atypical lymphoid cells in a background of mature lymphocytes, sometimes with associated macrophages, lymphoglandular bodies, and necrotic debris. Abundant apoptotic bodies are more frequently seen in lymphoma than in high-grade glioma.
On permanent sections, when lymphoma cells are scant, the differential diagnosis includes inflammatory lesions such as vasculitis, as reactive lymphocytes and a perivascular distribution are seen in both. If there has been exposure to steroids prebiopsy, the sample may lack viable tumor cells. CD20 immunostain may highlight nonviable tumor cells if they are present, but in some cases the diagnosis may prove impossible in this scenario. Metastatic disease and other primaries such as embryonal tumors can be differentiated morphologically or by IHC when necessary. Other lymphomas involving the CNS can be discerned with specific IHC or in situ hybridization, such as EBER for EBV+ immunodeficiency-related lymphoma and lymphomatoid granulomatosis, or T-cell markers for NK/T-cell lymphomas.
Survival in PCNSL is limited if left untreated; with the best treatment, median progression-free survival is about 12 months, and overall survival is approximately three years. High-dose methotrexate-based chemotherapy is the current standard therapy, and whole brain irradiation may contribute to increased survival, although its use is limited due to the risk of neurotoxicity.
Prognostic factors are not well established, but age and Karnofsky performance status (KPS) are used to stratify patients into three risk groups, from lowest to highest: <50 years old; >50 years old with KPS >70; and >50 years with KPS <70. Age >65 years is associated with an increased risk of iatrogenic neurotoxicity in addition to worse expected survival. In some studies, the presence of reactive perivascular CD3-positive T-cells has been associated with improved survival.
Take Home Points
- Primary diffuse large B-cell lymphoma of the CNS is a rare but distinct entity that occurs in immunocompetent adult patients.
- Tumor cells in most cases are positive for CD20, MUM1, and BCL6, and are negative for CD10 and EBV. PCNSLs that overexpress MYC and BCL2 are referred to as “double-expressor” lymphomas while those that demonstrate MYC/BCL2 and/or BCL6 rearrangements are labeled as “double-hit” lymphomas.
- Prognosis is grim if left untreated; high-dose methotrexate-based chemotherapy with or without radiation therapy is the standard treatment approach.
- Effort should be made to identify lymphoma during intraoperative consultation since surgical resection is typically not indicated.
- Steroid use should be avoided prior to biopsy since tumor response may severely limit the ability to make this diagnosis histologically.
- Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System, Rev 4th ed. Lyon, France: International Agency for Research on Cancer; 2016.
- Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed, Volume 2. Lyon, France: International Agency for Research on Cancer; 2017.
- Paulus W, Perry A. Lymphomas and histiocytic tumors. In: Perry A, Brat D, eds. Practical Surgical Neuropathology: A Diagnostic Approach. 2nd ed. Philadelphia, PA; 2018.
- What is the most likely diagnosis?
- A. CNS embryonal neoplasm
- B. CNS vasculitis
- C. Metastatic small cell carcinoma
- D. Primary CNS lymphoma
- E. Progressive multifocal leukoencephalopathy (PML)
- What IHC stain is most likely to be diffusely positive and confirm the diagnosis?
- A. CD3
- B. Cytokeratin
- C. CD20
- D. SV40
- E. Synaptophysin
- Which of the following markers is almost always absent in this entity and, if positive, should prompt an investigation for a systemic primary?
- A. CD3
- B. CD10
- C. CD20
- D. CD68
- E. CD163