Keiko Kuriyama

International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

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.

Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years

BACKGROUND Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on high-resolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. METHODS We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation-dose CT (low-dose CT), 7 at follow-up CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. RESULTS The median follow-up period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During follow-up, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with follow-up only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. CONCLUSIONS These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability.

Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma

BACKGROUND Bronchiolo-alveolar carcinoma (BAC) is often observed in lung adenocarcinoma, but its clinicopathological and prognostic significance, especially in small peripheral lung adenocarcinoma, remains undetermined. METHODS We assessed 206 consecutive cases of surgically resected small peripheral lung adenocarcinoma (less than 2 cm in diameter) recorded between 1973 and 1997. According to the component area of well differentiated BAC within maximally cut surface specimens of tumor tissue, we semiquantitatively classified the tumors into four types: those in which the BAC component comprised 0% (type I), 1% to 49% (type II), 50% to 99% (type III), and 100% (type IV) of the tumor tissue. RESULTS Forty tumors were classified as type I, 75 as type II, 74 as type III, and 17 as type IV. The tumors with less BAC, especially type I and II, showed a significantly more aggressive nodal involvement and tumor stage, and consequently a worse prognosis, while type IV tumors had no nodal involvement and the most favorable prognosis. The patients with type III showed clinicopathological characteristics somewhere between those of type II and type IV patients. Among stage I patients, however, those with type II had the worst prognosis, while those with type I showed as good a prognosis as the other two groups. CONCLUSIONS This novel classification based on the degree of BAC involvement in small peripheral lung adenocarcinoma may reflect clinicopathological and prognostic characteristics. This classification may prove practical for planning therapeutic strategies, in particular surgical treatment.

Radiologic Implications of the 2011 Classification of Adenocarcinoma of the Lung

Now the leading subtype of lung cancer, adenocarcinoma received a new classification in 2011. For tumors categorized previously as bronchioloalveolar carcinoma (BAC), criteria and terminology had not been uniform, so the 2011 classification provided four new terms: (a) adenocarcinoma in situ (AIS), representing histopathologically a small (≤3-cm), noninvasive lepidic growth, which at computed tomography (CT) is usually nonsolid; (b) minimally invasive adenocarcinoma, representing histopathologically a small (≤3-cm) and predominantly lepidic growth that has 5-mm or smaller invasion, which at CT is mainly nonsolid but may have a central solid component of up to approximately 5 mm; (c) lepidic predominant nonmucinous adenocarcinoma, representing histopathologically invasive adenocarcinoma that shows predominantly lepidic nonmucinous growth, which at CT is usually part solid but may be nonsolid or occasionally have cystic components; and (d) invasive mucinous adenocarcinoma, histopathologically showing lepidic growth as its predominant component, which at CT varies widely from solid to mostly solid to part solid to nonsolid and may be single or multiple (when multifocal, it was formerly called multicentric BAC). In addition, new histopathologic subcategories of acinar, papillary, micropapillary, and solid predominant adenocarcinoma are now described, all as nonmucinous, predominantly invasive, may include a small lepidic component, and at CT are usually solid but may include a small nonsolid component. The micropapillary subtype has a poorer prognosis than the other subtypes. In addition, molecular genetic correlations for the subcategories of adenocarcinoma of the lung are now a topic of increasing interest. As the new classification enters common use, further descriptions of related correlations can be anticipated.

Fractal analysis of small peripheral pulmonary nodules in thin-section CT: evaluation of the lung-nodule interfaces.

Objectives To analyze the lung-nodule interfaces on small peripheral pulmonary nodules (<2 cm) in thin-section CT (HRCT) images with fractal analysis. Methods Thin-section CT images from 70 patients with bronchogenic carcinomas (61 adenocarcinomas and 9 squamous cell carcinomas) and 47 patients with benign pulmonary nodules (23 hamartomas, 13 organizing pneumonias, and 11 tuberculomas) were used. For calculation of fractal dimensions (FDs), the authors used a box-counting method for binary- and gray-scale images of nodules. FD(two-dimensional [2D]) was an FD obtained from the binary image, and FD(three-dimensional [3D]) was an FD obtained from the gray-scale image. Results The FD(2D)s of hamartomas were smaller than those of other nodules (P < 0.05). The FD(3D)s obtained from the gray-scale images of organizing pneumonias and tuberculomas were greater than those of bronchogenic carcinomas (P < 0.0001) and hamartomas (P < 0.0001). In bronchogenic carcinomas, FD(3D)s of adenocarcinomas were greater than those of squamous cell carcinomas (P < 0.05). Conclusions Fractal dimensions reflect the characteristics of the lung-nodule interfaces of small peripheral pulmonary nodules. The FD(2D)s revealed the irregularities of the contours. On the other hand, FD(3D)s revealed the complexities of the heterogeneous textures. With use of FD(2D) and FD(3D), it may be possible to distinguish bronchogenic carcinomas from benign pulmonary nodules. Moreover, FD(3D) may make it possible to distinguish between adenocarcinomas and squamous cell carcinomas.

Fractal analysis of internal and peripheral textures of small peripheral bronchogenic carcinomas in Thin-section computed tomography: Comparison of bronchioloalveolar cell carcinomas with nonbronchioloalveolar cell carcinomas

Purpose To analyze the internal and peripheral textures of small peripheral bronchogenic carcinomas (<2 cm) in thin-section computed tomography (HRCT) images with fractal analysis. Method Thin-section computed tomography images from 70 patients with bronchogenic carcinomas (61 adenocarcinomas and 9 squamous cell carcinomas) were used. Regions of interest (ROIs) with a matrix size of 32 × 32 (0.326 mm per pixel) were selected manually on the lung-nodule interfaces and within the nodules on HRCT images. Three-dimensional density surfaces based on CT values of ROIs were characterized by fractal dimensions (FDs). Results When all the bronchogenic carcinomas were divided into bronchioloalveolar cell carcinomas (BACs) and other bronchogenic carcinomas (nonBACs), there were significant differences between BACs and nonBACs in the FDs obtained from the internal textures (mean: 2.38 ± 0.05 versus 2.19 ± 0.05;P < 0.0001) and in the FDs obtained from the peripheral textures (mean: 2.16 ± 0.01 versus 2.06 ± 0.01;P < 0.0001). Conclusion The textures of BACs that reveal ground-glass opacities are more complicated than those of nonBACs. The FDs can differentiate between small localized BACs, which have a good prognosis, and nonBACs, which have a poor prognosis. Fractal analysis is promising for characterization of small peripheral pulmonary bronchogenic carcinomas based on radiographic features of HRCT images.

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

Objective: To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). Methods: Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. Results: The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. Conclusions: Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.

Ng-nitro-L-arginine methyl ester inhibits bone metastasis after modified intracardiac injection of human breast cancer cells in a nude mouse model

We investigated the effects of NG‐nitro‐L‐arginine‐methyI ester (L‐NAME), a nitric oxide synthase (NOS) inhibitor, on hone metastasis of human breast cancer, MDA‐231 cells. Tumor cells (2 × 105 cells in 0.2 ml of phosphate‐buffered saline; PBS) were injected through the diaphragm into the left ventricle of the heart of laparotomized nude mice (male 5‐week‐old ICR‐nu/nu). L‐NAME (2 mg/ mouse/injection in 0.1 ml of PBS) was given intraperitoneally to mice 6 h and 3 h before and immediately, 3 h, 6 h, 18 h and 21 h after the intraeardlac injection of tumor cells. As a control, 0.1 ml of PBS was injected instead of L‐NAME. The effect of NG‐nitro‐D‐arginine‐methyl ester CD‐NAME; 2 mg/mouse/injection), an inactive analogue of L‐NAME, was also investigated to evaluate the specificity of L‐NAME action. Radiographical examination 31 days after the tumor‐cell injection showed that the incidence and number of osteolytic bone metastases and the number of bones with metastasis in L‐NAME‐treated mice were significantly reduced compared with those in PBS‐treated mice (P<0,05). The differences between PBS‐treated and D‐NAME‐treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacological approach to therapy for cancer patients at risk of developing osteolytic bone metastases.

Measurement of Focal Ground-glass Opacity Diameters on CT Images: Interobserver Agreement in Regard to Identifying Increases in the Size of Ground-Glass Opacities

PURPOSE To evaluate interobserver agreement in regard to measurements of focal ground-glass opacities (GGO) diameters on computed tomography (CT) images to identify increases in the size of GGOs. MATERIALS AND METHODS Approval by the institutional review board and informed consent by the patients were obtained. Ten GGOs (mean size, 10.4 mm; range, 6.5-15 mm), one each in 10 patients (mean age, 65.9 years; range, 58-78 years), were used to make the diameter measurements. Eleven radiologists independently measured the diameters of the GGOs on a total of 40 thin-section CT images (the first [n = 10], the second [n = 10], and the third [n = 10] follow-up CT examinations and remeasurement of the first [n = 10] follow-up CT examinations) without comparing time-lapse CT images. Interobserver agreement was assessed by means of Bland-Altman plots. RESULTS The smallest range of the 95% limits of interobserver agreement between the members of the 55 pairs of the 11 radiologists in regard to maximal diameter was -1.14 to 1.72 mm, and the largest range was -7.7 to 1.7 mm. The mean value of the lower limit of the 95% limits of agreement was -3.1 ± 1.4 mm, and the mean value of their upper limit was 2.5 ± 1.1 mm. CONCLUSION When measurements are made by any two radiologists, an increase in the length of the maximal diameter of more than 1.72 mm would be necessary in order to be able to state that the maximal diameter of a particular GGO had actually increased.