Nonmucinous Bronchioloalveolar Carcinoma Research Articles

Genotype–phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma: Relationship between histologic subtypes, TITF-1/SP-A expressions and EGFR mutations

This study aimed to explore the association between adenocarcinoma-related morphological and molecular characteristics and EGFR mutations in Chinese lung adenocarcinomas. A total of 139 consecutively resected pulmonary adenocarcinoma patients were screened for EGFR mutations by the amplification refractory mutation system assay. For the resected specimens, histologic subtypes were sub-classified using either the 2004 WHO classification or the 2011 IASLC/ATS/ERS classification. Meanwhile, TITF-1 (thyroid transcription factor 1) and SP-A (surfactant-associated protein A) immunohistochemistry staining was also detected. The results were correlated with EGFR mutations and clinicopathological features mentioned above. Both sub-classification methods reflected differences in frequencies of EGFR mutations in lung adenocarcinoma subtypes. In summary, mixed non-mucinous bronchioloalveolar carcinoma (BAC) or papillary components and papillary predominant adenocarcinoma showed a higher frequency of EGFR mutations than mucinous BAC components; Also, EGFR mutations were significantly more common in tumors with TITF-1 or SP-A expressions than in those without (p=0.002, p=0.026), especially the sensitivity of TITF-1 (96.9%) and the negative predictive value of TITF-1 (88.2%). Our data further showed significant genotype–phenotype correlations between EGFR mutations and adenocarcinoma-related morphological and molecular characteristics, and patients with special histologic and IHC staining features might have higher EGFR mutation rates. In addition, this study, for the first time, indicated the significant relationship between SPA IHC and EGFR mutations, which needed confirmation by further research.

Le carcinome bronchiolo-alvéolaire, une cause exceptionnelle de pneumopathie infiltrante diffuse au cours d’une leucémie aiguë myéloïde

Bronchiolo-alveolar carcinoma is a primary pulmonary adenocarcinoma developing in the terminal respiratory unit. An 84-year-old non-smoker woman with a history of untreated acute myeloid leukaemia was referred to the intensive care unit for pneumonia and acute respiratory failure. The patient reported dyspnoea and a productive cough for 3 months, treated by antibiotics and steroids without improvement. Thoracic CT-scan showed alveolar condensations and multiple nodular lesions. All microbiological samples were negative and the evolution was fatal within 72 hours despite empirical antibiotic therapy and noninvasive ventilation. Post-mortem lung biopsies gave a diagnosis of mucinous and non-mucinous bronchiolo-alveolar carcinoma with typical lepidic growth pattern of tumor cells and discrete septal thickening but no fibrosis, inflammation or local invasion. Bronchiolo-alveolar carcinoma is an alternative diagnosis in alveolar condensations associated with pulmonary nodules even in a patient with immunosupression. Early diagnosis allows effective treatment in some cases.

Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification.

A new lung adenocarcinoma classification has been published by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society. This new classification is needed to provide uniform terminology and diagnostic criteria, most especially for bronchioloalveolar carcinoma. It was developed by an international core panel of experts representing all 3 societies with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons.This summary focuses on the aspects of this classification that address resection specimens. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced, such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with either pure lepidic growth (adenocarcinoma in situ) and predominant lepidic growth with invasion of 5 mm or less (minimally invasive adenocarcinoma), to define the condition of patients who will have 100% or near 100% disease-specific survival, respectively, if they undergo complete lesion resection. Adenocarcinoma in situ and minimally invasive adenocarcinoma are usually nonmucinous, but rarely may be mucinous. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous bronchioloalveolar carcinoma), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma), colloid, fetal, and enteric adenocarcinoma.It is possible that this classification may impact the next revision of the TNM staging classification, with adjustment of the size T factor according to only the invasive component pathologically in adenocarcinomas with lepidic areas.

Expression of CLDN1 and CLDN10 in lung adenocarcinoma in situ and invasive lepidic predominant adenocarcinoma

BackgroundNon-mucinous bronchioloalveolar carcinoma (BAC) is considered the early stage of lung adenocarcinoma and is classified as the lung adenocarcioma in situ (AIS) by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. This study was designed to investigate the gene expression differences between AIS (formerly non–mucinous BAC) and invasive lepidic predominant adenocarcinoma (LPA, formerly non-mucinous BAC pattern with >5 mm invasion, mixed type adenocarcinoma with BAC features) and to investigate the mechanism of the progression of lung adenocarcinoma in situ to invasive adenocarcinoma.MethodsGene expression analysis was performed by using Agilent 4 × 44 K Whole Human Genome Oligo Microarray on 10 fresh frozen tissue samples of AIS and LPA, respectively. Real time RT-PCR was used to validate the differential expression of 13 genes selected by cDNA microarray on fresh frozen tissue samples from 41 patients with lung adenocarcinoma and 4 genes were confirmed. These 4 genes were then validated by western blotting. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffin-embedded tissue samples from 81 cases of lung adenocarcinomna.ResultsWe identified a 13 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between AIS and LPA. Four genes (MMP-2, c-fos, claudin 1 (CLDN1) and claudin 10(CLDN10)) were correlated with the results of microarray and real time RT-PCR analyses for the gene-expression data in samples from 41 patients with lung adenocarcinoma. As confirmed by western blotting, the expression levels of MMP-2 and c-fos were higher in LPA than those in AIS; the expression levels of CLDN1 and CLDN10 in LPA were lower than those in AIS. Immunohistochemical staining for these genes in samples from 81 cases of lung adenocarcinoma demonstrated the expressions of CLDN1 and CLDN10 were correlated with overall survival of patients with lung adenocarcinoma.ConclusionsCLDN1 and CLDN10 may play important roles in the development of AIS to LPA. Overexpression of CLDN1 and CLDN10 indicates a favorable prognosis for overall survival in some patients with lung adenocarcinoma. Expression of CLDN10 may be regulated by the c-fos pathway.

Abstract PR2: The genetic status of the EGFR, K-ras, and EML4-ALK genes in multiple primary noninvasive lung adenocarcinomas

Abstract Backgrounds: The development of high-resolution CT (HRCT) has enabled the detection of small-sized lung tumors and sometimes multiple tumors. In resected specimens, preinvasive lesions proposed as adenocarcinoma in situ (IASLC/ATS/ERS 2011) are often observed, and these lesions are recognized as primary lung cancer. Formerly, these lesions were classified as non-mucinous bronchioloalveolar carcinoma (BAC), of which non-invasive tumors were classified as Noguchi's type A or B. The mutations of EGFR, K-ras and ALK are defined as so-called driver mutations, which drive tumor formation and maintenance. We analyzed the genotype of the EGFR and K-ras genes, and the expression of EML4-ALK fusion gene in synchronous multiple non-invasive adenocarcinomas, to evaluate the possibility of multicentric carcinogenesis. Patients and Methods: There were 9 patients with synchronous multiple adenocarcinomas, 20 mm in diameter or less, who underwent surgery from March 2005 to July 2009. In total, 26 lesions were diagnosed as non-invasive adenocarcinoma. In these 9 patients, 2 tumors were detected in 5 cases, 3 tumors in 2 cases, and 5 tumors in 2 cases. A PCR-based fragment analysis was used as a screening method to detect, and direct sequencing was used to confirm the presence of EGFR (exon 19, 21) and K-ras mutations in macro-dissected materials from paraffin-embedded sections. The expression of EML4-ALK fusion gene was examined by an immunohistochemical analysis. Results: Seventeen of the 26 tumors (65%) had an EGFR or K-ras mutation, and nine tumors had wild type. In the EGFR gene, an exon 19 deletion (▵E746-A750) was detected in 11 tumors, and an exon 21 L858R mutation was detected in 4 tumors. A K-ras codon 12 mutation (G12D) was detected in 2 tumors. Two patients had the same EGFR 19 deletion in all of their tumors, and one had the same K-ras codon 12 mutation in all of their tumors. In one patient, 2 of their 3 tumors had the same EGFR 19 del mutation. In another patient with 5 tumors, 2 tumors had the L858R mutation, 2 had a different type of 19 del mutation, and one showed wild-type of EGFR. In one patient, one tumor showed a 19 del mutation and the other showed a L858R mutation. In 3 cases, same mutation was not detected in their tumors. Therefore, 5 of 9 cases (56%) had the same type of mutation in their multiple tumors. The expression of EML4-ALK, as determined by immunohistochemistry, was not detected in any of the tumors. Conclusion: The EGFR and K-ras genes, which are mutually exclusive, can be used to define clinically relevant molecular subsets of lung adenocarcinoma, and can also define tumor clonality. In several patients in this study, multiple tumors which were defined as pathologically non-invasive tumors, showed the same genetic mutation. These findings demonstrate that multicentric carcinogenesis under the same genetic backgrounds occurs in lung adenocarcinoma. This abstract is also presented as Poster A40.

Small non-mucinous bronchioloalveolar carcinoma with anaplastic lymphoma kinase immunoreactivity: A novel ALK fusion gene?

Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) and kinesin family member 5B (KIF5B)-ALK are newly identified transforming fusion oncogenes causing non-small-cell lung cancers. These molecular abnormalities have become detectable using not only molecular biological methods, but also highly sensitive immunohistochemistry. During the immunohistochemical study of ALK expression in adenocarcinoma of the lung, we unexpectedly discovered that a small bronchioloalveolar carcinoma (BAC) showed strong ALK immunoreactivity. However, FISH studies failed to reveal EML4-ALK and KIF5B-ALK fusion genes in this BAC. These findings suggest the possibility that a novel or unknown ALK fusion gene plays a crucial role in BAC development.

Small non-mucinous bronchioloalveolar carcinoma (BAC) with ALK immunoreactivity. Immunohistochemistry for ALK showing strong expression in the cytoplasm of small non-mucinous BAC cells.

Small non-mucinous bronchioloalveolar carcinoma (BAC) with ALK immunoreactivity. Immunohistochemistry for ALK showing strong expression in the cytoplasm of small non-mucinous BAC cells.

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

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. 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. 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. 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.

Relationship of aquaporin 1, 3, and 5 expression in lung cancer cells to cellular differentiation, invasive growth, and metastasis potential

An oncogenic capacity of aquaporins, transmembrane channels for water, was recently proposed. This study seeks to elucidate the involvement of aquaporin 1, 3, and 5 in the development and progression of lung cancer. Expression of aquaporin 1, 3, and 5 was examined by immunohistochemistry, Western blot, and laser-captured microdissection/real-time reverse transcription polymerase chain reaction in 160 lung cancers of various histologic subtypes; and its correlation with clinicopathological factors and survival was analyzed. Aquaporin 1, 3, and 5 were expressed in tumor cells in 71%, 40%, and 56% of lung cancers, respectively. Aquaporin expressions were frequent in adenocarcinomas, whereas aquaporin 1 and 5 were negative in squamous cell carcinomas. Bronchioloalveolar carcinoma cells exhibited an apicolateral aquaporin 1 and apicolateral or basolateral aquaporin 3 localization in nonmucinous type, and apical aquaporin 1 and 5 and basolateral aquaporin 3 expression in mucinous type, which corresponded to aquaporins expression of nonneoplastic lung tissue. Basolateral aquaporin 5 expression was acquired during tumorigenesis of nonmucinous bronchioloalveolar carcinoma. In contrast, invasive adenocarcinoma tumor cells overexpressed aquaporin 1 and 5 with loss of subcellular polarization and with an intracytoplasmic distribution. Overexpression of aquaporin 1 correlated with high postoperative adenocarcinoma metastasis ratios and unfavorable disease-free survival rates (P = .031). We conclude that expression patterns of aquaporin 1, 3, and 5 in lung cancer cells are mostly associated with cellular differentiation. However, the expression of aquaporin 1 and 5 is up-regulated in invading lung cancer cells, particularly in adenocarcinomas; and the overexpression of aquaporin 1 with loss of subcellular polarization is suggested to be involved in their invasive and metastatic potential.

Carcinoma bronquíolo-alveolar difuso em um cão: aspectos clínico-patológicos e imuno-histoquímicos

Um cão Poodle, 12 anos de idade, demonstrou marcada dispneia. Na radiografia, havia comprometimento difuso do pulmão e foi feito diagnóstico de pneumonia intersticial. Na necropsia, o pulmão continha múltiplos e pequenos nódulos coalescentes. Histologicamente, os nódulos eram compostos por células epiteliais cuboides ou colunares baixas atípicas, que eram PAS-negativa. A avaliação imuno-histoquímica revelou positividade para citoceratina, fator 1 de transcrição da tireoide (TTF-1) e apoproteína A surfactante (SP-A). O tumor foi negativo para vimentina e cromogranina A. As áreas necróticas não marcaram para TTF-1 e SP-A. Com base nos achados histopatológicos e imuno-histoquímicos, foi realizado o diagnóstico de carcinoma bronquíolo-alveolar não mucinoso com envolvimento difuso do pulmão. Essa é uma forma rara de apresentação desse tumor que pode mimetizar pneumonia na avaliação clínica e radiográfica. O diagnóstico definitivo é baseado na histopatologia e imuno-histoquímica.

A Single Institution-Based Retrospective Study of Surgically Treated Bronchioloalveolar Adenocarcinoma of the Lung: Clinicopathologic Analysis, Molecular Features, and Possible Pitfalls in Routine Practice

Prognostic evaluation of bronchioloalveolar carcinoma (BAC) from a homogenous population of Caucasian patients. Retrospective analysis of resected BAC reclassified according to the 2004 World Health Organization classification of lung tumors. Analyzed variables are clinicoradiologic presentation, histologic subtypes, stage, epidermal growth factor receptor (EGFR) and HER2/neu immunohistochemical expression, EGFR exons 18, 19, and 21 mutations, K-RAS exon 2 mutation. Univariate and multivariate analyses of survival were performed. Of 40 patients analyzed, EGFR and HER2/neu expression were detected in 72% and 20%, respectively. HER2/neu expression significantly characterized mucinous BAC (46% versus 7%; p = 0.014). EGFR mutations were identified in 17% (30% in nonmucinous BAC and none in mucinous BAC; p = 0.083). K-RAS mutations were found in 42.5% (92% in mucinous BAC versus 18% in other types; p 0.0001). Early stages (IA+IB) nonmucinous BAC had excellent prognosis: 5 years overall survival of 91% (100% for stage IA). Sixty six percent (4 of 6) of patients with multifocal disease died (two mucinous BAC and one nonmucinous BAC with recurrent disease). Seventy one percent (5 of 7) of patients with pneumonic-like tumor (all mucinous BAC) died of recurrent/progressive disease. Stage (p = 0.004) and histologic classifications (p = 0.035) resulted as independent prognostic factors at multivariate analysis. Early stage nonmucinous BAC has excellent prognosis, whereas mucinous BAC presents a poor prognosis. Locally advanced nonmucinous BAC has a poor prognosis: the diagnosis of nonmucinous BAC in large tumors should be interpreted with caution given the possible presence of invasive areas in incompletely sampled tumor. Coexpression of EGFR and HER2/neu in mucinous BAC could be considered for future trials on target therapies even in Caucasian population.

Mucinous and Nonmucinous Bronchioloalveolar Carcinoma and Smoking

The study by Sartori et al,1 from hospitals in 3 cities in Italy, using the 1999 World Health Organization lung cancer classification,2 found that “An active smoking habit was significantly associated with…mucinous-type BAC ( P <.001)….” It should be pointed …

Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons

We aimed to evaluate the CT, PET, and pathologic findings of solitary pulmonary nodular mucinous and nonmucinous bronchioloalveolar carcinomas (BACs). From August 2003 to March 2008, we saw 24 patients with solitary pulmonary nodular mucinous ( n = 6) or nonmucinous ( n = 18) BACs that were resected. CT and PET findings of the lesions were assessed in terms of size, solidity, morphologic characteristics, attenuation and maximum standardized uptake value (mSUV). All nonmucinous BACs appeared as a pure ground-glass opacity (GGO) nodule, whereas mucinous BACs appeared as solid ( n = 4) or part-solid ( n = 2) nodules. CT attenuation values were significantly higher for mucinous BACs (−21.0 HU ± 4.9) than for nonmucinous BACs (−491.8 HU ± 172.5) ( P < .001). Mean mSUVs were 2.3 ± 1.9 for mucinous BACs and 0.5 ± 0.8 for nonmucinous BACs ( P = .007), but mSUVs were not statistically different after size adjustment ( r = 0.371, P = .081). Mucinous BACs appear as solid or part-solid nodules at CT, whereas nonmucinous BACs present as pure GGO nodules. Both subtypes of tumors show scant FDG uptake at PET.

Current issues in pulmonary adenocarcinoma

Pulmonary adenocarcinoma is the most prevalent and histologically diverse subtype of lung cancer, many aspects of which pose considerable clinical problems. A putative pathway of peripheral pulmonary adenocarcinogenesis is now established, as are criteria for distinguishing the initial lesion, atypical adenomatous hyperplasia, from the next, localized non-mucinous bronchioloalveolar carcinoma (LNMBAC), effectively adenocarcinoma-in-situ. The appearance of stromal invasion, with neofibroplasia, within LNMBAC defines adenocarcinoma, but alveolar collapse, which often precedes invasion, is an important differential diagnosis. The extent and location of invasion and neofibroplasia in early adenocarcinoma appears to be important. Adenocarcinomas show a diverse range of patterns. The bronchioloalveolar pattern may herald earlier disease and a better prognosis; papillary and solid patterns, more advanced disease. Mucinous tumours are biologically and histologically variable and pose particular diagnostic problems. Bronchioloalveolar carcinoma currently describes several biologically different lesions; a confusing situation, particularly when, in some contexts, this may indicate likely sensitivity to certain chemotherapeutic agents.

Expression profile of early lung adenocarcinoma: identification of MRP3 as a molecular marker for early progression

Early lung adenocarcinoma is well-recognized as a small-sized non-invasive adenocarcinoma or localized non-mucinous bronchioloalveolar carcinoma (LNMBAC); however, the molecular events associated with these early lesions are not clear. To determine the genes involved in tumorigenesis at the early stage of lung adenocarcinoma, we compared the mRNA expression profiles of LNMBAC and normal lungs with an oligonucleotide array. Immunohistochemical analyses were performed to confirm the expression of detected genes. We identified 183 differentially expressed genes, of which 15 were up-regulated and 168 down-regulated. Among them, most up-regulated genes, such as AQP3 and Claudin-4, were expressed in both adenocarcinoma cells and type II alveolar pneumocytes, corresponding to the histological similarity between these cell types. However, multidrug resistant protein 3 (MRP3) was only expressed on tumour cell membranes and not in type II alveolar pneumocytes, as confirmed by immunohistochemistry. Moreover, the number of MRP3-positive cells significantly increased from AAH (the precursor lesion of lung adenocarcinoma) to LNMBAC. We conclude that MRP3 could be a novel molecular marker for LNMBAC, whose expression increases during the early progression of tumourigenesis.

Incidence of EGFR and K-ras mutations in Japanese patients with mucinous bronchiolo-alveolar cell carcinoma of the lung

14553 Background: In lung adenocarcinomas, especially Bronchiolo Alveolar Carcinomas (BACs), it has been reported that Epidermal Growth Factor Receptor- Tyrosine Kinase Inhibitors (EGFR-TKIs) have a high potency. But in fact, its efficacy differs among subtypes: in mucinous BACs (mBACs), it exhibits a poor effect compared to its performance in non-mucinous BACs (non-mBACs). One reason why is EGFR mutations are rare, and K-ras mutations are frequent, in mBACs relative to non-mBACs. Methods: From January 2004 to October 2007, 180 lung adenocarcinomas were diagnosed in pathological specimens after resections. 51 cases (28%) of BACs were classified. In these specimens, 17 mBACs (9%) and 34 non-mBACs (19%) were found. We extracted 41 cases of BACs (all mBACs and 24 cases of non-mBACs as control), and examined their EGFR mutations and K-ras mutations. We used the PNA-LNA PCR clump method to detect EGFR mutations, and K-ras mutations were explored by sequences after the enriched PCR method. Results: Only three EGFR mutations were found in 17 mBACs (18%), and 12 K-ras mutations were present (71%). By comparison, 14 EGFR mutations were detected in 24 non-mBACs (58%), and 11 K-ras mutations were identified (46%). Conclusions: In mBAC cases, the efficacy of EGFR-TKIs is poor, because EGFR mutation is rare and K-ras mutation is frequent. No significant financial relationships to disclose.

2007 Annual Meeting of the National Lung Cancer Partnership: A Summary of Meeting Highlights

This report presents highlights from The National Lung Cancer Partnership's Annual Meeting, held in June 2007 in Chicago. It discusses recent refinements in the histologic, genetic, and epigenetic subtyping of lung cancers and suggests reasons why certain therapies benefit only a subset of lung cancer patients. It also describes new molecular data about the subtype-specific differences in drug resistance among bronchioloalveolar-associated non-small cell lung cancers and discusses strategies to avoid or tackle specific drug-resistant tumors. Finally, it describes new findings about epigenetic differences-specifically in DNA hypermethylation-among lung tumors, including some male/female differences, which may prove useful as biomarkers for diagnosis, prognosis, and prediction of response to treatments.

Value of thyroid transcription factor-1 in identification of the prognosis of bronchioloalveolar carcinoma

To study the expression and clinical significance of cytokeratin subtypes CK7 and CK20 and thyroid transcription factor-1 (TTF-1) in bronchioloalveolar carcinoma (BAC), and to investigate the value of these factors in identification of the prognosis of BAC. Eighty-one specimens of BAC resected during operation, 68 of non-mucinous type and 13 of mucinous type, underwent immunohistochemical examination to detect the expression of CK7, CK20, and TTF-1. The value of these 3 factors in the identification of the prognosis of BAC was examined by survival analysis. All specimens showed positive expression of CK7, CK20, and TTF-1. There was no significant differences in CK7 expression rate among different ages, clinical stages, and pathological subtypes (all P > 0.05). Compared with that in the BAC of stage III and that of BAC of non-mucinous type, the CK20 positive rates of the BAC of stage I - II and mucinous type were both significantly higher (chi(2) = 3.928, P < 0.05, and chi(2) = 11.512, P < 0.05). The TTF-1 positive rates of the BAC of stage III and nonmucinous type were significantly higher than those of stage I - II and mucinous type respectively (chi(2) = 7.840, P < 0.05, and chi(2) = 19.497, P < 0.05). There was a statistically significant positive correlation between the expression of CK7 and expression of TTF-1 (r = 0.257, P = 0.021). Univariate analysis showed that the main prognostic factors were TTF-1 expression (P = 0.017), clinical stage (P = 0.000), tumor diameter (P = 0.017) and N stage (P = 0.000). Strata analysis suggested that in the nonmucinous type BAC patients the survival time of those positive for TTF-1 expression was superior to those negative for TTF-1 (P = 0.009); and in the stage III BAC patients the survival time of those positive for TTF-1 was superior to those negative for TTF-1 (P = 0.022). Cox regression analysis suggested that TTF-1 (P = 0.035), TNM stage (P = 0.000), tumor diameter (P = 0.034), and N stage (P = 0.000) were independent factors affecting the prognosis. There is a statistically significant positive correlation between the expression of CK7 and the expression of TTF-1. TTF-1 and CK20 provide a new evidence for the molecular staging of BAC. TTF-1, TNM stage, tumor diameter and N stage are all independent factors affecting the prognosis of BAC.

Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung

Activating epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung adenocarcinomas, especially adenocarcinomas with a nonmucinous bronchioloalveolar carcinoma component. EGFR-mutated lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors. We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the pathogenesis. We examined 54 atypical adenomatous hyperplasias, precursor lesions of lung adenocarcinomas, obtained from 28 Japanese patients for the hotspot mutations of EGFR exons 19 and 21 and K-ras codon 12. EGFR mutations were observed in 17 of the 54 (32%) atypical adenomatous hyperplasias examined: Ten and seven atypical adenomatous hyperplasias had deletion mutations at exon 19 or point mutations (L858R) at exon 21, respectively. We did not observe apparent histological differences between atypical adenomatous hyperplasias with and without EGFR mutations. K-ras mutation (G12S) was detected in only one atypical adenomatous hyperplasia. As EGFR mutational frequency of atypical adenomatous hyperplasias was much lower than that of nonmucinous bronchioloalveolar carcinomas, we surmise that EGFR-mutated atypical adenomatous hyperplasias, but not atypical adenomatous hyperplasias with wild-type EGFR, are likely to progress to nonmucinous bronchioloalveolar carcinomas.

PD1-2-7: Differences in high-resolution computed tomography (HRCT) Findings between mucinous and non-mucinous Bronchioloalveolar Carcinoma (BAC) less than 3cm

PD1-2-7: Differences in high-resolution computed tomography (HRCT) Findings between mucinous and non-mucinous Bronchioloalveolar Carcinoma (BAC) less than 3cm