Bronchioloalveolar Carcinoma Component Research Articles

Combined Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Epidermal Growth Factor Receptor Mutation in a Female Patient Who Never Smoked

A female patient in her sixties, who had never smoked, was found to have a 5-mm nodule in a computed tomography (CT) scan. The follow-up CT scan after 19 months showed that the nodule had grown to 26 mm. We performed a left upper lobectomy. Pathological examination revealed a combined large cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma with components of large cell carcinoma and bronchioloalveolar carcinoma (BAC). Tumor cells were separately collected from components of both the LCNEC and adenocarcinoma, and a mutational analysis of the epidermal growth factor receptor (EGFR) gene demonstrated that both components had the same L861Q mutation at exon 21. We assume that the LCNEC originated from the adenocarcinoma based on the fact that the patient was a non-smoking female, the tumor was located in the periphery, the tumor had a BAC component, and the same EGFR mutation was found in both the LCNEC and adenocarcinoma components.

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.

Aberrant Stratifin Overexpression Is Regulated by Tumor-Associated CpG Demethylation in Lung Adenocarcinoma

We previously have shown the aberrant overexpression of stratifin (SFN, 14-3-3 ς) in lung adenocarcinoma. Although SFN is known to facilitate tumor cell proliferation, the mechanism that underlies its aberrant expression has remained unclear. SFN, the downstream target of p53, often has been reported to be hypermethylated and subsequently silenced in certain cancers; however, its hypomethylation-linked reactivation has not yet been validated. In this study, we investigated the DNA methylation status of the SFN promoter region using 8 lung cancer cell lines and 32 specimens of adenocarcinoma tissue. Real-time methylation-specific PCR analysis showed that although both normal lung tissue and adenocarcinoma in situ bore a completely methylated SFN promoter, the promoter region in almost all invasive adenocarcinomas was at least partially methylated. The expression of SFN and its level of methylation were correlated strongly. Furthermore, statistical analysis revealed that the level of methylation became reduced with progression of the pathologic stage, although no clear relationship between methylation level and p53 abnormality was found. These results suggest that methylation-related silencing of SFN occurs in both normal lung tissues and adenocarcinoma in situ, and that demethylation of the SFN promoter participates in the aberrant expression of SFN in invasive adenocarcinoma cells, independently of p53 alteration. This novel finding might be informative for clarifying the mechanism that underlies the progression of early lung adenocarcinoma.

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1cm, 1-2 cm, and ≥2 cm in diameter, respectively, were analyzed. Of the 24 tumors ≤2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p<0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p=0.017). In the tumors ≤2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p=0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n=17) and 82% of the wild-type tumors (n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued.

How many adenocarcinoma lung cancers come from bronchioloalveolar carcinoma?

There is emerging evidence that bronchioloalveolar carcinoma (BAC) is the forerunner of peripheral adenocarcinoma lung cancers (ALC). Since advanced stage ALC is often diagnosed on cytology alone, we hypothesized that the incidence of BAC is underreported and that a large proportion of ALC in our population are part of the BAC-adenocarcinoma sequence. We reviewed the pretreatment computed tomographic (CT) scans of 69 patients with ALC and looked for characteristic features of BAC. The median patient age was 63, and the majority were of Chinese descent (75.4%). Women comprised 43.5% of the patients (30 patients) and never-smokers comprised 47.8% (33 patients). Only 15 patients (21.7%) had surgical specimens. The presence of BAC components was reported in the pathology of 16 patients (23.2%). CT features classically associated with BAC were found in 35 patients (50.7%). These included air bronchograms or bubble-like lucencies in 24 patients (34.8%), ground-glass opacities in 19 (27.5%), consolidation or pneumonic picture in 11 (15.9%), diffuse small or miliary nodules in 10 (14.5%), and the CT angiogram sign in 4 (5.8%). We found provocative radiologic evidence that a large proportion of our ALC cases arise from BAC. The CT findings are consistent with current understanding of the likely pathogenesis of peripheral ALC.

Clinicopathological features of lung adenocarcinoma with KRAS mutations

KRAS and epidermal growth factor receptor (EGFR) mutations are thought to play an important role in the carcinogenesis of lung adenocarcinoma. However, clinicopathological findings of KRAS mutated adenocarcinoma cases have not yet been fully clarified. The authors analyzed the relationship between the KRAS mutation and corresponding clinicopathological findings, focusing on nonmucinous and mucinous bronchioloalveolar elements. EGFR and KRAS mutations were detected in DNA samples extracted from 182 surgically resected tissues of lung adenocarcinomas by the Smart Amplification Process. The relations between gene mutation status and clinicopathological features were analyzed. All adenocarcinoma cases were divided into bronchioloalveolar carcinoma (BAC), adenocarcinoma with bronchioloalveolar features, and adenocarcinoma without BAC components (non-BAC). BAC/adenocarcinoma with bronchioloalveolar features tumors were further assessed for the presence of mucinous features. EGFR and KRAS mutations were found in 76 and 30 cases, respectively. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features was found in 22 cases, which included 10 nonmucinous and 12 mucinous tumors. Of 19 cases with mucinous BAC/adenocarcinoma with bronchioloalveolar features, KRAS mutations were detected in 12, but no EGFR mutation was detected. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features had significantly earlier pathological stages and more favorable prognoses than did non-BAC. Mucinous BAC/adenocarcinoma with bronchioloalveolar features showed less smoking history than did nonmucinous BAC/adenocarcinoma with bronchioloalveolar features and non-BAC. Furthermore, transversion type KRAS mutations were more common in non-BAC. KRAS mutated adenocarcinomas can be divided into BAC/adenocarcinoma with bronchioloalveolar features and non-BAC types. Non-BAC adenocarcinoma is related to smoking history and has a poor prognosis. BAC/adenocarcinoma with bronchioloalveolar features adenocarcinoma, however, has a more favorable prognosis, and mucinous BAC/adenocarcinoma with bronchioloalveolar features has little relationship to smoking history.

Ground-Glass Nodules on Chest CT as Imaging Biomarkers in the Management of Lung Adenocarcinoma

The purpose of this article is to review the clinical significance of ground-glass nodules (GGNs) in the management of lung adenocarcinoma. GGNs can serve as imaging biomarkers that represent the bronchioloalveolar carcinoma component in adenocarcinoma on histology and indicate a better prognosis in patients with lung adenocarcinoma. The evolution of GGNs reflects the multistep progression of adenocarcinoma. Despite the high probability of malignancy of GGNs, the possibility of overdiagnosis should be considered in the management of GGNs.

Risk of Bronchioloalveolar Carcinoma in Patients with Human T-cell Lymphotropic Virus Type 1 (HTLV-I): Case-control Study Results

Human T-cell lymphotropic virus type 1 (HTLV-I) causes not only adult T-cell leukemia (ATL) but also HTLV-I associated T-cell bronchioloalveolitis, which is often chronic and subclinical. We have experienced eight HTVL-I carriers with bronchioloalveolar carcinoma, which is known to arise from bronchioloalveolar pneumocytes. This case-control study clarified the risk of bronchioloalveolar carcinoma in HTLV-I carriers. During the past four years, 212 lung cancer patients were examined for serum anti-HTLV-I antibody. They underwent surgical treatment for lung cancer at Kumamoto University Hospital. Of these, 8 (4%) were HTLV-I carriers. As controls for this case-control study, we selected 24 HTLV-I negative-lung cancer patients (1:3 case-control ratio) matched for sex, age, and smoking status. The distributions of histological types of lung cancer were compared between the case (HTLV-I positive) and control (HTLV-I negative) groups. Histological types of the 8 HTLV-I carriers were bronchioloalveolar carcinoma in 6 patients and adenocarcinoma with bronchioloalveolar carcinoma component in 2. The prevalence of bronchioloalveolar carcinoma in HTLV-I carriers, 6 of 8 (75%), was significantly higher than the 6 of 24 (25%) in HTLV-I negative patients (p = 0.02). The prevalence of bronchioloalveolar carcinoma or adenocarcinoma with bronchioloalveolar carcinoma component in HTLV-I carriers, 8 of 8 (100%), was also significantly higher than the 13 of 24 (54%) in HTLV-I negative patients (p = 0.02). HTLV-I might be one risk of bronchioloalveolar carcinoma, probably because of inflammatory and/or immunologic responses involving bronchioloalveolar pneumocytes.

Association of CYP19A1 polymorphisms with risks for atypical adenomatous hyperplasia and bronchioloalveolar carcinoma in the lungs

Estrogen has been indicated to play an etiological role in the development of lung adenocarcinoma (ADC), particularly bronchioloalveolar carcinoma (BAC), a type of ADC that develops from a benign adenomatous lesion, atypical adenomatous hyperplasia (AAH). Polymorphisms in the CYP19A1 gene cause interindividual differences in estrogen levels. Here, 13 CYP19A1 single-nucleotide polymorphisms (SNPs) were examined for associations with lung AAH risk. AAH is detected as ground-glass opacity (GGO) by computed tomography (CT) examination, and this study consisted of 100 individuals diagnosed with GGO in their lungs among 3088 CT-based cancer screening examinees and 424 without. Minor allele carriers for the rs3764221 SNP showed an elevated risk for GGO [odds ratio (OR) = 1.72, P = 0.017]. Associations of this SNP with risks for lung AAH and BAC in the lungs were next examined using 359 ADC cases whose resected lung lobes were subjected to a histological examination for AAH accompaniment and the presence of BAC components and 330 controls without cancer. The ORs were also increased for lung ADC accompanied by AAH (OR = 1.74, P = 0.029) as well as lung ADC with BAC components (OR = 1.41, P = 0.091). The minor allele was associated with an increased circulating estradiol level (P = 0.079) in a population of 363 postmenopausal women without cancer. These results indicate that CYP19A1 polymorphisms are involved in the risk for lung AAH and BAC in the lungs by causing differences in estrogen levels.

The clinical application value of PET/CT in adenocarcinoma with bronchioloalveolar carcinoma features

The goal of our study was to demonstrate the clinical usefulness of positron emission tomography/computed tomography (PET/CT) for adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, through evaluating the relationship between the intrathoracic lymph node metastases and maximum standardized uptake value (SUVmax), tumor size of the primary tumor and the ratio of BAC component and analysing the correlation of SUVmax, tumor size and the ratio of BAC component. This was a retrospective study. Forty-five patients with focal peripheral lung adenocarcinoma with BAC features were included in this study and underwent the PET/CT scan. Twenty-one patients were women and 24 were men. None of the patients had insulin-dependent diabetes and the serum glucose levels in all patients just before (18)F-FDG was injected were less than 120 mg/dl. The diagnosis of the lesion was made by surgical histopathology. All patients underwent successful surgery, and pathologic examination confirmed that 34 of 118 excised nodal groups in 18 patients were proved to be positive for malignancy. Univariate analysis revealed 3 potential factors related to intrathoracic lymph node metastases: SUVmax (P = 0.002); the ratio of BAC component (P = 0.002); maximum dimension of a tumor on mediastinal window setting images (mDmax, P = 0.025). The maximum dimension of a tumor on pulmonary window setting images (pDmax, P = 0.373) had no significance. A receiver operating characteristic (ROC) curve based on SUVmax, mDmax and the ratio of BAC component was constructed, the area under curve (AUC) was 85.2, 70.3 and 81.5% separately. There was no statistical significance between AUC of SUVmax and AUC of the ratio of BAC component (Z = 0.901, P = 0.368). The AUC of SUVmax and AUC of the ratio of BAC component were significantly higher than AUC of mDmax (Z = 2.112, P = 0.035; Z = 2.016, P = 0.042).The SUVmax and the ratio of BAC component had significant inverse correlation (r = -0.85, P < 0.01). The mDmax and the ratio of BAC component had significant inverse correlation (r = -0.69, P < 0.01). The SUVmax and mDmax had significant correlation (r = 0.60, P < 0.01). PET/CT would be clinically useful for adenocarcinoma with BAC features, because SUVmax obtained by PET/CT can predict the incidence of intrathoracic lymph node metastases at preoperative stages and even for inoperable patients.

Combined mutation pattern analyses of epidermal growth factor receptor and K-ras genes for the differential diagnosis of primary versus metastatic lung adenocarcinomas.

e21010 Background: The differential diagnosis of multiple primary lung cancers (MPLCs) from pulmonary metastases (PMs) is sometimes difficult based solely on the Martini and Melamed's criteria. We investigated whether combined mutation pattern analyses of the epidermal growth factor receptor (EGFR) and K-ras genes were useful for differentiating between MPLCs and PMs. Methods: We conducted a retrospective review of 84 tumors (81 adenocarcinomas and three atypical adenomatous hyperplasias) in 36 patients with multifocal lung adenocarcinomas. Genomic DNA was extracted from paraffin-embedded tissue. The peptide nucleic acid (PNA)-locked nucleic acid polymerase chain reaction clamp method was used for EGFR mutation analysis. The PNA-mediated PCR clamping method was used for K-ras mutation analysis. We determined clonality status of secondary tumors based on the mutation patterns of EGFR and K-ras by comparing them with primary tumors. Correlations between the mutation status and the proportion of bronchioloalveolar carcinoma (BAC) component in a tumor were examined. Results: EGFR and K-ras mutations were detected in 38 (45%) and 24 (29%) of 84 tumors, respectively. Thirty-four (71%) of secondary tumors were diagnosed as a different clonality (MPLC). Seven (15%) of secondary tumors were classified into the same clonality (PM). Clonality status could not be determined for the seven (15%) remaining secondary tumors. A clonality assessment based on the EGFR and K-ras mutation status was possible in 41 (84%) of 48 secondary tumors, and it was consistent with the Martini and Melamed's criteria in 29 (71%) of 41 secondary tumors. The proportion of BAC component in a tumor did not correlate with the EGFR/K-ras mutation status. Conclusions: The combined mutation pattern analyses of EGFR and K-ras enabled a definite distinction between PMLCs and PMs in a large portion of multifocal lung adenocarcinomas. Mutations of EGFR and K-ras in multifocal lung adenocarcinomas frequently occurred randomly, which support the concept of “field cancerization.” No significant financial relationships to disclose.

Genetic Evolution of Epidermal Growth Factor Receptor in Adenocarcinoma With a Bronchioloalveolar Carcinoma Component

BackgroundEpidermal growth factor receptor (EGFR) mutations may accumulate during the multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. This study sought to determine whether metachronous adenocarcinomas with a BAC component emerging in the lung field arise from a single or multiple clones in the same individual. Materials and MethodsSamples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained upon detection of metachronous lesions in the lung field. Genomic DNA was extracted from specimens, and the presence of activating mutations in EGFR was determined via direct sequencing. Our pathologic findings, sequential image information, and genetic data were compared to track evidence of cancer evolution. ResultsBased on EGFR gene analyses of tumor specimens from 431 patients, 17 cases of sequential BAC-related adenocarcinomas, obtained by thoracotomy, were noteworthy. Upon alteration of the BAC/adenocarcinoma components, the EGFR tyrosine kinase inhibitor–untreated series, which had at least one episode of an EGFR-activating mutation, represented 3 potential hypotheses: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, or a switch from wild-type to mutant EGFR, leading to indeterminable cancer progression. ConclusionGenetic analysis, in conjunction with pathologic and radiologic diagnoses, can be used to explore the origin of multifocal BAC. The single-clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of second primary carcinoma. In cases when additional lesions emerge after the radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation.

Value of integrated positron emission tomography revised using a phantom study to evaluate malignancy grade of lung adenocarcinoma

The malignant biological behavior of small-sized lung adenocarcinomas remains obscure, although understanding this feature is important for selecting appropriate treatment. In the current study, the authors evaluated malignancy grades of small adenocarcinomas using fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) in addition to high-resolution CT (HRCT) and pathological analysis in a multicenter setting. A total of 201 patients with clinical T1N0M0 adenocarcinoma underwent PET/CT and HRCT followed by complete surgical resection. Associations between components of bronchioloalveolar carcinoma (BAC) in specimens and maximum standardized uptake values (maxSUV) on PET/CT and ground-glass opacity (GGO) ratios and tumor disappearance rate (TDR) on HRCT were analyzed, as well as associations between these findings and pathological features of the tumors. Variations in maxSUV among institutions and the underestimations derived from small tumors, which are limitations of PET performed in multicenter studies, were adjusted using a phantom study. The maxSUV, BAC ratio, TDR, and GGO ratio (in that order) reflected the grade of tumor invasiveness and lymph node metastasis. The maxSUV and BAC ratio were found to be significant prognostic predictors derived from disease-free survival curves. Although the BAC ratio was found to be significantly associated with preoperative radiographic parameters, the maxSUV, GGO ratio, and TDR (all P < .0001), the degree of correlation with maxSUV (correlation coefficient [R(2)] = 0.1699) was much weaker than that reported with the GGO ratio (R(2) = 0.5860) or TDR (R(2) = 0.5082). Phantom studies can overcome the difficulties of multicenter studies using PET. A higher maxSUV appears to reflect aggressive malignant behavior in clinical T1N0M0 adenocarcinomas, independent of BAC components. Preoperative PET/CT assessment in addition to HRCT could be used to construct hypotheses for a future clinical study of strategies for the treatment of patients with small lung adenocarcinoma.

Comparative analysis of lung cancer with features of bronchioloalveolar carcinoma and other types of adenocarcinoma

Objective The aim of this study was to investigate the clinicopathologic and prognostic factors of the partial subtypes of lung adenocarcinoma, including pure bronchioloalveolar carcinoma (BAC), adenocarcinoma (AC) with BAC component and AC without BAC component.

Is the Epidermal Growth Factor Receptor Status in Lung Cancers Reflected in Clinicopathologic Features?

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are molecular-targeted drugs that are innovatively effective for non-small cell lung carcinomas with EGFR mutations. Epidermal growth factor receptor is a transmembrane receptor forming dimers on ligand binding. These then stimulate signals by activating receptor autophosphorylation through tyrosine kinase activity. Autophosphorylation triggers intracellular pathways facilitating malignant conversion. The most clinically advanced EGFR inhibition strategies include small-molecule inhibition of the intracellular tyrosine kinase domain (gefitinib and erlotinib) and monoclonal antibody-mediated blockade of the extracellular ligand-binding domain (cetuximab). Lung cancers with EGFR mutations are prevalent among patients who are female, of Asian ethnicity, and nonsmokers; thus, they can obtain benefit from EGFR tyrosine kinase inhibitors. To survey histopathologic findings and examine correlations with EGFR mutations. We mainly focused on component cell types (hobnail, columnar, and polygonal) and presence or absence of bronchioloalveolar carcinoma elements and a micropapillary pattern. Although EGFR mutations can be detected by various methods, including polymerase chain reaction-Invader assay or direct sequencing, these are inconvenient. Review of the published literature. Detailed pathologic examination showed significant genotype-phenotype correlations between EGFR mutations and presence of a bronchioloalveolar carcinoma component, a micropapillary pattern, and the hobnail cell type. We conclude that these characteristic histologic features are good predictors of EGFR mutations, and patients with these features might be good candidates for and could benefit from therapy with EGFR tyrosine kinase inhibitors.

Increased cytoplasmic S100A6 expression is associated with pulmonary adenocarcinoma progression

S100A6 is a calcium-binding protein implicated in many cellular processes and frequently upregulated in cancer. Recently it was reported that S100A6 is one of the genes having higher expression in adenocarcinoma mixed subtype with a bronchioloalveolar carcinoma (BAC) component than in pure BAC. To clarify the association of S100A6 expression with stepwise progression of lung adenocarcinoma, S100A6 protein expression was examined on immunohistochemistry in 92 formalin-fixed and paraffin-embedded lung adenocarcinomas. Both the nucleus and cytoplasm of the tumor cells were stained, and the nuclear and cytoplasmic expression of S100A6 was assessed individually. In addition, six frozen surgical specimens were selected, and the expression of S100A6 was confirmed on western blotting. As a result, although it was not possible to detect any significant correlation between nuclear S100A6 immunoreactivity and tumor progression, advanced adenocarcinoma had significantly higher cytoplasmic S100A6 expression than non-invasive lesions or normal lung tissue (P < 0.05). Moreover, the BAC component tended to have weaker staining than any of the other components. These findings indicate that S100A6 may be associated with the stepwise progression and/or invasion of lung adenocarcinoma, especially BAC-type adenocarcinoma. The present results suggest the utility of S100A6 immunohistochemistry as a marker for estimation of malignancy in adenocarcinoma with a BAC component.

Surgical treatment for bronchioloalveolar carcinoma with ipsilateral intrapulmonary metastatic nodules

The staging and treatment of bronchioloalveolar carcinoma (BAC) with pulmonary metastasis are still controversial. This study aimed at evaluating the current staging of BAC with ipsilateral intrapulmonary metastatic nodules and the therapeutic effectiveness of surgical resection. The clinicopathological data of 729 completely and surgically resected patients with non-small cell lung cancer (NSCLC) from December 1999 to December 2006 were retrospectively reviewed. Prognostic factors affecting the overall survival were analyzed by the Kaplan-Meier method and compared by the log rank test. Among 67 NSCLC patients with ipsilateral intrapulmonary metastatic nodules, 54 had multiple nodules in the lobe with primary lesion (T4, PM1) and 13 had additional nodules in the other ipsilateral lobes (M1, PM2). This series consisted of 40 males and 27 females, with a median age of 60.0 years. Of those, 28 had the lesions containing pure or some bronchioloalveolar carcinoma component, while the other 39 had a NSCLC lesions containing non-bronchioloalveolar carcinoma components. The median overall survival time of this series was 24.0 months. Prognostic study demonstrated that bronchioloalveolar carcinoma histology and mediastinal lymph node metastasis had significant adverse impact on the overall survival. The median survival time of the patients with bronchioloalveolar carcinoma was 58.0 months versus 27.0 months in patients with other subtypes of NSCLC (P < 0.01). The median survival times were 39.0 months for the patients with N0 or N1 versus 14.0 months for patients with N2, with a significant difference between the two groups (P < 0.01). There was no significant difference in the survival time between the patients with PM1 (36 months) and those with PM2 (24 months) (P > 0.05). Surgical resection is effective for NSCLC patients with ipsilateral intra-pulmonary metastasis, especially for those with bronchioloalveolar carcinoma components. Our results suggest that the current TNM classification system may be inappropriate for the NSCLC patients with ipsilateral intrapulmonary metastatic nodules, and may need a modification.

Surgical treatment of ipsilateral multi-focal non-small cell lung cancer

The staging and treatment of multi-focal non-small cell lung cancer (NSCLC) are controversial. This study evaluated the effectiveness of surgical treatment for the ipsilateral multi-focal NSCLC. Sixty-eight patients with multi-focal NSCLC underwent complete resection from December 1999 to December 2006. This series included 44 males and 24 females, with a mean age of 60.3 years old (range from 33 to 81 years old). Fifty-four patients had multiple nodules in primary lobe (T4) and 13 patients had additional nodules in non-primary lobe (M1), and a patient was proved to have synchronous primary NSCLC lesions. Surgical treatments included lobectomy in 53 cases, bilobectomy in 4 cases, pneumonectomy in 2 cases, and lobectomy combined with wedge resection in 9 cases. The median overall survival time of this series was 30 months. Prognostic study demonstrated that mediastinal lymph node metastasis and bronchioloalveolar carcinoma histology had significant impact on overall survival. The median survival times were 39 months for patients with N0 and N1, and 14 months for patients with N2, respectively, and there was significant difference between the groups (P < 0.01). The difference in survival was significant between patients with bronchioloalveolar carcinoma components and other NSCLC histologic types (P < 0.01), and the median survival times were 46 months and 20 months, respectively. Surgery could provide choice for multi-focal NSCLC patients (T4 and M1), especially for patients with bronchioloalveolar carcinoma components and without mediastinal lymph node metastasis.

Subepithelial myofibroblast in lung adenocarcinoma: a histological indicator of excellent prognosis

We report here the presence of subepithelial myofibroblasts in pure bronchioloalveolar carcinoma and a subset of invasive lung adenocarcinoma. The subepithelial myofibroblasts we describe were observed in a peculiar location beneath the cancer cells in the alveolar septa. Immunohistochemically, they were positive for α-smooth muscle actin and calponin, but negative for desmin and h-caldesmon. To gain insight into their biological significance, we examined 116 surgically resected lung adenocarcinomas. The resected tumors included 13 bronchioloalveolar carcinomas, 20 mixed type adenocarcinomas with bronchioloalveolar carcinoma components, 57 papillary adenocarcinomas, 22 solid adenocarcinomas with mucin, and 4 acinar adenocarcinomas. All specimens were immunostained for α-smooth muscle actin to visualize the myofibroblasts. In all of the pure bronchioloalveolar carcinomas observed, the subepithelial myofibroblasts were completely preserved adjacent to the cancer cells. In mixed adenocarcinomas with bronchioloalveolar carcinoma components, subepithelial myofibroblasts were present in the bronchioloalveolar carcinoma components, but scanty in the invasive areas, where stromal myofibroblasts emerged between the cancer cell nests. Subepithelial myofibroblasts were retained, however, in the invasive areas of a subset of invasive adenocarcinomas. Survival analysis showed that the retention of subepithelial myofibroblasts in these invasive tumors was associated with low rates of lymphatic and vascular invasion, a low rate of lymph node involvement, and an excellent patient survival. These results suggest that subepithelial myofibroblasts increase in bronchioloalveolar carcinomas, but are gradually replaced by typical stromal myofibroblasts during progression into invasive cancer. A subset of invasive adenocarcinomas retains subepithelial myofibroblasts. Analysis of subepithelial myofibroblasts may be helpful in identifying a subset of lung adenocarcinoma with excellent prognosis.

Value of FDG-PET/CT findings revised using an anthropomorphic body phantom for the evaluation of tumor malignancy grade in small-sized lung adenocarcinomas: A multicenter study

7573 Background: The malignant behavior of small lung adenocarinomas (AD), which have been detected with increasing frequency recently, has not yet been clearly evaluated, and an understanding of this biological characteristic is vital for selecting the appropriate therapeutic strategy. We examined the malignancy grade of small lung ADs using FDG-PET/CT (PET), in addition to high-resolution CT (HRCT) and pathologic evaluation in a multicenter setting. Methods: A total of 204 patients with cT1N0M0 AD underwent PET and HRCT, followed by complete resection with lymph node dissection. The associations between components of bronchioloalveolar carcinoma (BAC) on pathologic examination and maximum standardized uptake value (maxSUV) on PET, ground-glass opacity (GGO) ratio and tumor disappearance rate (TDR) on HRCT were examined, and these findings were analyzed in relation to pathologic features and surgical outcomes. To reduce the errors in PET machines used for this analysis, maxSUV data were adjusted using an anthropomorphic body phantom of the NEMA standards (corrected maxSUV). Results: Examination of tumor aggressiveness based on the presence of lymphatic, vascular and pleural invasion, and of nodal metastasis, showed that maxSUV, BAC ratio, TDR, and GGO ratio, in the order, can reflect the malignancy grade. MaxSUV and BAC ratio were also valuable prognostic predictors of the disease-free survival. There were no significant differences in the values between maxSUV and corrected maxSUV. Although BAC ratio was significantly associated with maxSUV, GGO ratio and TDR (all p&lt;0.0001), the degree of association with maxSUV (R2=0.2533) was weaker than that with GGO (R2=0.5843) ratio or TDR (R2=0.5123). Conclusions: A higher maxSUV reflects an aggressive malignant behavior of cT1N0M0 ADs, independently of BAC component. Assessment by PET in addition to HRCT is useful for selection of the appropriate treatment strategy for small lung AD. [Table: see text] No significant financial relationships to disclose.