An Official publication of The Asian Congress of Neurological Surgeons (AsianCNS)

Search Article
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Advertise Subscribe Contacts Login  Facebook Tweeter
  Users Online: 115 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size  

   Table of Contents      
ORIGINAL ARTICLE
Year : 2020  |  Volume : 15  |  Issue : 3  |  Page : 560-565

Outcome and prognostic factors of primary central nervous system lymphoma in Southern Thailand


Neurological Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand

Date of Submission07-May-2020
Date of Acceptance09-Jul-2020
Date of Web Publication28-Aug-2020

Correspondence Address:
Dr. Anukoon Kaewborisutsakul
Neurological Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Songkhla 90110
Thailand
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajns.AJNS_208_20

Rights and Permissions
  Abstract 

Context: Primary central nervous system lymphoma (PCNSL) is an uncommon type of brain tumor that has an aggressive disease course. Its outcomes, including factor-related outcomes, are therefore not well established in our country. Aims: This study aims to investigate the outcome and prognostic factors in PCNSL patients at our institute. Settings and Design: Retrospective study in a single university hospital. Subjects and Methods: We reviewed consecutive cases of newly diagnosed PCNSL at Prince of Songkla University from 2005 to 2018. The data were collected to evaluate the treatment outcomes and prognostic factors. Statistical Analysis Used: The Kaplan–Meier method for survival analysis, and Cox regression for variable analysis. Results: Eighty-seven patients met the inclusion criteria. Patients were predominantly male, and their mean age was 58.8 ± 11.2 years. Only four patients were infected with HIV. Motor weakness was the most common presentation, and neuroimaging revealed multiple lesions in 56.3% of patients. The patients were divided into four groups according to treatment modality: palliative treatment, whole-brain radiotherapy (WBRT) alone, chemotherapy (CMT) alone, and combined WBRT and CMT groups. The median overall survival was 7 months. The 1-, 2-, and 5-year survival rates were 29%, 21.5%, and 4.6%, respectively. The age of >60 years was a significant poor prognostic factor. In addition, patients who received combined treatment exhibited the highest survival rate. Conclusions: PCNSL has a low survival rate, even in the present era. Older age is the most substantial factor associated with unfavorable outcomes. The most effective treatment is combined with WBRT and CMT.

Keywords: Brain tumor, chemotherapy, overall survival, primary central nervous system lymphoma, whole-brain radiotherapy


How to cite this article:
Sopittapan T, Tunthanathip T, Kaewborisutsakul A. Outcome and prognostic factors of primary central nervous system lymphoma in Southern Thailand. Asian J Neurosurg 2020;15:560-5

How to cite this URL:
Sopittapan T, Tunthanathip T, Kaewborisutsakul A. Outcome and prognostic factors of primary central nervous system lymphoma in Southern Thailand. Asian J Neurosurg [serial online] 2020 [cited 2020 Sep 30];15:560-5. Available from: http://www.asianjns.org/text.asp?2020/15/3/560/293720


  Introduction Top


Primary central nervous system lymphoma (PCNSL) is a rare cancer that has an aggressive course. PCNSL is a type of extranodal non-Hodgkin's lymphoma (NHL) located along the craniospinal axis. More than 95% of cases are diffuse large B-cell lymphoma (DLBCL).[1] The disease incidence is more common in immunocompromised patients.[2],[3] However, this rate has increased in healthy elderly within the current decade.[4]

In general, the outcomes of PCNSL patients are worse than those with extranodal NHL in other organs, for which the median survival rate ranges from 9 to 35 months.[2],[3],[5],[6],[7] Unfortunately, certain standard therapy components are still controversial including the extent of surgical resection [8] and the appropriate postoperative treatments (chemotherapy [CMT], whole-brain radiotherapy [WBRT], immunotherapy, or combined therapy).[7]

Patient prognosis depends on various patient factors, PCNSL factors itself, and whether or not a patient has received treatment.[9],[10] The prognostic models for predicting patient outcomes, such as the International Extranodal Lymphoma Study Group score,[6] Memorial Sloan Kettering Cancer Center score,[5] and the Nottingham-Barcelona score,[11] are well established.

In Thailand, the outcome of PCNSL patients is not well defined, especially in the era of CMT.[12] Accordingly, this study aims to evaluate the treatment result in terms of survival rate and prognostic factors in PCNSL patients at our institute.


  Subjects and Methods Top


Patients

After approval from the relevant Ethics Committees (REC 62-051-10-4), a retrospective review of consecutive cases of newly diagnosed PCNSL between January 2005 and June 2018 at a single institution was performed. Our institute, Prince of Songkla University, is a university hospital that serves as a referral neuro-oncologic center in the south of Thailand. We included patients aged 15 years and older. Every patient received a histopathologic diagnosis after stereotactic brain biopsy or tumor resection. The selection of cranial surgery depended on clinical conditions such as mass effect, neurological deficit, and the attending neurosurgeon's decision.

We critically reviewed relevant data from the institute's database, which included the patient characteristics (sex, age, and performance status with Eastern Cooperative Oncology Group [ECOG] score at the time of diagnosis), preoperative laboratory test results (HIV status, serum lactic acid dehydrogenase [LDH], and cerebrospinal fluid [CSF] protein), preoperative neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI] of the brain, size, location, and the number of lesions), type of surgery (biopsy, gross total resection, and subtotal resection), pathology report (DLBCL or another type), postoperative treatment (palliative, CMT, and WBRT), and status of the patient (deceased or alive). Experienced pathologists also reviewed all tissue pathologies. The selection of postoperative treatment depended on the patient's performance status, and the consulting hematologist and radiologist's opinion. A combined treatment group means patients receiving CMT and radiotherapy, which may or may not be accepted at the same time. Furthermore, we excluded patients with systemic lymphoma involvement diagnosed by CT scan of the chest, whole abdomen, and pelvis or bone marrow analysis.

The upper limit of normal serum LDH was 140 U/L.[13] The cut off level for normal CSF protein was <60 mg/dL in patients older than 60 years of age and <45 mg/dL in patients younger than 61 years.[6] Biopsy referred to when stereotactic surgery was performed or when <25% of the preoperative tumor volume was resected. Gross total resection was defined as craniotomy, complete tumor resection, and when the tumor was not detected on postoperative imaging. The remaining patients were classified into subtotal resection group. To determine their current status, we followed up all patients in February 2019 by telephone and reviewed the institute data and/or the civilian registration database.

Statistical analysis

The R Statistical Software version 3.5.0 (R Foundation, Vienna, Austria) was used for the statistical analysis. For descriptive purposes, the patient demographic data and clinical characteristics, total number, percent, and means with standard deviations were calculated. We used the Kaplan–Meier method for survival analysis. Cox regression was performed for univariable analysis, whereas backward stepwise analysis was used for multivariable analysis. In this study, a P < 0.05 represented a statistically significant difference.


  Results Top


Patient characteristics

At our center, 92 patients were diagnosed with lymphoma of the brain, of which five patients with secondary CNS lymphoma were excluded. Finally, this study enrolled the data of 87 patients. Patients were predominantly male (45 patients, 51.7%), and the average patient age was 58.8 years (range, 30–80 years). There were four HIV-positive patients (4.8%) and no other immunodeficiency diseases. The most prevalent underlying condition was hypertension (35.6%). Accordingly, most of the patients had ECOG scores >1.

Weakness was the most common presenting symptom (66.7%), followed by increased intracranial pressure-related symptoms such as headache (44.1%) and altered consciousness (37.9%). Most patients had multiple (56.3%), unilateral (52.9%), and cortical lesions (55.2%). More than 60% of patients had not undergone lumbar puncture to obtain CSF; thus, CSF protein level information was missing. In all patients, 2.3% of data on the LDH level were missing. Approximately 70% of the group had normal serum LDH levels. The clinical characteristics of the patients are shown in [Table 1].
Table 1: Characteristics of primary central nervous system lymphoma patients (n=87)

Click here to view


More than 80% of patients were diagnosed by stereotactic brain biopsy [Figure 1]a. Thirteen patients underwent craniotomy for tumor removal [Figure 1]b, [Figure 1]c. Most patients (8 out of 13) had a single infiltrative lesion with marked perilesional brain edema. Preoperative MRI and intraoperative frozen sections could not distinguish PCNSL from other malignant brain tumors such as brain metastasis or high-grade glioma. Three patients in the craniotomy group had an intraventricular tumor. One patient had a single lesion in the cerebellum. Furthermore, another patient had a lesion in the sellar region. The pathological diagnosis was DLBCL in 96.6% of cases. The other three patients were diagnosed with peripheral T-cell lymphoma.
Figure 1: Demonstration of three primary central nervous system lymphoma patients. (a) The MRI finding of typical primary central nervous system lymphoma. Tumors located at corpus callosal, periventricular, and subependymal. On T1W found hypointense, T2W and FLAIR are iso- to hyperintense, DWI is restricted, ADC is hypointense, and T1W gadolinium-enhanced image are homogeneous. This patient underwent a stereotactic biopsy for tissue diagnosis. (b and c). The MRI of non-typical cases of primary central nervous system lymphoma who received craniotomy for tumor removal. (b) They demonstrate a right temporal mass with central Gd enhancement. (c) They show posterior fossa tumor with heterogeneous enhanced

Click here to view


Most patients (77%) received at least one treatment, either CMT alone, brain radiation alone, or both. The remaining patients were classified into the palliative group and received the best supportive treatment. After 2013, the number of patients who received CMT was increased. The average time until therapy initiation was 27 days after surgery (range, 6–161 days). In the radiation (as a first treatment or single treatment in 32 patients) and CMT groups (as a primary treatment or only treatment in 35 patients), the average time to treatment initiation was 22 days after surgery (range, 6–161 days) and 30 days after surgery (range, 6–120 days), which was slower, respectively. The postoperative treatment details are shown in [Table 2].
Table 2: Postoperative treatment of primary nervous system lymphoma patients and time to treatment among treatment modalities

Click here to view


Survival outcome and prognostic factors

There were no missing data in this part of the study. The average follow-up time was 18.3 months (range, 0–109 months). At the end of February 2019, 23% of the patients were alive, and the median overall survival was 7 months. The 1-, 2-, and 5-year overall survival rates were 29%, 21.5%, and 4.6%, respectively [Figure 2]. The median overall survival of patients in the palliative group was only 1 month. However, the median overall survival of patients in the CMT only group, brain radiation alone group, and the combined treatment group was 2, 7, and 15 months, respectively [Figure 3].
Figure 2: Kaplan–Meier survival analysis with 95% confidence interval of overall survival duration in 87 primary central nervous system lymphoma patients

Click here to view
Figure 3: Survival of primary central nervous system lymphoma patients by postsurgical treatment subgroups. The log-rank test shows a statistically significant difference in survival by treatment subgroups (P < 0.001)

Click here to view


In the univariate analysis, the age of >60 years and palliative treatment were significant prognostic factors for death [Table 3]. Nevertheless, the only treatment modalities that were significant in the multivariable analysis treatment. Those who received CMT combined with radiotherapy exhibited the best survival (hazard ratio [HR], 0.18, P < 0.001).
Table 3: Factors associated with death in primary central nervous system patients by Cox regression analysis

Click here to view


We also evaluated the univariable analysis by excluding the palliative group and using the radiotherapy group as the reference. The significant factors were the same as those mentioned above. Age and treatment were significant prognostic factors for death in the univariable analysis. Correspondingly, the treatment factor of combined CMT and WBRT was substantial (HR, 0.47, P = 0.03).


  Discussion Top


Our study reported the experiences of a single institute over 14 years and evaluated the outcomes of PCNSL patients who were treated with limited available resources. Unfortunately, this study found that patients had a short survival time with a median overall survival of 7 months compared with previous studies that found that the median overall survival of PCNSL patients was higher and ranged from 9 to 100 months.[3],[5],[7],[10],[12],[14],[15],[16] Based on our knowledge, the different survival rates were primarily influenced by the patient's status and treatment options.

A patient's preoperative status plays a significant role in determining treatment outcomes. Currently, age, pretreatment PS, location, tumor number, absolute lymphocyte count, serum LDH, and CSF protein concentration are all generally accepted prognostic factors from four prognostic models.[5],[6],[11],[14] These models may help clinicians identify higher-risk patients and select proper treatment strategies. However, our result reveals that the only significant prognostic factor is postoperative treatment. Patients who received both CMT and brain radiation had better survival outcomes. In contrast, previous studies found that older age and pretreatment PS are significant prognostic factors.[2],[3],[5],[6],[10],[11],[13],[14] Most previous studies defined older age as >60 years,[3],[6],[13],[16],[17],[18] whereas others used >50 years as the cut off.[2],[5],[11],[14] In our study, older age was a significant predictor of poor outcomes in the univariable analysis, and age was a poor prognostic factor, but not significant, in the multivariable analysis. It should be caused by the majority of the patients in this study being elderly.

The standard treatment protocol for PCNSL has been widely adopted. However, the protocol differs among the many current guidelines [19],[20] and depends on existing evidence and resource availability. In the first half of this study, newly diagnosed PCNSL patients were treated with radiotherapy. Then, in 2011, the Thai Society of Hematology launched practical guidelines for PCNSL (http://tsh.or.th). From that time, CMT consisting of high-dose methotrexate became the mainstay of treatment. It provided more prolonged survival when combined with whole-brain radiotherapy as our demonstrated result (CMT alone vs. CMT + WBRT, median overall survival of 7 months vs. 15 months).

Some studies have noted that the choice of surgery might influence the treatment outcome. The extent of resection provides a theoretical benefit of decreased mass effect, cytoreduction, and improved tumor response to concurrent chemoradiotherapy in glioblastoma patients.[21] However, this strategy was found to be inconsistent with PCNSL patients.[8],[16],[22],[23] Similar to our results, surgical factors were previously not found to be related to survival benefits. In this study, the role of the neurosurgical intervention was limited to biopsy for tissue diagnosis. Tumor removal or debulking is not recommended.

This study has many limitations. First, the study design has a selection bias, given that it is a retrospective study that did not have specified patient selection criteria for any treatments. Second, this study was conducted at a single institute; therefore, the sample size is too small. Third, the treatment regimen changed over time, which may have contributed to chronological bias. Finally, we did not explore the molecular profiles (e.g., gene expression profiles and immunohistochemistry) of the PCNSL patients. These data are important prognostic factors in recent studies.[24] A future prognostic study should be included in this issue.


  Conclusions Top


According to the advance in CMT for PCNSL patients, the survival rate was improved. The most extended survival was found in combined therapy with WBRT and MTX-based CMT. However, the best regimen was still ongoing to study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Yang XL, Liu YB. Advances in pathobiology of primary central nervous system lymphoma. Chin Med J (Engl) 2017;130:1973-9.  Back to cited text no. 1
    
2.
Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer 2011;105:1414-8.  Back to cited text no. 2
    
3.
Shin SH, Jung KW, Ha J, Lee SH, Won YJ, Yoo H. Population-based Incidence and Survival for Primary Central Nervous System Lymphoma in Korea, 1999-2009. Cancer Res Treat 2015;47:569-74.  Back to cited text no. 3
    
4.
van der Meulen M, Dinmohamed AG, Visser O, Doorduijn JK, Bromberg JEC. Improved survival in primary central nervous system lymphoma up to age 70 only: A population-based study on incidence, primary treatment and survival in the Netherlands, 1989-2015. Leukemia 2017;31:1822-5.  Back to cited text no. 4
    
5.
Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, et al. Primary central nervous system lymphoma: The memorial Sloan-Kettering cancer Center prognostic model. J Clin Oncol 2006;24:5711-5.  Back to cited text no. 5
    
6.
Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, et al. Prognostic scoring system for primary CNS lymphomas: The International Extranodal Lymphoma Study Group experience. J Clin Oncol 2003;21:266-72.  Back to cited text no. 6
    
7.
Zeremski V, Koehler M, Fischer T, Schalk E. Characteristics and outcome of patients with primary CNS lymphoma in a “real-life” setting compared to a clinical trial. Ann Hematol 2016;95:793-9.  Back to cited text no. 7
    
8.
Yun J, Iwamoto FM, Sonabend AM. Primary central nervous system lymphoma: A critical review of the role of surgery for resection. Arch Cancer Res 2016;4:71.  Back to cited text no. 8
    
9.
Pollack IF, Lunsford LD, Flickinger JC, Dameshek HL. Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 1989;63:939-47.  Back to cited text no. 9
    
10.
Lin CH, Yang CF, Yang HC, Fay LY, Yeh CM, Kuan AS, et al. Risk prediction for early mortality in patients with newly diagnosed primary CNS lymphoma. J Cancer 2019;10:3958-66.  Back to cited text no. 10
    
11.
Bessell EM, Graus F, Lopez-Guillermo A, Lewis SA, Villa S, Verger E, et al. Primary non-Hodgkin's lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: Long-term survival and prognostic factors. Int J Radiat Oncol Biol Phys 2004;59:501-8.  Back to cited text no. 11
    
12.
Rujirojindakul P, Rohitoprakarn M, Kongkabpan D, Viboonjantra P, Lekhakula A. Incidence and radiographic findings of primary central nervous system lymphoma in immunocompetent patients in southern Thailand. Tumori 2008;94:304-8.  Back to cited text no. 12
    
13.
Lin TK, Yeh TH, Hsu PW, Chuang CC, Tu PH, Chen PY, et al. Primary central nervous system lymphomas of the brain: A retrospective analysis in a single institution. World Neurosurg 2017;103:550-6.  Back to cited text no. 13
    
14.
Jang JE, Kim YR, Kim SJ, Cho H, Chung H, Lee JY, et al. A new prognostic model using absolute lymphocyte count in patients with primary central nervous system lymphoma. Eur J Cancer 2016;57:127-35.  Back to cited text no. 14
    
15.
Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al. Primary intracerebral malignant lymphoma: Report of 248 cases. J Neurosurg 2000;92:261-6.  Back to cited text no. 15
    
16.
Shibamoto Y, Sumi M, Takemoto M, Tsuchida E, Onodera S, Matsushita H, et al. Analysis of radiotherapy in 1054 patients with primary central nervous system lymphoma treated from 1985 to 2009. Clin Oncol (R Coll Radiol) 2014;26:653-60.  Back to cited text no. 16
    
17.
Tomlinson FH, Kurtin PJ, Suman VJ, Scheithauer BW, O'Fallon JR, Kelly PJ, et al. Primary intracerebral malignant lymphoma: A clinicopathological study of 89 patients. J Neurosurg 1995;82:558-66.  Back to cited text no. 17
    
18.
Lee J, Shishido-Hara Y, Suzuki K, Shimizu S, Kobayashi K, Kamma H, et al. Prognostic factors for primary central nervous system lymphomas treated with high-dose methotrexate-based chemoradiotherapy. Jpn J Clin Oncol 2017;47:925-34.  Back to cited text no. 18
    
19.
Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol 2006;24:1281-8.  Back to cited text no. 19
    
20.
Hoang-Xuan K, Bessell E, Bromberg J, Hottinger AF, Preusser M, Rudà R, et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology. Lancet Oncol 2015;16:e322-32.  Back to cited text no. 20
    
21.
Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the extent of resection with survival in glioblastoma: A systematic review and meta-analysis. JAMA Oncol 2016;2:1460-9.  Back to cited text no. 21
    
22.
Weller M, Martus P, Roth P, Thiel E, Korfel A, German PCNSL Study Group. Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol 2012;14:1481-4.  Back to cited text no. 22
    
23.
Bellinzona M, Roser F, Ostertag H, Gaab RM, Saini M. Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: A series of 33 cases. Eur J Surg Oncol 2005;31:100-5.  Back to cited text no. 23
    
24.
Niparuck P, Boonsakan P, Sutthippingkiat T, Pukiat S, Chantrathammachart P, Phusanti S, et al. Treatment outcome and prognostic factors in PCNSL. Diagn Pathol 2019;14:56.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
<
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
  Subjects and Methods
  Results
  Discussion
  Conclusions
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed113    
    Printed4    
    Emailed0    
    PDF Downloaded28    
    Comments [Add]    

Recommend this journal