Approach to the patient with CNS lymphoma

Introduction

Primary central nervous system lymphoma (PCNSL) is defined as lymphoma confined to the central nervous system (CNS) at presentation. By contrast, secondary CNS lymphoma represents a systemic lymphoma (i.e., outside the CNS) that has metastasized to the CNS (e.g., secondary site) either as part of the initial presentation or at relapse. Secondary CNS lymphoma can also manifest as isolated CNS relapse despite systemic remission. Although this chapter focuses on PCNSL, secondary CNS lymphoma shares many similarities in the approach and management.

PCNSL is a rare, aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the CNS with no evidence of prior or current systemic disease. It may involve the brain, eyes, leptomeninges, or the spinal cord. Of note, eye involvement in this context refers to involvement of the vitreous and retina—i.e., ocular lymphoma. In contrast, orbital lymphoma refers to a non-CNS site of extranodal lymphoma; as such, it is not germane to the discussion of CNS lymphoma. PCNSL accounts for 2 to 3% of all primary CNS tumors. The median age of patients with PCNSL is approximately 60 years. Over 90% of cases of PCNSL are classified histologically as diffuse large B-cell lymphoma (DLBCL).

Patients present with progressive and relatively rapid progression of focal neurological symptoms. Over two-thirds of patients present with a focal neurological deficit and over 40% have neuropsychiatric symptoms. Other presenting symptoms include increased intracranial pressure, seizures, and visual disturbances.

Clinical case

Case 13.1

Primary CNS Lymphoma

Case. A 61-year-old female presented in 2009 to an outside hospital with confusion, word-finding difficulties, and absence episodes. MRI of the brain demonstrated a 1.8 cm × 1.4 cm diffusely enhancing mass in the left frontal lobe ( Fig. 13.1A–C ). The patient received corticosteroids. A lumbar puncture (LP) yielded cerebrospinal fluid (CSF) that was abnormal but nondiagnostic by cytology and flow cytometry. A brain biopsy was performed and the specimen was read as suspicious but nondiagnostic for lymphoma. The mass gradually shrunk, the corticosteroids were tapered off, and the patient felt well for 2 years. In 2011, the patient developed floaters; a vitrectomy showed scattered atypical cells but was nondiagnostic. Six months later, a brain mass appeared. A second brain biopsy demonstrated chronic inflammatory cells. The patient came off corticosteroids and was monitored until 2014, when the lesion grew ( Fig. 13.2A–C ). A brain biopsy demonstrated DLBCL. Systemic staging including CT chest, abdomen, and pelvis was negative for systemic involvement. Ocular examination did not reveal involvement of the vitreous. A diagnosis of primary CNS DLBCL was made and the patient enrolled in a clinical trial of high-dose methotrexate (HD-MTX)–based combination chemotherapy. She completed the 6-month regimen and achieved a complete response (CR) that lasted for 3 years. In 2017, the patient had a relapse. She was re-challenged with HD-MTX and again achieved a CR. In 2018, she developed an isolated ocular recurrence and received intravitreal chemotherapy. She continues with stable ocular disease on intravitreal therapy without relapse in the brain or CSF.

Teaching Points: Approach to Evaluation and Management of PCNSL. This patient’s case illustrates several important aspects of the evaluation and management of PCNSL. At presentation, she received corticosteroids, which likely contributed to the initial nondiagnostic pathological specimens. Because of this nondiagnostic pathology, she underwent an LP, vitrectomy, and three brain biopsies before her PCNSL was able to be diagnosed, 5 years after her initial symptoms. Thus, corticosteroids should be withheld in any patient for whom PCNSL (or any lymphoma) is suspected but not yet diagnosed.

In terms of management, she was enrolled in a clinical trial at diagnosis. Although she eventually relapsed, participation in a well-designed clinical trial is the treatment of choice for aggressive primary CNS malignancies including CNS lymphoma. She had a good initial response to HD-MTX–based chemotherapy and when her disease recurred 3 years later, she was able to be re-challenged with methotrexate with good response. Thus, for a patient with a durable response to chemotherapy, re-challenge with the same regimen is a reasonable option.

Her isolated ocular relapse was treated with isolated ocular therapy while her brain and CSF remained disease free. For a patient with isolated ocular disease, local therapy to the eyes is a reasonable option.

This case raises several important clinical questions for consultants evaluating and managing these patients. The remainder of the chapter will address each of these clinical questions:

• 1.

  Is lymphoma in the differential diagnosis for this new brain lesion?

• 2.

  In biopsied-confirmed CNS lymphoma, is this primary or secondary CNS lymphoma?

• 3.

  Is the patient immune competent or immunocompromised?

• 4.

  What is the approach to management of immunocompetent PCNSL?

• 5.

  What is the approach to management of immunocompromised PCNSL?

• 6.

  What is the approach to management of relapsed or refractory PCNSL?

Approach to the initial diagnosis of CNS lymphoma

About two-thirds of immunocompetent patients with PCNSL initially present with a solitary brain mass. Involvement of the brain hemispheres is the most common localization (38%), followed by thalamus and basal ganglia (16%), corpus callosum and related structures (14%), periventricular loci (12%), and the cerebellum (9%). MRI of the brain typically demonstrates periventricular homogenous contrast enhancement with well-defined borders, low signal on T2-weighted imaging, and restricted diffusion on diffusion-weighted imaging. Less typical presentations such as an intraventricular mass, cranial or radicular nerve enhancement, or isolated meningeal enhancement have been described. In patients who are immunocompromised, imaging findings may be atypical with multiple, ring-enhancing, or patchy enhancing lesions being observed.

Suggestive imaging must be followed by histopathologic confirmation. Tissue diagnosis is essential as the differential diagnosis on MRI of the brain includes multiple sclerosis, sarcoidosis, and occasionally gliomas. Like lymphoma, these entities may demonstrate a transient response to corticosteroids. Therefore, unless the patient is deteriorating, one must avoid corticosteroid administration prior to the proper evaluation of the patient with suspected PCNSL. The potent lympholytic property of corticosteroids will commonly lead to necrosis of lymphoma, rendering tissue nondiagnostic as occurred in the patient described above.

Differentiating primary and secondary CNS lymphoma

For a patient presenting with a possible CNS lymphoma on imaging, the initial decision on the site of tissue diagnosis will also depend on imaging of the chest, abdomen, and pelvis, typically with CT. Some centers use positron emission tomography (PET) CT scan with fluorodeoxyglucose (FDG) (PET-CT). Imaging of these sites accomplishes two purposes: (1) It distinguishes primary from secondary CNS lymphoma and, (2) if suggestive of systemic lymphoma, it determines a site for biopsy. If systemic lymphadenopathy is present, a lymph node biopsy is the biopsy site of choice, as it will reveal the lymph node architecture that informs the subtype of lymphoma and allows comprehensive molecular analysis, which in turn oftentimes will guide therapy. Men with negative systemic imaging should have a testicular ultrasound (US) to rule out primary testicular lymphoma, which, though uncommon as a primary site, has a significant risk of CNS metastasis. Bone marrow aspirate and biopsy have been recommended in some guidelines as part of the evaluation for systemic lymphoma. If the described staging is negative, however, the likelihood of finding isolated bone marrow lymphoma as a source of CNS involvement is 2.5%, calling into question the utility of this procedure.

Once the CT of chest, abdomen, and pelvis and, in men, testicular US are confirmed negative, three options exist for tissue diagnosis and should be pursued in order from least to most invasive.

• 1.

  Lumbar puncture. If not contraindicated by elevated intracranial pressure, the least invasive method to diagnose PCNSL is an LP. Importantly, the CSF analysis should be of high volume (>10 mL) and must include flow cytometry and ideally reviewed by a hematopathologist, in addition to routine analysis and cytology. CSF cultures are not necessary in the absence of symptoms or signs of infection and allows for prioritizing CSF to more relevant tests. MRI should be performed prior to the LP to avoid nonspecific meningeal enhancement caused by the procedure. This enhancement can mimic leptomeningeal disease. For patients with immunocompromised PCNSL, the presence of positive CSF Epstein-Barr virus (EBV)-polymerase chain reaction (PCR) in the setting of typical imaging of CNS lymphoma is diagnostic and can mitigate the need for brain biopsy.

• 2.

  Slit lamp examination (SLE). SLE should be performed to detect cells in the vitreous and/or retinal infiltrates. A suspicious finding on SLE would be followed by a vitrectomy or, in some cases, by a retinal biopsy.

• 3.

  Brain biopsy. If both the LP and SLE are negative, the patient should have a brain biopsy. Although a positive LP or vitrectomy will spare the patient a brain biopsy, the patient who has been diagnosed by brain biopsy first should still undergo an LP and SLE to establish the presence or absence of disease in the CSF and/or ocular compartment, respectively. The latter patient with suspicious findings on SLE would not require a vitrectomy to establish ocular involvement. As mentioned earlier, corticosteroid administration increases the risk of a nondiagnostic biopsy usually characterized by necrosis. In case of a nondiagnostic biopsy after corticosteroid administration, serial imaging after withdrawal of corticosteroid therapy may be performed with repeat biopsy after radiologic evidence of tumor regrowth.

Whereas the vast majority of PCNSL are DLBCL, the finding of Burkitt, low-grade, or T-cell lymphoma will alter the management. Clinically, the most important tumor cell marker is the lymphocyte surface CD20, which predicts therapeutic response to anti-CD20 antibodies such as rituximab.

The pathologic evaluation of CSF should include cell counts, protein, glucose, histology, cytology, and flow cytometry. The latter three tests should also be performed on vitreous fluid. The sensitivity of CSF cytology in diagnosis of PCNSL is only 15%. Flow cytometry is more sensitive. If the initial CSF analysis suggests but does not confirm (e.g., elevated protein concentration or presence of lymphocytes read as “atypical” or “suspicious”) lymphoma, a repeat LP may be diagnostic. If the initial CSF is normal, however, a repeat sample will have a low diagnostic yield. Finally, PCR detection of immunoglobulin (IgH) gene rearrangements in CSF may also be helpful, as it does not require intact cells.

Approach to the immunocompetent patient with PCNSL

Once a diagnosis of PCNSL is established, the immune function of the host is a critical first step in determining the optimal approach to managing the patient. Although immunodeficiency and immunosuppression are the main risk factors for the development of PCNSL, most cases occur in immunocompetent individuals.

PCNSL should be approached as a “whole brain disease.” Pretreatment clinical evaluation should include a detailed history and physical examination with careful assessment of neurologic deficits and lymphadenopathy that may suggest systemic disease. Cognitive function testing with neuropsychologic batteries should be performed at baseline and during follow-up visits to watch for potential treatment toxicities. Often, patients at diagnosis are floridly ill and cannot participate in such testing. Laboratory testing should include HIV and hepatitis serologies, lactate dehydrogenase, and hepatic and renal function tests. Although some guidelines recommend a bone marrow aspirate and biopsy, this procedure has a yield of only 2.5% in detecting isolated bone marrow lymphoma as a source of secondary CNS lymphoma. Therefore, many centers do not perform this procedure as part of the evaluation for CNS lymphoma.

Prognosis . The prognostic significance of the classic Ann Arbor staging system does not apply to PCNSL. Several prognostic scoring systems are used for PCNSL. ^, The simplest prognostic score distinguishes three groups on the basis of age and Karnofsky performance status (KPS)—age <50 years, age >50 years plus KPS >70, or age >50 years plus KPS less than 70—which correlate with median overall survivals of 8.5, 3.2, and 1.1 years, respectively. In daily practice, this system is simple to use and offers at least a rough estimate of prognosis.

Treatment of immunocompetent PCNSL

As with any serious illness, the optimal patient management is entry onto a clinical trial, as was the case in the patient described previously. Unlike most CNS malignancies, the goal of therapy for PCNSL is long-term disease control. Because PCNSL generally responds very well to therapy, most patients, even if severely ill, should be considered for aggressive treatment.

• Surgery. Traditionally, surgery has had no role in the management of PCNSL with the exception of placement of an Ommaya reservoir for the administration of intrathecal therapy. The rapid response to corticosteroids, chemotherapy, and radiation therapy obviate a role for surgical resection. The occasional patient whose brain mass has a radiographic appearance of a glioma may undergo a resection with the unexpected pathologic finding of lymphoma.

• Phases of treatment. Therapy for newly diagnosed hematologic malignancies including PCNSL is often divided into three phases: induction, consolidation, and maintenance. Induction refers to the initial therapy, generally with multiagent chemotherapy, with the goal of cure or at least a CR (i.e., no evidence of active cancer detectable on physical examination, CNS imaging, repeat SLE, and, if positive at diagnosis, a repeat LP). Successful induction is then followed by consolidation, which may involve chemotherapy and/or radiation therapy with the goal of consolidating the CR. Thereafter, maintenance therapy may be given with the goal of preventing or delaying disease recurrence, although the efficacy of maintenance therapy in PCNSL is unproven.