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Erschienen in: BMC Cancer 1/2017

Open Access 01.12.2017 | Research article

Clinicopathologic characteristics and prognostic factors for primary spinal epidural lymphoma: report on 36 Chinese patients and review of the literature

verfasst von: Le Xiong, Ling-Min Liao, Jian-Wu Ding, Zhi-Lin Zhang, An-Wen Liu, Long Huang

Erschienen in: BMC Cancer | Ausgabe 1/2017

Abstract

Background

Due to the uncommon nature of primary spinal epidural lymphomas (PSELs), there has been little research looking at prognostic indicators for the tumor. To our knowledge, this is the largest study to evaluate possible clinical and pathologic prognostic factors in PSEL patients.

Methods

We retrospectively reviewed 130 cases of PSEL, including 36 Chinese patients and 94 published case reports from 1985 to 2015. Patient treatment regimens included surgery (S; n = 119), surgery followed by chemotherapy (S + CT; n = 25), surgery followed by radiotherapy (S + RT; n = 26), and surgery followed by chemotherapy and radiotherapy (S + CT + RT; n = 50).

Results

Review of the most recent case follow-up data (time varied) found 51 patients (47%) alive and tumor-free, 10 patients (9%) alive with tumor present, and 47 patients (44%) deceased. The 3-year overall survival (OS) and disease-free survival (DFS) rates were 81.1% and 46.3%, respectively. Favorable prognostic factors found by univariate analysis were female sex, B-cell lymphoma diagnosis, cervical spine location, and combined modality treatment. Furthermore, multivariate analysis revealed that thoracic spine location (HR = 4.629, 95% CI = [1.911, 31.667], P = 0.042 for OS) and the lack of combined modality treatment (HR = 12.697, 95% CI = [2.664, 48.612], P < 0.0001 for DFS) were associated with poor survival in PSEL patients.

Conclusions

PSEL demonstrates specific clinical features and is associated with a relatively good prognosis. Thoracic spine location is a significant poor prognostic factor, and combined modality treatment is associated with improved disease-free survival, but not overall survival.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12885-017-3093-z) contains supplementary material, which is available to authorized users.
Abkürzungen
CI
Confidence interval
CT
Chemotherapy
DFS
Disease-free survival
HR
Hazard ratio
OS
Overall survival
PSELs
Spinal epidural lymphomas
RT
Radiotherapy
S
Surgery

Background

Primary spinal epidural lymphomas (PSELs) are very rare, and relatively few such tumors have been reported in the literature. Although PSEL accounts for 10% of all epidural spinal tumors [1], the epidural location is a rare site of presentation for lymphomas, characterizing only 0.1 to 3.3% of all lymphomas [2, 3]. Due to the rarity of the condition, it is difficult to enroll a sufficient number of patients with PSEL to adequately evaluate possible factors associated with survival. The largest series to date, reported by Monnard et al. [4], identified 52 patients over 20 years (1982–2002). However, the limited number of patients and the long time span have made it difficult to establish the disease parameters, such as the natural history of the disease, prognostic indicators, treatment techniques employed, and survival rates. For this study, we identified only retrospective studies, which included reports on relatively small numbers of patients or single case reports. The goal of this study was to help identify the clinical profile, treatment outcomes, and significant prognostic indicators in PSEL patients.

Methods

Patient characteristics

A total of 130 PSEL cases were retrospectively reviewed, including 36 Chinese patients and 94 published case reports from 1985 to 2015. Patients were selected if there was a conclusive histopathologic diagnosis of PSEL with complete clinical pathology, and there was no history of previous malignant disease or a second primary tumor. The 130 patients included 76 men (58%), 44 women (34%) and 10 unknown (8%), for a known male-to-female ratio of 1.73. The median age was 45 years (range, 3–80 years), and median follow-up was 32 months (range, 1–149 months). Clinical and pathological variables analyzed included patient age and gender; tumor stage, differentiation, location, and range; and treatment modalities employed (Table 1).
Table 1
Analysis of clinicopathological factors for chinese patients and report cases
Characteristics
Chinese patients
Report cases
P value
n = 36 (%)
n = 94 (%)
Median age (year)
26
48
/
Median survival (month)
12
27
/
Gender
 Male
26 (74.3)
50 (60.0)
 
 Female
9 (25.7)
34 (40.0)
0.640
Pathology
 B cell lymphoma
25 (78.1)
69 (74.2)
 
 T cell lymphoma
6 (18.8)
7 (7.5)
 
 Burkitt’s lymphoma
1 (3.1)
17 (18.3)
0.035
Stage
 I
13 (76.5)
44 (81.5)
 
 II-IV
4 (23.5)
10 (18.5)
0.651
Range
 1–2 spine
8 (22.9)
25 (50.0)
 
 3–4 spine
21 (60.0)
14 (28.0)
 
  ≥ 5 spine
6 (17.1)
11 (22.0)
0.010
S + RT + CT
 Yes
5 (14.3)
45 (48.9)
 
 No
30 (85.7)
47 (51.1)
<0.001
S + CT
 Yes
17 (56.7)
57 (62.0)
 
 No
18 (43.3)
35 (38.0)
0.172
S
 Yes
33 (94.3)
85 (92.4)
 
 No
2 (5.7)
7 (7.6)
0.710
S only
 Yes
15 (42.9)
3 (3.3)
 
 No
20 (57.1)
89 (96.7)
<0.001
S surgery, CT chemotherapy, RT radiotherapy, Bold indicates significant values

Treatment

Most patients diagnosed with stage IE–IIE PSEL had been treated with tumorectomy (n = 121, 93%); the rest had surgical contraindications or refused surgery. The primary treatment of patients consisted primarily of surgery. Individualized postoperative treatment consisted of radiation therapy alone (n = 26, 21%), chemotherapy alone (n = 20, 25%), or concurrent chemoradiation therapy (n = 41, 49%). The median radiotherapy dose was 40 Gy (range, 20–50 Gy), and the total dose was administered over 3–5 weeks. Twenty-eight patients (34%) had only focal treatment, whereas the remaining 55 (66%) received more than focal treatment. Eight-two patients (63%) had chemotherapy, which consisted of cyclophosphamide, doxorubicin, vincristine, and prednisone in the majority of patients; methotrexate, leucovorin, etoposide, and bleomycin were also used in some patients. Generally, 4–8 cycles of chemotherapy were administered at 3-week intervals. Methotrexate was administered in 21 patients (26%).

Statistical analysis

The Kaplan–Meier method and log-rank tests were used to determine overall survival (OS) and disease-free survival (DFS). Independent prognostic factors for OS and DFS were identified using the Cox proportional hazards model. SPSS software (version 13.0, SPSS Inc., Chicago, IL) was used for all statistical analyses, and P values < 0.05 were considered statistically significant.

Results

Clinical features

The median patient age was 45 years (range, 3–80 years). In three of the 130 patients (2%), PSEL was detected during a routine examination. Alternatively, 112 of the patients (86%) presented with neck, back, lumbosacral, or limb pain, or with cord compression syndrome. For 15 cases (12%) reviewed from published case reports, the details of presentation were not provided. The most commonly reported symptoms were motor weakness or hypoesthesia (62%), back pain (59%), lumbosacral pain (32%), limb pain (28%), neck pain (9%), bowel dysfunction (23%), bladder dysfunction (19%), and low-grade fevers (2%). The time from the first symptom to diagnosis varied from 3 days to 5 years. Patient characteristics are presented in Additional file 1: Table S1 and Additional file 2: Table S2.

Pathologic features

Case reviews showed tumor pathologies of B-cell lymphoma (n = 88, 76%), T-cell lymphoma (n = 13, 11%), or Burkitt’s lymphoma (n = 15, 13%). Subsets of cases were identified with tumor cells showing the strong expression of leukocyte common antigen (19/19, 100%) or the absence of CD20 expression (21/27, 78%). Additional immunohistochemical assays performed in a subset of the cases included detection of CD3 (8/13, 62%), CD45 (6/9, 67%), and CD79 (7/7, 100%). See Additional file 1: Table S1 and Additional file 2: Table S2.

Survival

The median follow-up period was 32 months. Relapses were observed in 21 patients (19%) after a median period of 12 months, primarily in the central nervous system (n = 11), lymph nodes (n = 4), chest or abdomen (n = 5), and liver (n = 2). The 3-year OS and DFS were 81.1 and 46.3%, respectively.

Prognostic factors

In order to identify potential prognostic factors associated with survival in PSEL patients, various clinicopathologic variables were evaluated (Table 2). Using univariate analysis, gender, pathological pattern, tumor differentiation, tumor location, and tumor range were found to be associated with OS (P < 0.05), but not with DFS. The 3-year OS rates for males and females were 60.3% and 100% (P = 0.002), respectively (Fig. 1a). The 3-year OS rates for thoracic, cervical, and lumbosacral spine locations were 64.1, 94.3, and 100% (P = 0.005), respectively (Fig. 1b). The 3-year OS rates for B-cell, T-cell, and Burkitt’s lymphoma were 87.7, 83.3, and 29.5% (P = 0.002), respectively (Fig. 1c). In terms of treatments received, the 3-year DFS rate for patients receiving S alone was 23.3% (P = 0.004, compared with the other treatment groups; Fig. 2), while patients receiving S + RT + CT had a 3-year DFS rate of 49.6% (P = 0.031, compared with the other treatment groups, Fig. 3); patients receiving S + CT had a 3-year DFS rate of 50.4% (P = 0.042, compared with the other treatment groups; Fig. 4). For the same patient treatment groups, the 3-year OS rates were 80.0, 81.7, and 79.5%, respectively; these did not significantly vary (P > 0.05 for all; Figs. 5, 6, and 7). Multivariate analysis revealed that thoracic spine location (HR = 4.629, 95% CI = [1.911, 31.667], P = 0.042 for OS) and the lack of combined modality treatment (HR = 12.697, 95% CI = [2.664, 48.612], P < 0.0001 for DFS) were associated with poor survival in PSEL patients.
Table 2
The 3-year' OS and DFS rates associated with primary spinal epidural lymphomas patients
Characteristics
Case (n)
3 year's
3 year's
DFS(%)
P
OS
P
Age (year)
  < 45
64
54.8
 
70.5
 
  ≥ 45
64
41.8
0.413
90.9
0.181
Gender
 Male
76
47.7
 
60.3
 
 Female
44
47.7
0.608
100.0
0.002
Pathology
 B cell lymphoma
88
47.6
 
87.7
 
 T cell lymphoma
13
53.6
 
83.3
 
 Burkitt’s lymphoma
15
25.0
0.081
29.5
0.002
Differentiate
 Poor
19
54.5
 
74.1
 
 Moderate
12
50.5
 
68.2
 
 High
8
60.0
0.309
100.0
0.035
Stage
 I
58
36.7
 
75.1
 
 II-IV
14
77.4
0.084
/
0.198
Location
 Cervical
14
74.0
 
94.3
 
 Thoracic
69
35.7
 
64.1
 
 Lumbosacral
25
57.4
 
100.0
 
 Sacral
3
/
0.089
/
0.005
Range
 1–2 spine
17
36.4
 
86.2
 
 3–4 spine
33
46.7
 
81.9
 
  ≥ 5 spine
18
41.2
0.698
74.4
0.013
S + RT + CT
 Yes
49
49.6
 
81.7
 
 No
56
38.0
0.031
81.4
0.955
S + CT
 Yes
65
50.4
 
79.5
 
 No
40
41.4
0.042
84.3
0.984
S
 Yes
96
46.8
 
80.0
 
 No
9
47.6
0.994
100.0
0.592
S only
 Yes
5
23.3
 
80.0
 
 No
100
75.6
0.004
81.6
0.437
S surgery, CT chemotherapy, RT radiotherapy, Bold indicates significant values

Discussion

With a study cohort of 130 patients treated over a 30-year period, the current study represents the largest one to focus on PSEL. Prior to this, the largest one reported on only 52 patients, and predated modern radiotherapy and chemotherapy protocols.
The origin of primary spinal epidural lymphomas (PSEL) remains controversial. It is known that lymphoma may arise anywhere lymphatic tissue is found. However, whether there is lymphoid tissue in the epidural space has been debated [5, 6]. Rubinstein was the first to demonstrate the presence of lymphoid cells in epidural tissue, and he introduced the theory of antigenic stimulation with a transformation cascade [7]. Some have suggested that PSEL may originate from either paraspinal, spinal, or retroperitoneal tissues, accessing the epidural space via the interspinal foramina [8, 9]. However, the occurrence of lymphoma in this location indicates that lymphoid precursor cells are present in the space. Metastasis is the most common sacral malignancy, whereas chordoma in the most common primary sacral tumor [10]. PSELs represent 10% of epidural spinal tumors, but the epidural location is a rare presenting site for lymphomas, being seen in only 0.1 to 3.3% of all lymphomas. When lymphoma has been found in the spine, it has been reported most often in the lumbar or lower dorsal area [11]. However, in this study, we found the thoracic spine to be the most common site (62%) for lymphoma.
The most common presenting symptoms reported in the literature have included lower limb weakness, localized back pain, and bladder dysfunction [8, 9]. However, in this study, the most common symptoms seen were motor weakness or hypoesthesia (62%), back pain (59%), lumbosacral pain (32%), limb pain (28%), neck pain (9%), bowel dysfunction (23%), bladder dysfunction (19%), and low-grade fevers (2%). It is noteworthy that most patients presented with persistent back pain for considerably long periods of time prior to diagnosis. Therefore, persistent back pain in a patient should be considered a warning symptom for a more serious illness.
On histopathological examination, these tumors show atypical lymphoid cell proliferation. On immunohistochemistry, tumor cells are positive for leukocyte common antigen (LCA) and CD20, but negative for CD138, CD30, and CD3. B-cell lymphoma is the most common type at this site [12], which is consistent with our findings. Our study found that tumor pathologies consisted of B-cell lymphoma (76%), T-cell lymphoma (11%), and Burkitt’s lymphoma (13%). Furthermore, tumor cells were associated with the strong expression of leukocyte common antigen (100%) and the absence of CD20 expression (78%). PSELs are almost invariably of the B-cell type, although indolent B-cell and T-cell variants are sometimes seen.
There has been no optimization of treatment strategies for PSEL patients to improve patient outcomes. Unfortunately, there is a high mortality rate within the first year of diagnosis due to early metastasis and tumor recurrences. Accordingly, the importance of aggressive, systemic therapy has been recognized over the last few decades, although there have been reports of patients being cured with local radiotherapy alone [13]. In cases of patients who present with signs of spinal cord compression, surgical intervention for tissue diagnosis and decompression is required. Aabo et al. [14] reported no difference between the outcomes in patients who underwent decompressive laminectomy and radiotherapy and those who received spinal radiation only. Chemoradiotherapy remains the mainstay of treatment because lymphomas are highly radio- and chemosensitive tumors. The CHOP regime, in particular, is still considered the gold standard for treatment. A radiotherapy dose of 3500 cGy to 4000 cGy delivered in 20–25 fractions over 3–4 weeks is required to achieve radical cure [9]. Intensive chemotherapy should also be initiated immediately following diagnosis and be delivered over a short period of time. From reviewing several studies, we found that combined modality treatment is associated with a lower recurrence rate and improved disease-free survival in PSEL, but not overall survival. Similar findings have not been reported by other researchers. In this study, the median survival time of 36 Chinese patients is 12 month. It shorter than non-Chinese cases (12 VS. 27). Optimization of treatment strategies for Chinese patients included surgery (33/35, 94.3%), surgery followed by chemotherapy (17/35, 56.7%), surgery only (15/35, 42.9%), and surgery followed by chemotherapy and radiotherapy (5/35, 14.3%). There are less Chinese patients with PSEL treated with combined modality treatment compared to non-Chinese cases because of medical expenses. Kaplan–Meier analysis revealed that combined modality treatment is associated with improved disease-free survival for all 130 PSEL cases. Therefore, to our knowledge, combined modality treatment should be considered an standardized treatment strategy for PSEL presently.

Conclusions

The results of the present study indicate that PSEL has a relatively good prognosis, that thoracic spine location is a significant poor prognostic factor, and that combined modality treatment is associated with improved disease-free survival, but not overall survival. This study represents the largest to date on PSEL although it is limited by its retrospective design and the relatively small patient cohort. Nevertheless, our findings give important insight into this rare, challenging disease, and expand our knowledge base on this aggressive tumor.

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 81460393], the Natural Science Foundation of Jiangxi Province, China [grant numbers 20142BAB215039, 20151BAB215020], the Project of Jiangxi Province Science and Technology Plan [grant number 20141BBG70041], the Project of Education Department of Jiangxi Province Science and Technology Plan [grant number GJJ14059], the Youth Science Fund Project of the Second Affiliated Hospital of Nanchang University [grant number 2014YNQN12004 to Long Huang], and supported in part by the Natural Science Foundation of China [grant number 81460449 to Ling-Min Liao]. The Grants-in-Aid supported this study just financially, and was not associated with study design, collection, analysis, interpretation of data, and writing the manuscript.

Availability of data and materials

The data supporting our findings was presented within additional supporting files.

Authors’ contributions

LX and LML participated in the study design, case collection, drafting, and revising the manuscript. JWD participated in the study design and revising the manuscript. ZLZ participated in the case collection. AWL and LH conceived the study, was responsible for its design and coordination, participated in the analysis and interpretation of the data, as well as in drafting and revising all versions of the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interest.
Not applicable.
This study was approved by the ethics committee of the Second Affiliated Hospital of Nanchang University. Authors obtained written informed consent and publication consent from the participants or their guardian in the case of children under 16.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
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Metadaten
Titel
Clinicopathologic characteristics and prognostic factors for primary spinal epidural lymphoma: report on 36 Chinese patients and review of the literature
verfasst von
Le Xiong
Ling-Min Liao
Jian-Wu Ding
Zhi-Lin Zhang
An-Wen Liu
Long Huang
Publikationsdatum
01.12.2017
Verlag
BioMed Central
Erschienen in
BMC Cancer / Ausgabe 1/2017
Elektronische ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3093-z

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