Bronchioloalveolar Adenocarcinoma Research Articles

Potent lung tumor promotion by inhaled MWCNT

In the lung, carcinogenesis is a multi-stage process that includes initiation by a genotoxic agent, promotion that expands the population of cells with damaged DNA to form a tumor, and progression from benign to malignant neoplasms. We have previously shown that Mitsui-7, a long and rigid multi-walled carbon nanotube (MWCNT), promotes pulmonary carcinogenesis in a mouse model. To investigate the potential exposure threshold and dose-response for tumor promotion by this MWCNT, 3-methylcholanthrene (MC) initiated (10 μg/g, i.p., once) or vehicle (corn oil) treated B6C3F1 mice were exposed by inhalation to filtered air or MWCNT (5 mg/m3) for 5 h/day for 0, 2, 5, or 10 days and were followed for 17 months post-exposure for evidence of lung tumors. Pulmonary neoplasia incidence in MC-initiated mice significantly increased with each MWCNT exposure duration. Exposure to either MC or MWCNT alone did not affect pulmonary neoplasia incidence compared with vehicle controls. Lung tumor multiplicity in MC-initiated mice also significantly increased with each MWCNT exposure duration. Thus, a significantly higher lung tumor multiplicity was observed after a 10-day MWCNT exposure than following a 2-day exposure. Both bronchioloalveolar adenoma and bronchioloalveolar adenocarcinoma multiplicity in MC-initiated mice were significantly increased following 5- and 10-day MWCNT exposure, while a 2-day MWCNT exposure in MC-initiated mice significantly increased the multiplicity of adenomas but not adenocarcinomas. In this study, even the lowest MWCNT exposure promoted lung tumors in MC-initiated mice. Our findings indicate that exposure to this MWCNT strongly promotes pulmonary carcinogenesis.

Postoperative survival of pulmonary invasive mucinous adenocarcinoma versus non-mucinous invasive adenocarcinoma

PurposeIn 2015, the World Health Organization renamed mucinous bronchioloalveolar adenocarcinoma as pulmonary invasive mucinous adenocarcinoma (IMA). Due to its low incidence and unclear prognosis with surgical treatment, previous studies have presented opposing survival outcomes. We aimed to investigate the differences in surgical prognosis and prognosis-related risk factors by comparing IMA with non-mucinous invasive adenocarcinoma (NMA).MethodsA total of 20,914 patients diagnosed with IMA or NMA from 2000 to 2014 were screened from the Surveillance, Epidemiology, and End Results database. The screened patients were subjected to propensity score matching (PSM) in a 1:4 ratio to explore the survival differences between patients with IMA and NMA and the factors influencing prognosis.ResultsFor all patients, IMA was prevalent in the lower lobes of the lungs (p < 0.0001), well-differentiated histologically (p < 0.0001), less likely to have lymph node metastases (94.4% vs. 72.0%, p < 0.0001) and at an earlier pathological stage (p = 0.0001). After PSM, the IMA cohort consisted of 303 patients, and the NMA cohort consisted of 1212 patients. Kaplan‒Meier survival analysis showed no difference in overall survival (OS) between patients in the IMA cohort and those in the NMA cohort (p = 0.7). Cox proportional hazards analysis showed that differences in tumor pathological type did not influence OS between the two cohorts (p = 0.65). Age (HR: 1.98, 95% CI 1.7–2.31, p < 0.0001), gender (HR: 0.64, 95% CI 0.55–0.75, p < 0.0001), and radiation treatment (HR: 2.49, 95% CI 1.84–3.37, p < 0.0001) were independent predictors of patient OS.ConclusionThere was no significant difference in OS between patients with IMA and those with NMA after surgical treatment. Age, sex, and radiation treatment can independently predict OS.

Downregulation of p38 MAPK Activation and Radiation-Sensitive 52 Expression Enhances 5-Fluorouracil and Erlotinib-Induced Cytotoxicity in Human Lung Squamous Cells

Introduction: 5-Fluorouracil (5-FU) is used to treat various cancers, including non-small-cell lung cancer (NSCLC). It inhibits nucleotide synthesis and induces single- and double-strand DNA breaks. In the homologous recombination pathway, radiation-sensitive 52 (Rad52) plays a crucial role in DNA repair by promoting the annealing of complementary single-stranded DNA and stimulating Rad51 recombinase activity. Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor with clinical activity against NSCLC cells. However, whether the combination of 5-FU and erlotinib has synergistic activity against NSCLC cells is unknown. Methods: After the 5-FU and/or erlotinib treatment, the expressions of Rad52 mRNA were determined by quantitative real-time polymerase chain reaction analysis. Protein levels of Rad52 and phospho-p38 MAPK were determined by Western blot analysis. We used specific Rad52 or p38 MAPK small interfering RNA and p38 MAPK inhibitor (SB2023580) to examine the role of p38 MAPK-Rad52 signal in regulating the chemosensitivity of 5-FU and/or erlotinib. Cell viability was assessed by MTS assay and trypan blue exclusion assay. Results: In 2 squamous cell carcinoma cell lines, namely, H520 and H1703, 5-FU reduced Rad52 expression in a p38 MAPK inactivation-dependent manner. Enhancement of p38 MAPK activity by transfection with MKK6E (a constitutively active form of MKK6) vector increased the Rad52 protein level and cell survival by 5-FU. However, in human lung bronchioloalveolar cell adenocarcinoma A549 cells, 5-FU reduced Rad52 expression and induced cytotoxicity independent of p38 MAPK. Moreover, 5-FU synergistically enhanced the cytotoxicity and cell growth inhibition of erlotinib in NSCLC cells; these effects were associated with Rad52 downregulation and p38 MAPK inactivation in H520 and H1703 cells. Conclusion: The results provide a rationale for combining 5-FU and erlotinib in lung cancer treatment.

The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management.

Purpose: To identify the incidence, preoperative risk factors, and prognosis associated with pathologically positive lymph node (pN+) in patients undergoing a sub-lobar resection (SLR).Methods: This is a retrospective study using the National Cancer Database (NCDB) from 2004 to 2014 analyzing SLR excluding those with any preoperative chemotherapy and/or radiation, follow-up <3 months, stage IV disease, or >1 tumor nodule. Multivariable modeling (MVA) was used to determine factors associated with overall survival (OS). Propensity score matching (PSM) was used to determine preoperative risk factors for pN+ in patients having at least one node examined to assess radiation's effect on OS in those patients with pN+ and to determine whether SLR was associated with inferior OS as compared to lobectomy for each nodal stage.Results: A total of 40,202 patients underwent SLR, but only 58.3% had one lymph node examined. Then, 2,615 individuals had pN+ which decreased progressively from 15.1% in 2004 to 8.9% in 2014 (N1, from 6.3 to 3.0%, and N2, from 8.4 to 5.9%). A lower risk of pN+ was noted for squamous cell carcinomas, bronchioloalveolar adenocarcinoma (BAC), adenocarcinomas, and right upper lobe locations. In the pN+ group, OS was worse without chemotherapy or radiation. Radiation was associated with a strong trend for OS in the entire pN+ group (p = 0.0647) which was largely due to the effects on those having N2 disease (p = 0.009) or R1 resections (p = 0.03), but not N1 involvement (p = 0.87). PSM noted that SLR was associated with an inferior OS as compared to lobectomy by nodal stage in the overall patient population and even for those with tumors <2 cm.Conclusion: pN+ incidence in SLRs has decreased over time. SLR was associated with inferior OS as compared to lobectomy by nodal stage. Radiation appears to improve the OS in patients undergoing SLR with pN+, especially in those with N2 nodal involvement and/or positive margins.

Lung cancer incidence in never smokers in the Southeast of Brazil: 10 years analysis.

e13571 Background: Lung cancer is a leading cause of cancer death worldwide. In Brazil, the Ministry of Health estimated an absolute incidence of 30,200 cases of lung cancer in 2020. Eighty-five percent of diagnosed cases are associated with consumption of tobacco products. Although smoking remains the predominant cause, lung cancer in never smokers is an increasingly prominent public health problem. However, data on this topic, particularly lung cancer incidence rates in developing countries in never smokers are limited. Methods: The data presented in this work correspond to the period from 2007 to 2017 and were extracted from the database of the Hospital Cancer Registry of the Evangelical Hospital of Cachoeiro de Itapemirim (RHC / HECI) through SisRHC, a computerized database management tool for Hospital Cancer Records. Results: Of the 494 patients who were diagnosed with lung cancer aged 18 years or over, 395 (80%) had complete information on a history of tobacco use, of which 68 patients denied smoking. Based on data from 68 patients, the years 2011 and 2012 had the lowest incidence, 6%, of non-smokers with lung cancer. 2009 and 2007 were the years with the highest incidence, 24 and 33% respectively. In the remaining years, the percentage varied between 15 and 23%. Regarding gender, 47 (69%) of the cases were women and 21 (31%) were men. Adenocarcinoma without a specific origin (NOS) was the most frequent histological type in non-smoking patients, with 33 (48.5%) of the cases, followed by malignant neoplasia 10 (14.7%), squamous cell carcinoma NOS 8 (11, 8%) and NOS carcinoma 7 (10.3%), the types of NOS large cell carcinoma, NOS small cell carcinoma, NOS papillary carcinoma, NOS bronchioloalveolar adenocarcinoma and adenosquamous carcinoma account for 10 (14.7%) cases. Analyzing the clinical staging (CE) at the time of diagnosis, 1 (1.5%) had EC 1, 4 (5.9%) EC 2, 12 (17.6%) EC 3, 42 (61.8%) EC 4 and 9 (13.2%) had no reports of staging. The median incidence rate was 17%, confirming that smoking remains the biggest cause of lung cancer, and reinforcing the need for more comprehensive epidemiological analyzes for this population. As the data can reach even higher percentages, as the information is provided by patients, without an available reliability assessment method. Conclusions: Lung cancer in never smokers is a major public health problem and further exploration of its patterns of incidence, etiology and biology is needed.

Lymphangioleiomyomatosis and Micronodular Pneumocyte Hyperplasia in a Patient With Tuberous Sclerosis Complex

Abstract Lymphangioleiomyomatosis (LAM) is a rare progressive disease characterized by proliferation of smooth muscle–like cells in the lung, mediastinum, and abdomen. In the lung, it is seen with cystic destruction of the lung parenchyma, which occurs almost exclusively in premenopausal women. It occurs in about 1% of patients with tuberous sclerosis complex (TSC). MNPH is an extremely rare pulmonary manifestation of TSC, comprising type 2 pneumocytes in a pattern resembling bronchioloalveolar adenocarcinoma. We report a case of both pulmonary LAM and MNPH associated with TSC. A 35-year-old female with a past medical history of TSC with multiple complications was admitted with iatrogenic pneumothorax following nasopharyngeal intubation during a dental procedure. A blebectomy with wedge resection and mechanical pleurodesis was performed. On gross examination, the wedge specimens revealed multiple cysts in a random distribution. Microscopic examination of the lung parenchyma revealed prominent smooth muscle cells with focal nodule formation. Immunohistochemical stains for SMA and HMB-45 were found to be positive and corroborated these findings. Areas of localized nodular proliferation of benign cuboidal type II pneumocytes lining alveolar walls were also identified. These findings are consistent with LAM and MNPH. Clinicopathological correlation with surgical investigation is indispensable in diagnosing LAM and MNPH, especially when radiologic findings are not definitive in these entities.

Effect of invasive mucinous adenocarcinoma on lung cancer-specific survival after surgical resection: a population-based study.

In 2015, the World Health Organization (WHO) announced a new classification of lung tumors. Mucinous bronchioloalveolar adenocarcinomas were reclassified as invasive mucinous adenocarcinomas (IMAs). Due to the rarity or this tumor type, conflicting clinical outcomes have been reported based on small patient numbers. Patients diagnosed as primary lung nonmucinous adenocarcinoma (NMA) or IMA from 2000 to 2014 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. General features of each IMA were explored and the effect of histological characteristics on lung cancer-specific survival was analyzed in matched samples using the TNM staging system. The incidence of IMA among all primary lung cancer patients was 0.2% (1,783/1,154,742), and the incidence of IMA among patients with a primary resected lung adenocarcinoma was 1.5% (531/35,406). IMAs tended to be located in the lower lobe (P<0.001), be well differentiated (P<0.001), and be N0 (91.7% vs. 72.3%, P<0.001), T1 or T2 (P<0.001), and stage I tumors (P<0.001) when compared with NMAs. After matching by stages, a stratified Cox PH analysis revealed that the tumor histologic type (P=0.2) did not increase the risk of lung cancer-specific death, while advanced age (HR 1.03, P<0.001), male sex, and the need for radiation, pneumonectomy or sublobar resections increased the risk of cancer-specific death. The histologic type of the tumor, whether IMA or not, did not affect lung cancer-specific survival times among patients with a primary M0 stage lung adenocarcinoma. When stratified by the TNM staging system, patents that required pneumonectomy, sublobar resection or radiation had shorter lung cancer-specific survival times.

Validating the use of napsin A as a marker for identifying tumorigenic potential of lung bronchiolo-alveolar hyperplasia in rodents

There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is “inflammatory hyperplasia” that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is “latent tumorigenic hyperplasia”, which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma. Previously, lung samples with hyperplastic lesions were obtained from rats exposed to N-bis (2-hydroxypropyl) nitrosamine (DHPN) and fine particles (e.g. quartz), and 19 specific markers were examined immunohistochemically to identify latent tumorigenic hyperplasia. In the cytoplasm of the cells that make up the alveolar wall, we found that napsin A was weakly expressed in the inflammatory hyperplastic lesions, and was strongly expressed in the latent tumorigenic hyperplastic lesions induced by DHPN.To validate the possibility that napsin A may serve as a tumorigenic hyperplastic marker, additional experiments were performed with rats and mice. Latent tumorigenic hyperplasia induced by various carcinogens were positive for napsin A, similar to hyperplasia induced by DHPN. Thus, high expression of napsin A in alveolar walls may serve as a useful marker for detecting the tumorigenic potential of lung hyperplasia in rodents.

Lung Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane in CB6F1-Tg rasH2 Mice.

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks. As a positive control, 10 mice of each sex received a single intraperitoneal injection of 75 mg/kg of N-methyl- N-nitrosourea. Bronchiolo-alveolar adenomas and adenocarcinomas were significantly increased in 1,2-DCE-treated rasH2 mice of both sexes, and bronchiolo-alveolar hyperplasias were significantly increased in female mice. Overall, almost all mice of each sex developed adenomas and/or adenocarcinomas with 100% of female rasH2 mice developing bronchiolo-alveolar adenocarcinomas.

Can CT Screening Give Rise to a Beneficial Stage Shift in Lung Cancer Patients? Systematic Review and Meta-Analysis

ObjectivesTo portray the stage characteristics of lung cancers detected in CT screenings, and explore whether there’s universal stage superiority over other methods for various pathological types using available data worldwide in a meta-analysis approach.Materials and MethodsEMBASE and MEDLINE were searched for studies on lung cancer CT screening in natural populations through July 2015 without language or other filters. Twenty-four studies (8 trials and 16 cohorts) involving 1875 CT-detected lung cancer patients were enrolled and assessed by QUADAS-2. Pathology-confirmed stage information was carefully extracted by two reviewers. Stage I or limited stage proportions were pooled by random effect model with Freeman-Tukey double arcsine transformation.ResultsPooled stage I cancer proportion in CT screenings was 73.2% (95% confidence interval: 68.6%, 77.5%), with a significant rising trend (Ptrend<0.05) from baseline (64.7%) to ≥5 repeat rounds (87.1%). Relative to chest radiograph and usual care, the increased stage I proportions in CT were 12.2% (P>0.05), and 46.5% (P<0.05), respectively. Pathology-specifically, adenocarcinomas (66%) and squamous cell lung cancers (17%) composed the majority of CT-detected lung cancers, and had significantly higher stage I proportions relative to chest radiograph (bronchioloalveolar adenocarcinomas, 80.9% vs 51.4%; other adenocarcinomas, 58.8% vs 38.3%; squamous cell lung cancers, 52.3% vs 38.3%; all P<0.05). However, the percentage of small cell lung cancer was lower using CT than other detection routes, and no significant difference in limited stage proportion was observed (6.8% vs 10.8%, P>0.05).ConclusionCT screening can detect more early stage non-small cell lung cancers, but not all of them could be beneficial as there are a considerable number of indolent ones such as bronchioloalveolar adenocarcinomas. Still, current evidence is lacking regarding small cell lung cancers.

MRNAs and miRNAs in whole blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma after multi-walled carbon nanotube inhalation exposure in mice.

Inhalation exposure to multi-walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma. Six-week-old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA-damaging agent methylcholanthrene (MCA, 10 µg g(-1) body weight) or vehicle (corn oil). One week after injections, mice were exposed by inhalation to MWCNT (5 mg m(-3), 5 hours per day, 5 days per week) or filtered air (control) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for the development of pathological changes in the lung, and whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. Numerous mRNAs and miRNAs in the blood were significantly up- or down-regulated in animals developing pathological changes in the lung after MCA/corn oil administration followed by MWCNT/air inhalation, including fcrl5 and miR-122-5p in the presence of hyperplasia, mthfd2 and miR-206-3p in the presence of fibrosis, fam178a and miR-130a-3p in the presence of bronchiolo-alveolar adenoma, and il7r and miR-210-3p in the presence of bronchiolo-alveolar adenocarcinoma, among others. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT-induced lung pathological changes.

Prevalence of EGFR mutations in newly diagnosed locally advanced or metastatic non-small cell lung cancer Spanish patients and its association with histological subtypes and clinical features: The Spanish REASON study

Background and objectivesThe aim of the REASON study is to determine the frequency of EGFR mutation in advanced non-small cell lung cancer (aNSCLC) patients in Spain (all histologies), and to better understand the clinical factors (gender, smoking habits and histological subtypes) that may be associated with EGFR mutations, in an unselected sample of aNSCLC patients. MethodsAll newly diagnosed aNSCLC patients from 40 selected centers in Spain were prospectively included for a 6-month period. Patient characteristics were obtained from clinical records. Mutation testing was performed on available tumor samples. Exploratory analyses were performed to characterize the clinico-pathological factors associated with presence of EGFR mutations. ResultsFrom March 2010 to March 2011, 1113 patients were included in the study, of which 1009 patients provided sample for EGFR mutation analysis (90.7%). Mutation analysis was not feasible in 146/1113 patients (13.1%) due to either sample unavailability (79/1113; 7.1%) or sample inadequacy (67/1113; 6.0%). Twenty-five out of 1113 patients (2.3%) were excluded due to unavailable information. Most patients (99.5%) were Caucasian, 74.5% were male, and predominantly were current (38.1%) or former smokers (44.0%). Median age was 66 years (range 25–90) and 70.7% of patients had non-squamous histology (57.8% adenocarcinoma, 1.8% bronchoalveolar, 11.1% large-cell carcinoma). Exon 19 deletions and the exon 21 L858R point mutation were analyzed in 942/1009 (93.4%) samples. Mutation rate was 11.6% (82.6% exon 19 dels and 17.4% L858R). To be never smoker (38.1%), female (25.4%), with bronchioloalveolar carcinoma (22.2%) or adenocarcinoma (15.4%) histology was associated with a higher prevalence of EGFR mutations. Exons 18, 20 and 21 (excluding L858R) were analyzed in 505/942 samples, and EGFR mutations were found in 22/505 samples (4.4%). ConclusionThe estimated prevalence of sensitizing EGFR mutations (exon 19 del, exon 21 L858R) in an unselected samples of newly diagnosed aNSCLC patients in Spain (all histologies) is consistent with previous published data in Caucasian patients. When a sample is available, EGFR mutation testing is feasible in over 90% of cases, and may therefore be suitable for routine clinical practice. ClinicalTrials.gov IdentifierNCT01081496.

Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes.

BackgroundEngineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation.ResultsTwenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms.ConclusionsThese data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.

Adenokarzinome der Lunge - die neue Klassifikation

The new, interdisciplinary IASLC/ATS/ERS classification of lung adenocarcinoma has achieved a considerable impact since its publication in the year 2011. It separates tumours into preinvasive, minimally invasive and invasive subtypes. The preinvasive lesions atypical, adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) together with the minimally invasive adenocarcinoma (MIA), have an excellent prognosis after complete resection with 100 % survival. It enables a reproducible tumour grading by the determination of the predominant histological growth pattern which could be confirmed in several follow-up studies. Thereby the mixed subtype was eliminated which formerly represented about 80 % of all adenocarcinomas. Similarly, the terms bronchioloalveolar adenocarcinoma and bronchioloalveolar tumour growth were eliminated because they represented several distinct entities, specifically the in-situ lesions AAH and ACIS as well as the non-in-situ/invasive tumours like minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA). Although the classification is based on data from tumour resections it accommodates the fact that most tumours are diagnosed on biopsies and cytological specimens and includes recommendations for an efficient work-up to preserve tissue for molecular testing. Furthermore, the morphological analysis may provide hints for molecular changes including mutations with therapeutic relevance that may enable targeted molecular diagnostics. This review presents essentials facts of the new classification that will be part of the next WHO classification of lung tumors and its follow-up publications.

Lung Cancer, Histologic Stratification, and Resection Extent: Something for Surgeons to Think About

You would think that thoracic surgeons have plenty to consider when planning for a lung cancer resection in 2013. We have been bombarded with “the small nodule” less than 2 mm, which we have learned can have various inhomogeneities in its computerized tomographic (CT) analysis (1); we have to decide whether the nodule merits a lobectomy (the standard of care) or a sublobar resection (2) (for those heretics in the minority who feel that we don’t need a randomized trial to answer the sublobar vs lobectomy debate); whether we should mark the nodule preoperatively so we will be able to find it because we are sometimes trying to feel a 2-cm sponge within a giant sponge; and whether to perform the case as a video-assisted resection, a robotic resection, or (shudder) as an open procedure with rib resection/spreading. As if those deliberations were not enough, now we must start to worry about whether the (presumed lung cancer) solid or part-solid nodule presented to us on the CT scan has a critical quantifiable element of micropapillary disease, which may be associated with tumor recurrence if we do a wedge resection or a segmentectomy (which, of course, will only be the standard of care for intentional lung cancer resections if this is confirmed by the results of CALGB 140503 “A Phase III Randomized Trial of Lobectomy Versus Sublobar Resection for Small (<2 cm) Peripheral Non–Small Cell Lung Cancer” (3). The article by Nitadori et al. (4) in this issue of the Journal is a continuation of the milestone publications by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society, which have revolutionized the pathologic classification of lung adenocarcinoma (5). As reviewed by Suh (6), the new classification eliminates the categories of bronchioloalveolar carcinoma and mixed subtype adenocarcinoma to achieve precise correlations between predominant histologic subtypes of lung adenocarcinoma and survival in surgically resected patients. The Nitadori et al. article (4) retrospectively analyzed 476 lobectomies and 258 limited resections (either by wedge resection or anatomic segmentectomy) at a single institution in patients with lung adenocarcinomas of 2 cm or less. An important validation of the prognostic importance of the new classification system was demonstrated in the patients who had lobectomies for these small tumors; however, this was not seen in the limited resection group. Why is this? Is it because of the heterogeneity of the procedures performed? Is it because of the absence of clear-cut large margins? There are some other intriguing aspects of the limited resection group in these patients that also should be mentioned. The authors specify that the limited resection group is a combination of compromised (77.1%) patients and patients having intentional resection by less than a lobectomy (22.9%). The literature has documented that wedge resections performed in this population have a substantially higher incidence of local recurrence (7,8); yet, in this series the wedge resections (which were 2.6-fold more frequent than segmentectomies) did not reach statistical significance with regard to the cumulative incidence of recurrences compared with segmentectomies. One could speculate that this lack of recurrences in the wedge resection group was because of larger than average margins taken at the time of resection; however, another interesting finding in this series is that the size of the margin in the sublobar resection group did not influence the cumulative incidence of recurrence. This lack of margin size influence is also disturbingly different from publications com

PET/CT Imaging in Oncology: Exceptions That Prove the Rule

18F-FDG PET/CT is a diagnostic three-dimensional non-invasive device, routinely employed in neurology, cardiology, and oncology, and which contributes to patient care giving functional informations about glucose metabolism. In particular, staging, restaging, follow-up and response to treatment of tumors are the most common applications in oncologic field. Many neoplasms show increased glucose metabolism and consequent 18F-FDG uptake. Nevertheless, some relative differentiated cancers, such as clear cell carcinoma of the kidney and bronchioloalveolar adenocarcinoma, show tipically faintly/no uptake resulting in a consequent negative PET/CT scan. This case report represents an extreme case in which three relative well-differentiated cancer forms, all characterized by low glucose metabolism, affect the same patient at the same time while 18F-FDG PET/CT scan is negative.

NEW LUNG ADENOCARCINOMA CLASSIFICATION IN DAILY PRACTICE

Although histologic criteria remain the foundation of this new classification, it is based on an integrated multidisciplinary platform and defines pathologic entities. One of the novelties is discontinuing the use of the term bronchioloalveolar adenocarcinoma (BAC). New entities are described: “Adenocarcinoma in situ “(AIS) and “Minimally invasive adenocarcinoma (MIA). These modifications of the classification have implications for surgeons with new surgical strategies in the future. For invasive adenocarcinomas, the proposition described here is to present a comprehensive histologic subtyping: individual tumors are then classified according to the predominant pattern and the percentages of the subtypes are also reported. The other part of the work is the establishment of a classification of non-small cell lung carcinomas (NSCLC) for small biopsies and cytology. Subclassification in small biopsies is more problematic. There is however universal agreement that most NSCLC can be classified on H&E stained slides alone without using any immunohistochemical stains and tumors that are readily classifiable on H&E-stained slides should not be stained with immunohistochemical markers because of the obligation for the pathologist to keep tissue for molecular testing. However, some NSCLC are too poorly differentiated to be accurately subclassified by standard H&E criteria. Some markers, especially when used in combination, are indeed useful and accurate in subclassifying poorly differentiated NSCLC. Strategic use of small biopsy and cytology samples is important in order to preserve as much tissues as possible for potential molecular studies. One way to attain this is for each institution to develop a multidisciplinary team that coordinates the optimal approach to obtaining and processing biopsy/cytology specimens to provide expeditious diagnostic and molecular results. In conclusion, the new lung adenocarcinoma classification will not only modify daily practice but will also improve the management of patient.

Lung Inflammatory Effects, Tumorigenesis, and Emphysema Development in a Long-Term Inhalation Study with Cigarette Mainstream Smoke in Mice

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation–induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development.

Relationship between EGFR and KRAS mutations and prognosis in Chinese patients with non-small cell lung cancer: a mutation analysis with real-time polymerase chain reaction using scorpion amplification refractory mutation system

To investigate the gene mutation of EGFR and KRAS in Chinese patients with non-small cell lung cancer (NSCLC), and to analyze the relationship between the gene mutations and the clinicopathological features and EGFR-TKI efficiency. EGFR mutation was detected in 120 patients and KRAS mutation in 104 patients with NSCLC in Peking Union Medical College Hospital from March 2009 to December 2010, and the correlation of the gene mutations with the clinicopathological features and EGFR-TKI efficiency was analyzed in the study. EGFR mutation was detected in 44 of 120 (36.7%) patients with NSCLC, in which three types of EGFR gene mutations were found: deletion in exon 19, exon 21 L858R (2573T > G) and Exon 21 L861Q (2582T > A) mutations. There were 29(24.2%) patients with EGFR exon 19 deletion, 14 (11.7%) patients with EGFR exon 21 L858R mutation and one (0.8%) with EGFR exon 21 L861Q mutation in the patients. All the mutations were single point mutations, and no multiple points mutations detected. EGFR mutation rate of bronchioloalveolar carcinoma and adenocarcinoma were higher than that of non-adenocarcinoma (P = 0.009). EGFR mutation rate was higher in female patients or patients without smoking history than male patients or patients with smoking history (P = 0.014, P = 0.001, respectively) in NSCLC patients. EGFR mutation rate was higher in patients without smoking history or patients with well-differentiated carcinoma than patients with smoking history or patients with moderately-and poorly-differentiated carcinoma (P = 0.008, P = 0.018, respectively). There was no difference in prognosis and EGFR-TKI treatment response rate between EGFR mutation patients and EGFR wild-type patients. Nine (8.7%) patients with KRAS mutation were detected in 104 NSCLC patients. There were four types of KRAS gene mutations detected: KRAS Gly12Ala (GGT > GCT), KRAS Gly12Arg (GGT > CGT), KRAS Gly12Val (GGT > GTT) and KRAS Gly12Cys (GGT > TGT). There were 4 patients with Cys mutation, 2 with Arg mutation, 2 with Val mutation and 1 with multiple points mutation of both Cys and Arg in exon 12. No relationship was found between KRAS mutation and clinicopathological feature either in NSCLC or in adenocarcinoma. Prognosis was worse in patients with KRAS mutation than in wild-type patients (P = 0.008). No patient with both EGFR and KRAS mutation was detected. EGFR mutation rate is related with gender, smoking history and pathological type in NSCLC patients, and is also related with differentiation and smoking history in adenocarcinoma patients. And prognosis is worse in patients with KRAS mutation than that with wild type.

SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa).

7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]