Lepidic Component Research Articles

Correlation of EGFR mutation and predominant histologic subtype according to the new lung adenocarcinoma classification in Chinese patients

A new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has recently been published. However, the relationship between EGFR mutations and subtype of adenocarcinoma remains unclear. A total of 161 surgically resected lung adenocarcinomas in Zhejiang Cancer Hospital were reviewed using the new classification system. Epidermal growth factor receptor (EGFR) mutations were observed in 67 cases (41.6%). EGFR mutations were found to be closely associated with the micropapillary predominant subtype (P=0.0068) and lepidic component (P=0.005). The frequency of EGFR mutation was found to be lower in the solid predominant subtype than other subtype (P=0.04). In conclusion, histologic subtyping was found to be associated with EGFR mutations. The EGFR mutation frequency of micropapillary and lepidic predominant subtypes was found to be more pronounced than that of other subtypes.

Low papillary structure in lepidic growth component of lung adenocarcinoma: a unique histologic hallmark of aggressive behavior

Small-sized lung adenocarcinomas often contain a lepidic growth component in part. The term lepidic growth has recently been used to represent a growth pattern of neoplastic cells along preexisting alveolar structures. We reviewed 91 small-sized (≤3 cm) invasive lung adenocarcinomas with a lepidic component to study the histopathologic and clinicopathologic characteristics. In the lepidic component of invasive adenocarcinoma, we have identified a morphologically unique structure characterized by proliferation of low papillae, consisting of neoplastic cells piling up toward the alveolar space, and we defined this architecture as "low papillary structure." There were 18 cases with the low papillary structure in the lepidic components, whereas 73 cases did not have the structure. In the lepidic component, the cases with the low papillary structure had higher Ki-67 labeling index (15.7%) and more frequent p53 overexpression (50.0%) than did those without the structure (9.4% and 16.4%, respectively). Based on clinicopathologic findings, the presence of low papillary structure was significantly associated with lymphatic invasion (P = .023) and lymph node metastasis (P = .001). Furthermore, the patients with the low papillary structure in the lepidic components demonstrated significantly shorter disease-free and overall survival than did those without the structure (P = .001 and P = .010, respectively). We conclude that the low papillary structure is a significant histologic feature in a lepidic component and is associated with aggressive cancer behavior in lung adenocarcinoma.

Editorial Comment: Clinical relevance and TNM implications of the new concept of minimally-invasive adenocarcinomas in situ with a lepidic pattern

The most significant recent change in the pathological classification of lung cancer occurred with the 2011 classification of lung adenocarcinoma sponsored by the International Association of the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiration Society (ERS). This classification outlines many paradigm shifts that affect clinical practice and patient management and opens new avenues for research [1]. This new classification was a multidisciplinary effort at emphasizing the correlations in tumour pathology among clinical, radiological and molecular characteristics. With this classification, a new concept of adenocarcinoma in situ (AIS) was added to the group of pre-invasive lesions along with atypical adenomatous hyperplasia, both presenting at HRCT (high resolution CT-scan) as circumscribed by ground glass opacities (GGO). AIS is defined as a localized, small (≤3 cm) adenocarcinoma consisting of pure lepidic growth characterized by neoplastic pneumocytes growing along pre-existing alveolar walls and lacking stromal, vascular and pleural invasion. This new concept of AIS (former pure bronchioloalveolar carcinoma [BAC]) correlates with 100% disease-free survival if completely resected. A new concept of minimally invasive adenocarcinoma (MIA) is created for small solitary adenocarcinoma (≤3 cm) with a predominant lepidic pattern and ≤5 mm invasion. By CT, this typically presents as a ground glass nodule with a solid component measuring 5 mm or less. Measurement of the invasive component of MIA includes the size of the invasive subtypes other than the lepidic pattern including tumour cells infiltrating myofibroblastic stroma. MIA is restricted to tumours showing neither lymph node blood vessel or pleural invasion nor necrosis. Moreover, MIA defines a population of patients with near 100% 5-year survival. Because the previous taxonomy of bronchioloalveolar carcinoma included a wide variety of different clinico-pathological entities, it was discarded. The current article [2] can be regarded as a validation of the concept that the pure lepidic pattern is biologically and clinically in situ. Correlation of the pathology with CT-findings is helpful in the evaluation of AIS, MIA and lepidic predominant adenocarcinomas since it can be difficult to appreciate tumour size by gross evaluation of a lepidic predominant tumour. It may be easier to identify the size of the lesion on HRCT, particularly in lepidic predominant tumours to distinguish the part solid nodule on a background of a mostly Ground Glass Opacity (GGO). In this article by Murakawa et al., 241 patients with stage I (T1-2N0M0) lung adenocarcinoma (3–5 cm) who were surgically resected were included and histologically reviewed according to the new classification, of which 68 cases with AIS and MIA exhibited 100% recurrence-free survival. Importantly, even in T2 cases, a multivariate analysis revealed that the maximum tumour diameter (solid part measured in mediastinal window), was a better predictor of survival than the diameter measured in the lung window (including solid part and ground glass opacity). The authors show the predictive performance of TDR ( tumour shadow disappearance rate) for recurrence, of which the 2-diameter and area size of the solid part of the mediastinal tumour were the only predictive factors of prognosis, even in the GGO-predominant groups. They conclude from the multivariate analysis that the T factor measured by size of the solid component may be a more accurate prognostic parameter and ab etter assessment of the Ts ize of the staging system, which includes the total tumour size including both the solid (invasive) and ground glass (lepidic) components of the tumour. This confirms previous hypotheses [3–5]. Briefly, GGO-component exclusion from the T size revealed an improved prognostic performance for recurrence-risk assessment and pathological vessel invasion. All together, in addition to the confirmed prognostic power of the predominant pattern (5–6), the Murakawa study provides a validation of the proposed implications of the IASLC/ATS/ERS classification for TNM classification of adenocarcinomas with a lepidic pattern: (1) AIS may be regarded as Tis (adenocarcinoma) in addition to Tis (squamous); (2) consideration of MIA as Tmi; and (3) use of the size of the solid or invasive tumour component both by CT or pathological assessment, respectively, for determining the T factor of size rather than total tumour size including the ground glass or lepidic component.

IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma

In 2011, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society proposed a new classification for lung adenocarcinoma that included a number of changes to previous classifications. This classification now considers resection specimens, small biopsies, and cytology specimens. Two former histopathologic terms, bronchioloalveolar carcinoma and mixed subtype adenocarcinoma, are no longer to be used. For resection specimens, the new terms of adenocarcinoma in situ and minimally invasive adenocarcinoma are introduced for small adenocarcinomas showing pure lepidic growth and predominantly lepidic growth, with invasion ≤5 mm, respectively. Invasive adenocarcinomas are now classified by their predominant pattern as lepidic, acinar, papillary, and solid; a micropapillary pattern is newly added. This classification also provides guidance for small biopsies and cytology specimens. For adenocarcinomas that include both an invasive and a lepidic component, it is suggested that for T staging the size of the T-factor may be best measured on the basis of the size of the invasive component rather than on the total size of tumors including lepidic components, both on pathologic and computed tomography assessment. This suggestion awaits confirmation in clinical-radiologic trials. An implication for M staging is that comprehensive histologic subtyping along with other histologic and molecular features can be very helpful in determining whether multiple pulmonary nodules are separate primaries or intrapulmonary metastases. In this review article, we provide an illustrated overview of the proposed new classification for lung adenocarcinoma with an emphasis upon what the radiologist needs to know in order to successfully contribute to the multidisciplinary strategic management of patients with this common histologic subtype of lung cancer.

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.

Histopathologic Characteristics of Lung Adenocarcinomas With Epidermal Growth Factor Receptor Mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Lung Adenocarcinoma Classification

The proposed International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinomas has been published. To evaluate the correlation between epidermal growth factor receptor mutations and histologic subtypes of lung adenocarcinomas according to the upcoming new classification of lung adenocarcinomas. Medical records and pathologic slides were reviewed for a total of 107 surgically resected lung adenocarcinomas. All tumors were reclassified according to the predominant histologic subtype, and comprehensive histologic subtyping with semiquantitative assessment of each of the histologic subtypes in increments of 5% was performed. Correlations with epidermal growth factor receptor status were then evaluated. Epidermal growth factor receptor mutations were found in 54 cases (50.5%). Epidermal growth factor receptor mutations were significantly associated with the micropapillary-predominant subtype (P = .02) and with the presence (any amount) of the lepidic component (P = .02). The upcoming International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma is relevant in that it shows a phenotype-genotype correlation. Comprehensive histologic subtyping should be recommended because of the association of particular subtypes with epidermal growth factor receptor mutations.

Expression of Matrix Metalloproteinases in Invasive Pulmonary Adenocarcinoma with Bronchioloalveolar Component and Atypical Adenomatous Hyperplasia

To investigate the association between the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) and the clinicopathological features in lepidic and invasive components of adenocarcinoma of the lung, we performed immunostaining for type IV collagen, various MMPs, and TIMPs in 27 cases of invasive adenocarcinomas and 5 cases of atypical adenomatous hyperplasia of alveolar epithelial cells (AAH). Mean extent of lepidic growth was 61% and the survival was significantly better in cases with 50% or more lepidic component. The preservation of type IV collagen in lepidic areas correlated inversely with lymphatic or vascular invasion (P = 0.02 and 0.002, respectively). Five-year survival was reduced in cases showing destruction of type IV collagen (P = 0.004) or expression of MMP-2 (P = 0.008) in lepidic areas. MMP-2 co-localized with MT-1-MMP (its activating enzyme) and TIMP-2 in neoplastic cells. Reactivity for other MMPs and TIMPs did not correlate with destruction of type IV collagen or prognosis. Type IV collagen was preserved in all cases of AAH. MMP-2, but not MT-1-MMP, was expressed in two of the five cases of AAH. Immunostaining for type IV collagen MMP-2 is useful in evaluating the prognosis of the lung.