Mean computed tomography value to predict spread through air spaces in clinical N0 lung adenocarcinoma

With the widespread use of low-dose CT screening for lung cancer, more early lung adenocarcinomas have been detected [1]. For stage IA lung adenocarcinoma, radical resection is still the preferred and recommended treatment according to guidelines [2]. The heterogeneity of malignant tumors still leads to differences in long-term prognosis after surgery [3]. Suzuki et al. [4] has reported that less-invasiveness stage IA lung adenocarcinoma may be more suitable for sublobar resection. Therefore, recognizing less-invasiveness stage IA lung adenocarcinoma prior to surgery has become a significant challenge for thoracic surgeons [5].

Spread through air spaces (STAS) is an extension of primary lung cancer in which tumor cells extend beyond the tumor margin into the alveolar space, and has been reported to occur 15–55% of the time in patients with early-stage lung adenocarcinoma [6, 7]. Furthermore, studies of non-small cell lung cancer have shown that the presence of STAS is an important predictor of recurrence, particularly in patients who have undergone surgical procedure [8]. Therefore, preoperative prediction of the presence or absence of STAS is important in determining the treatment strategy, including the surgical approach for patients with early-stage lung adenocarcinoma.

Quantitative densitometric methodologies, and mean computed tomography (mCT) value have been reportedly used to evaluate ground-glass opacity (GGO) lesions. We previously reported that the mCT value of GGO lesions is a risk factor associated with their future change [9], and the evaluation of mCT value is useful in predicting less invasive lung cancer [10]. There have been no studies regarding the use of mCT values in lung cancer and the presence of STAS, which can be of great significance for treatment decisions.

The objectives of this study were to investigate the usefulness of using mCT value for predicting STAS, and to assess whether they contribute to determining the benefits of performing a limited resection.

The CT findings of various nodule lesions are presented in Fig. 2. Figure 2A, B shows a typical pure GGO lesion. In Fig. 2C, D, the tumors are homogeneous in density, but are too dense to be considered pure GGO; therefore it is difficult to calculate the C/T ratio. The mCT values were − 324.9 ± 19.3 HU for STAS negative group and − 173.0 ± 26.3 HU for STAS positive group (p < 0.0001) (Fig. 3). Clinico-pathological characteristics are shown in Table 1. A total of 118 patients met both clinical and imaging criteria for inclusion in this study. Of these, 63 were men and 55 were women. Their ages ranged from 46 to 92 years, with a median of 73 years. Clinical T1 stage accounted for 80.5%. Four cases were upstaged to pathological N1 and 11 cases were upstaged to pathological N2. Forty-one lesions (34.7%) out of 118 lesions were positive for STAS. The comparison of clinico-radiological data between lesions in STAS negative and STAS positive are summarized in Table 2. The STAS positive group was strongly associated with a high mCT value, high C/T ratio, large solid tumor size, large tumor size and high SUVmax value. Among 41 STAS positive cases, 31 cases were pure solid and 10 cases were part-solid cases. We attempted to predict the presence of STAS based on the mCT value, SUVmax value, C/T ratio, solid tumor size, and ROC curve analysis was performed to determine the appropriate cutoff value (Fig. 4). The maximum sensitivity and specificity were obtained at a cutoff value of − 251.8 HU, 4.7, 100%, 2.3 cm, respectively. The ROC area under the curve value of the mCT value was the highest (0.738; 95% CI 0.78–0.94), followed by SUVmax value (0.720; 95% CI 0.74–0.91), C/T ratio (0.665; 95% CI 0.79–0.86), solid tumor size (0.649; 95% CI 0.68–0.87). Correlation coefficients between these factors were as follows, mCT value versus SUVmax value: r = − 0.57, p = 0.21; mCT value vs C/T ratio: r = − 0.76, p < 0.001 and mCT value vs solid size: r = − 0.60, p = 0.07. Table 3 shows the results of univariate and multivariate analyses for predicting STAS. Clinical T stage, mCT value and SUVmax value were selected for the multivariate analysis, but ruled out C/T ratio because relatively strong correlation could be found between mCT value (r = − 0.76). Multiple logistic regression analyses using the preoperatively determined variables revealed that mCT value (p = 0.015) are independent predictive factor of predicting STAS. However, clinical T stage and SUVmax valuewere not statistically significant (p = 0.42, 0.49, respectively).

The present study aimed to evaluate the relationship between STAS and the clinic- radiological factors of patients with clinical N0 lung adenocarcinoma. Evaluation of various CT features, such as the mCT values, C/T ratio, tumor size and SUV value of FDG-PET can be helpful in predicting the presence of STAS. In particular, we initially demonstrated that the mCT value of the GGO lesion is a sensitive marker for predicting STAS in clinical N0 lung adenocarcinoma.

The phenomenon of spread through air spaces (STAS) which was first identified by Kadota et al. [13], is defined as the spread of lung cancer tumor cells into the air spaces of the lung parenchyma adjacent to the main tumor. Recent studies on NSCLC have shown that STAS is a significant risk factor for recurrence and a prognostic factor for poor OS, especially after sublobar resection [8, 14‐16]. STAS not only affects patient prognosis but also influences the choice of surgical approach. Therefore, assessing the risk of STAS in the primary tumor through preoperative radiological imaging can provide important auxiliary diagnostic information for thoracic surgeons in selecting surgical approaches and can impact patient prognosis.

If we could predict the presence of STAS in the primary tumor through preoperative CT imaging, it would be very helpful for thoracic surgeon in selecting surgical approach. In a previous study, STAS was significantly related to solid nodules on computed tomography [17].

Currently, there are several clinical studies about C/T ratio with STAS and confirmed that the C/T ratio was associated with STAS positive tumors [18, 19]. In a previous study, STAS was significantly related to 18F FDG-PET findings, especially SUVmax value [20] and MTV/CTV ratio [21]. Kim et al. reported that STAS was more common in solid tumors than in part-solid or ground-glass lesions [18]. In the presented study, 10 out of 53 part-solid lesions and 31 out of 65 solid lesions revealed STAS. In subgroup analysis among part-solid nodules, SUVmax was significantly higher in STAS positive group comparing STAS negative group. On the other hand, there was no significant difference between the presence of STAS and PET parameters among solid nodule lesions.

With recent advances in diagnostic imaging technologies, GGO lesions are increasingly detected using HRCT scans [22]. In a clinical setting, several types of GGO can be encountered. Suzuki et al. [23] classified peripheral small-sized adenocarcinoma into six categories and reported that the classification was significantly associated with pathologic prognostic factors. It is difficult to measure the size of the solid part of the tumor when the nodule comprises a heterogeneous mixture of GGO and solid tumor. The mCT value is useful for tumors that are too dense to be called pure GGO but are not pure solid tumor. The mCT value adds a diagnostic value to the C/T ratio for tumors for which the size of solid portion is difficult to measure. Quantitative densitometric methodologies, and mCT value have been reportedly used to evaluate GGO lesions [24, 25]. We previously reported that the mCT value of GGO lesions is a risk factor associated with their future change [9], and the prediction of recurrence [26].

This study has several limitations. Firstly, it is a single-center retrospective study, which may have some selection bias, and lacks prospective validation. Secondly, the sample size needs to be further expanded.

The evaluation of the mCT value has a potential to predict STAS preoperatively. For such as patients with adenocarcinoma manifested as mixed GGO, added new information to the C/T ratio, and may contribute to establish the optimal treatment strategies for this disease.