Bronchioalveolar Cell Carcinoma Research Articles

Abstract 1302: Genetic analysis in a patient with nine primary malignant neoplasms: A rare case of Li-Fraumeni syndrome

Abstract The identification of patients with hereditary cancer predisposition syndromes has important clinical implications for early diagnosis, prevention, and treatment. We applied whole exome sequencing to identify mutations underlying a patient diagnosed with Li-Fraumeni syndrome, who had a first-degree family antecedent of breast cancer at age 42 years. Nine primary metachronous malignant neoplasms were developed in this patient within a period of 38 years, including upper lip neuroblastoma (7 years) and rhabdomyosarcoma (7 years), breast cystosarcoma phyllodes carcinoma (28 years), bronchioalveolar cell carcinoma (29 years), breast infiltrating ductal carcinoma (39 years), and thyroid papillary carcinoma (39 years), gastric adenocarcinoma (41 years), maxillary (41 years) and sternal osteosarcoma (43 years), as well as acute myeloid leukemia (45 years). Peripheral blood lymphocyte DNA from the patient was obtained. Exome capture was performed using the SureSelect Human All Exon 51Mb System, and paired-end sequencing was performed using Illumina HiSeq90 platform. A bioinformatics pipeline was used to analyze sequencing reads and call single nucleotide variants (SNVs). We used a candidate strategy to analyze mutations in the case of only a single dominantly affected individual available. Whole-exome sequencing of peripheral blood lymphocyte DNA resulted in an output of 30 GB of raw sequence. After quality control, we obtained clean reads with an average depth of coverage of 105× and 99.4% exome regions were covered at least four times. Analysis of 451,409 SNVs revealed increased genetic risk for some cancers, including genes related to hereditary cancer disposition syndromes [e.g., TP53 (p.P72R and p.R273H), BRCA1, and BRCA2], and genes associated with sporadic cancers. Pathway analysis found that, of 68 genes in p53-signaling pathway, the number of mutated genes (n=14) was significantly higher than expected (P=0.02). Of novel mutations, five nonsense mutations in four genes and 242 missense mutations in 233 genes were discovered. Whole-exome sequencing can identify known and/or novel mutations in cancer susceptibility genes and establish mutation profile in a rare case of Li-Fraumeni syndrome. Citation Format: Xiaoyuan Li, Juan Kang, Qi Pan, Wenwei Yin, Shiwen Tong, Dachun Zhao, Changting Meng, Chunmei Bai, Hong Ren, Keyue Ding. Genetic analysis in a patient with nine primary malignant neoplasms: A rare case of Li-Fraumeni syndrome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2014-1302

Imaging patterns and prognosis of patients with gefitinib-related interstitial lung disease

We aimed to summarize the imaging findings of 25 patients with gefitinib-related interstitial lung disease (ILD), and identify the factors related to prognosis of gefitinib-related ILD in patients with non-small-cell-lung cancer. Diagnosis of gefitinib-induced ILD by at least two chest radiologists was based on a review and analysis of the chest radiography and CT findings plus clinical data in the medical records. All patients were diagnosed with Stage III - IV non-small-cell carcinoma (adenocarcinoma (n = 24), bronchioalveolar cell carcinoma (n = 1)) and essential clinical data such as gefitinib as first-line use and survival status were recorded and analyzed to determine whether these were prognosis predictors. The imaging findings were classified into four patterns according to the previous largest study in Japan. The 25 chest radiographs were classified as Pattern A (n = 8), Pattern B (n = 3), Pattern C (n = 6), and pattern D (n = 8). Likewise the 23 CT images were classified as pattern A (n = 8; 34.8%), B (n = 3; 13%), C (n = 5; 21.7%), and D (n = 7; 30.4%). The mortality rate was significantly higher in patients with pattern D than in patients with the other patterns. Pattern D imaging findings were also significantly correlated with non first-line use of gefitinib (p = 0.007). We found an increase in mortality rate in patients with gefitinib associated ILD/pattern D compared to other radiological patterns. Familiarity with these imaging patterns can facilitate early and accurate diagnosis and help physicians gauge clinical prognosis of gefitinib-related ILD.

Abstract 2176: Vascular endothelial growth factor receptor-2 (VEGFR-2) gene variations in bronchioloalveolar cell carcinoma (BAC)

Abstract Background VEGF receptor-2 (VEGFR-2) is a key receptor in VEGF-mediated angiogenesis. It plays a significant role in tumor growth and development of metastases. A few studies suggested the angiogenic feature of bronchioalveolar cell carcinoma (BAC), a rare subtype of adenocarcinoma. However the biology of VEGFR-2 in BAC has not been clearly characterized, probably due to its rarity. We sought to determine whether differences in VEGFR-2 expression and microvessel density (MVD) in adenocarcinoma with BAC features (AWBF) might be due to heritable genetic variation in the VEGFR-2 gene. Differences in VEGFR-2 expression and MVD between the pure BAC component of tumor and AWBF, and their comparison with adjacent normal tissue, were also investigated. Methods DNA was extracted from 46 formalin-fixed paraffin embedded AWBF tissues. Four single-nucleotide polymorphisms (SNPs) and four in/dels were genotyped in all tumors. Tissue microarrays (TMAs) were constructed with tumor tissue (pure BAC component and AWBF component for each tumor) and paired adjacent normal lung tissue. TMAs were stained with anti-VEGFR-2 and anti-phosphorylated-VEGFR-2 (pVEGFR-2) antibodies (scoring: 0-9). MVD was determined by staining with an antibody against CD105, and 95% of the samples had either diffused high or focal high staining. Results The −271G>A genotype showed a clear gene-dosage effect on pVEGFR-2 expression (GG>GA>AA, p=0.04, linear trend analysis) in AWBF but not in BAC (p>0.1). The −271G>A genotype does not affect the MVD in both BAC and AWBF (linear trend analysis and Kruskal-Wallis, p>0.1). The other SNPs and in/dels did not show any significant association with VEGFR-2, pVEGFR-2, and MVD (p>0.1). VEGFR-2 and pVEGFR-2 expression in tumor (AWBF and pure BAC) was more than 10 times higher the paired normal tissue (p<0.001, Wilcoxon matched pairs test). A trend for higher VEGFR-2 expression in AWBF compared to pure BAC (mean score 4.2 vs. 3.8, p=0.08, Wilcoxon matched pairs test) was observed, while no difference was observed for pVEGFR-2 (p>0.1). For MVD, although the proportion of diffused high staining was higher in BAC (60%) vs. AWBF (47%), this difference is not statistically significant (p>0.1, Fisher's exact test). Discussion Our study shows that heritable gene variation of −271G>A in VEGFR-2 might reduce the expression of VEGFR-2 in AWBF. This is consistent with the effect of −271G>A in a luciferase assay (Ye et al., AACR 2007), as well as its effect on VEGFR-2 and pVEGFR-2 staining in breast cancer (Cerri et al., SABCS 2009, abstract #904). Although our data are suggestive of different pattern of angiogenesis between pure BAC and AWBF, our sample size is too small to draw any definitive conclusions. Additional studies are ongoing to replicate these findings that will establish the role of genetic variation as a determinant of VEGFR-2 expression in BAC, and the biology of angiogenesis in this rare tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2176.

The right operation for the wrong reason in multi-focal non-small cell lung cancer

In a sixty-seven year old female smoker, a right lower lobe mass, intimately related to the mediastinum, was detected on computed tomography (CT) scanning. Bronchoscopy confirmed non-small cell lung cancer (NSCLC) and a subsequent integrated 18F-FDG Positron Emission Tomography (PET)/CT scan demonstrated a rim of non-FDG avid tissue between the lung tumour and the mediastinum, and no nodal or distant metastases. The patient was pre-operatively staged as cT3N0M0 and proceeded to exploratory thoracotomy. On histological examination of the resected right lower lobe, multiple deposits of bronchioalveolar cell carcinoma (BAC) were found surrounding a central adenocarcinoma, in addition to a small deposit of adenocarcinoma in a right upper lobe wedge resection sample. Neither the BAC deposits nor the upper lobe disease had been detected on integrated FDG-PET/CT scanning. The final pathological staging of this case (pT4N0M1 (stage IV)) is inconsistent with the improved survival rate of patients with multi-focal intrapulmonary NSCLC confined to the lung over other forms of T4 or M1 disease, particularly when the BAC cell type is involved. This case highlights these major limitations of the current TNM classification and discusses the increased risk of false negative results from integrated FDG-PET/CT scanning in the BAC form of NSCLC.

Non-Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship

Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non-small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non-small cell lung cancer using computed tomography or positron emission tomography is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage III lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anti-cancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, erlotinib, and epidermal growth factor receptor.

Location as an important predictor of lymph node involvement for pulmonary adenocarcinoma

Increasing data implicate histologic grade and radiographic appearance along with tumor size as key prognostic indicators for pulmonary adenocarcinoma. The impact of tumor location on prognosis has not been examined. The records of 530 consecutive patients with pulmonary adenocarcinoma pathologically staged between June 1979 and July 2002 were reviewed. All patients had a preoperative computed tomographic scan of the chest and underwent surgical staging by mediastinoscopy, lymph node sampling, or lymph node dissection. Patients with bronchioalveolar cell carcinoma were excluded. Peripheral tumors were compared with central tumors with regard to stage and survival. A tumor was considered to be central if visualized within the inner third of the lung field or seen bronchoscopically. Patients with T1 cancers were further analyzed on the basis of tumor size. Survival was determined by the Kaplan-Meier analysis and comparisons were made by the log-rank method. Central tumors were more advanced and demonstrated a significantly (P < .0001) poorer survival than peripheral tumors (median 18 vs 39 months). Sixty percent of patients with central tumors had stage III or stage IV disease compared with 25% of those with peripheral tumors. Central T1 tumors, however, demonstrated a 50% incidence of lymph node involvement. Although the incidence of lymph node metastases increased incrementally with the size of peripheral T1 tumors, it remained 50% for central T1 tumors irrespective of size. Tumor location for pulmonary adenocarcinoma should be considered when planning therapy. Central tumors have a high incidence of lymph node metastases (regardless of size) and a poorer prognosis.

Percutaneous Lung Biopsy in a Patient with a Cavitating Lung Mass: Indications, Technique, and Complications

2Division of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, Boston, MA. Case History A 75-year-old man was admitted to the hospital with an acute myocardial infarction. The patient was a former heavy smoker. A chest radiograph revealed a left apical lung mass (Fig. 1). A CT scan showed a cavitary left upper lobe lung mass measuring 3.5 × 4 cm (Fig. 2A) with an additional 3 × 2 cm mass at the left hilum (Fig. 2B). A wholebody PET scan showed the left upper lobe mass and at the left hilum, increased 18F-FDG uptake that was suggestive of lung neoplasm metastatic to the left hilum (Fig. 3). Therefore, a thoracic radiologist was consulted for biopsy of the left upper lobe lung mass. Dr. Titton. It is interesting to note that a PET scan was obtained for this patient. What is the role of 18F-FDG PET in the evaluation of patients with a pulmonary nodule or lung cancer? Dr. Kalra. In the evaluation of patients with a solitary pulmonary nodule, 18F-FDG PET improves characterization of the nodule by estimating the probability of malignancy. The high positive predictive value for malignancy in nodules greater than 1 cm in diameter suggests that those with positive scan results should undergo either percutaneous biopsy or surgical resection. Histologic examination of PET-positive lesions is necessary because false-positive PET findings can be encountered with granulomatous lesions secondary to sarcoidosis, tuberculosis, or infection [1]. False-negative PET findings are seen in patients with small lesions (< 1 cm) and in selected malignancies, such as bronchioalveolar cell carcinoma or well-differentiated adenocarcinoma or carcinoid tumor. For this reason, regardless of PET findings,

Bronchioalveolar Cell Carcinoma: Radiologic Appearance and Dilemmas in the Assessment of Response

Bronchioalveolar cell carcinomas (BACs), a subset of primary lung adenocarcinomas, are uncommon. Histologically, they are a diverse group of malignancies. The diagnosis is restricted to adenocarcinomas that grow in a lepidic manner and that have no stromal, vascular, or pleural invasion. Their histologic diversity leads to varied radiologic manifestations that are often indistinguishable from those of other primary non–small-cell lung cancers (NSCLC). However, typical manifestations, many of which can be attributed to lepidic growth, have been reported. Radiologic manifestations include a solitary peripheral pulmonary nodule, airspace disease, and multiple nodules and a combination of these findings can be present in a single patient. The most common manifestation, a solitary pulmonary nodule, is usually indistinguishable from other primary NSCLC. However, pseudocavitation and air bronchograms within the nodule can be useful in suggesting the correct diagnosis. In addition to aiding in the diagnosis of BAC, radiologic imaging is an important component in the evaluation of the therapeutic efficacy of treatment; serial measurements of tumor size before and after treatment are commonly used to assess response. However, BACs that are consolidative or ground-glass in nature present challenges in tumor-response determination. Other imaging modalities, such as positron emission tomography scanning, may prove helpful in assessing the metabolic response to therapy but have yet to be proven effective.

Sclerosing hemangioma of the lung. An epithelial tumor composed of immunohistochemically heterogenous cells.

Lung tissues from 16 patients with pulmonary sclerosing hemangioma were studied with the use of serial sections and immunoperoxidase staining for surfactant apoprotein, secretory component (SC), and epithelial membrane antigen (EMA). The cells lining papillary projections or cystic spaces were stained with surfactant apoprotein, SC, and EMA. Characteristic round stromal cells, which were considered to be the main component of the sclerosing hemangioma, consisted of immunohistochemically heterogenous cells, that is, positive findings were attained with all three antigens, surfactant apoprotein- and EMA-positive ones, SC- and EMA-positive ones, only EMA-positive ones, and all three negative. When investigating the immunoreactivity of neoplastic type II pneumocytes in bronchioalveolar cell carcinoma and hyperplastic ones in nonneoplastic pulmonary disorders, the authors found that almost all the neoplastic type II pneumocytes had all three antigens. Many of the hyperplastic and normal type II pneumocytes, however, were stained with surfactant apoprotein and EMA but not with SC. The authors' findings add further support for the proposal that sclerosing hemangioma of the lung is epithelial in origin. In view of the various staining patterns found in the stromal cells, sclerosing hemangioma probably consists of immunohistochemically heterogenous epithelial cells. The staining pattern of the cells lining papillary projections or cystic spaces was similar to that of neoplastic type II pneumocytes rather than that of hyperplastic type II pneumocytes.

Mucin-producing bronchioalveolar-cell carcinoma. With special reference to a characteristic structure revealed by phosphotungstic acid-hematoxylin staining

Mucin-producing bronchioalveolar-cell carcinoma. With special reference to a characteristic structure revealed by phosphotungstic acid-hematoxylin staining