Higher frequency of occult lymph node metastasis in clinical N0 pulmonary adenocarcinoma with ALK rearrangement

Figures & data

Table 1 Characteristics of patients with cN0 pulmonary adenocarcinoma

Variables	Mutation (+) n=324	Triple negative n=135	p-value
Sex, (male/female)	127/197 (39.2%)	92/43 (68.1%)	<0.01*
Age (years)
Mean ± SD (range)	65±10 (29–87)	66±9 (32–83)	0.36
Smoking index
Mean ± SD (range)	269.2±438.6 (0–2500)	628.2±646.3 (0–2820)	<0.01*
CEA
Mean ± SD (range)	3.8±5.4 (0.5–53.4)	6.1±10.1 (0.6–57.7)	<0.01*
Tumor maximum size on CT (mm)
Mean ± SD (range)	26.5±12.8 (9–103)	28.5±15.7 (8–90)	0.46
C/T ratio (%) on CT
Mean ± SD (range)	74.6±27.4 (0–100)	77.2±28.1 (0–100)	0.13
SUV max
Mean ± SD (range)	3.3±4.8 (0–28)	4.8±6.3 (0–27)	0.06
Pathological maximum size (mm)
Mean ± SD (range)	22.7±13.1 (6–132)	25.4±15.1 (7–100)	0.94
Pathological LN status			0.27
N0	270 (83.3%)	118 (87.4%)
N1/2	54 (16.7%)	17 (12.6%)
Pathological stage			0.44
0	2 (0.6%)	1 (0.7%)
IA	204 (62.9%)	78 (57.8%)
IB	58 (17.9%)	29 (21.5%)
IIA	25 (7.8%)	14 (10.4%)
IIB	6 (1.9%)	5 (3.7%)
IIIA	28 (8.6%)	7 (5.2%)
IIIB	1 (0.3%)	1 (0.7%)
Procedure			0.59
Sublobar	60 (1.8%)	29 (21.5%)
Lobectomy	262 (80.6%)	106 (78.5%)
Pneumonectomy	2 (0.6%)	0 (0%)

Note: The * symbol indicates significant difference.

Abbreviations: CEA, carcinoembryonic antigen; CT, computed tomography; LN, lymph node; SD, standard deviation; SUV max, maximum standardized uptake value.

Table 2 Characteristics of patients with cN0 pulmonary adenocarcinoma who had gene mutations

Variables	EGFR N=266	KRAS N=39	ALK N=19	p-value
Sex, (male/female)	98/168 (36.8%)	21/18 (53.8%)	8/11 (42.1%)	0.12
Age (years)
Mean ± SD (range)	66±9 (29–87)	68±9 (46–83)	52±10 (33–66)	<0.01*
Smoking index
Mean ± SD (range)	235.4±426.9 (0–2500)	517.7±492.9 (0–1680)	231.6±321.1 (0–900)	<0.01*
CEA
Mean ± SD (range)	3.6±4.6 (0.5–53.4)	3.8±3.8 (0.6–21.7)	6.2±13.4 (0.5–52.6)	0.15
Tumor maximum size on CT (mm)
Mean ± SD (range)	26.3±11.0 (10–67)	30.8±21.3 (10–103)	20.6±12.6 (9–54)	0.01*
C/T ratio (%) on CT
Mean ± SD (range)	72.9±27.5 (0–100)	82.3±25.9 (26–100)	82.3±25.9 (26–100)	<0.01*
SUV max
Mean ± SD (range)	3.3±4.9 (0–28.0)	3.0±4.4 (0–14.5)	3.2±3.8 (0–11.2)	0.83
Pathological maximum size (mm)
Mean ± SD (range)	22.2±9.7 (7–70)	28.1±26.0 (10–132)	18.2±13.0 (6–55)	0.02*
Pathological LN status				0.02*
N0	222 (83.5%)	36 (92.3%)	12 (63.2%)
N1/2	44 (16.5%)	3 (7.7%)	7 (36.8%)
Pathological stage				0.84
0	1 (0.4%)	1 (2.6%)	0 (0%)
IA	169 (63.5%)	23 (59.0%)	12 (63.1%)
IB	50 (18.8%)	8 (20.5%)	0 (0%)
IIA	19 (7.1%)	2 (5.1%)	4 (21.0%)
IIB	2 (0.8%)	3 (7.7%)	1 (5.3%)
IIIA	25 (9.4%)	2 (5.1%)	1 (5.3%)
IIIB	0 (0%)	0 (0%)	1 (5.3%)
Procedure				0.92
Sublobar	49 (18.4%)	8 (20.5%)	3 (15.8%)
Lobectomy	216 (81.2%)	31 (79.5%)	15 (78.9%)
Pneumonectomy	1 (0.4%)	0 (0%)	1 (5.3%)

Note: The * symbol indicates significant difference.

Abbreviations: ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CT, computed tomography; EGFR, epidermal growth factor receptor; KRAS, kirsten ras genes; LN, lymph node; SD, standard deviation; SUV max, maximum standardized uptake value.

Figure 1 The proportion of patients with cN0 pulmonary adenocarcinoma found to have LN metastases on pathology (pN1, gray; pN2, black; node negative patients [cN0 → pN0], white) in each mutational classification.

Notes: Patients with ALK rearrangement tended to have a higher incidence of occult hilar or mediastinal LN metastases. Triple negative indicates patients with no mutation in ALK, EGFR, or KRAS.

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; KRAS, kirsten ras genes; LN, lymph node.

Table 3 Univariate and multivariate analyses of clinicopathological variables associated with occult LN metastases in pulmonary adenocarcinoma

Variables	Univariate	Multivariate
	p-value	HR (CI)	p-value
Patient characteristics
Sex: male vs female	0.97	–	–
Smoking: >600 vs ≤600	0.07	–	–
Tumor marker
CEA: >5 vs ≤5	<0.01	2.14 (1.19–3.88)	0.01
Preoperative radiological findings
Tumor maximum diameter on CT: >30.0 vs ≤30.0	<0.01	2.41 (1.36–4.27)	<0.01
C/T ratio: >50.0 vs ≤50.0	<0.01	3.87 (1.76–8.48)	<0.01
SUV: >3 vs ≤3	<0.01	1.35 (0.76–2.41)	0.31
Procedures
Lobectomy: vs sublobar	0.03	0.77 (0.31–1.85)	0.55
Pathological genomic mutation
ALK: vs non-ALK	0.01	4.57 (1.54–3.5)	<0.01

Note: The en-dashes indicate no verification of the significant difference by univariate analysis.

Abbreviations: ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CI, confidence interval; HR, hazard ratio; CT, computed tomography; LN, lymph node; SUV, standardized uptake value.

Figure 2 Kaplan-Meier curves for the disease-free survival: (A) comparison of triple negative (dotted line) versus any mutation status (solid line); and (B) comparison of each of the mutations: EGFR, KRAS, and ALK.

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; KRAS, kirsten ras genes.