肺磨玻璃结节的影像学、病理学特点及临床管理

随着CT应用于肺癌的筛查,检出了越来越多的肺癌玻璃结节（GGO）,不过这其中良恶性混杂,让人难以辨识。而本文总结了现今最新的GGO影像学及病理学特点,发现这两者之间并非绝无联系。同时我们还回顾了多个学会的最新指南,讨论了GGO的管理及随访。此外有创的活检和GGO标记后手术切除是亟待发展的领域。早期肺癌的标准治疗仍是微创的肺叶切除及淋巴结清扫术,不过近来有研究表明亚肺叶切除也有一定的可行性,这或许会引领未来肺癌的治疗方向。     

Correlation between computed tomography findings and epidermal growth factor receptor and KRAS gene mutations in patients with pulmonary adenocarcinoma

We examined the correlation between computed tomography (CT) findings and the incidence of epidermal growth factor receptor (EGFR) and KRAS mutations in lung adenocarcinoma. We analyzed the tumors of 136 patients with surgically resected primary lung adenocarcinoma. CT scans were evaluated for the presence of ground grass opacity (GGO), spiculation and the maximum diameter of the tumor was measured. SMart Amplification Process (ver. 2) was used to detect the presence of EGFR and KRAS mutations. EGFR and KRAS mutations were found in 56 (41.1%) and 25 (18.4%) of the 136 cases, respectively. Although no significant association was found between GGO and EGFR mutations (p=0.07), the EGFR mutation occurred more frequently in male patients with GGO than in those without GGO (p=0.04). The KRAS mutation occurred more frequently in patients whose tumor diameter was ≥ 31 mm than in those whose tumor diameter was <30 mm (p=0.003). Evaluation of CT findings may be helpful for determining the presence of EGFR and KRAS mutations, particularly when it is not possible to obtain a tumor specimen.     

Ground-glass opacity lesions on computed tomography during postoperative surveillance for primary non-small cell lung cancer

Improvement in chest high-resolution computed tomography (CT) has increased the detection of ground-glass opacity (GGO) lesions. However, there is no clear therapeutic consensus about concurrent GGO lesions detected during postoperative follow-up chest CT after treatment for primary lung cancer. This study retrospectively and prospectively investigated 21 patients in whom 53 GGO lesions were detected during postoperative follow-up CT of non-small cell lung cancer at Kyushu University Hospital from April 2009 to February 2010. We investigated clinicopathological factors, such as age, gender, lesion number, size, laterality, time of identification, and enlargement or emergence of the inner solid component. The malignancy rate of the concurrent GGO lesions was assessed by log-rank test in the Kaplan-Meier curves. Twenty percent of the 53 GGO lesions had malignant radiological findings during the 5-year follow-up after they were first identified by CT. The newly emerging GGO lesions at postoperative CT had significantly more malignant radiological findings (39.5%) than other GGO lesions (9.5%). Three potentially malignant GGO lesions were treated by surgical resection and three were treated by stereotactic radiotherapy. These six treated GGO lesions showed a good clinical course without recurrence after treatment. Special attention should be paid to newly emerging GGO lesions after resection of primary non-small cell lung cancer. It is necessary to select an appropriate treatment, taking account of various factors such as the laterality and number of GGO lesions or the pathological stage of the postoperative lung cancer.     

肺内磨玻璃影的分子生物学研究进展

近年来,低剂量CT广泛应用于早期肺癌的筛查,肺内磨玻璃影(ground-glass opacity,GGO)的检出率逐渐升高。多数学者认为它与早期肺腺癌密切相关,其定性诊断和早期治疗对于提高早期肺癌患者的诊断率与生存率具有重要意义。关于GGO的影像学诊断、定位方法及手术方式进展国内外已有许多报道,现重点将近年来与其分子生物学方面相关的研究进展综述如下。     

精准医学时代的肺癌外科治疗走向

精准医学是根据每个人从宏观到微观层面的个体差异,制定最为合适的个性化治疗方案。基因组、蛋白组、代谢组等海量生物学数据及大数据分析方法是精准医学模式的精髓。精准医学为人类攻克肿瘤带来了希望。肺癌是对人类危害最大的肿瘤。本文就肺癌的外科治疗在精准医学时代发展的方向进行了综述。     

Multiple "slow" CT scans for incorporating lung tumor mobility in radiotherapy planning.

PURPOSE: The high local recurrence rates after radiotherapy in early-stage lung cancer may be due to geometric errors that arise when target volumes are generated using fast spiral CT scanners. A "slow" CT technique that generates more representative target volumes was evaluated. METHODS AND MATERIALS: Planning CT scans (slice thickness 3 mm, reconstruction index 2.5 mm) were performed during quiet respiration in 10 patients with peripheral lung lesions. Planning CT scans were repeated twice, followed by three slow CT scans (slice thickness 4 mm, index 3 mm, revolution time 4 s/slice). All, except the first scan, were limited to the tumor region. Three-dimensional registration of all scans was performed. The reproducibility of the imaged volumes was evaluated with each technique using (1) the common overlapping volume (COM), the component of the clinical target volume (CTV) covered by all three CT scans, and (2) the encompassing volume (SUM), which is the volume enveloped by all CTVs. RESULTS: In all patients, the target volumes generated using slow CT scans were larger than those derived using planning scans (mean ratio of planning-CTV:slow-CTV of 88.8% +/- 5.6%), and also more reproducible. The mean ratio of the respective COM:SUM volumes was 62.6% +/- 10.8% and 54.9% +/- 12.9%. CONCLUSIONS: Larger, and more reproducible, target volumes are generated for peripheral lung tumors with the use of slow CT scans, thereby indicating that slow scans can better capture tumor movement.     

Molecular markers and changes of computed tomography appearance in lung adenocarcinoma with ground-glass opacity

BACKGROUND: High-resolution computed tomography (HRCT) of lung adenocarcinoma at early stage shows pure ground-glass opacity (GGO) and most cases of pure GGO remain stable during follow-up. There is no consensus on the strategy for follow-up. Identification of the molecular mechanisms that are associated with the natural history of lung adenocarcinoma should provide useful information. METHODS: Twenty-three lung adenocarcinomas that were followed-up for more than 6 months pre-operatively by HRCT were included in this study. Patterns of radiological changes during the follow-up period were classified into three groups; type 1, pure GGO without consolidation; type 2, appearance or increase in consolidation within pure GGO; type 3, consolidation without pure GGO. Mutational analysis of the epidermal growth factor receptor (EGFR) and K-ras genes and immunohistochemical staining of p53 protein were performed. RESULTS: EGFR mutations were found in 17 cases (74%), and there was no K-ras mutation. Positive staining of p53 was found in 8 cases (35%). As for radiological findings during the follow-up period, the frequencies of EGFR mutations and positive p53 staining were 67 and 0% in type 1 (n = 9), 89 and 44% in type 2 (n = 9) and 60 and 80% in type 3 (n = 5). CONCLUSIONS: EGFR mutations were frequently found in lung adenocarcinoma with GGO on HRCT in this study. Inactivation of p53 may be associated with the appearance of central consolidation within pure GGO on HRCT which reflects invasive features and may be useful as a molecular marker during the follow-up of pure GGO.     

Relation between radiation-induced whole lung functional loss and regional structural changes in partial irradiated rat lung

PURPOSE: Radiation-induced pulmonary toxicity is characterized by dose, region, and time-dependent severe changes in lung morphology and function. This study sought to determine the relation between the structural and functional changes in the irradiated rat lung at three different phases after irradiation. MATERIALS AND METHODS: Six groups of animals were irradiated to 16-22 Gy to six different lung regions, each containing 50% of the total lung volume. Before and every 2 weeks after irradiation, the breathing rate (BR) was measured, and at Weeks 8, 26, and 38 CT was performed. From the computed tomography scans, the irradiated lung tissue was delineated using a computerized algorithm. A single quantitative measure for structural change was derived from changes of the mean and standard deviation of the density within the delineated lung. Subsequently, this was correlated with the BR in the corresponding phase. RESULTS: In the mediastinal and apex region, the BR and computed tomography density changes did not correlate in any phase. After lateral irradiation, the density changes always correlated with the BR; however, in all other regions, the density changes only correlated significantly (r(2) = 0.46-0.85, p < 0.05) with the BR in Week 26. CONCLUSION: Changes in pulmonary function correlated with the structural changes in the absence of confounding heart irradiation.     

Loco-regional differences in pulmonary function and density after partial rat lung irradiation.

PURPOSE: The purpose of this study was to explore regional differences in radiosensitivity of rat lung using lung function and computed tomography (CT) density as endpoints. METHODS: At first, CT scans were used to determine rat lung volumes. The data obtained enabled the design of accurate collimators to irradiate 50% of the total lung volume for the apex, base, left, right, mediastinal and lateral part of the lung. Male Wistar rats were irradiated with a single dose of 18 Gy of orthovoltage X-rays. Further rat thorax CT scans were made before and 4, 16, 26, and 52 weeks after irradiation to measure in vivo lung density changes indicative of lung damage. To evaluate overall lung function, breathing frequencies were measured biweekly starting 1 week before irradiation. RESULTS: Qualitative analysis of the CT scans showed clear density changes for all irradiated lung volumes, with the most prominent changes present in the mediastinal and left group at 26 weeks after radiation. Quantitative analysis using average density changes of whole lungs did not adequately describe the differences in radiation response between the treated groups. However, analysis of the density changes of the irradiated and non-irradiated regions of interest (ROI) more closely matched with the qualitative observations. Breathing frequencies (BF) were only increased after 50% left lung irradiation, indicating that the hypersensitivity of the mediastinal part as assessed by CT analysis, does not result in functional changes. CONCLUSIONS: For both BF and CT (best described by ROI analysis), differences in regional lung radiosensitivity were observed. The presentation of lung damage either as function loss or density changes do not necessarily coincide, meaning that for each endpoint the regional sensitivity may be different.     

永久性肺毛玻璃样结节的CT与组织病理学比较

为了结合组织病理学回顾性分析薄层CT下肺毛玻璃样结节(GGO)的特征,分析49例(53个结节)永久性肺毛玻璃样结节(GGO)患者的临床资料。CT扫描包括结节大小、形状、外形和内部特征。采用Kruskal-Wallis检验和Fisher检验分析结果。49例患者中32例共40个GGO(75.47%)为细支气管肺泡细胞癌(BAC)或以BAC为主要成分的腺癌,3个GGO(5.67%)为非典型腺瘤性增生,10个(18.87%)为非特异性肺纤维化。这3种疾病的薄层CT表现差异无统计学意义,P>0.05。大约75.47%的GGO为细支气管肺泡细胞癌(BAC)或以BAC为主要成分的腺癌,在薄层CT上的表现与其他类型的GGO没有明显形态学差异。     

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.

OBJECTIVE: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. PATIENTS AND METHODS: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. RESULTS: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07). CONCLUSIONS: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.     

Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer

Purpose: To assess the recovery from early local pulmonary injury after irradiation and to determine whether regional differences exist.

Methods:: For 110 patients treated for breast cancer or malignant lymphoma, single photon emission computed tomography (SPECT) perfusion and ventilation scans and CT scans were made before, 3, 18, and 48 months after radiotherapy. Dose-effect relations for changes in local perfusion, ventilation, and density were determined for each individual patient using spatially correlated SPECT and CT data sets, for each follow-up period. Average dose-effect relations for both subgroups were determined, as well as dose-effect relations for different regions.

Results: In general, partial improvement of local pulmonary injury was observed between 3 and 18 months for each of the three endpoints. After 18 months, no further improvement was seen. Patients with breast cancer and malignant lymphoma showed a similar improvement (except for the perfusion parameter), which was attributed to a recovery from the early radiation response and could not be explained by contraction effects of fibrosis of lung parenchyma. No regional differences in radiosensitivity 18 months after treatment were observed, except for the dorsal versus ventral region. This difference was attributed to a gravity-related effect in the measuring procedure.

Conclusion: For all patients, a partial recovery from early local perfusion, ventilation, and density changes, was seen between 3 and 18 months after radiotherapy. After 18 months, local lung function did not further improve (lymphoma patients).     

螺旋CT及其图像后处理技术在中央型肺癌分期中的应用

目的 利用螺旋CT及MPR、VRT、SCTA对中央型肺癌(CLC)行术前分期并与横断面图像对比,探讨其临床应用价值。方法 46例CLC行前瞻性的CT检查,取得气管支气管树及纵隔、肺门大血管MPR和VRT图像。盲法阅片,影像诊断结果与手术及病理结果进行了比较。结果横断面图像和后处理图像对于T分类的准确性分别为82．6％(38／6)和95．7％(44/46),χ2＝4．039,P＝0．044,差异有显著性。N分类中,除4例N3末证实外,其余42例的敏感性为75．0％,特异性为26．9％,准确性为45．2％。横断面分期与病理分期的符合率为58．7％(27／46),后处理图像与病理分期的符合率为67．4％(31／46),χ2＝0．746,P＝0．338,差异无显著性。结论 图像后处理技术在中心型肺癌T分类中与病理的符合率显著高于横断面,对淋巴结的定位也有一定意义。     

磨玻璃型肺癌诊治研究进展

低剂量螺旋CT筛查可以降低肺癌致死率，同时随着计算机成像技术的普及，越来越多的人在行肺CT检查时发现肺内结节，其中有一部分表现为磨玻璃样阴影。磨玻璃样结节(ground-glass opacity，GGO)在胸部CT上表现为肺密度云雾样增高，但不掩盖支气管及肺血管结构的阴影。GGO是一种非特异性表现，病因包括肿瘤、感染、局部出血或间质纤维化等。近年来，表现为局灶性GGO的早期肺癌发病率逐渐增高，特别是亚洲、女性及非吸烟患者。因此，有必要对表现为GGO的结节进行良恶性鉴别，为临床治疗制定指导决策。     

Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: a retrospective study on 64 patients

OBJECTIVE: We studied the prognostic importance of high-resolution CT (HRCT) findings in lung adenocarcinomas. PATIENTS AND METHODS: HRCT findings (lesion size, percentage of ground-glass opacity (GGO) areas of lesion, and presence or absence of lobulation, coarse spiculation, air space, pleural tag, and multiplicity of lesion), clinical data (age and surgical method), and pathologic findings (tumor subtypes and presence or absence of nodal metastasis) in 64 consecutive patients with 64 peripheral adenocarcinomas of 20 mm or less (mean, 13 mm), including 36 women and 28 men with a mean age of 64 years were analyzed and correlated with survival of the patients using Kaplan-Meier method and stepwise Cox proportional hazards modeling. Follow-up periods of the patients ranged from 6 to 45 months (mean, 22 months). Tumors were classified into six subtypes (types A-F) according to tumor growth patterns defined by Noguchi et al. RESULTS: Six (9%) of the 64 patients died of lung cancer. In univariate analyses, a significant difference was noted for lesion size (P=0.043), the percentage of GGO areas (P=0.005), and tumor subtypes (P=0.006). Lesion size of <15 mm (n=35), a lesion with GGO areas of >57% (n=36), and type A (n=16) or type B adenocarcinomas (n=16) indicated a significantly better survival. In multivariate analyses using these three parameters as independent variables, the percentage of GGO areas was the only significant independent factor for survival (P=0.044, relative risk=0.95). CONCLUSION: GGO areas measured on HRCT may have an independent prognostic significance of small adenocarcinomas of the lung.     

Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images

BACKGROUND: While pulmonary nodules can be substantially divided into solid and ground-glass opacity (GGO) ones on CT image, they have different biological natures which could cause false positive or false negative to diagnose malignancy on positron emission tomography with fluorodeoxyglucose (FDG-PET). To determine the effectiveness of PET for small pulmonary nodules, the nodules were classified into solid and GGO ones, of which results were compared with the data of PET scans. The lower limit size of nodules for PET imaging was also evaluated. METHODS: Prospective FDG-PET scans were undertaken for 136 non-calcified nodules less than 3 cm in diameter. CT density histograms were made for each nodule to classify into solid and GGO ones. RESULTS: Eighty-one nodules were malignant and 55 were benign. All of the 20 nodules less than 1 cm in diameter (n = 8 in malignant, n = 12 in benign), were negative on PET regardless of the histology. In the 116 nodules 1-3 cm in diameter (n = 73 in malignant, n = 43 in benign), there were 15 false negative and 15 false positive nodules, with a sensitivity of 79% and specificity of 65%. CT density histograms showed 101 solid nodules (n = 63 in malignant, n = 38 in benign) and 15 GGO nodules ( n = 10 in malignant, n = 5 in benign). All of the 10 malignant nodules with GGO images were histologically well-differentiated adenocarcinoma and 9 of them (90%) were false negative on PET. Four of the 5 (80%) benign nodules with GGO images were focal pneumonia with well-preserved air spaces, causing false positive on PET. Sensitivity and specificity for nodules with GGO images were 10 and 20%, respectively, which were significantly lower than 90 and 71% for nodules with solid images (P < 0.001). CONCLUSION: Pulmonary nodules which are less than 1cm in size or show GGO images on CT cannot be evaluated accurately by PET.     

Accumulation of 99mTc methylene diphosphonate in malignant pleural and ascitic effusion

Increased accumulation of radioactivity was observed in malignant pleural and ascitic effusion as to a patient with stomach cancer and in malignant pleural effusions as to 2 patients (1 with breast cancer and another with lung cancer) during the performance of routine whole-body bone scans with 99mTc methylene diphosphonate. This finding should strongly suggest malignancy.     

Screening, diagnosis, and staging of non-small cell lung cancer and consideration of unusual primary tumors of the lungs.

Refinements of computed tomographic (CT) scanning techniques, such as high-resolution CT, CT densitometry, and contrast enhancement CT, have been shown to improve diagnostic accuracy in differentiating between benign and malignant lung nodules. Unfortunately, none of these techniques is fail proof, and, even when a lesion is considered to be benign, periodic observation is mandatory. In staging the locoregional extent of lung cancer, magnetic resonance imaging has not been shown to be superior to CT scanning and should not be substituted for or used in addition to CT except in special situations. Transesophageal ultrasonography, which identifies additional mediastinal lymph nodes that are not visualized by CT scanning, may become an important adjunct in the clinical staging of the regional extent of the disease. Study findings have supported the value of pleural lavage cytology at thoracotomy. Additional studies of the technique as a prognostic factor should be conducted in patients with resected early-stage disease. The high incidence of cerebral metastasis in patients with adenocarcinoma and stage III disease suggests the possible value of routine use of CT scans in this subset of patients who, otherwise, have potentially resectable lung tumors. However, no evidence supports routine scanning in patients with stage I or II disease. The low sensitivity of abdominal CT scans in identifying adrenal metastatic involvement further decreases the value of using this examination routinely to identify occult adrenal metastatic disease.     

Procollagen-III in serum, plasminogen activation and fibronectin in bronchoalveolar lavage fluid during and following irradiation of human lung.

In the search for predictors of late radiation-induced lung injury we studied procollagen type III peptide concentration (P-III-P) in serum as well as fibronectin and plasminogen activation in bronchoalveolar lavage (BAL) fluid during and following irradiation of human lung. The patients received either high-dose hemithorax irradiation for pleural mesothelioma (11 patients) or high-dose irradiation with individually shaped fields for non-small cell lung cancer (12 patients). The severity of radiation fibrosis was assessed clinically from CT scans 6 months and 12 months after treatment. Four scores were used: severe, moderate, mild, or normal. Radiological lung injury varied from "severe" (9 patients) to near absence of injury-"normal" (6 patients). Serum levels of P-III-P, when measured weekly during the 5-week period of radiotherapy or at several time-points after treatment, did not show consistent changes, nor did the levels correlate with the score for radiation fibrosis as assessed by CT scanning. Changes in fibronectin levels or in markers of plasminogen activation in BAL fluid did not correlate with the development of late lung injury. The levels of BAL fluid plasmin and plasminogen activator as assessed zymographically, but not the free net enzyme values, showed a tendency to be elevated in patients with severe radiation-induced lung injury, suggesting a possible role for inhibitors of the plasminogen activation cascade in the process of radiation-induced lung injury.     

Distinct Clinicopathologic Characteristics and Prognosis Based on the Presence of Ground Glass Opacity Component in Clinical Stage IA Lung Adenocarcinoma

Introduction

We evaluated differences in the clinicopathologic characteristics and prognosis based on the presence of ground glass opacity (GGO) components in small-sized lung adenocarcinoma.