26 Natural History and Management Options of Cerebral Lymphoma

Jordan Elizabeth Cory and Mohammed Awad

Abstract

Cerebral lymphomas are relatively uncommon tumors that affect the lymph tissues of the brain. By definition, there is no coexisting systematic disease at the time of diagnosis. The natural history is difficult to assess due to evolving treatment over time, heterogeneity of patient population, and early intervention. Most cases require stereotactic brain biopsy for formal histopathological diagnosis prior to chemotherapy with either WBRT or autologous stem cell transplant. There is growing evidence to suggest survival benefit from cytoreductive surgery in carefully selected patients.

The current (2016) World Health Organization (WHO) classification of central nervous system (CNS) tumors divides CNS lymphomas into a number of subtypes based on the cell of origin and histological features.1 These include the following:

●Diffuse large B-cell lymphoma (DLBCL) of the CNS:

○Primary CNS lymphoma (PCNSL).

○Secondary CNS DLBCL.

●Immunodeficiency-associated CNS lymphomas:

○Acquired immunodeficiency syndrome (AIDS) related DLBCL.

○Epstein–Barr virus (EBV) positive DLBCL, not otherwise specified (NOS).

○Lymphomatoid granulomatosis.

●Intravascular large B-cell lymphoma.

●Miscellaneous rare lymphomas:

○Low-grade B-cell lymphomas.

○T cell and natural killer (NK)/T-cell lymphomas.

○Anaplastic large cell lymphoma.

●Mucosa-associated lymphoid tissue (MALT) lymphoma of the dura.

PCNSLs are patternless, highly cellular, DLBCLs isolated to the CNS. PCNSLs are mature B cells that are PAX5, CD19, C30, CD33, and CD79a positive, most expressing BCL6.¹ Whereas MALT lymphoma of the dura and miscellaneous rare lymphomas also present confined to the CNS, they are considered a different entity to PCNSL as per the 2016 WHO classification of CNS tumors.¹

PCNSLs are a non-Hodgkin’s lymphoma and account for 2.4 to 3% of all primary brain tumors, correlating to an incidence rate of 4.7 per million person-years.^{1,​ 2} PCNSLs comprise 4 to 6% of extranodal lymphomas.¹ PCNSLs are most commonly associated with immunosuppression, either genetic (e.g., ataxia–telangiectasia, Wiskott–Aldrich syndrome, or IgA deficiency) or acquired (e.g., AIDS, post organ transplantation).² EBV exposure has been shown to be associated with PCNSLs in immunocompromised individuals.^{1,​ 3} Etiology in immunocompetent individuals remains to date unknown; genetic predisposition has not been described, and viruses, including EBV), have been shown to have no role.^{1,​ 2}

The characteristics and clinical presentation of PCNSL are summarized in Table 26.1. PCNSLs have a predominance in men, with a male-to-female ratio of 3:2.¹ The median age of diagnosis is 56 years for immunocompetent patients and younger in human immunodeficiency virus (HIV) associated PCNSLs at 37 years.^{4,​ 5} Typically, the duration of symptoms is short (at most a few months). In the recent years, there has been an increase in the incidence of sporadic, non-EBV-associated PCNSLs in immunocompetent individuals, which are particularly seen in older patients (50–80 years).^{5,​ 6} The rising incidence has been attributed by some to the increasing life expectancy and growing elderly population. Incidence rate in those older than 70 years is 10 times higher than in the general population.⁷ Historically, the incidence of PCNSLs rose throughout the 1980s and 1990s, attributable at least in part to the concurrent epidemic of AIDS and increasing use of immunosuppressant medications in patients.⁸ The rising incidence not explained by the AIDS epidemic has been attributed by some to the increasing life expectancy and growing elderly population.⁶

Table 26.1 Characteristics and clinical presentation of PCNSL^{1,​ 2,​ 9}

26.2 Diagnosis and Evaluation

Comprehensive neurological, cognitive, and physical examination should be performed in all patients including careful examination of peripheral lymph nodes, and testes in men.10 A guideline to diagnostic and prognostic investigations is summarized in Table 26.2. Age and performance status, Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status (KPS), should also be documented.

Table 26.2 Primary CNS lymphoma baseline diagnostic and prognostic evaluation⁹

Cerebrospinal fluid (CSF) analysis is recommended for evaluation of extent of disease, rather than diagnosis.⁹ Lumbar puncture should be performed in all patients, unless contraindicated, to assess for occult leptomeningeal disease. It is important to note CSF cytology has a low and variable sensitivity of 2 to 32%.³ In a systematic review of 472 patients, preoperative lumbar puncture obviated diagnostic surgery in only 7.4% of patients.¹¹ However, during follow-up, this positive CSF increases to 14.9%, suggesting yield increases with number of lumbar punctures.¹¹ Sensitivity increases with CSF volume analyzed and cytology of at least 3 mL, ideally greater than 10 mL, should be performed. It is important to note that corticosteroid use has been postulated to decrease sensitivity of cytology.³ However, one study showed no reduction in sensitivity with pretreatment with corticosteroids; however, this study was limited by a small noncorticosteroid cohort.¹² Including flow cytometry in addition to standard cytopathology has been suggested to increase sensitivity for occult leptomeningeal disease in the order of 43 to 50%.^{13,​ 14} Flow cytometry also limits false positives due to misinterpretation of reactive lymphocytes as malignant cells.¹⁴ To avoid false positives, CSF should be sampled before or 1 week after brain biopsy.⁹ Identification of lymphoma cells within CSF or vitreous fluid together only with high clinical and radiological suspicion for PCNSL can preclude the need for brain biopsy in high surgical risk patients.¹⁵ As outlined, cytological diagnosis is often difficult, and review by a specialist pathologist is recommended.

A detailed ophthalmologic examination of all patients, including those without ocular symptoms, with suspected PCNSL is necessary. In the 15 to 25% of PCNSL patients with intraocular involvement, it is possible to make a diagnosis without brain biopsy.³ The most common finding on examination and history is chronic posterior uveitis.¹⁶ Vitreal biopsy, chorioretinal biopsy, or fine-needle aspiration of subretinal lesions can confirm the diagnosis.¹⁶

Given the aggressive nature of PCNSLs, prompt diagnosis to aid early treatment is critical to improving survival.⁹ Significant diagnostic delay has been noted; PCNSLs compared with glioblastoma multiforme in one study noted mean time of 41.7 versus 16.2 days from initial neuroimaging to histologic diagnosis.¹⁷ Navigation-guided or stereotactic brain biopsy is the gold standard of immunohistochemical diagnosis of lymphoma and lymphoma type.^{2,​ 10} PCNSL diagnosis is made much less frequently via CSF cytology and flow cytometry or vitrectomy/chorioretinal biopsy. Given that stereotactic biopsy is safe and the diagnostic yield of lumbar puncture is low, early stereotactic brain biopsy is preferred as it can avert diagnostic delay.¹¹

26.2.1 Imaging

Imaging is not sufficient to differentiate PCNSL from other tumor types such as gliomas, space-occupying inflammatory lesions including tumefactive demyelination, acute disseminated encephalomyelitis and neurosarcoidosis, or more rarely infectious space-occupying lesions such as cerebral toxoplasmosis or abscess. Around 40 to 80% of PCNSLs initially treated with corticosteroids demonstrate radiological regression.^{18,​ 19} Magnetic resonance imaging (MRI) with gadolinium contrast is the most sensitive imaging modality in the diagnosis of PCNSL (Fig. 26.1). Characteristic lesions demonstrate homogenous contrast enhancement with well-defined borders.⁹ Radiologically, the MRI enhancement pattern is more variable in HIV-associated and immunosuppressed patients with ring enhancement in up to 75% of cases (vs. 0–13% in nonimmunosuppressed patients).²⁰ Multifocal disease is also more common in immunosuppressed patients.¹²

Vasogenic edema usually surrounds the lesion but is less prominent than in glioma or metastasis.^{9,​ 12} Fig. 26.1 demonstrates characteristic findings useful in differentiating PCNSLs from other lesions including a low signal on T2-weighted MRI and restricted diffusion on diffusion weighted imaging (DWI) MRI due to high nucleus-to-cytoplasm ratio and high cellular density.^{9,​ 21} Corticosteroid-induced radiological remission is common but is not diagnostic and does not rule out demyelinating or inflammatory diseases.^{9,​ 10} Rarely, PCNSLs can been seen as subtle focal abnormalities of cranial or radicular nerves or focal meningeal enhancement.^{9,​ 8} F-fluorodeoxyglucose (FDG) or ¹¹C-methionine positron emission tomography (PET) has been suggested to predict early response to therapy and early disease recurrence during posttreatment surveillance before it can be visualized on MRI; however, studies so far have been limited by small numbers.^{22,​ 23}

26.3 Selected Papers on Natural History of PCNSL

●Abrey LE, Ben-Porat L, Panageas KS, et al. Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 2006;24(36):5711–5715

PCNSL remains an aggressive disease with poor prognosis with age, performance status, and immune status universally accepted prognostic factors. PCNSL has a much poorer outcome than systemic DLBCL. The 5-year overall survival (OS) is 33% and if left untreated, the mean OS is 1.5 months.9 This has been postulated to be due to evasion of the neoplastic B cells from T-cell lymphocyte surveillance via frequent loss of human leukocyte antigen (HLA) class I and/or class II seen in PCNS DLBCL.⁹ Although similarly widely recognized to be a whole brain disease, unlike gliomas, when PCNSL relapses, it is often in a radiographic area remote to the primary site of disease suggesting microscopic early evasion from the neurovascular unit.²⁴ Occasionally, PCNSL can metastasize outside the CNS.² Prognosis of PCNSL has improved significantly, with median OS improving from 2.5 months in the 1970s to 26 months in the 2010s.⁷ This phenomenon likely represents natural history of untreated or poorly treated PCNSL in the early years with improving outcomes with modern treatment particularly increasing prevalence of high-dose methotrexate (HD-MTX) induction therapy. Interestingly, despite treatment advances, no improvement in median OS in those older than 70 years (OS: 6–7 months) has been observed in the same time period as seen in Fig. 26.2.^{5,​ 7} This is hypothesized to be due to deteriorating functional status and increasing comorbidities, particularly deteriorating renal function, limiting the use of HD-MTX induction therapy.

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