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Year : 2009  |  Volume : 55  |  Issue : 4  |  Page : 247-251

Primary central nervous system lymphoma: Prognostication as per international extranodal lymphoma study group score and reactive CD3 collar

1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
2 Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Date of Submission23-Jun-2008
Date of Decision19-Jun-2009
Date of Acceptance27-Aug-2009
Date of Web Publication14-Jan-2010

Correspondence Address:
N Kumari
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.58926

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 :: Abstract 

Background : Primary central nervous system (CNS) lymphoma is being increasingly recognized in immunosuppressed as well as immunocompetent individuals. It has a poor prognosis and the majority of these have diffuse large B-cell type of morphology. Aim : To categorize cases of primary CNS lymphoma according to the International Extranodal Lymphoma Study Group (IELSG) score and to correlate the score with reactive CD3 collar around blood vessels and necrosis. Materials and Methods : We reviewed the clinico-pathological, morphological and immuno-histochemical features of 30 cases of primary CNS lymphoma reported at our institute in the last nine years and categorized them according to the score given by IELSG. Results : All our cases were HIV-negative and had diffuse large cell histology. Twenty-seven of the 30 cases were associated with poor prognostic factors of intermediate to high risk according to the IELSG score. Reactive CD3 collar around the blood vessels was seen in seven cases which had low to intermediate IELSG score. However, no significant statistical difference of perivascular reactive CD3 collar and necrosis was seen with IELSG score. Conclusion : Approximately 90% (27 cases) were associated with poor prognostic factors in the present study according to the IELSG score. Perivascular reactive CD3 collar was seen in cases with low to intermediate IELSG score. A larger study is required to further validate that the presence of reactive perivascular CD3 collar is associated with good prognosis. This histological marker could be supplemented with IELSG score to stratify the patients of primary CNS lymphoma according to their aggressiveness.

Keywords: Central nervous system lymphoma, international extranodal lymphoma study group prognostic score, human immunodeficiency virus

How to cite this article:
Kumari N, Krishnani N, Rawat A, Agarwal V, Lal P. Primary central nervous system lymphoma: Prognostication as per international extranodal lymphoma study group score and reactive CD3 collar. J Postgrad Med 2009;55:247-51

How to cite this URL:
Kumari N, Krishnani N, Rawat A, Agarwal V, Lal P. Primary central nervous system lymphoma: Prognostication as per international extranodal lymphoma study group score and reactive CD3 collar. J Postgrad Med [serial online] 2009 [cited 2023 Sep 30];55:247-51. Available from:

Primary central nervous system lymphomas (PCNSL) account for approximately 7% of all primary brain tumors and 5-7% of all extra-nodal lymphomas. [1] Approximately 95% are of B-cell type, where as T-cell lymphomas form less than 5% of the total primary CNS lymphomas. [2] However, a majority of PCNSL are diffuse large cell type and intra-parenchymal. Low-grade lymphomas like small lymphocytic, lymphoplasmacytic, follicular and marginal zone lymphoma occur predominantly as dural-based lesions. [3],[4],[5],[6],[7] Five-year survival in immunocompetent patients is around 22-43% after receiving chemotherapy or combined chemo-radiotherapy. [8] Etiology of PCNSL in immunocompetent individuals is uncertain. Majority of PCNSL reported from India are in immunocompetent individuals and one study from India had suggested that Epstein-Barr virus has no etiologic role in PCNSL in immunocompetent individuals. [9] Identification of various prognostic factors is continuously being studied, which would be relevant in the management of PCNSL, and help in selection of more appropriate therapeutic strategies. The differences in outcome of PCNSL are attributed to heterogeneous distribution of prognostic factors rather than efficacy of therapeutic regimens alone. [10],[11]

In the present study, we retrospectively analyzed the spectrum of clinico-pathological and morphological features and categorized them according to the prognostic scoring system of primary CNS lymphoma as laid down by the International Extranodal Lymphoma Study Group (IELSG) and correlated them with the presence or absence of reactive CD3 collar around blood vessels. [12] Very few studies on PCNSL are available from India, and to the best of our knowledge this is the first study in our country to analyze the prognostic factors according to the IELSG Score and presence of reactive CD3 collar around blood vessels and necrosis.

 :: Materials and Methods Top

Records of all cases of non-Hodgkin's lymphoma occurring in our hospital over a nine-year period (January 1998-December 2006) were retrieved. Records of extra-nodal lymphoma obtained from the hospital information system. Out of these, primary CNS lymphoma constituted 30 cases. Clinical findings, results of laboratory investigations, especially for serum lactate dehydrogenase (LDH) and cerebrospinal fluid (CSF) protein levels and follow-up records were retrieved from the hospital records. Five-micron-thick sections stained with hematoxylin and eosin were reviewed by three pathologists for morphological features of the lymphoma along with other features like presence of necrosis, histiocytes, reactive CD3 collar around vessels and vessel wall infiltrate. All slides were stained with reticulin silver stain to highlight the architecture and the infiltration into the vessel wall. Immunohistochemistry was done in each case for LCA (DAKO clone 2B11 + PD7/26, dilution 1:50), CD20 (DAKO clone L26, dilution 1:25), and CD3 (polyclonal, dilution 1:200). CD30 (DAKO, clone Ber-H2, dilution 1:50), ALK-1 (DAKO, Clone SP-8, Dilution 1:100) cytokeratin (DAKO, Clone AE1/ AE3, Dilution 1:50) and NSE (DAKO, Clone BBS/NC/V1-H14, Dilution 1:50) using monoclonal antibodies were used as and when required. Prognostic factors were analyzed according to IELSG prognostic score.

 :: Results Top

Records of 693 cases of non-Hodgkin's lymphoma were retrieved. These included 250 (39.7%) cases with extranodal lymphomas. Out of these, primary CNS lymphoma constituted 30 cases. These included 18 male patients (M: F = 1.3:1). The mean age of PCNSL was 47.8 years (age range: 17-70 years; median-49.5 years). Twenty-four of these 30 patients were below the age of 60 years and six were 60 years and above. Duration of illness ranged from 1-24 mo before presentation. The demographic details and laboratory investigations are listed in [Table 1].

The presenting features included seizures, headache, vomiting, visual disturbances, altered speech, weakness of limbs and hemiparesis. Twenty-six cases were intracranial, two were dural-based lesions, one was in the orbit and another one was located in the spinal cord at the level of D1-D3 vertebrae. Within the intracranial tumors, 13 were located in the frontal lobe, either alone or in association with the parietal lobe in four cases and both parietal and temporal lobes in one case. Two cases were located in parietal lobe alone and one each was located in the temporal and occipital lobe. Another one was located in parieto-occipital region. Eight cases were located in the deeper regions including two in the cerebellum and six within the basal ganglia and thalamus.

Histological examination showed diffuse large cell type of morphology in all cases along with infiltrate of neoplastic lymphoid cells within the vessel wall [Figure 1] and [Figure 2]. Necrosis was present in eight cases and 11 cases showed presence of reactive histiocytes within the tumor. All cases were positive for CD20 + [Figure 3]a. CD3 staining was seen in seven cases in the perivascular reactive lymphoid infiltrate [Figure 3]b, [Table 2].

Twenty-one patients showed elevation of LDH (normal cutoff 450 U/L) and 18 had raised CSF protein levels (normal cutoff 45 mg/dL). HIV status was negative in all patients. One case of rheumatoid arthritis receiving steroids for a long time, later developed PCNSL. Nine patients had Eastern Cooperative Oncology Group performance (ECOG) status score of 0-1 who were able to perform their routine activities, 19 patients had restricted physical activity with ECOG score of 2-3 and two patients were non-ambulatory with ECOG score of 4.

Treatment history was available in 14 patients. Treatment regimen given was 40-52 Gy of radiation dose with a further boost-up dose of 10-16 Gy. This was followed by four to six cycles of chemotherapy (CHOP-cyclophosphamide, adriamycin, vincristine and prednisolone/PCV- procarbazine, CCNU, and vincristine).

Follow-up details were available in 13 patients in whom two patients are still alive with a follow-up period of 16 mo and 4 mo, respectively. Eleven patients died of disease in whom survival ranged from 1-39 months. The remaining 17 patients were lost to follow-up, therefore the relation of prognostic factors as well as any association of reactive perivascular CD3 collar with survival could not be ascertained. According to the IELSG score, three patients had low risk, 23 intermediate risks and four had high risk [Table 3]. Reactive perivascular CD3 collar was seen in two patients with low risk, five patients with intermediate and none with high-risk IELSG prognostic score. Necrosis was seen in one, six and one patients with low, intermediate and high-risk IELSG score, respectively. Statistical analysis was done using Z-test for set of proportions between two groups (low risk group and intermediate and high risk group) which did not show any significant difference with reactive perivascular CD3 collar (0.12) and necrosis (0.10). However, reactive perivascular CD3 collar was more commonly seen in low-risk IELSG score [Table 4].

 :: Discussion Top

PCNSLs in the present study accounted for 12% of total extranodal lymphomas and 4.3% of total non-Hodgkin's lymphomas (NHLs). The incidence reported in the literature is approximately 4.2% of extranodal lymphomas and 0.7-1.7% of total NHLs. [13],[14] The higher percentage of PCNSLs in the present study could be because of referral bias as our institute is a tertiary care hospital. However, the incidence of PCNSL in all intracranial tumors was is 0.7% in the present study is similar to that of the literature (> 1-2%), although some studies have reported as high as 5-7% of total intracranial tumors. [15],[16] Incidence of PCNSL in India seems to be fairly constant and one study recently published from India showed 1.07% of all intracranial tumors. [17] All our patients were middle-aged to elderly (17-70 years, mean age 47.8 years) with male to female ratio of 1.3:1. The mean age was a little lower than that reported in the Western literature (66.5 years) but almost similar or a little higher than that reported from other parts of India. [14],[18],[19]

Though patients with AIDS have approximately 20% more lifetime risk of developing PCNSL, incidence in patients without AIDS is also increasing rapidly. This rise seems to be unassociated with AIDS or immunosuppression and is being seen more commonly in HIV-negative individuals. [2],[16],[19],[20],[21],[22] All 30 cases in our study were HIV-negative. One patient was a case of rheumatoid arthritis who had been receiving high-dose steroids for seven years. We presume that long-term steroid use could have accounted for her immunosuppression.

In the present study, the commonest site involved was the frontal lobe (nine cases) combined with parietal in four, and temporal in one case similar to Tomlinson et al., and Sarkar et al. [2],[19] Powari et al., showed involvement of the parietal lobe to be common in their study. As described in the literature, the majority of CNS lymphomas are diffuse, large B-cell type and some are low-grade marginal zone which are mostly dural-based lesions. [14],[16] All our 30 cases were diffuse, large B-cell type including two meningial-based lesions.

Prognosis of CNS lymphomas has been poor despite the use of various combinations of radiotherapy and/or chemotherapy. Treatment history available in 14 patients was combination of radiotherapy and chemotherapy, therefore outcome of patients who received radiotherapy or combined radiotherapy and chemotherapy could not be correlated in the present study. Two of these 14 patients developed cognitive impairment and one patient developed ataxia during the follow-up period. ECOG performance status was poor in 70% (21/30) of our patients with a score of 2 or more which could be one of the factors for poor survival. Lesions occurring in the elderly aged over 60 years and those occurring at deeper sites like thalamus, basal ganglia, cerebellum, brainstem and periventricular areas have poor prognosis which is probably related to the significant neurologic impairment related to surgery as a result of deeper location. [23],[24] The higher grade of tumor and poor ECOG performance status with a high IELSG score in these patients could be because of their late presentation. According to the IELSG score, three (10%) patients had low risk, 23 (76.7%) intermediate risk and four (13.3%) had high risk. The IELSG score in another multicentre study of 100 cases of PCNSL were 19%, 59% and 22% in low, intermediate and high risk patients respectively. [25] In the present study approximately 90% (27) patients were in the intermediate and high-risk groups and the reason for this may be referral bias as well as either misdiagnosis or inadequate or inappropriate treatment.

Perivascular reactive CD3 collar in cases of CNS lymphomas is being studied as a potential prognostic factor. It has been seen that lymphomas with reactive perivascular T-cells are associated with improved survival. Presence of reactive perivascular T-cell infiltrate may act as specific anti-tumor activity and this parameter can be assessed during routine diagnosis on histopathology. [25] Seven patients in this study had reactive perivascular T-cell infiltrate [Table 3]. Statistical analysis using of proportions between low risk group and intermediate and high risk group did not show any significant difference with reactive perivascular CD3 collar and necrosis. Presence of histiocytes also did not show any relation with IELSG score. Association between perivascular T-cell collar and survival of PCNSL could not be assessed as the majority of patients were lost to follow-up.

CNS lymphomas may sometimes pose a problem while differentiating from other round cell tumors including neurocytoma, small cell glioblastoma, primitive neuroectodermal tumors and rarely viral encephalitis with perivascular reactive lymphoid cuffing. Misdiagnosis may be one of the reasons for not receiving appropriate treatment. High index of suspicion for lymphoma and a panel of antibodies should be used in differentiating lymphomas from other round cell tumors. In the present study, two patients were diagnosed as primitive neuroectodermal tumor and one as small cell glioblastoma outside and were referred for further management. However, on reviewing the histology, they were diagnosed as primary CNS lymphoma.

Thus, we report the clinico-pathologic features of 30 cases of primary CNS lymphomas from a tertiary care referral institution. All cases were HIV-negative and had diffuse, large cell histology with 90% of them having intermediate to high IELSG score. Perivascular reactive CD3 collar was seen in cases with low to intermediate IELSG score. No significant statistical difference was seen between T-cell collar or necrosis and IELSG score. Larger studies are required to validate the reactive perivascular CD3 collar as prognostic factor because this simple histological marker could be supplemented with IELSG score to stratify lymphoma patients according to their aggressiveness.

 :: References Top

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  [Figure 1], [Figure 2], [Figure 3]

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

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