High-grade tumor budding is a risk factor for survival in patients with laryngeal squamous cell carcinoma

Luo, Li; Liu, Honggang

doi:10.1016/j.bjorl.2023.101310

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Brazilian Journal of Otorhinolaryngology

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Sumário

ORIGINAL ARTICLE • Braz. j. otorhinolaryngol. 89 (5) • 2023 • https://doi.org/10.1016/j.bjorl.2023.101310 copy

High-grade tumor budding is a risk factor for survival in patients with laryngeal squamous cell carcinoma

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective:

With the increasing incidence and mortality of laryngeal squamous cell carcinoma worldwide, researchers continue to search for novel prognostic factors and treatment methods for preventing early laryngeal squamous cell carcinoma from becoming advanced laryngeal squamous cell carcinoma. This study aims to determine if tumor budding is an independent risk factor associated with the survival of patients with laryngeal squamous cell carcinoma.

Methods:

268 cases of laryngeal squamous cell carcinoma were studied, and tumor budding was analyzed for associations with clinicopathological features and clinical outcomes.

Results:

Tumor budding was divided into low-grade tumor budding (0-6/0.785mm²) and high-grade tumor budding (≥7/0.785 mm²) based on the results of the receiver operating characteristics curve analysis. Logistic regression analysis showed that smaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were the risk factors for high-grade tumor budding (p < 0.05). In the low-grade tumor budding group, there was no statistic difference in survival between patients without tumor budding and those with 1 -6/0.785 mm² tumor budding. Multivariate survival analysis showed high-grade tumor budding (p < 0.001) was independent prognostic factors for disease-free survival and overall survival in laryngeal squamous cell carcinoma. High-grade tumor budding was also an independent prognostic factor for disease-free survival (p = 0.037) and overall survival (p = 0.009) in T1-2N0 laryngeal squamous cell carcinoma.

Conclusions:

Smaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were closely associated with high-grade tumor budding in laryngeal squamous cell carcinoma. High-grade tumor budding may be an adverse risk factor that affects not only the disease-free survival and overall survival of laryngeal squamous cell carcinoma patients but also the survival of T1-2N0 laryngeal squamous cell carcinoma patients.

Level of Evidence:

Level 4.

Keywords
Laryngeal squamous cell carcinoma; Tumor budding; T1-2N0; Prognosis

Highlights

Novel prognostic factors need to be developed in laryngeal cancer.

Tumor budding is related to smaller tumor cell nest in laryngeal cancer.

Tumor budding is related to higher pT stage in laryngeal cancer.

Tumor budding is related to the low levels of TILs in laryngeal cancer.

Tumor budding may predict recurrence and death of laryngeal cancer patients.

n = 268		Chi-square tests analysis			Logistic regression
	n (%)	LG-TB, n (%)	HG-TB, n (%)	x²/p	OR (95% CI)	p
Age median 62 (35-86 years),				0.060/0.807
Mean±SD (61.96 ±9.117)
<62	142 (53.0)	42/29.6	100/70.4
≥62	126 (47.0)	39/31.0	87/69.0
Gender				5.798/0.016
Male	240 (89.6)	67/27.9	173/72.1		Reference
Female	28 (10.4)	14/50.0	14/50.0		0.538 (0.175-1.659)	0.281
Histologic grade				40.299/<0.001
Well-differentiated	64 (23.9)	34/53.1	30/46.9		Reference
Moderately differentiated	142 (53.0)	46/32.4	96/67.6		0.341 (0.129-0.900)	0.030
Poorly differentiated	62 (23.1)	1/1.6	61/98.4		1.223 (0.209-3.665)	0.508
Tumor cell nest size				105.111/<0.001
Large >15	59 (22.0)	49/83.1	10/16.9		Reference
Intermediate 5-15	162 (60.5)	31/19.1	131/80.9		2.644 (2.071-4.029)	<0.001
Small <5	47 (17.5)	1/2.1	46/97.9		2.829 (1.119-5.135)	0.001
Mitotic figure				7.345/0.007
>15/10 HPFs	162 (60.4)	39/21.7	123/78.3		Reference
1-15/10 HPFs	106 (39.6)	42/36.6	64/63.4		0.522 (0.212-1.286)	0.157
Tumor stroma ratio				6.876/0.009
>50%	115 (42.9)	25/21.7	90/78.3		Reference
≤50%	153 (57.1)	56/36.6	97/63.4		0.228 (0.081-0.639)	0.005
PT stage				49.643/<0.001
PT1	77 (28.7)	44/57.1	33/42.9		Reference
PT2	82 (30.6)	27/32.9	55/67.1		1.003 (0.366-2.747)	0.995
PT3+4	109 (40.7)	10/9.2	99/90.8		1.571 (1.059-2.040)	0.040
PN stage				7.591/0.006
PN0	214 (79.9)	72/34.3	138/65.7		Reference
PN1+N2	54 (20.1)	9/15.5	49/84.5		0.572 (0.132-2.479)	0.455
Angiolymphatic invasion				3.997/0.046
No	219 (81.7)	72/32.9	147/67.1		Reference
Yes	49 (18.3)	9/18.4	40/81.6		0.325 (0.071-1.484)	0.147
Perineural invasion				0.859/0.354
No	245 (91.4)	76/31.0	169/69.0
Yes	23 (8.6)	5/21.7	18/78.3
Stromal TILs				104.461/<0.001
>50%	51 (19.0)	44/86.3	7/13.7		Reference
11%-50%	137 (51.1)	34/24.8	103/75.2		2.785 (1.914-3.960)	0.001
0%-10%	80 (29.9)	3/3.8	77/96.2		2.120 (1.512-3.980)	<0.001

Prognostic factors	Univariate analysis		Multivariate analysis
	HR (95% CI)	p	HR (95% CI)	p
Age ≥ 62 years vs. <62 years	0.934 (0.594-1.469)	0.769
Female vs. male	1.010 (0.485-2.101)	0.980
Histologic grade
Moderately vs. well	1.430 (0.774-2.640)	0.253	0.638 (0.275-1.481)	0.296
Poorly vs. well	2.513 (1.294-4.880)	0.007	0.619 (0.232-1.648)	0.337
Tumor cell nest size
Small vs. large	4.789 (2.115-10.842)	<0.001	1.649 (0.549-4.960)	0.373
Intermediate vs. large	3.024 (1.425-6.417)	0.004	1.221 (0.444-3.359)	0.699
Mitotic figure ≥15% vs. <15%	1.850 (1.110-3.084)	0.018	1.231 (0.629-2.408)	0.545
Tumor stroma ratio ≥50% vs. <50%	1.704 (1.084-2.678)	0.021	0.857 (0.465-1.577)	0.619
PT stage
PT2 vs. pT1	1.585 (0.788-3.188)	0.196	1.058 (0.443-2.525)	0.899
PT3 vs. pT1	3.046 (1.559-5.952)	0.001	1.528 (0.606-3.855)	0.369
PT4 vs. pT1	4.004 (1.935-8.281)	<0.001	1.668 (0.590-4.717)	0.335
PN1+N2 vs. pN0	1.338 (0.803-2.230)	0.263
Angiolymphatic invasion (Yes vs. No)	1.485 (0.875-2.522)	0.143
Perineural invasion (Yes vs. No)	1.655 (0.851-3.220)	0.138
Stromal TILs
0%-10% vs. >50%	4.337 (2.023-9.298)	<0.001	0.866 (0.264-2.842)	0.813
11%-50% vs. >50%	1.549 (0.705-3.401)	0.276	0.410 (0.133-1.260)	0.120
HG-TB vs. LG-TB	7.815 (3.383-18.050)	<0.001	7.566 (2.529-22.638)	<0.001

Prognostic factors	Univariate analysis		Multivariate analysis
	HR (95% CI)	p	HR (95% CI)	p
Age ≥ 62 years vs. <62 years	1.036 (0.668-1.606)	0.876
Female vs. male	0.696 (0.303-1.599)	0.393
Histologic grade
Moderately vs. well	3.115 (1.399-6.937)	0.005	2.766 (1.087-7.040)	0.033
Poorly vs. well	6.092 (2.675-13.876)	<0.001	3.909 (1.381-11.061)	0.010
Tumor cell nest size
Small vs. large	3.675 (1.582-8.537)	0.002	1.120 (0.384-3.269)	0.836
Intermediate vs. large	3.377 (1.605-7.108)	0.001	1.814 (0.731-4.498)	0.199
Mitotic figure ≥15% vs. <15%	0.993 (0.635-1.554)	0.976
Tumor stroma ratio ≥ 50% vs. < 50%	1.116 (0.718-1.735)	0.624
PT stage
PT2 vs. pT1	1.689 (0.825-3.455)	0.152	0.854 (0.368-1.983)	0.714
PT3 vs. pT1	3.257 (1.645-6.452)	0.001	1.295 (0.557-3.014)	0.548
PT4 vs. pT1	5.069 (2.484-10.345)	<0.001	1.316 (0.509-3.402)	0.571
PN1+N2 vs. pN0	1.597 (0.990-2.576)	0.055
Angiolymphatic invasion (Yes vs. No)	1.768 (1.082-2.889)	0.023	1.250 (0.716-2.184)	0.433
Perineural invasion (Yes vs. No)	1.201 (0.578-2.495)	0.623
Stromal TILs
0%-50% vs. >50%	2.233 (1.115-4.474)	0.023	0.423 (0.148-1.211)	0.109
HG-TB vs. LG-TB	4.988 (2.484-10.015)	<0.001	4.279 (1.474-12.422)	0.008

Prognostic factors	DFS		OS
	HR (95% CI)	p	HR (95% CI)	p
Histologic grade
Moderately vs. well	0.748 (0.278-2.015)	0.566	2.844 (1.074-7.534)	0.035
Poorly vs. well	0.977 (0.196-4.878)	0.977	4.425 (0.880-22.240)	0.071
Tumor cell nest size
Small vs. large	11.962 (1.083-132.156)	0.043	1.094 (0.240-4.989)	0.908
Intermediate vs. large	5.952 (0.630-56.204)	0.119	1.328 (0.411-4.285)	0.635
Mitotic figure (≥15% vs. <15%)	1.014 (0.381-2.701)	0.978	0.914 (0.409-2.041)	0.826
Stromal TILs
0-10% vs. > 50%	0.413 (0.025-6.776)	0.535	0.168 (0.024-1.197)	0.075
11%-50% vs. > 50%	0.273 (0.021-3.498)	0.319	0.285 (0.059-1.381)	0.119
Angiolymphatic invasion (Yes vs. No)	0.919 (0.118-7.159)	0.936	6.339 (1.886-21.301)	0.003
HG-TB vs. LG-TB	13.052 (1.161-146.732)	0.037	7.202 (1.637-31.685)	0.009

Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Sede da Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial, Av. Indianópolia, 1287, 04063-002 São Paulo/SP Brasil, Tel.: (0xx11) 5053-7500, Fax: (0xx11) 5053-7512 - São Paulo - SP - Brazil
E-mail: revista@aborlccf.org.br

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[1] *Corresponding author. E-mail:hgLiu2022@163.com (H. Liu).