If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.
Methods
Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.
Findings
In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.
Implications
Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.
this term has now been replaced with newer designations. The 2011 revised classification of pulmonary adenocarcinoma, introduced by joint multidisciplinary specialists from the International Association for the Study of Lung Cancer, the American Thoracic Society (ATS), and the European Respiratory Society, now includes a spectrum of precursor lesions from lowest to highest risk: atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA).
International association for the Study of lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.
The tighter delineation of lesions has proven clinical significance, as several studies have shown the newer classification to have better prognostic value.
Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma.
Does lung adenocarcinoma subtype predict patient survival? A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification.
Tissue-sparing application of the newly proposed IASLC/ATS/ERS classification of adenocarcinoma of the lung shows practical diagnostic and prognostic impact.
Tumor invasiveness as defined by the newly proposed IASLC/ATS/ERS classification has prognostic significance for pathologic stage IA lung adenocarcinoma and can be predicted by radiologic parameters.
The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival.
Why do pathological stage IA lung adenocarcinomas vary from prognosis?: a clinicopathologic study of 176 patients with pathological stage IA lung adenocarcinoma based on the IASLC/ATS/ERS classification.
The relationship between precursor lesions and invasive adenocarcinoma can be further strengthened by the finding that individual precursor lesions often harbor the same genetic mutations found in adenocarcinomas, such as EGFR,
They typically present as multiple ground glass opacities, with or without small solid foci, on computed tomography (CT) scans. These lesions can progress slowly to standard invasive carcinoma and may eventually metastasize. Therefore, current management typically includes careful CT surveillance and surgical resection and/or radiotherapy to areas that grow beyond a certain size (some propose 2 cm if the lesion remains pure ground glass) or that develop a solid component of more than a few millimeters. Prognosis can be excellent, in contrast to the typical poor prognosis for patients with metastatic lung cancer.
In patients with multifocal adenocarcinomas, the separate adenocarcinomas may share a common genetic ancestry or arise divergently over time. Here we first report 4 patients with multifocal adenocarcinoma in whom we tested EGFR mutation status for more than 1 lesion. We then review our current understanding of the underlying molecular pathologies of multifocal adenocarcinoma lesions and the potential for targeted therapies in this setting.
Case Series
Based on the previously cited reports of interlesional heterogeneity, we were interested in examining available tumor molecular data from our patients with multifocal minimally invasive adenocarcinoma (mMIA). From 2009 to 2015, we identified 4 patients who had resection or biopsy of more than 1 adenocarcinoma lesion in the setting of additional ground glass opacities, with results of molecular testing available for multiple separate lesions. We report their clinical characteristics and molecular testing results. This retrospective chart review project was performed using an institutional review board–approved protocol. The clinical characteristics of these patients and representative images are reported in the following and shown in Figure 1 and Table I.
Figure 1Imaging of Lesions Studied in Case Series. Representative CT imaging of analyzed lesions in four patients with mMIA. (labeled with large light green arrow when there is more than one lesion present). RUL: right upper lobe; RML: right middle lobe; LUL: left upper lobe; LLL: left lower lobe.
Patient 1 is a 56-year-old Asian woman, a never smoker, who had first received a diagnosis of lung adenocarcinoma after presenting with atypical chest pain. A CT scan performed initially showed a 5-cm right upper lobe (RUL) nodule; then a subsequent positron emission tomography (PET)–CT scan showed 3 focal lesions: in the RUL, right middle lobe (RML), and left upper lobe (LUL). Biopsy of the RUL nodule showed adenocarcinoma with EGFR exon 19 deletion mutation (L747_T751) by outside EGFR testing, and the LUL nodule showed atypical cells. A subsequent workup, including magnetic resonance imaging of the brain and mediastinoscopy, was negative for metastases. The patient underwent an RML wedge resection 2 months later that revealed adenocarcinoma, 1.8-cm in the largest diameter, with an EGFR exon 21 (L858R) mutation. She was treated with erlotinib for 4 months with stable disease as her best response, with a plan to proceed with surgical resection of the RUL and RML and stereotactic ablative radiotherapy (SABR) to LUL nodule; however, repeat PET/CT then showed new mediastinal lymph node involvement. The patient was then started on systemic “neoadjuvant” chemotherapy with carboplatin and pemetrexed, followed by definitive surgery with a right thoracotomy and right upper and middle bilobectomy with mediastinal lymph node dissection.
Patient 2 is a 79-year-old Asian man with a distant 30-packs per year smoking history. He received an incidental diagnosis of multiple lung nodules, all ~1 to 2 cm in diameter, that appeared mostly to have mixed solid and ground glass components. Biopsy of the left lower lung nodule showed adenocarcinoma with an EGFR exon 21 (L861Q) mutation by multiplex polymerase chain reaction (PCR) followed by single nucleotide mutation detection, and a subsequent workup showed no metastases. He underwent left lower lobectomy that revealed T1N0M0 moderately differentiated adenocarcinoma, predominantly lepidic subtype. At delayed follow-up 3 years later, a repeat CT scan showed that 1 RUL nodule had been slowly growing, as well as multiple other sites that were likely low-grade adenocarcinoma. Biopsy of the RUL nodule showed well-differentiated adenocarcinoma, with EGFR exon 19 (L747_T751) deletion mutation and TP53 (H178D) mutation by next-generation sequencing (NGS). The patient declined surgery in favor of SABR to the RUL nodule with favorable response.
Patients With Concordant EGFR Mutations
Patient 3 is a 60-year-old Asian woman, a never smoker, who received a diagnosis of right pheochromocytoma when she presented with headaches, palpitations, flushing, and sweating. After surgical resection, she continued to experience occasional tachycardia. A PET-CT scan was ordered and showed a 3.9 cm hypermetabolic, spiculated RUL apical mass, as well as a 1-cm nodular opacity in the LUL. Patient eventually underwent right video-assisted thoracoscopic right upper lobectomy revealing a T3 N0 adenocarcinoma. The final pathology showed acinar adenocarcinoma with papillary and lepidic patterns, and molecular testing by NGS showed the following mutations: EGFR L858R, PIK3CA E545K, and FBXL7 H98Y. Six months after surgery, the patient’s repeat CT scan showed enlargement of the previously present small anterior LUL nodule and confluence/growth of a 10-mm spiculated multilobulated nodule in the posterior LUL. She then underwent LUL wedge excision 9 months after the initial lobectomy, and pathology showed invasive adenocarcinoma, 0.7-cm in diameter, with the same 3 mutations noted at the previous surgical resection by NGS. The patient was to undergo SABR for her other LUL lesion; however, biopsy-proven chest wall metastases then developed and she was started on systemic erlotinib.
Patient 4 is a 70-year-old Asian woman, a never smoker, who had a diagnosis of multiple lung lesions when a cough developed. A CT scan showed an ill-defined 1.8-cm nodule in the RUL, and 2 lesions in the LUL, 2.1 cm and 1.3 cm infiltrates. PET-CT and magnetic resonance imaging of the brain showed no metastatic disease, although PET-CT noted additional opacities in the RLL. A CT-guided biopsy of the right nodule revealed adenocarcinoma. She underwent surgical resection with an RML lobectomy as the tumor was palpated to be in the middle lobe during surgery, and pathology showed well-differentiated invasive adenocarcinoma, with mixed lepidic and acinar patterns, 1.3 cm, with an EGFR L858R mutation by NGS. The patient was under regular surveillance until 2 years later when a CT scan showed that the lesions in the LUL were slowly progressing. She then underwent left video-assisted thoracoscopic and lingual-sparing LUL lobectomy. Pathology showed a 1.6-cm and a 1.2-cm well-differentiated adenocarcinomas, lepidic predominant, the larger of which was positive for EGFR L858R mutation by NGS. A year later, a surveillance CT scan showed a slight gradual increase in nodularity along the R fissure, for which the patient underwent SABR. She continues to do well and remains under active surveillance.
Review of Current Literature
Molecular Tumor Biology
The understanding of how recurrent oncogenic mutations “drive” invasive lung adenocarcinoma has advanced over the years, with the research effort focused on development and testing of potential targeted therapies. However, a deeper understanding of molecular alterations in minimally invasive precursor lesions and their treatment is still lacking. Another challenge is that many of the studies were done using the previous designation of BAC rather than the newer term AIS or MIA. For clarity in this review, the term BAC will still be used for studies performed using this previous designation.
Whether multifocal adenocarcinomas share a common genetic origin or arise independently remains controversial. Barsky et al
showed BAC clonal nonidentity or multiclonality in 3 separate cases by using PCR amplification of a 511–base pair region located within the first intron of the human hypoxanthine phosphoribosyltransferase gene. On the other hand, Holst et al
studied multifocal BAC in 28 patients using a topographic genotyping approach for the presence of KRAS exon 1 mutations and p53 loss of heterozygosity (LOH) and suggested a monoclonal origin with spread via the intra-alveolar route, intrapulmonary lymphatics, or aerosolization, leading to implantation at different sites. In a study by Zhong et al
the authors addressed this question using next-generation sequencing performed using an Illumina mate-pair library protocol. A total of 41 tumor samples were sequenced, with a range of 3 to 276 break points per tumor identified. Lung tumors predicted to be independent primary tumors based on different histologic subtypes did not share any genomic rearrangements. In patients with primary lung tumors and paired distant metastases, shared rearrangements were identified in all tumor pairs, emphasizing the patient specificity of identified breakpoints. Concordance between histology and genomic data occurred in the majority of samples. Discrepant tumor samples were resolved by genome sequencing. This study suggests the importance of detailed molecular testing in distinguishing independent primary tumors from intrapulmonary metastases. However, a remaining question is how frequently do separate primary lesions share common underlying genetic driver mutations, especially in patients with little smoking history. In another similar study by Wu et al,
the authors analyzed tumors from 35 patients with multiple lesions resected, including confirmed nonsmall cell lung cancer (NSCLC) and at least 1 ground glass nodule (GGN), were analyzed for mutations in EGFR, KRAS, HER2, BRAF, and PIK3CA together with fusions in ALK, ROS1, and RET. A total of 72 lesions (60 were GGNs) were analyzed. Of these, 33 tumor lesions (45.8%) were found to harbor EGFR mutations: 13 tumors with exon 19 deletion, 18 with L858R on exon 21, and 2 with both exon 19 del and L858R mutation. There were 5 tumors (6.9%) harboring EML4-ALK fusion, 4 HER2 mutations (5.6%), 3 KRAS mutations (4.2%), 1 ROS1 fusion, and 1 BRAF mutation. Only 6 of 30 patients harbored identical mutations. The discordance rate of driver mutations was 80% (24 of 30) in those patients harboring at least 1 of the detected driver mutations. The authors concluded that there is a high discrepancy of driver mutations among NSCLC patients with GGNs and a favorable prognosis after multiple lesion resection.
Loss of Heterozygosity
LOH is an indirect index of genetic alterations in tumors. A number of markers have also been implicated in the stepwise progression from precursor lesions to fully invasive adenocarcinomas. LOH of 3p and 9p might be an early event of carcinogenesis, as in a study by Yamasaki et al
Correlation between genetic alterations and histopathological subtypes in bronchiolo-alveolar carcinoma and atypical adenomatous hyperplasia of the lung.
analyzed AAH and concomitant adenocarcinoma in 11 patients, and the results suggested a causal relationship of LOH on 9q and 16p in a fraction of AAH lesions and adenocarcinomas of the lung. In another study by Sasatomi et al,
Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs. stage I invasive adenocarcinoma.
the authors found the most frequently affected chromosome regions in BAC were 8q and 17p. LOH of 1p, 3p, 7q, and 18q as well as fractional allele loss were more frequent in stage 1 adenocarcinomas than BAC. Although these genomic alterations are present in many precursor lesions, it is challenging to use LOH analysis to identify shared ancestry between independent lesions.
KRAS, EGFR, and p53 Mutations
KRAS mutations are the primary driver genetic alterations in as many as 25% of NSCLC adenocarcinomas. It has been hypothesized that these lung adenocarcinomas develop through a series of genetic mutations that sequentially accumulate, leading eventually to the phenotype of invasive adenocarcinoma. This model was based on several lines of evidence. One mouse model study using a conditionally activated allele of oncogenic KRAS showed progression from AAH to conditions similar to BAC to adenocarcinoma.
In a separate study, regional pulmonary stem cells were identified, termed bronchioalveolar stem cells, that are capable of giving rise to bronchiolar Clara cells and alveolar cells of the distal lung. Bronchioalveolar stem cells expanded in response to oncogenic KRAS in culture and in precursors of lung tumors in vivo and thus may be the putative cells of origin for this subtype of lung cancer.
EGFR mutations are also frequently found in both precursor lesions and invasive adenocarcinomas, with the reported frequency ranging from 11% to 58% depending on the patient population.
EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.
EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.
Another distinction between these 2 mutations is that KRAS mutations are more frequently found in mucinous disease, whereas EGFR mutations are more frequently found in nonmucinous disease, with the latter more responsive to EGFR-targeted therapies even without EGFR mutation testing.
EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.
Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations.
EGFR mutations and HER2 overexpression (defined by positive immunohistochemistry staining) often coexist in BAC lesions, but the role of HER2 as a codriver or passenger genomic alteration remains unclear.
Clinicopathological and molecular evidence indicating the independence of bronchioloalveolar components from other subtypes of human peripheral lung adenocarcinoma.
examining genetic drivers in each of the precursor categories of adenocarcinoma (using the 2011 classification) ties some of the knowledge about individual gene alterations together. The authors studied the full spectrum of early histologic progression using next-generation sequencing of coding regions from 125 well-characterized cancer-driving genes. They found that in AAH lesions, the most frequently mutated genes were not the classic drivers, but rather genes involved in DNA repair and chromatin remodeling, suggesting that these lesions are predisposed to clonal expansion and acquisition of secondary genetic mutations. In AIS tumors, the mutational landscape varied considerably, but began to include more driver mutations such as EGFR and KRAS. In MIA tumors, even more driver oncogenes were identified, but mostly in the denser or invasive zones of tumors. Genes such as KRAS, EGFR, and TP53 are highly connected nodes in the mutational landscape, consistent with their potential as drivers of glandular tumorigenesis, and likely have a role in aggressive transformation of small premalignant lesions. In addition, there appears to be a high degree of intertumoral and even intratumoral genetic heterogeneity, even in a single patient.
Targeted Therapy in Multifocal Precursor Disease
As multifocal minimally invasive adenocarcinoma became recognized as a distinct clinical entity, it was recognized that this histology predicted a better response to gefitinib, an EGFR tyrosine kinase inhibitor. This is likely due to the high prevalence of EGFR mutations in these lesions.
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
69 patients with stage IIIB/IV inoperable NSCLC were found to have pure or mixed BAC and treated with erlotinib. Partial responses to erlotinib occurred in 15 of 59 patients evaluated (25% [95% CI, 15%–38%]). Responses occurred in 1 of 14 patients (7%) with “pure” BAC and 13 of 44 (30%) with adenocarcinoma with BAC features. Never smoking and a lower number of cigarettes smoked predict sensitivity to erlotinib in patients with BAC.
a total of 136 chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC were treated with gefitinib 500 mg/d until progression or prohibitive toxicity. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) in 69 previously untreated patients with measurable disease and 9% with no CRs in 22 pretreated patients. Exploratory subset analyses revealed improved survival among women (P = 0.031), patients in whom a rash developed (P = 0.003), never smokers (P = 0.061), and patients with a performance status of 0 or 1 (P = 0.015). Further analysis by Hirsch et al
Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study.
showed that increased EGFR gene copy number detected by fluorescence in situ hybridization is associated with improved survival after gefitinib therapy in patients with advanced BAC: 12 of 19 EGFR/fluorescence in situ hybridization–positive patients (63%) demonstrated disease control versus 14 of 36 patients (39%) in the fluorescence in situ hybridization–negative group (P = 0.087). In separate analysis, Franklin et al
showed low phosphorylated mitogen-activated kinase and combined low ErbB2 and phosphorylated mitogen-activated kinase predict increased survival with gefitinib therapy in patients with advanced BAC and that dual inhibition of ErbB1 and ErbB2 may lead to improved therapeutic efficacy.
101 patients were treated with BAC (n = 12) or adenocarcinoma, BAC subtype (n = 89) with erlotinib 150 mg/d. The overall response rate was 22% (95% CI, 14%–31%). In patients treated with pure BAC, the response rate and median survival were 20% and 4 months, respectively, compared with 23% and 19 months, respectively, in those with adenocarcinoma, BAC subtype. Patients with EGFR mutations had an 83% response rate (15 of 18; 95% CI, 65%–94%) and 23-month median overall survival (OS).
The Phase II IFCT-0401 trial enrolled 88 chemotherapy-naïve patients with BAC who were treated with 250 mg/d gefitinib. Disease control was achieved in 25 patients (29.4%); 11 patients (12.9%) had a partial response, and 14 (16.4%) had stable disease. Median progression-free survival was 2.9 months (95% CI, 2.3–3.2), and median OS was 13.2 months (95% CI, 10.2–17.3). Never smokers, patients with low respiratory symptoms score, occurrence of cutaneous rash, and nonmucinous subtype had an increased probability of disease control.
IFCT-0401 Trial: a phase II study of gefitinib administered as first-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype.
conducted a Phase II study using cetuximab in which patients with advance-stage pure BAC or adenocarcinoma with BAC features, >2 previous chemotherapy regimens and no previous EGFR therapy, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible. Approximately 50% of patients received >2 cycles of therapy (>8 weeks). The confirmed response rate was 7%, and stable disease was observed in 35%. The median survival and progression-free survival were 13 and 3.3 months, respectively.
Overall, response rates to EGFR inhibitor therapy (7%–25%) in these studies are substantially lower than in patients with widely metastatic EGFR in whom response rates of 60% or better are anticipated. This suggests that intralesional and interlesional heterogeneity may limit the effectiveness of a single targeted therapy in this patient population.
Prognostic Value of EGFR and KRAS in Early-stage NSCLC
The prognostic value of molecular testing of a single site of disease remains controversial and may depend on the mutation itself. In a systematic review and meta-analysis that included 16 studies (N = 3337) to determine the prognostic value of EGFR mutations in resected NSCLC by Zhang et al,
the combined hazard ratio evaluating EGFR mutations on disease-free survival (DFS) was 0.96 (95% CI, 0.79–1.16; P = 0.65). The combined hazard ratio evaluating EGFR mutations on OS was 0.86 (95% CI, 0.72–1.04; P = 0.12). The subgroup analysis based on univariate and multivariate analyses in DFS and OS showed no statistically significant difference. There was also no difference in DFS and OS of stage I NSCLC patients. In a separate study examining the prognostic value of KRAS mutation status in resected stage I lung adenocarcinoma, Izar et al
examined mutation status in a total of 312 patients who had complete resection of stage I lung adenocarcinoma without any adjuvant therapy, using a multiplex PCR-based assay; 127 patients harbored KRAS mutations (KRAS-MUT) and 185 had KRAS-wild type (KRAS-WT) tumors. Compared with KRAS-WT, KRAS-MUT was associated with significantly shorter OS and DFS. When stratifying KRAS-WT patients based on EGFR status, KRAS-MUT patients had worse OS and DFS than patients with EGFR-MUT and EGFR-WT/KRAS-WT (WT/WT). Multivariate analysis identified KRAS mutation as an independent predictor of worse OS (P = 0.001) and DFS (P < 0.0001). The authors concluded that KRAS appears to be an independent prognostic marker in resected stage I lung adenocarcinoma.
Conclusions
Multifocal adenocarcinoma remains a unique disease entity with a distinct presentation from typical NSCLC. It is important, but not always easy, to differentiate between multiple primary tumors versus metastatic intrapulmonary disease. Controversy also still exists as to how these lesions develop, whether through clonal expansion and metastasis or multiclonal origin. From our limited case series and review of the literature, we believe that molecular testing of >multiple lesions helps to distinguish these possibilities for staging and treatment purposes, with some tumors sharing a common genetic driver and some tumors appearing to have arisen independently. In our experience, molecular testing may not only provide treatment options but also potentially be of prognostic value because multifocal lesions that share the same mutations are more likely to behave like metastatic disease over time. Deeper NGS-based molecular analysis of these tumors may identify additional somatic tumor gene alterations helping resolve whether they are concordant or discordant. Targeted therapy based on the molecular status of a dominant lesion is an appropriate first step in therapy, as is often the practice for metastatic disease; however, the same targeted therapy may not be effective for all lesions. Further evaluation of underlying mutations in these synchronous and metachronous lesions can shed light on these pathogenic processes and potentially identify therapies to halt the process of tumorigenesis within these lesions before they progress.
J.C. Chuang were responsible for study design, patient identification, creation of the figures, literature search, and writing of the first draft.
J.B. Shrager were responsible for study design, patient identification, editing of manuscript. H.A.Wakelee were responsible for study design, editing of manuscript.
J.W. Neal were responsible for study design, patient identification, editing of manuscript.
Grant support: none reported.
Conflicts of Interest
The authors report no funding from industry that influenced this work. There was no industry sponsorship of this manuscript.
Acknowledgments
No one other than the authors listed helped write or revise this manuscript.
International association for the Study of lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma.
Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma.
Does lung adenocarcinoma subtype predict patient survival? A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification.
Tissue-sparing application of the newly proposed IASLC/ATS/ERS classification of adenocarcinoma of the lung shows practical diagnostic and prognostic impact.
Tumor invasiveness as defined by the newly proposed IASLC/ATS/ERS classification has prognostic significance for pathologic stage IA lung adenocarcinoma and can be predicted by radiologic parameters.
The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival.
Why do pathological stage IA lung adenocarcinomas vary from prognosis?: a clinicopathologic study of 176 patients with pathological stage IA lung adenocarcinoma based on the IASLC/ATS/ERS classification.
Correlation between genetic alterations and histopathological subtypes in bronchiolo-alveolar carcinoma and atypical adenomatous hyperplasia of the lung.
Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs. stage I invasive adenocarcinoma.
EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.
Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations.
Clinicopathological and molecular evidence indicating the independence of bronchioloalveolar components from other subtypes of human peripheral lung adenocarcinoma.
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study.
IFCT-0401 Trial: a phase II study of gefitinib administered as first-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype.
30396-4&id=gr1.jpg){kind=link}