The role of surgical resection and stereotactic radiosurgery in PCNS-DLBCL: a retrospective analysis of clinical benefits

Abstract

Background:

Surgery resection and Stereotactic radiosurgery (SRS) remain controversial in the management of primary central nervous system diffusing large cell lymphoma (PCNS-DLBCL).

Methods:

A retrospective analysis was conducted utilizing data from the United States Surveillance, Epidemiology, and End Results (SEER) database (2000-2021) and our hospital (2006-2023). Cox proportional hazards regression models were employed to evaluate overall survival and cancer-specific survival to identify significant prognostic factors. The Kaplan-Meier method was applied to estimate overall survival probabilities. The Fine-Gray competing risk model was utilized to calculate cumulative incidence functions.

Results:

The SEER dataset encompasses 5359 cases, whereas our Hospital offered data on 51 patients with pathologically confirmed PCNS-DLBCL. Only when surgical resection was combined with methotrexate (MTX) and radiotherapy [33 months, 95% confidence interval (CI): 22.90–43.10], did it demonstrate a superior prognosis compared to MTX alone (20 months, 95% CI: 17.98–22.02). The survival outcome of patients receiving SRS in combination with high-dose (HD)-MTX cycling therapy improved.

Conclusion:

Following a thorough evaluation, surgical treatment should be executed as an adjunctive therapeutic approach. For patients with failed HD-MTX, SRS ought to be prioritized over whole-brain radiotherapy and emerge as the preferred alternative modality.

Introduction

Primary central nervous system lymphoma (PCNSL) represents the second most prevalent primary malignant brain tumor in adults[1]. Epidemiological data from the Central Brain Tumor Registry of the United States demonstrate an annual age-adjusted incidence rate of 25.34 per 100 000 individuals for primary central nervous system (CNS) tumors encompassing both malignant and non-malignant subtypes[2]. PCNS-DLBCL is one of the pathological subtypes with a rather poor prognosis.

High-dose methotrexate (HD-MTX) remains the cornerstone of first-line therapy for PCNSL, while no consensus exists regarding alternative therapeutic approaches. For relapsed PCNSL patients or those ineligible for systemic chemotherapy, whole-brain radiotherapy (WBRT) and autologous stem cell transplantation represent potential therapeutic alternatives. This therapeutic limitation underscores the critical need for robust clinical trials to validate MTX-based combination regimens in refractory PCNSL management. Current evidence is insufficient to incorporate stereotactic radiosurgery (SRS) and tumor resection into standard therapeutic regimens[3]; however, the latest guidelines from the European Association of Neuro-Oncology recommend multidisciplinary assessment for specific surgically accessible lesions[4]. SRS demonstrates technical limitations in PCNSL management due to the characteristic diffuse infiltration pattern, which precludes precise target delineation. This pathophysiological feature has established WBRT as the first choice in the current treatment regimen for patients who have failed MTX treatment or are intolerant to MTX.

This investigation employs a multi-methodological approach to systematically assess therapeutic outcomes and prognostic factors associated with neurosurgical interventions and SRS in PCNSL management. The analytical framework integrates retrospective cohort analysis utilizing SEER database records (2000-2021), institutional case series from our Hospital (2006-2023), and advanced survival analytics including Kaplan-Meier estimation, Cox proportional hazards modeling, and Fine-Gray competing risk model. This cohort study has been reported in line with the STROCSS guidelines[5].

Method

Data sources from SEER

A retrospective cohort study was conducted using data extracted from the US Surveillance, Epidemiology, and End Results (SEER) database (January 2000–December 2021). Cases of PCNS-DLBCL were selected based on the International Classification of Diseases for Oncology, Third Edition histology codes and primary anatomical site codes (C71.0–C71.9). The inclusion criteria consisted of: (1) a histologically confirmed diagnosis of PCNS-DLBCL; (2) documented treatment regimens and surgical interventions. The exclusion criteria comprised: (1) secondary CNS lymphoma; (2) cases lacking survival status documentation.

Data sources from our hospital

Following the initial diagnosis, we will conduct follow-up assessments every 3 months. Patients are required to return to the hospital for outpatient re-evaluations. These patients received treatments such as surgical resection, chemotherapy, SRS, and targeted therapy. In our center, the treatment techniques for PCNSL have reached a high level of maturity. For patients with newly diagnosed and undiagnosed conditions, a biopsy is performed for a clear diagnosis. Subsequently, HD-MTX chemotherapy is administered for four to six cycles as induction therapy according to the standard treatment protocol. If the patient experiences recurrence or the lesion does not resolve, SRS or WBRT will be considered. HD-MTX treatment will continue in a repetitive manner. If the tumor in the initial stage poses a life-threatening and unexpected situation, surgical resection will be performed and the pathological findings confirmed PCNSL following the surgery.

A retrospective analysis was conducted on data from patients diagnosed with PCNS-DLBCL at our hospital between December 2006 and December 2023. A total of 76 patients were included in this study, with follow-up continuing until July 2024. Inclusion criteria comprised: (1) pathologically confirmed PCNS-DLBCL; (2) complete clinical records detailing treatment methods and surgical approaches. Exclusion criteria included: (1) incomplete systemic treatment data; (2) loss to follow-up after initial contact; (3) prior receipt of WBRT. The primary endpoint of the study was patient death, with overall survival (OS) serving as the primary metric. All treatment regimens were determined by two neurosurgeons with senior professional titles and implemented in strict accordance with established guidelines. The collection of patients’ relevant information was carried out by two professional follow-up staff members to ensure the authenticity of all data.

HIGHLIGHTS

• Prompt multidisciplinary team evaluation for primary central nervous system diffusing large cell lymphoma (PCNS-DLBCL) should prioritize assessing surgical resection feasibility over immediate initiation of chemotherapy.

• Surgical resection is beneficial for solitary, superficial tumors not located in functional areas and for male patients who have not received chemotherapy.

• Stereotactic radiosurgery should supplant whole-brain radiotherapy as the second-line treatment regimen following chemotherapy in the recurrence of PCNS-DLBCL.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics (Version 26.0) and R software (Version 4.3.3). Prognostic determinants of OS and cancer-specific survival (CSS) were identified through Cox proportional hazards regression modeling, with initial univariate screening followed by multivariate adjustment for clinically relevant covariates. Kaplan-Meier survival curves were generated with event definition as all-cause mortality. To evaluate the influence of competing risks on patient survival, univariate analysis was implemented employing the cumulative incidence function (CIF) and the intergroup differences were compared by means of the Gray test. Multivariate analysis was performed using the Fine-Gray model to calculate the subdistribution hazard ratio after adjusting for relevant covariates. Propensity Score Matching (PSM) serves to equalize the baseline features of distinct groups (Supplemental Digital Content Figure 2, available at http://links.lww.com/JS9/F159). Two-tailed P-values <0.05 were considered statistically significant. Continuous variables and hazard ratios (HRs) are reported as mean with 95% confidence intervals (95% CI). The work has been reported in line with the STROCSS criteria[5].

Result

Baseline information of patient in SEER database

The SEER database included 5359 patients with PCNS-DLBCL, with additional baseline characteristics detailed in Supplemental Digital Content Table 1, available at http://links.lww.com/JS9/F162.

Univariable Cox regression identified age, sex, race, primary site, radiotherapy, and chemotherapy as significant prognostic factors for OS and CSS. Complete resection would improve CSS significantly compared to simple biopsy (P < 0.001 for all) but not for OS (Table 1). Multivariable analysis demonstrated that radiotherapy did not independently improve OS (P = 0.345) but remained significant in CSS (P < 0.05). Age, sex, race, primary site, and chemotherapy, and complete resection remained independent risk factors for OS and CSS in PCNSL in multivariable analysis (P < 0.05 for all) (Table 2).

Table 1.

Univariate analyses of potential prognostic factors for survival time in patients with PCNSL

Clinical features	Overall survival			Cancer-specific survival
	HR	95% CI	P value	HR	95% CI	P value
Age
<60	-	-	<0.001	-	-	<0.001
60 ~ 74	1.536	1.420 ~ 1.420	<0.001	1.181	1.084 ~ 1.287	<0.001
≥75	2.635	2.418 ~ 2.418	<0.001	1.653	1.504 ~ 1.816	<0.001
Sex
Male: Female	0.912	0.856 ~ 0.972	0.004	0.958	0.893 ~ 1.027	0.226
Race
White	-	-	<0.001	-	-	<0.001
Black	1.062	0.927 ~ 1.216	0.388	1.379	1.189 ~ 1.600	<0.001
Other	0.829	0.753 ~ 0.914	<0.001	0.993	0.890 ~ 1.108	0.895
Unknown	0.415	0.198 ~ 0.872	0.020	0.868	0.389 ~ 1.934	0.729
Primary site
Supratentorial	-	-	0.001	-	-	<0.001
Subtentorial	1.085	0.963 ~ 1.223	0.179	1.034	0.907 ~ 1.179	0.614
Other/unknown	1.138	1.060 ~ 1.221	<0.001	1.161	1.074 ~ 1.255	<0.001
Surgery
No surgery/biopsy	-	-	0.571	-	-	<0.001
Partial resection	1.082	0.932 ~ 1.256	0.302	0.913	0.777 ~ 1.074	0.273
Complete resection	0.988	0.863 ~ 1.131	0.860	0.744	0.640 ~ 0.865	<0.001
Radiation
No: Done	0.813	0.760 ~ 0.869	<0.001	0.809	0.751 ~ 0.871	<0.001
Chemotherapy
No: Done	0.333	0.312 ~ 0.356	<0.001	0.441	0.409 ~ 0.475	<0.001

Table 2.

Multivariable analysis of potential prognostic factors for survival time in patients with PCNSL

Clinical features	Overall survival			Cancer-specific survival
	HR	95% CI	P value	HR	95% CI	P value
Age
<60	-	-	<0.001	-	-	<0.001
60 ~ 74	1.609	1.485 ~ 1.743	<0.001	1.181	1.082 ~ 1.289	<0.001
≥75	2.356	2.155 ~ 2.575	<0.001	1.461	1.325 ~ 1.611	<0.001
Sex
Male: Female	0.864	0.811 ~ 0.921	<0.001	0.901	0.839 ~ 0.967	0.004
Race
White	-	-	0.003	-	-	0.014
Black	1.101	0.959 ~ 1.265	0.173	1.285	1.105 ~ 1.495	0.001
Other	0.880	0.799 ~ 0.970	0.010	1.007	0.903 ~ 1.124	0.898
Unknown	0.430	0.205 ~ 0.902	0.026	1.001	0.447 ~ 2.240	0.998
Primary site
Supratentorial	-	-	<0.001			<0.001
Subtentorial	1.104	0.979 ~ 1.244	0.106	1.030	0.904 ~ 1.175	0.655
Other/unknown	1.187	1.106 ~ 1.274	<0.001	1.168	1.080 ~ 1.263	<0.001
Surgery
No surgery/biopsy	-	-	0.121	-	-	0.003
Partial resection	1.020	0.878 ~ 1.186	0.794	0.979	0.832 ~ 1.152	0.795
Complete resection	0.870	0.759 ~ 0.996	0.044	0.771	0.662 ~ 0.897	<0.001
Radiotherapy
No: Done	0.966	0.900 ~ 1.038	0.345	0.686	0.634 ~ 0.742	<0.001
Chemotherapy
No: Done	0.354	0.330 ~ 0.381	<0.001	0.415	0.384 ~ 0.449	<0.001

Kaplan-Meier survival curves delineated 12 distinct therapeutic cohorts. Notably, no statistically significant differences in survival were observed in surgical resection groups compared to simple biopsy (P = 0.28). The cohort receiving MTX-based chemotherapy exhibited a median OS of 20 months (95% CI: 17.98–22.02), which was significantly longer than that of patients treated with WBRT (median OS: 4 months, 95% CI: 3.25–4.75; P < 0.001). Only patients who received combination therapy, including partial resection, chemotherapy, and radiotherapy, showed statistical significance compared to the chemotherapy group (P < 0.05). This implies that the current WBRT and surgical treatment for PCNS-DLBCL have limited effects. For patients intolerant or resistant to MTX, novel treatment regimens are required (Fig. 1, Supplemental Digital Content Table 2, available at: http://links.lww.com/JS9/F163). The surgical option yielded distinct conclusions in both Kaplan-Meier analysis and COX analysis, suggesting that there exists a synergy between the surgical option and other confounding factors. Identifying patients suitable for the appropriate surgery is of particular significance.

Figure 1.

Kaplan-Meier survival comparisons of patients with PCNS-DLBCL in the SEER database under diverse treatment protocols: (A) Comparisons of survival periods among simple biopsy, partial resection, and complete resection. (B) Comparisons of survival periods among chemotherapy, radiotherapy, and combined chemotherapy and radiotherapy. (C) Comparisons of survival periods among partial resection or complete resection in combination with radiotherapy or chemotherapy. (D) Comparisons of survival periods among partial resection or complete resection in combination with both radiotherapy and chemotherapy.

Competing risks regression analysis based on the Fine-Gray model in SEER database

In conducting the survival analysis using the data of patients with PCNS-DLBCL from the SEER database, an in-depth comparison was made between the traditional Kaplan-Meier survival curve and the CIF based on the competing risk regression model. It was found that beyond the intersection point around 25 months, the Kaplan-Meier survival curve might overestimate the cumulative mortality risk of patients in the presence of competing risks, while the CIF offered a more accurate assessment of the risk of death due to cancer (Supplemental Digital Content Figure 1, available at http://links.lww.com/JS9/F158). In the competing risk model, the univariate analysis suggested that age, race, sex, chemotherapy, radiotherapy remained factors for disease prognosis (Supplemental Digital Content Table 3, available at http://links.lww.com/JS9/F164). However, radiotherapy ceased to be an independent risk factor influencing the prognosis of patients in the multivariate analysis. (Supplemental Digital Content Table 4, available at http://links.lww.com/JS9/F165). The cumulative incidence indicates that increasing age is significantly positively correlated with the cumulative incidence in patients with PCNS-DLBCL (95% CI: 1.018–1.024, P < 0.0001). Gender (95% CI: 0.811–0.933, P = 0.0001) and race (95% CI: 0.876–0.973, P = 0.0027) are significantly negatively correlated with the cumulative incidence. Chemotherapy significantly reduces the cumulative incidence (95% CI: 0.328–0.387, P < 0.0001). (Fig. 2, Supplemental Digital Content Table 4, available at http://links.lww.com/JS9/F165).

Figure 2.

Comparison of cumulative incidence of different treatment methods in competing risk models.

Propensity Score Matching (PSM): does surgery have an advantage?

To assess the value of surgical treatment in PCNSL, we compared the groups of no surgery, partial resection, and total resection. The findings revealed no significant differences among the three. Nevertheless, the number of patients in the non-surgical group was far greater than that in the other two groups, resulting in considerable discrepancies in baseline data among them. Hence, we conducted propensity score matching for the non-surgical group, partial resection group, and total resection group in pairs and compared their survival curves once again. The median survival times after matching for the non-surgical group and the partial resection group were 20 months and 22 months, respectively (p = 0.45), those for the non-surgical group and the total resection group were 20 months and 24 months, respectively (p = 0.38), and those for the partial resection group and the total resection group were 22 months and 24 months, respectively (p = 0.52). This implies that surgical treatment, be it partial resection or total resection, holds little significance in enhancing the survival period of patients with PCNSL (Fig. 3). Prior to propensity score matching, among male patients, the risk of death in the surgical group was 14.6% lower than that in the non-surgical group (HR = 0.854, 95% CI: 0.736–0.992). Among patients undergoing radiotherapy, the risk of death in the surgical group was 15.2% lower than that in the non-surgical group (HR = 0.848, 95% CI: 0.720–0.999). Among patients not undergoing chemotherapy, the risk of death in the surgical group was 18.3% lower than that in the non-surgical group (HR = 0.817, 95% CI: 0.693–0.962). After propensity score matching, the risk of death in the surgical group was 24.8% lower than that in the non-surgical group (HR = 0.752, 95% CI: 0.609 ~ 0.929). Among patients not undergoing chemotherapy, the risk of death in the surgical group was 25.0% lower than that in the non-surgical group (HR = 0.750, 95% CI: 0.602 ~ 0.934). This implies that for male patients who have not undergone chemotherapy, surgical options might be considered a more preferred choice. (Supplemental Digital Content Figure 2, available at: http://links.lww.com/JS9/F159, Supplemental Digital Content Table 5, available at http://links.lww.com/JS9/F166).

Figure 3.

Comparison of patient prognosis under distinct surgical modalities before and after Propensity Score Matching (PSM). (A) Before PSM, a comparison of survival periods under simple biopsy, partial resection, and complete resection. (B) After PSM, the comparison of survival periods between the simple biopsy group and the partial resection group. (C) After PSM, the comparison of survival periods between the simple biopsy group and the complete resection group. (D) After PSM, the comparison of survival periods between the partial resection group and the complete resection group.

Retrospection of cases and summary of clinical experience in our hospital

A total of 76 patients were diagnosed with PCNSL-DLBCL from December 2006 to December 2023. A total of 25 patients failed to meet the inclusion and exclusion criteria of our research. Of these, 11 patients lacked complete therapy, 11 patients only visited once at the initial diagnosis, and the remaining three patients underwent WBRT. This study encompassed the data of 51 DLBCL patients at length (Fig. 4). Among them, 33 (64%) were males and 18 (35%) were females, with a male-to-female ratio of 1.83:1.00; 19 (37%) were aged 60 years or above, 31 (60%) were younger than 60 years, and 1 (1%) had missing age data; the first-choice chemotherapy regimens were as follows: 12 (60%) were treated with MTX alone, 4 (20%) with MTX + Bevacizumab, 1 (5%) with MTX + Rituximab, 1 (5%) with MTX + Rituximab + Zanubrutinib + Bevacizumab, and 2 (10%) with MTX + Temozolomide; 22 (43%) were cases with solitary lesions, 28 (54%) were cases with multiple lesions, and 1 (1%) had missing data; the number of recurrences was 3 (23%) in the surgical treatment group, 16 (88%) in the SRS group, and 4 (20%) in the drug treatment group; the number of survivals was 4 (30%) in the surgical treatment group, 4 (22%) in the SRS group, and 6 (30%) in the drug treatment group (Table 3).

Figure 4.

Flowchart for the screening of PCNS-DLBCL patients in our hospital.

Table 3.

Baseline clinical characteristics in our hospital

Baseline characteristics	Value
Gender (n, %)
Male	33 (64)
Female	18 (35)
Age (n, %)
≥60	19 (37)
<60	31 (60)
Data missing	1 (1)
Prior chemotherapy (n, %)
MTX	12 (60)
MTX + Bevacizumab	4 (20)
MTX + Rituximab	1 (5)
MTX + Rituximab + Zanubrutinib + Bevacizumab	1 (5)
MTX + Temozolomide	2 (10)
Singular/Multiple (n, %)
Singular	22 (43)
Multiple	28 (54)
Data missing	1 (1)
Recurrence (n, %)
Surgery + Chemotherapy/Target/SRS	3 (13)
SRS + Chemotherapy/Target	16 (70)
MTX	0 (0)
MTX + Target	4 (17)
Alive (n, %)
Surgery + Chemotherapy/Target/SRS	4 (29)
SRS + Chemotherapy/Target	4 (29)
MTX	3 (21)
MTX + Target	3 (21)

The results of the Kaplan-Meier survival analysis indicated that among the 51 patients treated at our Hospital, the median survival time was 37 months (95% CI: 9.867–64.133). Among them, the median survival time for surgery + chemotherapy/targeted therapy/SRS was 37 months (95% CI: 0–74.719). For SRS + chemotherapy/targeted therapy, since most patients were still alive at the end of the follow-up, the median survival time could not be calculated currently. The median survival time for the MTX group was 12 months (95% CI: 1.816–22.814), and the median survival time for the patients in the MTX + targeted therapy group was 67 months (95% CI: 16.783–117.217). At present, the guidelines recommend that patients with relapsed and refractory PCNSL can choose WBRT. However, the experience of the Neurosurgery Center of our Hospital is that when patients have a recurrence after MTX treatment and receive gamma knife radiotherapy, MTX treatment can be continued. Moreover, due to the precision of SRS, the cytotoxicity problem brought by WBRT is avoided. It can be used multiple times to prolong the survival period of patients. The median survival time of patients treated with the SRS and MTX cycling therapy was significantly prolonged compared with the MTX group (P = 0.008), while the median survival time of the MTX plus targeted drug therapy method was superior to that of the SRS and MTX cycling therapy (P = 0.003). It was also longer than that of the group treated with MTX alone (P = 0.039). (Fig. 5).

Figure 5.

Survival curves of patients with PCNS-DLBCL in our hospital under various treatment regimens.

Systematic review of surgery and SRS in PCNSL

This study updated a previous systematic review[6], by searching PubMed and Scopus from 1 June 2018, to 1 August 2024, using keywords like “Surgery,” “Lymphoma,” and “Central Nervous System,” including terms “CyberKnife” and “Gamma knife” for radiosurgery. After deduplication and PRISMA-based screening, relevant studies were selected for qualitative analysis, with details provided in supplementary materials (Search term of Surgery, Search term of SRS, Supplemental Digital Content Figure 3, available at http://links.lww.com/JS9/F160 and Supplemental Digital Content Figure 4, available at http://links.lww.com/JS9/F161).

The potential positive impact of surgical resection on prognosis has long begun to challenge the traditional notion of relying solely on drug treatment^[7–10] (Table 4 and Table 5). In the database analysis, the combination of surgery and adjuvant therapy has a remarkable improvement effect on the prognosis of patients with PCNSL^[3,11–13]. Studies have shown that surgical resection is significantly correlated with an increased survival rate when compared with no surgery/biopsy, and this survival benefit is independent of baseline prognostic factors and chemotherapy after multivariate Cox analysis[14]. Postoperative chemotherapy significantly improves the prognosis of PCNSL patients^[11,15–17]. Prognostic outcomes vary significantly among PCNSL subtypes, with indolent subtypes such as FL and MZL have better outcomes, whereas PCNSL-DLBCL has a poorer prognosis than nodal DLBCL[18].

Table 4.

A systematic literature review of SRS for the treatment of PCNSL

Study	Year	Research overview	Outcome	Conclusions
Schep et al.	2023	Retrospective analysis of initial cases of CNS lymphoma treated with fractionated stereotactic(fSRS) radiotherapy.	14 patients who received fSRS was 36 months.	SRS may be a reasonable treatment option for CNS lymphoma patients who refuse WBRT or have poor tolerance to WBRT toxicity.
Alvarez-Pinzon et al.	2021	Prospective and observational clinical study evaluating the effectiveness of gamma knife radiosurgery and methotrexate therapy in primary CNS lymphoma.	MTX group (19.8 months) VS SRS and MTX treatment group (52.6 months); P = 0.0029	Compared with the MTX group, patients receiving combined SRS and MTX therapy had significantly higher average survival rates.
Foreman et al.	2023	Studies the long-term effects of reduced-dose WBRT and stereotactic radiosurgery boost on primary CNS lymphoma patients.	The 2-year overall survival (OS) rate of 23 patients who received rd-WBRT + SRS was 69%.	The combination of RD-WBRT and SRS appears to be well-tolerated and provides durable intracranial control.
Palmer et al.	2020	Analyzes the efficacy and complications of stereotactic radiosurgery for CNS lymphoma.	Median time to progression of 6 patients received SRS was 12.7 months	SRS may provide good local control for refractory CNS lymphoma patients.
Wu et al.	2023	Studies the application and efficacy of stereotactic radiosurgery in the treatment of primary CNS lymphoma.	20 patients who received SRS combined with chemotherapy and targeted therapy was 39 months (95% CI = 24–54 months).	Reports on the impact of SRS on PCNSL patients, potentially delaying WBRT or serving as a salvage after WBRT.

Table 5.

A systematic literature review of surgery for the treatment of PCNSL

Study	Year	Research overview	Outcome	Conclusions
Aliaga et al.	2022	Reported a case of a 55-year-old female with primary CNS Hodgkin’s lymphoma (PCNS-HL)	Surgical resection, in conjunction with intrathecal chemotherapy and whole-brain radiotherapy, achieved a disease-free survival (DFS) of 14 months	Primary PCNS-HL has a good prognosis with surgery combined with adjuvant therapy.
Brawanski et al.	2020	Retrospective analysis of patients with CNS lymphoma (CNSL) who underwent “unexpected” tumor resection between 2002 and 2013.	The median survival time of the 5 patients who underwent surgery was 22.6 months.	Resection of CNSL may improve prognosis
Chen et al.	2024	Studied the impact of postoperative chemotherapy on the survival of primary CNS lymphoma (PCNSL) based on the SEER database.	This study was based on the SEER database and did not incorporate data related to the authors’ affiliated institutions.	Postoperative chemotherapy significantly improves the prognosis of PCNSL patients.
Cheng et al.	2022	Single-center retrospective study comparing the prognosis of resection versus biopsy in patients with single-lesion PCNSL.	The median OS among 60 patients who received resection was 64.2 months (95% CI: 29.0–99.4 months). In contrast, the median OS of 45 patients in biopsy group was 59.9 months (95% CI: 32.6–87.2 months).	No significant difference in PFS and OS between resection and biopsy; younger age and postoperative treatment are indicators of good prognosis.
Chihara et al.	2018	Analyzed the prognosis of different histological subtypes of PCNSL based on the SEER database.	This study was based on the SEER database	Significant differences in prognosis among different subtypes of PCNSL.
Deng et al.	2020	Analyzed the impact of surgical resection on the survival of PCNSL based on the SEER database.	This study was based on the SEER database	Surgical resection significantly improves the survival of PCNSL patients, independent of baseline prognostic factors.
Fiedler et al.	2023	Reported a case of a 73-year-old female with PCNSL treated with surgery and combined therapy.	The patient has survived for more than 10 months by the end of the follow-up period.	Surgery combined with chemotherapy may be effective in certain PCNSL patients.
Furst et al.	2024	Analyzed the mortality trend of PCNSL patients over 70 years old based on the SEER database.	This study was based on the SEER database	Younger age and surgery are the best predictors of survival for elderly PCNSL patients.
Guo et al.	2024	Reported a multidisciplinary treatment experience of a 26-year-old male with multiple cerebellar PCNSL.	Not mentioned	Surgery combined with radiochemotherapy can significantly extend the survival of PCNSL patients.
Jahr et al.	2018	Retrospective analysis of the impact of surgery on the survival of PCNSL patients in a single center.	The median OS of 32 patients who underwent resection was 28.6 months.	Resection did not significantly improve OS or PFS of PCNSL patients and is not recommended as standard treatment.
Jiang et al.	2023	Built a prognostic model for PCNSL based on the SEER database and compared the effects of different treatments.	This study was based on the SEER database	Complete resection significantly improves OS and CSS; chemotherapy is more effective than radiotherapy.
Jiang et al.	2023	Retrospective analysis of the incidence of primary intracranial lymphoma in the United States and the impact of surgery on prognosis.	This study was based on the SEER database	Surgery significantly improves overall and cancer-specific survival rates.
Kinslow et al.	2020	Analyzed the impact of surgery combined with radiotherapy on the survival of PCNSL based on the SEER database.	This study was based on the SEER database	Surgery combined with radiotherapy significantly improves the survival of PCNSL patients.
Labak et al.	2019	Systematically reviewed the differences in prognosis between surgical resection and biopsy of PCNSL.	Not mentioned	Recent studies suggest that surgical resection may be beneficial for PCNSL, further research is needed.
Majovsky et al.	2024	Compared the value of intraoperative MRI and intraoperative pathological examination in the diagnosis of PCNSL.	Not mentioned	Intraoperative MRI is superior to intraoperative pathological examination in diagnostic accuracy.
Nien et al.	2024	Retrospective study of the impact of surgical resection on the survival and functional prognosis of PCNSL patients.	The median OS of 36 patients who underwent surgery was 38.6 months, which was significantly higher than that of patients who only received biopsy (22.3 months).	Complete resection significantly improves PFS, with no negative impact on functional prognosis.
Nizic et al.	2024	A single-center 10-year PCNSL treatment experience, evaluating treatment prognosis.	The OS of the 24 patients who underwent surgery was 45.9 months.	Comprehensive therapy can improve the prognosis of PCNSL patients.
Ouyang et al.	2020	Retrospective analysis of the surgical outcomes and prognostic factors of 89 patients with intracranial PCNSL.	The OS of the 71 patients who underwent surgical resection was 33 ± 2.998 months, while that of the 18 patients who only received biopsy was 26 ± 2.308 months.	Resection can improve PFS, but has no significant impact on OS.
Pan et al.	2024	Analyzed the prognostic factors and surgical effects of PCNSL-DLBCL based on the SEER database.	This study was based on the SEER database	Surgery combined with chemotherapy significantly improves survival.
Rae et al.	2019	Retrospective analysis of the impact of surgery on the survival of PCNSL.	The median survival period was increased in craniotomy and biopsy (19.5 vs 11.0 months).	Resection significantly improves survival compared to biopsy.
Schellekes et al.	2021	Retrospective analysis of the impact of surgical resection on the survival of patients with single-lesion PCNSL.	The OS of patients with superficial tumors who underwent excision was significantly longer than that of those who received puncture biopsy (median survival time 34.3 months vs 8.9 months, P = 0.014).	Certain subgroups of patients may benefit from surgical resection.
Villalonga et al.	2018	Retrospective study of the impact of resection versus biopsy on the survival of PCNSL patients.	Compared with the biopsy group (14.5 months), patients in the resection group (31 months) had a significantly longer median OS. p = 0.016	Resection significantly extends the survival time of PCNSL patients.
Wang et al.	2018	Single-center retrospective analysis of the treatment and prognosis of 34 PCNSL patients.	The OS of the surgery group was 8.5 months, while that of the surgery/biopsy combined with chemotherapy group was 54 months.	Chemotherapy combined with surgery is better than surgery alone; high-dose chemotherapy regimens may be effective.
Wong et al.	2023	Analyzed the prognostic value of comorbidity index and immunohistochemical markers in surgical and non-surgical PCNSL patients.	The median survival of 23 patients who received stereotactic biopsy and 18 patients who underwent surgical resection was 11.05 months.	Resection can predict improved PFS, but has no significant impact on OS.
Wu et al.	2021	Single-center retrospective analysis of the effects of surgical resection and biopsy in 70 PCNSL patients.	The average OS of patients who underwent surgical resection was 23.4 months (n = 28), while that of the stereotactic biopsy group was 16.1 months	Resection significantly improves OS and PFS.
Yuan et al.	2020	Single-center retrospective analysis of 167 Chinese PCNSL patients’ clinical pathological characteristics and prognostic factors.	The median overall survival was 37 months.	Surgical residue, non-high-dose chemotherapy, and palliative treatment are poor prognostic factors.
Sinhal et al.	2022	Explores the consideration of resection range in cell reduction surgery for primary CNS lymphoma.	The OS tended to be prolonged in the 12 patients who underwent cytoreductive surgery compared with the 46 patients who received stereotactic biopsy (29.8 months vs. 22.3 months, P = 0.672).	Cell reduction surgery has potential benefits for certain patients diagnosed with PCNSL.

The combination of SRS with HD-MTX therapy demonstrates improved survival rates over MTX monotherapy[19], potentially mitigates the toxicities associated with WBRT, and may serve as a salvage treatment option subsequent to WBRT^[20–22]. The research indicates that SRS is more appropriate for cases of multiple lesions, deep-seated tumors, recurrent or refractory PCNSL, as well as situations where the tumor volume is small or the patient is unable to tolerate surgery^[6,23,24]. These discoveries support the incorporation of surgery and SRS as components of a multimodal treatment strategy for PCNSL, particularly among selected patients[23].

Discussion

Due to the multifocal nature of PCNSL, surgical resection is not considered a standard therapeutic approach for PCNSL. Although traditional perspectives have discounted surgery due to the potential for severe neurologic deficits and poor prognosis, the analysis of data from the SEER database indicates that patients who underwent complete surgical resection in conjunction with radiotherapy and chemotherapy had a median survival time of 33 months, significantly higher than that of patients who received chemotherapy alone. Concurrently, we advocate for a reassessment of the possibility of surgical resection in patients with PCNSL under appropriate circumstances, particularly for solitary lesions that do not involve deep brain structures^[13,25–27]. Previous research leveraging the SEER database to evaluate the therapeutic efficacy of surgery for PCNSL did not adequately address the baseline disparities between surgical and non-surgical patient cohorts. Our study rectified this by employing propensity score matching and discovered that while surgery alone has limited efficacy in treating PCNSL, integrated treatment strategies combining surgery with chemotherapy or radiotherapy should be contemplated.

In the Cox regression analysis, radiotherapy was identified as an independent prognostic factor for CSS, yet it did not reach statistical significance in the Fine-Gray competing risk model. WBRT, serving as the primary consolidative treatment following HD-MTX and immunotherapy, has been less than satisfactory in improving the median survival period of patients[28], with a median survival of only 4 months for the radiotherapy-alone group and 19 months for the chemotherapy combined with radiotherapy group. In the treatment protocol of our Hospital, we employ gamma knife therapy in combination with chemotherapy for PCNSL, and the median survival is significantly higher than that of WBRT in combination with chemotherapy. Hence, it is recommended that HD-MTX in combination with SRS should supplant WBRT as the first-line treatment protocol. SRS nonetheless exhibits certain limitations. Specifically, inaccuracies in CT-MRI registration and ambiguous tumor margins can potentially introduce errors in target selection. The success of SRS hinges upon meticulous planning, accurate determination of the tumor margins, and achieving a delicate balance in radiation dosing that not only ensures an adequate margin but also safeguards critical organs. All these aspects pose significant challenges to the successful implementation of SRS^[29,30].

Conclusion

In summary, the therapeutic effects of surgical treatments for PCNSL, such as surgical resection and stereotactic radiotherapy, should be re-acknowledged. For single lesions that do not involve crucial structures, total resection should be pursued to the greatest extent possible to eliminate the visible lesions, followed by HD-MTX treatment in combination with rituximab^[15,31]. For patients with tumor recurrence or refractory conditions, WBRT should no longer be employed; instead, targeted SRS should be utilized to precisely reduce and eliminate tumor cells.

Strength and limitation

The strength of our study is that, by leveraging public datasets and patient data from our center, it identifies the limitations of the current guidelines. Our study was merely a single-center retrospective investigation with a limited sample size. Furthermore, because of the restricted information in the case materials, we were unable to offer more advice for patients on selecting gamma knife therapy or surgical resection based on their conditions.

The SEER database encompasses only select states/regions within the United States and spans an extended period. This situation may render historical and contemporary cohorts incomparable, potentially giving rise to loss-to-follow-up bias. Additionally, coding updates can introduce confounding factors that may impact the conclusions drawn in this study[32].

Ethical approval

This study was approved by the Ethics Committee of Nanfang hospital (No. NFEC-2025-095). The Research Registration Unique Identifying Number of this study is ChiCTR2500103591. The use of retrospective data complied with the principles of the Declaration of Helsinki.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. The research was retrospectively registered.

Sources of funding

Natural Science Foundation of Guangdong Province (2023A1515030233). They provided financial support for the analysis and interpretation of data.

This work was supported by grants from the Natural Science Foundation of Guangdong Province (2017A030313597, 2023A1515030233).

Author contributions

J.W.: Research project conception. J.D.: Research project conception and organization and critique. Y.Z.: Patients follow-up and organization and statistical analysis execution. J.W.: Conceptualization. P.Z., Y.B., J.D., Y.Z., C.C., Z.D., C.C., S.Z.: Methodology. J.W., P.Z., and J.D.: Formal Analysis; J.W., W.Z.: Investigation; J.W., J.D.: Writing – Original Draft; J.F. and J.D.: Visualization; J.W., W.Z., L.C.: Supervision; J.W.: Funding Acquisition.

Conflicts of interest disclosure

None of the authors has any conflict of interest to disclose.

Research Registration Unique Identifying Number (UIN)

ChiCTR2500103591.

Guarantor

Wang Jun would be the Guarantors.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data supporting the findings of this study are derived from two sources: The SEER database is a publicly accessible registry managed by the National Cancer Institute (USA). Researchers may request access to SEER data through the official portal (https://seer.cancer.gov/). The data are available from the corresponding authors.