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Year : 2016  |  Volume : 11  |  Issue : 3  |  Page : 232-239

Primary intracranial lymphomas

1 Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
2 Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
3 Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah; Department of Pathology, King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia

Date of Web Publication5-Apr-2016

Correspondence Address:
Jaudah A Al-Maghrabi
Department of Pathology, Faculty of Medicine, King Abdulaziz University, P. O. Box 80205, Jeddah 21589
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1793-5482.145082

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Background: Primary CNS lymphoma (PCNSL), a rare form of aggressive extranodal non-Hodgkin's lymphoma (NHL), has increased in incidence during the last three decades and occurs in both immune compromised and immune competent hosts. It has an overall poor prognosis.
Objective: This study attempts to further delineate the clinico-pathological, immunohistochemical and radiological profile of PCNSL at Jeddah to King Faisal Hospital and Research Center.
Methods: Computerized search through the archives of King Faisal Hospital and Research Centre between July 2000- December 2012 identified 15 patients with pathologically confirmed PCNSL.These were analyzed retrospectively. Their clinico-pathological, immunohistochemical and radiological data were analyzed.
Results: Of the 15 PCNSL patients, 8 (53.3%) were females and 7 (46.6%) were males. There was female predilection especially in the age group of 40-59 years. Mean age at diagnosis for all patients was 50.4 years. There was no patient in the pediatric age group. The most common location in the brain was the frontal region in 7 patients (46.6%), 7 (46.6%) had multiple intracranial masses; all 15 (100%) were Non Hodgkin B-cell lymphomas, among which 13 (86.6%) were diffuse large B-cell lymphomas. All 15 (100%) cases showed diffuse and strong positivity for CD 45, and CD 20. Fourteen patients were immune competent while one was immune compromised.
Conclusions: PCNSL often occurs in middle-aged and aged patients. There is female predilection especially in the middle age. Frontal region is the most common location with diffuse large B-cell lymphoma being the predominant subtype.

Keywords: Central nervous system, lymphoma, primary

How to cite this article:
Mufti ST, Baeesa SS, Al-Maghrabi JA. Primary intracranial lymphomas. Asian J Neurosurg 2016;11:232-9

How to cite this URL:
Mufti ST, Baeesa SS, Al-Maghrabi JA. Primary intracranial lymphomas. Asian J Neurosurg [serial online] 2016 [cited 2021 Jan 23];11:232-9. Available from:

  Introduction Top

Primary central nervous system lymphoma (PCNSL) is defined as an aggressive extranodal, high-grade B-cell neoplasm of the CNS and eye. Excluded are lymphomas of the dura and those with evidence of systemic disease, CNS secondary lymphomas and all immunodeficiency-associated lymphomas arising in the brain, spinal cord, cerebrospinal fluid and eyes in the absence of lymphoma outside the nervous system at the time of diagnosis. In the updated 2008 World Health Organization (WHO) classification of lymphomas, primary diffuse large B-cell lymphoma (DLBCL) of the CNS is recognized as a separate entity under “Aggressive lymphoma/leukemia”.[1],[2]

The incidence of CNS lymphoma has been increasing over the past two decades [3] and according to the most recent central brain tumor registry of united states (CBTRUS)[4] statistical reports it now represents 2.3% of all primary brain and central nervous system tumors in USA. The age-adjusted incidence is 0.46/100,000 and appears to be increasing over time. Approximately 1,000 new cases are diagnosed annually in the United States.[4]

The study of PCNSL is important for several reasons. Firstly because nothing is known about how lymphoma arises in an organ, which is immunologically privileged and gives sanctuary to the malignant lymphocytes among immune competent individuals.[5]

Secondly once a rare tumor and the subject of individual case reports, PCNSL now afflicts approximately 1,000 people in the United States each year [6] and has shown a trend towards an increase in incidence over the past three decades [3],[7] contributing to an increasingly important differential diagnosis of intracranial mass lesions.

Third, the blood-brain barrier (BBB) is critically important because much of the tumor resides behind an intact BBB and often cannot be visualized radiologically.[8] Finally, because the brain is the non-regenerative organ there has been a longstanding concern that even if effective therapy were to become available for malignant primary brain tumors, eradication of the tumor may not necessarily translate into improved neurologic outcome. However, PCNSL serves as a shining example that this is not the case. Since PCNSL is a highly radio and chemo sensitive tumor if treatment is effective and does not damage the brain, it can prolong remission and even cure patients.[6]


This study attempts to present the clinico-pathological, immunohistochemical and radiological profile of PCNSL at King Faisal Hospital and Research Center, Jeddah. We also present the most recent literature review in the understanding of PCNSL.

  Method Top

A computerized search through the archives of the Anatomical Pathology Department at King Faisal Hospital and Research Center, Jeddah between the years January 2000 and December 2012, was performed to identify all cases of PCNSL inclusive of all regions of the brain. For inclusion into this analysis, patients had to have a confirmed histological diagnosis of central nervous system lymphoma in the absence of any radiologic evidence of systemic involvement. The patient had to have a follow-up of 6 months to be included in this analysis. The data was filtered using appropriate morphology Systematized Nomenclature of Medicine codes indicating the following parameters: Date of receiving biopsy, personal identity (medical record number, age, sex etc.,) clinical diagnosis, morphology and topography. The data was rechecked manually to delete duplications. Computerized search was then exported to Microsoft Excel format and used for analysis. Specific target group of PCNSL was identified. 15 cases of PCNSL were retrieved. These were analyzed retrospectively. The clinical data analyzed were: Age at diagnosis, date of clinical onset, symptoms described, imaging data, tissue sampling method, primary CNS origin, past medical history, immune status and human immunodeficiency virus (HIV) serology findings, number and location of lesions, involvement of deep brain structures and outcome. Data were analyzed using the program Statistical Package for the Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA). Descriptive and frequency statistics were obtained for the variables studied. The procedures followed in the present study were in accordance with the ethical standards of the hospital ethical committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Lesions were reclassified using the Revised European American Lymphoma Classification WHO classification updated in 2008.[2]

The patients underwent magnetic resonance imaging (MRI) scan of the brain at diagnosis as well as computerized tomography (CT) scans of the chest, abdomen and pelvis and lumbar puncture at diagnosis. A repeat MRI scan to assess response was done after the end of chemotherapy in those who were managed with combined modality therapy. All patients had an evaluation of response at the end of all planned treatment with an MRI and were then followed at 3 monthly intervals with a follow-up MRI scan as well as clinical evaluation to assess residual neurologic deficit and/or long-term toxicity from treatment. Biopsies taken were subjected to five-micron-thick sections stained with hematoxylin and eosin which were reviewed by two pathologists for morphological features of the lymphoma. Immunohistochemical staining using Ventana automated stainer with the avidin-biotin-peroxidase complex method was performed using the antibodies CD45 (dilution 1:0; Dako, Denmark), CD20 (dilution 1:50; Dako, Denmark), CD3 (dilution 1:50; Nova, UK), CD30 (dilution 1:25 Dako, Denmark), CD79a (dilution 1:50; Dako, Denmark), CD10 (dilution 1:100; Nova, UK), Bcl-2 (dilution 1:25 Dako, Denmark), Bcl-6 (dilution 1:25; Nova, UK), Tdt (dilution 1:10 Dako, Denmark), CD68 (dilution 1:100; Dako, Denmark), CD1a (dilution 1:10; Cell Marque, USA), Cyclin D1 (dilution 1:10; Cell Marque, USA), Pancytokeratin (dilution 1:50; Dako, Denmark), GFAP (dilution 1:50; Dako, Denmark), Chromogranin (dilution 1:200; Nova, UK), Lambda light chain (One drop, Dako, Denmark) and Synaptophysin (dilution 1:10 Dako, Denmark). Antibodies were used to highlight the cell lineage and as the case scenario necessitated. Results were scored as follows: −, not seen; +/−, rare/focal positivity; and +/, diffuse positivity. Positive and negative controls were performed for the stains. Clinical data were obtained from the patients' hospital records and follow-up was obtained on a personal basis from the concerned neurosurgical and medical teams. Initial investigations performed in these patients were as follows CT MRI brain, chest X-ray, CT abdomen and chest and lesional biopsy, MRI was available in 13 cases while in two cases only CT findings were available.

  Results Top

All patients in the study group were Saudi nationals. Of the 15 PCNSL patients, 8 (53.3%) were females and 7 (46.6%) were males. There was female predilection especially in the age group of 40-59 years. Mean age at diagnosis for all patients was 50.4 years. Five patients (33.3%) were more than 45-year-old. There was no patient in the pediatric age group. The most common location in the brain was the frontal region in 7 patients (46.6%). Seven patients (46.6%) had multiple intracranial masses. All 15 (100%) were non Hodgkin B-cell lymphomas, among which 13 (86.6%) were DLBCL. All the cases displayed a characteristic nuclear and cytoplasmic pattern of lymphoid cell with an angiocentric pattern and variable parenchymal infiltration [Figure 1]. All cases showed diffuse and strong positivity for CD 20 [Figure 2]. A total of 14 patients were immune competent while one was immune compromised. Seven (46.6%) of the patients had multiple lesions. Three out of seven cases with multiple lesions were also bilateral.
Figure 1: The diffuse infiltration of glial parenchyma by atypical lymphocytes with irregular nuclear contours and prominent nucleoli

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Figure 2: The immunohistochemical marker CD20 as staining strongly positive in the atypical lymphocytes

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[Table 1] and [Illustration 1] presents the age and sex distribution of PCNSLs, [Table 2] presents the radiological features and [Table 3] presents the histological subtype and immunohistochemical features. [Illustration 2] illustrates the location and [Illustration 3] the number (frequency) of PCNSLs. Thirteen patients were diagnosed on MRI brain while 2 cases were diagnosed by CT brain. Radiological studies of chest, abdomen, pelvis and neck showed no evidence to suggest a nodal primary source.
Table 1: Age and sex distribution of PCNSLs at KFHRC, Jeddah, Saudi Arabia

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Table 2: Radiological features of PCNSLs at KFSHRC, Jeddah, Saudi Arabia

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Table 3: Histological subtype and immunohistochemical characteristics of PCNSLs at KFSHRC, Jeddah, Saudi Arabia

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Medical and radiological follow-up (MRI) was available in 5 cases with a mean survival time of 1 year 2 months.

  Discussion Top

The increase in incidence of PCNSL could be related partly to the acquired immune deficiency syndrome (AIDS) epidemic.[9],[10],[11] the other risk factors for PCNSL have included acquired or hereditary immune deficiency states, i.e. infection with human immune deficiency virus, organ transplantation, severe combined immmune deficiency, ataxia-telangiectasia, Wiskott-Aldrich syndrome as well as autoimmune or inflammatory disorders requiring long term immune suppression such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, myasthenia gravis and vasculitides.[12] It is over 1000 times greater in HIV positive than in non-HIV populations.[10],[11],[13] As in the present study, the incidence rates of PCNSL are also increasing among immune competent patients. Similar studies have been reported to literature.[3],[11],[14]

Evidence of Epstein-Barr virus (EBV) genome is present in more than 95% of AIDS-related PCNSL which suggests its major role in lymphoma pathogenesis in this group.[15] Incidence of EBV positive PCNSL is higher in Japanese than previously reported from western countries reflecting additional role of variable epidemiological factors.[16]

However, the etiology of PCNSL in immune competent patients is still unclear. Several hypotheses have been proposed to explain how lymphomas arise and grow primarily in the CNS. The theory of highly selective tropism of PCNSL suggests that B-cells may be transformed outside the CNS and then develop adhesion molecules specific for CNS tropism.[17] Recently, some specific genes involved in CNS tropism of PNCSL such as SPP1, a member of the extracellular matrix-related genes and DDR1, a member of a family of receptor tyrosine kinases involved in cell adhesion in several brain tumors, were found to be unregulated in PCNSL.[18] These findings support the theory of highly selective tropism of PCNSL. Alternatively polyclonal inflammatory cells in the brain may transform to monoclonal PNCSL. This theory is supported by occasional reports of “sentinel lesions” which are biopsy-proven demyelinating or non-neoplastic lesions but ultimately lead to PCNSL months to years later.[19]

We compared our results to other recent national and international studies on PCNSL [Table 4] and [Table 5].[20],[21],[22],[23],[24],[25],[26]
Table 4: Analytical comparison of PCNSL at KFSHRC, Jeddah with other national studies[20],[21],[22]

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Table 5: Analytical comparison of PCNSL at KFSHRC, Jeddah with other recent international studies[23],[24],[25],[26]

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Most of these studies indicate that percutaneous nephrolithotomy (PCNL) is common between 4th and 6th decade of life, with a male to female ratio of near unity, being predominantly of DLBC type located mainly in the cerebral hemispheres and having a mean survival time between 4 months and 17 months. An epidemiological study reported that PCNSL incidence for ages 20-49 years for Black patients was twice that for Whites.[27] Incidence for ages over 49 years for Whites was twice that for Blacks.[27] Earlier acquisition of PCNSL in Black populations could reflect environmental factors separate from HIV infection and genetic risks Survival at 12 months, 24 months and 60 months was higher among Whites than Blacks. Research is needed to determine the origin of these differences.[27]

DLBCL accounts for approximately 90% of all PCNSLs, affecting the brain parenchyma with or without concomitant ocular or leptomeningeal involvement. The remaining 10% of cases comprise even more rare pathological entities such as low-grade PCNSLs, T-cell lymphomas and Burkitt's lymphomas.[7],[28],[29] The indolent course of low-grade PCNSL, long-term survival compared with patients who have high-grade PCNSL and the possibility of disease control with focal treatment or even no treatment, all denote similarities to the clinical course of systemic low-grade lymphomas.[30] In most of the cases, the malignant B cells have a centroblastic morphology and are CD79a+, CD20+, PAX-5+, BCL-2+, MUM1/IRF4+. BCL-6 is frequently positive and CD10 is less so. PCNSL cells also express high levels of c-MYC, which has been associated with adverse prognosis in systemic DLBCL.[31]

Histologically, PCNSL is indistinguishable from systemic non-Hodgkin's lymphoma (NHL). Biologically, PCNSL behaves in an aggressive fashion and it should be considered a high-grade tumor.[5] Genetically, PCNSL has been found to demonstrate clonal abnormalities of chromosomes 1, 6, 7 and 14, identical to those detected in systemic NHL. Analysis of cell surface markers including neural cell adhesion molecule and integrins is also identical to that of systemic lymphoma. p15 and p16 deletions have also been reported in PCNSL tumors.[5] Pan genomic analyses of chromosomal imbalances by comparative genomic hybridization have shown frequent chromosome 6q loss (60-75%) in PCNSL patients.[32] Nakamura et al.[33] refined the candidate region suspected to contain a lymphoma-related tumor suppressor gene in the 6q22-23 locus by a fine loss of heterozygosity deletion mapping of 6q in PCNSL. The protein tyrosine phosphatase, receptor type, K (PTPRK) gene seems a relevant candidate gene, because it is involved in the regulation of cell contact and adhesion and a loss of protein expression was observed in most (76%) of the PCNSLs tested. The protein that this gene encodes belongs to the protein tyrosine phosphatase superfamily of enzymes. Further studies to identify gene mutations and/or rearrangements are needed to ascertain the involvement of PTPRK in PCNSL tumorigenesis. Interestingly, the authors showed that chromosome 6q loss was found at a significantly higher rate in PCNSL than in systemic DLBCL and was correlated with shorter survival.[32] An independent study of 75 newly diagnosed HIV-negative PCNSL patients investigated by interphase fluorescence in situ hybridization analysis confirmed frequent del (6)(q22) chromosome deletion, with prevalence of 45% and its negative impact on overall survival.[34] Chromosome 6q loss therefore represents a prognostic marker in PCNSL.

Recently, expression profiling and genomic screening have provided new insight into understanding the poor prognosis of PCNSL patients. Based on lymphochip complementary deoxyribonucleic acid (cDNA) microarrays, recently, three molecularly distinct forms of systemic DLBCL in immune competent patients were identified as germinal center B-cell–like (GCB), the activated B-cell–like (ABC) and the so-called type III.[35] Interestingly, patients with the GCB signature had a significantly better outcome than those with the ABC profile.[35] PCNSLs have been shown to frequently express BCL-6[31],[36] and to carry an extremely high load of somatic mutations of immunoglobulin genes and several oncogenes demonstrating aberrant ongoing hypermutation.[37] Because such ongoing hypermutation and BCL-6 expression are considered as germinal center (GC) markers, it has been postulated that the cell of origin of PCNSL passes through the GC microenvironment and that these neoplasms correspond to the GCB subgroup as defined for DLBCL [38] However, recent immunoprofiling [36] and gene expression studies using cDNA microarrays [31] demonstrated that PCNSL may exhibit characteristics associated with both the ABC and GCB subtypes. Thus, PCNSLs may correspond to an overlapping B-cell differentiation time slot, that is, the late GC/early post-GC. The fact that several studies have shown that the DLBCLs of the GCB group have a significantly better outcome than the others and have correlated these results with distinct oncogenic mechanisms it seems reasonable to emphasize diagnostic differentiate between the two cell lineages in order to predict the better outcome groups.

The lesion is single in 60-70% of patients.[3] The most common localization sites of PCNSL (both B and T cells type) are in the supratentorial white matter of the frontal parietal lobes [39] accounting for 38%.[3],[40] Other sites include thalamus/basal ganglia 16%, corpus callosum 14%, periventricular region 12%, cerebellum 9%, eyes 5-20%, meninges 16%.[3],[40] Gliomas, metastases, toxoplasmosis, sarcoidosis, abscesses and progressive multifocal leukoencephalopathy are the main differential diagnoses, requiring brain biopsy for definitive diagnosis. In addition to brain involvement, the eye is involved in ~20% of patients, only half of whom have any visual complaints; visual symptoms are typically floaters or blurred vision.[3]

CT scans and MRI typically show characteristic single or multiple periventricular, homogeneously enhancing lesions in 100% of PCNSL.[41] However, PCNSL is potentially associated with a large spectrum of radiological presentations and can simulate inflammatory (sarcoidosis, multiple sclerosis) or infectious (acute disseminated encephalomyelitis) diseases or other brain tumors (meningiomas, malignant gliomas, gliomatosis cerebri, brain metastases) as such diagnosis may be difficult to establish.[11] As such, patients with a radiologic suspicion of gliomas, metastasis, meningiomas, or other tumors are routinely referred for complete resection, sometimes resulting in an unexpected diagnosis of lymphoma. Other unusual presentations of PCNSL reported are neurolymphomatosis and pituitary lymphomas.[42] Magnetic resonance spectroscopy and perfusion MRI seem helpful tools when showing some suggestive abnormalities.[43],[44]

Chemotherapy and radiation, or chemotherapy alone may then be used as the primary treatment. Lymphomas are not usually treated with surgery as they tend to occur deep within the brain in which case the risk of neurological complications is high.[45] PCNSL surgery is therefore restricted to diagnostic biopsy. Stereotactic brain biopsy is the most appropriate method for diagnosis of PCNSL.[13],[45],[46]

Overall, PCNSL carries a worse prognosis compared with non-CNS extranodal DLBCL. With active chemotherapy/radiotherapy treatment, median survival up to 51 months has been reported.[45] In the present study, clinical follow-up at 12, 18, 24 months was available in 4 of 15 patients (26.66%) among which 3 (20%) are surviving at 24 months and one at 18 months. Three patients were declared as deceased. It remains unclear whether the dismal outcome of PCNSL patients compared with patients with systemic DLBCL is attributable to the immune-privileged cerebral location or reflects a specific aggressive intrinsic biologic behavior. The fact that unlike the western countries, the association of PCNSL with HIV/AIDS in India is very low in spite of substantial prevalence of HIV/AIDS [25] cases suggests that there is geographic variation in the risk factors.

The present study has certain limitations and the presented results should be interpreted keeping them in mind. The major limitation of the present study is the small number of cases and therefore the results do not reflect the pattern of PCNSL in the population of Saudi Arabia at large. The low overall median survival, also reflects the short follow-up duration in our study. A longer-term study would provide more data regarding survival in these patients.

  Conclusion Top

PCNSL in the present study is more common among immune competent middle-aged and aged patients. There is female predilection especially in the middle age. Frontal region is the most common location with DLBCL being the predominant histological subtype. Our study also confirms the rare occurrence of Burkitt's lymphoma and low grade marginal zone lymphoma presenting as PCNSL. PCNL among older adults showed a more aggressive pattern and male to female ratio of near unity. These findings are concordant with other studies from the region.[20],[21],[22]

PCNSL, continues to be a diagnostic challenge in part due to lack of suspicion at presentation. In addition to the variation in the incidence, there may be regional and geographical differences in response to treatment, prognosis and survival for various types of lymphomas. In view of this, there is a need for further studies to elaborate on these issues for a disease that is heterogeneous and appears to be on the rise.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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