Lung cancer ranks among the most frequently diagnosed types of cancer globally. It is classified into two primary subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC making up about 85% of cases. In China, an estimated 787,000 new NSCLC cases are diagnosed annually, representing 40% of the global burden, while the five-year survival rate remains as low as 19.7% (1). As public awareness increases and lung cancer screening programs are implemented, early-stage lung cancer detection has improved. The WHO categorizes NSCLC into three primary histopathological subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (2). Early detection of NSCLC is vital; however, due to the absence of dependable biomarkers, around 60% of patients are diagnosed at later stages (3). Studies suggest that the anatomical location of primary tumors in malignancies like esophageal cancer, colorectal cancer, and NSCLC correlates with prognosis (4, 5).Tumor location is a known prognostic factor in metastatic lung cancer. A significant link between tumor recurrence and lesions in the lower lobes of the lungs in NSCLC patients was found by Motono et al. (6). A multicenter retrospective analysis established tumor location as an independent predictor of survival in patients with completely resected pathologic stage I non-small cell lung cancer (NSCLC). This investigation identified that stage I NSCLC patients with lower lobe tumors experienced inferior survival outcomes compared to those with tumors located in the upper or middle lobes (7). A meta-analysis investigating tumor localization and survival in stage I-III non-small cell lung cancer demonstrated that upper lobe tumor location was associated with superior three-year survival, whereas lower lobe localization correlated with inferior survival outcomes (8). However, research on the spatial localization of primary lesions in NSCLC is limited. Identifying predictors for lesion location is therefore a crucial yet underexplored area.

Tumor localization in NSCLC is closely linked to disease progression and prognosis. Primary tumor location is a prognostic factor in several malignancies, including esophageal, colorectal, and NSCLC (10, 11). A Japanese study found a significant association between NSCLC recurrence and lower lobe tumors (12). Lee et al. reported that NSCLC individuals with tumors outside the lower lobes had better 5-year survival rates after surgical resection than those with lower lobe tumors (13). Multiple studies show that NSCLC patients with lower lobe tumors have worse outcomes than those with upper lobe tumors (14–19). Thus, early identification of tumor localization in NSCLC is clinically valuable.

This study identified WBC, LYM, α-HBDH, HDL, CEA, SF, CA153, and CA199 as key factors associated with lower lobe lesion localization in early-stage NSCLC. Physiologically, the lower pulmonary regions exhibit a relatively greater degree of vascular perfusion compared to the upper zones. This relative hyperperfusion may predispose to more aggressive tumor behavior and contribute to the higher incidence of primary carcinomas originating in the lower lobe (20). Chronic inflammation is a well-established risk factor for cancer development (21). Furthermore, evidence suggests that elevated total white blood cell and neutrophil (NEU) counts are positively associated with an increased risk of both lung cancer and benign pulmonary diseases (22). Elevated WBC count reflects systemic inflammation, a major contributor to tumor progression, promoting tumor cell proliferation, invasion, and metastasis (23). Neutrophil accumulation enhances the inflammatory microenvironment, promoting tumor invasiveness (24). Lower lobe NSCLC tumors are more likely to complicate obstructive pneumonia, with neutrophilic infiltration further elevating WBC levels (25). Both lymphocyte percentage (LYM%) and red cell distribution width (RDW) have been demonstrated as independent predictors of lung cancer risk, with marked variations in LYM% observed across different histological subtypes of pulmonary carcinoma (26). α-HBDH, an isoenzyme of LDH, serves as a marker of glycolytic activity, reflecting the Warburg effect. Tumor cells upregulate LDH/a-HBDH to convert pyruvate to lactate, creating an acidic microenvironment that promotes invasion and metastasis (27). Previous studies by Chinese researchers have shown a strong link between α-HBDH levels and lung cancer development, progression, and prognosis. α-HBDH was identified as an independent prognostic factor for overall survival (OS) in patients with lung cancer. The high α-HBDH group exhibited a significantly reduced median OS of 6.4 months (95% CI 0.2–26.0) compared to the normal α-HBDH group (12.7 months, 95% CI 0.8–46.4), a difference that reached statistical significance (P = 0.023) (28). This may result from the hypoxic microenvironment in the lower lobes, which promotes glycolysis by upregulating LDH-A expression via hypoxia-inducible factor-1α (HIF-1α), accelerating tumor growth. Although no consensus exists on the link between tumor location (upper vs. lower lobe) and HDL-C levels in NSCLC patients, studies and mechanistic insights provide preliminary clues. Evidence from epidemiological studies indicates a J-shaped association between HDL levels and cancer mortality (p for nonlinearity < 0.01), with the lowest risk observed at HDL-C concentrations ranging from 64 to 68 mg/dL ( Figure 5 ). For each 10 mg/dL increment in HDL-C beyond this range, the pooled risk ratio for cancer mortality was 1.02 (95% CI 0.98, 1.05) and 1.11 (95% CI 1.09, 1.14), respectively, compared to the reference interval (29). A case-control study conducted in China identified a strong link between low HDL-C levels and elevated NSCLC risk. The reduction in HDL-C may result from the increased cholesterol demand for tumor growth and membrane biosynthesis (30). HDL-C promotes cholesterol accumulation in tumor cell membranes, enhancing epidermal growth factor receptor (EGFR) signaling—an effect more commonly seen in adenocarcinomas in the lower lobes (31, 32).

Tumor markers are linked to tumor cell proliferation and differentiation. Dou et al. found that the median CEA level in lung adenocarcinoma patients was 6.6 ng/mL, confirming CEA as an independent predictor of lung adenocarcinoma (OR = 1.50, 95% CI: 1.04–2.16, p < 0.001) (33). A clinical investigation demonstrated that serum levels of CEA, SCC-AG, CYFRA 21-1, NSE, and CA199 exhibit a positive correlation with both tumor metastasis and disease staging (34). Lower lobe tumors are frequently associated with chronic inflammation, stimulating CEA secretion. Elevated SF levels release free iron (Fe²⁺), generating ROS through the Fenton reaction. These ROS cause DNA damage and activate matrix metalloproteinases (MMP-2/9), facilitating pleural invasion by enabling tumor cells to breach the pleural barrier—especially in lower lobe NSCLC tumors (35). This may be due to the anatomical proximity of the lower lobes to the diaphragm, where mechanical stress is more prominent, exacerbating pleural fissure formation through increased ROS generation. Previous studies identified SF as an independent factor associated with EGFR mutation status in NSCLC (36). In this study, CA153 and CA199 levels were significantly higher in patients with lower lobe NSCLC in relation to individuals with upper lobe tumors. Lower lobe tumors are more prone to pleural invasion, increasing the risk of poor prognosis. Gravitational effects cause secretions like mucus plugs to accumulate in the lower lobes, increasing susceptibility to chronic inflammation. This inflammation may further promote tumor aggressiveness and invasiveness. Previous studies have shown that both CA153 and CA199 are significantly associated with tumor development, progression, and poor prognosis (37, 38).Lower lobe tumors, particularly mucinous and adherent-type adenocarcinomas, often overexpress mucin1,the antigenic source of CA153, promoting its secretion (39). These tumors are more likely to invade the pleura, stimulating mesothelial cells to release CA153 (40). The hypoxic microenvironment may upregulate glycosyltransferases like fucosyltransferase 3 (FUT3) via HIF-1α, enhancing CA199 synthesis. A positive correlation between FUT3 mRNA expression and CA199 levels supports this mechanism (41).

This study is the first to combine inflammatory-lipid indices and tumor markers to predict the spatial localization of early-stage NSCLC lesions. It found significantly higher levels of WBC, LYM, α-HBDH, HDL, CEA, SF, CA153, and CA199 in lower lobe tumors compared to upper lobe tumors (all p < 0.05). These factors were independent predictors of lower lobe tumor localization. The research aims to provide a low-cost, dynamic diagnostic tool for clinical use. This predictive model could potentially be integrated with AI-driven systems in the future to achieve further refinement. AI-assisted interpretation may enhance its clinical applicability and strengthen its diagnostic or prognostic utility (42). However, this study is not without its limitations. First, the analysis focused on the upper and lower lobes, excluding the right middle lobe. Further investigations are needed to explore tumor localization in this region. Second, the study was conducted at the lobar level, thus necessitating further research involving more granular segmental-level analyses to refine spatial localization. Third, as a single-center retrospective study, the findings may be subject to selection bias and limited generalizability due to the absence of broader datasets. The study has strong clinical potential. Addressing the above revisions will enhance its robustness and generalizability. Further research should conduct large-scale, multi-center external validations to improve the generalizability of the model. Future studies should include larger, multicenter cohorts to refine the predictive model for more accurate spatial localization of early-stage NSCLC lesions.

This study confirms that white blood cell count, lymphocyte count, α-hydroxybutyrate dehydrogenase, high-density lipoprotein, carcinoembryonic antigen, serum ferritin, CA153, and CA199 are key predictors of tumor localization in non-small cell lung cancer. The nomogram model, built with these readily available clinical parameters, demonstrated strong predictive performance and offers a novel, low-cost tool for assessing early-stage NSCLC tumor distribution in clinical practice.