|Year : 2020 | Volume
| Issue : 5 | Page : 177-183
Solid-predominant ground-glass opacity has a higher recurrence rate
Hsin-Ju Han1, Han-Shui Hsu2, Yi-Han Lin3
1 Department of Surgery, Taipei Veterans General Hospital, Taoyuan, Taiwan
2 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital; School of Medicine, Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taoyuan, Taiwan
3 School of Medicine, Institute of Emergency and Critical Care Medicine, National Yang-Ming University; Division of Thoracic Surgery, Department of Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan
|Date of Submission||30-Mar-2020|
|Date of Decision||04-May-2020|
|Date of Acceptance||21-Jul-2020|
|Date of Web Publication||19-Oct-2020|
Division of Thoracic Surgery, Department of Surgery, Min-Sheng General Hospital, Taoyuan; Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei 100116
Source of Support: None, Conflict of Interest: None
Background: Although it is generally considered that ground-glass opacity (GGO) is less invasive and sublobar resection is adopted, recurrence still occurs in these patients. The risk factors that affect GGO recurrence need to be re-evaluated.Materials and Methods: We collect retrospectively the data of GGO patients and study the risk factors of tumor recurrence. Patients with T1N0M0 lung adenocarcinoma who underwent lung resection from 2011 to 2016 were enrolled in the study. The collected variables included GGO size, solid part size, consolidation/tumor ratio (CTR), clinical T stage, surgical procedure, and pathology report, from which the risk factors affecting tumor recurrence were analyzed.Results: A total of 28 recurred in 694 patients. Risk factors include age, tumor size, solid part size, CTR ≧50%, and surgical procedures. After multivariate analysis, the only risk factor was CTR ≧50% that will affect tumor recurrence (hazard ratio: 6.789, P < 0.001).Conclusion: CTR ≧50% is a risk factor affecting GGO recurrence. Clinicians should be more careful with such tumors.
Keywords: Ground-glass opacity, histology, lung tumor, lymph node, recurrence, staging
|How to cite this article:|
Han HJ, Hsu HS, Lin YH. Solid-predominant ground-glass opacity has a higher recurrence rate. Formos J Surg 2020;53:177-83
| Introduction|| |
Lung cancer is one of the most prevalent cancers in the world, and it is the third most prevalent cancer in Taiwan., Early lung cancer is mostly asymptomatic, but mortality from advanced lung cancer is extremely high. Although lung cancer has a high mortality rate, screening with computed tomography (CT) and early surgical treatment can reduce mortality by 20% and extend patient life expectancy.,, According to the National Comprehensive Cancer Network (NCCN) guideline, the standard treatment for lung cancer is lobectomy plus radical lymph node dissection. However, many studies have pointed out that ground-glass opacity (GGO)-type lung cancer has a good prognosis and low recurrence rate., The lobectomy can cause the patient's lung function to decline and reduce the quality of life. The sublobar resection is also recommended for peripheral type GGO.,,, However, Ginsberg and Rubinsteincriticized sublobar resection as increasing the recurrence rate of lung cancer. We should reanalyze the risk factors that affect GGO recurrence to assess the most appropriate treatment.
| Subjects and Methods|| |
From 2011 to 2016, patients who underwent lung surgery at Taipei Veterans General Hospital were included in the study. Exclusion criteria were benign tumors, metastatic tumors, received chemotherapy or radiation therapy before surgery, lack of preoperative CT, and solid tumors. Among primary lung tumors, clinical T2 stage, clinical N positive stage, death during hospitalization, and other cancers other than lung adenocarcinoma were excluded. Clinically, patients with T1N0 lung adenocarcinoma and a GGO component will be included in the analysis. All data were approved by the Institutional Review Board of Taipei Veterans General Hospital (Approve number: 2020-03-008AC). It is a retrospective study and the informed consent was waived by Institutional Review Board. The mean following period was 43.2 months.
In the study, we collected basic information such as the patient's age, gender, smoking history, and family history. The nodules were evaluated with chest CT with a high-frequency algorithm analysis. All CT images were tested with lung window (level, 550 Housfield unit (HU); width, 1600 HU) and mediastinum window (level, 40 HU; width, 400 HU). The CT thickness ranged from 1 mm to 5 mm. The Suzuki's classification was applied. Class I or II GGOs were categorized as pure GGO group, and Class III, IV, or V GGOs were categorized as part-solid GGO group. Class VI, so-called pure solid nodule, was excluded from the study. The part-solid GGOs were divided into GGO-predominant and solid-predominant groups by consolidation/tumor ratio (CTR) ≧50% or <50%. The patient's clinical T stage, surgical procedure, harvested lymph node station and numbers, pathologic T stage, pathologic N stage, and cytology category were also collected in this study. The staging system was based on the International Association of Study of Lung Cancer: 8th edition of the tumor-node-metastasis classification. Patients were followed up for chest CT every 3–6 months after surgery, every 6 months after 2 years, and every year after 5 years. Locoregional metastasis may be considered if the staple margin is thickened, new nodule hyperplasia occurs in the lung, or mediastinal cavity lymph nodes are enlarged during the tracking process. The clinician will arrange a biopsy or continuous follow-up as appropriate. For patients with bone pain, altered consciousness, and other symptoms of distal bone or brain metastases, the clinician will also arrange for additional positron emission tomography/CT or brain magnetic resonance imaging to check for distal metastases.
| Results|| |
A total of 2644 people were included in this study. Of these patients, 690 were metastatic tumors, 23 had preoperative chemotherapy or radiation therapy, 13 had no preoperative CT, and 1140 had solid nodules under chest CT. There were 46 patients classified as clinical T2 stage, 21 patients were clinical lymph node metastasis, 3 patients died during hospitalization, and 14 patients were cancer types other than lung adenocarcinoma. A total of 694 patients with clinical T1N0 lung adenocarcinoma and a GGO component were included in the study [Figure 1].
|Figure 1: Flow diagram of the study patients. The patients were separated as pure GGO group, GGO-predominant group, and solid-predominant GGO group according to their solid-part diameter ratio. GGO: Ground-glass opacity|
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The patient's basic information is presented in [Table 1]. The mean age was 60.7 ± 10.7 years, female (61.4%) predominant. About 17.3% had a history of smoking and 15.0% had a family history. The average GGO size is 1.49 ± 0.66 cm, the average solid size is 0.51 ± 0.65 cm, and the average CTR is 0.27 ± 0.31. The number and stations of the lymph node were 12.9 ± 8.2 and 4.0 ± 1.7, respectively. The T stage of patients was mainly T0 and T1a (46.9%). Lymph node metastasis was found in 2.2% of patients, and micropapillary or solid component was found on histological examination in 13.7% of patients.
|Table 1: Demographics for patients with clinical T1N0 adenocarcinoma with ground-glass opacity component|
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In [Table 2], patients were divided into no recurrence group and recurrence group to analyze the risk factors of recurrence. The recurrence group had a larger mean age (67.4 ± 10.2 vs. 60.4 ± 10.7, P = 0.001), larger GGO size (2.18 ± 0.53 vs. 1.46 ± 0.65 cm, P < 0.001), larger solid part size (1.44 ± 0.57 vs. 0.47 ± 0.62 cm, P < 0.001), larger CTR (0.66 ± 0.20 vs. 0.25 ± 0.30, P < 0.001), and more clinical T1c ratios (53.6 vs. 20.6%, P < 0.001). The no recurrence group had a higher ratio of pT0 + pT1a (48.0% vs. 21.4%, P = 0.001) and a lower ratio of pN1 + pN2 (1.7% vs. 14.2%, P < 0.001). Of these recurrence patients, 17 were locoregional recurrence and 11 patients were distant metastasis, and no variables significantly affected the difference between the two types of difference.
|Table 2: Demographics for patients with clinical T1N0 adenocarcinoma with ground-glass opacity component with/without recurrence|
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Multivariate analysis showed that the patient's age ≧65 years, clinical T stage, and surgical procedure did not affect recurrence. Moreover, CTR ≧50% is the only risk factor that will affect the patient's recurrence (hazard ratio [HR]: 6.789, P < 0.001) [Table 3]. In the log-rank test analysis, the disease-free interval and overall survival of the CTR ≧50% group were significantly worse (P< 0.001, P = 0.050) [Figure 2]. There were five tumor recurrences (including 3 T1b and 2 T1c) in the CTR <50% group and 23 tumor recurrences (including 7 T1b, 5 T1c, and 11 T2a) in the CTR ≧50% group. In the CTR <0% group, 2 patients suffered from cancer-specific death during follow-up (including 1 T1b and 1 T1c), and in the CTR ≧50% group, 8 patients suffered from cancer-specific death during follow-up (including 3 T1b, 1 T1c, and 4 T2a).
|Table 3: Multiple Cox regression for the ground-glass opacity patients with recurrence|
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|Figure 2: (a) Disease-free interval survival curve for GGO patients. (b) Overall survival curve for GGO patients. GGO: Ground-glass opacity. There were five tumor recurrences (including 3 T1b and 2 T1c) in the CTR <50% group and 23 tumor recurrences (including 7 T1b, 5 T1c and 11 T2a) in the CTR ≧50% group. In the CTR <50% group, two patients suffered from cancer-specific death during follow-up (including 1 T1b and 1 T1c), and in the CTR ≧50% group, 8 patients suffered from cancer-specific death during follow-up (including 3 T1b, 1 T1c, and 4 T2a)|
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| Discussion|| |
For early lung cancer, lobectomy plus radical lymph node dissection is the standard treatment. Ginsberg and Robinstein reported a randomized study that when compared with wedge resection, the lobectomy method reduced the tumor recurrence rate and mortality rate in clinical T1N0 non-small cell lung cancer patients., In the NCCN guideline, the sublobar resection is also only recommended for use in peripheral GGO. Lobectomy provided better treatment results, but it sacrificed a lot of lung function. Compared to lobectomy, although the sublobar resection has a higher recurrence rate and mortality rate, it can retain more lung function. More and more studies have pointed out that sublobar resection can be applied to GGO patients.,,,, For GGO patients, the risk factors that affect tumor recurrence remain controversial. We need to clarify which risk factors affect tumor recurrence to help us to obtain a better clinical diagnosis.,,,
In our study, the patients were majorly about 60-year old, female predominant, nonsmoker, and no family history. The characteristics of these patients are consistent with the previous study. Under the chest CT examination, the mean CTR was 0.27, and most nodules were GGO predominant rather than solid predominant. The sublobar resection patient number was 377 (54.3%) which was compatible with the NCCN guideline that sublobar resection is feasible with peripheral GGO-predominant nodules. Lobectomy patients all received radical lymph node dissection and most patients of sublobar resection received lymph node sampling. Pathologic T stage showed that 22.2% of patients were classified as T2a because of tumor invasion to visceral pleura and 0.4% of patients were classified as T3 because of tumor metastasis in the lung lobe. The pathologic lymph node metastasis rate was 2.2% which was compatible with previous studies that most GGOs did not present lymph node metastasis.,, The presence of micropapillary or solid histology ratio is relatively low in these GGO patients which was also compatible with Hattori et al. report that the GGO represents lepidic predominant adenocarcinoma.
To study the cause of tumor recurrence, all GGO patients were divided into no recurrence group and recurrence group for further research. In the recurrence group, the patient presented an older age than nonrecurrence group. A possible explanation is the GGO represents as an early-stage lung cancer, and it grows with time., If the onset time is the same in different groups, older patients have a longer time to disease progression. There were no significant differences in the recurrence of the disease between gender, smoking history, and family history. In terms of tumor size, the recurrence group had a larger GGO size, a larger solid-type size, a larger CTR, and a more advanced clinical T stage. This is consistent with previous research results.,, In the recurrence group, most patients received lobectomy, a higher rate than in the nonrecurrence group. This may be due to the larger tumor size, the larger CTR, and the more aggressive clinical T stage in the recurrence group. Despite the higher lobectomy rate in the recurrence group, there was no significant difference in the stations and number of lymph nodes harvested between the two groups. The recurrence group had a higher ratio of pathologic T stage, pathologic N stage, and micropapillary or solid pattern. This result is consistent with the previous studies.,
To identify the risk factors that affect tumor recurrence, we performed a further multivariate analysis. In the multivariate analysis, we analyzed variables such as age less/>65 years, CTR less/greater than 50%, clinical T stage, and surgical methods. The results showed that age, clinical T stage, and surgical procedure did not affect tumor recurrence or not. The only cause of tumor recurrence was CTR ≧50% (HR: 6.789, P < 0.001). After multivariate analysis, the age did not affect the patient's recurrence. This result is consistent with the previous studies., Clinical T stage is often an indicator for predicting the prognosis of patients, and then, previous studies have pointed out that most tumors with GGO properties are lepidic predominant adenocarcinoma.,,, It may be because the nature of GGO represents lepidic predominant adenocarcinoma, and the recurrence rate of this type of tumor is low, so it is difficult to evaluate the recurrence rate of patients if only looking at the clinical T stage., Ginsberg's research shows that wedge resection increases the chance of tumor recurrence. However, some studies have pointed out that for patients with Stage IA, the surgical procedure does not affect the patient's prognosis., In these studies, the authors did not separate ground-glass lesions from solid tumors.,, Many studies have pointed out that tumors with GGO properties have a better prognosis than solid tumors., It may be because they mixed two different types of tumors to discuss, and with the different proportions of GGO tumors, they have different research results.
CTR ≧50% is the only factor affecting the prognosis of patients. Many previous studies have pointed out that the GGO part of lung adenocarcinoma represents lepidic type adenocarcinoma, while the solid part represents invasive type adenocarcinoma.,, It can be seen from the patient's survival curve that the disease-free interval of patients with CTR ≧50% is significantly worse, but there is no significant difference in the overall survival. This may be due to the lower mortality of early-stage lung adenocarcinoma, although the recurrence rate is higher in patients with CTR ≧50%. After further chemotherapy or targeted treatment, the tumor is often controlled. Although there were no significant differences in overall survival rates in this study, statistically significant differences may only become apparent with a larger sample size.
Of the 28 recurrence patients, 14 were locoregional recurrence, 13 were distant metastasis, and 1 combined locoregional recurrence and distant metastasis. The patient's CTR and surgical procedure will not affect whether it is locoregional recurrence or distant metastasis.
This study has several limitations: (1) the retrospective study excluded patients due to missing data and (2) some GGO patients choose lobectomy because of the tumor location. There is no certain standard for the choice of surgical method. Despite these limitations, our study shows that GGO with a CTR ≧50% has a poor prognosis and recommends that clinicians adopt more appropriate tracking cycles and treatments. Once tumor recurrence is detected, early treatment can still improve patient survival.
| Conclusion|| |
For Stage I lung adenocarcinoma, patient age, tumor size, CTR, and surgical procedures are all risk factors that affect tumor recurrence. However, after multivariate analysis, only CTR ≧50% will affect tumor recurrence. When clinicians judge the treatment of GGO, CTR ≧50% should be listed as the highest priority factor. A shorter tracking interval or adjuvant therapy after surgery is arranged to achieve better treatment results.
We thank the Department of Surgery of Taipei Veterans General Hospital and the Institute of Emergency and Critical Care at National Yang-Ming University of their guidance on this research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]