The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group

doi:10.1016/j.lungcan.2011.10.017

Lung Cancer

Volume 76, Issue 1, April 2012, Pages 1-18

https://doi.org/10.1016/j.lungcan.2011.10.017 Get rights and content

Abstract

Until recently, the division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for therapy selection. Due to the emergence of new treatment options subtyping of NSCLC and predictive testing have become mandatory. A practical approach to the new requirements involving interaction between pulmonologist, oncologist and molecular pathology to optimize patient care is described. The diagnosis of lung cancer involves (i) the identification and complete classification of malignancy, (ii) immunohistochemistry is used to predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma), as in small diagnostic samples specific subtyping is frequently on morphological grounds alone not feasible (NSCLC-NOS), (iii) molecular testing. To allow the extended diagnostic and predictive examination (i) tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies and (ii) tissue handling, processing and sectioning should be optimized.

Complex diagnostic algorithms are emerging, which will require close dialogue and understanding between pulmonologists and others who are closely involved in tissue acquisition, pathologists and oncologists who will ultimately, with the patient, make treatment decisions. Personalized medicine not only means the choice of treatment tailored to the individual patient, but also reflects the need to consider how investigative and diagnostic strategies must also be planned according to individual tumour characteristics.

Highlights

► The diagnosis of lung cancer involves the identification and complete classification of malignancy. ► New therapeutic options require specific subtyping of NSCLCs and, increasingly, the identification of therapeutically predictive molecular markers, to determine the safest and most effective choice of drugs. ► Small diagnostic sample size and tumour complexity often prevent specific subtyping on morphological grounds alone (NSCLC-NOS). ► Immunohistochemistry can predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma) in most NSCLC-NOS cases. ► Tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies. ► Tissue handling, processing and sectioning should minimize wastage and optimize use of tissue for diagnosis.

Section snippets

Background

For decades the simple division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for the selection of patients for appropriate therapy. However, the emergence of new treatment options for subtypes of NSCLC has made definite histological subtyping mandatory. This is especially true for the distinction between squamous cell carcinomas (SqCC) from non-squamous cell carcinomas, the latter comprising mostly adenocarcinomas and large cell

General comments

Success in the cyto-histological diagnosis of lung cancer depends upon, among other things, the correct sampling and processing of tissue. For many patients this involves an invasive attempt to access intra-thoracic tumour at either the primary or a metastatic site. It is important to apply the correct methodology for obtaining and preserving these samples to be sent to the pathology laboratory. Although this is an important step in the diagnostic process, there are no guidelines to facilitate

General procedure and comments

The best strategy for the handling of small samples in suspected lung cancer is always based on accurate and relevant clinical information. The required clinical information is shown in Table 1. This information will be used by the pathologist to (i) determine priorities of the diagnostic approach (see below), (ii) determine how specific a diagnosis is required, (iii) plan the necessary investigations and anticipate the use of IHC and molecular biological tests, and (iv) prevent unnecessary

Mucin stain

The classical Alcian blue/periodic acid Schiff (AB/PAS) histochemical stain for mucin, when combined with p63 and TTF-1, represented the best panel for NSCLC subtyping with an accuracy of 86% and a reduction to 7% of the “NSCLC” diagnosis rate [64]. For resection specimens 5 vacuoles of mucin in two high power fields has been used as a criterion for solid adenocarcinoma with mucin [53], but for small biopsy samples even 1 or 2 unequivocal intracytoplasmic vacuoles may be diagnostic for

General comments

Biomarker analysis helpful in NSCLC therapy can be based on immunohistochemistry, FISH and DNA mutation analysis. As each successive handling and cutting of the paraffin block results in additional tissue loss ideally a standard preparation regimen for the handling of the biopsy should be implemented. Therefore procedures for EGFR testing cannot be addressed without covering other potential analyses to be performed on the same tissue.

As requirements regarding specific markers may vary

Conclusion

To provide meaningful information for treatment and making the best use of the available and often scarce material in the diagnostic work up of NSCLC applying quality approved and clinically relevant molecular testing only is mandatory. By additionally observing a simple procedure of specimen handling the need for rebiopsies and the rate of inconclusive molecular tests can be kept as low as possible. The pathologists in the hospital should take a major position in handling the specimens. Those

Conflict of interest statement

Thunnissen received consultant honoraria from Lilly, unrestricted grant from Lilly. Kerr, Herth, Lantuejoul, Weynand, Grünberg, Ninane, Olszewski, Rintoul, Jaume, Thiberville received consultant honoraria from Lilly. Papotti received consultant honoraria from Lilly, Novartis Pharma, unrestricted grant from Novartis. Rossi received grant/honoraria as consultant from Eli-Lilly, Hoffmann-La Roche, Novartis and Pfizer. Skov, López-Ríos, Schnabel, Laenger received consultant honoraria from Lilly and

References (233)

M. Reck et al.
Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)
Ann Oncol
(2010)
W.D. Travis et al.
International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma
J Thorac Oncol
(2011)
M.A. van der Drift et al.
A prospective study of the timing and cost-effectiveness of bronchial washing during bronchoscopy for pulmonary malignant tumors
Chest
(2005)
A. Fernandez-Villar et al.
Effect of different bronchial washing sequences on diagnostic yield in endoscopically visible lung cancer
Arch Bronconeumol
(2006)
M. Pirozynski
Bronchoalveolar lavage in the diagnosis of peripheral, primary lung cancer
Chest
(1992)
D. Shure et al.
Transbronchial needle aspiration in the diagnosis of submucosal and peribronchial bronchogenic carcinoma
Chest
(1985)
N. Kacar et al.
Effectiveness of transbronchial needle aspiration in the diagnosis of exophytic endobronchial lesions and submucosal/peribronchial diseases of the lung
Lung Cancer
(2005)
L.H. Hsu et al.
Education and experience improve the performance of transbronchial needle aspiration: a learning curve at a cancer center
Chest
(2004)
P. Gu et al.
Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis
Eur J Cancer
(2009)
F.J.F. Herth et al.
Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer
Chest
(2008)

T. Nakajima et al.

How I do it – optimal methodology for multidirectional analysis of endobronchial ultrasound-guided transbronchial needle aspiration samples

J Thorac Oncol

(2011)

C.G. Micames et al.

Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis

Chest

(2007)

F.J.F. Herth et al.

Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer

Chest

(2010)

N. Ikeda et al.

Comprehensive diagnostic bronchoscopy of central type early stage lung cancer

Lung Cancer

(2007)

C.L. Coghlin et al.

Quantitative analysis of tumor in bronchial biopsy specimens

J Thorac Oncol

(2010)

W.A. Baaklini et al.

Diagnostic yield of fiberoptic bronchoscopy in evaluating solitary pulmonary nodules

Chest

(2000)

R. Eberhardt et al.

Electromagnetic navigation diagnostic bronchoscopy in peripheral lung lesions

Chest

(2007)

M.S. Levine et al.

Transthoracic needle aspiration biopsy following negative fiberoptic bronchoscopy in solitary pulmonary nodules

Chest

(1988)

Y.C. Cheung et al.

Adequacy and complications of computed tomography-guided core needle biopsy on non-small cell lung cancers for epidermal growth factor receptor mutations demonstration: 18-gauge or 20-gauge biopsy needle

Lung Cancer

(2010)

J.A. Govert et al.

Cost-effectiveness of collecting routine cytologic specimens during fiberoptic bronchoscopy for endoscopically visible lung tumor

Chest

(1996)

H.S. Lee et al.

Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspirations per target lymph node station?

Chest

(2008)

D. Nonaka

Immunohistochemical differentiation of metastatic tumours

Diagn Histopathol

(2010)

W.D. Travis et al.

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

J Thorac Oncol

(2006)

A. Babic et al.

The impact of pre-analytical processing on staining quality for H&E, dual hapten, dual color in situ hybridization and fluorescent in situ hybridization assays

Methods

(2010)

M.D. McKinney et al.

Detection of viral RNA from paraffin-embedded tissues after prolonged formalin fixation

J Clin Virol

(2009)

P.S. Loo et al.

Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens

J Thorac Oncol

(2010)

N. Kalhor et al.

TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material

Mod Pathol

(2006)

H. Zhang et al.

Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach

Mod Pathol

(2005)

R. Camilo et al.

Expression of p63, keratin 5/6, keratin 7, and surfactant-A in non-small cell lung carcinomas

Hum Pathol

(2006)

A.G. Nicholson et al.

Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis

J Thorac Oncol

(2010)

G. Pelosi et al.

Immunohistochemistry by means of widely agreed-upon markers (cytokeratins 5/6 and 7, p63, thyroid transcription factor-1, and vimentin) on small biopsies of non-small cell lung cancer effectively parallels the corresponding profiling and eventual diagnoses on surgical specimens

J Thorac Oncol

(2011)

N. Nakamura et al.

Expression of thyroid transcription factor-1 in normal and neoplastic lung tissues

Mod Pathol

(2002)

L. Johansson

Histopathologic classification of lung cancer: relevance of cytokeratin and TTF-1 immunophenotyping

Ann Diagn Pathol

(2004)

J.A. Bishop et al.

Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma

Hum Pathol

(2010)

N. Rekhtman et al.

Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens

Mod Pathol

(2011)

B.Y. Wang et al.

P63 in pulmonary epithelium, pulmonary squamous neoplasms, and other pulmonary tumors

Hum Pathol

(2002)

R. Pirker et al.

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial

Lancet

(2009)

R. Pirker et al.

Monoclonal antibodies against EGFR in non-small cell lung cancer

Crit Rev Oncol Hematol

(2011)

N. Rekhtman et al.

Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing

J Thorac Oncol

(2011)

G.V. Scagliotti et al.

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

J Clin Oncol

(2008)

D.H. Johnson et al.

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer

J Clin Oncol

(2004)

A. Sandler et al.

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer

N Engl J Med

(2006)

T.J. Lynch et al.

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

N Engl J Med

(2004)

W. Pao et al.

Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain

PLoS Med

(2005)

E.L. Kwak et al.

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer

N Engl J Med

(2010)

T.S. Mok et al.

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma

N Engl J Med

(2009)

W.D. Travis et al.

J.S. Thomas et al.

How reliable is the diagnosis of lung cancer using small biopsy specimens? Report of a UKCCCR Lung Cancer Working Party

Thorax

(1993)

S.L. Edwards et al.

Preoperative histological classification of primary lung cancer: accuracy of diagnosis and use of the non-small cell category

J Clin Pathol

(2000)

V.H. Mak et al.

Value of washings and brushings at fibreoptic bronchoscopy in the diagnosis of lung cancer

Thorax

(1990)

Cited by (196)

Unresectable stage III non-small cell lung cancer: Insights from a Portuguese expert panel
2024, Pulmonology
The management of unresectable stage III non-small cell lung cancer (NSCLC) is clinically challenging and there is no current consensus on optimal strategies. Herein, a panel of Portuguese experts aims to present practical recommendations for the global management of unresectable stage III NSCLC patients.
A group of Portuguese lung cancer experts debated aspects related to the diagnosis, staging and treatment of unresectable stage III NSCLC in light of current evidence. Recent breakthroughs in immunotherapy as part of a standard therapeutic approach were also discussed. This review exposes the major conclusions obtained.
Practical recommendations for the management of unresectable stage III NSCLC were proposed, aiming to improve the pathways of diagnosis and treatment in the Portuguese healthcare system. Clinical heterogeneity of patients with stage III NSCLC hinders the development of single standardised algorithm where all fit.
A timely diagnosis and a proper staging contribute to the best management of each patient, optimizing treatment tolerance and effectiveness. The expert panel considered chemoradiotherapy as the preferable approach when surgery is not possible. Management of adverse events and immunotherapy as a consolidation therapy are also essential steps for a successful strategy.
Practical guidelines for molecular testing of cholangiocarcinoma in clinical practice: Italian experts’ position paper
2024, Critical Reviews in Oncology/Hematology
Biliary tract cancers (BTCs) represent a spectrum of malignancies associated with a dismal prognosis. Recent genomic profiling studies have provided a deeper understanding of the complex and heterogenous molecular landscape of BTCs, identifying several actionable genetic alterations, and expanding treatment options. Due to the high number and complexity of genetic alterations which require testing, next-generation sequencing (NGS) is currently the preferred approach over conventional methods (i.e., immunohistochemistry, fluorescence in-situ hybridization and PCR) for molecular profiling of BTCs and should be performed upfront in all BTC patients. However, BTC sampling often yields low tumor cellularity tissue, hampering NGS analysis. Future perspectives to overcome this obstacle include liquid biopsy and optimization of biopsy protocols. In this position paper, the authors discuss the current histopathologic, molecular, and therapeutic landscape of BTCs, provide a critical overview of the available testing methods for molecular diagnostics, and propose a practical diagnostic algorithm for molecular testing of BTC samples.
The impact of impaired tissue fixation in resected non-small-cell lung cancer on protein deterioration and DNA degradation
2023, Lung Cancer
The objective is to assess the impact of the quality of tissue fixation in surgical pathology on immunohistochemical (IHC) staining and DNA degradation.
Twenty-five non-small cell lung cancer (NSCLC) resection specimens were analyzed. After resection, all tumors were processed according to the protocols in our center. In haematoxylin and eosin (H&E) stained tissue slides, adequately- and inadequately fixed tumor areas were microscopically demarcated, based on basement membrane detachment. In 10 IHC stains ALK (clone 5A4), PD-L (clone 22C3), CAM5.2, CK7, c-Met, KER-MNF116, NapsinA, p40, ROS1, TTF1) the immunoreactivity in H-scores was determined in adequately- and inadequately fixed, and necrotic tumor areas. From the same areas DNA was isolated, and DNA fragmentation in base pairs (bp) was measured.
H-scores were significantly higher in H&E adequately fixed tumor areas in IHC stains KER-MNF116 (H-score 256 vs 15, p=0.001) and p40 (H-score 293 vs 248, p=0.028). All other stains showed a trend towards higher immunoreactivity in H&E adequately fixed areas. Independent of H&E adequatelty- or inadequately fixed areas, all IHC stains showed significant different IHC staining intensity within tumors, suggesting heterogeneous immunoreactivity (H-scores: PD-L1 123 vs 6, p = 0.001; CAM5.2 242 vs 101, p=<0.001; CK7 242 vs 128, p=<0.001; c-MET 99 vs 20, p=<0.001; KER-MNF116 281 vs 120, p=<0.001; Napsin A 268 vs 130, p = 0.005; p40 292 vs 166, p = 0.008; TTF1 199 vs 63, p=<0.001).
DNA fragments rarely exceeded a length of 300 bp, independent of adequate fixation. However, DNA fragments of 300 and 400 bp had higher concentrations in tumors with short fixation delay (<6 h vs >16 h) and short fixation time (<24 h vs >24 h).
Impaired tissue fixation of resected lung tumors results in decreased IHC staining intensity in some parts of the tumor. This may impact the reliability of IHC analysis.
Analytical validation of automated multiplex chromogenic immunohistochemistry for diagnostic and predictive purpose in non-small cell lung cancer
2022, Lung Cancer
The evaluation of an increasing number of diagnostic and predictive markers is playing a central role in precision thoracic oncology. Multiplex immunohistochemistry (mIHC), alongside next-generation sequencing, is ideally situated for this purpose and maximizes tumor tissue preservation for molecular analyses that use increasingly large panels. However, the standardization and validation of mIHC that supports routine clinical laboratory processes are mandatory. After a previous proof-of-concept study, we now (i) optimized two automated four-plex assays on a commercially available IHC autostainer for use in daily practices worldwide and (ii) evaluated the repeatability and concordance of the assessment of the cell density.
Two four-plex mIHC assays [i) TTF1, p40, PD-L1, CD8; and, ii) ALK, ROS1, BRAFV600E, NTRK] were optimized on the BenchMark ULTRA autostainer (Ventana Medical Systems, Inc.), as determined in comparison to conventional IHC chromogenic assays. Intra-site repeatability was evaluated on serial tumor sections from non-small cell lung carcinomas (NSCLC). The concordance was assessed by linear fit to plots of the percentage staining evaluated on tumor sections from 89 NSCLC patients.
Following optimization, an average concordance for a staining rate of 95.4% was achieved between conventional IHC and mIHC across all selected markers. Assessment of intra-site repeatability showed strong concordance for all these markers (average, R² = 0.96; P-value < 0.001).
Our optimized mIHC assay gave a sensitive and repeatable assessment of two panels of eight diagnostic and predictive biomarkers for NSCLC. The availability of standardized protocols to determine these biomarkers on a widely available IHC platform will expand the number of pathology laboratories able to determine the eligibility of patients with NSCLC for targeted treatment or immunotherapy in a reliable and concordant manner, thus providing a unique sample-sparing tool to characterize limited tissue samples in thoracic oncology.
Real-World Evidence of Diagnostic Testing for Driver Oncogene Mutations in Lung Cancer in Japan
2021, JTO Clinical and Research Reports
Diagnostic testing is important in determining appropriate treatment for individuals with lung cancer. In 2018, testing of five biomarkers (EGFR, ALK, ROS1, BRAF, programmed cell death-ligand 1 [PD-L1]) was approved in Japan. Information is lacking regarding real-world testing patterns.
This descriptive, retrospective observational study used the Japan Medical Data Vision Co., Ltd. (MDV), database (June 2017–November 2018) and covered data for EGFR, ALK, ROS1, and PD-L1; records on BRAF testing were not yet available. Adults diagnosed with having lung cancer (International Classification of Diseases-10 C34) with record of any biomarker test ordered were included.
Of 8323 patients with any biomarker test, 83.2% were tested for EGFR, 55.3% for ALK, 32.2% ROS1, and 77.2% PD-L1. Combinations of EGFR with other biomarkers accounted for approximately 80% of the testing patterns; 1427 patients (17.1%) had combination testing ordered for EGFR/ALK/ROS1/PD-L1, but some biomarker combinations were tested in less than 1% of the cases. Median time from first testing order to treatment order was 22 (range: 2–525) days overall and increased with number of testing instances: 21 (2–509) days for patients with one, 28 (3–525) days for patients with two, and 30 (9–502) days for patients with three. A 7-day pattern of peaks was observed in the test order date and time to treatment.
This real-world evidence revealed variations in diagnostic testing patterns, which could affect time to treatment in Japan. Variations are likely influenced by individual biomarker prioritization considering limited tissue samples in clinical practice.
An Unusual Presentation of Aggressive Primary Invasive Adenocarcinoma of Lung
2021, American Journal of the Medical Sciences
Citation Excerpt :
Most invasive subtypes of adenocarcinoma present as a solid or subsolid nodules and rarely as ground-glass nodules. 8,22 An exception would be invasive mucinous adenocarcinoma (previously mucinous BAC) with a variable appearance, including consolidation, air bronchograms, or multifocal subsolid nodules or masses. 8, 22 Bilateral infiltrates are uncommon with invasive adenocarcinoma and currently, there appears to be no consensus on the percentage of adenocarcinoma presenting as bilateral diffuse infiltrates, as seen in our case.
Bilateral diffuse infiltrates on chest imaging can present a diagnostic challenge due to a broader differential diagnosis which includes pulmonary and non-pulmonary causes. Malignancy is generally not considered under differential diagnosis at the time of initial presentation. Here we present a case of primary adenocarcinoma of lung manifesting as diffuse bilateral infiltrates on imaging. Our case is unique in regards to its acute presentation, rapid progression to respiratory failure, ultimately leading to the demise of the patient. This indicates the aggressive nature of this malignancy and its variable presentation, like male gender and young age, thus emphasizing the importance of entertaining malignancy in such presentations, especially if there is no response to conventional antibiotic therapy.

View all citing articles on Scopus

^☆: The considerations in this manuscript are authored by a working group which was formed as a result of initial discussions held by some of the authors in independent meetings convened by Eli Lilly and Roche Pharmaceuticals. Neither company has had any input, influence or any other connection with the subsequent project of formulating and writing this manuscript.

View full text

ReviewThe challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group☆

Abstract

Highlights

Section snippets

Background

General comments

General procedure and comments

Mucin stain

General comments

Conclusion

Conflict of interest statement

Ann Oncol

J Thorac Oncol

Chest

Arch Bronconeumol

Chest

Chest

Lung Cancer

Chest

Eur J Cancer

Chest

J Thorac Oncol

Chest

Chest

Lung Cancer

J Thorac Oncol

Chest

Chest

Chest

Lung Cancer

Chest

Chest

Diagn Histopathol

J Thorac Oncol

Methods

J Clin Virol

J Thorac Oncol

Mod Pathol

Mod Pathol

Hum Pathol

J Thorac Oncol

J Thorac Oncol

Mod Pathol

Ann Diagn Pathol

Hum Pathol

Mod Pathol

Hum Pathol

Lancet

Crit Rev Oncol Hematol

J Thorac Oncol

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

J Clin Oncol

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer

J Clin Oncol

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer

N Engl J Med

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

N Engl J Med

Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain

PLoS Med

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer

N Engl J Med

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma

N Engl J Med

How reliable is the diagnosis of lung cancer using small biopsy specimens? Report of a UKCCCR Lung Cancer Working Party

Thorax

Preoperative histological classification of primary lung cancer: accuracy of diagnosis and use of the non-small cell category

J Clin Pathol

Value of washings and brushings at fibreoptic bronchoscopy in the diagnosis of lung cancer

Thorax

Review
The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group☆