Clinical characteristics
Patients newly diagnosed with PE-DLBCL accounts for 30.6% (197/644) of all DLBCL patients in our study. The median age was 58 (range, 19-91) years and 90 (45.7%) patients were male. Patients with central nervous system, intraocular, bone and thyroid involvement had worse physical status than those with other areas involved. B symptom was less common in patients with CNS (7/48, 14.6%), nose/nasopharynx (1/14, 7.1%), breast (2/10, 20%) or testis (1/7, 14.3%) involvement.
No significant difference was seen in the number of patients whom were classified as clinical stages I-II (122, 61.9%) and III-IV (75, 38.1%). The major involvement sites of patients with PE-DLBCL are presented in Table 1.
The gastrointestinal tract (GIT) constituted the most common site of PE-DLBCL, accounting for 34% of cases (36 stomach, 20 duodenum/jejunum, and 11 colon). Patients with central nervous system and intraocular involvement rank second (62, 31.5%), followed by nose/nasopharynx (14, 7.1%), breast (10, 5.1%), testis (7, 3.6%), bone, skin, thyroid gland [6 patients (3%) each], female genital system (5, 2.5%), liver (4, 2%). Figure 1 shows the site distribution of extra-nodal lymphomas. Subgroups with less than 5 patients were excluded in the subsequent survival analysis.
Figure1. Anatomic Distributions in PE-DLBCL
Table 1. Patient characteristics according to the primary involved site.
Characteristics
|
GI tract
|
CNS+Eye
|
Nose/nasopharynx
|
Breast
|
Testis
|
Bone
|
Skin
|
Thyroid gland
|
FGS
|
Total
|
67
|
62
|
14
|
10
|
7
|
6
|
6
|
6
|
5
|
Age, years
|
|
|
|
|
|
|
|
|
|
Median
|
62
|
61
|
54
|
45
|
58
|
73
|
54
|
63
|
62
|
Range
|
19-75
|
31-74
|
28-70
|
28-65
|
43-52
|
60-83
|
52-83
|
34-91
|
45-67
|
Age>60years
|
35
|
34
|
6
|
2
|
3
|
6
|
2
|
3
|
3
|
Sex
|
|
|
|
|
|
|
|
|
|
Male
|
33
|
29
|
6
|
0
|
7
|
3
|
3
|
2
|
0
|
Female
|
34
|
33
|
8
|
10
|
0
|
3
|
3
|
4
|
5
|
ECOG status>1
|
13
|
51
|
2
|
1
|
1
|
4
|
2
|
4
|
1
|
Elevated LDH
|
15
|
17
|
2
|
0
|
3
|
5
|
4
|
3
|
1
|
B symptoms
|
24
|
7
|
1
|
2
|
1
|
4
|
3
|
2
|
2
|
Ann Arbor stage
|
|
|
|
|
|
|
|
|
|
I+II
|
53
|
40
|
10
|
8
|
4
|
0
|
0
|
1
|
0
|
III+IV
|
14
|
22
|
4
|
2
|
3
|
6
|
6
|
5
|
5
|
Lugano stage
|
|
|
|
|
|
|
|
|
|
I-IIE
|
53
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
IV
|
14
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
IELSG score
|
|
|
|
|
|
|
|
|
|
0-1
|
-
|
15
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
2-3
|
-
|
32
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
4-5
|
-
|
15
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
Hans classification
|
|
|
|
|
|
|
|
|
|
GCB
|
35
|
16
|
8
|
6
|
4
|
3
|
5
|
2
|
4
|
Non-GCB
|
30
|
24
|
6
|
4
|
3
|
3
|
1
|
4
|
1
|
DE
|
17
|
12
|
4
|
5
|
3
|
2
|
3
|
1
|
4
|
IPI score
|
|
|
|
|
|
|
|
|
|
Low
|
38
|
-
|
9
|
8
|
4
|
0
|
1
|
3
|
1
|
Low-intermediate
|
14
|
-
|
3
|
2
|
1
|
1
|
2
|
0
|
0
|
High-intermediate
|
9
|
-
|
2
|
0
|
0
|
3
|
1
|
2
|
3
|
High
|
6
|
-
|
0
|
0
|
2
|
2
|
2
|
1
|
1
|
Therapy
|
|
|
|
|
|
|
|
|
|
R-CHOP
|
58
|
-
|
9
|
7
|
5
|
2
|
4
|
4
|
5
|
R-EPOCH
|
4
|
-
|
5
|
1
|
2
|
0
|
0
|
1
|
0
|
Chemotherapy only
|
48
|
44
|
11
|
4
|
0
|
3
|
6
|
2
|
3
|
Chemo+ surgery
|
19
|
18
|
3
|
6
|
7
|
2
|
0
|
4
|
2
|
CNS prophylaxis
|
7
|
-
|
3
|
7
|
4
|
1
|
2
|
0
|
2
|
Received ASCT
|
2
|
4
|
0
|
1
|
0
|
0
|
1
|
0
|
1
|
ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell; ASCT, autologous hematopoietic stem cell transplantation; DE, double-protein-expression
|
Response to treatment and survival
9.1% patients with PE-DLBCL were lost to follow-up in this study. The median follow-up period was 31.8 (range, 0.2-80.8) months. At the last follow-up, 35.6% (69/194) patients had experienced relapse of disease and 19.6% (35/179) patients had been dead. The median PFS and OS were 23.8(range, 0.1-80.8) and 31.8 (range, 0.2-80.8) months, respectively (Figure 2). The 3-year OS rates of patients with primary GI tract, Eye+CNS, nose/ nasopharynx, breast, FGS, bone, thyroid gland, testis and skin involvement were 84%, 79%, 83%, 86%, 100%, 80%, 83%, 100%, 67%, respectively.
A total of 117(59.3%) patients achieved CR and 21(10.6%) achieved PR, leading to a total response rate (RR) of 70.1%. The RR for patients with PCNS-DLBCL and PVR-DLBCL was 67.8%, and nose/ nasopharynx, thyroid gland, testis, breast, GI tract, bone, skin, liver and FGS involvement was 92.9, 83.3, 75, 70, 68.7, 66.7, 57.1, 50 and 33.3%, respectively.
Figure 2. OS and PFS for patients with PE-DLBCL
The proportion of patients undergoing chemotherapy with surgery in PCNS-DLBCL, primary female genital system DLBCL(PFGS-DLBCL), primary breast-DLBCL(PB-DLBCL), primary thyroid gland DLBCL(PT-DLBCL) and primary GI DLBCL (PGI-DLBCL) was 37.5, 40, 60, 66.7 and 28.4%, respectively. There were no significant statistical differences between the clinical outcome in two groups of patients who had and had not undergone surgery both in PCNS-DLBCL and PGI-DLBCL (Figure 3).
Figure 3. OS (a) and PFS(b) of PCNS-DLBCL patients with or without surgery; OS (c) and PFS(d) of PGI-DLBCL patients with or without surgery. 1(9.1%) patient with primary vitreoretinal DLBCL(PVR-DLBCL) was dead during our study period. 64.3% (9/11) patients with PVR-DLBCL achieved CR after first-line therapy and 78.6% (11/14) patients experienced disease relapsed, of which 5 patients had central nervous system relapsed. Complete remission, relapse and mortality rates were 45.8% (22/48),56.2% (27/48) and 20.8% (10/48) for patients with PCNS-DLBCL, respectively. No statistically significant differences in the clinical outcome between two groups of patients (PCNS-DLBCL versus PVR-DLBCL) were observed. (Figure 4)
Figure 4. OS(a) and PFS(b) between patients with PCNS-DLBCL and PVR-DLBCL
Prognostic factors
Univariate and multivariate analysis results of patients with PE-DLBCL are presented in table 2. According to the univariate results, Ann Arbor stage, evaluated LDH, IPI>2, not received CR and double hit were related to survival significantly. However, in multivariate analysis, failure to achieve CR after first-line therapy was independent predictor of OS and PFS in patients with PE-DLBCL.
Table 2. Risk factors for survival of PE-DLBCL
Variables
|
Overall survival
|
Progression-free survival
|
|
Univariate
P value
|
Multivariate
|
Univariate
P value
|
Multivariate
|
|
|
HR
|
95%
|
P value
|
|
HR
|
95%
|
P value
|
Male
|
0.416
|
|
|
|
0.499
|
|
|
|
Age>60
|
0.127
|
|
|
|
0.115
|
|
|
|
Evaluated LDH
|
0.029
|
|
|
NS
|
0.005
|
|
|
NS
|
ECOG>1
|
0.200
|
|
|
|
0.147
|
|
|
|
With B symptom
|
0.503
|
|
|
|
0.417
|
|
|
|
Ann Arbor stage III-IV
|
0.031
|
|
|
NS
|
0.019
|
|
|
NS
|
IPI>2
|
0.047
|
|
|
NS
|
0.152
|
|
|
|
GCB
|
0.989
|
|
|
|
0.997
|
|
|
|
DE
|
0.308
|
|
|
|
0.300
|
|
|
|
DH
|
0.018
|
|
|
NS
|
0.000
|
|
|
NS
|
Not received CR
|
0.000
|
4.659
|
2.083-10.423
|
0.000
|
0.000
|
5.001
|
2.231-11.209
|
0.000
|
Primary organ
|
0.641
|
|
|
|
0.480
|
|
|
|
NS: not significant; DH: double hit; DE: double-protein-expression
|
The univariate and multivariate analysis results of PGI-DLBCL are presented in Table3. According to the univariate results, B symptom, evaluated LDH, IPI>2, Lugano stage, failure to achieve CR and double hit were related to survival of PGI-DLBCL significantly. The independent risk factors for PFS included not received CR and Lugano stage IV in multivariate analysis.
Table 3. Risk factors for survival of PGI-DLBCL
Variables
|
Overall survival
|
Progression-free survival
|
|
Univariate
P value
|
Multivariate
|
Univariate
P value
|
Multivariate
|
|
|
HR
|
95%
|
P value
|
|
HR
|
95%
|
P value
|
Male
|
0.640
|
|
|
|
0.678
|
|
|
|
Age>60
|
0.068
|
|
|
NS
|
0.093
|
|
|
NS
|
Evaluated LDH
|
0.000
|
|
|
NS
|
0.000
|
|
|
NS
|
Anemia
|
0.980
|
|
|
|
0.877
|
|
|
|
Albumin<35g/L
|
0.355
|
|
|
|
0.330
|
|
|
|
ECOG>1
|
0.426
|
|
|
|
0.419
|
|
|
|
With B symptom
|
0.042
|
|
|
NS
|
0.052
|
|
|
NS
|
Lugano stage IV
|
0.021
|
|
|
NS
|
0.015
|
3.395
|
1.033-11.162
|
0.044
|
IPI>2
|
0.043
|
|
|
NS
|
0.059
|
|
|
NS
|
GCB
|
0.744
|
|
|
|
0.700
|
|
|
|
DE
|
0.392
|
|
|
|
0.463
|
|
|
|
DH
|
0.012
|
|
|
NS
|
0.000
|
|
|
NS
|
Not received CR
|
0.001
|
2.555
|
1.296-5.037
|
0.007
|
0.000
|
2.304
|
1.145-4.639
|
0.019
|
NS: not significant; DH: double hit; DE: double-protein-expression
|