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NI FEATURE: PATHOLOGICAL PANORAMA - ORIGINAL ARTICLE
Year : 2015  |  Volume : 63  |  Issue : 1  |  Page : 77-82

Clinicopathological correlates of primary central nervous system lymphoma: Experience from a tertiary care center in South India


1 Department of General Pathology, Section of Neuropathology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Neurological Sciences, Section of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication4-Mar-2015

Correspondence Address:
Dr. Geeta Chacko
Section of Neuropathology, Department of Pathology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.152658

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 » Abstract 

Background: Primary central nervous system lymphomas (PCNSL) constitute a rare group of extranodal non-Hodgkin's lymphomas (NHLs).
Aim:
To study the clinical and immunophenotypic profile of patients with a PCNSL who presented between the years 2000 and 2013 in a tertiary care center in South India.
Materials and Methods:
This was a retrospective study. Demographic and clinical data were obtained from the clinical case records. Inclusion criteria: Cases of PCNSL involving brain. Exclusion criteria: Cases of PCNSL involving the spinal cord, meninges and orbit as well as intravascular large B-cell lymphoma, lymphomas with evidence of systemic disease or secondary lymphomas. Archived slides and tissue blocks were retrieved. All cases had hematoxylin and eosin stained sections and immunohistochemistry for CD20, CD3, and MIB-1. Additional immunohistochemistry was performed for CD10, BCL6, and MUM1 on paraffin blocks with sufficient tissue.
Results:
There were a total of 73 cases with the mean age of presentation being 45.9 years (range 8-71 years) and with a male predominance (male: female (M:F) = 2.3:1). Headache was the commonest presenting complaint. The mean duration of symptoms was 10.6 weeks. All patients were immunocompetent. Most tumors were supratentorial in location. Out of 73 cases, 70 presented with a diffuse large B-cell lymphoma (DLBCL), two with a Burkitt's lymphoma, and one with a lymphomatoid granulomatosis. Only 51 of the DLBCL cases had sufficient tissue for additional studies. Non-germinal center was the most common phenotype seen in 65.7% (33/51) of cases. Germinal center B-cell (GCB) phenotype was seen in 18/51 cases (34.3%).
Conclusion:
DLBCL constituted the majority of PCNSLs and although non-germinal center was the predominant phenotype, more than a third of the cases were of the GCB phenotype. As the germinal center phenotype is known to have a better prognosis, further studies to explore its relevance in the Asian population are indicated.


Keywords: Diffuse large B-cell lymphoma; immunophenotyping; primary CNS lymphoma


How to cite this article:
Patel B, Chacko G, Nair S, Anandan J, Chacko AG, Rajshekhar V, Turel M. Clinicopathological correlates of primary central nervous system lymphoma: Experience from a tertiary care center in South India. Neurol India 2015;63:77-82

How to cite this URL:
Patel B, Chacko G, Nair S, Anandan J, Chacko AG, Rajshekhar V, Turel M. Clinicopathological correlates of primary central nervous system lymphoma: Experience from a tertiary care center in South India. Neurol India [serial online] 2015 [cited 2019 Aug 17];63:77-82. Available from: http://www.neurologyindia.com/text.asp?2015/63/1/77/152658



 » Introduction Top


Primary central nervous system lymphomas (PCNSLs) are rare, extranodal, malignant lymphomas arising within the brain, eyes, leptomeninges, or spinal cord in the absence of systemic lymphoma at the time of diagnosis. In the Western world, the incidence of PCNSL is 3-4% of all non-Hodgkin's lymphomas (NHLs), [1] whereas in India, the incidence has been reported to range from 0.95 to 1.4%. [2] Although PCNSL has a strong association with acquired immunodeficiency syndrome (AIDS), and human immunodeficiency virus (HIV) infection carries a 3,600-fold increased risk of developing the disease compared to general population, [3] recent epidemiologic data suggest a decrease in the incidence of PCNSL, particularly among young patients suffering from AIDS. Amongst immunocompetent patients, a higher incidence is seen in older patients (> 60 years), and the overall improvement in longevity has been cited as a reason for this increasing incidence with age. [1],[4]

According to the World Health Organization (WHO) classification, most of the primary CNS lymphomas (> 95%) are diffuse large B-cell lymphomas (DLBCL); however, WHO does not identify PCNSL as a separate entity due to morphological similarity to nodal DLBCLs. [5] The exact pathogenesis of PCNSL is unclear. [6] Among systemic DLBCLs, gene expression profiling studies identified two subgroups (germinal center B-cell type (GCB) and activated B-cell type [ABC]) indicative of different stages of B-cell differentiation. [7] The two subgroups differ not only in the immunophenotypic profile but also in aggressiveness, prognosis, and treatment, with the GCB profile showing a significantly better outcome than those with the ABC profile. [7] Several of the antigens that are differentially expressed in germinal center and post-GCBs can be identified by immunohistochemical analysis on paraffin sections. For example, CD10 and BCL-6 are markers for GCB, [8],[9] MUM-1 is a marker for late germinal center/early post-GCB, [10],[11] and CD138 and VS38 are markers for plasmacytic and/or post-germinal center differentiation. [12],[13] Several algorithms for subtyping have been described in the literature. [14],[15],[16],[17],[18],[19],[20],[21] Of the various algorithms proposed for subtyping, Hans algorithm appears to be the most popular one. [22],[23],[24],[25],[26],[27],[28],[29],[30],[31] Expression of CD138 in PCNSL is rare; [22],[24],[29],[32] and hence in the context of PCNSL, CD138 has not been employed by several studies. The prognosis of PCNSL is poor with a 5-year overall survival (OS) rate of approximately 30% even for patients receiving best of treatment protocols. [33],[34],[35],[36] It is yet unclear whether the poor outcome is attributable to the fact that the tumor is located in the CNS or reflects an exceptionally aggressive biological behavior of tumor cells in the CNS.

The aim of this study was to determine the clinical profile and immunophenotype of PCNSL in patients who presented in this institution between the years 2000 and 2013.


 » Materials and Methods Top


Patients

This was a retrospective study. Clinical data of the patients were obtained from the hospital database.

Inclusion criteria: Only lymphomas involving the cerebral parenchyma were included in this study. Cases of PCNSL involving the spinal cord, meninges and the orbit and those with intravascular large B-cell lymphoma, lymphomas with evidence of systemic disease or secondary lymphomas were excluded.

All standard protocols were followed for the diagnosis and treatment with informed consent obtained from all these patients (Approval for the present study was obtained from the Institutional Review Board).

Tumor specimen

Paraffin blocks of archived biopsies were retrieved from the Department of Pathology of a tertiary care hospital in South India. The tumor specimens had been obtained by open or stereotactic procedure for diagnosis. The WHO classification of lymphoid and hematological malignancies was used for the histological diagnosis of PCNSL. Cases were selected on the basis of the availability of paraffin-embedded tumor tissues.

Histology and immunohistochemical analysis

Five micron (hematoxylin and eosin stained) sections of all the cases were reviewed. CD20, CD3, and MIB-1 immunostaining had been done at the time of primary diagnosis of PCNSLs using the following clones CD20 (Clone L26, Monoclonal mouse anti-human CD20cy, Dako), CD3 (Polyclonal rabbit anti-human CD3, Dako), and MIB-1 (Clone MIB-1, Monoclonal mouse anti-human Ki-67 antigen, Dako). Immunostaining was performed in the Ventana Autostainer using the Envision method.

After a review of cases, a panel of further immunohistochemical studies was done on paraffin-embedded tissue sections. Sections were cut at 4-μm thickness and deparaffinized. Antigen retrieval was carried out by pressure cooking method. Sections were then incubated with the working dilution of each antibody raised against the following antigens: CD10 (GCB marker; liquid mouse monoclonal antibody, Novocastra, Clone 56C6, dilution 1:100), BCL-6 (GCB marker; liquid mouse monoclonal antibody, Novocastra, Clone LN22, dilution 1:100); and MUM-1 (non-GCB marker; monoclonal mouse anti-human MUM1 protein, Dako, dilution 1:100).

For CD10, BCL-6 and MUM-1, positive expression was defined as positive staining in >30% of cells. [34] For CD10, only membrane and cytoplasmic staining were considered positive, and in the case of BCL-6 and MUM-1, only diffuse or granular nuclear staining was considered positive; CD10, BCL-6, and MUM-1 expression results were used to subclassify DLBCL cases into GCB or non-GCB subgroups as described below.

Classification of DLBCL into GCB and non-GCB

For classification of DLBCL into two immunophenotypic subgroups, Hans [14] algorithm [Figure 1] was used in the present study. Hans algorithm uses CD10, BCL-6, and MUM-1 immunoexpression with following two subsets of markers expression favoring GCB subtype: (CD10 (+), BCL6 (+), MUM-1 (-)) and (CD10 (−), BCL6 (+), MUM-1 (−)); while (CD10 (−), BCL6 (+), MUM-1 (+)) and (CD10 (−), BCL6 (-), MUM-1 (+)) subsets favoring non-GCB subtype.
Figure 1: Hans algorithm for classification of diffuse large B-cell lymphoma-not otherwise specified into germinal center type and non-germinal center type


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 » Results Top


A total of 73 cases of PCNSL involving the cerebral parenchyma were identified in the study period (2000-2013). A progressive increase in the hospital-based incidence of CNS lymphoma was noted during the study period, with a gradual increase from 0.09% of all biopsies received at the neuropathology laboratory for examination at the beginning of the study period to 0.38% at the end. There were four pediatric patients with a PCNSL (mean age: 9.7 years). The overall mean age was 46 years (range: 8-71 years) and twice as many males were affected (male: female (M:F) ratio = 2.3:1). All the patients were immunocompetent. The mean duration of symptoms was 10.6 weeks (range: <1-48 weeks). Headache was the most common symptom. About 86.3% (63/73) were supratentorial, and 35.6% (26/73) had one lobe involvement. Twenty-five (34.2%) PCNSLs were periventricular in location. Forty out of 73 patients (54.80%) had stereotactic biopsy (STB) for diagnosis while others had an open biopsy. Fourteen patients had received steroids prior to diagnosis. Atypical lymphoid cells were found in CSF of two patients. Histologic review of slides identified 70 cases (95.9%) of DLBCL, two cases (2.7%) of Burkitt's lymphoma, and one case (1.4%) of lymphomatoid granulomatosis. DLBCL was composed of cohesive clusters of atypical lymphoid cells arranged in sheets and in an angiocentric pattern with brisk mitotic activity and frequent apoptotic figures in the presence of necrosis. The cells were moderately large with round to oval nuclei containing one to two distinct nucleoli and moderate amounts of eosinophilic to vacuolated cytoplasm [Figure 2].
Figure 2: (a) Angiocentric arrangement of atypical lymphoid cells in a necrotic background. The cells are medium sized with round to oval pleomorphic nuclei containing vesicular chromatin with distinct nucleoli seen at higher power (×400) in the inset. Immunohistochemistry for CD 20(b), CD 3(c), and MIB-1 (d)


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All cases of DLBCL were positive for CD20 [Figure 2]. The proliferative index was high (60-98%) in all the cases. Few reactive CD3 positive T-cells were seen in the background. Fifty-one out of 70 cases of DLBCL had sufficient tissue for additional subtyping using CD10, BCL-6, and MUM-1.

Classification into GCB and non-GCB groups

Using Hans algorithm, 33 cases out of 51 (64.7%) were non-GCB type, while the rest were of GCB type (35.3%) [Figure 3] and [Table 1].
Figure 3: Immunohistochemistry marker combinations for GCB and non-GCB. GCB: CD10 (+), BCL6 (+), MUM-1 (–) and CD10 (–), BCL6 (+), MUM-1 (–). Non-GCB: CD10 (–), BCL6 (–), MUM-1 (+) and CD10(–), BCL6(+), MUM-1(+). GCB = Germinal center B-cell


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Table 1: Results of immunophenotypic subtyping of PCNSL


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There was no follow-up information available on any of our cases. Most of these patients had come from other states in India and returned to their domiciled state for further treatment.


 » Discussion Top


This study investigated the clinical and immunoprofile of PCNSL seen in a tertiary care center in South India. The clinical profile of patients in our study demonstrated similar differences in demographic and clinical presentation of PCNSL as reported by previous studies from India in comparison to the Western studies. [2],[37],[38],[39],[40] The mean age of presentation of 46 years was similar to that reported in other Indian studies; [2],[37],[38],[39],[40] however, it was a decade earlier as compared to that reported by Western studies. [22],[23],[24],[41] All the patients in the present study were immunocompetent. Sarkar et al., [39] and Manoj et al., [37] had one and three cases, respectively of HIV-infected patient with PCNSL; however, Powari et al., [40] and Pasricha et al., [2] had none. One patient in the study by Sarkar et al., [39] and two patients in the study by Powari et al., [40] were immunocompromised due to renal allograft transplant. The Western literature shows increase in the incidence of PCNSL in immunocompromised individuals of younger age group particularly with HIV/AIDS and in elderly immunocompetent patients. [6],[41],[42] Both Western and Asian literature do not support the association of Epstein-Barr virus (EBV) with PCNSL in immunocompetent individuals, [24],[29],[43],[44],[45],[46] and hence in the present study, EBV latent membrane protein (LMP) was not assessed by immunohistochemistry.

The location of the lymphoma in the CNS determines the clinical presentation. In a large series involving 248 patients, among the immunocompetent patients, focal neurological deficits (70%), neuropsychiatric symptoms (43%), signs of raised intracranial pressure (33%), and seizures (14%) were the presenting complaints. [47] However, in a review comparing PCNSL in 315 patients with AIDS and 792 immunocompetent patients, Fine and Mayer found that the occurrence of focal neurological deficits was similar, approximately 50%, in both groups. Mental status changes (including behavior changes) occurred in 53 and 35% of immunocompromised and immunocompetent patients, respectively, and seizures in 27% of immunocompromised patients and 11% of immunocompetent patients. [48] Neuropsychiatric symptoms were thus more frequent in immunocompromised patients. Similar to reports in the literature, [2],[37],[38],[39],[40],[49] headache was the most common symptom in our series (all our patients were immunocompetent). The majority (86.3%) of lesions were in a supratentorial location in the present study. [2],[37],[38],[39],[40],[47],[49] Twenty-five patients (34.2%) had lymphoma in the periventricular location. In a retrospective study conducted in our institution, which reviewed cases of NHL seen between January 2006 and April 2010, PCNSL constituted 5.5% of all NHLs and occurred exclusively in immunocompetent patients (unpublished data). As described in the literature, [6] we also found DLBCL (95%) to be the most common histologic type involving the cerebral parenchyma. Other types of lymphomas are rare in the central nervous system. [50],[51]

As mentioned earlier, there are several algorithms for subtyping described in the literature, [13],[14],[15],[16],[17],[18],[19],[20] of which Hans algorithm appears the most frequently used algorithm. Some algorithms like Chang's additionally use CD138. [52] However, expression of CD138 is rare in PCNSL, [22],[24],[29],[32] and hence in the context of PCNSL, CD138 has not been employed by several studies. [22],[23],[25],[28],[30],[31] With the limited resources available, we too deferred using CD138 for subtyping.

[Table 2] enlists the different studies done in PCNSL, which carried out subtyping. On comparing the subtypes (GCB versus non-GCB) of DLBCL of central nervous system in the Western and Asian population, we observed that although the non-GCB type was the most common subtype of DLBCL in both populations, the proportion of the subtypes differed in different studies. [22],[23],[25],[26],[27],[28],[29],[30],[31],[49],[52] In the cohorts from France, [24],[28] Turkey, [30] and the United States; [6],[23],[31] the incidence of the non-GCB type ranged from 84 to 96% of cases with the GCB subtype accounting only for 4-25% of cases. In the present study, 35% of the study population was of the GCB subtype. There are at least two other studies from the Asian subcontinent and one from France in which the GCB subtype was more than 20%, [22],[26],[28] although, there are studies from Asia in which the distribution of subtypes is comparable to that in the West. [27],[29],[52] This interesting observation of a higher proportion of PCNSL's being of the GCB subtype in at least three Asian studies; (21, 25 and present study) certainly needs further exploration, particularly as the GCB subtype is known to have a better prognosis as compared to the non-GCB subtype, [22],[23],[24],[31] and may imply that PCNSL seen in the Asian population have a better survival and would benefit from more aggressive therapy.
Table 2: Comparison of GCB versus non-GCB in different studies and present study


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In conclusion, in this 13-year retrospective study of PCNSL presenting to a tertiary care center in the Indian subcontinent, DLBCL was the most common type of PCNSL. Although the non-germinal center subtype was the predominant subtype, the proportion of GCB type was higher than that reported from the Western population. All patients were immunocompetent. Further studies with adequate follow-up information are indicated to corroborate our findings and to assess the prognostic significance of these subtypes in the Indian and Asian population.

 
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    Figures

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    Tables

  [Table 1], [Table 2]

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