INTRODUCTION — Infection with human immunodeficiency virus (HIV) predisposes individuals to the development of a range of cancers. There are four acquired immune deficiency syndrome (AIDS)-defining malignancies: Kaposi sarcoma, non-Hodgkin lymphoma (NHL) of high-grade pathologic type and of B cell or unknown immunologic phenotype, primary central nervous system lymphoma (PCNSL), and invasive cervical carcinoma.
HIV-related NHL is generally divided into three types: systemic NHL, PCNSL, and the primary effusion ("body cavity") lymphomas [1,2]. More unusual types, such as plasmablastic lymphoma, also occur. These disorders are primarily encountered in patients with more advanced HIV infection, with a CD4 count that is usually below 100 cells/microL . (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)
The clinical presentation, diagnosis, and management of HIV-related PCNSL will be reviewed here. Evaluation of the central nervous system (CNS) and treatment of secondary involvement of the CNS in patients with HIV-related systemic lymphoma is discussed separately. (See "HIV-related lymphomas: Clinical manifestations and diagnosis" and "HIV-related lymphomas: Treatment of systemic lymphoma".)
PATHOGENESIS — The pathogenesis of HIV-related PCNSL is strongly related to Epstein-Barr virus (EBV) infection, similar to other HIV-related lymphomas. This is described in more detail separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Pathobiology'.)
A variety of evidence demonstrates that EBV infection is central to the pathobiology of HIV-related PCNSL. Absence of EBV-specific CD4+ T cell effector function in patients with HIV infection is likely the main contributing factor . Evidence of EBV in PCNSL can be documented both on histopathologic specimens via in situ hybridization for EBV-encoded small nuclear RNA (EBER), and in the cerebrospinal fluid (CSF) of many patients by polymerase chain reaction (PCR). (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'EBV co-infection'.)
EBV-associated, HIV-related PCNSL has a distinct genetic landscape compared with PCNSL in immunocompetent hosts. Pathogenic variants in myeloid differentiation primary response gene 88 (MYD88), CD79B, and pim-1 proto-oncogene, serine/threonine kinase (PIM1) are absent . Copy numbers of HLA class I/II and antigen-presenting/processing genes are normal, and the activated B cell (ABC) cell-of-origin subtype is rare. (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'Pathology and pathogenesis'.)
The incidence of PCNSL in people living with HIV infection has declined with widespread adoption of antiretroviral therapy (ART). This was illustrated by a San Francisco AIDS registry study that identified 207 cases of HIV-related PCNSL from 1990 to 2000, among which 140 (68 percent) were diagnosed from 1990 to 1995, 52 from 1996 to 1998, and 15 (7 percent) from 1999 to 2002 .
Risk factors for NHL in people living with HIV include low CD4 count, high HIV viral load, and chronic co-infection with hepatitis B and hepatitis C virus in patients receiving ART. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)
Signs and symptoms — PCNSL can present with a variety of focal or nonfocal neurologic signs and symptoms, depending on the location and size of lesions within the brain and the amount of surrounding edema and mass effect.
The clinical presentation is typically acute to subacute, with symptoms such as confusion, lethargy, memory loss, hemiparesis, aphasia, and/or seizures progressing over days to weeks. Constitutional symptoms (systemic "B" symptoms) occur in over 80 percent of patients with PCNSL .
Degree of immunosuppression — The incidence of PCNSL increases with prolonged survival from HIV infection and requires a more severe degree of immunosuppression than most other AIDS-related illnesses. CD4 counts in affected patients are typically less than 50 cells/microL [7,10-12] but have been documented to range as high as 530 cells/microL .
Neuroimaging features — On noncontrast computed tomography (CT), PCNSL lesions are typically isodense or hyperdense to the gray matter and often have surrounding hypodensity indicative of cerebral edema [14,15]. Calcification, hemorrhage, and cysts are unusual .
On brain magnetic resonance imaging (MRI), PCNSL lesions may be solitary or multifocal, in roughly equal proportions [7,12,17]. The lesions themselves tend to be isointense or hypointense on T1-weighted images and hypointense, isointense, or hyperintense on T2-weighted images .
In the absence of glucocorticoid therapy (which can reduce or eliminate contrast enhancement associated with lymphoma in the brain), virtually all HIV-related PCNSLs show evidence of prominent enhancement following intravenous contrast injection (image 1). The enhancement is often irregular and inhomogeneous [15,17]. This is in contrast to non-HIV-related PCNSL, which is usually homogeneously enhancing [15,16]. This difference might be due to the more rapid growth rate of AIDS-related intracranial lymphomas, resulting in a high degree of central necrosis [16,17]. In addition, when the lesions exhibit necrosis and/or hemorrhage, there may be tumor-associated ring-like enhancement similar to that associated with toxoplasmosis. In such cases, distinguishing HIV-related primary CNS lymphoma from toxoplasmosis can be challenging .
MRI diffusion-weighted imaging (DWI) sequences in PCNSL are often abnormal, with elevated signal on DWI and low signal on apparent diffusion coefficient (ADC) maps indicative of restricted diffusion within the tumor mass (image 1). This appearance can be characteristic of PCNSL but importantly is not specific, and can also be seen in abscesses and acute infarcts. (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'Neuroimaging'.)
PCNSL can occur anywhere in the brain but has a tendency to involve certain areas most commonly, which can help to inform clinical suspicion:
●PCNSL most commonly affects deep structures and white matter. Lesions often involve the corpus callosum, periventricular regions, or periependymal areas [10,15].
●Less than 10 percent of lymphomas involve the posterior fossa; thus, posterior fossa lesions are more likely to be due to an alternative process such as infection .
A variety of specialized imaging studies have been investigated, including thallium-201 and 99Tc(m)-sestamibi single-photon emission computed tomography (SPECT) scans, perfusion MRI, magnetic resonance spectroscopy, and positron emission tomography (PET). PCNSL is usually associated with increased isotope uptake on thallium SPECT, increased perfusion on MRI, increased choline on spectroscopy, and increased glucose utilization on 18-F fluorodeoxyglucose (FDG)-PET scans. These techniques are more sensitive than specific, however, and their role in helping the clinician establish the cause of a CNS lesion remains unclear. (See "Approach to the patient with HIV and central nervous system lesions", section on 'Other imaging modalities'.)
Other brain lesions in patients with HIV — The differential diagnosis of PCNSL in a person living with HIV infection varies by the degree of immunosuppression.
●In patients with a low CD4 cell count (eg, <200 cells/microL), the main alternative causes of an enhancing mass lesion or lesions with surrounding edema are toxoplasmosis, progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) encephalitis, and other opportunistic infections, such as bacterial or fungal abscesses or, in the developing world, tuberculosis.
Other malignant brain tumors must also be considered , particularly as the incidence of toxoplasmosis decreases over time with use of trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis (which is also effective for the prevention of toxoplasmosis). The epidemiology and approach to brain lesions in patients with HIV infection are reviewed in detail separately. (See "Approach to the patient with HIV and central nervous system lesions".)
●In patients with a CD4 cell count >500 cells/microL, opportunistic infections as well as PCNSL become less likely, and the differential diagnosis of a new brain mass is more similar to that of an immunocompetent host. Considerations include primary brain tumors such as high-grade glioma, metastatic disease , and nonneoplastic conditions that can mimic the appearance of an aggressive tumor, such as subacute infarct or intracranial abscess. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Neuroimaging features'.)
Role of empiric toxoplasma therapy trial — Due to significant overlap in the clinical presentation, neuroimaging appearance, and risk factors for PCNSL and toxoplasma encephalitis in patients with HIV infection, empiric therapy for toxoplasma infection prior to diagnostic biopsy is sometimes reasonable. Importantly, however, PCNSL is an aggressive neoplasm, and diagnostic delay can have severe consequences.
Empiric toxoplasma therapy should only be used selectively and with close clinical and radiographic follow-up. It should be avoided in patients with very large solitary masses (eg, >4 cm), those with clinical or radiographic risk of herniation and sudden neurologic deterioration, and patients known to be seronegative for toxoplasma [14,20]. Decision-making with respect to empiric toxoplasma therapy in patients with HIV and brain lesions is discussed in more detail separately. (See "Approach to the patient with HIV and central nervous system lesions".)
DIAGNOSTIC EVALUATION — The diagnosis of PCNSL in a person living with HIV should be made by stereotactic biopsy or cerebrospinal fluid (CSF) flow cytometry and/or cytology in the majority of patients. In selected patients who cannot undergo biopsy and who have otherwise typical clinical and radiographic findings for PCNSL, detection of Epstein-Barr virus (EBV) DNA in the CSF may provide enough clinical certainty to treat.
In a contemporary series of 51 consecutive patients with HIV-related PCNSL, the majority of patients (71 percent) were diagnosed by stereotactic biopsy . The remaining patients were diagnosed based on the triad of compatible magnetic resonance imaging (MRI) with diffusion and perfusion sequences and spectroscopy, positive EBV DNA polymerase chain reaction (PCR) of CSF, and unresponsiveness to two to three weeks of toxoplasmosis treatment without glucocorticoids.
Lumbar puncture — Lumbar puncture should be performed in all patients with suspected HIV-related PCNSL unless contraindicated by mass effect or midline shift. In addition to routine cell count, differential, glucose, total protein, and culture, CSF testing should include cytology, flow cytometry, EBV PCR, and JC virus PCR. (See "Approach to the patient with HIV and central nervous system lesions", section on 'Lumbar puncture'.)
Cytology and flow cytometry — In the appropriate clinical context, a positive CSF cytology and/or flow cytometry for lymphoma is diagnostic of HIV-related PCNSL. In practice, diagnosis in this manner appears to be uncommon. Among 51 consecutive patients with HIV-related PCNSL in one series, for example, only 1 patient out of 40 tested had positive cytology .
In the HIV-seronegative population, the yield of CSF cytology for diagnosis of PCNSL is approximately 15 percent . In this population, the addition of flow cytometry to evaluate the presence of a monoclonal lymphoproliferative process likely increases the diagnostic yield . (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'CSF analysis'.)
EBV PCR — In selected cases in which diagnostic biopsy is contraindicated and cytology/cytometry is uninformative, the presence of EBV in CSF by PCR in conjunction with radiographic features that are consistent with HIV-related PCNSL may be used to establish the diagnosis and to motivate clinical intervention before irreversible neurologic deterioration occurs.
It is important to understand the limitations of EBV PCR testing in patients with HIV, however, especially with regard to specificity and positive predictive value for a diagnosis of PCNSL.
In small series, EBV analysis of CSF has been associated with a sensitivity of 80 to 90 percent, and a specificity that approaches 100 percent [23-26]. For example, in one series of HIV-seropositive patients with focal brain lesions, EBV DNA sequences were detected in 24 of 30 patients (80 percent) with PCNSL, compared with none of 61 patients without PCNSL . In another report, the probability of PCNSL in toxoplasma-seronegative patients with a mass effect increased from 74 percent overall to more than 96 percent if EBV DNA were present .
However, as with other tests, the positive predictive value depends upon the prevalence of disease within the population. Several investigators have demonstrated the poor predictive value of quantitative EBV DNA in the CSF of HIV-seropositive patients and correlate its association with miscellaneous neurologic diseases [27-29]. As an example, EBV DNA was detected by PCR in the CSF of 7 out of 26 HIV-seropositive patients in one series . Notably, only two of the patients with EBV DNA detected in the CSF received a diagnosis of PCNSL; five had alternative diagnoses including HIV encephalopathy, toxoplasmosis encephalitis, and cryptococcoma. Moreover, none of these five patients went on to develop HIV-related PCNSL over a median follow-up of 37 months. Thus, EBV DNA detection by PCR had a positive predictive value of 29 percent for the diagnosis of HIV-associated PCNSL.
Measurement of EBV DNA may have value in patients in whom a brain biopsy may not be acceptable to the patient or the neurosurgeon . In the first study referred to above, measurement of EBV DNA would have allowed the diagnosis of 63 percent of the case patients and exclusion of PCNSL in 76 percent of the control patients . These numbers are lower than the sensitivity and specificity because the test could not be performed in some patients due to perceived danger of lumbar puncture. The Eastern Cooperative Oncology Group has agreed to use EBV DNA measurement as a surrogate for brain biopsy in a new treatment trial .
Stereotactic biopsy — It is critical to note that HIV-related PCNSL can be an extremely aggressive neoplasm, and diagnostic delay can have devastating consequences. Therefore, diagnostic biopsies should be considered early after presentation. Glucocorticoids should be avoided if possible before biopsy in cases of suspected PCNSL to maximize diagnostic yield.
Stereotactic brain biopsy is an effective diagnostic procedure in HIV-seropositive patients with focal brain lesions with high diagnostic yield, particularly in the absence of prebiopsy glucocorticoid exposure [14,32,33]. The safety and yield of stereotactic biopsy was evaluated in a retrospective review of 435 HIV-seropositive patients presenting with focal intracranial lesions . The postbiopsy morbidity within 30 days was 8.4 percent and mortality was 2.9 percent. Similar values (12 percent morbidity and 2 percent mortality) were noted in another report , but the risk is likely to vary with local expertise.
In an older study, definitive diagnosis was obtained by brain biopsy in 88 percent of patients :
●PCNSL – 30 percent overall but 65 percent in those biopsied after failure of antitoxoplasma therapy
●Progressive multifocal leukoencephalopathy (PML) – 25 percent
●Toxoplasmosis – 16 percent
●Other – 17 percent; as an example, primary intracranial tumors (such as gliomas) can occur in HIV-infected patients 
It is likely that these percentages are changing since the advent of antitoxoplasma chemoprophylaxis has led to a decline in toxoplasmic encephalitis as a cause of focal brain lesions and a relative increase in PCNSL and PML .
EXTENT OF DISEASE EVALUATION — Staging is of value in only a minority of patients with systemic lymphoma and is generally not indicated in patients with PCNSL. This disorder almost always remains confined to the CNS, but within this space may spread to all compartments including the leptomeninges, spinal cord, and eye . Ocular involvement documented by slit lamp examination has been described in 5 to 20 percent of patients .
First-line therapy — PCNSL tends to be a multifocal/disseminated disease within the CNS, even if apparently localized on neuroimaging and cerebrospinal fluid (CSF) cytologic examination at the time of diagnosis. Therefore, optimal therapy generally requires systemic therapy with adequate CNS penetration (eg, high-dose intravenous methotrexate [MTX]) along with contemporary combination antiretroviral therapy (ART).
For both immunocompetent and HIV-related PCNSL, the field has moved increasingly away from whole brain radiation therapy (WBRT) as first-line or consolidative therapy due to poor durability of responses, poor survival when used as a standalone therapy, and risks of irreversible neurocognitive decline in survivors.
High-dose methotrexate — For most patients with HIV-related PCNSL, we suggest the use of high-dose MTX given in conjunction with ART.
The dose of MTX used for PCNSL varies across centers and patient groups. For patients with HIV-related PCNSL, we typically use an MTX dose of 3 g/m2 given every two weeks. Most patients require six to eight doses to achieve maximum response (see 'Assessment of response' below). After the initial response and resolution of tumor-associated mass effect, glucocorticoids should be tapered and discontinued in order to avoid side effects.
The administration of high-dose MTX must be performed at a center that has expertise in its use and appropriate laboratory support for the measurement of MTX levels. Adjustment for renal dysfunction is necessary. The administration and monitoring of high-dose MTX is reviewed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate".)
There is increasing evidence that induction high-dose MTX, used in conjunction with effective ART, can be used in the majority of patients with HIV-related PCNSL, and remarkably, depending on medical comorbidities, can be used with curative intent, without WBRT or other consolidative therapies [12,13,36-40].
Outcomes with this approach are illustrated by a single-center retrospective study of 51 consecutive patients with HIV-related PCNSL diagnosed from 1996 to 2014 . The median duration of HIV prior to PCNSL was 87 months, and 83 percent were on combination ART at the time of diagnosis (median duration, 11 months). HIV control was suboptimal as reflected by a high median plasma HIV load (175,600 copies/mL) and low median CD4 cell count (24 cells/microL). High-dose MTX (3 g/m2) every two weeks until best response was planned in all patients, and 45 patients received at least 1 dose (median 6 doses, range 1 to 15). Only one patient was treated with brain radiation (WBRT as second-line therapy). Median overall survival was 5.7 years and median time to progression was not reached (69 percent at 10 months) with a median follow-up of 76 months in surviving patients. There were no observed complications of immune reconstitution inflammatory syndrome.
Further support for the efficacy of high-dose MTX can be extrapolated from its use in non-HIV-related PCNSL in the general population . This is discussed in more detail separately. (See "Primary central nervous system lymphoma: Treatment and prognosis".)
Concurrent antiretroviral therapy — ART is a critical component of successful therapy in patients with HIV-related PCNSL, which allows for immune reconstitution and likely contributes to long-term disease control. The specific ART regimen should be individualized based on the patient's HIV genotype, comorbidities, prior treatment history, and drug interactions in consultation with infectious disease specialists. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Patients with HIV-related PCNSL usually have advanced AIDS, often with strains of HIV-1 that are resistant to many of the currently available antiretroviral medications. Nevertheless, every effort should be made to find an ART regimen that is effective, since enhancement of the immune system is one of the major therapeutic interventions that can be made for PCNSL.
Immune reconstitution is critical to monitor during high-dose MTX. We believe early improvements in CD4 count and reduction in HIV viral load associated with combination ART are important parameters to monitor, and that adjustment of ART early in the course of therapy may be requisite in order to achieve optimal outcome .
Evidence to support the benefit of concurrent ART in the treatment of PCNSL consists primarily of older observational studies spanning a time when not all patients received ART. In such studies, receipt of potent or combination ART after a diagnosis of HIV-related PCNSL was associated with improved survival compared with those who receive only radiation therapy and steroids, without ART [37,38,42,43]. The survival benefit was particularly evident in those who attained at least a 0.5 log(10) decrease in the viral load and an increase in the CD4 lymphocyte count by at least 50 cells/microL. Support for the role of ART is also derived from case reports of rapid immune recovery and prolonged lymphoma regression with potent ART alone in patients who declined WBRT .
Role of rituximab — We do not routinely add rituximab to first-line chemotherapy in patients with HIV-related PCNSL. Although the addition of rituximab to combination chemotherapy is feasible in the treatment of HIV-related lymphomas [13,40,45], it is not yet clear whether it adds benefit in patients with PCNSL. Most patients in the observational studies reviewed above did not receive rituximab. (See 'High-dose methotrexate' above.)
Indirect data in non-HIV-related PCNSL are also inconclusive. A randomized trial found similar event-free survival among groups assigned to receive MTX-based chemotherapy with and without rituximab as upfront therapy, and mature survival data are not yet available . (See "Primary central nervous system lymphoma: Treatment and prognosis", section on 'Patients with adequate fitness and kidney function'.)
Alternatives in patients not eligible for MTX — Moderate to severe renal insufficiency is the most common comorbidity that precludes safe use of high-dose MTX. Treatment decisions in such patients should be individualized, and there is a paucity of evidence for alternative agents to MTX in patients with HIV-related PCNSL. WBRT is an option, particularly in patients with poor functional status in whom the goals of care are primarily palliative. (See 'Options for recurrent/refractory disease' below.)
For patients who are otherwise considered to be candidates for chemotherapy, we consider agents such as temozolomide and rituximab, drawing primarily on literature and experience in patients with non-HIV-related PCNSL. (See "Primary central nervous system lymphoma: Treatment and prognosis", section on 'Relapsed/refractory disease'.)
Assessment of response — Brain magnetic resonance imaging (MRI) with and without contrast is used to assess treatment response compared with baseline scans. Clinical examination and brain MRI should be performed at regular intervals (eg, every two to three cycles) during initial high-dose MTX therapy to assess response to therapy. (See "Primary central nervous system lymphoma: Treatment and prognosis", section on 'Response assessment'.)
Following completion of therapy, a reasonable protocol is to obtain a brain MRI at least every three months for the first year and every three to four months during the second year. Repeat CSF evaluation by lumbar puncture with cytology and flow cytometry is indicated to confirm remission status if disease was evident in the leptomeningeal compartment at presentation.
Options for recurrent/refractory disease — Although WBRT should be avoided if possible as a first-line therapy, it remains reasonable to consider in patients with chemotherapy-refractory disease and those who cannot tolerate systemic therapy. Focal irradiation followed by immunotherapy with lenalidomide may be a therapeutic option as well .
Based on older literature in patients with HIV-related PCNSL, WBRT is associated with a response rate of 20 to 50 percent and a median survival of approximately three months [7,9,10,32,48]. Many deaths in this setting are due to opportunistic infections due to profound immunodeficiency [36,39]. In an analysis of 163 patients treated with WBRT, the overall palliative response was 53 percent . The two predictors of a complete response were high performance status and the delivery of higher, biologically effective radiation doses. However, many patients cannot tolerate the full course of radiation therapy [7,48]. In one series of 75 patients in which the median survival was only 1.3 months, cranial radiation was given to 72 percent of patients, but only one-half completed the course of therapy . Longer survival was associated with better performance status. In another review, the median survival of patients who received cranial irradiation was only 29 days longer than untreated patients (50 versus 21 days) .
For patients with a single or dominant focus of recurrent or refractory disease, focal irradiation may be a reasonable salvage option. Adjuvant immunomodulation with maintenance lenalidomide or pomalidomide should also be considered in HIV-related PCNSL, based on limited direct experience in HIV-related PCNSL as well as data in immunocompetent PCNSL [47,49,50]. (See "Primary central nervous system lymphoma: Treatment and prognosis", section on 'Systemic therapies'.)
PROGNOSIS — The prognosis of PCNSL in persons living with HIV appears to have improved significantly since the early HIV era, when the median survival was several months with or without lymphoma-directed therapy (typically whole brain radiation therapy [WBRT]).
In a single-center retrospective series of 51 consecutive patients diagnosed over a 20-year period from 1996 to 2014 in France, median overall survival was 5.7 years, with 5- and 10-year survival rates of 48 and 41 percent, respectively . All 14 PCNSL-related deaths occurred within the first 10 months after diagnosis. Another series found similarly favorable outcomes in patients treated with high-dose methotrexate (MTX) and contemporary antiretroviral therapy (ART) without WBRT .
Population-based survival estimates for HIV-related PCNSL suggest that progress may be more modest in the general population, however. In an analysis of the National Cancer Center database in the United States, for example, median overall survival for patients with HIV-related PCNSL diagnosed between 2004 and 2012 was only 3.6 months . Survival improved over time, as did the proportion of patients receiving chemotherapy. Another registry study also noted that survival had improved over time among cases diagnosed between 1990 and 2000 but remained poor, particularly among African Americans .
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) is an acquired immune deficiency syndrome (AIDS)-defining malignancy that is strongly related to Epstein-Barr virus (EBV) infection and immunosuppression. (See 'Pathogenesis' above and 'Degree of immunosuppression' above.)
●Signs and symptoms – HIV-related PCNSL can present with a variety of focal or nonfocal signs and symptoms including confusion, lethargy, memory loss, hemiparesis, aphasia, and/or seizures. (See 'Signs and symptoms' above.)
●Neuroimaging – On brain magnetic resonance imaging (MRI), PCNSL lesions may be solitary or multifocal, in roughly equal proportions. In the absence of glucocorticoid therapy, which can reduce or eliminate contrast enhancement associated with lymphoma in the brain, virtually all HIV-related PCNSLs show evidence of prominent enhancement following intravenous contrast injection (image 1). (See 'Neuroimaging features' above.)
●Differential diagnosis – The differential diagnosis of PCNSL in a person living with HIV varies by the degree of immunosuppression. In patients with a low CD4 cell count (eg, <200 cells/microL), the main alternative causes of an enhancing mass lesion or lesions with surrounding edema are toxoplasmosis, progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) encephalitis, and other opportunistic infections, such as bacterial or fungal abscesses or, in the developing world, tuberculosis. (See 'Differential diagnosis' above.)
●Diagnosis – The diagnosis of PCNSL in a person living with HIV should be made by stereotactic biopsy or cerebrospinal fluid (CSF) flow cytometry and/or cytology in the majority of patients. In selected patients who cannot undergo biopsy and who have otherwise typical clinical and radiographic findings for PCNSL, detection of EBV DNA in the CSF may provide enough clinical certainty to treat. (See 'Diagnostic evaluation' above.)
•First-line chemotherapy – For most patients with HIV-related PCNSL, we suggest initial therapy with high-dose methotrexate (MTX) rather than radiation therapy or antiretroviral therapy (ART) alone (Grade 2C). We typically use an MTX dose of 3 g/m2 every two weeks with appropriate adjustments for baseline renal function. (See 'High-dose methotrexate' above.)
•Antiretroviral therapy – In addition to tumor-directed therapy, all patients should receive concurrent treatment of HIV with ART. Every effort should be made to find an antiretroviral regimen that is effective, since enhancement of the immune system is a key therapeutic intervention against PCNSL. (See 'Concurrent antiretroviral therapy' above.)
•Refractory disease – The field has moved increasingly away from whole brain radiation therapy (WBRT) as first-line therapy in PCNSL due to poor durability of responses, poor survival when used as a standalone therapy, and risks of irreversible neurocognitive decline in survivors. WBRT remains reasonable to consider in patients with chemotherapy-refractory disease and those who cannot tolerate systemic therapy. Focal irradiation and immunomodulatory therapies may also be options in selected patients. (See 'Options for recurrent/refractory disease' above.)
●Prognosis – The prognosis of HIV-related PCNSL appears to have improved significantly since the early HIV era, when the median survival was several months with or without lymphoma-directed therapy (typically WBRT). (See 'Prognosis' above.)
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