Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of diffuse large B-cell lymphoma with lung involvement

doi:10.3969/j.issn.1674-8115.2025.09.013

Abstract

Abstract:

Objective ·To investigate the clinicopathologic features, gene mutation profile, and real-world survival prognosis of diffuse large B-cell lymphoma (DLBCL) with pulmonary involvement. Methods ·The clinical data of 110 patients with newly diagnosed, pathologically confirmed DLBCL and pulmonary involvement at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, between August 2003 and December 2022 were retrospectively collected and analyzed. Evaluation of the efficacy of treatment, survival analyses, and univariate and multivariate analyses were performed in 88 patients who received a first-line regimen based on rituximab in combination with cyclophosphamide, doxorubicin/epirubicine, vincristine, and prednisone (R-CHOP). A total of 74 patients underwent targeted DNA sequencing of 55 lymphoma-related genes and were evaluated for mutations. Results ·Among the 110 patients, 72 (65.5%) were >60 years old, 52 (47.3%) were female, 92 (83.6%) presented with Ann Arbor stage Ⅲ‒Ⅳ, 20 (18.2%) had ECOG scores≥2, 75 (68.2%) had elevated lactate dehydrogenase (LDH) levels, 79 (71.8%) had ≥2 extranodal involvements, 32 (31.4%) were classified as germinal center B-cell subtype, 22 (26.8%) were diagnosed with double expressor lymphoma, and 4 (4.6%) with double-hit lymphoma. Among the patients treated with R-CHOP-based first-line regimens, the objective response rate (ORR) was 68.2%, the 5-year progression-free survival (PFS) rate was 43.7%, and the 5-year overall survival (OS) rate was 65.4%. Univariate analysis showed that elevated LDH and ECOG score≥2 were poor prognostic factors for PFS and OS, and mutations in PIM1 and CD79B were poor prognostic factors for PFS among high-frequency mutations. Multivariate analysis showed that elevated LDH was an independent adverse prognostic factor for PFS (HR=2.47, 95%CI 1.28‒4.77) and OS (HR=2.71, 95%CI 1.21‒6.07). Targeted sequencing results showed that PIM1 (25.7%), MYD88 (24.3%), TP53 (18.9%), CD79B (17.6%), KMT2D (17.6%), and TNFAIP3 (16.2%) were the high-frequency mutations with mutation rates over 15%. Conclusion ·Elevated LDH is an independent adverse prognostic factor for PFS and OS in DLBCL with pulmonary involvement. Mutations in PIM1, MYD88, TP53, CD79B, KMT2D, and TNFAIP3 are frequently observed in this population.

Key words: diffuse large B-cell lymphoma (DLBCL), lung, gene mutation, prognosis

CLC Number:

R733.4

CHEN Siyuan, SHI Qing, FU Di, WANG Li, CHENG Shu, XU Pengpeng, ZHAO Weili. Clinicopathologic characteristics, gene mutation profile, and prognostic analysis of diffuse large B-cell lymphoma with lung involvement[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1214-1220.

Figures/Tables 6

TrendMD

References 17

[1]	SEHN L H, SALLES G. Diffuse large B-cell lymphoma[J]. N Engl J Med, 2021, 384(9): 842-858.
[2]	OLLILA T A, OLSZEWSKI A J. Extranodal diffuse large B cell lymphoma: molecular features, prognosis, and risk of central nervous system recurrence[J]. Curr Treat Options Oncol, 2018, 19(8): 38.
[3]	LI S Y, YOUNG K H, MEDEIROS L J. Diffuse large B-cell lymphoma[J]. Pathology, 2018, 50(1): 74-87.
[4]	MIAN M, WASLE I, GRITSCH S, et al. B cell lymphoma with lung involvement: what is it about?[J]. Acta Haematol, 2015, 133(2): 221-225.
[5]	REQUENA E D A, OCROSPOMA D V, RUIZ J S, et al. Primary pulmonary lymphoma in Peru[J]. Ecancermedicalscience, 2023, 17: 1559.
[6]	SWERDLOW S H, CAMPO E, PILERI S A, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms[J]. Blood, 2016, 127(20): 2375-2390.
[7]	CHESON B D, FISHER R I, BARRINGTON S F, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[J]. J Clin Oncol, 2014, 32(27): 3059-3068.
[8]	YAO D, ZHANG L, WU P L, et al. Clinical and misdiagnosed analysis of primary pulmonary lymphoma: a retrospective study[J]. BMC Cancer, 2018, 18(1): 281.
[9]	PARISSIS H. Forty years literature review of primary lung lymphoma[J]. J Cardiothorac Surg, 2011, 6: 23.
[10]	SHEN R, XU P P, WANG N, et al. Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma[J]. Clin Transl Med, 2020, 10(7): e221.
[11]	ZHANG H L, LU Y X, ZHANG T T, et al. PIM1 genetic alterations associated with distinct molecular profiles, phenotypes and drug responses in diffuse large B-cell lymphoma[J]. Clin Transl Med, 2022, 12(4): e808.
[12]	XIE Z C, QIN Y, CHEN X R, et al. Deciphering the prognostic significance of MYD88 and CD79B mutations in diffuse large B-cell lymphoma: insights into treatment outcomes[J]. Target Oncol, 2024, 19(3): 383-400.
[13]	DENG T, ZHANG S Y, XIAO M, et al. A single-centre, real-world study of BTK inhibitors for the initial treatment of MYD88 ^mut/CD79B ^mut diffuse large B-cell lymphoma[J]. Cancer Med, 2024, 13(4): e7005.
[14]	DU K X, WU Y F, HUA W, et al. Identify truly high-risk TP53-mutated diffuse large B cell lymphoma patients and explore the underlying biological mechanisms[J]. Cell Commun Signal, 2024, 22(1): 401.
[15]	ZHANG M C, TIAN S, FU D, et al. Genetic subtype-guided immunochemotherapy in diffuse large B cell lymphoma: the randomized GUIDANCE-01 trial[J]. Cancer Cell, 2023, 41(10): 1705-1716.e5.
[16]	LIU Q X, ZHU Y, YI H M, et al. KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-β1 axis[J]. Int J Biol Sci, 2024, 20(10): 3972-3985.
[17]	LUO C, ZHANG R, GUO R, et al. Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells[J]. Immunity, 2025, 58(3): 745-765.e9.

Clinical characteristic	Total (n=110)	Primary lung involvement (n=31)	Secondary lung involvement (n=79)	P value
Gender/n (%)				0.883
Female	52 (47.3)	15 (48.4)	37 (46.8)
Male	58 (52.7)	16 (51.6)	42 (53.2)
Age/n (%)				0.752
>60 years	72 (65.5)	21 (67.7)	51 (64.6)
≤60 years	38 (34.5)	10 (32.3)	28 (35.4)
ECOG score/n (%)				0.147
≥2	20 (18.2)	3 (9.7)	17 (21.5)
0‒1	90 (81.8)	28 (90.3)	62 (78.5)
Ann Arbor stage/n (%)				<0.001
Ⅰ‒Ⅱ	18 (16.4)	15 (48.4)	3 (3.8)
Ⅲ‒Ⅳ	92 (83.6)	16 (51.6)	76 (96.2)
Elevated LDH/n (%)	75 (68.2)	17 (54.8)	58 (73.4)	0.060
Extranodal lesion/n (%)				<0.001
≥2	79 (71.8)	0 (0.0)	69 (87.3)
1	31 (28.2)	31 (100.0)	10 (12.7)
IPI/n (%)				<0.001
0‒1	13(11.8)	13 (41.9)	0 (0)
2	19(17.3)	11 (35.5)	8 (10.1)
3	34(30.9)	6 (19.4)	29 (36.7)
4‒5	44(4.0)	1 (3.2)	42 (53.2)
Hans type/[n/N (%)]				0.044
GCB	32/102 (31.4)	13/28 (46.4)	19/74 (25.7)
non-GCB	70/102 (68.6)	15/28 (53.6)	55/74 (74.3)
DE lymphoma/[n/N (%)]	22/82 (26.8)	5/22 (22.7)	17/60 (28.3)	0.612
DH lymphoma/[n/N (%)]	4/87 (4.6)	0/23 (0)	4/64 (6.3)	0.220

Clinical characteristic	Total (n=110)	Primary lung involvement (n=31)	Secondary lung involvement (n=79)	P value
Gender/n (%)				0.883
Female	52 (47.3)	15 (48.4)	37 (46.8)
Male	58 (52.7)	16 (51.6)	42 (53.2)
Age/n (%)				0.752
>60 years	72 (65.5)	21 (67.7)	51 (64.6)
≤60 years	38 (34.5)	10 (32.3)	28 (35.4)
ECOG score/n (%)				0.147
≥2	20 (18.2)	3 (9.7)	17 (21.5)
0‒1	90 (81.8)	28 (90.3)	62 (78.5)
Ann Arbor stage/n (%)				<0.001
Ⅰ‒Ⅱ	18 (16.4)	15 (48.4)	3 (3.8)
Ⅲ‒Ⅳ	92 (83.6)	16 (51.6)	76 (96.2)
Elevated LDH/n (%)	75 (68.2)	17 (54.8)	58 (73.4)	0.060
Extranodal lesion/n (%)				<0.001
≥2	79 (71.8)	0 (0.0)	69 (87.3)
1	31 (28.2)	31 (100.0)	10 (12.7)
IPI/n (%)				<0.001
0‒1	13(11.8)	13 (41.9)	0 (0)
2	19(17.3)	11 (35.5)	8 (10.1)
3	34(30.9)	6 (19.4)	29 (36.7)
4‒5	44(4.0)	1 (3.2)	42 (53.2)
Hans type/[n/N (%)]				0.044
GCB	32/102 (31.4)	13/28 (46.4)	19/74 (25.7)
non-GCB	70/102 (68.6)	15/28 (53.6)	55/74 (74.3)
DE lymphoma/[n/N (%)]	22/82 (26.8)	5/22 (22.7)	17/60 (28.3)	0.612
DH lymphoma/[n/N (%)]	4/87 (4.6)	0/23 (0)	4/64 (6.3)	0.220

Index	Total (n=110)	R-CHOP treatment group (n=88)	Non-R-CHOP treatment group (n=22)	P value
CR/n (%)	58 (52.7)	51 (58.0)	7 (31.8)	0.028
PR/n (%)	13 (11.8)	9 (10.2)	4 (18.2)	0.301
OR/n (%)	71 (64.5)	60 (68.2)	11 (50.0)	0.111
SD/n (%)	15 (13.6)	13 (14.8)	2 (9.1)	0.530
PD/n (%)	24 (21.8)	15 (17.0)	9 (40.9)	0.015

Index	Total (n=110)	R-CHOP treatment group (n=88)	Non-R-CHOP treatment group (n=22)	P value
CR/n (%)	58 (52.7)	51 (58.0)	7 (31.8)	0.028
PR/n (%)	13 (11.8)	9 (10.2)	4 (18.2)	0.301
OR/n (%)	71 (64.5)	60 (68.2)	11 (50.0)	0.111
SD/n (%)	15 (13.6)	13 (14.8)	2 (9.1)	0.530
PD/n (%)	24 (21.8)	15 (17.0)	9 (40.9)	0.015

Variable	PFS		OS
Variable	HR (95%CI)	P value	HR (95%CI)	P value
Male	1.02 (0.61‒1.71)	0.942	0.99 (0.53‒1.84)	0.975
Age>60 years	1.21 (0.70‒2.09)	0.487	1.69 (0.85‒3.37)	0.132
Elevated LDH	2.74 (1.44‒5.22)	0.002	3.00 (1.36‒6.61)	0.007
ECOG score≥2	2.22 (1.21‒4.07)	0.010	2.27 (1.10‒4.67)	0.027
Ann Arbor stage Ⅲ‒Ⅳ	1.38 (0.62‒3.05)	0.427	1.82 (0.65‒5.12)	0.255
Extranodal lesion≥2	1.33 (0.74‒2.41)	0.339	1.40 (0.68‒2.87)	0.362
Non-GCB type	1.46 (0.80‒2.66)	0.214	1.46 (0.70‒3.03)	0.311
DE lymphoma	1.20 (0.59‒2.46)	0.616	1.68 (0.70‒4.06)	0.246
DH lymphoma	1.80 (0.43‒7.55)	0.421	1.69 (0.22‒12.83)	0.610
PIM1 mutation	4.18 (1.93‒9.05)	<0.001	1.40 (0.45‒4.33)	0.556
MYD88 mutation	1.01 (0.43‒2.38)	0.978	0.85 (0.28‒2.62)	0.778
TP53 mutation	1.19 (0.48‒2.94)	0.713	1.25 (0.36‒4.38)	0.130
CD79B mutation	2.60 (1.14‒5.93)	0.023	2.26 (0.79‒6.49)	0.723
KMT2D mutation	1.21 (0.46‒3.20)	0.697	0.69 (0.16‒3.04)	0.625
TNFAIP3 mutation	0.14 (0.02‒1.04)	0.421	0.27 (0.04‒2.01)	0.610