Differentiation of Primary Lung Cancer from Solitary Lung Metastasis in Patients with Colorectal Cancer Using Computed Tomography Features and Clinical Characteristics : A Retrospective Cohort Study

Purpose: To evaluate the features of solitary pulmonary nodule (SPN) that can be used to differentiate between primary lung cancer (LC) and solitary lung metastasis (LM) in patients with colorectal cancer (CRC). Materials and Methods: This retrospective study included SPNs resected in CRC patients between 2011 and 2019. The diagnosis of primary LC or solitary LM was based on histopathologic report by thoracoscopic wedge resection. Chest computed tomography (CT) images were assessed by two thoracic radiologists, and features were identied by consensus. Predictive parameters for the discrimination of primary LC from solitary LM were evaluated using multivariate logistic regression analysis. Results: We analyzed 199 patients (mean age, 65.95 years; 131 men). The clinical characteristics suggestive of primary LC rather than solitary LM was clinical stage I-II CRC (P < 0.001, odds ratio (OR): 21.70). The CT features of SPNs indicative of primary LC rather than solitary LM were a spiculated margin (P = 0.020, OR: 8.34), a sub-solid density (P < 0.001, OR: 115.56), and presence of an airbronchogram (OR: 5.32; P = 0.032). Conclusions: CT features and clinical characteristics of SPNs in patients with CRC could help differentiate between primary LC and solitary LM.


Introduction
Chest computed tomography (CT) is an important surveillance tool for pulmonary metastases. As the lung is a common site of metastasis in colorectal cancer (CRC) and chest CT supports improved identi cation of pulmonary nodules, many current guidelines recommend chest CT in pre-operative evaluation and post-operative surveillance of patients with CRC [1]. Detection of multiple pulmonary nodules supports a diagnosis of metastasis [2]. However, diagnosis is more di cult when a solitary pulmonary nodule (SPN) is detected because primary lung cancer (LC) can mimic a solitary lung metastasis (LM) in patients with CRC. Furthermore, 10% of pulmonary metastases are present as SPNs in patients with CRC. This rate is higher than that in patients with other extra-thoracic malignancies [3,4]. Therefore, it is sometimes di cult to determine whether a SPN is a primary LC or a solitary LM.
Surgical strategies for treating primary LC and solitary LM are quite different. The treatment of choice for LM is minimally invasive surgical resection in order to preserve as much healthy lung parenchyma as possible in case repeat operations are needed. However, complete surgical resection with lobectomy and mediastinal lymph node dissection is the gold standard for LC [5].
Image-guided needle biopsies may be useful for distinguishing between primary LC and solitary LM before surgical planning. However, it is di cult and risky to perform needle biopsies in some cases, especially for those with small lesions. Additionally, the small volume of biopsy specimen obtained can sometimes impede histological differentiation between primary LC and solitary LM.

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Imaging characteristics of SPN can be used for non-invasive alternatives to determine whether a SPN is a primary LC or a solitary LM. However, compared to the generally accepted imaging ndings of metastatic nodules including multiple peripherally located round variable sized nodules [4], the comparison of imaging ndings between primary LC and solitary LM are not well established. Therefore, the aim of this study was to determine clinical characteristics and CT features that could be used to differentiate between primary LC and solitary LM in patients with CRC.

Patients
We retrospectively reviewed CRC patients by searching electronic medical records from January 2011 to December 2019 at a single tertiary referral center. Patients with the following criteria were included: presence of a SPN which measured less than 30 mm on pre-diagnostic chest CT image, evidence of malignant potential such as size growth of a SPN that has increased in diameter of at least 2 mm, and availability of histopathologic report by thoracoscopic wedge resection. To this initial inclusion of 224 patients, we applied the exclusion criteria of patients whose SPN was not diagnosed as either primary LC or solitary LM (n = 13) and patients whose SPN deemed too small to characterize at pre-diagnostic chest CT image (less than 8 mm) (n = 12). Finally, 199 CRC patients were enrolled in this study (Table 1).

Analysis of CT features
Chest CT images were interpreted independently by two thoracic radiologists with 20 and 8 years of experience, respectively. They were blinded to clinical and histopathologic information of patients. If interpretations differed, the decision was made based on consensus reading of two designated thoracic radiologists.
Qualitative CT features such as location (upper or non-upper, central or peripheral), margin (smooth, lobulated, or spiculated), and density (solid or sub-solid) of pulmonary nodules and the presence of an air-bronchogram, cavitation, pleural tags, pleural abutment, or background emphysema were assessed. A central location was de ned as the area within 2 cm of the pulmonary hilum [7]. Nodules were classi ed as smooth, lobulated, or spiculated based on margin characteristics ( Fig. 1). Nodules were classi ed as having a sub-solid density if they contained a portion of ground-glass opacity (GGO) without completely obscuring bronchial or vascular margins of the lung parenchyma ( Fig. 1) [8]. An air-bronchogram was de ned as a gas-lled bronchus surrounded by abnormal lung parenchyma ( Fig. 1) [8]. Pleural tags were de ned as linear strands that extended between nodule surface and adjacent pleural surface [9].
Quantitative CT features such as sizes of lung nodules were also assessed. The size of a nodule was measured using the longest diameter, including any portion of GGO seen on axial CT images obtained with lung window settings.

Statistical analysis
All statistical analyses were performed using SPSS software, version 25.0 (IBM Corp., Armonk, NY, USA). CT features of primary LC and solitary LM were compared using Pearson Chi-square test for categorical variables and independent t-test for continuous variables.
Inter-reader agreement for CT features was assessed by percent of concordant cases and Kappa of agreement with 95% con dence intervals [10]. Univariate and multivariate logistic regression analyses were used to evaluate which factors were predictive of differentiation between the two groups. In initial univariate analysis, a P value of < 0.25 was used as the threshold for retaining factors in multivariate analysis [11]. A receiver operating characteristic (ROC) curve was drawn to discriminate LC from LM according to each signi cant clinical characteristic and CT feature. Corresponding area under the curve (AUC) was calculated. Statistical signi cance was considered when p-value was less than 0.05.

Results
Clinical characteristics of patients enrolled in this study are summarized in  The proportion of nodules with spiculated margins was signi cantly higher in the primary LC group than in the solitary LM group (47.1% vs. 5.4%, P < 0.001). The proportion of nodules with a sub-solid density was signi cantly higher in the primary LC group than in the solitary LM group (32.9% vs. 0.8%, P < 0.001). Air-bronchograms were signi cantly more frequent in the primary LC group than in the solitary LM group (42.9% vs. 5.4%, P < 0.001). Pleural tags were signi cantly more frequent in the primary LC group than in the solitary LM group (58.6% vs. 19.4%, P < 0.001). There were no statistically signi cant differences in the location of nodules or the presence of cavitation between the two groups ( Table 2).

Discussion
CT features can be used to differentiate between primary LC and solitary LM. In our multivariate analysis, three CT features of nodules were found to be useful for differentiating primary LC and solitary LM. These were nodules with spiculated margins, sub-solid density, and a presence of air-bronchogram.
Marginal characteristics of nodules can be used to determine whether these nodules are primary or metastatic and whether they are benign or malignant. Previous studies have reported that a smooth or well-de ned margin is more common in metastatic nodules than an irregular margin [4,13]. In contrast, up to 80% of primary lung cancer can present with non-smooth margin, especially a spiculated margin which is already well known to be associated with primary lung cancer [14,15]. The proportion of nodules with spiculated margins was signi cantly higher in patients with primary LC than in patients with solitary LM in both univariate and multivariate analyses of our study. The margin of a nodule appeared more irregular even in solitary LM as the size increased. But a solitary LM tended to show a lobulated margin rather than a spiculated margin in our study.
Nodules with a sub-solid density contain a GGO component commonly seen in lepidic growth of primary lung adenocarcinomas [16,17]. Lepidic growth is de ned as tumor progression along the alveolar wall. It is typically observed in primary lung adenocarcinomas. Only a few reports have described cases of lepidic growth of pulmonary metastases [18,19]. Typically, pulmonary metastases present as solid, round nodules that are peripherally located [4]. In our study, sub-solid density of nodules was mostly observed in primary LC. It was rarely observed in solitary LM. Thus, sub-solid density of SPNs can be used to support a diagnosis of a primary LC rather than a solitary LM.
An air-bronchogram is de ned as an air-containing bronchus or bronchioles within an area of opaci cation of the surrounding alveoli. The presence of an air-bronchogram within a nodule raises a high suspicion of a primary lung malignancy [20]. Air-bronchograms have been reported to occur in primary LC of all histological types [21]. Only a few reports have described cases of pulmonary metastases showing air-bronchograms [18]. The rate of air-bronchograms within nodules was signi cantly higher in primary LC than in solitary LM in both univariate and multivariate analysis of our study.
Pleural tags are known as interlobular septal thickening of the lung between the nodule and visceral pleura. They may result from localized edema, tumor extension within or outside lymphatic vessels, in ammatory cells, or brosis [9]. A previous study has reported that pleural tags are commonly seen in primary LC and in up to 80% of surgically resected primary LC without abutting the pleura [22]. In the present study, pleural tags were found in 56.4% of primary LC. They were also signi cantly more frequent in primary LC than in solitary LM in univariate analysis of our study.
Besides CT features, clinical characteristics can also aid the differentiation between primary LC and solitary LM. Several studies have previously characterized indeterminate pulmonary nodules in patients with CRC [23][24][25][26]. Among factors predicting pulmonary metastasis, presence of lymph node metastasis in patients with CRC has been identi ed as a signi cant risk factor [23][24][25][26]. Kim et al. [27] have reported that the probability of pulmonary metastasis is low in patients with CRC without hepatic or lymph node metastasis, that is, in clinical stage I-II CRC patients. Similarly, the present study showed that solitary LM was associated with higher clinical stage (III-IV) CRC patients than lower clinical stage CRC patients (I-II) in both univariate and multivariate analyses.
Previous studies have reported that the location of the index tumor in the rectum rather than the colon is a risk factor of pulmonary metastasis in patients with CRC [23,25]. The venous bloodstream of the rectum bypasses the liver, meaning that the rst organ encountered is the lung [28]. Similarly, the proportion of index tumors located in the rectum was signi cantly higher in the solitary LM group than in the primary LC group in univariate analysis of the present study.
This study has several limitations. Firstly, only nodules con rmed as either primary LC or solitary LM on histopathological analysis after surgical resection were included. There was an inherent selection bias towards patients who underwent surgery. Prospective studies (particularly randomized, controlled trials) is needed to con rm our results. Secondly, as this was a single-center and retrospective study, the sample size was relatively small. A study with a larger sample size is needed to validate our results. Thirdly, visual analysis of CT features raises the possibility of inter-observer and intra-observer variability regarding categorization despite the use of consensus reading. For a more accurate interpretation, more quantitative analysis tool such as radiomics would be more helpful.  Receiver operating characteristic curves for assessing the ability of CT features, both alone and in combination with clinical characteristics, to discriminate primary lung cancer from solitary lung metastases.