Article

Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens

February 2010
Journal of Thoracic Oncology 5(4):442-7

February 2010
5(4):442-7

DOI:10.1097/JTO.0b013e3181d40fac

Source
PubMed

Authors:

Marianne Nicolson

NHS Grampian

Nicky Fyfe

University of Aberdeen

Show all 5 authorsHide

The emergence of treatments for non-small cell lung carcinoma (NSCLC) with differential efficacy and toxicity between subtypes has highlighted the importance of specific pathologic NSCLC subtyping. Most NSCLCs are inoperable, and pathologic diagnosis is made only on small tissue samples that are prone to diagnostic inaccuracy. In a substantial proportion of cases, standard morphology cannot specifically subtype the tumor, necessitating a diagnosis of NSCLC-not otherwise specified (NOS). Histochemical staining for mucin and immunohistochemical (IHC) identification of NSCLC subtype-associated markers could help predict the final subtype of resected NSCLCs diagnosed as NSCLC-NOS on preoperative bronchial biopsy samples. Paraffin sections of 44 bronchial biopsy samples diagnosed as NSCLC-NOS were stained for mucin (Alcian blue/periodic acid Schiff) and thyroid transcription factor 1 by IHC-(markers of adenocarcinoma), and for S100A7, cytokeratin 5/6, high molecular weight cytokeratins, and p63 proteins-markers of squamous cell carcinoma. A predictive staining panel was derived from statistical analysis after comparing staining profiles with the final postsurgical NSCLC subtype. This panel was prospectively applied to 82 small biopsy samples containing NSCLC. True NSCLC subtype of undifferentiated NSCLC samples was best predicted using Alcian blue/periodic acid Schiff plus p63 and thyroid transcription factor 1 IHC, allowing specific subtyping in 73% of NSCLC-NOS cases with 86% accuracy. When applied prospectively, this staining panel showed 100% concordance with specific NSCLC morphologic subtyping in small biopsies. This approach can facilitate treatment selection by accurately predicting the subtype in undifferentiated NSCLC biopsies, reducing to 7% the proportion of cases without a definite or probable histologic subtype.

Lung Cancer and the Future of Pathology

Article

Mar 2011

Non-small cell lung carcinoma subtyping; double staining is not the remedy!

Article

Jan 2019

High-grade non-small cell lung carcinoma: a comparative analysis of the phenotypic profile in small biopsies with the corresponding postoperative material

Article

Full-text available

Apr 2019
Pol J Pathol

The most recent classification of the lung cancer expanded the diagnostic criteria of its histological subtypes and included its immunophenotypic profile. We performed the study to compare the reliability of selected markers in high-grade non-small cell lung carcinoma (NSCLC) in the oligobiopsies with the matched postoperative samples. We evaluated expression of p40, p63, TTF1, cytokeratin 5/6, cytokeratin 7, napsin A, desmoglein 3, desmocollin 3 and mucin secretion as detected by mucicarmine staining. The study cohort included 123 cases of poorly-differentiated NSCLC. The tissue oligobiopsy material was available in 38 cases. Tissue microarrays (TMAs) from all postoperative cases were constructed. Comparing the immunophenotype between postsurgical samples and oligobiopsies we found an almost perfect agreement for most of performed IHC reactions. The highest concordance of results was found for desmoglein 3, CK7, and p40, whereas the lowest – for desmocollin 3. Immunoprofile of the oligobiopsies corresponded well to that in the resection specimens. The most useful markers in poorly differentiated ADs are: TTF1 and napsin A, and for non-keratinizing SCCs: p40, p63, CK5/6 and desmoglein 3.

Guidelines for molecular testing in non-small cell lung cancer – recommendations from the Brazilian Society of Pathology

Article

Full-text available

Oct 2023

The Brazilian Society of Pathology Guidelines project aims to provide recommendations for clinicians and pathologists based on the best available scientific evidence adapted from the International Guidelines, with emphasis in the practice of Brazilian pathologists. It reviews currently available and emerging molecular tests. In this paper, a combined effort from members of the Brazilian Society of Pathology describes the essential pre-analytical issues, the required clinical information to allow proper molecular testing interpretation, and the important role of pathologists in multidisciplinary tumor boards.

Multi-lesion radiomics of PET/CT for non-invasive survival stratification and histologic tumor risk profiling in patients with lung adenocarcinoma

Article

Jul 2022
EUR RADIOL

Objectives: This study investigates the ability of machine learning (ML) models trained on clinical data and 2-deoxy-2-[18F]fluoro-D-glucose(FDG) positron emission tomography/computed tomography (PET/CT) radiomics to predict overall survival (OS), tumor grade (TG), and histologic growth pattern risk (GPR) in lung adenocarcinoma (LUAD) patients. Methods: A total of 421 treatment-naive patients with histologically-proven LUAD and available FDG PET/CT imaging were retrospectively included. Four cohorts were assessed for predicting 4-year OS (n = 276), 3-year OS (n = 280), TG (n = 298), and GPR (n = 265). FDG-avid lesions were delineated, and 2082 radiomics features were extracted and combined with endpoint-specific clinical parameters. ML models were built for the prediction of 4-year OS (M4OS), 3-year OS (M3OS), tumor grading (MTG), and histologic growth pattern risk (MGPR). A 100-fold Monte Carlo cross-validation with 80:20 training to validation split was employed as a performance evaluation for all models. The association between the M4OS and M3OS predictions with OS was assessed by the Kaplan-Meier survival analysis. Results: The area under the receiver operator characteristics curve (AUC) was the highest for M4OS (AUC 0.88, 95% confidence interval (CI) 86.7-88.7), followed by M3OS (AUC 0.84, CI 82.9-84.9), while MTG and MGPR performed equally well (AUC 0.76, CI 74.4-77.9, CI 74.6-78, respectively). Predictions of M4OS (hazard ratio (HR) -2.4, CI -2.47 to -1.64, p < 0.05) and M3OS (HR -2.36, CI -2.79 to -1.93, p < 0.05) were independently associated with OS. Conclusion: ML models are able to predict long-term survival outcomes in LUAD patients with high accuracy. Furthermore, histologic grade and predominant growth pattern risk can be predicted with satisfactory accuracy. Key points: • Machine learning models trained on pre-therapeutic PET/CT radiomics enable highly accurate long-term survival prediction of patients with lung adenocarcinoma. • Highly accurate survival predictions are achieved in lung adenocarcinoma patients despite heterogenous histologies and treatment regimens. • Radiomic machine learning models are able to predict lung adenocarcinoma tumor grade and histologic growth pattern risk with satisfactory accuracy.

PET/CT radiomics and machine learning enable non-invasive survival stratification and histologic tumor risk profiling in patients with lung adenocarcinoma

Preprint

Full-text available

Aug 2021

Purpose Risk stratification in patients with lung adenocarcinoma (LUAD) is mandatory for treatment guiding and outcome prediction. Amongst clinical parameters including histological analyses, imaging procedures provide important information. The present study aimed to investigate the ability of machine learning models trained on clinical and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) derived radiomic data to predict overall survival (OS), tumor grade (TG), and histologic growth pattern risk (GPR) in treatment naïve LUAD patients. Methods 421 treatment naïve patients with histologically diagnosed lung adenocarcinoma and available [¹⁸F]FDG PET/CT imaging were retrospectively analyzed. Four patient cohorts were generated based on the available data for predicting 4-year OS (n = 276), 3-year OS (n = 280), TG (n = 298) and GPR (n = 265). [¹⁸F]FDG-positive lesions were delineated semiautomatically, from which 2082 radiomic features were extracted and combined with endpoint-specific clinical and demographic parameters. Machine learning models were built for the prediction of 4-year OS (M4OS), 3-year OS (M3OS), tumor grading (MTG) and histologic growth pattern risk (MGPR), respectively. Monte Carlo (MC) cross-validation with 100-folds and 80:20 training to validation split was employed as a performance evaluation for all models. Kaplan-Meier survival analysis was performed to assess the association between the M4OS and M3OS predictions with OS. Results Area under the receiver operator characteristics curve (AUC) was highest for M4OS (AUC 0.88), followed by M3OS (AUC 0.84), while MTG and MGPR performed equally well (AUC 0.76). Predictions of M4OS (HR 0.128, p < 0.000001) and M3OS (HR 0.0942, p < 0.000001) were independently associated with OS. Conclusion In our retrospective cohorts, machine learning models demonstrated the ability to prognosticate long-term survival outcomes in patients with lung adenocarcinoma. Furthermore, tumor lesions could be characterized according to their histologic grade and predominant growth pattern risk with high accuracy.

The value of AGR2 and KRT5 as an immunomarker combination in distinguishing lung squamous cell carcinoma from adenocarcinoma

Article

May 2021

With the advancement of tumor subtype-specific treatments, precise histopathologic distinction between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is of significant clinical importance. Nevertheless, the current markers are insufficiently precise in poorly differentiated tissue. This study aimed to establish a histology-specific immunomarker combination to subclassify non-small cell lung cancer (NSCLC) specimens. Based on previous work, we assessed the differential expression of anterior gradient 2 (AGR2) and keratin 5 (KRT5) in ADC and SCC by analyzing public datasets and postoperative specimens. Subsequently, we established a train set (n = 188) and a validation set (n = 42) comprised of NSCLC surgical specimens for training and verifying the subtype-identification capabilities of the two biomarkers separately and in combination, and contrasted the diagnostic utility of AGR2-KRT5 with that of the classic immunomarker combination, TTF1-P40. Differential expression of the two genes was statistically significant in ADC and SCC samples, both at the mRNA and protein levels. The specificity and sensitivity of AGR2 to detect ADC in the training set were 97.0% and 94.4%, while the sensitivity and specificity of KRT5 to determine SCC were 93.9% and 98.9%, respectively. The accuracies of AGR2-KRT5 in ADC, SCC, and across all samples were 93.3%, 92.0% and 92.6% respectively. In the validation cohort, the predictive accuracy of AGR2-KRT5 was up to 100% for ADC and 86.7% for SCC. Compared with TTF1-P40 in ADC samples, AGR2-KRT5 had 8.4% higher accuracy. In summary, the AGR2-KRT5 immunomarker combination reliably distinguished SCC from ADC, and was more accurate than TTF1-P40 in ADC.

OPTIMIZATION OF MOLECULAR GENETIC DIAGNOSTICS OF PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER BY INTRODUCING ROS1 TESTING IN THE REPUBLIC OF KAZAKHSTAN

Article

Jun 2023

Relevance: Currently, molecular diagnosis in NSCLC in Kazakhstan includes detection of EGFR, ALK driver mutations status, and PD-L1-status, but not ROS1, what limits the access of patients with this driver mutation to vital therapy. The study aimed to optimize the methods of molecular genetic diagnosis of patients with NSCLC by introducing ROS1 testing in the Republic of Kazakhstan. Methods: The biopsy and surgical material of non-small cell lung cancer (NSCLC) fixed in 10% buffered formalin was studied. After the initial morphological diagnosis of adenocarcinoma, EGFR, and ALK mutation status determination, EGFR, and ALK-negative tumor assays were sent for further determination of ROS1 mutation status. First, we performed immunohistochemistry (IHC) using the Ventana BenchMark Ultra platform using the ROS1 antibody (SP283) and the OptiView DAB Detection Kit imaging system. After that, samples with positive and doubtful IHC results were sent for RT-PCR (reverse transcriptase polymerase chain reaction) to confirm the ROS1 mutation status. Results: A total of 99 tumor samples from patients with EGFR-negative and ALK-negative lung adenocarcinoma were studied by IHC from January 01 till September 30, 2022. The results of IHC staining were assessed as: 0 (negative) – 59 samples, 1+ (negative) – 25 samples, 2+ (doubtful) – 12 samples, 3+ (positive) – 3 samples. Cases with ≥70% immunostaining were considered positive. Samples with an IHC stain score of 2+ (doubtful), 3+ (positive), and a few samples of 1+ were sent for confirmation by PCR. Overall, 22 samples were tested using RT-PCR, and results were considered as follows:1 (4%) – positive, 13 (59%) – negative, 8 (37%) -– invalid. Conclusion: A large proportion of positive and questionable results were obtained when determining ROS1 mutation status using IHC, and a large proportion of invalid results during subsequent RT-PCR testing. Choosing methods for nationwide ROS1 implementation, one should evaluate the economics of the methods to be implemented and compare them with a standard validated FISH method.

The role of adenocarcinoma subtypes and immunohistochemistry in predicting lymph node metastasis in early invasive lung adenocarcinoma

Preprint

Full-text available

May 2023

Background: Identifying lymph node metastasis areas during surgery for early invasive lung adenocarcinoma remains challenging. The aim of this study was to develop a nomogram mathematical model before the end of surgery for predicting lymph node metastasis in patients with early invasive lung adenocarcinoma. Methods: A total of 522 patients with invasive lung adenocarcinoma between January 2020 and January 2022 were reviewed at our center and randomized into a training cohort and a validation cohort in a 7:3 ratio. Their histopathological features were extracted from paraffin sections, while frozen sections were reviewed to confirm the concordance between frozen and paraffin sections. A prediction model and a nomogram were developed using one-way and multi-way logistic regression analysis. The nomograms were self-lifted for internal validation and external validation. Recipient operating characteristic (ROC) curves were used to assess the discrimination ability of the model. Calibration capability was assessed using the Hosmer-Lemeshow test and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). The consistency index (C-index) was applied to assess the accuracy and discriminative power of the predictions. Results: The overall incidence of lymph node metastasis was 13.23% (61/461). Six indicators were finally determined to be independently associated with lymph node metastasis. These six indicators were: age (P<0.001),SA (P=0.008); CA125 (P=0. 042); mucus composition (P=0.003); Napsin A (P=0.007); and CK5/6 (P=0.042). The area under the ROC curve (AUC) was 0.843 (95% CI: 0.779-0.908) in the training cohort and 0.838 (95% CI: 0.748-0.927) in the validation cohort. the P-value of the Hosmer-Lemeshow test was 0.0613 in the training cohort and 0.8628 in the validation cohort. the bias of the training cohort corrected C-index was 0.8444 and the bias-corrected C-index for the validation cohort was 0.8375. demonstrating that the prediction model has good discriminative power and good calibration. Conclusions: The column line graphs created showed excellent discrimination and calibration to predict lymph node status in patients with ≤2 cm invasive lung adenocarcinoma. In addition, the predictive model has predictive potential before the end of surgery and can inform clinical decision making.

Revolution in Lung Cancer: New Challenges for the Surgical Pathologist

Article

Jan 2011

Context—Traditionally, lung cancer has been viewed as an aggressive, relentlessly progressive disease with few treatment options and poor survival. The traditional role of the pathologist has been primarily to differentiate small cell carcinoma from non–small cell carcinoma on biopsy and cytology specimens and to stage non–small cell carcinomas that underwent resection. In recent years, our concepts of lung cancer have undergone a revolution, including (1) the advent of successful, new, molecular-targeted therapies for lung cancer, many of which are associated with specific histologic cell types and subtypes; (2) new observations on the natural history of lung cancer derived from ongoing high-resolution computed tomography screening studies and recent histologic findings; and (3) proposals to revise the classification of lung cancers, particularly adenocarcinomas, in part because of the first 2 developments. Objective—To summarize the important, new developments in lung cancer, emphasizing the role of the surgical pathologist in personalized care for patients with lung cancer. Data Sources—Information about the new developments in lung cancer was obtained from the peer-review medical literature and the authors' experiences. Conclusions—For decades, we have perceived lung cancer as a relentlessly aggressive and mostly incurable disease for which the surgical pathologist had a limited role. Today, surgical pathologists have an important and expanding role in the diagnosis and treatment of lung cancer, and it is essential to keep informed of new advances.

Immunocytochemical Evaluation of TTF-1, Napsin-A, and p-63 for Subtyping of Non-Small Cell Lung Carcinoma and Clinicopathological Correlation

Article

Full-text available

Nov 2022

Background: Carcinoma of lung is the most common cause of cancer-associated mortality worldwide. About 70% of lung cancer cases are unresectable and present in advanced stages. So, cytology and small core needle biopsy specimen are available for diagnostic as well as prognostication workup. Subtyping of non-small cell lung cancer (NSCLC) is essential for the treatment and further workup study. For this, immunocytochemistry (ICC) plays a crucial role that helps in early diagnosis. Subtyping of NSCLC from cytology samples using ICC markers like TTF-1, Napsin-A, and p63 and their clinicopathological correlation are the aims of the study. Materials and methods: This ambispective study was conducted in the pathology department of a tertiary care hospital of eastern India for a 2-year period from 2018 to 2020. In our study, 46 cytologically diagnosed cases of NSCLC were included. Subtyping was done by cytomorphology and correlated with ICC expression, histopathology, and clinicopathological parameters. Results: In our study, adenocarcinoma (ADC) was the most common (32.61%) cancer. Most cases of ADC showed positive expression of TTF-1 and Napsin-A, and p63 was positive in most cases of squamous cell carcinoma (SCC). Concordance with cytomorphology and ICC was 87.50% and 81.81% with ADC and SCC, respectively. Cyto-ICC-histo concordance was observed in 85.51% of ADC and 66.66% of SCC cases. Sensitivity was 100%, 93.1%, and 100% for TTF-1, Napsin-A, and p63, respectively. Specificity of both TTF-1 and Napsin-A was 88.2% and for p63 was 93.8%. Conclusion: In small biopsy along with cytology samples, ICC is cost-effective and plays an important role in early diagnosis along with management of NSCLC.

2021 WHO Classification of Lung Cancer: A Globally Applicable and Molecular Biomarker-Relevant Classification

Article

Full-text available

Sep 2022
J THORAC ONCOL

Mid-Infrared Imaging Characterization to Differentiate Lung Cancer Subtypes

Article

Full-text available

Aug 2022
PATHOL ONCOL RES

Introduction: Lung cancer is the most common malignancy worldwide. Squamous cell carcinoma (SQ) and adenocarcinoma (LUAD) are the two most frequent histological subtypes. Small cell carcinoma (SCLC) subtype has the worst prognosis. Differential diagnosis is essential for proper oncological treatment. Life science associated mid- and near-infrared based microscopic techniques have been developed exponentially, especially in the past decade. Vibrational spectroscopy is a potential non-destructive approach to investigate malignancies. Aims: Our goal was to differentiate lung cancer subtypes by their label-free mid-infrared spectra using supervised multivariate analyses. Material and Methods: Formalin-fixed paraffin-embedded (FFPE) samples were selected from the archives. Three subtypes were selected for each group: 10-10 cases SQ, LUAD and SCLC. 2 μm thick sections were cut and laid on aluminium coated glass slides. Transflection optical setup was applied on Perkin-Elmer infrared microscope. 250 × 600 μm areas were imaged and the so-called mid-infrared fingerprint region (1800-648cm ⁻¹ ) was further analysed with linear discriminant analysis (LDA) and support vector machine (SVM) methods. Results: Both “patient-based” and “pixel-based” approaches were examined. Patient-based analysis by using 3 LDA models and 2 SVM models resulted in different separations. The higher the cut-off value the lower is the accuracy. The linear C-support vector classification (C-SVC) SVM resulted in the best (100%) accuracy for the three subtypes using a 50% cut-off value. The pixel-based analysis gave, similarly, the linear C-SVC SVM model to be the most efficient in the statistical indicators (SQ sensitivity 81.65%, LUAD sensitivity 82.89% and SCLC sensitivity 88.89%). The spectra cut-off, the kernel function and the algorithm function influence the accuracy. Conclusion: Mid-Infrared imaging could be used to differentiate FFPE lung cancer subtypes. Supervised multivariate tools are promising to accurately separate lung tumor subtypes. The long-term perspective is to develop a spectroscopy-based diagnostic tool, revolutionizing medical differential diagnostics, especially cancer identification.

Expert opinion on NSCLC small specimen biomarker testing — Part 1: Tissue collection and management

Article

Full-text available

Jul 2022
Virchows Arch

Biomarker testing is crucial for treatment selection in advanced non-small cell lung cancer (NSCLC). However, the quantity of available tissue often presents a key constraint for patients with advanced disease, where minimally invasive tissue biopsy typically returns small samples. In Part 1 of this two-part series, we summarise evidence-based recommendations relating to small sample processing for patients with NSCLC. Generally, tissue biopsy techniques that deliver the greatest quantity and quality of tissue with the least risk to the patient should be selected. Rapid on-site evaluation can help to ensure sufficient sample quality and quantity. Sample processing should be managed according to biomarker testing requirements, because tissue fixation methodology influences downstream nucleic acid, protein and morphological analyses. Accordingly, 10% neutral buffered formalin is recommended as an appropriate fixative, and the duration of fixation is recommended not to exceed 24–48 h. Tissue sparing techniques, including the ‘one biopsy per block’ approach and small sample cutting protocols, can help preserve tissue. Cytological material (formalin-fixed paraffin-embedded [FFPE] cytology blocks and non-FFPE samples such as smears and touch preparations) can be an excellent source of nucleic acid, providing either primary or supplementary patient material to complete morphological and molecular diagnoses. Considerations on biomarker testing, reporting and quality assessment are discussed in Part 2.

The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015

Article

Full-text available

Nov 2021
J THORAC ONCOL

The 2021 World Health Organisation (WHO) Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are 1) broader emphasis on genetic testing than in the 2015 WHO Classification, 2) a chapter entirely dedicated to the classification of small diagnostic samples, 3) continued recommendation to document percentages of histological patterns in invasive non-mucinous adenocarcinomas, with utilization of these features to apply a formal grading system, as well as using only invasive size for T-factor size determination in part lepidic non-mucinous lung adenocarcinomas as recommended by the 8th Edition TNM Classification, 4) recognition of spread through airspaces (STAS) as a histological feature with prognostic significance, 5) moving lymphoepithelial carcinoma to squamous cell carcinomas, 6) update on evolving concepts in lung neuroendocrine neoplasm classification, 7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT) as a new entity within the adenoma subgroup, 8) recognition of thoracic SMARCA4-deficient undifferentiated tumor, and 9) inclusion of essential and desirable diagnostic criteria for each tumor.

Prediction of Target-Drug Therapy by Identifying Gene Mutations in Lung Cancer With Histopathological Stained Image and Deep Learning Techniques

Article

Full-text available

Apr 2021

Lung cancer is a kind of cancer with high morbidity and mortality which is associated with various gene mutations. Individualized targeted-drug therapy has become the optimized treatment of lung cancer, especially benefit for patients who are not qualified for lung lobectomy. It is crucial to accurately identify mutant genes within tumor region from stained pathological slice. Therefore, we mainly focus on identifying mutant gene of lung cancer by analyzing the pathological images. In this study, we have proposed a method by identifying gene mutations in lung cancer with histopathological stained image and deep learning to predict target-drug therapy, referred to as DeepIMLH. The DeepIMLH algorithm first downloaded 180 hematoxylin-eosin staining (H&E) images of lung cancer from the Cancer Gene Atlas (TCGA). Then deep convolution Gaussian mixture model (DCGMM) was used to perform color normalization. Convolutional neural network (CNN) and residual network (Res-Net) were used to identifying mutated gene from H&E stained imaging and achieved good accuracy. It demonstrated that our method can be used to choose targeted-drug therapy which might be applied to clinical practice. More studies should be conducted though.

Reflex Testing for Epidermal Growth Factor Receptor Mutation and Anaplastic Lymphoma Kinase Fluorescence In Situ Hybridization in Non–Small Cell Lung Cancer

Article

May 2011

Context.—Non–small cell lung cancer (NSCLC) is a poor-prognosis malignancy for which more effective treatments are needed, with accumulating clinical experiences supporting benefits of receptor tyrosine kinase inhibitors for patients with tumors harboring an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement. Objective.—To review completed and ongoing clinical trials of EGFR tyrosine kinase inhibitors for EGFR mutation–positive NSCLC and an ALK inhibitor for those with ALK rearrangement, while also exploring practical issues surrounding the implementation of molecular testing as a routine component of the diagnostic workup of NSCLC in the United States. Data Sources.—Published biomedical literature, abstracts presented at recent major oncology meetings, and ClinicalTrials.gov. Conclusions.—Continually evolving evidence indicates the possible efficacy of molecularly targeted agents for the treatment of advanced NSCLC, especially adenocarcinoma. To identify patients who will most likely benefit from the targeted therapy, routine determination of the corresponding genetic alterations after histologic diagnosis of NSCLC (reflex molecular testing for EGFR mutations and ALK rearrangement) should be considered.

Difficulties in diagnostics of lung tumours in biopsies: an interpathologist concordance study evaluating the international diagnostic guidelines

Article

Full-text available

Feb 2021
J Clin Pathol

Aims: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria. Methods: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary. Results: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment. Conclusions: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.

Pathology: Tissue Economıcs in the Transition From Molecular Analysis to Morphology

Article

Aug 2020

Buge OZ

TTF-1/p63-Positive Poorly Differentiated NSCLC: A Histogenetic Hypothesis from the Basal Reserve Cell of the Terminal Respiratory Unit

Article

Full-text available

Jan 2020

TTF-1 is expressed in the alveolar epithelium and in the basal cells of distal terminal bronchioles. It is considered the most sensitive and specific marker to define the adenocarcinoma arising from the terminal respiratory unit (TRU). TTF-1, CK7, CK5/6, p63 and p40 are useful for typifying the majority of non-small-cell lung cancers, with TTF and CK7 being typically expressed in adenocarcinomas and the latter three being expressed in squamous cell carcinoma. As tumors with coexpression of both TTF-1 and p63 in the same cells are rare, we describe different cases that coexpress them, suggesting a histogenetic hypothesis of their origin. We report 10 cases of poorly differentiated non-small-cell lung carcinoma (PD-NSCLC). Immunohistochemistry was performed by using TTF-1, p63, p40 (ΔNp63), CK5/6 and CK7. EGFR and BRAF gene mutational analysis was performed by using real-time PCR. All the cases showed coexpression of p63 and TTF-1. Six of them showing CK7+ and CK5/6− immunostaining were diagnosed as “TTF-1+ p63+ adenocarcinoma”. The other cases of PD-NSCLC, despite the positivity for CK5/6, were diagnosed as “adenocarcinoma, solid variant”, in keeping with the presence of TTF-1 expression and p40 negativity. A “wild type” genotype of EGFR was evidenced in all cases. TTF1 stained positively the alveolar epithelium and the basal reserve cells of TRU, with the latter also being positive for p63. The coexpression of p63 and TTF-1 could suggest the origin from the basal reserve cells of TRU and represent the capability to differentiate towards different histogenetic lines. More aggressive clinical and morphological features could characterize these “basal-type tumors” like those in the better known “basal-like” cancer of the breast.

Fourier Transform Infrared Spectroscopy as a Cancer Screening and Diagnostic Tool: A Review and Prospects

Article

Full-text available

Jan 2020

Infrared spectroscopy has long been used to characterize chemical compounds, but the applicability of this technique to the analysis of biological materials containing highly complex chemical components is arguable. However, recent advances in the development of infrared spectroscopy have significantly enhanced the capacity of this technique in analyzing various types of biological specimens. Consequently, there is an increased number of studies investigating the application of infrared spectroscopy in screening and diagnosis of various diseases. The lack of highly sensitive and specific methods for early detection of cancer has warranted the search for novel approaches. Being more simple, rapid, accurate, inexpensive, non-destructive and suitable for automation compared to existing screening, diagnosis, management and monitoring methods, Fourier transform infrared spectroscopy can potentially improve clinical decision-making and patient outcomes by detecting biochemical changes in cancer patients at the molecular level. Besides the commonly analyzed blood and tissue samples, extracellular vesicle-based method has been gaining popularity as a non-invasive approach. Therefore, infrared spectroscopic analysis of extracellular vesicles could be a useful technique in the future for biomedical applications. In this review, we discuss the potential clinical applications of Fourier transform infrared spectroscopic analysis using various types of biological materials for cancer. Additionally, the rationale and advantages of using extracellular vesicles in the spectroscopic analysis for cancer diagnostics are discussed. Furthermore, we highlight the challenges and future directions of clinical translation of the technique for cancer.

The value of desmosomal plaque-related markers to distinguish squamous cell carcinoma and adenocarcinoma of the lung

Article

Full-text available

Dec 2019

Background: An antibody panel is needed to definitively differentiate between adenocarcinoma (AC) and squamous cell carcinoma (SCC) in order to meet more stringent requirements for the histologic classification of lung cancers. Staining of desmosomal plaque-related proteins may be useful in the diagnosis of lung SCC. Materials and methods: We compared the usefulness of six conventional (CK5/6, p40, p63, CK7, TTF1, and Napsin A) and three novel (PKP1, KRT15, and DSG3) markers to distinguish between lung SCC and AC in 85 small biopsy specimens (41 ACs and 44 SCCs). Correlations were examined between expression of the markers and patients’ histologic and clinical data. Results: The specificity for SCC of membrane staining for PKP1, KRT15, and DSG3 was 97.4%, 94.6%, and 100%, respectively, and it was 100% when the markers were used together and in combination with the conventional markers (AUCs of 0.7619 for Panel 1 SCC, 0.7375 for Panel 2 SCC, 0.8552 for Panel 1 AC, and 0.8088 for Panel 2 AC). In a stepwise multivariate logistic regression model, the combination of CK5/6, p63, and PKP1 in membrane was the optimal panel to differentiate between SCC and AC, with a percentage correct classification of 96.2% overall (94.6% of ACs and 97.6% of SCCs). PKP1 and DSG3 are related to the prognosis. Conclusions: PKP1, KRT15, and DSG3 are highly specific for SCC, but they were more useful to differentiate between SCC and AC when used together and in combination with conventional markers. PKP1 and DSG3 expressions may have prognostic value.

IHC–The need of the hour in classifying lung tumours effectively on guided biopsies!

Article

Nov 2019

Quantitative Expressionsanalyse von TTF-1 in NSCLC und pulmonalen Metastasen

Thesis

Jan 2018

Veit Bertram

EXPRESSION OF TTF-1, NAPSIN-A, P63 AND P40 IN DIFFERENTIAL DIAGNOSIS OF NON-SMALL CELL LUNG CARCINOMA ORIGINAL ARTICLE

Article

Full-text available

Jul 2019

Background: Non-small cell lung cancer is classified into different subtypes. It is now mandatory for the histopathologists to classify the NSCLC into its exact classification because of the increase in promising personalized therapy against each of its subtypes. In order to better classify non-small cell lung cancers, the current study evaluates the diagnostic value of p40 and Napsin-A along with the comparison with the conventional markers TTF-1 and P63.

Analyzing the Dynamics of Lung Cancer Imaging Data Using Refined Fuzzy Entropy Methods by Extracting Different Features

Article

Full-text available

May 2019

Lung cancer is the major cause of cancer related deaths worldwide with poor survival due to poor diagnostic system at the advanced cancer stage. In the past, researchers developed computer aided diagnosis (CAD) systems which were greatly used by the radiologist for identifying the abnormalities and applied few features extracting methods. The physiology and behavior of various physiological systems can be best investigated using nonlinear dynamical measures for capturing the intrinsic dynamics which is influenced due to multiple pathologies by degradation of structural and functional components. As cancer images contain hidden information which can be best analyzed using these dynamical measures. In this research, we proposed multiscale sample entropy (MSE) with mean and KD-tree algorithmic approach, multiscale permutation entropy (MPE), multiscale fuzzy entropy (MFE) and refined composite multiscale fuzzy entropy (RCMFE) with mean, variance and standard deviation. The statistically significant results were computed to distinguish non small cell lung cancer (NSCLE) from small cell lung cancer (SCLC) by extracting morphological, texture and elliptic Fourier descriptors (EFDs). The highest significant results obtained based on texture features using MFE with standard deviation gives P-value of 1.95E-50, morphological features using RCMFE with mean provides P-value of 3.01E-14 and EFDs features using MFE with variance gives P-value of 1.04E-13. The results reveal that improved complexity measures based on refined fuzzy entropy outperformed in analyzing the dynamics of lung cancer and will provide a new insight to extract meaningful hidden information present in the Lung cancer images which will be very helpful to further distinguish NSCLC and SCLC for early diagnosis and prognosis.

Role of Immunocytochemistry in the Cytological Diagnosis of Pulmonary Tumors

Article

Full-text available

Mar 2019

Pulmonary cytology is a challenging diagnostic tool, and it is usually evaluated considering medical history and radiological findings in order to reach an accurate diagnosis. Since the majority of lung cancer patients have an advanced stage at diagnosis, a cytological specimen is frequently the only material available for diagnosis and further prognostic/pre-dictive marker determination. Several types of specimens can be obtained from the respiratory system (including spu-tum, bronchoalveolar lavage, bronchial brushing, fine needle aspiration, and pleural fluid) with different technical preclinical management protocols and different diagnostic yields. Immunocytochemistry (ICC) has a pivotal role in the determination of diagnostic, prognostic, and predictive markers. Therefore, limited cytology samples are to be used with a cell-sparing approach, to allow both diagnostic ICC evaluation as well as predictive marker assessment by ICC or specific molecular assays. In this review, we describe the most common ICC markers used for the diagnosis and prog-nostic/predictive characterization of thoracic tumors in different cytological specimens.

Pseudosquamous Adenocarcinoma of the Lung: Clinicopathologic and Immunohistochemical Study of 10 Cases

Article

May 2024

Pseudosquamous adenocarcinoma of the lung is an unusual morphologic variant of poorly differentiated non–small cell lung carcinoma that superficially resembles a squamous cell carcinoma. We have examined 10 cases of these tumors in 4 women and 6 men, aged 47 to 93 years. The tumors were all peripheral and measured from 1.5 to 5.5 cm. All cases were characterized by solid nests of large polygonal tumor cells containing atypical nuclei with abundant cytoplasm and sharp cell borders, adopting a pavement-like architecture that simulated squamous cell carcinoma. Some cases demonstrated intracytoplasmic hyaline inclusions suggestive of keratinization. The nests of tumor cells often showed central comedo-like areas of necrosis. Intercellular bridges were not seen in any of the cases. The tumors often displayed marked clearing of the cytoplasm enhancing their epidermoid appearance. In 4 cases, the solid pseudosquamous areas were seen to merge with a focal lepidic adenocarcinoma component, and in 1 case, abortive microscopic foci of acinar differentiation were also noted within the tumor. One case showed focal sarcomatoid spindle cell areas. The tumor cells were negative for p40 and CK5/6 and labeled with TTF1 or Napsin-A, confirming an adenocarcinoma phenotype. Clinical follow-up information was available in 8 patients; 6 patients died of their tumors between 6 months to 11 years after diagnosis (mean: 3.1 y). One patient died of complications related to surgery and one patient with a low-stage tumor died at 27 years from other causes. Solid pattern adenocarcinomas can be confused for squamous cell carcinoma and may require immunohistochemistry to determine their true phenotype.

The role of adenocarcinoma subtypes and immunohistochemistry in predicting lymph node metastasis in early invasive lung adenocarcinoma

Article

Full-text available

Jan 2024
BMC CANCER

Background Identifying lymph node metastasis areas during surgery for early invasive lung adenocarcinoma remains challenging. The aim of this study was to develop a nomogram mathematical model before the end of surgery for predicting lymph node metastasis in patients with early invasive lung adenocarcinoma. Methods In this study, we included patients with invasive lung adenocarcinoma measuring ≤ 2 cm who underwent pulmonary resection with definite pathology at Qilu Hospital of Shandong University from January 2020 to January 2022. Preoperative biomarker results, clinical features, and computed tomography characteristics were collected. The enrolled patients were randomized into a training cohort and a validation cohort in a 7:3 ratio. The training cohort was used to construct the predictive model, while the validation cohort was used to test the model independently. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. The prediction model and nomogram were established based on the independent risk factors. Recipient operating characteristic (ROC) curves were used to assess the discrimination ability of the model. Calibration capability was assessed using the Hosmer–Lemeshow test and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). Results The overall incidence of lymph node metastasis was 13.23% (61/461). Six indicators were finally determined to be independently associated with lymph node metastasis. These six indicators were: age (P < 0.001), serum amyloid (SA) (P = 0.008); carcinoma antigen 125 (CA125) (P = 0. 042); mucus composition (P = 0.003); novel aspartic proteinase of the pepsin family A (Napsin A) (P = 0.007); and cytokeratin 5/6 (CK5/6) (P = 0.042). The area under the ROC curve (AUC) was 0.843 (95% CI: 0.779–0.908) in the training cohort and 0.838 (95% CI: 0.748–0.927) in the validation cohort. the P-value of the Hosmer–Lemeshow test was 0.0613 in the training cohort and 0.8628 in the validation cohort. the bias of the training cohort corrected C-index was 0.8444 and the bias-corrected C-index for the validation cohort was 0.8375. demonstrating that the prediction model has good discriminative power and good calibration. Conclusions The column line graphs created showed excellent discrimination and calibration to predict lymph node status in patients with ≤ 2 cm invasive lung adenocarcinoma. In addition, the predictive model has predictive potential before the end of surgery and can inform clinical decision making.

Molecular testing in lung cancer

Chapter

Jan 2024

Optimizing tissue stewardship in non-small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists

Article

Nov 2023
HISTOPATHOLOGY

Many patients with non‐small cell lung cancer do not receive guideline‐recommended, biomarker‐directed therapy, despite the potential for improved clinical outcomes. Access to timely, accurate, and comprehensive molecular profiling, including targetable protein overexpression, is essential to allow fully informed treatment decisions to be taken. In turn, this requires optimal tissue management to protect and maximize the use of this precious finite resource. Here, a group of leading thoracic pathologists recommend factors to consider for optimal tissue management. Starting from when lung cancer is first suspected, keeping predictive biomarker testing in the front of the mind should drive the development of practices and procedures that conserve tissue appropriately to support molecular characterization and treatment selection.

Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation

Article

Jun 2023

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

PD-L1 Testing in Urothelial Carcinoma: Analysis of a Series of 1401 Cases Using Both the 22C3 and SP142 Assays. In: J Tímár, L Kopper, A Ladányi, A Sebestyén (eds). Pathology & Oncology Research – Editors' Picks from 2022

Chapter

Full-text available

Mar 2023

Immune checkpoint blockade (ICB) drugs are a novel, effective treatment for advanced urothelial carcinoma. Worldwide, several different ICB drugs are approved, each developed and clinically validated with a specific PD-L1 compound diagnostic assay. As a result, PD-L1 testing workflows in routine practice are complex: requiring multiple assays across two platforms, with each assay having a different method of interpretation. Our service tested 1,401 urothelial carcinoma cases for PD-L1 expression, using both the 22C3 PharmDx assay (required prior to Pembrolizumab therapy) and SP142 assay (required prior to Atezolizumab therapy). Of the 1,401 cases tested, 621 cases (44%) were tested with both the 22C3 PharmDx and SP142 assays, 492 cases (35%) with 22C3 PharmDx only, and 288 cases (21%) with SP142 only. Each assay was used and interpreted according to the manufacturer’s guidelines. The rate of positivity we observed was 26% with the 22C3 assay and 31% with the SP142 assay, similar to the pre-licensing studies for both drugs. The discrepancy observed between the assays was 11%, which reinforces the requirement for utilisation of the correct assay for each agent, and limits potential cross-utility of assays. This aspect must be considered when setting up a PD-L1 testing strategy in laboratories where both Pembrolizumab and Atezolizumab are available for the treatment of urothelial carcinoma but also has broader implications for testing of other cancers where multiple ICB drugs and their respective assays are approved.

Clinicopathological correlation of p40/TTF1 co-expression in NSCLC and review of related literature

Preprint

Full-text available

Sep 2022

TTF1 and {\Delta}Np63/p40 have been used to differentiate ADC and SQC in hypofractionated NSCLC because of their sensitivity and specificity. There are few cases where TTF1 and {\Delta}Np63/p40 are expressed together in the same tumour cells, and little is known about the clinicopathological features, treatment and prognosis of such cases. We investigated the electron microscopic features, immunohistochemical expression and molecular variation of a case of TTF1/p40 co-expressing NSCLC and reviewed and summarised the relevant literature. Our patient was a 58-year-old male with a CT showing a left-sided lung occupancy. As in all other cases reported in the literature, the tumour showed a solid growth pattern with polygonal cells, eosinophilic cytoplasm and clearly visible nuclear fission. Immunohistochemistry showed positive for TTF-1, p40, CK5/6, CK7, P63 and p53, and negative for NapsinA and ALK. Electron microscopy showed tumour cells characterised by bidirectional differentiation of adenocytes and squamous cells, consistent with previous reports. Second-generation sequencing suggested co-mutation of STK11/LKB1 and NF1 genes in this case. Mutations in STK11/LKB1 and NF1 genes have been found in ADC and SQC and are often associated with drug resistance and poor prognosis, but STK11/NF1 co-mutation has not been reported and more cases are needed to reveal the association. p40/TTF1 co-expression in NSCLC may be an under-recognised variant of NSCLC The origin may be a double positive stem cell-like basal cell located in the distal airway, with rapid clinical progression and poor prognosis.

Feature Ranking Importance from Multimodal Radiomic Texture Features using Machine Learning Paradigm: A Biomarker to Predict the Lung Cancer

Article

Jul 2022

The machine learning based techniques for detection of lungs cancer can assist the clinicians in assessing the risk of pulmonary nodules being malignant. We are developing non-invasive methods to accurately distinguish the non-small cell cancer carcinoma (NSCLC) from small cell cancer carcinoma (SCLC) brain metastases. In this study, we extracted multimodal radiomic features including texture and statistical Haralick texture, gray level co-occurrence matrix (GLCM) features, Gray level size-zone matrix (GLSZM) features, Gray-level run-length matrix (GLRLM) features. We also applied image enhancement contrast stretching and gamma correction to further improve the classification performance. We then Ranked these features in order to investigate that which features category is more important to accurately distinguish the lung cancer subtypes. We employed robust machine learning techniques. We evaluated the performance based on top ranked 03 and 05 features and last ranked 05 and 02 features based on the receiver operating curve (ROC). The highest classification performance in terms of accuracy and AUC was obtained with all Haralick texture features using SVM polynomial with accuracy (99.89%) and AUC (0.9984). The classification performance with contrast stretching [0.02,0.08; 0.05,0.95] and gamma correction with gamma = 0.5 yielded highest accuracy of 100% and AUC of 1.00. The top three ranked features using image enhancement methods also yielded accuracy more than 95% which indicates that these top ranked features contributed higher in accuracy classifying the lung cancer subtypes. The results revealed that proposed model with multimodal features, image enhancement techniques and features ranking methods improved the classification performance which can used for better diagnostic aid to improve the decision making to treat the patients suffering from SCLC and NSCLC.

CT-Guided Percutaneous Core Needle Biopsy in Typing and Subtyping Lung Cancer: A Comparison to Surgery

Article

Full-text available

Mar 2022
TECHNOL CANCER RES T

Background: Lung cancer histologic types and subtypes are closely associated with treatment selection and prognosis prediction. In this study, we aim to evaluate the suitability of computed tomography-guided percutaneous core needle biopsy (CT-guided PCNB) in typing and subtyping lung cancer. Methods: From August 2007 to December 2015, the patients who underwent CT-guided PCNB and lung lesion resection were retrospectively collected and analyzed. All pathological sections were reassessed in consensus by 2 junior pathologists (group A) and 2 senior pathologists (group B), respectively. All cases were diagnosed on 3 levels: first, malignant and benign diagnosis; second, histologic types diagnosis; and third, histologic subtypes diagnosis and compared with surgery results. Pearson chi-square test was used to compare the differences of diagnostic accuracy between pathologists in group A and group B. Results: A cohort of 160 patients was included in this study. On the first level, the diagnostic accuracy was 90.63% (group A) and 94.38% (group B), ( P = .20). On the second level, the diagnostic accuracy for malignant lesions, adenocarcinoma (ADC), and squamous cell carcinoma (SQC) were, respectively, 72.66%, 84.72%, and 69.05% (group A) and 76.98%, 90.28%, and 71.43% (group B) ( P > .05). On the third level, the diagnostic accuracy for ADC subtypes were 26.39% (group A) and 55.56% (group B) ( P < 0.01); for SQC subtypes were 28.57% (group A) and 38.10% (group B) ( P = 0.36). Conclusion: Small specimens obtained by CT-guided PCNB were suitable for the diagnosis of lung cancer histologic types, which may contribute to the selection of a suitable treatment strategy for the unresectable lung cancers. While for the diagnosis of subtypes, discussion with experienced pathologists was recommended.

Odontologia em Oncologia.

Chapter

Full-text available

Oct 2017

Immunoexpression of TTF1 and p63 Differentiates Lung Adenocarcinomas in Sputum Samples

Article

Full-text available

Jul 2021

Context: Differentiating NSCLC as either adeno or squamous type and identification of Epidermal Growth Factor Receptor (EGFR) mutations is clinically relevant for lung cancer patients for selecting treatment. Thyroid transcription factor-1 (TTF-1) and p63 were demonstrated as useful markers for histologic typing of lung cancer. Mutation and overexpression of EGFR has been reported in a subset of non-small cell lung cancers. If these markers can be validated for the differential diagnosis of adenocarcinoma in a sputum sample itself, it will be highly beneficial for lung cancer patients. Aims: To evaluate whether immunocytochemical expression of TTF-1, p63, and EGFR proteins in sputum samples can be used for differential diagnosis of lung adenocarcinoma by comparing with that of the corresponding tissue samples. Settings and design: Ninety sputum samples and matched tissue samples were used for the study. Subjects and methods: Monolayered smears and cell blocks of sputum and the corresponding tissue samples were immunostained with the standard ABC method. The expression patterns of these markers were analyzed statistically and compared with clinic-pathological parameters. Statistical analysis used: Chi-square test and paired t-test. Results: The p63 protein had a positive expression in 73.9% of SCC whereas TTF1 had positive expression in 75.8% of ADC. The EGFR expression was positive in 27 cases of adenocarcinoma, 21 cases of SCC and 19 cases of NSCLC. Conclusions: Immunocytochemistry of the aforementioned antibodies in sputum samples can be used as supplementary evidence for the subtyping of NSCLC.

Respiratory cytology in malignant lung disease - The thoracic oncologist's perspective

Article

Jun 2021

Respiratory cytology continues to play a central role in the diagnosis and staging of thoracic malignancy, although over time indications have changed. Historically, sputum cytology and endobronchial brushings and washings figured prominently, but with the advent of endobronchial and endoscopic ultrasound much greater emphasis is placed on fine needle aspirates from lymph nodes. The advent of targeted sequencing panels for genomic profiling to identify driver mutations and PD-L1 directed immunotherapy means that there is a need to extract increasing amounts of diagnostic and predictive information from ever smaller amounts of diagnostic material. Recent work has demonstrated that cytology samples are well suited to delivering the information required, but in order to understand the limitations of clinical and laboratory techniques, a close working relationship between pathologist and thoracic oncologist is needed to optimise sample procurement and utilisation. Abstract Respiratory cytology plays a central role in diagnosis of thoracic malignancy but indications have changed with the development of endobronchial ultrasound. The advent of genomic profiling to identify actionable driver mutations means that increasing amounts of diagnostic and predictive information are required from ever smaller amounts of diagnostic material. In this article we reflect on the relationship between thoracic oncologist and Cytopathologist to optimize diagnostic algorithms.

Quantum Cascade Laser–Based Infrared Imaging as a Label-Free and Automated Approach to Determine Mutations in Lung Adenocarcinoma

Article

May 2021
Am J Pathol

Therapeutic decisions in lung cancer critically depend on the determination of histologic types and oncogene mutations. Therefore, tumor samples are subjected to standard histological and immunohistochemical analyses and examined for relevant mutations using comprehensive molecular diagnostics. In this study, an alternative diagnostic approach for automatic and label-free detection of mutations in lung adenocarcinoma tissue using quantum cascade laser (QCL)-based infrared imaging is presented. For this purpose, a 5-step supervised classification algorithm was developed, which was not only able to detect tissue types and tumor lesions, but also the tumor type and mutation status of adenocarcinomas. Tumor detection was verified on a dataset of 214 patient samples with a specificity of 97% and a sensitivity of 95%. Furthermore, histology typing was verified on samples from 203 out of the 214 patients with a specificity of 97% and a sensitivity of 94% for adenocarcinoma. The most frequently occurring mutations in adenocarcinoma (KRAS, EGFR, and TP53) were differentiated by this technique. Detection of mutations was verified on 60 patient samples from the dataset with a sensitivity and specificity of 95% for each mutation. This demonstrates that QCL IR imaging can be used to analyze morphological differences as well as molecular changes. Therefore, this single, one-step measurement provides comprehensive diagnostics of lung cancer histology types and most frequent mutations.

A deep learning model for the classification of indeterminate lung carcinoma in biopsy whole slide images

Article

Full-text available

Apr 2021

The differentiation between major histological types of lung cancer, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC), and small-cell lung cancer (SCLC) is of crucial importance for determining optimum cancer treatment. Hematoxylin and Eosin (H&E)-stained slides of small transbronchial lung biopsy (TBLB) are one of the primary sources for making a diagnosis; however, a subset of cases present a challenge for pathologists to diagnose from H&E-stained slides alone, and these either require further immunohistochemistry or are deferred to surgical resection for definitive diagnosis. We trained a deep learning model to classify H&E-stained Whole Slide Images of TBLB specimens into ADC, SCC, SCLC, and non-neoplastic using a training set of 579 WSIs. The trained model was capable of classifying an independent test set of 83 challenging indeterminate cases with a receiver operator curve area under the curve (AUC) of 0.99. We further evaluated the model on four independent test sets—one TBLB and three surgical, with combined total of 2407 WSIs—demonstrating highly promising results with AUCs ranging from 0.94 to 0.99.

Machine learning-based lungs cancer detection using reconstruction independent component analysis and sparse filter features

Article

Mar 2021

In the present study, based on the multivariate nature of images from lung cancer, we extracted autoencoder, reconstruction independent component analysis (RICA) and sparse filters features along with traditional texture and morphological features. The machine learning techniques such as Support Vector Machine (SVM) with Gaussian, radial base function (RBF) and polynomial kernels, decision tree and Naïve Bayes were used classification purpose. The Jackknife 10-fold cross validation (CV) was used for training/testing data formulation and performance was evaluated in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), total accuracy (TA), false positive rate (FPR) and area under the receiving operating curve (AUC) to distinguish the small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) images. The highest detection performance was obtained by extracting RICA and Sparse filters with 100% of sensitivity, specificity, PPV, NPV and TA using SVM with RBF, polynomial kernels and Naïve Bayes followed by Sparse filter with decision tree with TA (99.78%). The highest AUC of 1.00 was obtained by extracting RICA and Sparse filters using decision tree, SVM Gaussian, RBF and polynomial and Naïve Bayes. The results showed the good potential of these methods for lung cancer detection (LCD).

Automated TTF-1 Immunohistochemistry Assay for the Differentiation of Lung Adenocarcinoma Versus Lung Squamous Cell Carcinoma

Chapter

Mar 2021

Due to therapeutic advances, the subclassification of non-small cell lung carcinomas (NSCLC) between the adenocarcinomas and squamous cell carcinomas subtypes is essential for the practice of personalized and targeted medicine. The clinical management for these two NSCLC subtypes is different due to their different molecular properties and histological origins. Immunohistochemistry (IHC) markers such is TTF-1 play a key role in the differentiation of lung adenocarcinomas and squamous cell carcinomas. However, immunohistochemistry is a complex process involving many critical steps and the reliability of results depends on the standardization of the assay as well as the appropriate interpretation. Different laboratories use different reagents and different IHC approaches for the detection of TTF-1 in lung cancer tumors. Here we describe an automated IHC protocol used in our laboratory for the detection of TTF-1 in formalin-fixed, paraffin-embedded (FFPE) tissue sections from lung tumors.

Non-Small Cell Carcinoma-Not Otherwise Specified on Cytology Specimens in Patients with Solitary Pulmonary Lesion: Primary Lung Cancer or Metastatic Cancer?

Article

Jan 2021

Context: Subtyping of solitary pulmonary lesion (SPL) in small amount of cytology specimen using a limited panel of immunohistochemistry (IHC) markers is very important to the correct choice of treatment. This study was performed to categorize non-small cell carcinoma-not otherwise specified (NSCC-NOS) on cytology in patients with SPL, especially with regard to the incidence of metastatic cancer. Materials and methods: We reviewed 91 cases, in which a precise morphology-based, lineage-specific IHC-aided subtyping was not possible, that qualified as NSCC-NOS on cytology. A stepwise clinical approach and IHC of organ-specific markers was performed on each cell block (CB) to exclude metastasis from extrapulmonary malignancies. Results: Of the 91 evaluated cases, 65 (71.4%) were diagnosed as non-small cell lung carcinoma (NSCLC)-NOS, 24 (26.4%) were metastatic cancer, and the remaining 2 (2.2%) had undetermined diagnoses. The most frequent primary tumor site was the colorectum (41.7%), followed by breast (20.8%), kidney (8.3%), and then stomach, duodenum, liver, pancreas, gallbladder, prostate, and skin (4.2% each, 1 of 24). Moreover, we found that 7 of the 24 patients with metastatic cancer had a history of extrapulmonary malignancy that was unknown at the time of cytology-based diagnosis. Conclusions: These results underscored the need for accurate and stepwise clinical correlation to rule out the possibility of pulmonary metastasis from other sites and appropriate but judicious IHC (i.e., CDX2) on CB for SPL to increase refinement of the cytology diagnosis of NSCC-NOS.

Classic Anatomic Pathology and Lung Cancer

Chapter

Jan 2018

Diagnostic Patterns of Non-Small-Cell Lung Cancer at Princess Margaret Cancer Centre

Article

Full-text available

Jun 2020
Curr Oncol

Background: Accurate classification of lung cancer subtypes has become critical in tailoring lung cancer treatment. Our study aimed to evaluate changes in diagnostic testing and pathologic subtyping of advanced non-small-cell lung cancer (nsclc) over time at a major cancer centre. Methods: In a review of patients diagnosed with advanced nsclc at Princess Margaret Cancer Centre between 2007-2009 and 2013-2015, diagnostic method, sample type and site, pathologic subtype, and use of immunohistochemistry (ihc) staining and molecular testing were abstracted. Results: The review identified 238 patients in 2007-2009 and 283 patients in 2013-2015. Over time, the proportion of patients diagnosed with adenocarcinoma increased to 73.1% from 60.9%, and diagnoses of nsclc not otherwise specified (nos) decreased to 6.4% from 18.9%, p < 0.0001. Use of diagnostic bronchoscopy decreased (26.9% vs. 18.4%), and mediastinal sampling procedures, including endobronchial ultrasonography, increased (9.2% vs. 20.5%, p = 0.0001). Use of ihc increased over time to 76.3% from 41.6% (p < 0.0001). Larger surgical or core biopsy samples and those for which ihc was performed were more likely to undergo biomarker testing (both p < 0.01). Conclusions: Customizing treatment based on pathologic subtype and molecular genotype has become key in treating patients with advanced lung cancer. Greater accuracy of pathology diagnosis is being achieved, including through the routine use of ihc.

Programmed death-ligand 1 (PD-L1)/thyroid transcription factor-1 double immunohistochemical staining facilitates scoring of tumor PD-L1 expression in cytopathology specimens from lung adenocarcinoma patients

Article

Sep 2020
CANCER CYTOPATHOL

Background: Immune checkpoint inhibitor therapy has revolutionized lung adenocarcinoma therapy. Treatment with antibodies against the immune checkpoint molecules programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) can induce a durable response in a subset of patients. Immunohistochemistry characterization of tumor PD-L1 expression using either a histopathology specimen or a cytopathology specimen has been shown to correlate with treatment response. However, the current practice relies on pathologists' visual estimation of tumor PD-L1 staining, which can be variable in certain conditions. Highlighting tumor cells via double immunostaining with PD-L1 and thyroid transcription factor-1 (TTF-1) may improve estimation accuracy. Methods: We performed PD-L1 single staining and PD-L1/TTF-1 double staining in 42 pairs of cytopathology and histopathology specimens from lung adenocarcinoma patients. An experienced pathologist visually estimated PD-L1 expression in each case and placed tumor PD-L1 expression into 1 of 3 categories: <1%, 1%-49%, or ≥50%. A medical technologist also performed estimations of the same cases based on a count of 200 tumor cells, and the results were compared. Results: PD-L1/TTF-1 double immunohistochemistry could better identify the PD-L1-positive tumor cells in cytopathology specimens compared with PD-L1 single staining. The concordance of PD-L1 expression categorization between the pathologist's visual estimation and the medical technologist's counting was increased by double staining in cytopathology specimens (Cohen's weighted kappa: single stain, 0.784; double stain, 0.880). Double staining reduced possible error in the pathologist's visual estimation of PD-L1 expression from 9.5% to 4.8%. The benefit was not observed in histopathology specimens. Conclusion: A simple PD-L1/TTF-1 double immunohistochemistry technique can be applied successfully to cytopathology specimens in better identifying patients who can potentially benefit from immune checkpoint blockade treatment.

Lung Cancer Cytology: Can Any of the Cytological Methods Replace Histopathology?

Article

Jul 2020

Background: Diagnosis of lung cancer can be made in two ways: histopathological and cytopathological. Cytological methods in the diagnosis of lung lesions are generally thought to be one of the most successful tactics. Aims: This study aimed at comparing the efficiency of selected cytological techniques in lung lesions by correlating them with histopathological diagnosis. In addition, we had answered the question whether any of the cytological methods can replace histopathology. Materials and methods: The study group consisted of 633 patients and 1085 cytological specimens. Cytology samples included: induced sputum, bronchial washing (BW), bronchial brushing (BB), fine needle aspiration (FNA), and cell block (CB). In every case of CB immunocytochemistry (ICC) was performed. For each cytological method sensitivity, specificity, effectiveness, positive predictive value, and negative predictive value were assessed. Results: BW and BB showed the lowest diagnostic parameters. The most valuable diagnostic procedure was CB based on FNA. Close by CB, FNA had the highest diagnostic rate. However, possibility to evaluate tumor cell structure and apply the ICC, give CB an advantage over FNA. Using only morphologic criteria, we had subclassified nonsmall-cell lung cancer (NSCLC) into squamous cell carcinoma (SCC) and adenocarcinoma (AC) as 60.04% of SCC and 32.52% of AC. The use of CB and ICC decreased the NSCLC diagnoses from 22.1% to 2.8% while the percentage of AC and SCC diagnoses increased from 4.11% to 12.64% and from 6.64% to 11.06%, respectively. Metastatic lung tumors were diagnosed based on both the cell morphology and according to the ICC results. Conclusion: Despite the limitations of the cytological procedures, we recommend using CB and ICC to evaluate cytological samples derived from FNA. It can in many cases replace a conventional histopathology.

Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy

Article

Dec 2019

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM. Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen. Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943). EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.

THE ROLE OF IMMUNOHISTOCHEMISTRY IN DIAGNOSIS OF LUNG CANCER WITH CORRELATION OF SERUM TUMOUR MARKER CARCINOEMBRYONIC ANTIGEN

Article

Mar 2019

Gefitinib or CarboplatinΓÇôPaclitaxel in Pulmonary Adenocarcinoma

Article

Full-text available

Aug 2009
NEW ENGL J MED

Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Desmocollin-3: A new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Article

Full-text available

Apr 2009
Mod Pathol

Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno- and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno- and large-cell types.

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

Article

Full-text available

Dec 1993

A study was undertaken to investigate the accuracy of typing of a series of bronchial carcinomas by experienced pathologists with an interest in lung cancer from the examination of bronchoscopic biopsy specimens. Eighty bronchial biopsy specimens showing positive results for bronchial carcinoma were circulated to five pathologists, who recorded diagnostic criteria and diagnosis for each. Diagnoses were then compared with the diagnosis agreed from the resection specimen corresponding to each biopsy specimen. A "non-small cell carcinoma, not further specified" classification group was introduced for small biopsy specimens. A diagnostic accuracy of 75% was achieved for squamous cell carcinomas, 66% for small cell carcinomas, and 50% for adenocarcinomas. There was diagnostic confusion between small cell and non-small cell carcinoma in less than 10% of cases. The introduction of a non-specific non-small cell classification improved diagnostic accuracy by 10-15% for each non-small cell tumour group. There are appreciable inaccuracies in applying the World Health Organisation's 1981 classification of lung cancer to the diagnosis of bronchial carcinoma from small biopsy specimens and these inaccuracies have been measured. They can be diminished by introducing a less specific "non-small cell" category for use with this sort of biopsy material. Care should be taken not to overinterpret small biopsy specimens in lung cancer.

Cell Type Accuracy of Bronchial Biopsy Specimens in Primary Lung Cancer

Article

Full-text available

Jun 1996

To evaluate the diagnostic accuracy of bronchial biopsy (BB) specimens in establishing the specific cell type in primary lung cancer (LC), and to study the influence of several factors on this accuracy. Tertiary health-care center. One hundred forty-six patients with LC diagnosed by BB specimens who underwent thoracotomy (T). We have studied the specific LC cell type observed in the BB specimen and compared it with the T specimen (reference diagnosis). Age, location and type of bronchial lesion, number and size of the biopsy fragments, tumoral size, sample necrosis, degree of cell differentiation, tumoral stage, pathologist's experience, and the presence of other diagnostic tests with the same cell type were analyzed to assess their influence on the concordance between the two diagnoses. The overall concordance between BB and T histologic diagnosis was 0.70 (kappa coefficient [K]). Of the different histologic types, the worst result was obtained in large cell carcinoma (LLC) (K, 0.49). Squamous carcinoma and adenocarcinoma gave similar results (0.74 and 0.77, respectively), while small cell lung cancer (SCLC) only reached a value of 0.60. The degree of cell differentiation, the absence of necrosis, and presence of other preoperative diagnoses were the variables that most influenced the histologic accuracy of BB specimens. Therefore, the probability of BB accuracy was 2.7, 7.7, and 25 times higher in well-differentiated, than in poorly differentiated, moderately differentiated, or undifferentiated carcinomas; 5.2 times higher when there was no necrosis in the sample; and 7.43 higher when there was another preoperative diagnosis. The histologic results of BB must be examined carefully, especially in cellular subtypes like LLC. The absence of differentiation and presence of necrosis in BB samples were the factors that require the greatest caution in ascertaining the cell type. When they are involved and also in all cases in which identifying the specific cell type has important implications, we prefer to classify the patients as having SCLC or non-small cell lung cancer, and then reclassify them later after using a second diagnostic technique.

Value of p63 and Cytokeratin 5/6 as Immunohistochemical Markers for the Differential Diagnosis of Poorly Differentiated and Undifferentiated Carcinomas

Article

Full-text available

Jan 2002

To facilitate the differential diagnosis of poorly differentiated metastatic carcinomas of unknown primary site, we evaluated p63 and cytokeratin (CK) 5/6 as immunohistochemical markers for squamous cell carcinomas. The study cases were as follows: squamous cell carcinoma of the lungs, head/neck, esophagus, cervix uteri, or anal canal, 73; non-squamous cell carcinomas of various primary sites, 141; and urothelial carcinoma, 20. We also tested 14 malignant mesotheliomas. Immunoreactivity for p63 was as follows: squamous cell carcinomas, 59 (81%); urothelial carcinoma, 14 (70%), most often with diffuse staining patterns; non-squamous cell carcinomas, 20 (14.2%), resulting in a specificity of 0.86 of p63 for squamous cell carcinomas. Coexpression of p63 and CK5/6 had a sensitivity of 0.77 and a specificity of 0.96 for squamous cell carcinomas. Increasing the minimal criterion of positive immunostaining for both markers to more than 50% of immunoreactive tumor cells resulted in a specificity of 0.99, although the sensitivity diminished to 0.66. All malignant mesotheliomas were negative for p63. Our data suggest that positive immunostaining for both p63 and CK5/6 in poorly differentiated metastatic carcinomas is highly predictive of a primary tumor of squamous epithelial origin.

p63 and TTF-1 Immunostaining A Useful Marker Panel for Distinguishing Small Cell Carcinoma of Lung From Poorly Differentiated Squamous Cell Carcinoma of Lung

Article

Full-text available

Jun 2003

We studied the usefulness of p63 and thyroid transcription factor-1 (TTF-1) immunostains for differentiating poorly differentiated squamous cell carcinoma (PDSCC) from small cell lung carcinoma (SCLC). We used monoclonal antibodies reactive to p63 or TTF-1 to stain 4-microns-thick sections from 30 formalin-fixed, paraffin-embedded lung biopsy and resection specimens and 7 alcohol-fixed, formalin-postfixed, paraffin-embedded cell blocks from lung fine-needle aspirations (FNAs). For p63, we used a streptavidin-biotin kit, diaminobenzidine as the chromogen, and a hematoxylin counterstain. We used automated immunostaining for TTF-1. The 37 cases included 23 SCLCs, 13 PDSCCs, and 1 carcinoma initially diagnosed as PDSCC. All 23 SCLCs were negative or, rarely, equivocal for p63; 20 (87%) of 23 were TTF-1+; nuclear staining ranged from strong and/or frequent to weak and/or uncommon. All 13 PDSCCs were TTF-1-/p63+ with intense staining of 50% to 100% of tumor cells. One case originally diagnosed as PDSCC was TTF-1+/p63-, suggestive of SCLC; after morphologic reexamination and immunostaining for neuroendocrine markers, it was reclassified as intermediate-type SCLC. TTF-1 immunostaining showed equal or increased sensitivity in alcohol-fixed cytologic cell block samples compared with formalin-fixed biopsy material; in 1 SCLC case, the biopsy specimen was TTF-1-; however, the FNA cell block stained positively. p63 and TTF-1 appear to be useful for differentiating SCLC from lung PDSCC in formalin-fixed and alcohol-fixed, formalin-postfixed material.

Thyroid transcription factor 1 in pulmonary adenocarcinoma

Article

Full-text available

May 2004

To discover whether variations in thyroid transcription factor 1 (TTF-1) staining in different subtypes and patterns of pulmonary adenocarcinoma are related to the putative origin of the tumour. In addition, to confirm the specificity of TTF-1 for pulmonary (as opposed to other sites) adenocarcinoma, to examine the possible prognostic relevance of TTF-1 positivity in lung cancer, and to review this laboratory's experience of TTF-1 in diagnostic practice. In total, 128 primary lung adenocarcinomas, 106 primary non-pulmonary adenocarcinomas, and 37 pulmonary non-adenocarcinoma tumours were studied. In addition, 100 cases where TTF-1 was used in routine surgical pathology practice were investigated. Immunoperoxidase staining was performed on formalin fixed, paraffin wax embedded sections using anti-TTF-1 antibody. Staining was evaluated semiquantitatively using the frequency and intensity of nuclear positivity. None of the 106 non-pulmonary adenocarcinomas expressed TTF-1 and only three of the 37 non-adenocarcinoma lung cancers, all neuroendocrine carcinomas, were positive. Of the pulmonary adenocarcinomas, 75% were strongly positive for TTF-1. Mucinous (two of six) and poorly differentiated adenocarcinomas (four of 10) were less likely to stain. Of the peripheral adenocarcinomas, 33 of 37 were positive, whereas only seven of 14 of those of bronchial origin stained strongly. Atypical adenomatous hyperplasia strongly expressed TTF-1. No "false positives" were encountered in the 100 routine diagnostic cases. Positive TTF-1 staining is useful in the differential diagnosis of pulmonary adenocarcinomas. TTF-1 may be a lineage marker for tumours arising from the peripheral airway or alveolar epithelium and has no prognostic relevance.

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

Article

Full-text available

Feb 2005

Accurate morphologic distinction between small cell carcinoma and poorly differentiated squamous cell carcinoma has critical therapeutic significance, but can be limited by crush artifact, tumor necrosis, limited tumor representation, and overlapping morphologic features. We evaluated a panel of antibodies for their efficacy in distinguishing between these neoplasms. Formalin-fixed paraffin-embedded tissue sections of small cell carcinomas and poorly differentiated squamous cell carcinomas underwent immunohistochemical staining with antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A). Of 28 small cell carcinomas, 26 (93%) small cell carcinomas showed diffuse moderate or strong staining for thyroid transcription factor-1 with no staining for high molecular weight keratin and p63. In contrast, 27/28 (96%) poorly differentiated squamous cell carcinomas manifested opposite immunoreactivities, with diffuse moderate or strong staining for high molecular weight keratin and p63, and no or minimal staining for thyroid transcription factor-1. In two additional cases originally interpreted as small cell carcinoma, high molecular weight keratin highlighted small numbers of neoplastic large cells, leading to reclassification as combined small cell and non-small cell carcinomas. p16(INK4A) expression varied widely in poorly differentiated squamous cell carcinomas, but was consistently moderate or strong and diffuse in small cell carcinomas, and proved helpful in the two thyroid transcription factor-1-negative small cell carcinomas. This study demonstrates that a panel consisting of antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A) is highly effective for distinguishing between small cell carcinoma and poorly differentiated squamous cell carcinoma. This panel also facilitates diagnosis of combined small cell and non-small cell carcinomas.

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

Article

Full-text available

Sep 2006

In histology and cell block sections, antibodies to thyroid transcription factor-1 (TTF-1) and p63 have been demonstrated to be useful markers for distinguishing between small-cell lung carcinoma and poorly differentiated pulmonary squamous cell carcinoma. In this study, we assessed the utility of TTF-1 and p63, as an antibody panel, for differentiating between these two neoplasms in previously Papanicolaou (Pap)-stained cytologic smears and cytospin slides. Twenty-six lung carcinomas (13 small-cell lung carcinomas, 13 poorly differentiated pulmonary squamous cell carcinomas) were evaluated. One or two previously 95% ethanol-fixed, Pap-stained smears or cytospin slides were selected from each case. The cytologic material from these slides was transferred to positively charged slides. Unstained recuts were obtained from the corresponding histologic specimens or cell blocks. Immunohistochemical staining for TTF-1 and p63 was performed on the paired samples from each tumor. All (13/13) small-cell lung carcinomas were negative for p63 and 92% (12/13) were positive for TTF-1. Conversely, all (13/13) poorly differentiated pulmonary squamous cell carcinomas expressed p63 and did not express TTF-1. Immunoreactivity for p63 was also noted in bronchial reserve cells and metaplastic squamous cells. The immunostaining results obtained from the cytology slides were concordant with those of the histology or cell block sections in all cases. The results of this study show that TTF-1 and p63 immunostaining can be successfully applied to previously Pap-stained cytologic material, as an antibody panel, to facilitate pathologic differentiation between small-cell lung carcinomas and poorly differentiated pulmonary squamous cell carcinomas. p63 immunostaining, however, must be interpreted in conjunction with cytomorphology to distinguish between poorly differentiated pulmonary squamous cell carcinomas and benign cellular constituents of the lung.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer

Article

Full-text available

Jul 2008
J CLIN ONCOL

Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles. Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

p63 and TTF-1 immunostaining: A useful marker panel for distinguishing small cell carcinoma of lung from poorly differentiated squamous cell carcinoma of lung

Article

May 2003

We studied the usefulness of p63 and thyroid transcription factor-1 (TTF-1) immunostains for differentiating poorly differentiated squamous cell carcinoma (PDSCC)from small cell lung carcinoma (SCLC). We used monoclonal antibodies reactive to p63 or TTF-1 to stain 4-μm-thick sections from 30 formalin-fixed, paraffin-embedded lung biopsy and resection specimens and 7 alcohol-fixed, formalin-postfixed, paraffin-embedded cell blocks from lung fine-needle aspirations (FNAs). For p63, we used a streptavidin-biotin kit, diaminobenzidine as the chromogen, and a hematoxylin counterstain. We used automated immunostaining for TTF-1. The 37 cases included 23 SCLCs, 13 PDSCCs, and 1 carcinoma initially diagnosed as PDSCC. All 23 SCLCs were negative or, rarely, equivocal for p63; 20 (87%) of 23. were TTF-1+; nuclear staining ranged from strong and/or frequent to weak and/or uncommon. All 13 PDSCCs were TTF-1-/p63+ with intense staining of 50% to 100% of tumor cells. One case originally diagnosed as PDSCC was TTF-1+/p63-, suggestive of SCLC; after morphologic reexamination and immunostaining for neuroendocrine markers; it was reclassified as intermediate-type SCLC. TTF-1 immunostaining showed equal or increased sensitivity in alcohol-fixed cytologic cell block samples compared with formalin-fixed biopsy material; in 1 SCLC case, the biopsy specimen was TTF-1-; however, the FNA cell block stained positively. p63 and TTF-1 appear to be useful for differentiating SCLC from lung PDSCC in formalin-fixed and alcohol-fixed, formalin-postfixed material.

The Prognostic and Predictive Role of Histology in Advanced Non-small Cell Lung Cancer A Literature Review

Article

Dec 2008
J THORAC ONCOL

Introduction: The importance of non-small cell lung cancer (NSCLC) histologic subtype has increased during the last few decades because of an unprecedented shift in epidemiology and an increasing number of target-specific chemotherapeutic agents. This review examined histology as a potential prognostic and/or predictive factor of clinical outcomes in advanced NSCLC. Methods: Literature searches of articles from 1982 to 2007 were conducted. We identified publications detailing phase II or III studies, retrospective analyses, and meta-analyses that reported a statistically significant prognostic or predictive role for histology. Results: Of 408 publications identified, II reported a prognostic association between histology and clinical outcomes, and 7 suggested that histologic subtype was predictive of outcomes in patients with advanced NSCLC treated with specific cytotoxic chemotherapy regimens. Fourteen publications reported histology was prognostic and/or predictive in patients treated with epidermal growth factor receptor inhibitors. Inadequate data collection, test methodology, or Study design-including insufficient sample size, misclassified samples, and grouping of histologic subtypes for analysis-may have obscured the interpretation of the role of histology in many of the Studies. Conclusions: Although differences in Study design and analyses make definitive Conclusions difficult, evidence suggests that histology may be prognostic or predictive of clinical efficacy outcomes. To determine which patients would benefit from specific treatments and to further understand the role of histology, future studies should focus on establishing a definitive histologic diagnosis, and should include an analysis of histologic subtypes and efficacy outcomes.

The diagnosis of lung cancer in bronchial biopsy samples

Article

Jan 2006

Primary lung carcinomas are frequently diagnosed on bronchoscopic biopsy samples. Most patients are inoperable so this may be the only tumour tissue obtained. In this situation, diagnosis and classification of lung cancer is challenging since samples are often small, tumours range widely in type and appearance, and individual tumours are often heterogeneous, yet the WHO definitions refer to resected tumours. While bronchial biopsy can achieve high sensitivity for a diagnosis of malignancy, there are issues around accuracy of cell typing. Small cell carcinoma is most reliably diagnosed, squamous cell carcinoma reasonably so, but diagnostic accuracy in adenocarinoma is relatively poor. Most other cell types cannot be reliably classfited in this context and the descriptor 'non-small cell carcinoma' should be used.

World health organization classification tumors of the lung, pleura, thymus and heart

Article

Jan 2004

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

Article

Jul 2000

S L Edwards

Aims—To compare the preoperative classification of lung carcinoma made on cytological and histological specimens with the postoperative classification made on the resected specimen. In addition, to find out how often the term “non-small cell lung cancer, not otherwise specified” (NSCLC) was used, and in such cases to note the final diagnosis. Methods—Between 1991 and 1995, 303 patients had a lung resection in Aberdeen for primary carcinoma. For each patient, the departmental records were examined for preoperative specimens (cytological and histological). A note was made of whether each specimen was positive or negative for malignancy and, if positive, what the cell type was. Where patients had more than one sample submitted, the most specific result was taken. Results—Fifty four per cent of patients had a correct specific preoperative diagnosis of malignancy, whereas 34% were labelled as NSCLC. Patients with squamous carcinoma were more likely to have a diagnosis of malignancy (88%) that was specifically correct (75%). Patients who had adenocarcinoma were less likely to have a preoperative diagnosis of malignancy (64%) that was specifically correct (35%). For those in whom a diagnosis of NSCLC was made, 55% turned out to have adenocarcinoma whereas 24% had squamous carcinoma. Conclusions—By adhering strictly to criteria, a high accuracy of diagnosis can be achieved for squamous carcinoma, but the diagnosis of adenocarcinoma seems to be more of a challenge. NSCLC is a useful and appropriate classification, the use of which reduces the rate of inaccurate specific diagnosis. There are occasions when pathologists can provide a more accurate diagnosis by being less precise.

TTF-1, Cytokeratin 7, 34bE12, and CD56/NCAM Immunostaining in the Subclassification of Large Cell Carcinomas of the Lung

Article

Dec 2004

We selected a 4-stain immunopanel including thyroid transcription factor (TTF)-1, cytokeratin (CK) 7, 34betaE12, and CD56/neural cell adhesion molecule (NCAM) to subclassify a series of 45 pulmonary large cell carcinomas (LCCs) on bronchial biopsy. All cases consisted of a large tumor cell proliferation with abundant cytoplasm, vesicular nuclei, and prominent nucleoli. Immunohistochemically, 27 tumors (60%) were subclassified as adenocarcinoma (TTF-1+/CK7+, 24; CK7+ only, 3), 10 (22%) as squamous cell carcinoma (34betaE12+ only), and 4(9%) as LCC with neuroendocrine differentiation (CD56+, variably stained with TTF-1 and CK7, 34betaE12-). In 4 cases, the tumors coexpressed CK7 and 34betaE12 (3 cases) or were completely unstained (1 case). Surgically resected tumors matched exactly with the corresponding original biopsy specimens in 21 of 23 cases; consistent CD56 expression was a reliable marker in confirming a diagnosis of large cell neuroendocrine carcinoma even on biopsy. Our results suggest that the proposed 4-stain set of commercially available markers might help subclassify LCC even in small biopsy material, validating expression-profiling studies aimed at lung cancer classification and permitting more consistent patient enrollment for trials with targeted treatments.

Value of P63 and CK5/6 in Distinguishing Squamous Cell Carcinoma From Adenocarcinoma in Lung Fine-Needle Aspiration Specimens

Article

Mar 2009
DIAGN CYTOPATHOL

The current FDA-approved standard of care for nonsmall cell lung cancer is Carboplastin/Taxol/Avastin based upon an impressive survival benefit; however, patients with squamous carcinoma (SQCC) cannot receive Avastin because of a 30% mortality rate due to fatal hemoptysis. In this study we evaluated the role of cytomorphology and immunohistochemistry in differentiating SQCC from adenocarcinoma (ADC) in lung FNA specimens. The case cohort included 53 FNA cases of nonsmall cell lung carcinoma with surgical pathology follow-up. All FNA specimens were reviewed independently by a panel of cytopathologists to differentiate between SQCC and ADC. The cell block material was available in 23 cases (11 ADC and 12 SQCC) to perform immunohistochemical stains for TTF-1, CK7, CK20, P63, and CK5/6. On surgical resection, 35/53 (66%) cases were diagnosed as ADC and 18/53 (34%) as SQCC. The number of cases classified correctly on the basis of cytomorphology was 66% for ADC and 53% for SQCC (combined accuracy 60%). By immunohistochemical staining, 14/23 (61%) cases expressed TTF-1. Nine cases were TTF-1 negative; eight of the TTF-1 negative cases (89%) were SQCC. Twenty-three cases expressed CK7 (87%); one ADC case (4%) showed focal CK20 positivity. Both P63 and CK5/6 expression was seen in 9/12 (75%) SQCC cases; none of the ADC cases showed this dual expression. Cytomorphology alone may not be able to stratify all cases of nonsmall cell lung carcinoma into ADC and SQCC in FNA specimens. The immune-panel of TTF-1, CK7, CK20, P63, and CK5/6 is useful in differentiating SQCC from ADC. Diagn. Cytopathol. 2009.

The Prognostic and Predictive Role of Histology in Advanced Non-small Cell Lung Cancer

Article

Jan 2009

The importance of non-small cell lung cancer (NSCLC) histologic subtype has increased during the last few decades because of an unprecedented shift in epidemiology and an increasing number of target-specific chemotherapeutic agents. This review examined histology as a potential prognostic and/or predictive factor of clinical outcomes in advanced NSCLC. Literature searches of articles from 1982 to 2007 were conducted. We identified publications detailing phase II or III studies, retrospective analyses, and meta-analyses that reported a statistically significant prognostic or predictive role for histology. Of 408 publications identified, 11 reported a prognostic association between histology and clinical outcomes, and 7 suggested that histologic subtype was predictive of outcomes in patients with advanced NSCLC treated with specific cytotoxic chemotherapy regimens. Fourteen publications reported histology was prognostic and/or predictive in patients treated with epidermal growth factor receptor inhibitors. Inadequate data collection, test methodology, or study design-including insufficient sample size, misclassified samples, and grouping of histologic subtypes for analysis-may have obscured the interpretation of the role of histology in many of the studies. Although differences in study design and analyses make definitive conclusions difficult, evidence suggests that histology may be prognostic or predictive of clinical efficacy outcomes. To determine which patients would benefit from specific treatments and to further understand the role of histology, future studies should focus on establishing a definitive histologic diagnosis, and should include an analysis of histologic subtypes and efficacy outcomes.

A comparison of different methods of detecting mucin in adenocarcinomas of the lung

Article

May 1975
Br J Dis Chest

The correct classification of carcinoma of the lung is not only of therapeutic and prognostic importance but is also considered to have epidemiological and aetiological significance. Histological tests for mucin are essential in the classification of lung tumours but there is little information available about the influence of the method of detection used on the results of classification. Five established staining techniques were tested using paraffin blocks from surgical specimens of 81 human lung tumours diagnosed as adenocarcinoma, i.e. tumours of WHO Type III. Mowry's alcian blue-periodic acid-Schiff (AB-PAS) technique gave the highest proportion of positives (93%) slightly fewer (90%) being obtained by the PAS technique alone. Both these methods were influenced by the presence of cytoplasmic hyaline globules, structures which cannot be regarded as mucin. The stain recommended by the World Health Organization was also influenced by the presence of hyaline globules, was less frequently positive than the PAS techniques and was considered to have no special advantages. The aldehyde fuchsin-alcian blue sequence was positive in only 83% of cases but provided some information about the type of mucin present. Southgate's mucicarmine also detected mucin in only 83% of cases. It was concluded that the apparent incidence of adenocarcinomas may be influenced by staining methods used. Some standardization of technique is desirable and the AB-PAS combination appears to be the most satisfactory.

Bronchial brushing and bronchial biopsy: Comparison of diagnostic accuracy and cell typing reliability in lung cancer

Article

Jul 1986

A total of 443 patients with lung cancer underwent brush and forceps biopsy through a fibreoptic bronchoscope. The biopsy was taken from the area of suspected malignancy which had been brushed. Of 443 patients, 400 (90.3%) showed positive results on brushing and 287 (64.8%) on biopsy. A combination of both techniques yielded the highest percentage of positive diagnosis (93.7%). Histologically, there was a high incidence of positive diagnosis for squamous and small cell carcinoma. One hundred and three (83.7%) of 123 specimens obtained by brushing and 75 (81.5%) of 92 specimens obtained by biopsy agreed with the cell type found in the surgical or necropsy specimen. Cell typing accuracy was higher in squamous and in small cell carcinoma in both techniques. As the cell typing accuracy of the two methods is similar, the results obtained by both techniques should be taken into consideration in the management of individual cases of lung cancer.

Diagnosis of lung cancer by fibreoptic bronchoscopy: Problems in the histological classification of non-small cell carcinomas

Article

Apr 1984

Specific cell typing in lung cancer has important implications for assessment of prognosis and the planning of treatment. Cell typing is, however, often difficult and the problem has been compounded by the universal use of the flexible fibreoptic bronchoscope, which yields specimens only 2 mm in diameter. We have reviewed the records of 107 patients who had a diagnosis of lung cancer established by fibreoptic bronchoscopy and who subsequently underwent staging biopsy or surgical resection. Examination of tissue obtained by surgical resection yielded a different cell type from that identified in specimens obtained at fibreoptic bronchoscopy in 11 of 32 patients with a bronchial biopsy specimen diagnostic of squamous cell, three of 44 patients with a diagnosis of adenocarcinoma, six of seven thought to have a poorly differentiated carcinoma, and 21 of 24 patients with a diagnosis of large cell carcinoma. In all, 41 of the 107 surgically removed specimens (38%) differed in cell type from their corresponding bronchoscopic specimens. Accurate cell typing by specimens obtained at fibreoptic bronchoscopy may be extremely difficult. If clearcut morphological criteria cannot be satisfied, the diagnosis of "lung cancer, non-small cell type" should be made.

Observer variability in histopathological reporting of malignant bronchial biopsy specimens

Article

Sep 1994

To evaluate the ability of histopathologists to classify lung carcinomas on bronchial biopsy material using the current World Health Organisation (WHO) classification. Eleven histopathologists each reviewed 100 randomly selected bronchial biopsy specimens which had originally been reported as showing lung carcinoma. A single haematoxylin and eosin stained section from each case was circulated and a standard proforma completed. These were analysed using kappa statistics. The histopathologists were excellent at distinguishing between small cell and non-small-cell carcinoma kappa = 0.86), but not so good at subclassifying the non-small cell carcinoma group kappa = 0.25). The clinically important distinction between small cell and non-small cell carcinoma of the lung is reliably made by competent histopathologists even on limited material.

Observer variability in the histopathological reporting of abnormal rectal biopsy specimens

Article

Feb 1994

To study the consistency of reporting of abnormal rectal biopsy specimens, especially in the differentiation of inflammatory bowel disease from other causes of abnormality. Sixty rectal biopsy specimens were identified from patients presenting with bloody diarrhoea. These were then circulated to the 11 consultant pathologists in the study who filled in a proforma with a list of 12 diagnostic categories and 22 features. Forty one of the 60 cases were examples of inflammatory bowel disease. In 33 of these cases nine or more pathologists had made the diagnosis. Further categorisation into ulcerative colitis and Crohn's disease showed better recognition of ulcerative colitis. In the 19 cases of non-inflammatory bowel disease recognition of pseudomembranous colitis and solitary rectal ulcer syndrome was good, but the results were poorer in the case of infective colitis. The findings suggest that a group of consultant pathologists can differentiate between inflammatory bowel disease and other causes of an abnormal rectal biopsy specimen and can also recognise pseudomembranous colitis and solitary rectal ulcer syndrome satisfactorily.

Observer variability in histopathological reporting of non-small cell lung carcinoma on bronchial biopsy specimens

Article

Mar 1996

To evaluate the ability of histopathologists to sub-classify non-small cell lung carcinomas on bronchial biopsy material using the current World Health Organisation (WHO) classification. Twelve histopathologists each reviewed 100 randomly selected bronchial biopsy specimens which had originally been reported as showing non-small cell lung carcinoma. For each case, two sections were circulated, one stained by haematoxylin and eosin and the other by a standard method for mucin (alcian blue/periodic acid Schiff). The participants were allowed to indicate their degree of confidence in their classification of each case. A standard proforma was completed and the results were analysed using kappa statistics. Where the participants were confident in their classification, they were actually quite good at sub-classifying the non-small cell carcinoma sections (kappa = 0.71, standard error = 0.058). Overall, however, the results were only fair (kappa = 0.39, standard error = 0.034). The majority of non-small cell lung carcinomas can be correctly categorised on adequate bronchial biopsy material. Where a confident diagnosis was made, both squamous carcinoma (kappa = 0.73) and adenocarcinoma (kappa = 0.83) were well recognised.

Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B

Article

Feb 2000

Antibodies against the thyroid transcription factor-1 (TTF-1) and the surfactant proteins A and B (SPA, SPB) were compared as paraffin-reactive immunohistochemical markers for non-small cell carcinomas of pulmonary origin. We studied 138 carcinomas of pulmonary origin (98 adenocarcinomas, 20 non-neuroendocrine large cell carcinomas, 20 squamous cell carcinomas) and a total of 276 extrapulmonary carcinomas of various primary origins. Using the monoclonal antibody 8G7G3/1, TTF-1 was detectable in 75% of non-mucinous pulmonary adenocarcinomas and in 40% of large cell carcinomas but in only 10% of mucinous adenocarcinomas and not in squamous cell carcinomas. In contrast, both SPA and SPB were positive in only 45% of pulmonary adenocarcinomas and in 10% and in 5% of the large cell carcinomas, respectively. TTF-1 had a specificity of 0.98 for pulmonary carcinomas as 5/7 thyroid carcinomas were the only TTF-1-positive extrapulmonary tumours. Anti-SPB and anti-SPA had specificities of 1. 00 and 0.97, respectively. The monoclonal antibody 8G7G3/1 against TTF-1 should be the first choice as a component of an antibody panel aiming to prove or to exclude the pulmonary origin of non-mucinous adenocarcinomas and non-neuroendocrine poorly differentiated carcinomas, especially in patients presenting with metastatic carcinomas of unknown primary site.

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

Article

Aug 2000

To compare the preoperative classification of lung carcinoma made on cytological and histological specimens with the postoperative classification made on the resected specimen. In addition, to find out how often the term "non-small cell lung cancer, not otherwise specified" (NSCLC) was used, and in such cases to note the final diagnosis. Between 1991 and 1995, 303 patients had a lung resection in Aberdeen for primary carcinoma. For each patient, the departmental records were examined for preoperative specimens (cytological and histological). A note was made of whether each specimen was positive or negative for malignancy and, if positive, what the cell type was. Where patients had more than one sample submitted, the most specific result was taken. Fifty four per cent of patients had a correct specific preoperative diagnosis of malignancy, whereas 34% were labelled as NSCLC. Patients with squamous carcinoma were more likely to have a diagnosis of malignancy (88%) that was specifically correct (75%). Patients who had adenocarcinoma were less likely to have a preoperative diagnosis of malignancy (64%) that was specifically correct (35%). For those in whom a diagnosis of NSCLC was made, 55% turned out to have adenocarcinoma whereas 24% had squamous carcinoma. By adhering strictly to criteria, a high accuracy of diagnosis can be achieved for squamous carcinoma, but the diagnosis of adenocarcinoma seems to be more of a challenge. NSCLC is a useful and appropriate classification, the use of which reduces the rate of inaccurate specific diagnosis. There are occasions when pathologists can provide a more accurate diagnosis by being less precise.

Immunoreactivity for Thyroid Transcription Factor-1 in Stage I Non???Small Cell Carcinomas of the Lung

Article

Apr 2001
AM J SURG PATHOL

Thyroid transcription factor-1 (TTF-1) is a nuclear protein regulating the transcriptional activity of lung-specific genes in the normal and neoplastic bronchioloalveolar cells. It has been implicated in the normal growth and development of the lung, and the disruption of the TTF-1 locus leads to neonatal death with pulmonary hypoplasia. We evaluated retrospectively the prevalence and clinical significance of TTF-1 immunoreactivity in 222 patients with stage I non-small cell lung carcinoma (NSCLC) with a follow-up time of at least 5 years, and we investigated its relationship with other markers of tumor growth, namely cell proliferation and angiogenesis. TTF-1 immunoreactivity was documented by using the commercially available monoclonal antibody 8G7G3/1 in 72% of 97 adenocarcinomas, 5% of 119 squamous cell carcinomas, and in the glandular component of two adenosquamous carcinomas. Four large cell carcinomas were completely unreactive. In adenocarcinomas, but not squamous cell carcinomas, TTF-1 immunoreactivity correlated significantly with microvessel density (p = 0.04) and inversely with the tumor proliferation fraction assessed by Ki-67 immunostaining (p = 0.03). Also, TTF-1-immunoreactive adenocarcinomas showed a trend for a size less than 3 cm (p = 0.08). TTF-1 expression was not related to specific growth patterns, tumor grade, or tumor cell typing. TTF-1 immunoreactivity did not significantly affect patient survival, although patients with more than 75% immunoreactive neoplastic cells showed a trend for longer overall and disease-free survival. Our findings suggest that TTF-1 could be involved in the development of small pulmonary adenocarcinomas, but it has not prognostic implications in patients with stage I NSCLC.

TTF-1 Expression in Pulmonary Adenocarcinomas

Article

Jun 2002
AM J SURG PATHOL

Tissue-specific gene expression is mediated largely by transcription factors, and a master regulatory gene is thus a potential marker of cellular lineage. Using normal fetal through adult pulmonary tissues and 64 consecutive lung adenocarcinomas, we examined the expression of thyroid transcription factor (TTF-1), which plays a crucial role in normal lung function and morphogenesis. TTF-1 was expressed consistently throughout the life stages and uniformly in the terminal respiratory unit, which is comprised of peripheral airway cells and small-sized bronchioles. Furthermore, the expression was maintained in 72% of adenocarcinomas that exhibited high correlation with surfactant apoprotein (p <0.001) and morphologic resemblance to terminal respiratory unit cells (p <0.001). The staining pattern was also uniform in the adenocarcinomas despite histologic and microenvironmental diversity in individual tumors and their metastatic foci. This consistency and uniformity, therefore, suggested that TTF-1 expression could be used as a lineage marker of terminal respiratory unit. We also identified interesting distinctions between TTF-1-positive and -negative adenocarcinomas based on their clinicopathologic features and expression of various cancer-associated genes. TTF-1-positive adenocarcinomas had statistically significant prevalence of female (p <0.01), nonsmoker (p <0.05), negative p53 staining (p <0.01), less frequent RB loss (p <0.05), and preserved expression of p27 (p <0.01). The results supported the TTF-1 lineage marker and suggested that molecular pathogenesis may in part be characterized by cellular lineage.

Diagnosis of lung cancer - The guidelines

Article

Feb 2003

Lung cancer is usually suspected in individuals who have abnormal chest radiograph findings or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of suspected lung cancer depends on the type of lung cancer (ie, small cell lung cancer or non-small cell lung cancer), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. Achieving a diagnosis and staging are usually done in concert because the most efficient way to make a diagnosis often is dictated by the stage of the cancer. The best sequence of studies and interventions in a particular patient involves careful judgment of the probable reliability of a number of presumptive diagnostic issues, so as to maximize the sensitivity and to avoid performing multiple or unnecessary invasive procedures. In this article, we consider all manner of clinical presentations of lung cancer in light of currently available diagnostic procedures. Published data supporting a particular diagnostic approach is weighed based on the quality of the benefit as well as the estimated net benefit. Recommendations are graded in terms of strength to provide clinicians with guidance as to the most efficient and approach to the diagnosis of lung cancer in individual patients.

Performance Characteristics of Different Modalities for Diagnosis of Suspected Lung Cancer *

Article

Jan 2003

To determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer. A systematic search of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies was performed to identify studies comparing the results of sputum cytology, bronchoscopy, transthoracic needle aspirate (TTNA), or biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer. For sputum cytology, the pooled specificity was 0.99 and the pooled sensitivity was 0.66, but sensitivity was higher for central lesions than for peripheral lesions (0.71 vs 0.49, respectively). Studies on bronchoscopic procedures provided data only on diagnostic yield (sensitivity). The diagnosis of endobronchial disease by bronchoscopy in 30 studies showed the highest sensitivity for endobronchial biopsy (0.74), followed by cytobrushing (0.59) and washing (0.48). The sensitivity for all modalities combined was 0.88. Thirty studies reported on peripheral lesions. Cytobrushing demonstrated the highest sensitivity (0.52), followed by transbronchial biopsy (0.46) and BAL/washing (0.43). The overall sensitivity for all modalities was 0.69. Peripheral lesions < 2 cm or > 2 cm in diameter showed sensitivities of 0.33 and 0.62, respectively. Updating a previous meta-analysis with 19 studies revealed a pooled sensitivity of 0.90 for TTNA. A trend toward lower sensitivity was noted for lesions that were < 2 cm in diameter. The accuracy in differentiating between small cell and non-small cell cytology for the various diagnostic modalities was 0.98, with individual studies ranging from 0.94 to 1.0. The average false-positive and false-negative rates were 0.09 and 0.02, respectively. The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions that are < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease. The distinction between small cell lung cancer and non-small cell lung cancer by cytology appears to be accurate.

Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: A high-throughput tissue microarray and immunohistochemistry study

Article

Jun 2003
Hum Pathol

Thyroid transcription factor 1 (TTF-1), a homeodomain-containing transcription factor, plays a pivotal role in lung development, cell growth, and differentiation processes. The current literature reports considerable variation in frequency of TTF-1 protein expression in human non-small cell lung cancer (NSCLC). TTF-1 expression has not been extensively investigated as a prognostic marker in NSCLC. To assess the prevalence of TTF-1 expression, and to evaluate its potential role in disease prognosis, 140 stage I-IIIA NSCLCs with long-term follow-up were studied under uniform conditions using high-density tissue microarray (TMA) combined with immunohistochemistry. Patient survival and association of TTF-1 expression with clinicopathologic parameters were analyzed. One hundred twenty-six tumor samples were fully assessable after tissue processing. Sixty-four samples (50.8%) expressed TTF-1 and 62 (49.2%) displayed no expression. TTF-1 expression was significantly (P < 0.001) correlated with histological subtype: 51 adenocarcinomas (AdCs) (51 of 75; 68%) versus 9 squamous cell carcinomas (SCCs) (9 of 43; 21%) were TTF-1 positive. TTF-1 expression, performance status, nodal status, and tumor stage were significantly related to patient survival. In multivariate analysis, positive TTF-1 expression tended to favor a better patient outcome (P = 0.05). Overall, NSCLC patients with positive TTF-1 expression had a median survival of greater than 57.3 months, whereas those with negative expression had a median survival of 39.4 +/- 5.2 months (log-rank test, P = 0.0067). In this study we found that TTF-1 is predominately expressed in adenocarcinoma. The loss of TTF-1 expression was associated with aggressive behavior of NSCLCs. The results from this study strongly indicate that further investigation is warranted to better define the role of TTF-1 as a prognostic factor in this malignancy.

Immunostaining for Thyroid Transcription Factor-1 on Fine-Needle Aspiration Specimens of Lung Tumors: A Comparison of Direct Smears and Cell Block Preparations

Article

May 2004

Background: Fine-needle aspiration (FNA) is used commonly for the diagnosis of pulmonary neoplasms. It has been reported that thyroid transcription factor-1 (TTF-1) is a sensitive and specific marker for certain primary lung tumors. To the authors' knowledge, the use of TTF-1 immunostaining on FNA smears has not been documented in the literature. This study was designed to examine the utility of TTF-1 immunostaining on FNA specimens from various types of lung tumors by comparing the expression rates on Papanicolaou (Pap)-stained and Diff-Quik (DQ)-stained smears with the expression rates on cell block (CB) sections. Methods: Forty-three FNA specimens of lung tumors were studied, including 34 primary tumors (14 adenocarcinomas, 12 squamous carcinomas, and 8 small cell carcinomas) and 9 metastatic tumors. One Pap-stained slide and one DQ-stained slide were selected from each tumor. The cytologic material from the slides was transferred to positively charged slides. Unstained recuts were obtained from the CB sections. All slides were stained with TTF-1 monoclonal antibody using heat-induced epitope retrieval and a labeled polymer detection system. Results: Twelve of 14 pulmonary adenocarcinomas were positive for TTF-1 (11 specimens on both CB sections and Pap-stained smears and 1 specimen on all 3 preparations, including the DQ-stained smear). Two of 14 adenocarcinomas were negative for TTF-1. Of 12 pulmonary squamous carcinomas, only 1 was positive for TTF-1 (on the CB section and the Pap-stained smear); the others were negative in all 3 preparations. Of eight small cell lung carcinomas, six specimens showed positive staining for TTF-1 on both CB and Pap-stained preparations; one of those also was positive on the DQ-stained smear. The remaining two small cell lung carcinomas were negative for TTF-1 in all three preparations. All metastatic tumors were negative for TTF-1. Conclusions: TTF-1 immunostaining of pulmonary neoplasms was applicable to FNA smears that were stained previously with the Pap technique, and the rate of positive staining in each tumor type was identical to the rate of positive staining in CB sections and was comparable to that reported in previous publications. Smears previously stained with the DQ method were unreliable for TTF-1 immunostaining.

p63 Expression in Lung Carcinoma: A Tissue Microarray Study of 408 Cases

Article

Sep 2004

p63 is a recently discovered member of the p53 family that has been shown to be important in the development of epithelial tissues. p63 may also play a role in squamous cell carcinomas of the lung, head and neck, and cervix, and its expression is increased in these tumors. The purpose of this study was to investigate the expression of p63 in a broad spectrum of histologic types of lung tumors. A total of 441 cases of primary lung tumors with follow-up data were identified, and the paraffin-embedded tissue blocks were used to construct a duplicate core tissue microarray. After review of the tissue cores, 408 cases, consisting of 123 squamous cell carcinomas, 93 adenocarcinomas, 68 large cell carcinomas, 68 classic carcinoids, 31 atypical carcinoids, 11 large cell neuroendocrine carcinomas, and 14 small cell carcinomas, were adequate for analysis. Immunohistochemistry was performed at 2 different laboratories using monoclonal antibody 4A4 to detect the expression of p63, using different staining protocols. p53 expression was also studied with immunohistochemistry using monoclonal antibody DO-7. Kaplan-Meier curves were plotted to compare the survival of p63-expressing versus nonexpressing tumors. A large proportion of squamous cell carcinomas expressed p63 (96.9%), most showing strong positive nuclear immunoreactivity. Expression in other nonsmall cell lung cancers was also present. Thirty percent of adenocarcinomas and 37% of large cell carcinomas showed p63 expression. In the neuroendocrine tumors, an increasing proportion of tumors stained for p63 as tumor grade increased; 1.9% of classic carcinoids, 30.8% of atypical carcinoids, 50% of large cell neuroendocrine carcinomas, and 76.9% of small cell carcinomas were positive. Approximately half of the positively staining neuroendocrine cases showed strong staining. Expression of p63 was of prognostic significance in neuroendocrine tumors (P < 0.0001), with higher-grade tumors more likely to express p63. Correlation between p63 and p53 expression was not observed (P = 0.18) in nonsmall cell lung cancer; however, a significant correlation between the 2 markers was found in neuroendocrine tumors (P < 0.0001). p63 staining was repeated with a different staining protocol, yielding similar results overall but a lower percentage of positive cases (34.2% vs. 48.4% of tumors positive). In conclusion, p63 expression is consistently expressed in squamous cell carcinoma in the lung, but is also expressed in a subset of adenocarcinomas and large cell carcinomas. Pulmonary neuroendocrine tumors also show p63 staining in some instances, particularly in higher-grade tumors, and the majority of small cell carcinomas are p63-positive. These results suggest that p63 may be involved in oncogenesis in a broader range of tumors than was previously thought.

P63 immunostaining in destained bronchoscopic cytological specimens

Article

Apr 2005

The p53 homologous squamous stem-cell regulatory protein p63 is expressed in squamous carcinomas but is not characteristically detected in small-cell carcinomas (SCCs). A panel of thyroid transcription factor (TTF) 1 and p63 has been shown to be useful in distinguishing SCCs from poorly differentiated squamous carcinoma of the lung (PDSLC) in small biopsies and cytological cell blocks. Because tumor samples frequently are limited to cytological smears, we attempted to detect p63 in destained slides from a spectrum of pulmonary malignancies.

Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers

Article

Oct 2005

The pathologic distinction of small cell from non-small cell-lung carcinoma is of considerable therapeutic significance. In particular, the ability to distinguish poorly differentiated non-small-cell lung cancer from small-cell lung carcinoma (SCLC) is at times difficult based upon morphology alone; available immunohistochemical markers such as neuroendocrine markers are of limited utility. We have demonstrated the role of p63 and thyroid transcription factor-1 (TTF-1) in the differential diagnosis of poorly differentiated squamous-cell carcinoma (PDSCC) versus SCLC, mostly in biopsy samples (Wu et al., American Journal of Clinical Pathology 2003;119:696–702). Here, we examine further the utility of this panel in cytologic cell-block samples of lung cancers including both primary and metastatic cancers of pulmonary origin, and cases of nonpulmonary cancers metastatic to lung in which differential diagnoses included a lung primary.

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

Article

Jun 2006
Hum Pathol

In this study, we sought to validate the importance of p63, CK5/CK6, CK7, and surfactant-A (SP-A) to classify 42 non-small cell lung cancers in autopsy and surgical resection specimens and to study the usefulness of these markers in distinguishing between squamous cell carcinomas and adenocarcinomas because of their different implications regarding treatment and prognosis. All adenocarcinoma cases were negative for p63; 9 (56.2%) of 16 were CK5/CK6 positive, 16 (94.1%) of 17 were CK7 positive, and 4 (26.6%) of 15 were SP-A positive. In squamous cell carcinoma, 1 case was CK7 and SP-A positive and 14 (77.8%) of 18 were p63 positive. The latter appears to be useful in differentiating squamous cell carcinoma from adenocarcinoma of the lung in small biopsies without keratinization or glandular differentiation; thus, for advanced-stage cases, where there is no possibility of surgical resection and the treatment of choice is radiotherapy plus chemotherapy, we would be able to differentiate between the two histological types, establishing then a different therapy.

Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer

Article

Jan 2007
NEW ENGL J MED

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)

Identification and validation of S100A7 associated with lung squamous cell carcinoma metastasis to brain

Article

Aug 2007
LUNG CANCER

To identify potential markers associated with non-small cell lung cancer (NSCLC) metastasis to brain, comparative proteome analysis on two lung squamous cell carcinoma (SCC) cell lines, NCI-H226 and H226Br (the brain metastatic cell line of NCI-H226), was performed using two-dimensional electrophoresis (2-DE) followed by a tandem mass spectrometer with a matrix-assisted laser desorption/ionization (MALDI) source. Twenty differential proteins were identified, of which 6 proteins were up-regulated in H226Br cell compared with NCI-H226 cells, whereas 14 proteins were down-regulated. S100A7 and 14-3-3sigma, two of candidate proteins significantly upregulated and downregulated in H226Br cell, were selected to verify the liability of the differential proteins by Western blot. The results were in accordance with 2-D data. To determine whether S100A7 overexpression is actually associated with SCC metastasis to brain, S100A7 protein was testified in 10 brain metastasis tissues from NSCLC, 38 primary NSCLC tissues including half matched local positive lymph nodes, 5 primary brain tumors and 2 non-cancer brain tissues by immunohistochemistry. Of particular interest to us was that the positive staining of S100A7 could be found in 3/5 (60%) brain metastases tissue from SCC and 8/21 (38%) the primary lung SCC tissues, while no positive staining was observed in the brain metastases tissue from Ad (n=5), the primary adenocarcinoma (Ad) tissues (n=17), the primary brain tumors (n=5), all local positive lymph nodes from the primary NSCLC (n=19) and non-cancer brain tissues (n=2). These findings suggest that S100A7 expression is closely associated with SCC metastasis to brain and may be a potential biomarker for monitoring the development of SCC.

The Diagnostic Value of TTF-1, CK 5/6, and p63 Immunostaining in Classification of Lung Carcinomas

Article

Jan 2008

This study was aimed to evaluate the utility of a panel of antibodies, consisting of thyroid transcription factor-1 (TTF-1), p63, and cytokeratins (CK) 5/6 for distinguishing between small cell lung carcinoma (SCLC) and nonsmall cell lung carcinoma, as well as for identifying glandular or squamous differentiation in small tissues obtained by bronchoscopy. Bronchoscopic biopsies of 77 lung carcinoma cases with easily recognizable morphologic features were included in this study. All the cases were immunohistochemically stained for p63, CK5/6 [indicators of squamous cell carcinoma (SCC)] and TTF-1 [indicator of SCLC and adenocarcinoma (AC)]. Although, 28 SCLC displayed TTF-1 positive, p63 negative immunoprofile, most of the SCC (32/39) had the opposite immunoprofile. All of the 10 ACs were negative for p63 and most of them (8/10) were negative for CK5/6. p63 and CK 5/6 seem to be useful for differentiating AC and SCLC from SCC with 100% specificity and 82% sensitivity, 89% specificity and 79% sensitivity, respectively. It seems that to achieve histologic typing of lung cancer as accurate as possible, TTF-1 in combination with p63 and CK 5/6 might be useful components of immunohistochemical analysis of poorly differentiated lung carcinomas in biopsy tissues.

Selective expression of S100A7 in lung squamous cell carcinomas and large cell carcinomas but not in adenocarcinomas and small cell carcinomas

Article

May 2008
THORAX

S100A7 is a secreted protein and its overexpression has been previously associated with carcinogenesis of certain cancers. This study was undertaken to investigate the possibility that overexpression of S100A7 protein might be detected in the sera of patients with lung cancer. RNA and protein levels of S100A7 were examined in 60 pairs of frozen lung cancer tissues by RT-PCR and western blot. The specific expression of this protein and its cellular distribution were investigated in 145 paraffin embedded lung cancer samples, six benign lung disease and 21 normal lung tissues by immunohistochemistry. The S100A7 protein level was further analysed in serum from 112 patients with lung cancer, 20 with benign lung diseases and 31 healthy individuals by ELISA. Specific expression of both S100A7 mRNA and protein was found in squamous cell carcinomas, adenosquamous carcinomas and large cell lung carcinomas, whereas neither was detected in adenocarcinomas or paired non-cancerous lung tissues. Further immunohistochemical analysis identified positive staining of S100A7 only in squamous cell carcinomas and large cell lung carcinomas, but not in other subtypes of lung cancer and normal lung tissues. Weak expression was also found in the inflammatory cells of benign lung diseases. Our most important finding is that elevated S100A7 protein could be detected in the sera of patients with squamous cell carcinomas. S100A7 was only expressed in squamous cell carcinomas and large cell lung carcinomas and an increase in the level of S100A7 protein in serum may serve as a potential marker for lung cancer diagnosis.

World Health Organisation Classification of Tumours

Jan 2004

Wd Travis
E Brambilla
Muller
Hk

Travis WD, Brambilla E, Muller-Hermelink HK, et al. (Eds.) World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC press; 2004.

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

Jan 2006
542-546

Capelozzi R Camilo
Vl
Siqueira
Sa

Camilo R, Capelozzi Vl, Siqueira SA, et al. Expression of p63, keratin 5/6 and surfactant-A in non-small cell lung carcinomas. Hum Pathol 2006;37:542–546.

May 2010

Performance characteristics of different modalities for diagnosis of suspected lung cancer: summary of published evidence

Jan 2003
115S

Schreiber

Pattern Recognition Using Neural Networks: Theory and Algorithms for Engineers and Scientists 1997

CG Looney

The diagnosis of lung cancer on bronchoscopic biopsy

Jan 2006
20

Lyall

Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens

Abstract

No full-text available

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