Primary CNS Lymphoma

Primary central nervous system lymphoma (PCNSL) has been known by many other names, including reticulum cell sarcoma, diffuse histiocytic lymphoma, and microglioma. The proliferation of names reflects initial uncertainty about the cell of origin.

PCNSL is now known to be a form of extranodal, high-grade non-Hodgkin B-cell neoplasm, usually large cell or immunoblastic type. It originates in the brain, cerebrospinal fluid, spinal cord, or eyes. It typically remains confined to the central nervous system (CNS), but 4%–7% of patients with newly diagnosed PCNSL ^[1] and 10% of patients with relapsed PCNSL ^[2] may have systemic disease. Because the affected areas of the CNS differ from patient to patient, clinical signs and symptoms of the disease are variable, and diagnosis requires a high level of suspicion.

PCNSL occurs at an incidence of 0.47 per 100,000 person-years, accounting for 4%–6% of extranodal lymphomas and 4% of newly diagnosed CNS tumors. It is more common in males than females ^[3]  and can occur both in immunocompromised patients and in patients who are immunocompetent.

Although the cells of origin are lymphocytes, PCNSL should be considered a brain tumor, because the therapeutic challenges resemble those of other brain tumors. In particular, drug delivery is impaired by the blood-brain barrier, and cerebral toxicity limits the use of treatment modalities.

Most PCNSLs (about 90%) are diffuse large B-cell lymphomas (DLBCLs); the remaining 10% are T-cell, mantle cell, Burkitt, or indolent B-cell lymphomas. ^[4]  Clinical outcomes differ by histologic subtype with 5-year overall survival rates ranging from 30% in DLBCL to 79% in marginal zone lymphoma. ^[5]

Also see Non-Hodgkin Lymphoma.

Diagnostic considerations

Since the clinical and neuroimaging presentation of PCNSL can be varied and the differential diagnostic possibilities are therefore large, no patient should be treated for PCNSL without definitive cytologic proof of diagnosis, either by vitrectomy, CSF sampling, or brain biopsy. Corticosteroids should be avoided when possible in acute management of a patient in whom PCNSL is a consideration. Corticosteroids have a cytotoxic effect on lymphoma cells and can induce a radiographic response in up to half of patients, which limits the sensitivity of diagnostic tools like biopsy or lumbar puncture. ^[6] Additionally, a biopsy of lymphoma pre-treated with corticosteroids may reveal only gliosis or lymphocytic and histiocytic infiltrates without identifiable neoplastic cells. ^[7] Responses to corticosteroids are not durable and thus only delay definitive diagnosis and treatment.

Patients with human immunodeficiency virus (HIV) may have coexisting infections; any change in neurologic examination findings or neuroimaging studies should be accordingly investigated broadly for the possibility of a diagnosis other than PCNSL. Cerebral toxoplasmosis can present identically to PCNSL; other infectious considerations in these patients include progressive multifocal leukoencephalopathy and, less commonly, tuberculoma, Cryptococcus, nocardia infections, and others. HIV-related PCNSL is almost always positive for Epstein-Barr virus (EBV), which can differentiate it from cerebral toxoplasmosis. ^[8]

The predilection of PCNSL for certain cerebral sites gives rise to its characteristic appearance on neuroimaging studies. Seventy-five percent of immunocompetent patients will present with solitary lesions. The dense cellularity of the tumor accounts for its isodense or hyperdense appearance on nonenhanced CT scan and hypointense appearance on long TR-weighted MRI imaging. ^[9]  While lesions in immunocompetent patients tend to be solitary, periventricular, and homogenously enhancing, lesions in immunocompromised patients may be cortical or subcortical with a variable enhancement pattern, with ring enhancement most commonly seen. ^[8]

PCNSLs are assumed to be diffusely infiltrative at the time of presentation and considered a “whole brain” disease. The areas of disease are not visible on neuroimaging studies because they are behind a relatively intact blood–brain barrier.

The DLBCL type of primary central nervous system lymphoma (PCNSL) is composed of immunoblasts or centroblasts that have a predilection for blood vessels and thus demonstrate a typical angiocentric growth pattern. Lymphoid clustering around small cerebral vessels is typically seen. Reactive T-cell infiltrates can also be present in varying degrees.

The B-cell receptor pathway, suppressed tumor immune microenvironment, and immune evasion have recently been suggested to contribute to the etiology of PCNSL.

Evidence from a study by Sugita et al supported the concept that PCNSLs originate from a later germinal center to an early postgerminal center, and they may be capable of further maturation steps. ^[10] Mutations in the B-cell receptor pathway, MYD88 L265P mutation, and loss of CDKN2A were recently identified as early genetic alterations in DLBCL PCNSL, suggesting either of these pathways could significantly contribute to initial tumorigenesis. ^[11]  The same study identified programmed death ligand 1 (PD-L1) expression in 30% of patients, while other studies have described copy number gains at PD-L1/PD-L2, bringing into question the role of the tumor microenvironment and immune evasion in PCNSL development. ^[11]

HIV-associated PCNSL is thought to be highly driven by Epstein-Barr virus (EBV)-induced malignant transformation of cells. EBV causes expression of oncogenic genes including latent membrane activity proteins (LMP-1 and 2), EBC nuclear antigen, and EBV-encoded nuclear RNA (EBERs). Since EBV does not replicate in the CNS, it is hypothesized that infected cells originate outside the CNS and infiltrate as the patient’s immune system continues to decline. ^[8]

Risk factors in immunocompetent patients

No clear risk factors for PCNSL in immunocompetent patients are known.

The disease is more common in men and in elderly persons. ^[12]  The incidence is also higher in blacks aged 0–49 years compared to whites, and whites aged 50+ compared to blacks. ^[3]

Risk factors in immunocompromised patients

The nature, intensity, and duration of immune suppression are factors in determining the risk of developing PCNSL. ^[13]

The incidence of PCNSL is inversely proportionate to the CD4 count in patients with HIV. Patients with HIV-associated PCNSL have an average CD4 of 30x10⁶/L and have often had prior opportunistic infections. ^[8]

Virtually all PCNSLs in patients with HIV express EBV-related genome. PCNSL is less frequently associated with EBV in patients without HIV. Human herpes virus 8 (HHV-8) is known as a virus with oncogenic potential in immunocompromised patients and has been associated with Kaposi sarcoma; it has also been suggested to have a potential role in development of PCNSL in these patients.

Corboy et al reported that 56% of a group of immunocompetent and immunocompromised patients had HHV-8 in their tumors. This is the same herpes virus that is associated with Kaposi sarcoma and with primary effusion (ie, body-cavity-based lymphomas); however, a direct causal relationship of this herpes virus to any PCNSL has not yet been established. ^[14] (HHV-8 has been detected in PCNSLs by PCR at low copy number, suggesting that HHV-8 is present in a cell compartment other than the malignant one.)

Gomez-Brouchet et al studied 35 patients (17 with and 18 without AIDS) with PCNSL for the presence of HHV-8 in tumor cells. The antibody LN53, which reacts with the latent nuclear antigen 1 (LNA1) of HHV-8, was used on tissue sections from these patients and in addition, DNA was available for PCR. They found none of the 35 cases contained either DNA sequences or LNA1-positive cells in the tumor cells of PCNSL. ^[15]

Patients on chronic immunosuppression, particularly after solid-organ transplantation, are at increased risk of PCNSL as well. The vast majority of these patients have a history of kidney transplant. ^[16] While this may reflect the high rate of kidney transplants in the United States, some have suggested kidney transplant as an independent risk factor for the development of PCNSL. ^[17] Mycophenolate is a common immunosuppressant in these patients and may carry an increased risk for PCNSL. ^[17]

 

Incidence

Incidence of primary central nervous system lymphoma (PCNSL) in immunocompetent patients is approximately 51 cases per 10,000,000 per year.

PCNSL has been reported in 6-20% of patients infected with HIV, and the incidence is expected to rise as patients with low CD4⁺ counts survive longer.

Similar trends toward rising frequency of diagnosis of PCNSL are reported internationally.

Sex predilection

Among immunocompetent patients with PCNSL, males have a higher incidence of PCNSL than females.

Patients with HIV-associated PCNSL are more likely to be male. In one study, 74% or HIV patients with PCNSL were male. ^[18]

Age predilection

The median age of immunocompetent patients with PCNSL is 55 years. There is an increased incidence with advancing age with the highest rate of PCSNL in patients aged 75 years or older. ^[3]

The median age of HIV-infected patients with PCNSL is 35 years.

Race predilection

Black males aged younger than 50 years have greater than twice the incidence of white males, while white males aged 50+ years have twice the incidence of black males. A similar pattern to a lesser magnitude is present in females. ^[3]

Patients with primary central nervous system lymphoma (PCNSL) develop progressive neurologic deficits fairly rapidly, over weeks to months. These deficits are variable depending on the affected location within the CNS. About 40%–50% of patients present with nonspecific neurocognitive symptoms, and about 50%–70% present with focal neurologic signs. ^[19]  Seizures may occur but are less common than in other mass lesions due to relative cortical sparing.

Patients with HIV may be more likely to present with an encephalopathy than other patients with PCNSL. This correlates with the more often multifocal, diffuse enhancement pattern seen on magnetic resonance imaging (MRI) scans. A history of concurrent infections is quite common, and the median CD4⁺ count is 30 cells/µL. ^[8]

In contrast to systemic DLBCL, patients with PCNSL do not typically present with B symptoms of weight loss, fever, and/or night sweats.

As the presence of immune deficiency guides both the diagnosis and the treatment of PCNSL, much of the history taking should be devoted to establishing whether the patient may be immunocompromised. A careful sexual and drug abuse history is necessary. If the patient is a transplant recipient, the nature and duration of immune suppression must be clarified.

Although ocular involvement is not infrequent, it is often asymptomatic; if visual symptoms are present, patients may describe blurred vision, decreased acuity, or floaters.

Relapsing, remitting lesions may disappear for periods of as long as several months to a year or more. Administration of corticosteroids may cause prolonged remission of clinical and radiographic signs and symptoms, but remission inevitably occurs.

Other manifestations

Rarely, lymphoma can involve only the eyes or the small blood vessels. It can also present in the setting of systemic lymphoma.

Primary vitreoretinal lymphoma is confined to the eye and is rare. Patients may be asymptomatic or describe blurred vision, decreased visual acuity, or floaters. It is often misdiagnosed initially as uveitis and treated with corticosteroids, which delays diagnosis. It commonly involves both eyes. Diagnosis is made by vitreous fluid cytology and flow cytometry. A majority of patients will progress to CNS involvement within about 2 years. A high IL-10-to-IL-6 ratio in the vitreous fluid is also suggestive of the diagnosis but should not be used as a sole indicator of disease. ^[20]

Intravascular large B cell lymphoma is characterized by lymphoma cell proliferation within small blood vessels’ lumen. While extremely rare, it can affect the CNS, skin, bone marrow, spleen, and liver. Sixty percent of cases are stage IV at diagnosis. When the CNS is involved, presentation most often mimics stroke. In contrast to other PCNSLs, B symptoms are more commonly seen in this subtype. ^[20]

Secondary CNS lymphoma describes CNS involvement of lymphoma in the setting of systemic disease. In general, the risk of CNS relapse in DLBCL is about 5%, but in high-risk groups (eg, patients with adrenal or kidney involvement), CNS relapse can be up to 40%. ^[21]  Any CNS compartment can be affected, but most typically the parenchyma is involved. Clinical presentation depends on the area of CNS involved.

The goal of the physical examination is to establish a neurologic baseline and detect possible extraneural sources of lymphoma. Examine for lymphadenopathy, abdominal masses, and skin lesions (sarcoidosis may mimic primary central nervous system lymphoma (PCNSL) on neuroimaging studies, or cutaneous lymphoma may be present).

Neurologic examination should be directed toward determining which compartments of the nervous system are involved, as follows:

• Examination for focal deficits
• Examination of peripheral nerves for evidence of neuropathy (suggestive of systemic process or neurolymphomatosis)
• Eye examination for vitreous involvement

The eye examination will require ophthalmologic consultation and slit-lamp examination and is a necessary part of the workup in all patients with PCNSL.

Differential diagnosis of a patient with suspected primary central nervous system lymphoma (PCNSL) depends on the patient's immune status and the radiographic appearance of the lesions. For example, the major differential diagnostic possibilities raised in an immunocompetent patient with a solitary lesion (besides PCNSL) are high-grade primary brain tumor, such as glioblastoma, and isolated metastasis.

In patients with HIV, multifocal, ring-enhancing lesions raise the question of toxoplasmosis or another opportunistic infection. HIV-associated PCNSL almost always is associated with Epstein-Barr virus (EBV), and the presence of EBV DNA in the CSF detected by PCR has a high sensitivity and specificity of 97% and 98%, respectively, helping to differentiate PCNSL from toxoplasmosis, which would not be expected to show positive EBV DNA. ^[8]  In addition, increased uptake of the lesion in ²⁰¹thallium SPECT scans suggests the diagnosis of PCNSL over toxoplasmosis. ^[8] More diffuse cognitive and MRI abnormalities suggest the possibility of some infectious encephalitic process, such as herpes zoster, cytomegalovirus encephalitis, cryptococcal meningitis, or AIDS/dementia complex.

Other differentials to consider in PCNSL are myriad due to the variable clinical presentation and include the following:

• Abducens nerve (cranial nerve VI) palsy

• Acute disseminated encephalomyelitis

• Aseptic meningitis

• Brainstem gliomas

• Cauda equina and conus medullaris syndromes

• Glioblastoma multiforme

• Granulomatous angiitis of the CNS

• Herpes simplex encephalitis

• HIV-1 associated CNS complications

• HIV-1 associated CNS conditions: meningitis

• HIV-1 associated opportunistic infections: CNS cryptococcosis

• HIV-1 associated opportunistic infections: CNS toxoplasmosis

• HIV-1 associated opportunistic infections: cytomegalovirus encephalitis

• HIV-1 associated opportunistic infections: PML

• HIV-1 encephalopathy and AIDS dementia complex

• Leptomeningeal carcinomatosis

• Low-grade astrocytoma

• Multi-infarct dementia

• Multiple sclerosis

• Neurological infections

• Neurosarcoidosis

• Neurosyphilis

• Paraneoplastic encephalomyelitis

• Longitudinally extensive transverse myelopathy

Uncommonly, primary CNS lymphoma (PCNSL) can present as longitudinally extensive transverse myelopathy (LETM). Then the condition often mimics transverse myelitis. PCNSL may be noncontrast enhancing on gadolinium-enhanced MRI. Failure to suspect and evaluate leads to delay in diagnosis and treatment of LETM of PCNSL. CSF analysis should always be done in transverse myelitis before starting corticosteroids as is usual practice in this condition because steroids may lead to transient improvement and mask the correct diagnosis. Repeated CSF examinations may be needed to finalize the diagnosis of PCNSL or LETM of PCNSL. ^[22]

The following should be ordered in an immunocompetent patient whose computed tomography (CT)/MRI scan suggests primary central nervous system lymphoma (PCNSL):

• Withhold corticosteroids, as their use may complicate diagnosis; except in the case of emergent use for control of life-threatening cerebral edema
• Whole-body fluorodeoxyglucose-PET or, if PET scanning not available, CT of the chest/abdomen/pelvis and testicular ultrasound to evaluate for systemic disease
• Bone marrow biopsy
• HIV testing
• Lactate dehydrogenase
• Slit-lamp examination for vitreal involvement
• Lumbar puncture for cells, glucose, protein, flow cytometry, IgH gene rearrangement and cytology in the cerebrospinal fluid (CSF). Additionally, the presence of MYD88 L265P and elevated levels of IL-10 in the CSF are highly suggestive of the diagnosis. ^[23]
• Brain biopsy of CNS lesion; this should not be delayed while awaiting completion of above tests

In addition to the above, the following should be ordered in an HIV-infected or otherwise immunocompromised patient whose CT/MRI scan suggests PCNSL:

• Toxoplasma gondii serology
• Lumbar puncture for cells, glucose, protein, cytology, EBV DNA by PCR, syphilis testing, and cryptococcal antigen

Fischer et al presented the first prospective comparison of the diagnostic value of cerebrospinal fluid (CSF) cytomorphology, polymerase chain reaction (PCR) assay of the rearranged immunoglobulin heavy-chain (IgH) genes, and MRI in conjunction with cell count and protein concentration for the detection of meningeal dissemination in patients with PCNSL treated in a large multicenter study. They found a low rate of meningeal dissemination in primary CNS lymphoma in this large prospective study. The rate of discordant PCR and cytomorphologic results was high. Thus, they feel that these methods should be regarded as complementary. CSF pleocytosis had predictive value for meningeal dissemination detection. ^[24]

MRI of the brain shows a hypointense lesion or lesions on long TR-weighted images, which enhance densely and homogeneously after contrast administration. In HIV patients, lesions more often show a rim-enhancement pattern. Lesions can be solitary or multifocal. They are most often supratentorial. In immunocompetent patients, lesions are typically periventricular but can present in other locations. MRI also gives information about leptomeningeal enhancement, hydrocephalus, and concurrent alternative diagnoses, such as infections in patients with HIV.

Patients with focal spinal, root, or cord symptoms should undergo MRI of the spine with and without contrast to localize the deposits of lymphoma. These lesions, when found, may be amenable to radiation therapy.

The international primary CNS lymphoma group consensus recommendations propose, if possible, obtaining three dimensional images at 1–1.5mm isotropic voxel size and < 4mm two-dimensional contiguous slices on a 3 Tesla machine. If this technology is not available, imaging with a 1.5 Tesla machine with contrast enhancement is recommended at minimum. ^[25]

Goyal et al. found that the enhancing component of CNS lymphomas were found to have significantly lower mean relative cerebral blood volume ( rCBV) compared to the enhancing component of GBM (1.2 versus 4.3; P< 0.001), metastasis (1.2 versus 2.7; P< 0.001), and anaplastic-enhancing gliomas (1.2 versus 2.4; P< 0.001). Also, the maximum rCBV of the enhancing component of lymphoma were significantly lower than GBM (3.1 versus 6.5; P< 0.001) and metastasis (3.1 versus 4.9; P< 0.013), and not significantly lower than anaplastic enhancing gliomas (3.9 versus 4.2; P< 0.08). The researchers conclude that  enhancement-perfusion (E-P) mismatch in dynamic susceptibility weighted magnetic resonance perfusion (DSC-MR) (i.e., low mean rCBV in an enhancing portion of the tumor) is strongly suggestive of lymphoma and should allow differentiation of CNS lymphoma from other enhancing malignant lesions. ^[26]

Fluorodeoxyglucose-PET of the whole body should be performed on every patient. If this technology is not available, chest and abdominal CT scans and testicular ultrasound should be performed for initial staging.

Thallium-201 single-photon emission computed tomography (SPECT) scanning is appropriate in patients with HIV to help distinguish between infectious processes and primary central nervous system lymphoma (PCNSL). Patients with HIV may have a cystic, ring-enhancing lesion with PCNSL instead of the homogeneously enhancing abnormalities seen in immunocompetent patients. The presence of single or multiple ring-enhancing lesions in patients with AIDS raises suspicion of toxoplasmosis, Nocardia asteroides infection, or neurosyphilis.

Liver function tests

Because the mainstay of treatment for many patients is high-dose methotrexate, hepatic function must be evaluated. Tests should include serum bilirubin (total/direct), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.

Twenty-four-hour urine collection for creatinine clearance

Patients being considered for methotrexate chemotherapy should have a glomerular filtration rate (GFR) of greater than 100 mL/min, because inadequate renal clearance enhances methotrexate toxicity. However, patients with reduced kidney function may still benefit from a reduction in methotrexate dose. Further, the use of aggressive intravenous hydration may improve GFR.

Hepatitis Panel

Patients being considered for rituximab therapy should have a hepatitis panel completed prior to initiation of therapy.

Bone marrow biopsy

Bone marrow biopsy to evaluate for abnormal lymphomatous cells should be completed for staging purposes.

Lumbar puncture

Lumbar puncture should be performed to evaluate CSF profile (glucose, protein, and cell count) and cylology and flow cytometry for detection of abnormal lymphomatous cells. Lumbar puncture is low-yield as the majority of patients with primary central nervous system lymphoma (PCNSL) will not have leptomeningeal or CSF involvement; however, if lumbar puncture identifies lymphoma cells, this may obviate the need for brain biopsy. Brain biopsy should not be delayed while awaiting this procedure.

Testing for MYD88 gene products and elevated IL-10 can assist in solidifying the diagnosis if other testing is negative or if brain biopsy is unable to be performed. These tests are limited by low sensitivity and often long wait times for results.

Slit-lamp examination and possible vitrectomy

Although fewer than 10% have vitreous involvement at initial presentation, all patients should undergo slit-lamp examination. Vitrectomy may establish the diagnosis, sparing brain biopsy in these patients. Brain biopsy should not be delayed to complete this evaluation.

Brain biopsy

Stereotactic brain biopsy is the most appropriate method for the diagnosis of PCNSL. However, open brain biopsy may be necessary in those patients who have lesions located in areas of the brain that are difficult to access (eg, brainstem). If possible, the procedure should be performed before corticosteroids have been administered.

Primary central nervous system lymphoma (PCNSL) is a densely cellular, aggressive non-Hodgkin B-cell lymphoma. Immunocompetent patients usually have a small, noncleaved cell or immunoblastic subtype. Perivascular clusters of lymphocytes and T-lymphocyte infiltrates are common in immunocompetent patients. T-lymphocyte infiltrates are not found in patients with HIV.

The goal of treatment is eradication of contrast-enhancing mass lesions and microscopic infiltration of brain, spine, leptomeninges, and vitreous. Successful therapy in immunocompetent patients leads to a median survival duration as long as 44 months. Treatment must be designed to maximize efficacy and minimize toxicity.

The optimal treatment regimen for primary central nervous system lymphoma (PCNSL) has not been established. Standard systemic chemotherapy regimens such as CHOP (ie, cyclophosphamide, doxorubicin, vincristine, prednisone) are ineffective, which presumably reflects the difficulty of penetration of the blood-brain barrier by chemotherapeutic drugs.

Methotrexate is the single most effective chemotherapeutic agent for PCNSL. For this reason, methotrexate-based chemotherapy regimens are used as first line treatment. The optimal combination of chemotherapies that include methotrexate is not known, however, literature supports the use of ;mulit-agent chemotherapy over methotrexate monotherapy.

Initial chemotherapy without radiation therapy results in excellent initial tumor response rates and avoids the toxicity associated with whole brain radiation.

Induction

Induction treatment aims to eradicate radiographic evidence of disease. When this is achieved, it is called a complete response (CR).

Methotrexate

Methotrexate-based chemotherapy regimens have been the most successful treatment strategies to date. Methotrexate is a folate analogue that interferes with DNA synthesis and repair. For treatment of PCNSL, patients receive high-dose systemic methotrexate. When the drug is administered in high doses systemically (> 1.5gm/m2), it achieves therapeutic levels in brain parenchyma and obviates intrathecal therapy as an initial treatment for PCNSL.

To date, there has been no prospective study to elucidate the most effective methotrexate dose or the most effective combination chemotherapy regimen. Rituximab, a monoclonal antibody against the B-cell surface antigen CD20, is often incorporated due to its efficacy in DLBCL. Addition of cytarabine to methotrexate and whole brain radiation therapy was shown to improve both progression-free survival and CR rate, which suggested that combination chemotherapy was more effective than methotrexate alone. ^[27] Unfortunately, whole brain radiation therapy, while effective, causes significant neurotoxicity and neurologic dysfunction, especially in patients older than 60 years. For this reason, chemotherapy alone is the preferred treatment for induction therapy of PCNSL.

Commonly used induction regimens include rituximab/methotrexate/vincristine/procarbazine (R-MVP), rituximab/methotrexate/temozolomide (R-MT), rituximab/methotrexate/cytarabine/thiotepa (MATRix), and rituximab/methotrexate/temozolomide (R-MT).

Aggressive IV hydration, alkalization of urine, close monitoring of kidney function and methotrexate levels and calcium leucovorin rescue necessitates inpatient administration of methotrexate.

Whole brain radiation therapy

PCNSL patients have been treated with whole brain radiation therapy alone. This has yielded high CR rates, but sustained responses are rare with a median overall survival of around a year. Focal radiation results in increased relapses outside of the radiation field, presumably because of microscopic diffuse infiltrative disease thought to be present at initial diagnosis. A randomized trial investigated whether the addition of whole brain radiation therapy to methotrexate based chemotherapy regimens affected survival and found no survival benefit. ^[28]

Surgery

The role of surgery in treatment of PCNSL is limited to biopsy for confirmation of diagnosis or for rapid reduction of intracranial pressure to prevent imminent herniation. Small retrospective studies have shown no benefit in outcomes when comparing surgical resection to supportive care ^[29]

Consolidation

Consolidation therapy aims to eradicate microscopic infiltrative disease.

High-dose chemotherapy with autologous peripheral blood stem cell transplant

In young patients (< 65 years) with few comorbidities and high performance status, high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) is the preferred consolidation treatment. This treatment can result in high response rates with prolonged progression free survival. ^[29]  The optimal conditioning regimen with high dose chemotherapy prior to stem cell transplant is not currently known. High-dose thiotepa-based regimens such as TBC (thiotepa, busulfan, cyclophosphamide) are more effective than carmustine (BCNU)/etoposide/cytarabine/melphalan (BEAM)-based regimens. ^[29]

Radiation therapy

Consolidation whole brain radiation therapy has been studied in patients who achieved a complete response to induction chemotherapy. In these patients, there was a progression-free survival benefit that was non-significant, and there was no difference in overall survival. ^[28]  Some experts, however, criticize this study for its non-inferiority endpoint and for many variations from protocol and advocate for WBRT as the standard consolidation treatment. Delaying radiotherapy until recurrence may lead to similar overall survival with less neurocognitive effects. ^[29]

Reduced-dose radiotherapy is another consolidation option, and one small study of R-MPV, reduced dose radiotherapy (2340 cGy) and cytarabine showed high response rates, long-term disease control and low rates of neurotoxicity. ^[30]

Treatment of Recurrence and Refractory Disease

There is no standard approach to treatment of recurrent or refractory PCNSL. Survival rates after recurrence and chance of response to further treatment are much lower than at initial diagnosis.

In patients with initial prolonged responses to methotrexate-based chemotherapy, rechallenge is reasonable. Studies have investigated pemetrexed, topotecan, temozolomide, and rituximab and have shown significant response rates {ref 37}. HCT-ASCT as described above can also be used at relapse but has lower response and survival than when used as consolidation therapy.

Because of the newly discovered expression of PD-1 in many PCNSL cases, ^[11]  investigations are ongoing into PD-1 inhibitors. In one case series, four patients with recurrent PCNSL were treated with nivolumab and had a progression-free survival from 14 to 17 months. ^[31]

Other novel targeted therapies that have proven successful include ibrutinib and lenalidomide. Ibrutinib is an oral bruton tyrosine kinase (BTK) inhibitor and has shown efficacy in relapsed/recurrent disease; the National Comprehensive Cancer Network guidelines now include the use of ibrutinib alone and when used in combination with methotrexate and rituximab. These guidelines also include lenalidomide, an immunomodulatory medication, both alone and in combination with rituximab.

Whole brain radiation can be used as salvage therapy as it has a good response rate; however, it can cause significant neurotoxicity as is best used in a palliative only setting.

Ocular therapy

Primary intraocular lymphoma can be treated with systemic chemotherapy or intravitreal chemotherapy with or without ocular radiotherapy. Intravitreal chemotherapy choices include methotrexate and rituximab. Lack of clinical trials in this population limits definitive treatment standards. Given the high rates of CNS spread, many recommend aggressive systemic methotrexate-based chemotherapy regimens in this population.

Concurrent ocular lymphoma with PCNSL should not be treated differently than PCNSL alone. ^[29]

Treatment complications

Long-term sequelae of radiation therapy and chemotherapy in PCNSL are significant. Although median survival duration has been extended with combined chemotherapy and radiation therapy, the percentage of survivors with late cerebral white-matter toxicity resulting in cognitive dysfunction approaches 50%.

Serious leukoencephalopathy also is seen in patients receiving methotrexate chemotherapy alone, but the incidence appears to be lower than that of the cerebral white-matter toxicity seen with combination therapy.

Ophthalmologic consultation is required as part of the initial workup and staging of primary central nervous system lymphoma (PCNSL), in order to exclude vitreous involvement. Vitrectomy may be performed to establish diagnosis for patients with abnormal findings on slit-lamp examination.

Medical oncologic consultation is appropriate for any patient with suspected PCNSL who has evidence of systemic involvement. Before initiation of treatment for PCNSL, systemic disease that would alter the chemotherapy regimen must be ruled out. Early involvement of a lymphoma specialist may be indicated if peripheral stem cell transplant is being considered.

Neurosurgical consultation is required for stereotactic brain biopsy.

During chemotherapy with high-dose methotrexate, primary central nervous system lymphoma (PCNSL) patients must be hydrated aggressively with IV fluids. Urine is alkalinized to a pH >7.0 with the addition of sodium bicarbonate. They should avoid fruit juices that might acidify the urine. Drugs to be avoided during methotrexate therapy include salicylates, nonsteroidal anti-inflammatory drugs, and sulfonamides. The addition of procarbazine should prompt avoidance of tyramine in the diet as well as medications such as monoamine oxidase inhibitors (MAOIs).

No major activity restrictions apply to patients with PCNSL.

After biopsy, some patients may require inpatient care because of neurologic deficits related to the primary site of the tumor.

The use of corticosteroids to control symptoms may be unavoidable, but administration of dexamethasone or its equivalent, in doses greater than 8 mg/day for more than 2 weeks, raises the risk of steroid myopathy. Patients with muscle weakness due to steroids may require inpatient rehabilitation. Steroids should be tapered as rapidly as safely possible.

High-dose systemic methotrexate must be administered in the hospital.

As the cause of primary central nervous system lymphoma (PCNSL) is known, there are known preventative strategies in the immunocompetent population.

Patients receiving immunosuppressive therapy after organ transplantation should receive the smallest effective doses compatible with the viability of the transplant. Corticosteroid-sparing therapy is advised, and lowering of the intensity of immunosuppression, if feasible, is advised for transplant recipients who develop PCNSL.

Patients with HIV who have low CD4⁺ counts are at the greatest risk for PCNSL. The extent to which highly effective antiretroviral therapy will affect the incidence and prognosis of PCNSL in AIDS is not yet known.

Elderly patients

Roth et al found, in a large cohort of 526 PCNSL patients, about 126 who were ≥70 years old. The success with high-dose methotrexate-based chemotherapy was 44% in the elderly versus 57% in the younger patients. The risk of severe leukopenia was greater in the older patients, and the risk of death while on chemotherapy was also greater in this cohort. Progression-free survival was 4.0 months in the elderly compared to 7.7 months in the younger group. Overall survival was shorter, 12.5 months in the elderly group, contrasting with 26.5 months in younger patients. Lastly, older patients were less likely to undergo salvage therapy.

Based on their observations, the authors postulate that PCNSL in older patients is a biologically different tumor that is typically more resistant to treatment. Despite this, older patients with PCNSL can be treated aggressively with prolonged survival. ^[32]  Therefore, a nihilistic approach should be avoided and older patients offered definitive and vigorous therapy aimed an long-term disease control.

The awareness of a different prognosis in different age groups is a significant contribution. The possible benefit of newly developed agents may also identify better treatments for the older PCNSL patient. ^[33]

Immunocompetent patients

The Memorial Sloan Kettering Cancer Center model and the International Extranodal, Lymphoma Study Group  (IELSG) scoring system are the most commonly used indices to estimate prognosis.

The IELSG incorporates both clinical and laboratory radiographic features (age, performance status, serum LDH, CSF protein concentration and involvement of deep brain structures). ^[34]

The Memorial Sloan-Kettering Cancer Center model is a simpler and more widely used model. This model identified age and Karnofsky performance status (KPS) as the two most important variable. Patients age < /= 50 years (class 1) had the best prognosis, those age >/= 50 and KPS < 70 (class 3) had the worst prognosis with those age >/= 50 and KPS > 70 (class 2) had intermediate prognosis. ^[35]

Patients with HIV/AIDS

Prognosis in patients with HIV may be worse than in immunocompetent patients.

One small study showed an average survival of 4 months in patients with HIV compared to 14 months in non-HIV patients. ^[36] More recently two small studies showed that HIV patients treated with active retroviral therapy and high-dose methotrexate based chemotherapy regimens had survival similar to non-HIV patients.{ref49,50} This may reflect more current aggressive treatment practices.

Patients receiving chemotherapy must be educated carefully about the drugs to be avoided in the week prior to chemotherapy and about the fluid and intensive monitoring requirements of their inpatient stay.

Patients who have left the hospital should be encouraged to pursue physical therapy to maximize motor function.

Patients with AIDS should continue to follow the antiretroviral regimen recommended by their physician.

For patient education resources, visit the Cancer and Tumors Center, as well as Brain Cancer.