Association between hepatitis B and C viruses and head and neck lymphoma: A case-control study

Tsai, Wan-Hsun; Lee, Ching-Chih; Chang, Ting-Shou

doi:10.1016/j.bjorl.2025.101701

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Original article • Braz. j. otorhinolaryngol. 92 • 2026 • https://doi.org/10.1016/j.bjorl.2025.101701 linkcopy

Association between hepatitis B and C viruses and head and neck lymphoma: A case-control study

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective This study aims to assess the relationship between Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections and Head and Neck (H&N) lymphoma in a region where HBV and HCV are highly prevalent.

Methods Patients diagnosed with H&N lymphoma between 2013 and 2022 at our institution were eligible for the study, with exclusion criteria applied to patients with a history of recurrence, other cancers, HIV infections, organ transplantation, and those below 18-years of age. The first and the second control group comprised outpatients and patients diagnosed with Head and Neck Squamous Cell Carcinoma (HNSCC) who were gender and age-matched at the same hospital. Logistic regression analysis, which was adjusted for sex, age, smoking, alcohol consumption, Rheumatoid Arthritis (RA), and Systemic Lupus Erythematosus (SLE), was utilized to estimate the Odds Ratio (OR) and 95% Confidence Interval (95% CI) for HBV and HCV infection status.

Results From 2013 to 2022, 304 patients with H&N lymphoma were identified. After excluding those with a history of other cancers or recurrences, 262 patients remained. The first control group included 1048 matched outpatients. Additionally, 262 patients diagnosed with HNSCC during the same period were selected as the second control group. Of the 242 Non-Hodgkin Lymphoma (NHL) patients, 102 had Extranodal Lymphoma (ENL). Of these ENL patients, 49 tested positive for HBV and 17 for HCV. After controlling for the confounding factors, NHL patients with HBsAg positivity had a significantly higher prevalence rate than healthy controls, particularly among B-cell Lymphoma and Diffuse Large B-Cell Lymphoma (DLBCL) patients. Furthermore, there were no significant differences in HCV infections between the three groups.

Conclusions In conclusion, the study found a significant link between HBV infection and H&N NHL, particularly DLBCL in Taiwan. However, no significant link was discovered between HCV infection and H&N lymphoma. These findings suggest a potential role for HBV in the development of H&N NHL and DLBCL. Level of evidence: 4.

Keywords
Head and neck lymphoma; Non-Hodgkin Lymphoma; Diffuse large B cell lymphoma; Hepatitis B virus; Hepatitis C virus

A potential role for HBV in the development of H&N NHL and DLBC.
No significant link between HCV infection and H&N lymphoma.
Extranodal lymphomas are more commonly found in Waldeyer’s ring.

Variable	Total (n = 1572)	H&N lymphoma (n = 262)	HNSCC (n = 262)	General population (n = 1048)	p-value
Variable	n (%)	n (%)	n (%)	n (%)	p-value
Age	63.6 ± 15.8	63.4 ± 15.9	64.2 ± 15.2	63.4 ± 15.9	0.764
Sex, male	909 (57.8)	151 (57.6)	154 (58.8)	604 (57.6)	0.943
Smoking	533 (30.7)	82 (31.3)	129 (49.2)	322 (30.7)	<0.001*
Drinking	427 (27.2)	70 (26.7)	102 (38.9)	255 (24.3)	<0.001*
Betel nut	230 (14.6)	26 (9.9)	89 (34)	115 (11)	<0.001*
DM	453 (28.8)	60 (22.9)	65 (24.8)	328 (31.3)	0.008*
HTN	729 (46.4)	102 (38.9)	108 (41.2)	519 (49.5)	0.002*
RA	24 (1.5)	6 (2.3)	2 (0.8)	16 (1.5)	0.362
SLE	39 (2.5)	9 (3.4)	3 (1.2)	27 (2.6)	0.228
HBV	187 (11.8)	52 (19.5)	16 (6.1)	119 (11.4)	<0.001*
HCV	115 (7.3)	17 (6.5)	16 (6.1)	82 (7.8)	0.541

Variable	H&N lymphoma (n = 262)	HL (n = 20)	NHL (n = 242)	p-value
Variable	n (%)	n (%)	n (%)	p-value
Age	63.4 ± 15.9	42.8 ± 21.4	65.1 ± 14.2	<0.001
Sex, male	151 (57.6)	16 (80)	135 (55.8)	0.035*
Smoking	82 (31.3)	7 (35)	75 (31)	0.710
Drinking	70 (26.7)	3 (15)	67 (27.7)	0.296
Betel nut	26 (9.9)	2 (10)	24 (9.9)	1.000
DM	60 (22.9)	2 (10)	58 (24)	0.265
HTN	102 (38.9)	5 (25)	97 (40.1)	0.184
RA	6 (2.3)	0 (0)	6 (2.5)	1.000
SLE	9 (3.4)	0 (0)	9 (3.7)	1.000
Lymphoma stage				0.210
Stage I	42 (16)	2 (10)	40 (16.5)
Stage II	58 (22.1)	6 (30)	52 (21.5)
Stage III	61 (23.3)	5 (25)	56 (23.1)
Stage IV	78 (29.8)	3 (15)	75 (31)
n/a	23 (8.8)	4 (20)	19 (7.9)
Subsite				<0.001*
NL	160 (61.1)	20 (100)	140 (57.9)
ENL	102 (38.9)	0	102 (42.2)
Tonsil	‒	‒	34 (33.3)
Nasopharynx	‒	‒	18 (17.6)
Sinonasal	‒	‒	16 (15.7)
Parotid gland	‒	‒	14 (13.7)
Tongue base	‒	‒	7 (6.9)
Scalp	‒	‒	2 (2)
Submandibular gland	‒	‒	1 (1)
Soft palate	‒	‒	2 (2)
Others	‒	‒	8 (7.8)
HBV	52 (19.85)	3 (15)	49 (20.3)	0.904
HCV	17 (6.5)	0 (0)	17 (7)	0.220

	All	HBV (%)	aOR (95% CI)	p-value	HCV (%)	Aor (95% CI)	p-value
General population	1048	119 (11.4)	Reference		82 (7.8)	Reference
H&N lymphoma	262	52 (19.9)	1.94 (1.35–2.79)	<0.001^*	17 (6.5)	0.83 (0.48–1.43)	0.507
HL	20	3 (15.0)	0.94 (0.26–3.38)	0.929	0	‒	‒
cHL	18	2 (11.1)	0.65 (0.14–2.98)	0.584	0	‒	‒
NLPHL	2	1 (50.0)	5.69 (0.35–92.21)	0.221	0	‒	‒
NHL	242	49 (20.3)	2.07 (1.42–3.00)	<0.001^*	17 (7.0)	0.89 (0.52–1.54)	0.687
B-cell	205	43 (21.0)	2.17 (1.47–3.21)	<0.001^*	14 (6.8)	0.86 (0.47–1.55)	0.609
DLBCL	131	31 (23.7)	2.76 (1.74–4.36)	<0.001^*	13 (9.9)	1.27 (0.68–2.37)	0.451
FL	29	6 (20.7)	1.89 (0.74–4.81)	0.181	0	‒	‒
MALT	13	2 (15.4)	1.38 (0.30–6.41)	0.680	1 (7.7)	1.01 (0.13–8.01)	0.989
SLL/CLL	15	2 (13.3)	1.22 (0.27–5.53)	0.794	0	‒	‒
Other B-cell	17	2 (11.8)	0.89 (0.20–4.05)	0.883	0	‒	‒
T-cell	37	6 (16.2)	1.53 (0.62–3.82)	0.358	3 (8.1)	1.12 (0.33–3.75)	0.859
Nasal Extranodal	10	1 (10.0)	0.77 (0.09–6.39)	0.812	0	‒	‒
Nodal TFH	17	2 (11.8)	1.11 (0.24–5.04)	0.896	2 (11.8)	1.68 (0.37–7.65)	0.502
Other T-cell	10	3 (30.0)	3.57 (0.89–14.22)	0.072	1 (10)	1.30 (0.16–10.47)	0.803
ENL subsite	102	22 (21.6)	2.38 (1.42–4.01)	0.001^*	7 (6.9)	0.87 (0.39–1.95)	0.738
Tonsil	34	7 (20.6)	2.25 (0.95–5.33)	0.067	3 (8.8)	1.09 (0.32–3.64)	0.892
Nasopharynx	18	4 (22.2)	2.27 (0.71–7.23)	0.166	0	‒	‒
Sinonasal	16	4 (25.0)	3.12 (0.97–10.04)	0.057	1 (6.3)	0.85 (0.11–6.59)	0.874
Parotid gland	14	2 (14.3)	1.49 (0.32–7.00)	0.609	1 (7.1)	1.14 (0.14–9.05)	0.901
Tongue base	7	3 (42.9)	6.72 (1.45–31.17)	0.015^*	0	‒	‒
Scalp	2	2 (100.0)	‒	‒	0	‒	‒
Submandibular	1	0	‒	‒	0	‒	‒
Soft palate	2	0	‒	‒	0	‒	‒
Others	8	0	‒	‒	2 (25)	4.11 (0.80–20.97)	0.089
HL
Stage I	2	0	‒	‒	0	‒	‒
Stage II	6	0	‒	‒	0	‒	‒
Stage III	5	2 (40)	3.35 (0.53–21.13)	0.198	0	‒	‒
Stage IV	3	1 (33.3)	3.79 (0.31–45.66)	0.294	0	‒	‒
NHL
Stage I	40	7 (17.5)	1.52 (0.65–3.55)	0.329	1 (2.5)	0.31 (0.04–2.31)	0.254
Stage II	52	11 (21.2)	2.12 (1.05–4.27)	0.037^*	6 (11.5)	1.55 (0.64–3.76)	0.334
Stage III	56	13 (23.2)	2.63 (1.36–5.09)	0.004^*	5 (8.9)	1.14 (0.44–2.94)	0.791
Stage IV	75	18 (24)	2.61 (1.47–4.61)	0.001^*	5 (6.7)	0.87 (0.34–2.22)	0.766

	All	HBV (%)	Aor (95% CI)	p-value	HCV (%)	aOR (95% CI)	p-value
HNSCC	262	16 (6.1)	Reference		17 (6.6)	Reference
H&N lymphoma	262	52 (19.9)	3.66 (1.98–6.75)	<0.001^*	17 (6.5)	1.41(0.67–2.95)	0.363
HL	20	3 (15)	1.87 (0.45–7.82)	0.389	0	‒	‒
cHL	18	2 (11.1)	1.27 (0.24–6.63)	0.778	0	‒	‒
NLPHL	2	1 (50)	11.43 (0.68–195.70)	0.093	0	‒	‒
NHL	242	49 (20.3)	3.83 (2.07–7.09)	<0.001^*	17 (7)	1.47(0.70–3.07)	0.306
B-cell	205	43 (21)	4.01 (2.15–7.50)	<0.001^*	14 (6.8)	1.42(0.66–3.07)	0.374
DLBCL	131	31 (23.7)	5.09 (2.59–10.00)	<0.001^*	13 (9.9)	1.97(0.89–4.37)	0.093
FL	29	6 (20.7)	3.62 (1.26–10.82)	0.017^*	0	‒	‒
MALT	13	2 (15.4)	2.48 (0.49–12.56)	0.274	1 (7.7)	2.11(0.24–18.37)	0.497
SLL/CLL	15	2 (13.3)	2.17 (0.43–10.81)	0.345	0	‒	‒
Other B-cell	17	2 (11.8)	1.63 (0.32–8.30)	0.556	0	‒	‒
T-cell	37	6 (16.22)	2.74 (0.96–7.89)	0.060	3 (8.1)	1.78 (0.47–6.79)	0.398
Nasal Extranodal	10	1 (10)	1.32 (0.14–12.25)	0.809	0	‒	‒
Nodal TFH	17	2 (11.8)	1.83 (0.36–9.29)	0.467	2 (11.8)	2.25 (0.44–11.62)	0.331
Other T-cell	10	3 (30)	7.13 (1.63–31.27)	0.009^*	1 (10)	2.39 (0.27–20.98)	0.433
ENL subsite	102	22 (21.6)	4.27 (2.08–8.76)	<0.001^*	7 (6.9)	1.35 (0.52–3.54)	0.538
Tonsil	34	7 (20.6)	4.06 (1.48–11.13)	0.007^*	3 (8.8)	2.07 (0.54–8.02)	0.291
Nasopharynx	18	4 (22.2)	3.90 (1.07–14.19)	0.039^*	0	‒	‒
Sinonasal	16	4 (25)	5.66 (1.51–21.29)	0.010^*	1 (6.3)	1.52 (0.17–13.37)	0.706
Parotid gland	14	2 (14.3)	2.19 (0.40–11.89)	0.363	1 (7.1)	2.37 (0.26–21.84)	0.447
Tongue base	7	3 (42.9)	13.00 (2.55–66.27)	0.002^*	0	‒	‒
Scalp	2	2 (100)	‒	‒	0	‒	‒
Submandibular	1	0	‒	‒	0	‒	‒
Soft palate	2	0	‒	‒	0	‒	‒
Others	8	0	‒	‒	2 (25)	11.90 (1.75‒80.91)	0.011^*
HL
Stage I	2	0	‒	‒	0	‒	‒
Stage II	6	0	‒	‒	0	‒	‒
Stage III	5	2 (40)	6.94 (1.00–48.07)	0.050	0	‒	‒
Stage IV	3	1 (33.3)	7.40 (0.58–94.15)	0.123	0	‒	‒
NHL
Stage I	40	7 (17.5)	2.94 (1.10–7.89)	0.032^*	1 (2.5)	0.63 (0.08–5.06)	0.665
Stage II	52	11 (21.2)	3.94 (1.67–9.25)	0.002^*	6 (11.5)	2.68 (0.96–7.54)	0.061
Stage III	56	13 (23.2)	4.74 (2.06–10.91)	<0.001^*	5 (8.9)	1.84 (0.62–5.48)	0.274
Stage IV	75	18 (24)	4.98 (2.33–10.63)	<0.001^*	5 (6.7)	1.54 (0.52–4.51)	0.433

Studies	Authors	Nº of Cases	Published Year	Findings	Location
Incidence of non‐Hodgkin's lymphoma among individuals with chronic hepatitis B virus infection. (Cohort study)	Ulcickas Yood M, Quesenberry Jr CP, Guo D, et al.	209,091	2007	chronic HBV infected patients were nearly 3 times more likely to develop NHL than comparison patients	United States
High prevalence of hepatitis B virus infection in patients with B‐cell non‐Hodgkin's lymphoma in Korea. (Case-control study)	Park SC, Jeong SH, Kim J, et al.	470	2008	HBV infection, but not HCV infection, was associated with B-cell non-Hodgkin’s lymphoma in Korea	Korea
High prevalence of hepatitis B virus infection in patients with aggressive B cell non-Hodgkin’s lymphoma in China. (Case‐control study)	Wang C, Xia B, Ning Q, et al.	1030	2017	HBV seems to have a very important role in the pathogenesis of aggressive B-NHL in China	China
The impact of hepatitis B virus infection and vaccination on the development of non‐Hodgkin lymphoma. (Cohort study)	Huang CE, Yang YH, Chen YY, et al.	983,237	2017	HBV confers a greater risk for developing NHL, especially CD20+ aggressive lymphoma. The impact of HBV vaccination is protective against lymphoma development in the teenagers in an endemic area.	Taiwan
Hepatitis virus B and C infections are associated with an increased risk of non‐Hodgkin lymphoma: a nested case‐control study using a national sample cohort. (Case‐control study)	Kim M, Lee YK, Park B, Oh DJ, Choi HG	4645	2019	Infection with either HBV or HCV is associated with NHL in Koreans	Korea
Risk of Non-Hodgkin Lymphoma among patients with hepatitis B virus and hepatitis C virus in Taiwan: a nationwide cohort study. (Cohort study)	Lai Y-R, Chang Y-L, Lee C-H, Tsai T-H, Huang K-H, Lee C-Y	324,942	2022	HBV and HCV infections play a significant role in the development of NHL. In addition, the relative risk of developing NHL increases with increasing age and some comorbidities (such as HPL, CKD, SLE, HIV, and organ transplant).	Taiwan
Our study (Case‐control study)	Tsai W-H, Lee C-C, Chang T-S	50,030	‒	HBV infection raises the risks of NHL, B-cell lymphoma, and DLBCL at H&N in Taiwan. HCV did not play a significant role in the development of NHL or HL.	Taiwan

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[1] H&N, Head and Neck; HNSCC, Head and Neck Squamous Cell Carcinoma; DM, Diabetes Mellitus; HTN, Hypertension; RA, Rheumatoid Arthritis; SLE, Systemic Lupus Erythematosus; HBV, Hepatitis B Virus; HCV, Hepatitis C Virus.

[TN1] ^*
Statistical significance.