Abstract
Background/Aim: Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed. Materials and Methods: The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm. Results: Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC. Conclusion: The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC.
- Computed tomography
- small-cell lung cancer
- surgery
Small-cell lung cancer (SCLC) is a devastating neoplasm. Unlike NSCLC, its prognosis is yet to be fully prolonged because of its more aggressive and metastatic natures (1). Chemotherapy and radiotherapy are considered to be the standard-of-care treatment options for SCLC patients. SCLC patients with limited-disease and extensive-disease are usually treated with chemoradiotherapy and chemotherapy, respectively (2, 3). Antibodies against immune checkpoint factors, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), are expected to become the standard treatment option for both SCLC and NSCLC (4, 5). However, surgical resection can be performed for patients with clinical stage I SCLC because of its survival benefit: the five-year survival rates as high as 60-70% can be achieved by surgical treatment combined with chemotherapy (6-9).
When performing surgical resection in lung cancer patients, a precise interpretation of the pulmonary nodular shadows on computed tomography (CT) prior to the operation is important, because the findings can help the thoracic surgeons to predict whether they are malignant or benign (10). The radiological features on CT include surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. With regard to adenocarcinoma (ADC) that is radiologically smaller than 2.0 cm, a consolidation/tumor (C/T) of >0.25 is known to indicate radiological invasiveness, since it reflects pathological invasiveness with very high sensitivity (11). This finding is important in determining operative procedures, such as lobectomy or limited resection, such as segmentectomy or partial resection. However, the CT features of early-stage SCLC have not been fully clarified, and predicting SCLC, while discriminating it from other histologies (specifically ADC), would be useful for determining the optimal treatment strategies for small pulmonary nodules for which the preoperative diagnosis is not determined.
In the study, we investigated CT characteristics, such as surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation, in a total of 17 SCLC patients and 296 ADC patients. All of the patients had undergone resection for tumors smaller than 3.0 cm in size and had undergone preoperative thin-section CT. The CT and histological findings were compared
Patients and Methods
Patients. We retrospectively examined patients who underwent surgical resection of primary lung SCLC and ADC between January 2003 and December 2012 at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University. The study population included 17 patients with SCLC and 296 patients with ADC whose resected tumors were smaller than 3.0 cm and who had undergone preoperative thin-section CT. The CT characteristics of the patients, such as convergence, surrounding GGO, air bronchogram, notching, pleural indentation, spiculation and cavitation, were analyzed. The clinicopathological features, including age at surgery, gender, smoking history, radiological tumor diameter, pathologic tumor-node-metastasis (TNM) stage (seventh edition of the lung cancer staging system), were examined. Briefly, systemic dissection of the hilar and mediastinal lymph nodes was performed at the same time as pulmonary lobectomy. Perioperative therapy was administered in compliance with the clinical practice guidelines for lung cancer in Japan. After surgery, routine checkups, including a physical examination, blood tests (including serum tumor marker levels) and chest X-ray, were performed at 3-month intervals for the first 3 years and at 6-month intervals thereafter. CT was performed twice a year for the first 3 years and then at least annually thereafter. The clinical information and follow-up data were obtained from the patients' medical records. This study was approved by our institutional review board.
Chest CT. Chest CT was performed in the supine position during inspiratory breath-hold using various multi-detector row scanners: Aquilion 4 (TOSHIBA), Aquilion 64 (TOSHIBA), Aquilion ONE (TOSHIBA), Aquilion ONE Vision (TOSHIBA), SOMATOM Plus4 Volume Zoom (SIEMENS), Briliance CT (Phillips), Briliance iCT (Phillips). The imaging parameters for thin-section CT were as follows: tube voltage, tube current; 100-500 mA; 120 kVp; scan field of view (FOV), 320 to 360 mm; slice-thickness, 2 mm. A real exposure control (TOSHIBA) or automatic exposure control (SIEMENS and Phillips) was added in each study. All of the CT data sets were transferred to a Picture Archiving and Communication System (PACS), which was accessible by the workstations (Volume Analyzer, SYNAPSE-VINCENT, Fujifilm, Tokyo) with a specialized application for the lungs. G.T., K.T. and M.K. evaluated all of the CT images, and if the independent assessments did not agree, the slides were reviewed together to achieve consensus. The consensus judgments were adopted as the final results.
Statistical analysis. Associations between the histology and the patient characteristics were analyzed using Fisher's exact test. Univariate and multivariate analyses of the relationship between the histology and the CT features of convergence, surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation were performed using a logistic regression analysis with backward elimination. All statistical analyses were conducted using the JMP version 12 software program (SAS Institute, Cary, NC, USA). p-Values of <0.05 were considered to indicate statistically significant differences.
Results
Clinicopathological characteristics of the patients with SCLC and ADC. Table I shows the clinicopathological features of the patients who were examined in the current study. The median age of 17 SCLC and 296 ADC patients was 66 and 69 years (ranges were 60-84 and 29-85 years, respectively), respectively. The SCLC group included a significantly higher percentage of male patients than the ADC group (82.4% and 48.0%, p=0.006), while 88.2% of the SCLC patients and 49.3% of the ADC patients had a history of smoking (p=0.006). There were no significant differences in the tumor sizes of the patients between SCLC and ADC. Lymph node metastasis was observed more frequently in SCLC than in ADC (47.1% and 14.2%, p=0.002). There were significant differences in the rates of lymphatic invasion (p=0.038) and vascular invasion (p=0.040) in the patients with SCLC and ADC, but no significant difference was observed in the rates of pleural indentation (p=0.194).
Relationship between histology and CT features. Among the 17 patients with SCLC, convergence, surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation were observed in one (47.1%), one (5.9%), three (17.6%), 12 (70.6%), four (23.5%), two (11.8%), and one (5.9%) patient, respectively (Table II). With regard to the 296 patients with ADC, convergence, surrounding GGO, air bronchogram, notching, pleural indentation, spiculation, and cavitation were observed in 177 (59.8%), 156 (52.7%), 227 (76.7%), 87 (29.4%), 223 (75.3%), 114 (38.5%), and 39 (13.2%) patients, respectively (Table II). A univariate analysis demonstrated that SCLC was significantly associated with the presence of notching (odds ratio [OR], 5.766; 95% confidence interval [CI], 2.072-18.569; p<0.001) and the absence of surrounding GGO (OR, 0.056; 95% CI, 0.003-0.280; p<0.001), air bronchogram (OR, 0.065; 95% CI, 0.015-0.207; p<0.001), pleural indentation (OR, 0.101; 95% CI, 0.028-0.295; p<0.0001), and spiculation (OR, 0.213; 95% CI, 0.033-0.773; p=0.016) in comparison to ADC (Table II). The following factors remained significant in a multivariate analysis: the presence of notching (OR, 5.145; 95% CI, 1.403-22.094; p<0.001) and the absence of surrounding GGO (OR, 0.088; 95% CI, 0.004-0.578; p=0.009), air bronchogram (OR, 0.195; 95% CI, 0.039-0.767; p=0.019), pleural indentation (OR, 0.181; 95% CI, 0.041-0.693; p=0.012), and spiculation (OR, 0.164; 95% CI, 0.022-0.806; p=0.025; Table III).
CT features according to radiological tumor diameter. A subset analysis according to the tumor size (≤2.0 cm or >2.0 cm) was performed. Tables III and IV show the CT features of the SCLC and ADC patients according to the radiological tumor diameter (≤2.0 cm or >2.0 cm). Fisher's exact test revealed that the tumor diameter did not exert a significant effect on the rates at which the seven CT features were observed among the SCLC patients (Table III). In contrast, the tumor diameter significantly affected the frequency of convergence, air bronchogram, pleural indentation, and spiculation in patients with ADC (Table IV).
Discussion
The present study demonstrated that the SCLC histology presenting as pulmonary nodular shadows of ≤3.0 cm in size was significantly associated with the presence of notching and the absence of surrounding, air bronchogram, pleural indentation, and spiculation. in comparison to patients with ADC. To our knowledge, this is the first study to show the close association between the CT characteristics and histological SCLC of ≤3.0 cm. The findings obtained in the present study are considered beneficial in differentiating SCLC from other histologies, specifically ADC, before surgery in light of determining optimal treatment strategies.
Furthermore, the findings may help determine whether a more invasive examination, including CT-guided biopsy, is necessary for making an exact diagnosis in high-risk patients, such as elderly individuals and those with a poor performance status or a bleeding tendency. As described above, the indication for surgical resection in SCLC patients is generally confined to clinical stage I (6-9); while chemotherapy and radiotherapy are the standard-of-care in the treatment of SCLC. Given the finding in the present study that as many as 47.1% of the patients with SCLC were positive for lymph node metastasis in contrast to the low frequency of lymph node metastasis in ADC (14.2%), patients with lymph node metastasis-positive SCLC should have been treated with chemoradiotherapy instead of surgical resection, if the exact diagnosis had been clarified. Thus, pulmonary nodular shadows of ≤3.0 cm in size with findings that are suggestive of SCLC should be aggressively diagnosed to determine the optimal treatment strategy.
There are several possible reasons for the association between the histology of SCLC and the CT features, such as the presence of notching and the lower incidence of surrounding GGO and air bronchogram. The notch sign reflects the expansive growth of the tumor and is a CT finding that is known to predict malignancy, since they indicate different growth rates with various cells at the periphery of the tumor (12, 13). Given the more proliferative nature of SCLC in comparison to ADC, our result showing that notching was found in SCLC more frequently than in ADC appears to be reasonable. Intriguingly, as shown in Table III, the incidence of notching in SCLC was not significantly affected by the tumor size. Future investigations are warranted to confirm these findings.
Surrounding GGO can be seen in tumors (specifically adenocarcinomas) with a replacement growth pattern of alveolar lining cells (14). In addition, air bronchogram is not found in invasive tumors that destroy the alveolar septa, bronchi, or vasculature. Our study demonstrated the lower incidence of surrounding GGO and air bronchogram in SCLC histology in comparison to ADC. Surrounding GGO was observed in 5.9% and 52.7% of the patients with SCLC and ADC, respectively; while air bronchogram was observed in 17.6% and 76.7% of the patients, respectively. This suggests that SCLC, which does not grow in a manner that replaces the alveolar lining cells. This is in line with the pathological features of SCLC, i.e., histologically destructive and proliferative nature.
The present study is associated with several limitations. First, it was a retrospective study that was performed in a single institution and only 17 cases of resected SCLC ≤3.0 cm in size were included. However, we did examine a relatively large group of patients with resected ADC (n=296). Thus, further studies in a larger cohort of SCLC patients will be needed to validate the present results. Second, the present study focused on SCLC and ADC. Third, surgically resected cases, not advanced cases, were enrolled in the present study. Thus, our findings might not represent the radiological features of advanced SCLC.
In conclusion, the CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation, and spiculation were observed less frequently than in ADC. The obtained findings may help predict SCLC histology on CT, eventually determine the optimal treatment strategies prior to surgical resection.
Acknowledgements
The Authors thank Brian T. Quinn for his critical comments on the manuscript.
Footnotes
Conflicts of Interest
The Authors declare no conflicts of interest in association with this study.
- Received December 9, 2016.
- Revision received January 19, 2017.
- Accepted January 25, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved