Intracranial lymphomas

Intracranial lymphomas represent all malignant intracranial lymphoid proliferations, whether primary or secondary. They are rare and generally have a very poor prognosis even with treatment.

General information regarding malignant lymphomas is covered in another chapter.

Primary Cerebral Lymphomas (PCL)

These are Non-Hodgkin lymphomas (NHL) that develop in the brain, meninges, and/or eye without any other localization. They represent 1% of NHL and 5% of brain tumors. Incidence is ~3-5/million people/year in the USA. The median age of occurrence in immunocompetent individuals is 50-60 years.

Risk factors: immunosuppression (relative risk x10, causing the death of nearly 10% of HIV+ patients... however, the majority of PCL patients are immunocompetent).

There are exceptional primary leptomeningeal and medullary forms.

Clinical presentation

Neurological symptoms

They are polymorphic and nonspecific:

• Signs of diffuse brain damage, often the main presenting feature: confusion, ideomotor slowing, signs of intracranial hypertension (ICH)
• Focal deficits (present in 50% of cases initially)
• Seizures are rarer than in other tumors (10% of cases)
• Various: diabetes insipidus, panhypopituitarism (more frequent than in other tumors)

Ocular manifestations (uveitis, hyalitis)

Associated with brain involvement in 10-20% of cases. Half of these cases are asymptomatic. 10% of ocular involvement precedes brain involvement by months to years, and the discovery of isolated ocular lymphoma predicts the development of cerebral lymphoma in ~80% of cases in the following years !

Additional tests: diagnosis and staging

Imaging, though often suggestive, is not specific enough to confirm the diagnosis. Definitive diagnosis is obtained through histology and immunohistochemistry (lumbar puncture [or vitreous puncture] or biopsy if lumbar puncture is negative). Corticosteroids should be avoided as much as possible before diagnostic sampling (they reduce target lesions and make pathology harder to interpret).

Brain CT scan

• Non-contrast CT → hyperdense lesions ++, sometimes iso- or hypodense
• Contrast-enhanced CT → contrast uptake

Brain MRI

• Non-contrast MRI: ++ iso-signal in T1 and iso- or hypo-signal in T2
• Contrast-enhanced MRI → intense and homogeneous gadolinium uptake ("snowball", cotton-like appearance), generally solitary (70%) except in immunosuppressed individuals where lesions are often large and multiple
• Diffusion restriction (hypercellularity) ++: increased DWI, decreased ADC

Lesions are generally located in deep regions (gray matter, corpus callosum, periventricular white matter, subependymal, intraventricular areas suggesting ventriculitis). Edema and mass effect are usually minimal compared to lesion size.

Atypical presentations are unfortunately common : superficial localization with dural extension (differential diagnosis = meningioma) in 5-10% of cases, diffuse infiltration with multiple areas of T2 hypersignal without mass effect or contrast uptake (up to 10% of cases ?, diagnosis = gliomatosis, multiple sclerosis, neurosarcoidosis, cerebral vasculitis, progressive multifocal leukoencephalopathy, post-infectious leukoencephalitis), exceptional pseudo-abscess forms with peri-annular contrast uptake (but found in ~50% of PCL in immunosuppressed patients → in such a radiological pattern, always search for an immunosuppression cause).

Laboratory tests

Routine: complete blood count (systemic lymphoma ?), CRP-ESR, HIV serology

Lumbar puncture (classic + pathology + lymphocyte immunophenotyping / monoclonality search by PCR, EBV DNA search)

The presence of lymphoma cells confirms the diagnosis in 10-30% of cases.

Other nonspecific CSF abnormalities are common : elevated protein levels, pleocytosis, increased LDH and β-2-microglobulin,… Cytology can sometimes suggest chronic meningitis (Lyme disease,…) as a differential diagnosis.

Fundus examination (FO) and slit lamp exam +- vitreous puncture

The presence of hyalitis necessitates vitrectomy in case of negative lumbar puncture → confirms diagnosis in 50% of cases.

Brain biopsy

Necessary only if lumbar puncture (or vitrectomy) does not confirm the diagnosis. ++ via stereotactic biopsy.

Staging

Given the rarity of systemic lymphoma revelation by PCL (4% of cases), the indication for a full staging workup (bone marrow biopsy, thoraco-abdomino-pelvic CT scan, testicular ultrasound, whole-body PET-CT) is debated… however, chemotherapy for systemic lymphomas is different… this should be discussed.

Pathology

The vast majority of cases are diffuse large B-cell lymphomas (>80%). T-cell lymphomas represent <2% of cases. Other types are exceptional: anaplastic large cell lymphoma, lymphocytic lymphoma, etc. A histological study with paraffin embedding is necessary to confirm the diagnosis and classification.

PCL in HIV+ patients is characterized by immunoblastic predominance, large areas of necrosis, and EBV presence.

Etiopathogenesis

The central nervous system is not an "immune sanctuary" as often described but a specialized site of immune response (absence of lymphatic vessels and antigen-presenting cells, presence of the blood-meningeal barrier) with surveillance primarily carried out by T lymphocytes… and rare B lymphocytes... yet B-cell PCLs predominate → Why? Two hypotheses:

• Malignant transformation of pre-existing chronic or dysimmune brain inflammation?
• Extracerebral B-cell transformation followed by secondary migration via a particular marker?

The role of different pathogens has been suggested. However, only the association of EBV (almost 100%) with PCL in HIV+ patients has been demonstrated.

Various genetic abnormalities (inactivation of the tumor suppressor p16/ CDKNA2) have been identified, but none specific to PCL.

Prognosis

Median survival is 2 to 5 years with a 5-year survival rate of 20-30% with optimal treatment. If remission is achieved, recurrence, sometimes more than 5 years later, is common.

Poor prognostic factors include: age >60 years, poor Karnofsky score, immunosuppression (median survival of 3-5 months with optimal treatment). Discussed factors: serum LDH, CSF protein levels, multiple deep localizations. Histology does not appear to be related to prognosis.

Therapeutic management - Treatments

Surgery is useless. Initial treatment is now based on the combination of radiotherapy and chemotherapy. Chemotherapy alone as initial treatment is an alternative, especially for elderly patients, currently under evaluation. Associated or isolated ocular lymphoma should receive the same treatment. Corticosteroids may be useful in catastrophic situations while waiting for definitive treatment (but preferably after sampling, as the symptomatic and radiological effect is often spectacular but rebound effect +++).

Chemotherapy

• Corticosteroids: cytolytic activity on lymphoma cells→ rapid response (a few hours to a few days) in 40% of cases (complete in 10%) with spectacular clinical improvement, but transient (response typically lasting a few weeks).
• Methotrexate (> 1 g/m²) and/or Ara-C via systemic or intrathecal routes
  • Intrathecal chemotherapy via lumbar or ventricular route (++ via intraventricular injection through Ommaya reservoir)
    • Discussed efficacy! Especially since doses > 3 g/m² IV methotrexate can achieve sufficient concentrations in the CSF
• Other drugs used: vincristine, carmustine, ardamycin, cyclophosphamide, teniposide,…
• Most teams recommend high-dose methotrexate alone (no radiotherapy) as initial treatment for patients > 60 years → comparable survival to combined treatment but better quality of life and relative preservation of cognitive function !
• Intra-arterial chemotherapy after osmotic disruption of the blood-brain barrier or chemotherapy intensification associated with peripheral stem cell transplantation remains within the scope of research protocols.

Whole-brain radiotherapy

If used alone → total dose of 40-50 Gy in daily fractions of 1.8 to 2 Gy. Additional irradiation of the lesion or spinal cord is not recommended.

Combination of radiotherapy and chemotherapy

Remains the standard treatment : chemotherapy followed by radiotherapy. Ex : methotrexate 3g/m² IV followed by whole-brain radiotherapy of 40 Gy with second-line chemotherapy : carmustine, teniposide, intrathecal Ara-C,…

The main risk is the development of delayed iatrogenic leukoencephalopathy (→ severe subcortical dementia), particularly in patients > 60 years old (50% at 1 year after radiotherapy, 100% at 2 years).

Specifics of immunocompromised patients

PCLs usually occur at severe stages of immunodepression → radiotherapy alone is the treatment of choice (risk of worsening immunodepression with chemotherapy). However, chemotherapy may be considered for the rare patients with satisfactory immune status (ex : CD4 > 200/ mm³ for HIV+), offering the hope of prolonged survival for a few years.

Primary Dural Lymphomas

These involve localized infiltration of the dura mater by a monomorphic lymphoid proliferation of small "centrocyte-like" lymphocytes associated with variable intensity plasmacytic differentiation. They are rare (< 20 cases in the literature). Typically small B-cell lymphomas. Predominantly female patients. Commonly revealed by epileptic seizures. Radiologically resemble a meningioma. Most cases have been treated with surgery and radiotherapy. Given the small number of reported cases, the prognosis appears better than that of PCL.

Secondary Cerebral Lymphomas

Systemic NHLs are complicated by cerebral involvement in < 10% of cases, typically in late stages. Thus, it is rare for cerebral involvement to be the initial clinical manifestation. They are classically associated with testicular and/or bone marrow involvement.

The clinical and radiological presentation is similar to that of PCL. Median survival is ~5 months, reflecting the generally advanced stage of the underlying pathology.

Intravascular Lymphomas

These are rare. They are malignant NHLs characterized by lymphocytic proliferation within the lumen of small vessels, causing their dilation and/or occlusion. Tumor lymphoid cells are large and of B phenotype (CD20+, CD79a+).

It is a multisystem disease with a preference for the nervous system and skin, although in most cases, the clinical presentation is purely neurological (mainly ischemic in origin : subacute to progressive encephalopathy or dementia, sometimes interrupted by ischemic strokes. Rarely : hemorrhages, progressive or acute myelopathy, seizures). Skin manifestations can be highly variable.

MRI is nonspecific (hypointense areas on T1 and hyperintense on T2, predominantly periventricular, which may enhance with contrast or mimic strokes). Cerebral angiography is usually normal. FDG-PET can show hypermetabolic areas. Blood tests may reveal an inflammatory syndrome or increased LDH.

Median survival is ~ 6 months. No standardized treatment exists. Definitive diagnosis relies on skin or brain biopsy... procedures that, given the poor prognosis, should only be considered if there is diagnostic uncertainty with a treatable condition.

Bibliography

EMC, traité de neurologie, Elsevier, 2018

Jameson JL et al., Harrison's Principles of Internal Medicine, 20th edition, McGraw Hill Higher Education, 2018