Journal of Thoracic Imaging:
IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma: Novel Concepts and Radiologic Implications
Lee, Hyun-Ju MD*; Lee, Chang Hun MD†; Jeong, Yeon Joo MD‡; Chung, Doo Hyun MD§; Goo, Jin Mo MD*; Park, Chang Min MD*; Austin, John H.M. MD∥
Departments of *Radiology
§Pathology, Seoul National University Hospital, Seoul
Departments of †Pathology
‡Radiology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Pusan, Korea
∥Department of Radiology, Columbia University Medical Center, New York, NY
The authors declare no conflicts of interest.
Reprints: Hyun-Ju Lee, MD, Department of Radiology, Seoul National University Hospital, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea (e-mail: firstname.lastname@example.org).
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.
Lung adenocarcinoma is the most common histologic subtype of lung cancer worldwide, accounting for almost half of all lung cancers.1 Reflecting this importance, advances have taken place in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma during the past few decades. However, the histologic subclassification of lung adenocarcinoma has remained difficult because of the heterogenous nature of lung adenocarcinomas pathologically, molecularly, clinically, and radiologically. Given this background, in 2011 an international multidisciplinary classification sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) was proposed1 (Table 1). This new adenocarcinoma classification provides uniform terminology and diagnostic criteria for multidisciplinary strategic management and also provides improved guidelines reflecting the latest understanding of lung adenocarcinomas (Table 2).
COMPARISON WITH 2004 WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION
Major Alteration (1): Discard the Term “Bronchioloalveolar Carcinoma (BAC)”
In this new classification, the term “BAC” is no longer used. “BAC” was originally defined by pathologists as a noninvasive lesion in 1999,2 but since then the term has been used to represent a broad spectrum of tumors, including (a) small noninvasive peripheral adenocarcinomas with 100% 5-year survival, formerly known as nonmucinous BAC3; (b) small minimally invasive peripheral adenocarcinomas with approximately 100% 5-year survival4; (c) invasive adenocarcinomas of mixed subtype5; (d) the mucinous subtype of adenocarcinomas formerly known as mucinous BAC6,7; and (e) advanced-stage IV mucinous adenocarcinomas with a very low survival rate.1,2,8 Consequently, there has been considerable confusion in both clinical and molecular research with regard to this former category.7 To clarify the nomenclature, the term BAC is now referred to as “former BAC” in the new classification. The former BAC concept is applicable to multiple categories in the new classification (Table 3).
Major Alteration (2): Adenocarcinoma In Situ (AIS) and Minimally Invasive Adenocarcinoma (MIA)
For resection specimens, new concepts have now been adopted, including adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small peripheral adenocarcinomas with either pure lepidic growth (AIS) or predominantly lepidic growth with invasion ≤5 mm (MIA), respectively, to define patients who will have 100% or near 100% disease-specific survival if they undergo complete resection. AIS and MIA are typically nonmucinous but in rare cases may be mucinous.3,4
Major Alteration (3): Predominant Pattern Replaces Former Mixed Subtype in Invasive Adenocarcinoma
In the new classification, invasive adenocarcinomas are classified according to their predominant pattern using comprehensive histologic subtyping. The term “predominant” is added to all categories of invasive adenocarcinomas, as most invasive adenocarcinomas are composed of a mixture of several histologic subtypes. This replaces the previous classification of mixed subtype adenocarcinoma, and the term “mixed subtype” is no longer to be used. Recent investigations have indicated that >90% of lung adenocarcinomas correspond to the mixed subtype according to the 2004 WHO classification.8 Comprehensive histologic subtyping improves molecular, therapeutic, and prognostic correlations.1,5
Choosing a single predominant pattern after semiquantitative recording of the patterns in 5% increments is recommended. Semiquantitative recording of the patterns in 5% increments can be carried out in every pathologic slide containing the tumor and can be summed up. Histopathologic classification according to the predominant pattern as well as reporting the percentages of the subtypes is recommended. In this manner, invasive adenocarcinomas are classified as lepidic (formerly “mixed subtype with nonmucinous bronchioloalveolar”), acinar, papillary, and solid predominant invasive adenocarcinomas. Micropapillary predominant adenocarcinoma is added as a new histologic subtype of invasive adenocarcinomas.1
Major Alteration (4): Changes in Variants of Adenocarcinoma
In the new classification, invasive mucinous adenocarcinomas (formerly “mucinous BAC”) and colloid, fetal, and enteric adenocarcinoma are included as variants of invasive adenocarcinomas.1 Enteric adenocarcinoma is added to the variants on the basis of histologic and immunohistochemical features that are shared with colorectal adenocarcinoma. For the diagnosis of enteric adenocarcinoma, a primary gastrointestinal origin should be excluded.
The rationale for changes in the classification of adenocarcinoma variants is based on 3 new concepts.1 First, the separation of invasive mucinous adenocarcinoma (formerly “mucinous BAC”) is based on many investigations showing that former “mucinous BACs” are significantly different from former “nonmucinous BACs” in terms of major clinical, radiologic, pathologic, and genetic aspects, in particular because of different frequencies of epidermal growth factor receptor (EGFR) and KRAS mutations.7,9–11 EGFR mutations are more frequent in nonmucinous adenocarcinomas, whereas KRAS mutations are more frequent in mucinous adenocarcinomas. Second, the rare mucinous cystadenocarcinoma is now reclassified as colloid adenocarcinoma, as these likely represent a spectrum of colloid adenocarcinoma. Finally, clear cell and signet ring cell features are removed from histologic subtypes and are now regarded as cytologic changes. Their presence and extent will continue to be reported with an association with molecular features. For example, signet ring cell features are present in up to 56% of tumors with echinoderm microtubule–associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusions.1
Major Alteration (5): Classification Guidance for Different Types of Samples
As approximately 70% of lung cancers are detected in advanced stage and are unresectable,12 diagnosis is frequently established on the basis of small biopsies and/or cytology. In the new classification, for the first time in the history of lung cancer classification, standardized criteria and terminology for the pathologic diagnosis of lung cancer in small biopsies and cytology have been proposed (Fig. 1). This had not been addressed in prior WHO classification systems.1 Recently, 3 major advances have made histologic subclassification important for therapeutic decision making in advanced lung cancer patients, particularly for the distinction between adenocarcinoma and squamous cell carcinoma. First, EGFR mutations have been found to be associated with improved responsiveness to first-line EGFR tyrosine kinase inhibitors and with improved clinical outcome in advanced lung adenocarcinoma patients.13,14 Second, bevacizumab is contraindicated in patients with advanced squamous cell carcinoma because of increased risk of life-threatening hemorrhage.15 Third, pemetrexed is more effective in patients with adenocarcinoma compared with those with squamous cell carcinoma.16
On the basis of these observations, the following recommendations for advanced-stage non–small cell lung cancer (NSCLC) were made. First, the EGFR mutation test is recommended for patients with advanced lung adenocarcinoma. Second, NSCLC should be further classified into a more specific type, such as adenocarcinoma or squamous cell carcinoma, and the term NSCLC—not otherwise specified (NSCLC—NOS) is to be used as little as possible for small biopsies and cytology samples.1
CLINICAL, RADIOLOGIC, AND PATHOLOGIC FEATURES OF SUBTYPES
Atypical Adenomatous Hyperplasia (AAH)
AAH is defined as a localized, small (usually ≤5 mm) proliferation of atypical type II pneumocytes and/or Clara cells lining the alveolar walls and respiratory bronchioles (Fig. 2).17 A continuum of morphologic changes between AAH and nonmucinous AIS has been suggested.17–19 Differentiation between highly cellular and atypical AAH and AIS can be difficult histologically and impossible cytologically. On chest computed tomography (CT), AAH is characteristically shown as a small pure ground-glass nodule (GGN) usually measuring <5 mm.20 It can be either single or multiple.21,22
AIS (one of the lesions formerly known as BAC) is a localized small (≤3 cm) adenocarcinoma in which growth of neoplastic cells is restricted to preexisting alveolar structures (lepidic growth) that lack stromal, vascular, or pleural invasion. Papillary or micropapillary patterns and intra-alveolar tumor cells are absent. Although most AIS lesions are nonmucinous, several cases of mucinous AIS have been reported.3 Nonmucinous AIS consists of type II pneumocytes and/or Clara cells (Fig. 3). The rare cases of mucinous AIS consist of tall columnar cells and abundant cytoplasmic mucin (Fig. 4). Tumors that meet the criteria for AIS have been documented to have 100% disease-free survival.3,23–25
On CT, nonmucinous AIS appears typically as a pure GGN (Fig. 3).10 In contrast, localized BAC and Noguchi type A adenocarcinomas can appear as partly solid nodules because of focal collapsed alveoli or focal thickened alveolar septa.26,27 These articles were published in the early 2000s; thus, the classification scheme of small adenocarcinomas was different from that in the current classification. Therefore, further radiologic-pathologic correlation studies in numerous cases can identify the CT features of nonmucinous AIS. Mucinous AIS can appear as a solid nodule or as a consolidation28 (Fig. 4). The pure GGN of AIS usually appears on thin-section CT as slightly higher attenuation compared with the very faint GGN of AAH.29,30 AIS also can be either single or multiple.20
MIA is a small, solitary adenocarcinoma (≤3 cm), with a predominantly lepidic pattern and invasion ≤5 mm in its greatest dimension.1 MIA is usually nonmucinous (Fig. 5) but in rare cases can be mucinous. The invasive component of MIA is defined as follows: (a) histologic subtype other than a lepidic pattern (ie, acinar, papillary, micropapillary, or solid); or (b) tumor cells infiltrating myofibroblastic stroma. MIA should be excluded if the tumor (a) invades lymphatics, blood vessels, or pleura or (b) contains tumor necrosis. If multiple microinvasive areas are found in 1 tumor, the largest dimension in the largest invasive area should be measured, and it should be ≤5 mm in size. The size of invasion is not the summation of all invasive foci, if multiple foci occur. If the measurement of the size of invasion is impossible because of the manner of histologic sectioning, invasive size can be estimated by multiplying the total percentage of the invasive (nonlepidic) components by the total tumor size. Many investigators have demonstrated a near 100% disease-specific or very favorable overall survival in patients diagnosed as having adenocarcinomas meeting the criteria of MIA.3,4,31,32
Imaging features of MIA are as yet not fully described. A provisional description of nonmucinous MIA on thin-section CT is a part-solid nodule consisting of a predominant ground-glass component and a small solid component measuring 5 mm or less (Fig. 5).33 Mucinous MIA can appear as a solid or part-solid nodule.28 There is an overlap among imaging features of AAH, AIS, and MIA.
Lepidic Predominant Invasive Adenocarcinoma, Nonmucinous (LPA)
LPA is defined as nonmucinous adenocarcinomas previously classified as a mixed subtype in which the lepidic component is predominant. A diagnosis of LPA rather than MIA can be made if the tumor (a) contains >5 mm of a histologic subtype other than a lepidic pattern (ie, acinar, papillary, micropapillary, or solid) or >5 mm of myofibroblastic stroma with invasive tumor cells; (b) invades lymphatics, blood vessels, or pleura; or (c) contains tumor necrosis (Fig. 6). The term LPA should not be used in the context of invasive mucinous adenocarcinoma with predominantly lepidic growth. Most LPAs have been buried in the categories of mixed subtype in the 1999/2004 WHO classifications as there was no assessment of the percentage of lepidic growth (former BAC pattern). Nevertheless, several studies have demonstrated that predominantly lepidic growth is associated with a more favorable survival in small resected lung adenocarcinomas with an invasive component.23,32 A 90% 5-year recurrence-free survival was reported in a recent study on stage I adenocarcinomas using this approach.34 On CT, it can be shown as a part-solid opacity with variable proportions of ground-glass and solid components.
Acinar, Papillary, Micropapillary, and Solid Predominant Adenocarcinomas
Histopathologically, acinar predominant adenocarcinoma consists mainly of glands with a central luminal space surrounded by tumor cells (Fig. 7).8 Papillary predominant adenocarcinoma is composed of a growth of glandular cells along central fibrovascular cores (Fig. 8).8 The new category of micropapillary predominant adenocarcinoma has tumor cells growing in papillary tufts that lack fibrovascular cores (Fig. 9).8 Solid predominant adenocarcinoma with mucin production reveals a major component of polygonal tumor cells forming sheets and lacks the recognizable patterns of acinar, papillary, micropapillary, or lepidic growth (Fig. 10).8 If the tumor is 100% solid, intracellular mucin should be found in at least 5 tumor cells in each of 2 high-power fields (Fig. 10).8 Solid and micropapillary predominant subtypes are associated with a poorer prognosis compared with the other subtypes.34–36 These subtypes of adenocarcinomas appear as a solid nodule but can also be partly solid if lepidic components are included (Figs. 7–10).
Invasive Mucinous Adenocarcinoma
The rationale for separation of invasive mucinous adenocarcinoma (formerly mucinous BAC) from nonmucinous adenocarcinoma is that invasive mucinous adenocarcinoma has different clinical, radiologic, pathologic, and genetic features.7,9–11 In particular, invasive mucinous adenocarcinomas are usually thyroid transcription factor-1 negative and show a very strong correlation with KRAS mutation. Nonmucinous adenocarcinomas are frequently thyroid transcription factor-1 positive and are more likely to show EGFR mutations. Invasive mucinous adenocarcinomas have a distinctive histologic appearance with goblet or columnar tumor cells with abundant intracytoplasmic mucin. Alveolar spaces often contain mucin. These tumors may show a similar heterogenous mixture of lepidic, acinar, papillary, micropapillary, and solid growth as that in nonmucinous tumors. These tumors differ from mucinous AIS and MIA by 1 or more of the following criteria: size (>3 cm), amount of invasion (>5 mm), multiple nodules, or lack of a discrete border with miliary spread into adjacent lung parenchyma. Multicentric, multilobar, and bilateral lung involvements, which may reflect aerogenous spread, are frequent.
The imaging spectrum of invasive mucinous adenocarcinoma is variable and ranges from nodules to lobar consolidation (Fig. 11).37,38 Although these tumors can appear as ground-glass–containing masses, intra-alveolar mucus may make the CT finding solid or nearly solid.10,39 On contrast-enhanced CT scans, vessels are well shown to be traversing areas of consolidation (CT angiogram sign).40 However, the previously described imaging spectrum of invasive mucinous adenocarcinoma could be fraught with problems, as the classification of tumors in the previous literature is inconsistent. Radiologic-pathologic correlation in early and small invasive mucinous adenocarcinomas needs to be performed in numerous cases. In addition, distinctive clinical and radiologic features between small nodular type of invasive mucinous adenocarcinomas and extensive consolidation type of tumors need to be described.
Colloid, Fetal, and Enteric Variants
Colloid adenocarcinoma shows features similar to those of tumors of the same name seen in the gastrointestinal tract. Abundant pools of extracellular mucin are found with distended alveolar spaces and destruction of alveolar walls. Fetal adenocarcinoma exhibits characteristics that resemble fetal lung tissue and consists of glandular elements with tubules composed of nonciliated cells that resemble fetal lung tubules. Enteric adenocarcinoma shares characteristics with colorectal adenocarcinoma, which consists of glandular structures, sometimes with a cribriform pattern, lined by columnar tumor cells with nuclear pseudostratification, luminal necrosis, and prominent nuclear debris.1
IMPLICATIONS FOR T STAGING
The new seventh edition Union for International Cancer Control/American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system for NSCLC41 was released recently. There are important implications of the new adenocarcinoma classification for TNM staging. With respect to T staging, although the prognostic impact of tumor size was emphasized in the seventh edition of the staging system, that is, size thresholds of 2, 5, and 7 cm were added to the threshold of 3 cm from the sixth edition,41 the clinical implication of LPAs needs to be considered for the next revision of TNM classification. LPAs with an extensive ground-glass component are known to be associated with a favorable prognosis.23,34 In this context, several reports have demonstrated that survival was a function of the diameter of the invasive component and not of the total diameter that includes the lepidic component.32,42 Therefore, for subsolid adenocarcinomas, measurement of the solid component on CT and of the invasive component on histology as opposed to measurement of the total tumor diameter is suggested.43,44 If further studies validate this observation, measuring the solid component of subsolid adenocarcinomas should be considered as the appropriate method for size measurement (T staging) in the next revision of TNM classification. AIS and MIA may be classified as Tis (T stage of in situ carcinoma) and T1mi (T1 stage of minimally invasive carcinoma) in the next TNM classification, respectively, similar to the system of breast cancer.1
IMPLICATIONS FOR MULTIPLE ADENOCARCINOMAS AND M STAGING
Multifocal lung adenocarcinomas are not uncommon. Eighteen percent of adenocarcinomas detected in screening programs23 and 8% to 22% of surgically resected adenocarcinomas have been reported to be multifocal adenocarcinomas.45,46 Pathologically, multiple lung adenocarcinomas can be multiple AAH, AIS, and invasive adenocarcinoma, and they can appear as multiple subsolid nodules.20 Subsolid nodules are reported only very rarely to be metastatic.47 Comprehensive histologic subtyping can be helpful in multiple lung adenocarcinomas to differentiate multiple primary tumors from intrapulmonary metastases. Recording the percentages of each histologic subtype at 5% increments, not just recording the most predominant subtype, allows the data to be utilized to compare multiple adenocarcinomas, particularly if the slides of a previously diagnosed tumor are not available at the time of review of additional lung adenocarcinomas.48 With respect to molecular biomarker expression, DNA mutation sequencing,49,50 immunohistochemistry,51 and gene expression analysis have been tested to distinguish metastases from synchronous primary tumors; however, these approaches need to be prospectively validated. Multiple adenocarcinomas are not a contraindication for surgical exploration23,52,53 if there is no evidence of mediastinal lymph node metastasis, although a standard treatment algorithm for multiple adenocarcinomas has not been established yet.
IMPLICATIONS FOR MANAGEMENT AND QUANTITATIVE ANALYSIS OF SUBSOLID NODULES
Subsolid nodules are now known to represent the histologic spectrum of peripheral adenocarcinomas that includes AAH, AIS, MIA, LPA, and other subtype predominant adenocarcinomas with a lepidic component.1 Recommendations for management of subsolid nodules have not been established yet, but interim guidelines have been proposed by Godoy and Naidich.54 As most pure GGNs <10 mm are known to be AAH or AIS that may not progress or may very slowly grow without metastasis, the interim guidelines recommend CT follow-up rather than immediate surgical resection for these lesions until definite evidence of malignancy or growth is observed (Table 4).54
Size measurement and growth assessment of subsolid nodules are very important but clinically problematic. In this context, a thin-section CT technique (≤3 mm reconstruction thickness) is helpful for recording the size of both the solid and ground-glass components.54 Although volumetric measurements have been suggested as a promising tool for assessing size changes in indeterminate solid nodules,55 few attempts have been made to measure the volume of subsolid nodules, especially the separate volumes of the solid component and ground-glass component. Changes over time in the diameters and/or the volumes of the solid component and of the ground-glass component may possibly provide important prognostic information. Quantitative analysis of CT attenuation and histogram analysis have been recognized as an approach to differentiate AAH and AIS (usually the 1-peak pattern on CT attenuation histogram) from LPA (frequently the 2-peak pattern) (Fig. 12).30 Differences in CT scanners and interobserver and intraobserver measurement variability are common and may critically impact the performance of CT quantification of subsolid nodules.55,56
MOLECULAR BIOMARKERS FOR PREDICTING RESPONSE TO CHEMOTHERAPY
Molecular biomarkers for predicting response to therapy have become prominent after the discovery of EGFR mutations and their association with responsiveness to erlotinib and gefitinib.12,13 KRAS mutations are mutually exclusive with EGFR mutations,57,58 but their clinical role as predictive and prognostic biomarkers remains controversial. Recent phase 3 trials have demonstrated that patients with EGFR-mutated lung cancers show better treatment outcomes (response rate and progression-free survival) when treated with the EGFR tyrosine kinase inhibitor gefitinib than with conventional platinum-based chemotherapy.12,13
Other molecular predictors such as EGFR gene copy number have also been explored. Data from a phase 3 randomized, placebo-controlled trial of erlotinib in advanced NSCLC demonstrated that EGFR copy number (but not EGFR mutation status) was associated with a better response to erlotinib and with worse survival.57 Very recently, a new predictive biomarker, the transforming fusion gene EML4-ALK, was identified.59 This fusion gene is prevalent in approximately 5% of lung adenocarcinomas and is usually found in EGFR/KRAS mutation–negative cases.59 Younger age, male sex, and never or light smokers may harbor this aberration.60 A recent study demonstrated a 57% overall response and a 72% 6-month PFS for crizotinib, an inhibitor of ALK, in tumors harboring ALK fusion.60
RADIOLOGIC FINDINGS—MOLECULAR BIOMARKER CORRELATION
Several reports have correlated imaging features with EGFR mutation, although not many studies have attempted to do so. As the original biological character of the tumor can be preserved before progression to advanced stages or metastasis, these studies were performed in surgically resected adenocarcinomas.61–63 A Japanese group reported that a high ratio of ground-glass component and a smaller diameter, especially tumors ≤3 cm with ≥50% ground-glass components, may predict the presence of EGFR mutations.61 Another study demonstrated that 27.5% of adenocarcinomas presented as a solid mass on CT and 38.5% of adenocarcinomas presented as a ground-glass–containing mass showing EGFR mutation.62 Correlation studies with other molecular biomarkers have been performed. High EGFR gene copy number was reported as correlating with adenocarcinomas that show high glucose metabolism at positron emission tomography and a low ground-glass proportion.63 More correlative series are needed to assess the possible association of molecular and imaging findings.
The new IASLC/ATS/ERS classification based on a multidisciplinary approach incorporating the latest clinical, molecular, radiologic, and surgical findings offers promise to assist in improving clinical management in the rapidly progressing field of lung adenocarcinoma.
The authors thank Binsheng Zhao, DSc, Yongqiang Tan, PhD, and Lawrence H. Schwartz, MD, for their technical assistance in the preparation of CT histograms of AIS and LPA cases.
1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thoracic Oncol. 2011;6:244–285
2. Travis WD, Colby TV, Corrin B, et al. Histological Typing of Lung and Pleural Tumors. 1999 Berlin Springer
3. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844–2852
4. Yim J, Zhu LC, Chiriboga L, et al. Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Mod Pathol. 2007;20:233–241
5. Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32:810–827
6. Goldstein NS, Thomas M. Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies. Am J Clin Pathol. 2001;116:319–325
7. Garfield DH, Cadranel J, West HL. Bronchioloalveolar carcinoma: the case for two diseases. Clin Lung Cancer. 2008;9:24–29
8. Travis WD, Brambilla E, Muller-Hermelink HK, et al. Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. 2004 Lyon IARC Press
9. Wislez M, Antoine M, Baudrin L, et al. Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib. Lung Cancer. 2010;68:185–191
10. Lee HY, Lee KS, Han J, et al. Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons. Lung Cancer. 2009;65:170–175
11. Casali C, Rossi G, Marchioni A, et al. A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice. J Thorac Oncol. 2010;5:830–836
12. Howlander N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2009. [database online]. 2009 Bethesda, MD National Cancer Institute Updated April 2012
13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957
14. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388
15. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–2191
16. Scagliotti GV, Parikh P, von PJ, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551
17. Mori M, Rao SK, Popper HH, et al. Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. Mod Pathol. 2001;14:72–84
18. Noguchi M. Stepwise progression of pulmonary adenocarcinoma—clinical and molecular implications. Cancer Metastasis Rev. 2010;29:15–21
19. Soda H, Nakamura Y, Nakatomi K, et al. Stepwise progression from ground-glass opacity towards invasive adenocarcinoma: long-term follow-up of radiological findings. Lung Cancer. 2008;60:298–301
20. Lee HJ, Goo JM, Lee CH, et al. Predictive CT findings of malignancy in ground-glass nodules on thin-section chest CT: the effects on radiologist performance. Eur Radiol. 2009;19:552–560
21. Kim TJ, Goo JM, Lee KW, et al. Clinical, pathological and thin-section CT features of persistent multiple ground-glass opacity nodules: comparison with solitary ground-glass opacity nodule. Lung Cancer. 2009;64:171–178
22. Lee HJ, Goo JM, Lee CH, et al. Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J Radiol. 2007;8:22–31
23. Sakurai H, Dobashi Y, Mizutani E, et al. Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment. Ann Thorac Surg. 2004;78:1728–1733
24. Vazquez M, Carter D, Brambilla E, et al. Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications. Lung Cancer. 2009;64:148–154
25. Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg. 2009;88:1106–1111
26. Aoki T, Tomoda Y, Watanabe H, et al. Peripheral lung adenocarcinoma: correlation of thin-section CT findings with histologic prognostic factors and survival. Radiology. 2001;220:803–809
27. Takashima S, Maruyama Y, Hasegawa M, et al. CT findings and progression of small peripheral lung neoplasms having a replacement growth pattern. Am J Roentgenol. 2003;180:817–826
28. Sawada E, Nambu A, Motosugi U, et al. Localized mucinous bronchioloalveolar carcinoma of the lung: thin-section computed tomography and fluorodeoxyglucose positron emission tomography findings. Jpn J Radiol. 2010;28:251–258
29. Nagao M, Murase K, Yasuhara Y, et al. Measurement of localized ground-glass attenuation on thin-section computed tomography images: correlation with the progression of bronchioloalveolar carcinoma of the lung. Invest Radiol. 2002;37:692–697
30. Ikeda K, Awai K, Mori T, et al. Differential diagnosis of ground-glass opacity nodules: CT number analysis by three-dimensional computerized quantification. Chest. 2007;132:984–990
31. Sakurai H, Maeshima A, Watanabe S, et al. Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol. 2004;28:198–206
32. Borczuk AC, Qian F, Kazeros A, et al. Invasive size is an independent predictor of survival in pulmonary adenocarcinoma. Am J Surg Pathol. 2009;33:462–469
33. Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol. 2005;23:3279–3287
34. Yoshizawa A, Motoi N, Riely GJ, et al. Prognostic significance of the proposed IASLC/ATS/ERS revised classification of lung adenocarcinoma in 514 stage I lung adenocarcinomas. Mod Pathol. 2011;24:653–664
35. Amin MB, Tamboli P, Merchant SH, et al. Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol. 2002;26:358–364
36. Miyoshi T, Satoh Y, Okumura S, et al. Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis. Am J Surg Pathol. 2003;27:101–109
37. Miyake H, Matsumoto A, Terada A, et al. Mucin-producing tumor of the lung: CT findings. J Thorac Imaging. 1995;10:96–98
38. Akira M, Atagi S, Kawahara M, et al. High-resolution CT findings of diffuse bronchioloalveolar carcinoma in 38 patients. Am J Roentgenol. 1999;173:1623–1629
39. Gaeta M, Vinci S, Minutoli F, et al. CT and MRI findings of mucin containing tumors and pseudotumors of the thorax: pictorial review. Eur Radiol. 2002;12:181–189
40. Im JG, Han MC, Yu EJ, et al. Lobar bronchioloalveolar carcinoma: “angiogram sign” on CT scans. Radiology. 1990;176:749–753
41. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706–714
42. Sakao Y, Miyamoto H, Sakuraba M, et al. Prognostic significance of a histologic subtype in small adenocarcinoma of the lung: the impact of nonbronchioloalveolar carcinoma components. Ann Thorac Surg. 2007;83:209–214
43. Sakao Y, Nakazono T, Tomimitsu S, et al. Lung adenocarcinoma can be subtyped according to tumor dimension by computed tomography mediastinal-window setting. Additional size criteria for clinical T1 adenocarcinoma. Eur J Cardiothorac Surg. 2004;26:1211–1215
44. Tsutani Y, Miyata Y, Nakayama H, et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study. J Thorac Cardiovasc Surg. 2012;143:607–612
45. Nakata M, Sawada S, Yamashita M, et al. Surgical treatments for multiple primary adenocarcinoma of the lung. Ann Thorac Surg. 2004;78:1194–1199
46. Zwirewich CV, Miller RR, Muller NL. Multicentric adenocarcinoma of the lung: CT-pathologic correlation. Radiology. 1990;176:185–190
47. Park CM, Goo JM, Kim TJ, et al. Pulmonary nodular ground-glass opacities in patients with extrapulmonary cancers: what is their clinical significance and how can we determine whether they are malignant or benign lesions? Chest. 2008;133:1402–1409
48. Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33:1752–1764
49. Lau DH, Yang B, Hu R, et al. Clonal origin of multiple lung cancers: K-ras and p53 mutations determined by nonradioisotopic single-strand conformation polymorphism analysis. Diagn Mol Pathol. 1997;6:179–184
50. Girard N, Deshpande C, Azzoli CG, et al. Use of epidermal growth factor receptor/Kirsten rat sarcoma 2 viral oncogene homolog mutation testing to define clonal relationships among multiple lung adenocarcinomas: comparison with clinical guidelines. Chest. 2010;137:46–52
51. Nonami Y, Ohtuki Y, Sasaguri S. Study of the diagnostic difference between the clinical diagnostic criteria and results of immunohistochemical staining of multiple primary lung cancers. J Cardiovasc Surg
52. Finley DJ, Yoshizawa A, Travis W, et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. J Thorac Oncol. 2010;5:197–205
53. Lee HJ, Ahn MI, Kim YK, et al. Notes from the 2010 annual meeting of the Korean Society of Thoracic Radiology: pure ground-glass nodules, part-solid nodules and lung adenocarcinomas. J Thorac Imaging. 2011;26:W99–W104
54. Godoy MC, Naidich DP. Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology. 2009;253:606–622
55. Yankelevitz DF, Reeves AP, Kostis WJ, et al. Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology. 2000;217:251–256
56. Zhao B, James LP, Moskowitz CS, et al. Evaluating variability in tumor measurements from same-day repeat CT scans of patients with non-small cell lung cancer. Radiology. 2009;252:263–272
57. Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR. 21. J Clin Oncol. 2008;26:4268–4275
58. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17
59. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566
60. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–1703
61. Yano M, Sasaki H, Kobayashi Y, et al. Epidermal growth factor receptor gene mutation and computed tomographic findings in peripheral pulmonary adenocarcinoma. J Thorac Oncol. 2006;1:413–416
62. Glynn C, Zakowski MF, Ginsberg MS. Are there imaging characteristics associated with epidermal growth factor receptor and KRAS mutations in patients with adenocarcinoma of the lung with bronchioloalveolar features? J Thorac Oncol. 2010;5:344–348
63. Park EA, Lee HJ, Kim YT, et al. EGFR gene copy number in adenocarcinoma of the lung by FISH analysis: investigation of significantly related factors on CT, FDG-PET, and histopathology. Lung Cancer. 2009;64:179–186
adenocarcinoma; lung; classification
© 2012 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read