Kavita Garg

International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary.

INTRODUCTION The American Thoracic Society is a cosponsor of a newly published lung adenocarcinoma classification. METHODS An international multidisciplinary panel of experts was formed. A systematic review was performed and recommendations were graded by strength and quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS The classification addresses both resection specimens and small biopsies/cytology. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with pure lepidic growth and predominant lepidic growth with ≤ 5 mm invasion, respectively. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added. In the new aspect of this classification that provides guidance for small biopsies and cytology specimens, non-small cell lung carcinomas (NSCLC), in patients with advanced stage disease, are to be classified into more specific types, such as adenocarcinoma or squamous cell carcinoma, whenever possible, for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for EGFR mutations, because the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy, and (3) squamous histology is a risk factor for life-threatening hemorrhage with bevacizumab therapy. NSCLC- not otherwise specified by light microscopy alone should be studied with immunohistochemistry and/or mucin stains. CONCLUSIONS This classification is intended to support clinical practice as well as research investigation and clinical trials.

Pathologic Diagnosis of Advanced Lung Cancer Based on Small Biopsies and Cytology: A Paradigm Shift

With some exceptions, the field of lung cancer disease has been relatively static during the past several decades with few major practice-changing advances. In this issue of the journal 2, articles address the diagnosis of non-small cell lung cancer (NSCLC) based on small biopsies and/or cytology, an area of lung cancer diagnosis in which a paradigm shift has occurred for both pathologists and clinicians. 1,2 This topic is important because the majority patients with lung cancer present with unresectable disease, and the diagnosis is established based on such small specimens. Moreover, with increasing use of minimally invasive biopsy methods, pathologists are being asked to do more with less tissue. HISTORY OF LUNG CANCER DIAGNOSIS IN SMALL BIOPSIES AND CYTOLOGY The World Health Organization classifications of lung tumors through the 1999 edition 3‐5 did not address lung cancer diagnosis based on small biopsies and cytology, because these were recommendations for the histologic classifications of resection specimens. In the 2004 World Health Organization classification, cytology was addressed for the first time, but classification in small biopsies was not addressed. 6 Currently, no internationally recognized standard of criteria or terminology for the diagnosis of lung cancer in small biopsies is available.

Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria. Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a “minimally invasive” adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated. Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of “minimally invasive” BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor. Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.

Radiologic Implications of the 2011 Classification of Adenocarcinoma of the Lung

Now the leading subtype of lung cancer, adenocarcinoma received a new classification in 2011. For tumors categorized previously as bronchioloalveolar carcinoma (BAC), criteria and terminology had not been uniform, so the 2011 classification provided four new terms: (a) adenocarcinoma in situ (AIS), representing histopathologically a small (≤3-cm), noninvasive lepidic growth, which at computed tomography (CT) is usually nonsolid; (b) minimally invasive adenocarcinoma, representing histopathologically a small (≤3-cm) and predominantly lepidic growth that has 5-mm or smaller invasion, which at CT is mainly nonsolid but may have a central solid component of up to approximately 5 mm; (c) lepidic predominant nonmucinous adenocarcinoma, representing histopathologically invasive adenocarcinoma that shows predominantly lepidic nonmucinous growth, which at CT is usually part solid but may be nonsolid or occasionally have cystic components; and (d) invasive mucinous adenocarcinoma, histopathologically showing lepidic growth as its predominant component, which at CT varies widely from solid to mostly solid to part solid to nonsolid and may be single or multiple (when multifocal, it was formerly called multicentric BAC). In addition, new histopathologic subcategories of acinar, papillary, micropapillary, and solid predominant adenocarcinoma are now described, all as nonmucinous, predominantly invasive, may include a small lepidic component, and at CT are usually solid but may include a small nonsolid component. The micropapillary subtype has a poorer prognosis than the other subtypes. In addition, molecular genetic correlations for the subcategories of adenocarcinoma of the lung are now a topic of increasing interest. As the new classification enters common use, further descriptions of related correlations can be anticipated.

Interstitial Lung Abnormalities in a CT Lung Cancer Screening Population: Prevalence and Progression Rate

PURPOSE To determine the prevalence of interstitial lung abnormalities (ILAs) at initial computed tomography (CT) examination and the rate of progression of ILAs on 2-year follow-up CT images in a National Lung Screening Trial population studied at a single site. MATERIALS AND METHODS The study was approved by the institutional review board and informed consent was obtained from all participants. Image review for this study was HIPAA compliant. We reviewed the CT images of 884 cigarette smokers who underwent low-dose CT at a single site in the National Lung Screening Trial. CT findings were categorized as having no evidence of ILA, equivocal for ILA, or ILA. We categorized the type of ILA as nonfibrotic (ground-glass opacity, consolidation, mosaic attenuation), or fibrotic (ground glass with reticular pattern, reticular pattern, honeycombing). We evaluated the temporal change of the CT findings (no change, improvement, or progression) of ILA at 2-year follow-up. A χ(2) with Fisher exact test or unpaired t test was used to determine whether smoking parameters were associated with progression of ILA at 2-year follow-up CT. RESULTS The prevalence of ILA was 9.7% (86 of 884 participants; 95% confidence interval: 7.9%, 11.9%), with a further 11.5% (102 of 884 participants) who had findings equivocal for ILA. The pattern was fibrotic in 19 (2.1%), nonfibrotic in 52 (5.9%), and mixed fibrotic and nonfibrotic in 15 (1.7%) of the 86 participants with ILA. The percentage of current smokers (P = .001) and mean number of cigarette pack-years (P = .001) were significantly higher in those with ILA than those without. At 2-year follow-up of those with ILA (n = 79), findings of nonfibrotic ILA improved in 49% of cases and progressed in 11%. Fibrotic ILA improved in 0% and progressed in 37% of cases. CONCLUSION ILA is common in cigarette smokers. Nonfibrotic ILA improved in about 50% of cases, and fibrotic ILA progressed in about 37%.

Inflammatory airways disease in ulcerative colitis: CT and high-resolution CT features

Inflammatory airways disease is an uncommon but recognized complication of ulcerative colitis (UC). The present study was undertaken to determine the computed tomographic (CT) and high-resolution CT appearances of this entity. A retrospective review was performed of the radiographs and CT scans of seven patients (ages 24 to 54 years) with UC who presented with cough and recurrent respiratory infections. Four patients had total colectomies, and one had sigmoid colectomy. Fiberoptic bronchoscopy in six subjects showed diffuse mucosal erythema and edema that was most severe in the proximal airways. Sinus radiographs revealed maxillary sinus mucosal thickening in four patients and ethmoid sinus involvement in two. Chest radiographs showed bronchiectasis in two patients and bronchial wall thickening in three; radiographs were normal in two patients. CT features included bronchiectasis in six patients, peripheral airways involvement in four, and airway stenosis in three.

Evaluation of Reader Variability in the Interpretation of Follow-up CT Scans at Lung Cancer Screening

PURPOSE To measure reader agreement in determining whether lung nodules detected at baseline screening computed tomography (CT) had changed at subsequent screening examinations and to evaluate the variability in recommendations for further follow-up. MATERIALS AND METHODS All subjects were enrolled in the National Lung Screening Trial (NLST), and each participant consented to the use of their de-identified images for research purposes. The authors randomly selected 100 cases of nodules measuring at least 4.0 mm at 1-year screening CT that were considered by the original screening CT reader to be present on baseline CT scans; nodules considered by the original reader to have changed were oversampled. Selected images from each case showing the entire nodule at both examinations were preloaded on a picture archiving and communication system workstation. Nine radiologists served as readers, and they evaluated whether the nodule was present at baseline and recorded the bidimensional measurements and nodule characteristics at each examination, presence or absence of change, results of screening CT, and follow-up recommendations (high-level follow-up, low-level follow-up, no follow-up). RESULTS On the basis of reviews during case selection, five nodules seen at follow-up were judged not to have been present at baseline; for 19 of the remaining 95 cases, at least one reader judged the nodule not to have been present at baseline. For the 76 nodules that were unanimously considered to have been present at baseline, 21%-47% (mean ± standard deviation, 30% ± 9) were judged to have grown. The κ values were similar for growth (κ = 0.55) and a positive screening result (κ = 0.51) and were lower for a change in margins and attenuation (κ = 0.27-0.31). The κ value in the recommendation of high- versus low-level follow-up was high (κ = 0.66). CONCLUSION Reader agreement on nodule growth and screening result was moderate to substantial. Agreement on follow-up recommendations was lower.

Early detection and screening of lung cancer

Accounting for 28% of all cancer deaths and causing 1.3 million deaths worldwide every year, lung cancer is the most lethal cancer. Diagnosing and treating cancer at its early stages, ideally during precancerous stages, could increase the 5-year survival rate by three- to four-fold with a potential for cure. Thus far, no screening method has been shown to decrease disease-specific mortality rate. The present review describes the rationale and issues related to early lung cancer screening, the management of screen-detected primary cancers and different approaches that have been tested for screening. These include imaging techniques, bronchoscopies, molecular screenings from different noninvasive or invasive sources, such as blood, sputum, bronchoscopic samples and exhaled breath.

CT Quality Assurance in the Lung Screening Study Component of the National Lung Screening Trial: Implications for Multicenter Imaging Trials

OBJECTIVE The purpose of this study was to describe the effect of implementing an imaging quality assurance program on CT image quality in the Lung Screening Study component of the National Lung Screening Trial. MATERIALS AND METHODS The National Lung Screening Trial is a multicenter study in which 53,457 subjects at increased risk of lung cancer were randomized to undergo three annual chest CT or radiographic screenings for lung cancer to determine the relative effect of use of the two screening tests on lung cancer mortality. Of the 26,724 subjects randomized to the CT screening arm of the National Lung Screening Trial, the Lung Screening Study randomized 17,309 through 10 screening centers. The others were randomized through the American College of Radiology Imaging Network. Quality assurance procedures were implemented that included centralized review of a random sample of 1,504 Lung Screening Study CT examinations. Quality defect rates were tabulated. RESULTS Quality defect rates ranged from 0% (section reconstruction interval) to 7.1% (reconstructed field of view), and most errors were sporadic. However, a recurrently high effective tube current-time product setting at one center, excessive streak artifact at one center, and excessive section thickness at one center were detected and corrected through the quality assurance process. Field-of-view and scan length errors were less frequent over the second half of the screening period (p < 0.01 for both parameters, two-tailed, paired Students t test). Error rates varied among the screening centers and reviewers for most parameters evaluated. CONCLUSION Our experience suggested that centralized monitoring of image quality is helpful for reducing quality defects in multicenter trials.