Lung cancer is the leading cause of cancer-related mortality around the world. When it is diagnosed, only a small number of lung cancer patients present with early-stage disease that is resectable by surgery. Most patients present with advanced disease and are faced with a dismal prognosis and a life expectancy of less than 1–2 years.1–4 In recent years, more people have undergone high-resolution computed tomography (HRCT) with a physical check-up, hoping to detect lung cancer at an earlier stage. This has resulted in an increasing number of patients being detected with pulmonary ground-glass opacity (GGO) lesions that were not previously visualized by conventional radiography methods.5,6 A GGO lesion is characterized by an area of haziness with preservation of bronchial and vascular margins.7,8 The pathological components of GGOs have usually been diagnosed as papillary adenocarcinomas, bronchioloalveolar carcinomas (BACs), atypical adenomatous hyperplasias (AAHs), and organizing pneumonias.9
Many patients with risk factors chose to undergo surgical resection for the GGOs; however, management and treatment guidelines for GGO lesions are still lacking. Furthermore, there are only a few reports in the literature that present the surgical outcomes of GGO lesions.10–12 In this study, we retrospectively reviewed the clinical and pathological characteristics and the surgical outcomes of patients undergoing resection for GGOs in our institute.
We retrospectively reviewed the chart records of our patients who presented with GGOs and received surgical resection at the Taipei Veterans General Hospital (Taipei, Taiwan) between January 2004 and December 2008. Patients undergoing resection for a solitary pulmonary GGO for a tumor of 3 cm or less were included. For mixed GGOs, only nodules with less than 50% solid part at the maximal lesion diameter were included (Fig. 1). Patients with solid tumors were excluded. Patients with a past history of lung cancer, multiple GGOs at presentation, or GGOs accompanying large solid tumor were also excluded.
All patients underwent physical examination, chest radiograph, and chest computed tomography (CT) scan. They also provided extensive medical history information. Laboratory studies, electrocardiography, spirometry, and sputum cytologic studies were also obtained. A small proportion of patients underwent a positron emission tomography (PET) scan at their request. All patients had complete pulmonary function testing. Most patients older than 50 years had a cardiac persantin scan.
All patients underwent a complete resection of the pulmonary GGO with mediastinal lymph node dissection or sampling. Histological typing was based on the 2004 World Health Organization classification.13,14 Disease stages were designated, based on the TNM classification by the American Joint Committee on Cancer and the International Union Against Cancer.15 The new classification of lung adenocarcinoma—proposed by International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS)—was used for histological classification.16
For statistical analysis of survival, the Kaplan-Meier method with a log-rank test and the Cox proportional hazard model were used. All statistical analyses were performed by using SPSS software (Version 19.0; SPSS Inc., Chicago, IL, USA).
Fifty patients were eligible and were included in the study. There were 46 (92.0%) patients who had malignant lesions and only four (8.0%) patients who had benign lesions. Table 1 summarizes the clinical characteristics of the patients. Most patients in both groups were nonsmokers. For five patients in the malignant group, two patients had gastric cancers, one patient had breast cancer, one patient had tonsillar cancer, and one patient had lymphoma. The only patient with a previous malignancy in the benign group had breast cancer.
The mean interval between the time of the first CT scan and the operation was 4.56 months (Table 2), and the time range was 0.13–4.3 months. Forty-three (86%) patients underwent surgery almost immediately after the GGO lesion was detected by the initial HRCT scan. The remaining seven patients underwent surgery after the second HRCT performed 3 months later. Of these seven patients, four patients remained stable (the follow-up times were 8.1 months, 17.9 months, 3.46 months, and 16 months), but the cancer of the other three patients had progressed by the second HRCT (the follow-up times were 11.36 months, 31.9 months, and 32.4 months).
Table 3 lists the surgical interventions used for these patients. Most patients received an intraoperative diagnosis by frozen section. Only five patients received a preoperative tissue proof either by CT-guided biopsy or by bronchoscopic transbronchial lung biopsy. Thirty-nine (84.8%) of 46 patients diagnosed with lung cancer received a lobectomy, whereas the remaining seven (15.2%) patients underwent a sublobar resection. Wedge resection was performed in four patients with benign lesions. The right upper lobe and left upper lobe were the most common sites for lung cancer tumors. No surgical mortality occurred and there were only three complications: one patient had postoperative upper gastrointestinal bleeding and two patients had prolonged chest tube insertion because of a persistent air leak. The overall complication rate was low at 6%.
Table 4 lists the pathological characteristics of the 46 patients with lung cancer. The most common histological pattern was the papillary predominant type (52.2%), followed by the acinar predominant type (28.3%) and the lepidic predominant type (17.4%). One patient had an adenocarcinoma mixed with small-cell carcinoma. There was no adenocarcinoma in situ or minimally invasive adenocarcinomas identified in our cohort. There was a low percentage of patients with lymphocytic infiltration, angiolymphatic spreading, perineural invasion, and tumor necrosis. Two patients were diagnosed as having PL2 visceral pleural invasion and seven patients were diagnosed as having PL1 visceral pleural invasion. The patients' stage was placed at T2aN0M0 (Stage IB). The other 43 patients were placed at T1a-bN0M0 (Stage IA). There was no nodal involvement in any of the 46 patients.
Table 5 lists the pathological characteristics of the four benign tumors. All four tumors were less than 20 mm. There were two cases of hyalinized granulomas, one case of mild fibrosis, and one case of necrotizing granulomatous inflammation with cryptococcus infection.
The median follow-up time was 4.46 years (range, 2.77–6.75 years), and the five-year overall survival rate for the patients was 97.6% (Fig. 2). During the follow-up period, only one patient died of a disease other than lung cancer, making the disease-specific survival rate 100%. There was also no evidence of disease recurrence during the follow-up period and the disease-free survival rate was 100%.
The addition of chest CT to an otherwise routine physical checkup has increased the number of patients being diagnosed with GGO lesions. However, there is no widely accepted definition of a GGO lesion. In our study, lesions in which vascular structures were recognized were defined as GGO, and tumors with less than 50% solid part at the maximal diameter were included.
Pulmonary GGOs are reportedly slow-growing tumors. The current strategy for the management of GGOs remains controversial. During a ten-year period, Min et al17 demonstrated a stepwise evolution from a focal pure pulmonary GGO to an invasive lung adenocarcinoma. Yoshida et al18 report that GGOs are slow growing and frequently remain unchanged for several years; therefore, they recommend a watchful waiting strategy for pulmonary GGO lesions. Detterbeck et al19 stated that surgical intervention is advised if a pure GGO lesion is more than 10 mm in diameter or if it presents with a solid component. In our cohort, most patients underwent surgery almost immediately after the first chest CT examination. Of the few patients who chose to undergo more than one CT, more than one-half of them presented with no interval change.
In the current study, we presented the surgical outcomes of GGOs. Only five (10%) of 50 patients underwent CT-guided biopsy or bronchoscopic biopsy to obtain pathological proof prior to surgery. The remaining patients had no preoperative biopsy for a variety of reasons such as difficult surgical approach because of a tumor's small size or location, and because of the risks of complications and tumor seeding. Of the 50 patients with GGO lesions, 46 (92%) of the patients had malignant tumors. This further supports that the likelihood of malignancy is extremely high in patients with GGOs.
Clinical frequencies have been reported in the literature by using the new IASLC/ATS/ERS (The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society) classification for lung adenocarcinoma.20,21 In patients with Stage I lung adenocarcinomas, Yoshizawa et al20 reported that the frequencies of lepidic, acinar, papillary, micropapillary, and solid predominant patterns were 5.6%, 45.1%, 27.8%, 2.3%, and 13.0%, respectively. In Stages I–IV lung adenocarcinomas, Warth et al21 reported that the frequencies of lepidic, acinar, papillary, micropapillary, and solid predominant patterns were 8.1%, 42.5%, 4.7%, 6.8%, and 37.6%, respectively. In our current cohort of GGO lesions of 3 cm or less, the frequencies of lepidic, acinar, and papillary predominant patterns were 17.4%, 28.3%, and 52.2%, respectively. No micropapillary predominant or solid predominant pattern were identified in our study.
Park et al22 reported an excellent prognosis in a cohort of 58 patients with malignant pure GGOs who underwent surgical resection. There was no incidence of local recurrence or metastasis occurring in any of these patients after 24 months of follow up. Kondo et al23 and Ichiki et al24 also demonstrated a 100% five-year survival rate for patients with resected malignant GGO lesions. In our study, the median follow-up time was 4.46 years after surgery. No procedure-related deaths or complications were observed. Of the 46 patients with malignant tumors, only one patient died of another cause. The overall survival, disease-free survival, and disease-specific survival were extremely good in our patients with GGO who were treated with surgery. We also demonstrated that surgery for GGO patients can be conducted in a safe manner.
There were some limitations in our study. It is retrospective in nature and the number of cases was rather small. Selection bias may exist when choosing patients with GGO for surgery. A longer follow-up time is also needed. We were also lacking data concerning patients who opt to follow-up their GGOs for an extended duration.
In conclusion, there is a high percentage of malignancy associated with pulmonary GGOs. However, the prognosis for the patients undergoing surgical resection is excellent. Of the various alternatives available for medical treatment of GGOs, surgery appears to be one of the best options. Further study is necessary to define more effectively GGO lesions and establish guidelines to treat the patients with GGOs detected by HRCT.
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