Redefining bronchioloalveolar carcinoma

Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. Although BAC appears to be on a pathologic continuum with adenocarcinoma, the most recent World Health Organization (WHO) classification system has set stringent criteria for the diagnosis. Though malignant, these cancers tend to be peripheral and grow in a lepedic fashion along the alveolar septae without parenchymal invasion. This clear distinction based on histopathology allows for a more definite separation of the natural history and behavior of BAC in clinical studies. Recent clinical trials of molecular targeted anticancer therapies have led to a deeper understanding of the unique features of this cancer and suggest that BAC may require a different therapeutic paradigm from other NSCLCs.     

Targeted therapies in bronchioloalveolar carcinoma

Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other non-small cell lung cancer (NSCLC) subtypes. According to criteria of the revised 2004 World Health Organization classification it accounts for only 5% of all cases of NSCLC. BAC cases are mostly represented by females and non-smokers and are diagnosed at a younger age. Patients with resected BAC have prolonged survival and a lower recurrence rate after surgical resection than other NSCLC subtypes. In advanced BAC cytotoxic chemotherapy seems as effective as in other NSCLC, although studies on pure BAC are based on small numbers of patients and mainly tested paclitaxel based regimens on preclinical activity on cell lines. A higher than expected response rate to the epidermal growth factor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib was recorded in BAC or in adenocarcinomas with BAC features compared with other NSCLC subtypes, mainly due to a higher rate of never-smoking patients. In fact, these agents demonstrated activity in the first-line setting especially in patients harboring EGFR mutations. The role of molecular predictors of response and survival such as EGFR gene amplification or EGFR mutations is an open field of research in fine-tuning BAC management. New drugs are being tested in advanced BAC, while more prospective data must be collected on predictive and prognostic factors.     

High-dose-rate intraluminal brachytherapy for bile duct carcinoma after surgery.

Five patients with recurrent or residual bile duct carcinoma after surgery were treated with high-dose-rate intraluminal brachytherapy (HDRIBT) using a remote afterloader. External radiotherapy was also given in three cases. HDRIBT is considered to be an effective mode of radiotherapy for residual or recurrent bile duct tumors.     

细支气管肺泡癌的分子生物学研究

目的 细支气管肺泡癌(BAC)发病率呈明显上升趋势,靶向药物已成为BAC治疗热点.本文探索BAC分子生物学特点,包括EGFR-TK结构域的突变、EGFR和HER2的基因拷贝数和蛋白表达,以便探讨它们与BAC的治疗反应及预后关系.方法 采用PCR和DNA测序法检测中国人BAC石蜡包埋组织标本EGFR基因突变情况;EGFR...     

Emerging approaches to advanced bronchioloalveolar carcinoma

Opinion statement Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung adenocarcinoma that has distinct epidemiologic, histologic, radiographic, and clinical features. The strict pathologic definition requires an absence of any invasion through the basement membrane into pulmonary parenchyma, but there is a growing consensus based on recent clinical studies that this diagnosis should be considered to be based on the clinical features of diffuse ground-glass opacities with minimal or no extra-thoracic spread and histology demonstrating adenocarcinoma with a lepidic growth pattern characteristic of BAC, even if there is a component of invasive adenocarcinoma. Although unifocal or even potentially oligometastatic disease is appropriately treated with resection, advanced BAC is generally treated with systemic therapy. However, multifocal BAC may be indolent enough to follow asymptomatic patients without any systemic therapy if patients are comfortable with this approach, because the rate of disease progression may be slow enough to warrant no therapy for many months or even years. For patients who have symptoms and/or clear evidence of progression over a short interval, standard chemotherapy is appropriate, but I would consider treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to be the most appropriate initial therapy. This is based on the well-documented activity of the EGFR TKIs erlotinib and gefitinib, the latter no longer commercially available in advanced BAC. Advanced BAC is now emerging as an area of significant research, and clinical trials are particularly appealing considerations for such patients.     

Fine-needle aspiration biopsy of bronchioloalveolar carcinoma

BACKGROUND: The purpose of the current study was to determine the accuracy of the cytologic diagnosis of bronchioloalveolar carcinoma (BAC) by fine-needle aspiration biopsy (FNAB). METHODS: During a 4-year period (1994-1998), 1664 lung FNABs were performed. Forty-nine patients with BAC diagnosed by FNAB and/or surgical biopsy formed the basis of this study. RESULTS: Twenty-four patients diagnosed with BAC by FNAB had histologic confirmation. Surgical pathology revealed BAC in 15 patients with a cytologic diagnosis of large cell carcinoma (LCA) or adenocarcinoma (ACA). Nine patients diagnosed with BAC by FNAB were found to have ACA histologically. One unsatisfactory aspirate was diagnosed as BAC by surgical pathology. Review of 15 FNAB specimens with a diagnosis of LCA or ACA revealed cytologic features typical of BAC. In six aspirates, additional features such as pronounced nuclear crowding and overlapping, variation in nuclear size, and increased number of pleomorphic cells interfered with the FNAB diagnosis of BAC. Nine FNABs with a diagnosis of BAC were found histologically to have ACA with a focal BAC growth pattern. One unsatisfactory FNAB aspirate diagnosed as BAC histologically was due to sampling error. CONCLUSIONS: A diagnosis of BAC by FNAB is possible using conventional cytologic criteria. Some BACs show pronounced nuclear crowding and overlapping, variation in nuclear size, and an increased number of pleomorphic cells cytologically, which may interfere with an FNAB diagnosis of BAC. FNABs from ACA cases with a focal BAC pattern remain a diagnostic dilemma due to the nature of the lesion. In addition, sampling error by FNAB can be a diagnostic pitfall. Cancer (Cancer Cytopathol) Copyright 2001 American Cancer Society.     

A case of bronchioloalveolar carcinoma. Ultrastructural and lipid-biochemical studies

A case of bronchioloalveolar carcinoma was studied electron microscopically and lipid biochemically. Electron microscopic examination revealed that the tumor was composed of three different types of cells, undifferentiated cells, cells possessing lamellar inclusion bodies within the cytoplasm, and cells containing mucus droplets. The characteristic findings in the phospholipid profiles of this case of bronchioloalveolar carcinoma were a high content of saturated classes of phosphatidylcholine, especially of the dipalmitoyl type, and the occurrence of appreciable amounts of phosphatidylglycerol. These observations indicate that some of the tumor cells examined in this study had the characteristic feature of alveolar type II cell differentiation which is responsible for production of pulmonary surface-active materials. The value of phospholipid analysis in assessing such tumors is emphasized.     

单纯性细支气管肺泡癌的CT诊断

 目的　探讨单纯性细支气管肺泡癌的高分辨CT（HRCT）特点。方法　收集经病理证实的单纯性细支气管肺泡癌患者21例（22处病变），对照术后病理进行回顾性分析。结果　术后病理结果非黏液产生型单纯性细支气管肺泡癌20例，21处病变，黏液产生型单纯性细支气管肺泡癌1例。野口分类：A型3例，B型12例，C型5例，黏液型未作分类。病期分类：21例均为ⅠA期，肿瘤最大径0.3～3.0 cm（平均1.3 cm）。全病例均无胸膜和脉管浸润，无淋巴结转移。HRCT所见：根据磨玻璃密度影（GGO）的含量多少，将病变分为4种类型，病变全部呈GGO为A型（5例）；GGO中心少量线状影为B型（7例）；GGO中心及周边线状影散在为C型（7例）；结节形成型为D型（3例）。伴有胸膜牵引11例。肿瘤境界清晰，边缘光整的病例5例，余17处病变边缘不规则，境界不清。阴影中心部伴有血管、支气管阴影者21例。结论　HRCT能够反映细支气管肺泡癌的病理组织学的结构特征，对于病理侵袭度的预测及预后评估起着重要的作用。     

Computer-assisted image analysis of bronchioloalveolar carcinoma

In clinical trials, response rate is an important endpoint for assessing the efficacy of an anticancer drug. The Response Evaluation Criteria for Solid Tumors (RECIST) has been widely used as a standard method to assess response. The RECIST requires only 1-dimensional measurement of tumor size. However, bronchioloalveolar carcinoma (BAC), which commonly presents as infiltrative or micronodular lesions, is not always readily assessable by RECIST. During the past 2 years, we have been developing computer-based programs to more accurately measure tumor size on chest computed tomography (CT) scans. In a first-generation computer-assisted image analysis (CAIA) system, we were able to capture and quantify lesions on CT scans by linking the software programs of eFilm, HyperSnap, and Scion. We have applied this CAIA approach to measuring BAC response to gefitinib in the Southwest Oncology Group (S0126) trial. However, this first-generation CAIA system involves multiple manual steps and is therefore labor intensive. We are now developing a fully automated CAIA program based on a versatile software platform, ImageJ, created at the National Institutes of Health. Taking theoretical and physical considerations into account, Java plug-in programs for ImageJ are created to automatically analyze CT scans in the Digital Imaging and Communications in Medicine format. We have demonstrated the feasibility of an ImageJ-based automated CAIA program for measuring BAC bidimensionally on CT scans. This automated CAIA system will be applied in a prospective clinical trial of the GVAX vaccine in patients with BAC.     

细支气管肺泡癌的诊断及治疗

细支气管肺泡癌（BAC）是肺腺癌的重要亚型,由于其发病率在逐年增加以及对表皮生长因子受体酪氨酸激酶抑制剂较为敏感而越来越引起人们的关注。现综述细支气管肺泡癌诊断和治疗的研究进展。     

Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma

Mutations of the epidermal growth factor receptor gene (EGFR) have been reported to be present in a considerable fraction of lung adenocarcinomas showing dramatic response to EGFR tyrosine kinase inhibitors. To clarify pathogenic significance of the mutations for the development of lung adenocarcinoma, we investigated stage I lung adenocarcinomas for the mutations. First, 107 cases of macrodissected stage I adenocarcinomas were examined for mutations in exons 18-21 of the EGFR gene. EGFR mutations were detected in 36 of the 107 cases (34%). In particular, among the stage I cases, the mutations were detected in 17 of 42 small-sized adenocarcinomas (相似文献   

Pulmonary Atypical Adenomatous Hyperplasia And Bronchioloalveolar Carcinoma

Objective To study the relationship between atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC). Methods Morphometric, immunohistochemical and ultrastructural analyses were performed in 4 patients with low grade AAH, 5 with high grade AAH and 7 with BAC. Results The mean nuclear areas of high grade AAH and BAC were greater than those of low grade AAH (P<0.05); p53 protein expression was negative in 4 cases of low grade AAH,while the positive rates in high grade AAH and BAC were 40% (2/5) and 57% (4/7), respectively. Conclusiion The development of BAC is stepwise. AAH appears to be a lesion closely related with BAC, probably as its genuine precursor.     

伴有肺内转移细支气管肺泡癌的外科治疗

目的 探讨外科手术对伴有肺内转移的细支气管肺泡癌(BAC)的治疗作用.方法 回顾性分析67例行完全性手术切除并存在肺内转移的非小细胞肺癌(NSCLC)患者的临床病理特征和生存资料,比较含BAC成分的患者(研究组)与其他病理类型患者(对照组)的手术效果和预后差异.结果 研究组28例,对照组39例.研究组患者的术后中位生存时间为58.0个月,明显高于对照组患者(27.0个月,P<0.01).无纵隔淋巴结转移患者的术后中位生存时间为39.0个月,明显高于有纵隔淋巴结转移的患者(14.0个月,P<0.01).同一肺叶内转移和不同肺叶内转移患者的术后生存时间分别为36.0个月和24.0个月,差异无统计学意义(P>0.05).结论 外科手术可有效治疗伴有肺内转移的BAC,尤其是对无纵隔淋巴结转移的患者,手术可取得与早期NSCLC患者类似的效果.目前的TNM分期对伴有肺内转移的NSCLC患者的预后判断不够准确,需要进一步修正.     

Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities.

Bronchioloalveolar cell carcinoma (BAC) has fascinated physicians with its unique epidemiology, pathology, clinical manifestations, and natural history when compared with other non-small-cell lung cancer (NSCLC) subtypes. However, the relative rarity of pure BAC as defined by the WHO, and the inconsistent definitions used in various series, has limited systematic study of this entity. Retrospective and prospective studies suggest that patients with BAC treated with cytotoxic chemotherapy have a longer median survival than those with other subtypes of NSCLC. However, the widely accepted view that BAC is less chemosensitive than other NSCLCs is not clearly supported by the small body of available literature. Antitumor activity of cytotoxic agents and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has been documented in phase II trials but no phase III trials have been conducted in this disease. The observation that profound responses to gefitinib and erlotinib often occurred in NSCLC patients with BAC, and that EGFR tyrosine kinase domain mutations were identified in large part by careful study of such patients, serves as a paradigm for translational research in this disease. The recognition that pure BAC and adenocarcinoma with BAC features behave similarly and as such represent a relatively common entity will facilitate accrual to BAC specific studies. Alternatively, stratification of these histologic subtypes in broader clinical trials in NSCLC is warranted. However, for either strategy to succeed in advancing our understanding of the molecular biology of BAC, it must be accompanied by central pathologic review with detailed classification of such, and of adequate tissue for measurement of known or putative targets of action of the agent under study.     

23例细支气管肺泡癌胸部CT和HRCT分析

目的：分析细支气管肺泡癌的胸部CT和HRCT的影像学特征，提高肺泡癌的诊断水平。方法：对经病理组织学确诊的23例肺泡细胞癌的临床症状、胸部CT和HRCT的影像学特征进行回顾性分析。结果：在23例肺泡癌中，女性15例占65％，最常见症状是咳嗽。按CT和HRCT特征将病变分为局限型（10例）和弥漫型（13例）。局限型呈胸膜下分布，含磨玻璃密度结节和实性结节，有分叶、毛刺、胸膜凹陷征、空泡征和细支气管充气征等。弥漫型可见肺实变征或多发性结节改变。实变区内可见枯树枝征、蜂窝征、磨玻璃密度影，腺泡结节分布于实变影的边缘和／或非实变区的肺叶。结论：胸部CT和HRCT的特征性表现有助于肺泡癌的早期诊断。     

Neutrophils promote aerogenous spread of lung adenocarcinoma with bronchioloalveolar carcinoma features.

PURPOSE: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non-small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features. EXPERIMENTAL DESIGN: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features. RESULTS: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor alpha/tumor necrosis factor alpha receptor inhibitor, interleukin-1alpha /interleukin-1alpha receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis). CONCLUSIONS: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.