INTRODUCTION — Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin lymphoma (NHL) restricted to the brain, spinal cord, cerebrospinal fluid (CSF), and/or eyes. PCNSL is a rare but well-described central nervous system (CNS) malignancy with distinct treatment and prognostic implications compared with other brain tumors [1-5]. Diagnosis typically requires brain biopsy to confirm the pathologic diagnosis and exclude radiographic mimics.
This topic will review the epidemiology, pathology, clinical features, and diagnosis of PCNSL. Related topics on treatment as well as other forms of lymphoma involving the nervous system are presented separately.
EPIDEMIOLOGY — PCNSL is a rare primary brain cancer accounting for 2 percent of all brain tumors and 4 to 6 percent of non-Hodgkin lymphomas (NHLs). The estimated incidence rate is 0.45 per 100,000 population . Approximately 1700 new cases are diagnosed in the United States every year.
The incidence of PCNSL has changed over time. Beginning in the 1980s, the incidence of PCNSL began to rise due to cases associated with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) . Since the 1990s, the contribution of HIV-associated cases has dropped, while the incidence in people >60 years of age has been rising. The incidence of PCNSL in the United States peaks at 4.32 per 100,000 population in the 70- to 79-years age group . The reason for this increase is unclear.
RISK FACTORS — PCNSL is largely a disease of adults, and the risk rises with advancing age. The median age at diagnosis is 67 years, and there is a slight male predominance.
Immunosuppression is the most important risk factor for PCNSL aside from age. PCNSL is seen with increased frequency in the following groups, often but not always in association with Epstein-Barr virus (EBV) proliferation [8-11]:
●Individuals with HIV/AIDS. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
●Organ transplant recipients. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
●Patients with autoimmune disorders such as systemic lupus erythematosus, polyarteritis nodosa, autoimmune hepatitis, myasthenia gravis, and uveitis . This is likely related to the immunosuppressive agents used for treatment, although there may be other shared risk factors in these patients. (See "Malignancy and rheumatic disorders".)
PATHOLOGY AND PATHOGENESIS — Approximately 90 percent of PCNSL cases are diffuse large B cell lymphoma (DLBCL). The remaining 10 percent of cases are made up of T cell lymphomas, low-grade lymphomas, and Burkitt lymphomas .
●Histopathology – Microscopically, primary central nervous system (CNS) DLBCL is composed of malignant B cells clustered in the perivascular space, with reactive lymphocytes, macrophages, and activated microglial cells intermixed with the tumor cells [13,14]. Tumor cells express pan-B cell markers, including CD19, CD20, CD22, and CD79a . PCNSLs typically have high proliferative activity, with a Ki67 index of 70 to 90 percent.
●Molecular subclass – Gene expression profiling of DLBCL distinguishes three molecular subclasses: germinal center B cell-like (GCB) lymphoma, activated B cell-like (ABC) lymphoma, and type 3 large B cell lymphoma. Among these, ABC lymphoma is associated with worse prognosis. In PCNSL, the ABC subclass accounts for more than 80 percent of cases [16,17]. This is higher than what is seen in systemic DLBCL and may partially account for the relatively inferior prognosis of PCNSL compared with other forms of DLBCL.
●Genomic landscape – The genomic landscape of PCNSL is complex, and studies are hindered by the rarity of the disorder and the small size of tissue samples obtained by stereotactic biopsy. Alterations consistent with activation of the B cell receptor, toll-like receptor, and nuclear factor-κB pathways are observed in >90 percent of cases.
Commonly observed recurring alterations include MYD88 and CD79B mutations, inactivation of cyclin-dependent kinase inhibitor 2A (CDKN2A), chromosomal translocations of the BCL6 gene, deletions in 6q, and aberrant somatic hypermutation in proto-oncogenes, including MYC and paired box 5 (PAX5) [18-21]. Less frequent alterations include mutations in caspase recruitment domain family member 11 (CARD11), TNF alpha-induced protein 3 (TNFAIP3), PIM1, BTG2, PR/SET domain 1 (PRDM1), thymocyte selection-associated high-mobility group box (TOX), and interferon regulatory factor 4 (IRF4).
Rare cases in adolescents and young adults with PCNSL may have a largely distinct genetic landscape, often lacking MYD88 mutations and enriched in others, including tumor protein p53 (TP53), NFKB inhibitor epsilon (NFKBIE), and G protein subunit alpha 13 (GNA13) .
●Molecular pathogenesis – The molecular mechanisms underlying transformation and localization to the CNS are poorly understood [23,24]. One hypothesis is that PCNSL is secondary to antigen-dependent activation of circulating B cells, which subsequently localize to the CNS by expression of various adhesion- and extracellular matrix-related genes. Gene expression profiles of PCNSL have shown differential expression of genes related to adhesion and the extracellular matrix pathways, including IRF4, CXCL13, and CHI3L1. Somatic hypermutation has also been observed, with biased use of heavy chain variable (VH) gene segments suggestive of antigen-dependent proliferation.
Clinical presentation — PCNSL is an aggressive neoplasm. Most patients present with acute to subacute neurologic symptoms progressing over the course of days to weeks. The median time from symptom onset to diagnosis is approximately 30 days . The nature of the symptoms depends on the location and overall burden of disease within the central nervous system (CNS). (See 'Sites of involvement' below.)
More insidious presentations are rare. However, clinicians should be aware that empiric therapy with glucocorticoids can alter the natural history of PCNSL and result in more protracted presentations . This is especially common in vitreoretinal lymphoma, which may be mistaken for uveitis and treated with glucocorticoids on and off for months or even years before the disease declares itself. (See 'Eyes' below.)
Constitutional or "B" symptoms (eg, fever, weight loss, and night sweats) are uncommon in patients with PCNSL, in contrast to patients presenting with systemic non-Hodgkin lymphoma (NHL). (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Clinical presentation'.)
Sites of involvement — Brain is the most common site of involvement (>80 percent of cases), either alone or with evidence of concurrent eye and/or cerebrospinal fluid (CSF) disease [7,27]. Isolated vitreoretinal, leptomeningeal, and spinal cord presentations can occur but are much less common.
Involvement of the peripheral nerves (neurolymphomatosis) is usually a manifestation of secondary CNS lymphoma, although rare cases without systemic involvement have been described. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Neurolymphomatosis'.)
Brain parenchyma — In large series of patients, the most common presenting symptoms of brain involvement are [25,28]:
●Focal neurologic deficits, such as motor weakness and language disturbance (70 percent)
●Gait abnormality (60 percent)
●Mental status changes, including confusion, cognitive and behavioral changes, and impaired level of consciousness (40 to 60 percent)
●Signs and symptoms of raised intracranial pressure such as nausea, vomiting, headaches, and visual changes (25 to 33 percent)
Seizures are reported in 10 to 15 percent of patients at presentation, a relatively low percentage that may be explained by the deep location of most lesions.
PCNSL can present as a solitary brain lesion or as multifocal disease. A single mass lesion is seen in just over one-half of cases, whereas multifocal disease is seen in 35 to 45 percent. Forty to 80 percent of lesions are located in the cerebral hemispheres, most commonly in the frontal lobes [29-31]. Lesions are often periventricular in the white matter and located in deep brain structures such as thalamus, basal ganglia, and corpus callosum . Infratentorial lesions including cerebellum are less common, seen in less than 10 percent of patients.
Eyes — The eyes can be involved by PCNSL at the time of initial presentation as an isolated site of disease or along with brain involvement . They can also be a site of relapse in patients with PCNSL elsewhere in the CNS. It is estimated that eye involvement occurs in 15 to 25 percent of all cases of PCNSL [1,34,35].
Eye involvement in PCNSL usually consists of cellular infiltration of the vitreous humor (figure 1); cells can also infiltrate the retina and spread under the retinal pigment epithelium (picture 1), causing pigmentary changes and focal areas of detachment. Optic nerve infiltration is rare .
The most common presenting symptoms of eye involvement are floaters, which may be ascribed to age or inflammation (eg, uveitis). Blurry vision may occur due to vitreous cellular infiltration. Visual acuity is typically preserved unless there is direct lymphomatous infiltration of the central macula. Approximately one-half of patients with eye involvement are asymptomatic, underscoring the importance of eye staging in all patients presenting with a new diagnosis of PCNSL. (See 'Extent of disease evaluation' below.)
A slit lamp examination is required to visualize cells in the vitreous. Cells are often numerous and grouped together in clumps or sheets (picture 2), causing a hazy appearance to the vitreous. The characteristic fundoscopic appearance is yellowish-orange subretinal infiltrates (picture 3) .
Primary vitreoretinal lymphoma (PVRL) refers to the subset of cases in which PCNSL arises first in the eye without brain involvement. Such cases account for approximately 5 percent of all PCNSL presentations . PVRL is mainly bilateral, although asymmetric presentations can occur. PVRL can present insidiously and is often mistaken for vitreitis or uveitis, leading to delayed diagnosis . Although limited to the eye initially, the main cause of death in PVRL is CNS relapse, which occurs in 60 to 90 percent of patients within several years of diagnosis . It is not clear whether CNS relapse results from subclinical brain disease that is not detectable at the time of diagnosis or is due to spread from the eye through the retina and optic nerve.
PVRL is distinguished from choroidal lymphomas, which are usually associated with low-grade pathology and do not carry risk of CNS involvement. (See 'Vitreoretinal disease' below.)
Leptomeninges — Approximately 15 to 20 percent of patients with PCNSL in the brain have concurrent involvement of the CSF based on CSF cytology, flow cytometry, and molecular testing. Such patients are often asymptomatic and may not have evidence of abnormal leptomeningeal enhancement on brain and spine magnetic resonance imaging (MRI). Basic CSF parameters are often but not always abnormal, including a high protein in 75 percent of cases and an elevated cell count in 50 percent .
More rarely, patients present with isolated or primary leptomeningeal lymphoma without synchronous brain, spine, or systemic disease [38,39]. Symptoms of primary leptomeningeal lymphoma are highly variable. Patients may have cranial neuropathies; encephalopathy; radicular symptoms from involvement of spinal nerve roots, including the cauda equina; leg weakness; bowel or bladder dysfunction; and headaches from increased intracranial pressure and/or hydrocephalus. CSF is almost always abnormal, with elevated protein (>90 percent), low glucose (50 percent), and lymphocytic pleocytosis (>90 percent) . Diagnosis may require serial CSF samples or meningeal biopsy. (See 'Patients without a brain lesion' below.)
Spinal cord — Intramedullary spinal cord lesions are infrequent, seen in 1 to 2 percent of patients with PCNSL. Isolated or primary spinal cord lymphoma, without synchronous brain or systemic disease, is described in case reports and likely represents <1 percent of PCNSL cases [40,41].
When lymphoma involves the spinal cord, symptoms may include progressive weakness, sensory loss, and bladder or bowel dysfunction, depending on the level of the lesion. Symptoms and imaging are overlapping with more common causes of myelopathy, and diagnosis is challenging due to its rarity, frequent treatment with glucocorticoids for alternative diagnoses, and difficulties in obtaining diagnostic tissue.
Neuroimaging — MRI of the brain with contrast is the most sensitive and informative imaging study in patients with PCNSL involving the brain. Contrast-enhanced computed tomography (CT) is useful to show mass lesions in patients with contraindications to MRI but does not provide nearly as much definition.
Lymphoma lesions on MRI are usually iso- or hypointense on T1-weighted images and iso- to hyperintense on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images. Lesions involving the brain parenchyma typically appear irregular in shape, with homogeneous contrast enhancement after gadolinium administration in most immunocompetent patients. Peritumoral edema is moderate compared with that seen with other brain tumors or metastases. The lesions show restricted diffusion on diffusion-weighted images in 90 percent of cases (image 1). Leptomeningeal enhancement can occasionally be seen, particularly periventricularly.
In cases of primary leptomeningeal lymphoma, brain and spine MRI typically show abnormal leptomeningeal enhancement involving the surface of the spinal cord and, less commonly, brain. There may be abnormal thickening and enhancement of cranial nerves or the cauda equina (image 2) .
Multiple ring-enhancing lesions, necrosis, and bleeding are unusual features in immunocompetent patients with PCNSL but are often seen in patients with immunocompromised or HIV-associated PCNSL (image 3) . (See "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'Neuroimaging features'.)
In patients with possible vitreoretinal involvement, optical imaging techniques, including fluorescein angiography and optical coherence tomography (OCT), are used by ophthalmologists to supplement the slit lamp examination, help narrow the differential diagnosis, and define the compartment of involvement .
Avoidance of glucocorticoids — Glucocorticoids are cytotoxic to lymphoma cells and can result in tumor shrinkage, resolution of contrast enhancement on imaging, and increased risk for a nondiagnostic biopsy [2,26]. When possible, steroids should be deferred until after biopsy has been performed and histopathologic confirmation has been made.
If a patient is on glucocorticoids and relatively neurologically stable with improvement on imaging, discontinuation of steroids is recommended, followed by repeat imaging and biopsy when tumor regrowth is noted . However, this approach may take several weeks until imaging findings reappear and results in delayed diagnosis and treatment.
Brain biopsy (most patients) — Diagnosis of PCNSL requires histopathologic confirmation. The diagnostic procedure of choice is biopsy of the brain lesion seen on imaging. When multiple lesions are present, the safest and easiest lesion to access is usually chosen.
A stereotactic biopsy provides sufficient tissue to diagnose lymphoma. Open biopsies are reserved for cases in which there is increased diagnostic uncertainty going into the procedure, to allow for a resection if frozen pathology indicates a glial or metastatic neoplasm.
Surgical debulking is not typically performed for PCNSL, assuming high preoperative suspicion and/or a frozen section indicating lymphoma, based on the diffuse/multifocal nature of the disease and its chemosensitivity. However, patients with very large, symptomatic lesions associated with mass effect and edema may, in selected cases, benefit from debulking to improve functional status and facilitate early start to chemotherapy . Interestingly, some studies have suggested a possible survival advantage to gross total resection in PCNSL, including post hoc evaluation of a prospective phase III trial [25,44,45]; however, at this time the role of surgery is primarily to obtain a diagnosis.
Of note, vitrectomy and cerebrospinal fluid (CSF) analysis can be also performed with diagnostic intent in patients with suspected disease in multiple compartments. However, because there can be delay in diagnosis and subsequent treatment with these techniques, prompt biopsy is advised in all cases that are surgically accessible.
Patients without a brain lesion — In patients without brain lesions who are suspected to have leptomeningeal, spinal, or vitreoretinal lymphoma, CSF analysis and vitreous analysis are the primary methods for achieving a definitive diagnosis.
CSF analysis — When leptomeningeal lymphoma is suspected, CSF should be analyzed for all of the following, optimally in the absence of glucocorticoid exposure:
●Immunoglobulin heavy chain (IgH) and immunoglobulin light chain gene rearrangement
●MYD88 mutational analysis and interleukin (IL) 10 levels, where available
Evidence of a monoclonal malignant cell population by cytology and flow cytometry is diagnostic of lymphoma in the CSF. Low cell counts may affect evaluation by flow cytometry and decrease sensitivity. IgH and immunoglobulin light chain gene rearrangement polymerase chain reaction (PCR) analysis can be helpful in making the diagnosis when cytology is unrevealing.
Newer techniques to detect genetic mutations by PCR that are commonly found in PCNSL, such as MYD88 point mutations, as well as IL-10 levels, also appear to have high specificity and may improve diagnostic yield [46-48]. In a study that included CSF from 63 patients with newly diagnosed or relapsed PCNSL and 162 controls with other central nervous system (CNS) disorders or extra-CNS lymphomas, combined analysis of CSF MYD88 L265P mutation and IL-10 levels had high sensitivity and specificity (94 and 98 percent, respectively) for the diagnosis of PCNSL .
Patients with primary leptomeningeal lymphoma may require multiple CSF samples to obtain diagnostic confirmation. In a multicenter series of 48 cases, CSF was diagnostic for lymphoma after a median of two lumbar punctures (range, zero to five), and 33 percent of patients required a meningeal biopsy . (See 'Other methods' below.)
Vitreous analysis — Vitreous analysis is recommended when the eyes are the only site of disease, as seen in primary vitreoretinal lymphoma (PVRL) . Due to the limited amount of material obtained from vitrectomy, the diagnostic yield from cytology or flow cytometry is often low. To maximize yield, glucocorticoids should be discontinued several weeks before vitrectomy, and fluid must be processed immediately without fixative .
As in CSF testing, IgH gene rearrangement, MYD88 PCR, high IL-10 level, and high IL-10-to-IL-6 ratios should be performed when possible, as these tests can be diagnostic in the absence of positive cytology in the appropriate clinical context .
Other methods — Rare patients with primary intramedullary spine or leptomeningeal lymphoma can pose significant diagnostic challenges and may require targeted biopsies of involved tissue if serial CSF testing is not informative. An open spinal cord or meningeal biopsy is appropriate in selected cases in which less invasive tests have failed and the clinical syndrome is progressive [39-41].
EXTENT OF DISEASE EVALUATION — A detailed diagnostic evaluation is recommended to exclude lymphoma outside the nervous system and establish the extent of the compartments of the central nervous system (CNS) involved. Accordingly, the International PCNSL Collaborative Group (IPCG) has developed guidelines to determine extent of disease .
●Physical examination – Physical examination should consist of a lymph node examination and a comprehensive neurologic examination.
In males, a testicular examination should be performed to investigate for testicular lymphoma, which has a high propensity of CNS involvement and can present with synchronous parenchymal brain and testicular disease. Many clinicians also obtain a testicular ultrasound for this reason. (See "Anatomy and pathology of testicular tumors", section on 'Testicular lymphoma'.)
●Eye examination – Involvement of the optic nerve, retina, or vitreous humor should be excluded with a comprehensive eye evaluation by an ophthalmologist that includes a slit lamp examination. (See 'Eyes' above.)
●Blood tests – Blood tests should include a complete blood count, a comprehensive metabolic panel, serum lactate dehydrogenase, and HIV serology . Hepatitis B surface antigen and core antibody testing is also typically performed in anticipation of receipt of rituximab and chemotherapy.
●Lumbar puncture – A lumbar puncture should be performed if not contraindicated, and cerebrospinal fluid (CSF) should be assessed by flow cytometry, cytology, and IgH gene rearrangement. (See 'CSF analysis' above.)
●Neuroimaging – Brain MRI with contrast should be performed in all patients, including those with disease limited to the eyes. A spine MRI with contrast is indicated for patients with spine symptoms or suspicion for leptomeningeal involvement. We do not routinely obtain fluorodeoxyglucose-positron emission tomography (FDG-PET) of the brain in patients with PCNSL.
●Body imaging – PET/CT scans of the chest, abdomen, and pelvis are recommended. Testicular ultrasound should be performed in older males and if testicular examination is abnormal.
Based on retrospective studies, approximately 2.5 to 8 percent of patients with newly diagnosed CNS lymphoma are found to have concurrent systemic disease on extent of disease evaluation [52-54]. PET/CT is more sensitive that contrast-enhanced CT in detecting extracranial lymphoma. When systemic disease is present, it usually involves other extranodal sites, including the testis, which are known to be higher risk for CNS involvement. Secondary malignancies involving the prostate, skin, or gastrointestinal tract are occasionally identified.
●Bone marrow biopsy – A bone marrow biopsy and aspirate can be considered to exclude occult systemic disease, although some experts do not stage the bone marrow in patients with PCNSL unless there is clinical or radiographic suspicion of involvement. Approximately 6 percent of patients with presumed PCNSL will have an abnormal bone marrow result at the time of staging, which is almost always discordant with brain pathology (eg, a low-grade lymphoma) and of uncertain clinical significance .
Brain lesions — Lymphoma in the brain has overlapping radiographic features with many other neoplastic and nonneoplastic conditions, most of which are more common than PCNSL.
As reviewed separately, the differential diagnosis of an enhancing mass lesion on brain MRI includes not only high-grade glioma/glioblastoma and brain metastases but also subacute infarction, tumefactive demyelination, inflammatory conditions, and infections including bacterial or fungal abscess and toxoplasmosis, particularly in immunocompromised patients . (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis'.)
Vitreoretinal disease — Primary vitreoretinal lymphoma (PVRL) is commonly misdiagnosed as uveitis and treated with injectable or oral glucocorticoids with temporary resolution of symptoms. Any older adult with noninfectious uveitis who fails to respond to anti-inflammatory therapy should be evaluated for lymphoma and other uveitis mimics. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)
PVRL must also be distinguished from secondary lymphomatous involvement of the eye and other neoplasms (table 1). Secondary vitreoretinal or choroidal invasion can occur due to systemic lymphoma and from primary uveal lymphomas, which arise in the choroid, iris, or ciliary body and are mainly mucosa-associated lymphoid tissue (MALT) lymphomas . Leukemia and ocular melanoma can also present with uveitis-like symptoms. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
Leptomeningeal presentations — The differential diagnosis of leptomeningeal lymphoma includes a wide range of infectious and noninfectious entities that can result in chronic meningitis (table 2). An approach to diagnosis is presented separately. (See "Approach to the patient with chronic meningitis".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Primary central nervous system lymphoma (PCNSL) is a rare primary brain cancer accounting for 2 percent of all brain tumors and 4 to 6 percent of non-Hodgkin lymphomas (NHLs). (See 'Epidemiology' above.)
●Risk factors – PCNSL is largely a disease of adults, and the risk rises with advancing age. PCNSL usually occurs in immunocompetent individuals. Less commonly, it is seen in patients with immunosuppression, often but not always in association with Epstein-Barr virus (EBV) proliferation. (See 'Risk factors' above.)
●Pathology – Approximately 90 percent of PCNSL cases are diffuse large B cell lymphoma (DLBCL). The remaining 10 percent of cases are made up of T cell lymphomas, low-grade lymphomas, or Burkitt lymphomas. (See 'Pathology and pathogenesis' above.)
●Clinical features – Most patients present with acute to subacute neurologic symptoms progressing over the course of days to weeks. Chronic or relapsing presentations are uncommon except in the context of glucocorticoid exposure. (See 'Clinical presentation' above.)
Brain is the most common site of involvement (>80 percent of cases), either alone or with evidence of concurrent eye and/or cerebrospinal fluid (CSF) disease. Isolated vitreoretinal, leptomeningeal, and spinal cord presentations can occur but are much less common. (See 'Brain parenchyma' above and 'Eyes' above and 'Leptomeninges' above and 'Spinal cord' above.)
Contrast-enhanced MRI of the brain is the preferred imaging modality. Lesions involving the brain parenchyma typically appear irregular in shape, with homogeneous contrast enhancement and restricted diffusion (image 1). (See 'Neuroimaging' above.)
●Diagnosis – Histopathologic diagnosis is essential and brain biopsy, if feasible, is recommended as soon as possible, before institution of glucocorticoids. Extent of disease evaluation helps to rule out systemic involvement. (See 'Diagnosis' above and 'Extent of disease evaluation' above.)
●Differential diagnosis – Lymphoma in the brain has overlapping radiographic features with many other neoplastic and nonneoplastic conditions, most of which are more common than PCNSL, including glioblastoma, brain metastases, subacute infarction, demyelination, inflammatory conditions, and infections. (See 'Differential diagnosis' above.)
The UpToDate editorial staff acknowledges the seminal contributions of Fred H Hochberg, MD [1-5,8-11,14,15,26,33,56], who contributed to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Jay S Loeffler, MD, who contributed to earlier versions of this topic.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟