Primary Brainstem Lymphoma: A Population-Based Study

doi:10.21203/rs.3.rs-728975/v1

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Primary Brainstem Lymphoma: A Population-Based Study

https://doi.org/10.21203/rs.3.rs-728975/v1

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Purpose. Primary brainstem lymphoma (PBSL) is rare and malignant. Understanding of this disease is lacking. We aimed to characterize clinical features, estimate survival and explore survival-related factors of PBSL.

Methods. Patients with a histological diagnosis of primary lymphoma in the brainstem (C71.7) from 1975 to 2016 were retrieved from Surveillance, Epidemiology, and End Results (SEER) program. Log-rank tests, univariate and multivariate Cox proportional hazard analyses were used to identify survival-related factors.

Results. PBSL constituted 2.7% of brainstem malignancies. The median age of the PBSL patients were 59.5 years. Diffuse large B cell lymphoma (n = 49, 84.5%) was the most prevalent histology among the 58 cases with reported specific lymphoma subtype. The majority of PBSLs were localized (n = 46, 52.3%), at low Ann Arbor Stage (I/II, n = 63, 70.5%), and presented as a single primary (n = 71, 80.7%). Chemotherapy was applied in 50 (56.8%) cases. Three-year overall survival (OS) and disease-specific survival (DSS) rates were 42.7% and 53.5%, respectively. Multivariate analyses showed that independent predictive/prognostic factors for OS were age (P = 0.004), tumor number (P = 0.029), and chemotherapy (P = 0.001); DSS-related factors only included age (P = 0.014) and chemotherapy (P = 0.008).

Conclusions. We estimated survival rates for PBSL patients. Factors associated with OS and DSS were also identified. Our findings addressed the importance of chemotherapy in treating PBSL patients.

Neurology

Oncology

brainstem

glioma

incidence

survival

SEER

Our study represented the first study to comprehensively investigate PBSL based on a population dataset. We identified several independent predictors for overall survival (OS) and disease-specific survival (DSS). Demographical features, tumor-related characteristics, and therapeutical details were reported.

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL). This disease involves the eye, brain, spinal cord, etc., but without evidence of systemic disease. It accounts for 1.9% of all primary central nervous system (CNS) neoplasms and 6.4% of primary CNS malignancies[1]. Patients with acquired or congenital immunodeficient disease are susceptible to PCNSL[2]. The current treatment strategy consisted of biopsy followed by high-dose methotrexate-based chemotherapy[3]. The efficacy of craniotomy is controversial[3, 4]. However, the outcomes of these patients remain dismal, with 5-year overall survival being 37.6%[1].

Primary brainstem lymphoma (PBSL) was rarely encountered in clinical practice. But PCNSL located at the brainstem predicts more severe surgical complications[5]. At present, there are only several case reports from a single institute[6–18]. The existing published studies failed to estimate the survival of PBSL, let alone to explore survival-related factors. As nationwide datasets, the Surveillance, Epidemiology, and End Results (SEER) datasets are an ideal platform to study rare malignant entities, e.g., PBSL[19]. Previous studies leveraged the SEER dataset to characterize primary spinal lymphoma[20]. However, no research yet applies the SEER dataset to study PBSL. Clinical characteristics and prognostic/predictive factors of PBSL patients remain poorly understood. We aim to elucidate survival and survival-associated factors for overall survival (OS) and disease-specific survival (DSS) based on a population-based dataset.

Case Selection from the SEER Database

The SEER program of the National Cancer Institute is an authoritative source for cancer statistics in the United States. Since all the information is collected in a de-identified manner, the Institutional Review Board's approval was exempted. This study extracted data from incidence-SEER 18 Registries Custom Data (with additional treatment fields), Nov 2018 Sub (1975–2016 varying). This dataset covers 27.8% of the United States population (based on the 2010 census). To obtain quantified PBSL cases, we queried the program by defining the first ICD-O-3 primary site (brainstem, C71.7) and then histology record (lymphoma). Our selecting strategy was detailed in Fig. 1, where the goal is to obtain histologically confirmed PBSL cases and exclude patients without qualified survival time. SEER*Stat (Version 8.3.9, https://seer.cancer.gov/seerstat/) was used to retrieve the data.

Definitions of variables

OS and DSS were our main and additional endpoints, respectively. Although both marked the length of time from the date of diagnosis to the date of death, OS took into account deaths irrespective of causes; in contrast, when measuring DSS, patients who died from causes other than PBSL were uncounted. We divided surgery extent into gross total resection (GTR), partial resection (PR), and no surgery, following the decoding strategy described by Dudley et al. [21]. The Arbor staging system is widely applied to stage lymphoma anatomically[22] and was reclassified into low stage (stage I/II) and high stage (stage III/IV). The sequence number informs the sequence of PBSL among all neoplasms over the patient's lifetime. We replaced sequence number in SEER with tumor number, where "one primary only" in sequence number was defined as a single lesion in tumor number and others as multiple lesions.

Meanwhile, we dichotomized diagnosis year (1975–1996 vs. 1997–2016), sex (female vs. male), marital status (married vs. unmarried/unknown), lymphoma type (diffuse B cells vs. others), stage (localized vs. regional/distant), radiotherapy (with radiotherapy vs. no/unknown), and chemotherapy (with chemotherapy vs. no/unknown). Age at diagnosis (0–50, 51–70, and 71+) and race (white, black, and others) were classified into three groups.

Statistical Analysis

All statistical analyses were conducted using R (version 3.8.0, 2019, http://www.r-project.org/). Since the distribution of age (p < 0.05) and follow-up time (p < 0.001) were non-normal in the Shapiro-Wilk Normality Test, a median with interquartile range (IQR) was used to describe the two parameters. Prognostic/predictive factors for both OS and DSS were evaluated by Cox proportional hazards regression. Kaplan-Meier curves were used to estimate survival and significant predictors of OS and DSS. Candidates with a P-value < 0.05 in univariate Cox analysis were subject to multivariate analyses. All tests were two-sided, and a P-value < 0.05 was considered statistically significant.

Demographics and Clinical Characteristics of Cohort for Survival Analysis

We identified 143 PBSL cases, constituting 2.7% (n = 5391) patients with brainstem malignancies. Finally, 88 PBSL cases met our criteria (Fig. 1A). The median age of the cohort was 59.5 (IQR 45.8–68.3) years. Children (≤ 18 years) PBSL patient was found only in one case. The proportion of male patients was 52.3% (n = 46). The majority of the patients were while (n = 77, 87.5) and got married (n = 51, 58%).

All the 58 cases with reported specific lymphoma subtypes were NHL. B-cell-derived lymphoma (n = 55, 95.8%) represented the most dominant variants, most of which (n = 49, 84.5%) were diffuse large B cell lymphoma (DLBCL). There were two cases with T-cell lymphoma and one case with mixed small and large cell lymphoma. The details of the remaining variants were plotted in Fig. 1B. Based on the Ann Arbor Staging system, stage I, stage II, and stage IV were respectively found in 62 (70.5%) cases, 1 (1.1%) case, and 13 (14.8%) cases, without PBSL at stage III being identified. Just over half the lesions (52.3%, n = 46) were localized at diagnosis. In terms of tumor number, single and multiple PBSLs were found in 71 (80.7%) and 17 (19.3%) patients (Table 1).

Therapeutical details and survival

More than half patients (n = 51, 58.0%) did not receive surgical treatment. The diagnosis of these patients was based on positive cytology or histology. GTR and PR were achieved in 3 (3.4%) and 27 (30.6%) cases, respectively. Radiotherapy and chemotherapy were applied in 49 (55.7%) and 50 (56.8%) cases, respectively.

The median follow-up time of the cohort was 12 (IQR 3–50) months. Only 20 (22.7%) patients survived. Among the 68 (77.3%) dead patients, 47 (53.4%) cases succumbed to PBSL, while the other 21 (23.9%) patients died from causes other than PBSL progression. The 1-year, 3-year, and 5-year OS of patients with PBSL were 51.3%, 42.7%, and 32.1%, respectively; the figures for DSS were 64.3%, 53.5%, and 45.0%, respectively (Fig. 2).

Prognostic/predictive factors

Kaplan-Meier long-rank tests showed patients diagnosed during 1975–1996 (Fig. 2A), older age (Fig. 2B), single PBSL (Fig. 2C), and no use of chemotherapy (Fig. 2D) was related to a poor OS. In the univariate Cox analyses, consistent results were found. Subsequent multivariate tests revealed that age (3-year OS of ≥ 71 years vs. ≤ 50 years = 14.6% vs. 50.6%, HR [95% CI] = 2.957 [1.416,6.178], P = 0.004), tumor number (3-year OS of single vs. multiple = 32.4% vs. 45.4%, HR [95% CI] = 2.083 [1.078,4.022], P = 0.029), and use of chemotherapy (3-year OS of no/unknown vs. with chemotherapy = 23.7% vs. 57.5%, HR [95% CI] = 2.558 [1.498,4.368], P = 0.001, Fig. 3).

In contrast, both DSS-associated factors, identified in Kaplan-Meier long-rank tests, older age (Supplementary Fig. 1A) and no use of chemotherapy (Supplementary Fig. 1B), were verified in univariate and multivariate Cox analyses (Supplementary Fig. 2). The 3-year DSS of ≥ 71 years vs. ≤ 50 years (HR [95% CI] = 2.938 [1.241,6.952], P = 0.014) and no/unknown vs. with chemotherapy (HR [95% CI] = 2.288 [1.244,4.209], P = 0.008), were 22.6% vs. 60% and 35.9% vs. 64.5%, respectively.

To the best of our knowledge, our study represented the first study to investigate PBSL based on a population dataset comprehensively. With the power of the SEER database, we were able to collect 88 cases with PBSL to characterize the survival and prognostic/predictive factors of PBSL patients. In a nutshell, most patients were diagnosed in their sixth decade. Overall, only around half PBSL patients survived one year after diagnosis. Age at diagnosis and sequence number were independent predictors for OS; age at diagnosis independently predicted DSS. The application of chemotherapy improved both OS and DSS.

Clinical features, survival and prognostic factors of PBSL

The common location of PCNS is the frontal lobes[23, 24]. The proportion of PBSL in brainstem malignancies remains unknown. Our SEER data showed PBSL accounted for 2.7% of malignant brainstem tumors, indicating the rare nature of this entity. The literature search revealed only one study reported a child with a brainstem DLBCL[11]. Likewise, our study unveiled only one child suffered PBSL. PBSL mainly affected adults in their sixth decade with a slight male predominance. Parallel to previous case reports[6–18], our study confirmed that all PBSLs were NHLs. The prognosis of PBSL is poor. We found that major PBSL patients died during the study. Nearly half of patients died within one year after diagnosis; only 32.1% survived three years after diagnosis. This finding was similar to previous studies. Among the published 10 cases[6–9, 11–13, 16, 17] with survival status, 7 died 1 ~ 18 months after diagnosis[7, 8, 11–13, 16, 17]. In addition, we identified older age was associated with poorer OS and DSS and multiple PBSLs with a poorer OS.

Predictive factors of PBSL (chemotherapy)

Combined modality therapy (chemotherapy plus radiotherapy) was an effective initial treatment for PCNSL[25]. Accordingly, our SEER study findings showed that the use of chemotherapy prolonged both OS and DSS. However, chemotherapy regimens were unfeasible in the SEER database, precluding us from investigating the effectiveness of individual chemotherapy regimens. For these PBSLs reported previously, regimens contained HDMTX alone[11, 16], HDMTX plus cytarabine (AraR)[9], HDMTX plus HD dexamethasone[6] and HDMTX plus rituximab plus temozolomide[8].

Radiotherapy in PBSL

Gamma knife radiotherapy (GKS) was reported as a safe and effective approach for PCNSL[26]. The accurately targeted ability of GKS made it an ideal method for managing brainstem lesions. Campbell et al. [7] treated PBSL patients by delivering GKS to tumor margin with a dose of 11 Gy. Two months later, they observed a 50% size reduction of the enhanced lesion. Kim et al.[11] also applied GKS at 12 Gy in addition to high-dose methotrexate and found the patient tolerated GKS well. Unfortunately, evaluation of the long-term benefit of radiotherapy treatment was inaccessible, as both cases died of causes other than PBSL 6 and 10 months, respectively. Instead of GKS, Sato et al.[16] combined high-dose methotrexate and 30 Gy of whole-brain radiation and 10 Gy focal radiation in 2 Gy fractions in two PBSL cases. One patient achieved remission 14.4 months in their study, and another patient succumbed to death 18 months after diagnosis. Due to the limited case number, we could not identify a significant role of radiotherapy. Therefore, the efficacy of radiotherapy needs to be investigated.

Surgical treatment for PBSL

According to recently released National Comprehensive Cancer Network (NCCN) guidelines, the treatment strategy for PCNSL patients incorporated biopsy with the least invasive approach, followed by clinical trial or high-dose methotrexate-based regimen[27]. Distinct from other CNS malignancies, cytoreductive surgery is not a standard of care for PCNSL[28]. This resulted from no gain of survival benefit or even worsened prognoses after surgery[29, 30]. However, Rae et al. recently reported that the survival of craniotomy-treated PCNSL patients was significantly improved compared to biopsy-treatment PCNSL patients in The National Cancer Database-Participant User File (NCDB) and SEER database. They argued previous studies were conducted in the pre-modern neurosurgical era, when the assistance of intraoperative monitoring, neuro-navigation, fluorescent-guided tumor resection was lacking [3]. In their study, the authors further established a risk category (RC), where high RC involved deep location (e.g., brainstem and basal ganglia), age > 55 years, etc. Subsequently, they found survival benefits could be obtained in low RC but not in high RC based on their institutional series[3]. In specific to PBSL, our study failed to identify the benefits of OS or DSS from GTR/PR over no surgery. The brainstem is a critical anatomical structure, and injury involving the brainstem leads to disastrous consequences[5]. Taken together, aggressive tumor resection of PBSL was not advocated.

Study limitations and strengths

Our study contained several limitations. First, chemotherapy prolonged both OS and DSS, indicating its significant role in the survival of PBSL patients. However, the administration of specific compounds or combinations of compounds was unavailable in the SEER database. Second, it was known that patients with lymphoma subtypes had different outcomes. Due to its rarity, we could only identify 9 cases with non- DLBCL. Merging these 9 PBSLs into one subgroup (to achieve DLBCL vs. non-DLBCL) was not suitable and resulted in misleading as outcomes of these subtypes differed significantly[3]. Thus, we did not investigate the impact of the lymphoma subtype on the survival of PBSL patients. Moreover, as a retrospective review, this study suffered from inherent selection bias. Nevertheless, the present study represents the first to comprehensively characterize PBSL patients based on the largest cohort size. These findings are valued tremendously in terms of future clinical evaluation of survival and designation of clinical trials.

Our study revealed the prognosis of PBSL was poor. Only around half PBSL patients survived one year after diagnosis. While sequence number affected OS but not DSS, age influenced both OS and DSS. The use of chemotherapy prolonged OS and DSS, addressing the significance of chemotherapy in treating PBSL patients. Future studies should focus on investigating effective chemotherapeutical regimes.

Funding source: None

Conflict of interest: None declared.

Availability of data and material: available on request

Code availability: available on request

Author's contributions

Junyu Chen: Conceptualization; Data curation; Formal analysis; Methodology; Resources; Roles/Writing - original draft

Bo Cen: Resources; Visualization; Supervision

Fei Hu: Supervision; Validation

Yong Qiu: Resources; Writing - review & editing

Guomin Xiao: Validation; Writing - review & editing

Junge Zhou: Resources; Visualization

Xiujian Ma: Conceptualization; Methodology; Writing - review & editing

Fangcheng Zhang: Conceptualization; Methodology; Writing - review & editing

Ethics approval: Not applicable

Consent to participate Not applicable. Our study is based on SEER, information of which is collected in a de-identified manner.

Consent for publication Not applicable. Our study is based on SEER, information of which is collected in a de-identified manner.

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Table 1

Demographic, histological and therapeutic details of primary brainstem lymphoma
Variables	Overall (N = 88)	Variables	Overall (N = 88)
Diagnosis year		Ann_Arbor_Stage
1997–2016	62 (70.5%)	Stage I	62 (70.5%)
1975–1996	26 (29.5%)	Stage II	1 (1.1%)
Age at diagnosis (years)		Stage IV	13 (14.8%)
Median	59.5	Missing	12 (13.6%)
Interquartile range (IQR)	45.8–68.3	Tumor number
Sex		Single	71 (80.7%)
Female	42 (47.7%)	Multiple	17 (19.3%)
Male	46 (52.3%)	Surgical extent
Race		GTR	3 (3.4%)
White	77 (87.5%)	PR	27 (30.6%)
Black	5 (5.7%)	No surgery	51 (58.0%)
Other	6 (6.8%)	Missing	7 (8.0%)
Marital status		Radiotherapy
Married	51 (58.0%)	Yes	49 (55.7%)
Single	23 (26.1%)	No/unknown	39 (44.3%)
Widowed	7 (8.0%)	Chemotherapy
Divorced	2 (2.3%)	Yes	50 (56.8%)
Separated	1 (1.1%)	No/unknown	38 (43.2%)
Missing	4 (4.5%)
Stage
Localized	46 (52.3%)
Reginal	1 (1.1%)
Distant	10 (11.4%)
Missing	31 (35.2%)

SupplementaryFigure1.png
Supplementary Fig. 1. 4: Kaplan-Meier disease-specific survival curves of PBSL patients stratified by age at diagnosis (A) and use of chemotherapy (B).
SupplementaryFigure2.png
Supplementary Fig. 2: Forest plot based on univariate and multivariate Cox proportional hazard analysis of disease-specific survival (DSS) for PBSL patients. DSS, disease-specific survival; GTR, gross total resection; PR, partial resection. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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Primary Brainstem Lymphoma: A Population-Based Study

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