Cigarette smoking associated with lung adenocarcinoma in situ in a large case-control study (SFBALCS).

INTRODUCTION: Adenocarcinoma in situ (AIS), formerly bronchioloalveolar carcinoma, is an uncommon subtype of lung adenocarcinoma and accounts for approximately 3% to 4% of lung cancers. Compared with other lung cancer histologies, AIS patients are less likely to be smokers, yet associations with other lung cancer risk factors and differences by sex have not been determined. METHODS: A total of 338 AIS patients and frequency-matched controls from the parent study (cases = 6039, controls = 2073) were included in these analyses. Odds ratios and 95% confidence intervals as estimates of the relative risk were obtained from multivariable unconditional logistic regression analyses. RESULTS: Risk of AIS was associated with ever smoking (OR = 2.7, 95% confidence intervals: 2.1, 3.6), increased 20% to 30% for each 10-year increase in pack-years of smoking and decreased with increased years since quitting (p for trend <0.0001). There was no evidence that risk differed by sex but there was some suggestion that risk may differ by exposure to asbestos and by second-hand tobacco smoke exposure in whites. CONCLUSION: There is an association between AIS and smoking, which is smaller in magnitude than the association between other subtypes of non-small-cell lung cancer and smoking. Our findings suggesting that effects may differ by exposure to asbestos and second-hand tobacco smoke should be interpreted conservatively and warrant validation and further evaluation in larger studies of AIS.

Influence of cigarette smoking on histological subtypes of stage I lung adenocarcinoma.

BACKGROUND: The purpose of this study was to examine the association between cigarette smoking and histological subtypes of lung adenocarcinoma. METHODS: We reviewed a total of 320 consecutive patients with stage I adenocarcinoma who underwent complete resections with systematic node dissections from January 2004 to December 2006 at the National Cancer Center Hospital East. RESULTS: A statistically significant difference was observed in recurrence-free probabilities between never smokers and ever smokers (3-year recurrence-free probabilities of 95.6% and 88.6%, respectively, p = 0.034). Among adenocarcinoma histological subtypes, only a solid component was significantly more frequent in ever smokers than in never smokers (p < 0.001). Among patients with solid components, significantly more cases had lymphatic permeation (p = 0.007), intratumoral vascular invasion (p < 0.001), and visceral pleural invasion (p < 0.001). Multivariate analysis revealed that ever-smoking history was the only statistically significant independent clinical predictor for a solid component (p < 0.001). Among ever smokers, smoking extent in pack-years of patients with solid components was significantly greater than that of those without solid components (p < 0.001). With respect to predominant subtypes, smoking extent in pack-years of patients with predominantly solid adenocarcinomas was significantly greater than that of patients with predominantly bronchioloalveolar carcinoma, papillary, or acinar adenocarcinomas (all p < 0.001). CONCLUSION: A greater smoking extent was associated with the presence of adenocarcinoma solid components, which may have more aggressive biological features resulting in poorer outcomes.

Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case-control studies in the International Lung Cancer Consortium (ILCCO).

BACKGROUND: The International Lung Cancer Consortium (ILCCO) was established in 2004, based on the collaboration of research groups leading large molecular epidemiology studies of lung cancer that are ongoing or have been recently completed. This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer. METHODS: Our pooled data comprised seven case-control studies from the United States, with detailed information on tobacco smoking and histology, which contributed 799 cases of BAC and 15,859 controls. We estimated the odds ratio of BAC for tobacco smoking, using never smokers as a referent category, after adjustment for age, sex, race, and study center. RESULTS: The odds ratio of BAC for ever smoking was 2.47 (95% confidence interval [CI] 2.08, 2.93); the risk increased linearly with duration, amount, and cumulative cigarette smoking and persisted long after smoking cessation. The proportion of BAC cases attributable to smoking was 0.47 (95% CI 0.39, 0.54). CONCLUSIONS: This analysis provides a precise estimate of the risk of BAC for tobacco smoking.

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.

Congenital cystic adenomatoid malformation of the lung: hazards of delayed diagnosis.

Congenital cystic adenomatoid malformation is a rare pulmonary developmental anomaly, which typically manifests in neonates and infants. Presentation in adulthood is uncommon, with <60 cases reported in the literature. The majority of cases involve one lobe only. We report a case of type 1 congenital cystic adenomatoid malformation in an adult presenting with a respiratory tract infection and haemoptysis. At thoracotomy, complex cystic masses were noted in the right upper and lower lobes. Lung-sparing surgery, in the form of two segmentectomies and a non-anatomical resection, was performed in order to avoid pneumonectomy. Such presentations may be problematic as potentially incomplete resections may increase the risk of complications and malignant transformation. This suggests the importance of appropriate clinical and radiological follow up.

Bronchioloalveolar carcinoma as a second malignancy in osteosarcoma survivors.

Second malignancies occur in 2-3% of survivors of pediatric osteosarcoma; treatment-related hematologic and solid malignancies have both been described. We present two cases of patients with pulmonary nodules that developed more than 2 years after treatment of osteosarcoma. Both lesions were completely resected and pathology revealed bronchioloalveolar carcinoma (BAC). Primary BAC is extremely rare in children; however, cases of this malignancy have been described in survivors of pediatric cancer. BAC may present as a solitary pulmonary nodule indistinguishable from a metastatic lesion and should be included in the differential diagnosis of pulmonary nodules in survivors of pediatric cancer.

Prenatal N-acetylcysteine prevents cigarette smoke-induced lung cancer in neonatal mice.

Certain adult diseases may have their origin early in life, and perinatal exposures may contribute to cancers both during childhood and later in life. We recently demonstrated that mainstream cigarette smoke (MCS) induces a potent carcinogenic response in mice when exposure starts soon after birth. We also showed that the antioxidant N-acetylcysteine (NAC) prevents the extensive nucleotide and gene expression alterations that occur 'physiologically' at birth in mouse lung. The present study was designed to evaluate whether administration of NAC during pregnancy may affect the yield of tumors in mice exposed to MCS, starting after birth and continuing for 120 days. The results obtained showed that 210 days after birth, one adenoma only was detectable in sham-exposed mice. In contrast, as much as the 61.1% (33/54) of MCS-exposed mice born from untreated dams had lung tumors, including both benign tumors and bronchoalveolar carcinomas. Treatment with NAC during pregnancy strikingly inhibited the formation of benign lung tumors and totally prevented occurrence of carcinomas. In addition, prenatal NAC inhibited the MCS-induced hyperplasia of the urinary bladder epithelium. These findings demonstrate for the first time that treatment during pregnancy with an antioxidant chemopreventive agent can affect the induction of tumors consequent to exposure to a carcinogen after birth.

The impact of cigarette smoking on prognosis in small adenocarcinomas of the lung: the association between histologic subtype and smoking status.

OBJECTIVE: In this retrospective study, we clarified the impact of smoking on prognosis and the association of clinicopathological factors, particularly histologic subtype, in patients with small adenocarcinoma of the lung. METHODS: Between 1996 and December 2006, 121 patients presenting with adenocarcinomas that had a diameter

Histological evaluation of the effect of smoking on peripheral small adenocarcinomas of the lung.

INTRODUCTION: As there is little information on the histologic characteristics of adenocarcinoma in smokers, we histologically examined the effect of smoking on the carcinogenesis and progression of peripheral small lung adenocarcinomas. METHODS: Two hundred thirty-six consecutive patients with peripheral adenocarcinoma of the lung 30 mm or less in diameter were studied. Prognosis, histology, and location of the adenocarcinoma were compared among patients with a Brinkman index (B.I.) of 0, 1 to 500, and more than 500. RESULTS: The ratio of smokers to nonsmokers was 1.4:1. The rate of carcinogenesis in the upper region of the lung (S1-3) was 1.4 times as high that in the lower region (S4-10) in smokers, but almost equal in the two regions in nonsmokers. Outcome tended to be worse in patients with a B.I. of more than 500 than in those with a B.I. of less than or equal to 500 for adenocarcinomas 30 mm or less in diameter (p = 0.0855), and was significantly worse for adenocarcinomas 20 mm or less in diameter (p = 0.0359). Patients with a high B.I. tended to have invasive adenocarcinoma (IAC) without a bronchioloalveolar carcinoma (BAC) component (IAC - BAC) or IAC with a BAC component (IAC + BAC) rather than noninvasive adenocarcinoma. For adenocarcinomas as a whole, B.I. was correlated with several pathologic prognostic factors, including pathologic stage, lymphatic permeation, vascular invasion, presence of a solid component, necrosis, and modified scar grade, particularly in the upper region. Specifically, in IAC + BAC, B.I. was correlated with modified scar grade and the presence of a solid component. In IAC - BAC, B.I. was correlated with the presence of a solid component and necrosis. CONCLUSIONS: Small adenocarcinoma in smokers seems to occur frequently in the upper region of the lung, shows invasive features more frequently, and shows greater progression and dedifferentiation than that in nonsmokers. Tobacco-smoking may have an effect on the carcinogenesis and multistep progression of peripheral lung adenocarcinoma 30 mm or less in diameter.

Mucinous cells in type 1 pulmonary congenital cystic adenomatoid malformation as mucinous bronchioloalveolar carcinoma precursors.

Type 1 congenital cystic adenomatoid malformation (CCAM), the most frequent malformation of the lung, is the only type to present intracystic mucinous cell clusters, which may form beyond the cysts extracystic mucinous proliferation resembling mucinous bronchioloalveolar carcinomas (BACs). As mucinous BACs are increasingly described in the literature in young patients with CCAM, we hypothesized that type 1 CCAM mucinous cells could represent BAC precursors. We reviewed 7 cases of type 1 CCAM including 6 with intracystic mucinous cell clusters, 3 with extracystic mucinous proliferations, and 4 with mucinous BAC or mixed adenocarcinoma with predominant BAC. K-ras mutations at codon 12 were detected in 3/3 intracystic mucinous cell clusters, in 2/3 extracystic mucinous proliferations, and in 3/4 BAC. Loss of heterozygosity (LOH) at p16(INK4) locus, with microsatellite alterations in 3 cases, was observed in 2/3 intracystic mucinous cell clusters, in 2/3 extracystic mucinous proliferations, and in all BAC. Two extracystic mucinous proliferations showed LOH at FHIT and Rb loci, respectively. P16(INK4) expression was lost in 2 intracystic mucinous cell clusters, 1 extracystic mucinous proliferation, and 1 BAC. Neither epidermal growth factor receptor mutation on exons 18, 19, and 21 nor P53 accumulation was observed. All lesions expressed MUC5AC, but were negative for MUC2, CDX2, and TTF-1. In conclusion, type 1 CCAM mucinous cells share the same differentiation profile with corresponding mucinous BAC, consistent with a common bronchial origin. Moreover, the high frequency of K-ras mutation and LOH and/or microsatellite alterations at p16(INK4) locus presented by these mucinous cells justifies their consideration as BAC precursors.

[A case of surgically treated primary lung cancer with myasthenia gravis].

A 62-year-old woman, who had received immunosuppressive treatment for myasthenia gravis, was admitted to our hospital for the treatment of a right pulmonary tumor. In October 2003, a chest computed tomography showed a nodule-like lesion in the right lung. Two years later, the lesion was shown to have increased in size, and a right upper lobectomy was performed using video-assisted thoracic surgery. A tumor biopsy showed histological features of bronchioloalveolar carcinoma. It has been reported that malignant tumors occur more frequently in patients with myasthenia gravis with concurrent thymoma. Therefore, such patients need to be followed closely for a long period of time for any possible malignant tumor occurring in different organs. In addition, protection of the bronchial stump may be necessary to prevent a bronchial fistula, because wound healing can be delayed due to immunosuppressive treatment.

Bronchioloalveolar carcinoma in congenital cystic adenomatoid malformation of lung.

Congenital cystic adenomatoid malformation (CCAM) of lung is a rare condition with the potential for malignant transformation. We report a patient who underwent lobectomy for a cystic lung lesion, which was found to be a type 1 CCAM associated with a mucinous bronchioloalveolar carcinoma. Retrospective review of a biopsy specimen from the same lobe excised during an ipsilateral empyema drainage 11 years previously showed similar foci of bronchioloalveolar carcinoma. The patient remains well 3 years after surgery. This case demonstrates the indolent nature of malignancies seen in association with type 1 CCAMs and also that complete excision, probably by lobectomy, is the treatment of choice to avoid recurrence.

Multiple bronchioloalveolar carcinomas in acromegaly: a potential role of insulin-like growth factor I in carcinogenesis.

The molecular pathogenesis of lung cancer, especially multiple and synchronous bronchioloalveolar carcinomas (BACs), is still unknown. Here, we report two cases of multiple BACs associated with acromegaly, and discuss about the possible relationship between these two pathological condition. The first patient was a 52-year-old female with a history of Hardy's surgery for pituitary growth hormone cell adenoma 2 years earlier. The second patient was a 57-year-old female with acromegaly and obstructive sleep apnea syndrome. Both patients were non-smokers and showed a high serum level of insulin-like growth factor I (IGF-I) at the time of admission, even though the level of growth hormone had decreased. High-resolution computed tomography (HRCT) revealed multiple small nodules with pure ground-glass opacity (GGO) in both lungs of the first patient and a small nodule with pure GGO in the right lung of the second one. Partial resection for these tumors were performed under video-assisted thoracoscopic surgery. Resected lung specimens of the first case revealed one papillary adenocarcinoma, seven BACs, and 11 atypical adenomatous hyperplasias (AAHs). The second case showed two foci of BACs. Immunohistochemically, all BACs were strongly positive for IGF-IR which is a specific receptor for IGF-I, and all AAHs were also weakly positive for IGF-IR. Since IGF-I is known as a potent growth factor for normal as well as cancerous cells, it might play an important role for tumorigenesis and/or tumor progression of BACs through its interaction with and/or upregulation of IGF-IR. In addition, much attention should be paid to detect lung lesions in acromegaly with high serum level of IGF-I.

Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.

Several studies have suggested a possible role of the hepatocyte growth factor (HGF)/c-Met system in lung tumor development and progression. Extent of expression of both HGF and c-Met have been shown to be negative prognostic indicators of survival and recurrence in non-small-cell lung cancer, especially adenocarcinoma. To further define a role for HGF in lung cancer development and growth, we have generated transgenic mice that overexpress HGF in the airway epithelium. HGF transgenic and wild-type mice were exposed to the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or saline control and killed 10-38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. It was verified that the HGF transgene was expressed only in the lungs of transgenic mice. The transgenic mouse lung histology exhibited congestion in the alveolar spaces, excess production of blood vessels and a convoluted pattern of airways with wide bifurcations. The number of lung tumors from NNK-treated transgenic animals versus the number of lung tumors from NNK-treated wild-type animals was significantly higher (P = 0.0001, Poisson regression). The percentage of animals with tumors was 75% in the transgenic group compared with 48.8% in the wild-type group. The main effect was an increase in tumor multiplicity; average size of tumors was not different between the groups. Additionally, the tumors that arose in the transgenic mice contained increased HGF protein compared with tumors from the wild-type mice. These results indicate that lung carcinogenesis induced by a tobacco carcinogen is enhanced by expression of the HGF transgene. This model recapitulates the phenotype of aggressive lung adenocarcinoma that overexpresses HGF and will be useful in evaluating antitumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.

Bronchioloalveolar carcinoma is not associated with younger age at diagnosis: an analysis of the SEER database.

INTRODUCTION: Bronchioloalveolar carcinoma (BAC) is a unique subtype of non-small cell lung cancer (NSCLC) that is associated with female gender, Asian ethnicity, and never-smoking status. Although BAC is commonly reported to occur more frequently in young people with lung cancer, there is a lack of evidence to support this association. METHODS: We analyzed the association between age at diagnosis and NSCLC histology among 293,417 incident cases of NSCLC in the Surveillance Epidemiology, and End Results (SEER) database during the years 1973 to 2002. RESULTS: The mean age of patients with BAC (66.99 years) was similar to the mean age of all patients with NSCLC (66.44 years). The proportion of patients younger than 50 years of age was significantly smaller among patients with BAC than the overall cohort (6.06% compared with 6.90%). Although a greater percentage of women and Asian patients with lung cancer were younger than 50 years old, the proportion of patients with BAC was similar to the proportion of men and non-Asians with BAC. Finally, the prevalence of BAC histology among patients younger than 50 years did not change significantly after revision of the 1999 World Health Organization pathologic criteria for the diagnosis of BAC (risk ratio 0.93 versus 0.87, p = 0.31). CONCLUSION: BAC is not associated with a younger mean age at diagnosis, nor is it associated with an age of less than 50 years at diagnosis. Patients with mixed BAC probably have similar age characteristics compared with patients with pure BAC.

The bronchioloalveolar carcinoma and peripheral adenocarcinoma spectrum of diseases.

Bronchioloalveolar carcinoma (BAC) develops from terminal bronchiolar and acinar epithelia, growing along alveolar septa but without evidence of vascular or pleural involvement. A final diagnosis of BAC can only be achieved from a surgical specimen. Problematically, BAC may exhibit multifocal involvement by means of diffuse aerogenous metastatic spread, making this definition inapplicable for patients with stage IIIB to IV disease from whom only small size biopsy or cytological specimens are obtained. The recent interest and potential importance of BAC and the related peripheral adenocarcinoma (ADC), mixed subtype, is attributable to mounting evidence that some, perhaps many, of what are called peripheral ADCs have arisen from and often contain BAC. BAC, in turn, appears to arise from smaller peripheral nodules, called atypical adenomatous hyperplasia. These developments could account for part of the increase in ADCs noted in some countries, in particular, in East Asia. Interest also stems from the observation that advanced ADC, often with BAC features, are responding in surprising fashion to tyrosine kinase inhibitors. Furthermore, some of the more rapid, dramatic, and durable responses occur when specific mutations in the epidermal growth factor receptor are present. Clinical characteristics often differ from other types of non-small cell lung cancers. These include frequent female occurrence, especially in East Asians; no or less smoking history; an often indolent course; distinctive chest computed tomographic findings; frequent presentation as an asymptomatic, sometimes small, peripheral nodule(s)/mass; multifocal/synchronous primary tumors; and less frequently as pneumonic-type consolidation or diffuse, inoperable lesions, the latter two often with bronchorrhea, and with chest-only disease. Relapses also are predominantly pulmonary, perhaps related to aerogenous spread, and responsible for mortality. Lobectomy is the treatment of choice for cure, even with pneumonic consolidation, but lesser procedures such as wedge resection or segmentectomy may be considered for what might be multifocal, synchronous primary tumors and for pulmonary relapses. Because of frequent lung-only recurrences, lung transplantation, although performed rarely, may hold promise.

High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor.

Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands.

IGF-II induces CREB phosphorylation and cell survival in human lung cancer cells.

We have previously shown that lung tumors arising in MMTV-IGF-II transgenic mice displayed elevated levels of phosphorylated cAMP response element binding protein (CREB). To investigate the role that insulin-like growth factor II (IGF-II) and CREB play in human lung tumorigenesis, A549 and NCI-H358 cells were examined. In these cell lines, IGF-II administration enhances human tumor cell survival and CREB phosphorylation. Further, the effects of IGF-II on cell survival and CREB phosphorylation appeared to be mediated, at least in part, by activation of the Erk pathways, as inhibition of these signaling pathways reduced tumor cell survival and CREB phosphorylation. Specifically, Erk5 appeared as the predominant mediator of CREB phosporylation. To further verify the importance of CREB in human lung tumorigenesis, A549 and NCI-H358 cells were stably transfected with a vector containing a dominant negative CREB construct (KCREB). KCREB transfection significantly inhibited the soft agar growth of both human tumor cell lines. In contrast, overexpression of wild-type CREB in the normal human bronchial epithelial cell line, HBE135, enhanced soft agar growth. Therefore, our results indicate that CREB and its associated proteins play a significant role in lung adenocarcinoma and IGF-II induces CREB phosphorylation, at least in part, via the Erk5 signaling pathway.