Prognostic Value of Ki-67 and 18F-FDG PET/CT SUVmax in Non–Small Cell Lung Cancer

doi:10.21203/rs.3.rs-8413587/v1

Download PDF

Research Article

Prognostic Value of Ki-67 and 18F-FDG PET/CT SUVmax in Non–Small Cell Lung Cancer

https://doi.org/10.21203/rs.3.rs-8413587/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

Accurate prognostic stratification remains challenging in non–small cell lung cancer (NSCLC). Beyond TNM staging, biomarkers reflecting tumor biology may improve risk assessment. The Ki-67 proliferation index and maximum standardized uptake value (SUVmax) derived from 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) represent tumor proliferative and metabolic activity; however, their combined prognostic significance in NSCLC remains incompletely defined.

Methods

This single-center retrospective study included 205 patients with newly diagnosed NSCLC between January 2017 and April 2024 who underwent 18F-FDG PET/CT and had immunohistochemical assessment of Ki-67. Patients were stratified according to Ki-67 levels (≤ 10% vs. > 10%) and SUVmax values (≤ 2.5 vs.> 2.5). Associations with clinicopathologic characteristics were analyzed. Overall survival (OS) was evaluated using Kaplan–Meier analysis, and correlations between variables were assessed using Pearson correlation analysis.

Results

High Ki-67 (> 10%) and high SUVmax (> 2.5) were significantly associated with adverse clinicopathologic features, including male sex, smoking history, larger tumor size, higher tumor grade, advanced stage, and unfavorable histologic subtypes. SUVmax showed a significant positive correlation with Ki-67 (r = 0.278, p < 0.001) and tumor size (r = 0.371, p < 0.001). Kaplan–Meier analysis demonstrated significantly shorter OS in patients with high Ki-67 (log-rank p = 0.002) and high SUVmax (log-rank p = 0.033).

Conclusions

Ki-67 proliferation index and SUVmax are associated with aggressive tumor characteristics and poorer survival in NSCLC. The combined evaluation of metabolic and proliferative biomarkers, together with established clinical factors, may improve prognostic stratification. Prospective multicenter studies are warranted to further clarify the clinical utility of these parameters.

Non–Small Cell Lung Cancer

Ki-67 Proliferation Index

18F-FDG PET/CT

SUVmax

Survival

Lung cancer is the second most commonly diagnosed malignancy worldwide and remains the leading cause of cancer-related mortality [1, 2]. Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases [3]. Although tumor–node–metastasis (TNM) staging remains the most important determinant of prognosis in NSCLC, additional factors such as histopathological subtype, tumor proliferative activity, and the development of recurrence or metastasis also play a critical role in patient management [3, 4].

The Ki-67 proliferation index is a widely used immunohistochemical marker reflecting tumor cell proliferation and has been reported to be associated with survival outcomes in NSCLC in several studies [5]. However, the prognostic significance of Ki-67 remains controversial, particularly across different histological subtypes.

In parallel, the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) provides important information regarding tumor metabolic activity and biological behavior [6]. Higher SUVmax values have been associated with more aggressive tumor characteristics and poorer survival, making SUVmax an attractive noninvasive prognostic biomarker in clinical decision-making.

Ki-67 reflects tumor proliferative activity, whereas SUVmax represents metabolic activity, providing complementary insights into NSCLC tumor biology. The combined evaluation of these parameters may therefore offer a more comprehensive assessment of tumor aggressiveness. Previous studies have demonstrated variability in Ki-67 expression and SUVmax values among different histological subtypes, such as adenocarcinoma and squamous cell carcinoma; however, their combined prognostic impact has not been clearly established [5, 6].

The aim of this single-center retrospective study was to compare SUVmax values and the Ki-67 proliferation index in patients with newly diagnosed NSCLC, to evaluate these parameters according to histological subtypes, and to investigate their prognostic value in predicting survival, metastasis, and recurrence.

Study Design and Patient Selection

This single-center retrospective study was conducted after approval was obtained from the Institutional Scientific Research Ethics Committee (approval number: 05.12.2024–36). Patients diagnosed with NSCLC at our institution between January 2017 and April 2024 were retrospectively reviewed. Among these, patients who underwent 18F-FDG PET/CT during the diagnostic workup and had immunohistochemical evaluation of the Ki-67 proliferation index (%) performed on biopsy or surgical resection specimens were included. A total of 205 patients with NSCLC met the inclusion criteria and were enrolled in the study.

Patients with lung cancer diagnoses other than NSCLC and those with missing 18F- FDG PET/CT data were excluded.

Data Collection and Variables

Demographic characteristics (age, sex), smoking history, and comorbidities were recorded. Tumor-related variables included 18F-FDG PET/CT findings (SUVmax), tumor location, tumor size, histopathological subtype, tumor grade, Ki-67 proliferation index, presence of visceral pleural invasion, lymphovascular invasion, perineural invasion, and spread through air spaces (STAS).

Tumor size was defined as the largest tumor diameter measured in millimeters (mm) based on the pathological report. Diagnostic date, surgical procedures, pathological nodal status (N0–N2), tumor stage, length of hospital stay, follow-up duration, and the presence of recurrence or distant metastasis were documented. Outcome measures included in-hospital mortality, postoperative complications (such as hemorrhage and pneumonia), receipt of neoadjuvant or adjuvant therapy, all-cause mortality, and long-term survival.

All data were obtained from the institutional hospital database. Missing data not available in the electronic system were completed through review of archived patient medical records.

Definitions and Staging

Overall survival (OS) was defined as the time from surgery to death from any cause or, for surviving patients, to the date of last clinical follow-up. Primary tumors and involved lymph nodes were staged according to the 9th edition of the American Joint Committee on Cancer (AJCC) TNM staging system.

The SUVmax cutoff value of 2.5 and the Ki-67 cutoff value of 10% were selected based on thresholds commonly reported in previous NSCLC studies. SUVmax was analyzed as a categorical variable using a cutoff of ≤ 2.5 versus > 2.5, while the Ki-67 proliferation index was evaluated both as a continuous variable and as a categorical variable using a cutoff of ≤ 10% versus > 10%.

Statistical Analysis

Statistical analyses were performed using SPSS version 22.0 (Statistical Package for the Social Sciences; IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation, minimum, and maximum values, while categorical variables were presented as frequencies and percentages.

Comparisons between groups were conducted using the Pearson chi-square test for categorical variables and the independent samples t-test for continuous variables. Pearson correlation analysis was used to assess relationships between variables. Survival analyses were performed using the Kaplan–Meier method, and differences between groups were evaluated using the log-rank (Mantel–Cox), Breslow, and Tarone–Ware tests. A p value < 0.05 was considered statistically significant for all analyses.

Patient Characteristics

A total of 205 patients were included in the study. Of these, 82.9% were male (n = 170) and 17.1% were female (n = 35). The mean age was 64.21 ± 8.74 years (range, 37–83). A history of smoking was present in 94.6% of patients (n = 194). The most common tumor location was the right upper lobe (38.5%), followed by the left upper lobe (25.4%), right lower lobe (20.0%), and left lower lobe (16.1%).

The mean tumor size was 37.47 ± 23.53 mm (range, 3–130 mm). The mean SUVmax was 10.33 ± 7.23 (range, 1–43), and 90.2% of patients had SUVmax values > 2.5. Surgical resection was performed in 83.9% of patients, while 16.1% underwent biopsy only.

Adenocarcinoma was the most common histological subtype (42.0%), followed by squamous cell carcinoma (38.5%) and large cell neuroendocrine carcinoma (19.5%). Most tumors were Grade 3 (65.8%). Pathological N0 disease was present in 72.3% of patients, and distant metastasis was detected in 12.2%. Visceral pleural invasion was observed in 35.3%, lymphovascular invasion in 14.0%, and perineural invasion in 4.7%.

Stage distribution showed that 29.3% of patients were Stage IA, 18.5% Stage IB, 13.7% Stage IIB, and 13.2% Stage IV. The mean overall survival (OS) was 33.04 ± 25.53 months (range, 0–101), and 44.9% of patients died during follow-up (Table 1).

Table 1

Patient Characteristics
Groups	Frequency (n)	Percentage (%)
Sex
Male	170	82.9
Female	35	17.1
History of Smoking
Yes	194	94.6
No	11	5.4
Tumor Localization
Right Lower Lobe	41	20.0
Right Upper Lobe	79	38.5
Left Lower Lobe	33	16.1
Left Upper Lobe	52	25.4
Suvmax
≤ 2,5	20	9.8
> 2,5	185	90.2
Surgery
Biopsy	33	16.1
Resection	172	83.9
Histopathological Type
Adenocarcinoma	84	42.0
Large Cell Neuroendocrine Carcinoma	39	19.5
Squamous Cell Carcinoma	77	38.5
Tumor Grade
Grade 1	27	18.5
Grade 2	23	15.8
Grade 3	96	65.8
Ki-67 Expression
≤ %10	35	17.1
> %10	170	82.9
Lymph Node Involvement
N0	138	72.3
N1	27	14.1
N2	20	10.5
N3	6	3.1
Distant Metastasis
No	180	87.8
Yes	25	12.2
Visceral Pleural Invasion
No	110	64.7
Yes	60	35.3
Lymphovascular Invasion
No	147	86.0
Yes	24	14.0
Perineural Invasion
No	161	95.3
Yes	8	4.7
Stage
Stage 1A	60	29.3
Stage 1B	38	18.5
Stage 2A	16	7.8
Stage 2B	28	13.7
Stage 3A	24	11.7
Stage 3B	12	5.9
Stage 4	27	13.2
Status
Alive	113	55.1
Deceased	92	44.9
	Mean ± SD, Min -Max
Age (years)	64.210 ± 8.742 (37–83 years)
Tumor Size (mm)	37.470 ± 23.527 (3-130 mm)
Suvmax Value	10.331 ± 7.228 (1–43)
Overall Survival (months)	33.044 ± 25.529 (0-101 months)

Comparison According to Ki-67 Proliferation Index

Patients were stratified into low (≤ 10%; n = 35, 17.1%) and high (> 10%; n = 170, 82.9%) Ki-67 groups. Sex distribution differed significantly between groups (p = 0.001), with a higher proportion of females in the low Ki-67 group. Smoking history was more frequent in the high Ki-67 group (96.5%; p = 0.023).

SUVmax was strongly associated with Ki-67 expression (p < 0.001); low SUVmax (≤ 2.5) was more frequently observed in patients with low Ki-67 levels than in those with high Ki-67. Histological subtype distribution differed significantly (p < 0.001), with adenocarcinoma predominating in the low Ki-67 group and squamous cell carcinoma and large cell neuroendocrine carcinoma more frequent in the high Ki-67 group.

Tumor grade also differed significantly (p < 0.001); 70.8% of low Ki-67 tumors were Grade 1, whereas 75.4% of high Ki-67 tumors were Grade 3. Early-stage disease (Stage IA) was more frequent in the low Ki-67 group (48.6% vs. 25.3%; p = 0.036). Other clinicopathological variables did not differ significantly between groups (p > 0.05).

Mean tumor size (26.83 ± 23.77 vs. 39.66 ± 22.94 mm; p = 0.003) and mean SUVmax (5.92 ± 5.51 vs. 11.24 ± 7.22; p < 0.001) were significantly lower in the low Ki-67 group. Age and OS did not differ significantly between groups (Table 2).

Table 2

Distribution According to Ki-67 Proliferation Groups
		≤ 10% (Low Ki-67 Expression)			> 10% (High Ki-67 Expression)			p
		n		%	n		%	p
Sex	Male	22		62.9	148		87.1	X² = 12.007 p = 0.001
Sex	Female	13		37.1	22		12.9	X² = 12.007 p = 0.001
History of Smoking	Yes	30		85.7	164		96.5	X² = 6.613 p = 0.023
History of Smoking	No	5		14.3	6		3.5	X² = 6.613 p = 0.023
Tumor Localization	Right Lower Lobe	9		25.7	32		18.8	X² = 2.235 p = 0.525
	Right Upper Lobe	13		37.1	66		38.8
	Left Lower Lobe	7		20.0	26		15.3
	Left Upper Lobe	6		17.1	46		27.1
Surgery	Biopsy	5		14.3	28		16.5	X² = 0.103 p = 0.488
Surgery	Resection	30		85.7	142		83.5	X² = 0.103 p = 0.488
Histopathological Type	Adenocarcinoma	29		85.3	55		33.1	X² = 32.293 p = 0.000
	Large Cell Neuroendocrine Carcinoma	0		0.0	39		23.5
	Squamous Cell Carcinoma	5		14.7	72		43.4
Tumor Grade	Grade 1	17		70.8	10		8.2	X² = 53.264 p = 0.000
Tumor Grade	Grade 2	3		12.5	20		16.4	X² = 53.264 p = 0.000
			Grade 3			4
Lymph Node Involvement	N0	28		87.5	110		69.2	X² = 5.786 p = 0.123
	N1	1		3.1	26		16.4
	N2	3		9.4	17		10.7
	N3	0		0.0	6		3.8
Distant Metastasis	No	32		91.4	148		87.1	X² = 0.518 p = 0.347
Distant Metastasis	Yes	3		8.6	22		12.9	X² = 0.518 p = 0.347
Visceral Pleural Invasion	No	20		66.7	90		64.3	X² = 0.061 p = 0.491
Visceral Pleural Invasion	Yes	10		33.3	50		35.7	X² = 0.061 p = 0.491
Lymphovascular Invasion	No	28		93.3	119		84.4	X² = 1.637 p = 0.161
Lymphovascular Invasion	Yes	2		6.7	22		15.6	X² = 1.637 p = 0.161
Perineural Invasion	No	30		100.0	131		94.2	X² = 1.812 p = 0.202
Perineural Invasion	Yes	0		0.0	8		5.8	X² = 1.812 p = 0.202
Stage	Stage 1A	17		48.6	43		25.3	X² = 13.470 p = 0.036
	Stage 1B	9		25.7	29		17.1
	Stage 2A	0		0.0	16		9.4
	Stage 2B	2		5.7	26		15.3
	Stage 3A	3		8.6	21		12.4
	Stage 3B	1		2.9	11		6.5
	Stage 4	3		8.6	24		14.1
Status	Alive	29		82.9	84		49.4	X² = 13.124 p = 0.000
Status	Deceased	6		17.1	86		50.6	X² = 13.124 p = 0.000
		Mean		SD	Mean		SD	t/p
Age		63.140		8.892	64.430		8.721	-0.792/0.429
Tumor Size (mm)		26.830		23.777	39.660		22.937	-2.996/0.003
Overall Survival (months)		36.571		21.676	32.318		26.250	0.897/0.371
* Statistical tests: Chi-square test and independent samples t-test.

Comparison According to SUVmax

Patients were stratified into SUVmax ≤ 2.5 (n = 20) and > 2.5 (n = 185) groups. Female sex was more common in the low SUVmax group (50.0% vs. 13.5%; p < 0.001). All patients in the low SUVmax group underwent surgical resection (p = 0.025).

Adenocarcinoma was more frequent in the low SUVmax group (80.0%), whereas squamous cell carcinoma predominated in the high SUVmax group (42.2%) (p = 0.001).

Tumor grade differed significantly (p < 0.001), with Grade 1 tumors predominating in the low SUVmax group and Grade 3 tumors in the high SUVmax group. Visceral pleural invasion (p = 0.033), lymphovascular invasion (p = 0.040), and clinical stage (p < 0.001) also differed significantly. Stage IA disease was observed in 80.0% of the low SUVmax group compared with 23.8% of the high SUVmax group.

Tumor size was significantly smaller in the low SUVmax group (17.50 ± 13.18 vs. 39.63 ± 23.40 mm; p < 0.001). Survival status differed significantly between SUVmax groups (p = 0.004), whereas age and OS duration did not differ significantly (Table 3).

Table 3

Distribution According to SUVmax Groups
		≤ 2,5		> 2,5		p
		n	%	n	%	p
Sex	Male	10	50.0	160	86.5	X² = 16.971 p = 0.000
Sex	Female	10	50.0	25	13.5	X² = 16.971 p = 0.000
History of Smoking	Yes	17	85.0	177	95.7	X² = 4.051 p = 0.079
History of Smoking	No	3	15.0	8	4.3	X² = 4.051 p = 0.079
Tumor Localization	Right Lower Lobe	4	20.0	37	20.0	X² = 4.825 p = 0.185
	Right Upper Lobe	4	20.0	75	40.5
	Left Lower Lobe	6	30.0	27	14.6
	Left Upper Lobe	6	30.0	46	24.9
Ki-67 Proliferation	≤ %10	13	65.0	22	11.9	X² = 35.955 p = 0.000
Ki-67 Proliferation	> %10	7	35.0	163	88.1	X² = 35.955 p = 0.000
Surgery	Biopsy	0	0.0	33	17.8	X² = 4.252 p = 0.025
Surgery	Resection	20	100.0	152	82.2	X² = 4.252 p = 0.025
Histopathological Type	Adenocarcinoma	16	80.0	68	37.8	X² = 14.349 p = 0.001
	Large Cell Neuroendocrine Carcinoma	3	15.0	36	20.0
	Squamous Cell Carcinoma	1	5.0	76	42.2
Tumor Grade	Grade 1	8	66.7	19	14.2	X² = 20.557 p = 0.000
	Grade 2	0	0.0	23	17.2
	Grade 3	4	33.3	92	68.7
Lymph Node Involvement	N0	18	94.7	120	69.8	X² = 5.524 p = 0.137
	N1	1	5.3	26	15.1
	N2	0	0.0	20	11.6
	N3	0	0.0	6	3.5
Distant Metastasis	No	20	100.0	160	86.5	X² = 3.078 p = 0.065
Distant Metastasis	Yes	0	0.0	25	13.5	X² = 3.078 p = 0.065
Visceral Pleural Invasion	No	17	85.0	93	62.0	X² = 4.088 p = 0.033
Visceral Pleural Invasion	Yes	3	15.0	57	38.0	X² = 4.088 p = 0.033
Lymphovascular Invasion	No	20	100.0	127	84.1	X² = 3.698 p = 0.040
Lymphovascular Invasion	Yes	0	0.0	24	15.9	X² = 3.698 p = 0.040
Perineural Invasion	No	20	100.0	141	94.6	X² = 1.127 p = 0.357
Perineural Invasion	Yes	0	0.0	8	5.4	X² = 1.127 p = 0.357
Stage	Stage 1A	16	80.0	44	23.8	X² = 28.678 p = 0.000
	Stage 1B	2	10.0	36	19.5
	Stage 2A	1	5.0	15	8.1
	Stage 2B	0	0.0	28	15.1
	Stage 3A	1	5.0	23	12.4
	Stage 3B	0	0.0	12	6.5
	Stage 4	0	0.0	27	14.6
Status	Alive	17	85.0	96	51.9	X² = 7.998 p = 0.004
Status	Deceased	3	15.0	89	48.1	X² = 7.998 p = 0.004
		Mean	SD	Mean	SD	t/p
Age (years)		61.750	9.508	64.480	8.641	-1.327/0.186
Tumor Size (mm)		17.500	13.181	39.630	23.403	-4.153/0.000
Overall Survival (months)		32.150	21.685	33.141	25.959	-0.164/0.870

Correlation Analysis

Pearson correlation analysis demonstrated a significant negative correlation between age and OS (r = − 0.145; p = 0.038) and between tumor size and OS (r = − 0.233; p = 0.001).

SUVmax showed a moderate positive correlation with tumor size (r = 0.371; p < 0.001) and a significant positive correlation with Ki-67 levels (r = 0.278; p < 0.001). Ki-67 was weakly but significantly correlated with tumor size (r = 0.206; p = 0.003). No significant correlations were observed between OS and either SUVmax or Ki-67 (Table 4).

Table 4

Results of Correlation Analysis
		Yaş	Tumor Size (mm)	Suvmax Value	Ki-67 Proliferation	Overall Survival (months)
Age	r	1.000
Age	p	0.000
Tumor Size (mm)	r	-0.029	1.000
Tumor Size (mm)	p	0.679	0.000
Suvmax Value	r	0.111	0.371**	1.000
Suvmax Value	p	0.112	0.000	0.000
Ki-67 Proliferation	r	0.056	0.206**	0.278**	1.000
Ki-67 Proliferation	p	0.429	0.003	0.000	0.000
Overall Survival (months)	r	-0.145*	-0.233**	-0.051	-0.063	1.000
Overall Survival (months)	p	0.038	0.001	0.470	0.371	0.000

Survival Analysis

Kaplan–Meier analysis demonstrated significantly poorer OS in patients with high Ki-67 levels (> 10%) compared with those with low Ki-67 levels (≤ 10%). Mortality rates were 50.6% and 17.1%, respectively (Table 5). Log-rank (χ² = 9.303; p = 0.002), Breslow (p = 0.005), and Tarone–Ware (p = 0.003) tests all showed significant differences (Fig. 1). Mean OS was 77.36 months (95% CI, 66.75–87.97) in the low Ki-67 group and 52.67 months (95% CI, 45.78–59.56) in the high Ki-67 group. Median OS was reached only in the high Ki-67 group (47 months; 95% CI, 37.67–56.33).

Table 5

Survival Analysis Results According to Ki-67 Proliferation Level
Group	n	Number of Deaths	Survival (%)	Mean Survival (months)	Median Survival (months)	95% GA (Median)	p value
≤ %10	35	6	82,9%	77,36 ± 5,41	NR*	-
> %10	170	86	49,4%	52,67 ± 3,52	47,00 ± 4,76	37,67–56,33
General (total)	205	92	55,1%	57,26 ± 3,28	66,00 ± 11,30	43,86–88,14	0.002*
*NR: median survival not reached.

Similarly, patients with SUVmax > 2.5 had significantly worse OS than those with SUVmax ≤ 2.5. Mortality rates were 48.1% and 15.0%, respectively (Table 6). Log-rank (χ² = 4.560; p = 0.033), Breslow (p = 0.038), and Tarone–Ware (p = 0.032) tests were significant (Fig. 2). Mean OS was 65.05 months (95% CI, 51.89–78.21) in the low SUVmax group and 55.22 months (95% CI, 48.56–61.87) in the high SUVmax group. Median OS was reached only in the high SUVmax group (48 months; 95% CI, 25.08–70.92).

Table 6

Kaplan–Meier Analysis of Survival According to SUVmax Value
Group	n	Number of Deaths	Survival (%)	Mean Survival (months)	Median Survival (months)	95% GA (Median)	p value
≤ 2.5	20	3	85,0%	65,05 ± 6,71	NR*	–
> 2.5	185	89	51,9%	55,22 ± 3,39	48,00 ± 11,69	25,08–70,92
General	205	92	55,1%	57,26 ± 3,28	66,00 ± 11,30	43,86–88,14	p = .033
* NR: median survival not reached

In this single-center retrospective study including 205 patients with NSCLC, we investigated the prognostic significance of the Ki-67 proliferation index and SUVmax measured by 18F-FDG PET/CT. Our findings indicate that higher Ki-67 and SUVmax levels are associated with inferior overall survival and that these parameters are positively correlated with each other. In addition, both biomarkers were closely linked to multiple clinicopathologic features, including sex distribution, smoking history, tumor size, histologic subtype, tumor grade, and stage, supporting their relevance as indicators of tumor aggressiveness.

Patients with higher Ki-67 levels were more frequently male and smokers, and the distribution of histologic subtypes differed significantly: adenocarcinoma predominated in the low Ki-67 group, whereas squamous cell carcinoma and large cell neuroendocrine carcinoma were more common in the high Ki-67 group. High Ki-67 was also associated with higher tumor grade and more advanced stage. These patterns align with prior reports linking Ki-67 expression to biologically aggressive disease in NSCLC [7–9].

Importantly, the prognostic value of Ki-67 may vary by histologic subtype [8]. Yang et al. reported distinct associations across adenocarcinoma and squamous cell carcinoma, emphasizing that Ki-67 should be interpreted within histology-specific biological contexts rather than as a uniform prognostic marker [10].

SUVmax-based comparisons revealed clinically meaningful differences. Lower SUVmax values were more frequently observed in females and in adenocarcinoma, whereas higher SUVmax values were associated with male sex, squamous histology, Grade 3 tumors, and advanced stage. Prior studies have reported that SUVmax varies across histologic subtypes and is associated with aggressive tumor characteristics [11, 12]. In our cohort, high SUVmax was additionally associated with adverse pathologic features such as visceral pleural invasion and lymphovascular invasion.

The relationship between SUVmax and tumor size observed in our data is consistent with prior reports describing a positive correlation between metabolic activity and tumor burden [12–14]. Cerfolio et al. reported increasing SUVmax with advancing stage [15], and we similarly observed significant differences across clinical stage categories. Meta-analyses have shown that higher SUVmax is associated with increased risk of recurrence and mortality, adversely affecting both DFS and OS [16–18]. Although some studies have not identified a significant survival association [19], our results demonstrated shorter OS in patients with high SUVmax.

Notably, Iguchi et al. identified preoperative SUVmax as one of the strongest predictors of recurrence, suggesting that even in earlier-stage disease, elevated SUVmax may reflect increased aggressiveness [20]. In addition, metrics that adjust SUVmax for tumor size—such as the SUVmax/tumor size ratio—have been proposed to better characterize metabolic activity independent of lesion size and have been associated with lymphovascular invasion, nodal metastasis, higher grade, and increased recurrence risk, particularly in adenocarcinoma [21].

Prior literature reports mixed findings regarding the relationship between SUVmax and Ki-67. Some studies have described a positive correlation [3, 11], whereas others have not observed a meaningful association [22, 23]. From a biological standpoint, SUVmax reflects tumor glucose metabolism, whereas Ki-67 is a nuclear protein widely used as a proliferation marker. Taken together, the heterogeneity of published results suggests that the SUVmax–Ki-67 relationship may be influenced by factors such as histologic subtype, tumor microenvironment, and methodological variability, highlighting the need for additional studies integrating PET-derived parameters and histopathology.

In our cohort, the positive association between SUVmax and Ki-67 supports the hypothesis that metabolic activity and proliferative activity provide complementary information on NSCLC tumor biology. Palumbo et al. reported that SUVmax and tumor diameter can be used to predict Ki-67 proliferative activity [13], and Tabata et al. similarly linked higher Ki-67 to larger tumor size in NSCLC [9].

We also observed a negative association between age and OS, consistent with evidence that advanced age may adversely affect outcomes in early-stage NSCLC [24]. The inverse relationship between tumor size and OS aligns with established knowledge that tumor burden remains a key prognostic determinant [25]. Given that SUVmax and Ki-67 correlated with these traditional factors, our findings support evaluating metabolic and proliferative biomarkers alongside age and tumor size to refine prognostic assessment [26].

This study has several strengths. First, the relatively large sample size compared with many previously published single-center series allowed for a comprehensive evaluation of the relationship between SUVmax, Ki-67 proliferation index, and a wide range of clinicopathologic variables. Second, the simultaneous assessment of metabolic activity (18F-FDG PET/CT–derived SUVmax) and tumor proliferative activity (Ki-67) enabled an integrated analysis of distinct but complementary aspects of tumor biology in NSCLC.

Nevertheless, several limitations should be acknowledged. The retrospective and single-center design may introduce selection bias and limit the generalizability of the results. SUVmax measurements may be influenced by technical factors related to PET/CT acquisition and reconstruction protocols, and Ki-67 assessment is subject to interobserver variability and intratumoral heterogeneity. These limitations should be considered when interpreting the results.

Kaplan–Meier analyses demonstrated that both SUVmax and the Ki-67 proliferation index are associated with overall survival in patients with NSCLC, with shorter median survival observed in those with higher values, suggesting more aggressive tumor biology. These findings indicate that integrating metabolic and proliferative markers with conventional clinicopathologic factors such as age, tumor size, histologic subtype, and stage may refine prognostic stratification beyond TNM staging alone. Further prospective, multicenter studies using standardized imaging protocols and incorporating molecular biomarkers are warranted to validate these results and clarify the clinical utility of SUVmax and Ki-67 in NSCLC.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Scientific Research Ethics Committee of Health Sciences University Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital (Protocol code: 2024-36; approval date: 05 December 2024). Due to the retrospective design of the study, the requirement for written informed consent was waived by the ethics committee.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to patient confidentiality but are available from the corresponding author on reasonable request for academic and review purposes.

Competing interests

The authors declare that they have no competing interests.

Funding

The authors disclosed that they did not receive any grant during the conduction or writing of this study.

Authors’ contributions

EEK and SKM contributed to the conception and design of the study. EEK was responsible for materials, data collection, and data processing, and performed the statistical analysis and data interpretation. SKM provided supervision throughout the study. EEK and SKM conducted the literature review and prepared the manuscript. Both authors critically reviewed the manuscript and approved the final version.

Acknowledgements

Not applicable.

Declaration of AI use

AI tools were used only for language editing and clarity; authors take full responsibility.

Riely GJ, Wood DE, Ettinger DS, Aisner DL, Akerley W, Bauman JR, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024;22(4):249–74. https://doi:10.6004/jnccn.2204.0023.
Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45. https://doi:10.3322/caac.21871.
Aydos U, Ünal ER, Özçelik M, Akdemir D, Ekinci Ö, Taştepe Aİ, et al. Texture features of primary tumor on ¹⁸F-FDG PET images in non-small cell lung cancer: The relationship between imaging and histopathological parameters. Rev Esp Med Nucl Imagen Mol (Engl Ed). 2021;40(6):343–50. https://doi:10.1016/j.remnie.2020.09.012.
Wei DM, Chen WJ, Meng RM, Zhao N, Zhang XY, Liao DY, et al. Augmented expression of Ki-67 is correlated with clinicopathological characteristics and prognosis for lung cancer patients: an up-dated systematic review and meta-analysis with 108 studies and 14,732 patients. Respir Res. 2018;19(1):150. https://doi:10.1186/s12931-018-0843-7.
Yonechi A, Suzuki H, Sakuma H, Higuchi M, Ohsugi J, Okabe N, et al. Prediction of recurrence for non-small cell lung cancer by combined analysis of molecular markers and 18F 2-fluoro-2-deoxy-D-glucose positron emission tomography. Fukushima J Med Sci. 2014;60(1):47–56. https://doi:10.5387/fms.2010-20.
Murakami S, Saito H, Sakuma Y, Mizutani Y, Ishikawa Y, Kondou T, et al. Correlation of 18F-fluorodeoxyglucose uptake on positron emission tomography with Ki-67 index and pathological invasive area in lung adenocarcinomas 30 mm or less in size. Eur J Radiol. 2010;75(2):62–6. https://doi:10.1016/j.ejrad.2009.11.020.
Wen S, Zhou W, Li CM, Hu J, Hu XM, Chen P, et al. Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies. BMC Cancer. 2015;15:520. https://doi:10.1186/s12885-015-1524-2.
Warth A, Cortis J, Soltermann A, Meister M, Budczies J, Stenzinger A, et al. Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role. Br J Cancer. 2014;111(6):1222–9. https://doi:10.1038/bjc.2014.402.
Tabata K, Tanaka T, Hayashi T, Hori T, Nunomura S, Yonezawa S, et al. Ki-67 is a strong prognostic marker of non-small cell lung cancer when tissue heterogeneity is considered. BMC Clin Pathol. 2014;14:23. https://doi:10.1186/1472-6890-14-23.
Yang Y, Shao X, Li Z, Zhang L, Yang B, Jin B, et al. Prognostic heterogeneity of Ki67 in non-small cell lung cancer: A comprehensive reappraisal on immunohistochemistry and transcriptional data. J Cell Mol Med. 2024;28:18521. https://doi:10.1111/jcmm.18521.
Vesselle H, Salskov A, Turcotte E, Wiens L, Schmidt R, Jordan CD, et al. Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 proliferation index. J Thorac Oncol. 2008;3(9):971–8. https://doi:10.1097/JTO.0b013e31818307a7.
Aytaç A, Demir B, Barutca S, Yürekli Y. Impact of Primary Tumor Diameter and SUVmax on Pathological Lymph Node Involvement in Non-small Cell Lung Cancer. Acta Haematol Oncol Turc. 2024;57(3):67–72. https://doi:10.4274/ahot.galenos.2024.88785.
Palumbo B, Capozzi R, Bianconi F, Fravolini ML, Cascianelli S, Messina SG, et al. Classification Model to Estimate MIB-1 (Ki 67) Proliferation Index in NSCLC Patients Evaluated With ¹⁸F-FDG-PET/CT. Anticancer Res. 2020;40(6):3355–60. https://doi:10.21873/anticanres.14318.
Özgül M, Kirkil G, Seyhan E, Çetinkaya E, Özgül G, Yüksel M. The maximum standardized FDG uptake on PET-CT in patients with non-small cell lung cancer. Multidiscip Respir Med. 2013;8(1). https://doi:10.1186/2049-6958-8-69.
Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum standardized uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival. J Thorac Cardiovasc Surg. 2005;130(1):151–9. https://doi:10.1016/j.jtcvs.2004.11.007.
Liu J, Dong M, Sun X, Li W, Xing L, Yu J. Prognostic Value of 18F-FDG PET/CT in Surgical Non-Small Cell Lung Cancer: A Meta-Analysis. PLoS ONE. 2016;11(1):e0146195. https://doi:10.1371/journal.pone.0146195.
Paesmans M, Garcia C, Wong CY, Patz EF Jr, Komaki R, Eschmann S, et al. Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data. Eur Respir J. 2015;46(6):1751–61. https://doi:10.1183/13993003.00099-2015.
Berghmans T, Dusart M, Paesmans M, Hossein-Foucher C, Buvat I, Castaigne C, et al. European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. Primary tumor standardized uptake value (SUVmax) measured on fluorodeoxyglucose positron emission tomography (FDG-PET) is of prognostic value for survival in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis (MA) by the European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. J Thorac Oncol. 2008;3(1):6–12. https://doi:10.1097/JTO.0b013e31815e6d6b.
Paesmans M, Berghmans T, Dusart M, Garcia C, Hossein-Foucher C, Lafitte JJ, et al. European Lung Cancer Working Party, and on behalf of the IASLC Lung Cancer Staging Project. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J Thorac Oncol. 2010;5(5):612–9. https://doi:10.1097/JTO.0b013e3181d0a4f5.
Iguchi T, Kojima K, Hayashi D, Tokunaga T, Okishio K, Yoon H. Preoperative maximum standardized uptake value emphasized in explainable machine learning model for predicting the risk of recurrence in resected non–small cell lung cancer. JCO Clin Cancer Inf. 2025;9:e2400194. https://doi:10.1200/CCI-24-00194.
Kim SJ, Lee K, Lee HJ, Kang DY, Kim YH. Maximum standardized uptake value-to-tumor size ratio in fluorodeoxyglucose F18 positron emission tomography/computed tomography: a simple prognostic parameter for non-small cell lung cancer. Diagn Interv Radiol. 2025;31(3):274–9. https://doi:10.4274/dir.2024.242837.
Park S, Lee E, Rhee S, Cho J, Choi S, Lee S, et al. Correlation between Semi-Quantitative (18)F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer. Nucl Med Mol Imaging. 2016;50(1):24–30. https://doi:10.1007/s13139-015-0363-z.
Kucukosmanoglu I, Karanis MIE, Unlu Y, Erol M. Correlation of [18F] FDG PET activity with expressions of Ki-67 in non-small-cell lung cancer. Nucl Med Rev Cent East Eur. 2022;25(2):73–7. 10.5603/NMR.a2022.0017. https://doi.
Dogru MV, Sezen CB, Erdogu V, Aker C, Alp A, Erduhan S. Prognostic Factors of Operated Stage I Non-Small Cell Lung Cancers: A Tertiary Center Long-Term Outcomes. Med Bull Haseki. 2021;59(3):221–7. https://doi:10.4274/haseki.galenos.2021.6997.
Zhang K, Cai J, Lu C, Zhu Q, Zhan C, Shen Y, et al. Tumor size as a predictor for prognosis of patients with surgical IIIA-N2 non-small cell lung cancer after surgery. J Thorac Dis. 2021;13(7):4114–24. https://doi:10.21037/jtd-21-428.
Del Gobbo A, Pellegrinelli A, Gaudioso G, Castellani M, Zito Marino F, Franco R, et al. Analysis of NSCLC tumour heterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas. Histopathology. 2016;68(5):746–51. https://doi:10.1111/his.12808.

No competing interests reported.

Download PDF

Reviewers agreed at journal
26 Dec, 2025
Reviewers invited by journal
26 Dec, 2025
Editor invited by journal
23 Dec, 2025
Editor assigned by journal
21 Dec, 2025
Submission checks completed at journal
21 Dec, 2025
First submitted to journal
20 Dec, 2025

You are reading this latest preprint version

Prognostic Value of Ki-67 and 18F-FDG PET/CT SUVmax in Non–Small Cell Lung Cancer

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Materials and Methods

Study Design and Patient Selection

Data Collection and Variables

Definitions and Staging

Statistical Analysis

Results

Patient Characteristics

Comparison According to Ki-67 Proliferation Index

Comparison According to SUVmax

Correlation Analysis

Survival Analysis

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1