Combination of circulating tumor cells and 18F-FDG PET/CT for precision diagnosis in patients with non-small cell lung cancer

Abstract

Purpose: To investigate the value of 2-deoxy-18f-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and circulating tumor cells (CTCs) for the differential diagnosis of patients with benign lung diseases and those with NSCLC. To explore the phenotypic heterogeneity of CTCs and their correlation with FDG uptake in patients with Stage I-IV NSCLC.

Methods: Blood specimens from patients with benign lung diseases and patients with primary NSCLC were collected for the detection of CTCs and their subtypes (epithelial, mixed, and mesenchymal) and analyzed for 18F-FDG PET/CT tumor metabolic parameters, including the maximum standardized uptake value (SUV_max), standard uptake value (SUL), metabolic tumor volume of primary lesion (MTV), total lesion glycolysis of primary lesion (TLG). Clinical data including age, gender, smoking history, tumor size, TNM stage and pathology type were also collected. The value of the two method alone and in combination for the differential diagnosis of benign and malignant was comparatively analyzed. Finally, the differences in CTC and its subtypes in different stages of NSCLC were compared, and FDG metabolic parameters were correlated with CTC subtypes.

Results: There were a total of 65 patients with pulmonary diseases, including 12 patients with benign pulmonary diseases and 53 patients with NSCLC. The mean age was 67 ± 10 (38-89 years), 27 were females and 38 were males. 31 (22 males and 9 females) had a long history of smoking. The mean size of the largest diameter of all single lesions was 36 ± 22 mm with a range of 10-108 mm. Seven out of 12 benign diseases were inflammatory granulomatous lesions and 5 were inflammatory pseudotumours. Twenty-four out of 53 NSCLC were adenocarcinomas and 29 were squamous carcinomas. Twelve out of 53 patients with NSCLC were in Stage I, 10 were in Stage II, 17 were in Stage III and 14 were in Stage IV. SUV_max, SUL, MTV, TLG, total CTCs, epithelial CTCs, and mixed CTCs were all valuable in the differential diagnosis of benign and malignant. TLG combined with mixed CTCs was statistically different from all other diagnostic methods (p < 0.05) and higher than any other diagnostic criteria. In the differential diagnosis of benign and Stage I NSCLC, only total CTC (Z = -2.188 p = 0.039) and mixed CTCs (Z = -3.020 p = 0.014) had certain diagnostic efficacy, and there was no statistical difference between them (p = 0.480). Only mesenchymal CTCs differed in Stage I-IV NSCLC, with a higher number of those who developed distant metastases than those who had non-distant metastases. Epithelial CTCs correlated with SUV_max (r = 0.333, p = 0.015) and SUL (r = 0.374, p = 0.006). Mmesenchymal CTCs correlated with MTV (r = 0.342, p = 0.018) and TLG (r = 0.319, p = 0.02). Further subgroup analyses revealed epithelial CTCs were correlated with SUV_max (r = 0.543, p = 0.009) and SUL (r = 0.552, p = 0.008), and the total CTCs was correlated with SUV_max (r = 0.622, p = 0.003), SUL (r = 0.652, p = 0.003), MTV (r = 0.460, p = 0.031), and TLG (r = 0.472, p = 0.027) in the early group (Stage I-II). Only mesenchymal CTCs was associated with MTV (r = 0.369, p = 0.041), and TLG (r = 0.415, p = 0.02) in the intermediate-late group (Stage III-IV).

Conclusion: Both FDG PET metabolic parameters and CTCs demonstrated diagnostic value for NSCLC, and combining TLG with mixed CTCs could enhance their diagnostic efficacy. The total CTCs and mixed CTCs showed greater diagnostic value than FDG PET in distinguishing benign lesions from Stage I NSCLC. In NSCLC patients, the epithelial CTCs exhibited a positive correlation with SUV_max and SUL, while mesenchymal CTCs correlated with MTV, and TLG. Besides, epithelial CTCs showed stronger correlations with SUV_max and SUL, and total CTCs showed stronger correlations with SUV_max, SUL, MTV, and TLG in Stage I-II NSCLC. Only mesenchymal CTCs in Stage III-IV NSCLC showed correlations with MTV and TLG. Stage IV NSCLC cases displayed a higher number of mesenchymal CTCs.

Keywords: 18F‐FDG PET/CT; circulating tumor cells (CTCs); diagnosis; non‐small‐cell lung cancer (NSCLC).

FIGURE 1

The differences between maximum diameter (A; p = 0.001), SUV_max (B; p = 0.001), SUL (C; p = 0.001), MTV (D; p < 0.001), TLG (E; p < 0.001), total CTCs (F; p = 0.001), epithelial CTCs (G; p = 0.04), and mixed CTCs (H; p < 0.001) by Mann–Whitney U‐nonparametric test in patients with benign lung diseases and NSCLC, respectively.*p < 0.05, ***p < 0.01. ****p < 0.001. E⁺ CTCs, Epithelial CTCs; E⁺/M⁺ CTCs, Mixed CTCs; NSCLC, Non‐small cell lung cancer.

FIGURE 2

The differences between total CTCs (A; Z = −2.188, p = 0.039) and mixed CTCs (B; Z = −3.020, p = 0.014) by Mann–Whitney U‐nonparametric test in patients with benign lung diseases and Stage I NSCLC, respectively.*p < 0.05, **p < 0.01. NSCLC, non‐small cell lung cancer. E⁺/M⁺, epithelial and mesenchymal expressing.

FIGURE 3

Receiver operating characteristic curve analyses in patients with NSCLC or benign disease. CTC, circulating tumor cell; E⁺, epithelial expressing; E⁺/M⁺, epithelial and mesenchymal expressing; M⁺, mesenchymal expressing; MTV, tumor volume of primary lesion; NSCLC, non‐small cell lung cancer; SUL, standard uptake value metabolic; SUV_max, maximum standardized uptake value; TLG, total lesion glycolysis of primary lesion.

FIGURE 4

Receiver operating characteristic curve analyses in patients with Stage I NSCLC or benign disease. CTC, circulating tumor cell; E⁺/M⁺, epithelial and mesenchymal expressing; NSCLC, non‐small cell lung cancer.

FIGURE 5

Differences in CTC characteristics in Stage I–IV NSCLC. Stage IV NSCLC exhibited a higher number of mesenchymal CTCs compared to those without distant metastases (Stage I–III) (p = 0.020, 0.027, and 0.011). E⁺, epithelial expressing; E⁺/M⁺, epithelial and mesenchymal expressing; M⁺, mesenchymal expressing; NSCLC, non‐small cell lung cancer.

FIGURE 6

Differences in the SUV_max (A; p = 0.002) and SUL (B; p = 0.006) between patients with adenocarcinoma and squamous carcinoma. AC, adenocarcinoma; SCC, squamous carcinoma. ***p < 0.01.

FIGURE 7

Heat map of correlation between FDG uptake parameters and CTC features. Red indicates positive correlation and blue indicates negative correlation. The number of epithelial CTCs correlated with SUV_max (r = 0.33, p = 0.015) and SUL (r = 0.37, p = 0.006). Mesenchymal CTCs exhibited correlations with MTV (r = 0.32, p = 0.018), and TLG (r = 0.32, p = 0.02). E⁺, epithelial expressing; E⁺/M⁺, epithelial and mesenchymal expressing; M⁺, mesenchymal expressing.

FIGURE 8

(A) Adenocarcinoma, Stage IVA, SUV_max was 5.46, SUL was 4.35, MTV was 7.77 cm³. A low MTV and TLG value of the primary site with pleural and mediastinal lymph node metastases occurred. The number of total CTCs was 20/5 mL, Epithelial CTCs was 9/5 mL, mixed CTCs was 10/5 mL and mesenchymal CTCs was 1/5 mL. (B) Squamous carcinoma, Stage IIIB, SUV_max was 11.32, SUL was 9.8, MTV was 50.54 cm³, TLG was 240.17 cm³, and central necrosis of the primary lesion resulted in reduced MTV and TLG. The number of total CTCs was 6/5 mL, Epithelial CTCs was 6/5 mL, mixed CTCs and mesenchymal CTCs was 0/5 mL.