Primary CNS lymphoma (PCNSL) and metastases to the brain are non-glial malignancies that arise either from immune cells within the CNS or from cancers elsewhere in the body. Each has distinctive pathology, imaging appearance, and treatment approach. Brain metastases are the most common intracranial neoplasm overall — far more common than primary brain tumors. PCNSL has become more common in the era of immunosuppression and is now treatable in many cases. This page covers PCNSL and brain metastasis pathology.

Primary CNS Lymphoma (PCNSL)

Epidemiology

  • Comprises ~3% of primary CNS tumors.
  • Mostly diffuse large B-cell lymphoma (DLBCL) subtype (>95%).
  • Two major populations: immunocompetent older adults (median 60-65) and immunocompromised (HIV/AIDS, transplant, immunosuppressive therapy).
  • HIV-related PCNSL is EBV-positive in essentially 100% of cases.

Pathology

  • Highly cellular tumor of large lymphocytes.
  • Atypical lymphoid cells with large nuclei, prominent nucleoli.
  • Apoptotic bodies and mitoses common.
  • Angiocentric pattern (concentric perivascular lymphoid cuffs).
  • Infiltrating brain parenchyma diffusely.
  • Sometimes geographic necrosis (resembles GBM).
  • Reactive astrogliosis.

Immunohistochemistry

  • CD20 + (B-cell lymphoma); CD3 – (excludes T-cell).
  • CD79a +.
  • PAX5 +.
  • Ki-67 typically > 70% (high proliferation index).
  • MUM1 +, BCL6 +/-, CD10 +/- (typically MUM1+, BCL6+, CD10- — non-germinal center B-cell phenotype).
  • BCL2 + commonly.
  • EBER (Epstein-Barr virus encoded RNA) by in situ hybridization: positive in HIV-PCNSL, negative in immunocompetent PCNSL.

Genetics

  • MYD88 L265P mutation: very common in PCNSL (~60-80%).
  • CD79B mutations: common.
  • NFKB pathway activation.
  • 6q deletions.
  • BCL6 translocations: subset.

Locations

  • Periventricular (deep gray, periventricular white matter).
  • Often crosses midline (corpus callosum involvement).
  • Multifocal in 30-40%.
  • Leptomeningeal involvement in 20-30%.
  • Eye (vitreoretinal lymphoma) in ~20%.

Imaging

  • Hyperdense on CT (highly cellular).
  • Homogeneously enhancing mass (often “fluffy” or “cotton ball” appearance).
  • Restricted diffusion centrally: due to high cellularity (key feature; differentiates from many other tumors).
  • T1 hypointense, T2 iso to slightly hyperintense.
  • Periventricular location.
  • Multifocal common in HIV-PCNSL.

Differential

  • Toxoplasmosis (in HIV): both can be multifocal ring-enhancing.
  • HIV-PCNSL typically: solitary or fewer lesions, periventricular, EBV-positive CSF.
  • Toxoplasmosis typically: multiple ring-enhancing, basal ganglia, restricted diffusion variable.
  • Empirical anti-toxo trial for 2 weeks; lack of response prompts biopsy for PCNSL.

Diagnosis

  • AVOID STEROIDS before biopsy: PCNSL is dramatically steroid-responsive and steroids can obscure the diagnosis. If steroids necessary, biopsy promptly.
  • Stereotactic brain biopsy is standard.
  • CSF cytology + flow cytometry: low sensitivity but specific.
  • Vitreous biopsy if ocular involvement.
  • EBV PCR in CSF: highly sensitive and specific for HIV-PCNSL.
  • MYD88 L265P mutation in CSF: emerging biomarker.

Treatment

  • High-dose methotrexate: backbone of PCNSL chemotherapy.
  • Rituximab (anti-CD20).
  • Cytarabine, thiotepa.
  • Whole brain radiation (avoided in older patients due to leukoencephalopathy; reserved for selected cases).
  • Consolidation with autologous stem cell transplant in eligible patients.
  • Long-term remission achievable in ~30-50% of older immunocompetent PCNSL.
  • For HIV-PCNSL: ART optimization + chemotherapy.
  • BTK inhibitors (ibrutinib): activity in relapsed PCNSL.
  • CAR-T cell therapy in trials.

Brain Metastases

Epidemiology

  • Most common intracranial neoplasm overall.
  • About 20-40% of cancer patients develop brain metastases.
  • Common primary sites: lung (most common), breast, melanoma, renal cell, colorectal.

Patterns by Primary

Primary Frequency Notes
Lung Most common NSCLC > SCLC; often multiple; supratentorial more than infratentorial
Breast Second Often single or limited; HER2+ subtype higher risk
Melanoma Per patient highest rate Often multiple; often hemorrhagic; cortical/subcortical
Renal cell Often hemorrhagic Late metastasis common
Colorectal Less common Often posterior fossa
Other Variable Lymphoma, sarcoma, GI, prostate (rare)

Pathology

  • Well-circumscribed (in contrast to diffuse infiltration of gliomas).
  • Often at gray-white junction (where small vessels lodge emboli).
  • Histology reflects the primary: adenocarcinoma, squamous, neuroendocrine, melanoma cells, sarcoma, etc.
  • IHC panel often needed to identify primary if unknown: TTF1 (lung), CDX2 (GI), GATA3 (breast), PAX8 (thyroid, kidney), HMB45 (melanoma), CD20 (lymphoma), etc.
  • Often necrotic, with surrounding edema.
  • Often multiple.

Hemorrhagic Metastases

Some tumors are particularly prone to hemorrhage: melanoma, renal cell, choriocarcinoma, lung, breast. Hemorrhagic metastasis should raise the question of melanoma or hypervascular tumor.

Imaging

  • Ring-enhancing or solid enhancing mass.
  • Vasogenic edema (often disproportionate to mass size).
  • Often multiple.
  • Gray-white junction predilection.
  • ADC: facilitated diffusion (bright) in necrotic centers — distinguishes from abscess.
  • Hemorrhagic foci in melanoma, RCC, choriocarcinoma.

Treatment

  • Surgery for single accessible lesions: SBRT or whole-brain RT.
  • Stereotactic radiosurgery (SRS) for multiple lesions (up to 10+).
  • Whole brain radiation: less commonly used now due to cognitive toxicity.
  • Systemic therapy: increasingly important. Targeted therapies (BRAF, MEK, EGFR, ALK inhibitors) and immunotherapy (anti-PD1) have transformed outcomes for selected metastases (melanoma, lung NSCLC).
  • BBB penetration variable; some agents have good CNS activity.

Leptomeningeal Metastases (Carcinomatous Meningitis)

  • Cancer cells disseminate through subarachnoid space.
  • Common primaries: lung, breast, melanoma, lymphoma, leukemia.
  • Cranial neuropathies, headache, altered mental status, radiculopathy.
  • CSF: malignant cells on cytology (low sensitivity, often requires multiple LPs).
  • MRI: pia/dural enhancement, nodular leptomeningeal lesions.
  • Treatment: intrathecal chemotherapy (methotrexate, cytarabine), targeted radiation, systemic therapy if BBB-penetrant.
  • Poor prognosis overall.

🔍 Did You Know?

The recognition that steroids dramatically suppress PCNSL but obscure the histologic diagnosis has shaped the diagnostic approach to suspected lymphoma. PCNSL responds so dramatically to corticosteroids that lesions can shrink markedly within days — sometimes to undetectable on imaging — only to recur weeks later. Steroids can also cause the histologic appearance to evolve so that biopsied tissue may not be diagnostic of lymphoma even though the underlying disease is present. The clinical implication is direct: in a patient with a brain lesion that could be PCNSL, biopsy should be performed BEFORE starting steroids if at all possible. Steroids should be withheld unless the patient has signs of mass effect that demand them, in which case biopsy should be expedited. This stands in contrast to most other ring-enhancing brain lesions (toxoplasmosis, abscess, glioblastoma) where steroids do not preclude diagnostic biopsy. The lesson is operationally important: a clinician confronted with a brain lesion and considering empirical steroids should pause to consider whether PCNSL is in the differential. If it is, biopsy first. The 2-3 days of waiting is preferable to a non-diagnostic biopsy after steroids have begun the lymphoma’s transient response. Once the diagnosis is made, treatment with high-dose methotrexate-based regimens has transformed the prognosis of PCNSL from a uniformly fatal disease to one with long-term remission rates of 30-50% in immunocompetent patients.

Pitfalls and Pearls

  • PCNSL: usually diffuse large B-cell lymphoma; angiocentric pattern; CD20+; MYD88 L265P.
  • PCNSL imaging: periventricular, homogeneously enhancing, restricted diffusion centrally.
  • HIV-PCNSL: EBV-positive in 100%; multifocal often; CSF EBV PCR positive.
  • Avoid steroids before PCNSL biopsy.
  • PCNSL treatment: high-dose methotrexate ± rituximab + consolidation.
  • BTK inhibitors: activity in relapsed PCNSL.
  • Brain metastases: most common intracranial neoplasm; gray-white junction; vasogenic edema disproportionate.
  • Most common primaries: lung > breast > melanoma > renal cell > colorectal.
  • Hemorrhagic metastases: melanoma, renal cell, choriocarcinoma, lung, breast.
  • Facilitated diffusion (bright ADC) in center: necrotic tumor (distinguishes from abscess which restricts).
  • SRS for multiple metastases: increasingly used; preserves cognitive function vs WBRT.
  • Targeted therapy + immunotherapy: changing outcomes for melanoma, lung NSCLC metastases.
  • Leptomeningeal carcinomatosis: cranial neuropathies + multi-level radiculopathy + CSF cytology positive.
  • Carcinomatous meningitis from breast, lung, melanoma, lymphoma; poor prognosis.
  • IHC panel: identifies primary if unknown — TTF1, GATA3, PAX8, CDX2, HMB45, etc.

References

  1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.
  2. Hoang-Xuan K, Bessell E, Bromberg J, et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol. 2015;16(7):e322-e332.
  3. Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma. J Clin Oncol. 2008;26(15):2512-2518.
  4. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3). Lancet Oncol. 2017;18(8):1049-1060.
  5. Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL. Current approaches to the management of brain metastases. Nat Rev Clin Oncol. 2020;17(5):279-299.
  6. Houillier C, Soussain C, Ghesquières H, et al. Management and outcome of primary CNS lymphoma in the modern era: an LOC network study. Neurology. 2020;94(10):e1027-e1039.