Timeliness of Evaluation of Patients with Suspected Lung Cancer
Based on the Tumor Doubling Time Data Presented Above in the Physiology/Histology Section (and in the Absence of Consensus Guideline Recommendations Related to the Timeliness of Initial Diagnostic Testing), It is Generally Recommended that the Initial Evaluation of a Patient with Suspected Lung Cancer Be Completed in <6 wks (Chest, 2013) [MEDLINE]
If the Initial Evaluation Takes ≥8 wks, Repeat Imaging is Probably Suggested to Reevaluate the Disease Stage
General Evaluation of Pulmonary Nodules
General Comments
Observation of Pulmonary Lesions Over Time
Based on Expected Tumor Doubling Times, Solid-Appearing Lesions on Chest CT Which are Stable in Size for ≥2 Years are Highly Unlikely to Represent Lung Carcinoma (Chest, 2013) [MEDLINE]
However, Malignant Non-Solid and Part-Solid Nodules Often Grow MOre Slowly, So a Longer Period of Stability is Required to Exclude the Diagnosis of Lung Cancer
Chest CT Features Which are Suggestive of Malignancy (in the Setting of a Solitary Pulmonary Nodule)
Detection of Growth by Follow-Up Imaging
Irregular or Spiculated Borders
Presence or Development of a Solid Component within a Ground Glass Lesion
Recommendations-General (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Indeterminate Pulmonary Nodule, Prior Imaging Studies Should Be Reviewed (Grade 1C Recommendation)
In Patient with Indeterminate Pulmonary Nodule on CXR, Chest CT (Preferably with Thin Sections Through the Nodule) is Recommended for Evaluation (Grade 1C Recommendation)
With Solid, Indeterminate Nodule that Has Been Stable for at Least 2 Years, No Additional Diagnostic Evaluation is Recommended (Grade 2C Recommendation)
Assessment of Probability of Malignancy
Recommendations-Solid Nodules ≤8 mm (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
With Solid ≤8 mm Nodule and No Risk Factors for Lung Cancer, Frequency/Duration of Serial Chest CT Surveillance Should Be Chosen Based on Size of the Nodule (Grade 2C Recommendation): with thin sections and non-contrast, low-dose CT technique
Nodule ≤4 mm: no need for follow-up imaging, but patient should be informed of risk/benefits of this approach
Nodule 4-6 mm: repeat imaging at 12 mo
Nodule 6-8 mm: repeat imaging between 6-12 mo and again between 18-24 mo (if unchanged)
Multiple Small Solid Nodules: frequency/duration of follow-up should be determined by the size of the largest nodule
With Solid ≤8 mm Nodule and One or More Risk Factors for Lung Cancer, Frequency/Duration of Serial Chest CT Surveillance Should Be Chosen Based on Size of the Nodule (Grade 2C Recommendation): with thin sections and non-contrast, low-dose CT technique
Nodule ≤4 mm: repeat imaging at 12 mo
Nodule 4-6 mm: repeat imaging between 6-12 mo and again between 18-24 mo
Nodule 6-8 mm: repeat imaging between 3-6 mo, again between 9-12 mo, and again at 24 mo
Multiple Small Solid Nodules: frequency/duration of follow-up should be determined by the size of the largest nodule
Recommendations-Solid Nodules >8 mm (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Pretest Probability Should Be Estimated Qualitatively Using Clinical Judgment or Quantitatively Using a Validated Model (Grade 2C Recommendation)
With Solid, Indeterminate >8 mm Nodule and Low-Moderate Pretest Probability of Malignancy (5-65%), PET Scanning is Recommended to Characterize the Nodule (Grade 2C Recommendation)
With Solid, Indeterminate >8 mm Nodule and Pretest Probability of Malignancy (>65%), PET Scan is Not Recommended to Characterize the Nodule (Grade 2C Recommendation)
However, PET Scan May Be Indicated for Pre-Treatment Staging When Malignancy is Strongly Suspected or Confirmed
With Solid, Indeterminate >8 mm Nodule, Serial Chest CT Surveillance is Recommended Under the Following Circumstances (Grade 2C Recommendation): serial CT scans should be performed at 3, 6, 9, 12, 18, and 24 mo using thin-sections and non-contrast, low-dose CT technique (preferably with computer-assisted measurements of area/volume/mass to facilitate early detection of nodule growth) (Grade 2C Recommendation)
Clinical Probability of Malignancy is Very Low (<5%)
Clinical Probability of Malignancy is Low (<30-40%) and Functional Tests are Negative (PET-Negative, Lack of Enhancement of >15 Hounsfield Units on Dynamic Contrast CT) -> Resulting in a Very Low Post-Test Probability of Malignancy
Non-Diagnostic Needle Biopsy and PET-Negative
When Informed Patient Prefers this Non-Aggressive Approach
With Solid, Indeterminate >8 mm Nodule with Clear Evidence of Malignant Growth on Serial Imaging, Non-Surgical Biopsy or Surgical Resection is Recommended (Grade 1C Recommendation)
With Solid, Indeterminate >8 mm Nodule, Non-Surgical Biopsy (by an Appropriate Technique, Given Nodule Location and Size) is Recommended for the Following Indications (Grade 2C Recommendation)
Clinical Pretest Probability and Findings on Imaging Tests are Discordant
Low-Moderate Probability of Malignancy (10-60%)
When a Benign Diagnosis Requiring Specific Medical Treatment is Suspected
When an Informed Patient Desires Proof of Malignancy Prior to Surgery (Especially When the Risk of Surgical Complications is High)
With Solid, Indeterminate >8 mm Nodule with Plan for Surgical Diagnosis, Video-Assisted Thoracoscopy (VATS) with Diagnostic Wedge Resection is Recommended (Grade 1C Recommendation)
Recommendations-Non-Solid (Pure Ground Glass) Nodule (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
With Non-Solid, (Pure Ground Glass) ≤5 mm Nodule, No Further Evaluation is Recommended (Grade 2C Recommendation)
With Non-Solid, (Pure Ground Glass) >5 mm Nodule, Annual Surveillance for at Least 3 Years is Recommended (Grade 2C Recommendation): thin sections and non-contrast, low-dose CT technique
Non-Solid Nodules Which Grow or Develop a Solid Component are Often Malignant
With Non-Solid, (Pure Ground Glass) >10 mm Nodule, Repeat Imaging at 3 mo is Probably Indicated: non-surgical biopsy and/or surgical resection may be required for nodules which persist
Recommendations-Part-Solid (>50% Ground Glass) Nodule (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
With Part-Solid (>50% Ground Glass) ≤8 mm Nodule, Repeat Imaging at 3, 12, and 24 mo (Followed by Annual Surveillance for 1-3 yrs) is Recommended (Grade 2C Recommendation): thin sections and non-contrast, low-dose CT technique
Part-Solid Nodules Which Grow or Develop a Solid Component are Often Malignant
With Part-Solid (>50% Ground Glass) >8 mm Nodule, Repeat Imaging at 3 mo is Recommended (Grade 2C Recommendation): PET scan, as well as non-surgical biopsy and/or surgical resection may be required for nodules which persist
PET San Should Not Be Used to Evaluate Nodules with a Solid Component Measuring ≤8 mm
With Part-Solid (>50% Ground Glass) >15 mm Nodule Should Proceed Directly to PET Scan, Non-Surgical Biopsy, and/or Surgical Resection
Recommendations-Multiple Nodules (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
With a Dominant Nodule and ≥1 Additional Nodules, Each Nodule Should Be Evaluated Individually and Curative Treatment Not Be Denied Unless there is Pathologic Confirmation of Metastasis (Grade 2C Recommendation)
Evaluation of Primary Parenchymal Lung Nodule/Mass
Allows Precise Localization of Areas of FDG Uptake to Normal Structures or to Abnormal Soft Tissue Masses
Integrated PET-CT is Slightly More Accurate than PET Alone
Clinical Data
Radiologic Data Correlated with Lung Cancer Pathology from Lung Cancer Screening Experience Over 5 Years at Mayo Clinic (Radiology, 2007) [MEDLINE]
Bronchioloalveolar Carcinoma (BAC)
Ground-Glass Attenuation was Present in 67% of Cases
Smooth Margins were Present in 33% of Cases
Irregular Margins were Present in 33% of Cases
Spiculated Margins were Present in 33% of Cases
Non-BAC Adenocarcinoma
Semi-Solid Attenuation was Present in 44% of Cases
Solid Attenuation was Present in 48% of Cases
Irregular Margins were Present in 56% of Cases
Squamous Cell Carcinoma
Solid Attenuation was Present in 86% of Cases
Irregular Margin was Present in 71% of Cases
Small Cell Carcinoma/Mixed Small and Large Cell Neuroendocrine Carcinoma
Solid Attenuation was Present in 86% of Cases
Irregular Margin was Present in 71% of Cases
Non-Small Cell Carcinoma Not Otherwise Specified
Solid Attenuation was Present in 80% of Cases
Irregular Margin was Present in 60% of Cases
Large Cell Carcinoma
Solid Attenuation and Spiculated Shape was Present in 100% of Cases
Mean Volume Doubling Time: 518 Days
Approximately 27% of Cancers Had a Volume Doubling Time >400 Days
Volumetric Analysis Data from Pittsburgh Lung Cancer Screening Study (Am J Respir Crit Care Med, 2012) [MEDLINE]
Doubling Times were Divided into 3 Groups
Rapid Doubling Time: <183 Days
Typical Doubling Time: 183–365 Days
Slow Doubling Time: >365 Days
Adenocarcinoma/Bronchioloalveolar Carcinoma (BAC) Comprised 86.7% of the Slow Doubling Time Group, as Compared with 20% of the Rapid Doubling Time Group
Squamous Cell Cancer Comprised 60% of the Rapid Doubling Time Group, as Compared with 3.3% of the Slow Doubling Time Group
For Lung Adenocarcinoma, Lepidic Tumor Growth Corresponds to Ground-Glass Opacity, While Invasive Solid Tumor Growth Appears as a Solid Opacity on Chest CT (Radiology, 2001) [MEDLINE] (Ann Thorac Surg, 2002) [MEDLINE] (Proc Am Thorac Soc, 2011) [MEDLINE] (AJR Am J Roentgenol, 2014) [MEDLINE] (Diagn Interv Imaging, 2016) [MEDLINE] (Eur Radiol, 2016) [MEDLINE]
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer Who are Eligible for Treatment, Chest CT with Intravenous Contrast is Recommended (Grade 1B Recommendation)
If PET Scan is Unavailable for Staging, Chest CT Should Be Extended to Include the Liver and Adrenal Glands
Standardized Uptake Value (SUV) is a Simple Measurement of Determining Activity Using Fluorodeoxyglucose Imaging
SUV is the Mathematically-Derived Ratio of Tissue Radioactivity Concentration at a Point in Time and the Injected Dose of Radioactivity Per Kilogram of the Patient’s Body Weight
SUV is Considered a Semi-Quantitative Value as it is Vulnerable to Other Sources of Variabilities
SUV May Be Influenced by Image Noise, Low Image Resolution, and Variable User-Biased Region of Interest Selection
The Cutoff Between Benign and Malignant Lesion/Nodule is in the SUV Range of 2.0-2.5 [LINK] (Radiology, 1993) [MEDLINE]
Typical SUV for Lung: 0.7
Typical SUV for Bone Marrow: 1.0
Typical SUV for Breast: 0.5
Typical SVU for Liver: 2.5
Lower Limit of Spacial Resolution of Modern PET Scanners is 4 mm
This Allows Accurate Characterization of Lesions >8 mm in Diameter
Sensitivity/Specificity of Positron Emission Tomography for Primary Tumor
Reported Sensitivity/Specificity of PET Scan (Data from a Meta-Analysis of Cross-Sectional Imaging Techniques in the Diagnosis of Solitary Pulmonary Nodules (Radiology, 2008) [MEDLINE]
Sensitivity: 95%
Specificity: 82%
Positive Predictive Value: 91%
Negative Predictive Value: 90%
Range of Sensitivities of PET Scan from Various Studies (Chest, 2013) [MEDLINE]
Sensitivity: 72-94%
False-Negative PET Scan
Study of Factors Contributing to False-Negative PET Scan in Lung Cancer (Lung Cancer, 2013) [MEDLINE]
Among Solid-Type Lung Cancers, Lesion Size and Histopathology were Significantly Associated with FDG Uptake
Lesions ≤2 cm, Bronchioloalveolar Carcinoma, and Well-Differentiated Adenocarcinoma Have a Tendency to Demonstrate Negative PET Findings
Study of PET Scan in Solid-Type p-Stage 1 Lung Adenocarcinoma (Eur J Cardiothorac Surg, 2017) [MEDLINE]: n = 255
International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) Pattern Significantly Influences FDG Uptake in Solid-Type p-Stage 1 Lung Adenocarcinoma
Colloid/Mucinous/Lepidic Adenocarcinomas Have a Notable Tendency to Produce False-Negative Findings on PET Scan (with a Low Level of Metabolic Uptake in These Lesions) (Clin Adv Hematol Oncol, 2014) [MEDLINE]
Integrated PET-CT (in a Single Gantry)
Allows Precise Localization of Areas of FDG Uptake to Normal Structures or to Abnormal Soft Tissue Masses
Clinical Efficacy
Study of PET-CT Staging in Non-Small Cell Lung Cancer (Ann Intern Med, 2009) [MEDLINE]
Preoperative PET-CT (with Cranial Imaging) Identifies More Patients with Mediastinal/Extrathoracic Disease than Conventional Staging
This Spares More Patients from Stage-Inappropriate Surgery (But Also Incorrectly Upstages Disease in More Patients)
Randomized Trial of PET-CT vs Conventional Staging in Non-Small Cell Lung Cancer (NEJM, 2009) [MEDLINE]
Preoperative PET-CT Decreased the Total Number of Thoracotomies and the Number of Futile Thoracotomies, But Did Not Impact the Overall Mortality Rate
Meta-Analysis of the Prognostic Value of Standardized Uptake Value (SUV) in Non-Small Cell Lung Cancer (Eur Respir J, 2015) [MEDLINE]
SUV Seems to Have Independent Prognostic Value in Stage I-III Non-Small Cell Lung Cancer (for Squamous Cell Carcinoma and for Adenocarcinoma)
Prospective Trial of PET Scanning in Non-Small Cell Lung Cancer (Ann Thorac Surg, 2020) [MEDLINE]
Maximum Standard Uptake Value (SUVm) Does Not Correlate with Glycolytic Metabolism in Human Non-Small Cell Lung Cancer, But Does Correlate with Proliferation Index
PET-CT SUVmax and endobronchial ultrasound features for prediction of malignancy: A prospective study. Clin Lung Cancer. 2023 Aug 7;S1525-7304(23)00150-X. doi: 10.1016/j.cllc.2023.08.005 [MEDLINE]
Introduction: Accurate and early staging of lung cancer has a critical impact on its prognosis. EBUS-TBNA is often the procedure of choice for mediastinal staging. Comprehension of the likelihood of malignancy of each lymph node (LN) can assist puncture decision-making during EBUS and offer insight of the procedure expected diagnostic yield
Methods: Prospective analysis of mediastinal LN of patients undergoing EBUS-TBNA from April 2021 to May 2022. The relationship between PET-CT SUVmax levels, EBUS features, and malignancy on LN was investigated. For statistical analysis, patients were assigned to 3 groups: suspected malignancy (diagnosis and/or staging), confirmed malignancy (staging) or suspected benign disease
Results: A total of 363 LN from 132 patients (71% male, mean 62 years old) were analyzed. Among those with suspected benign disease, no LN puncture resulted in a diagnosis of malignancy. PET-CT SUVmax and short axis size were independent factors for malignancy in LN of patients who underwent EBUS for suspected (p < .001 and p = .047, respectively) or confirmed malignancy (p < .001 and p < .001, respectively). All malignant LN presented SUVmax≥1.85 (≥2.85 for staging EBUS cases) and/or short axis size ≥4.28mm. Vascularized LN were more often malignant in either those with suspected (p = .087) or confirmed (p = .095) malignancy, although not statistically significant. LN that were simultaneously vascularized and lacked central hilar structure were also more commonly malignant (p = .013)
Conclusion: LN that has higher SUVmax and are larger should be prioritized for puncture, followed by those vascularized and lacking central hilar structure. In staging EBUS cases, a systematic sampling (N3-N2-N1) is required and must precede any malignancy yield rationale
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In a Patient with Suspected Lung Cancer with Normal Clinical Evaluation and No Suspicious Extrathoracic Abnormalities on Chest CT Being Considered for Curative Treatment, PET Scan is Recommended to Evaluate for Metastases (Except in the Brain) (Grade 1B Recommendation) (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Presence of Ground-Glass Opacities Only on Chest CT Does Not Require PET Scan for Staging
Presence of Peripheral Stage cIA Tumor Does Not Require PET Scan for Staging
If PET Scan is Not Available, Bone Scan and Abdominal CT Scan are Reasonable Alternatives
With Abnormal PET Scan Suggestive of Metastasis, Tissue Sampling of Abnormality is Recommended Prior to Treatment (Grade 1B Recommendation)
Tissue Sampling is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Sites
Tissue Sampling of Mediastinal Lymph Nodes is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Distant Sites
Patient Characteristics Which Increase Diagnostic Yield of Sputum Cytology
Bloody Sputum
Low FEV1
Large Lung Tumors (>2.4 cm): sensitivity of sputum cytology is increased for large, central-located tumors (and conversely, decreased for small, peripheral tumors)
Centrally Located Tumors: sensitivity of sputum cytology is increased for large, central-located tumors (and conversely, decreased for small, peripheral tumors)
Squamous Cell Histology
Clinical Efficacy
Meta-Analysis Studying the Sensitivity of Sputum Cytology for the Diagnosis of Lung Cancer (Chest, 2013) [MEDLINE]
Sensitivity (Mean): 66% (Range: 42-97%)
Specificity: 99%
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient Suspected of Having Lung Cancer, If Sputum Cytology is Negative, Further Testing Should Be Performed (Grade 1C Recommendation): sensitivity of sputum cytology varies by location of the tumor and with frequency and processing of of the sputum at the laboratory
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Conventional Bronchoscopy Involves Airway Inspection, Brush/Forceps Biopsy, Bronchial Wash, and/or Transbronchial Needle Aspiration of Endobronchial Mass Lesions
Conventional Bronchoscopy is Best Utilized for Obtaining Diagnostic Material from Large, Central Tumors with Airway Involvement
Transbronchial Biopsy (TBB) of Peripheral Lesions
Transbronchial Biopsy is Usually Performed Under Fluoroscopic Guidance
Clinical Efficacy
As Adenocarcinoma is Now the Most Prevalent Histopathologic Subtype of Non-Small Cell Lung Cancer (Resulting in More Peripheral Cancers), Conventional Bronchoscopy is Frequently Insufficient to Obtain Adequate Tissue Samples for Diagnosis (J Clin Med, 2018) [MEDLINE]
While Radiologically-Guided Transthoracic Need Aspiration (TTNA) is Sensitive, it Carries Risk, Which Has Driven the Development of Complimentary Bronchoscopic Navigation Techniques (See Below for Electromagnetic Navigation Bronchoscopy and Endobronchial Ultrasound-Transbronchial Needle Aspiration) for Peripheral Tumor Localisation and Sampling
Review of Performance Characteristics of Various Diagnostic Methods for Suspected Lung Cancer (Chest, 2003) [MEDLINE]
Endobronchial Lesions
Endobronchial Biopsy: 74% sensitivity
Cytobrush: 59% sensitivity
Washing: 48% sensitivity
Peripheral Lesions of All Sizes
Transthoracic Needle Aspiration: 90% sensitivity (with a trend toward lower sensitivity with lesions <2 cm in diameter)
Peripheral Lesions (Broken Down by Size of the Lesion)
For Peripheral Lesion <2 cm, the Overall Sensitivity for Cytobrush/Transbronchial Biopsy/Bronchoalveolar Lavage (BAL)/Washing is Only 33%
For Peripheral Lesion >2 cm, the Overall Sensitivity for Cytobrush/Transbronchial Biopsy/Bronchoalveolar Lavage (BAL)/Washing is 62%
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient Suspected of Having Lung Cancer Who Has a Central Lesion, Bronchoscopy is Recommended (Grade 1B Recommendation)
If Bronchoscopy is Negative/Non-Diagnostic and Suspicion of Lung Cancer Remains, Further Testing Should Be Performed
In Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Radial Endobronchial Ultrasound (Radial EBUS) is Recommended as an Adjunctive Modality (Grade 1C Recommendation)
Radial EBUS Can Confirm in Real-Time the Ideal Location for Bronchoscopic Sampling and Increase the Diagnostic Yeield Over Conventional Bronchoscopy for Peripheral Nodules
In Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Electromagnetic Navigation is Recommended, if Expertise is Available (Grade 1C Recommendation)
Electromagnetic Navigation May Be Performed with/without Fluoroscopy and is Complementary to Radial EBUS
If Electromagnetic Navigation is Not Available, Transthoracic Needle Aspiration (TTNA) is Recommended
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Electromagnetic Navigation (EMN) Bronchoscopy (see Bronchoscopy)
Technique
Best Utilized for Peripheral Lung Lesions
Also Allows Access to Lobar/Segmental/Subsegmental Lymph Nodes (12-14) (Which are Difficult to Access Via Linear EBUS-FNA
Clinical Efficacy
Review of Diagnostic Methods for Lung Cancer (J Clin Med, 2018) [MEDLINE]
Electromagnetic Navigation for Peripheral Lesions: 68% sensitivity
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In a Patient Suspected of Having Lung Cancer Who Has a Central Lesion, Bronchoscopy is Recommended (Grade 1B Recommendation)
If Bronchoscopy is Negative/Non-Diagnostic and Suspicion of Lung Cancer Remains, Further Testing Should Be Performed
In a Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Radial Endobronchial Ultrasound (EBUS) is Recommended as an Adjunctive Modality (Grade 1C Recommendation)
Radial EBUS Can Confirm in Real-Time the Ideal Location for Bronchoscopic Sampling and Increase the Diagnostic Yeield Over Conventional Bronchoscopy for Peripheral Nodules
In a Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Electromagnetic Navigation is Recommended, if Expertise is Available (Grade 1C Recommendation)
Electromagnetic Navigation May Be Performed with/without Fluoroscopy and is Complementary to Radial EBUS
If Electromagnetic Navigation is Not Available, Transthoracic Needle Aspiration (TTNA) is Recommended
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Bronchoscopy with Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) (see Bronchoscopy)
Technique
Radial Endobronchial Ultrasound (Radial EBUS): uses a catheter deployed through the working channel of a standard bronchoscope
Most Commonly Used for Sampling Parenchymal Lung Lesions
Linear (Convex Probe) Endobronchial Ultrasound (Linear EBUS): incorporated into the distal tip of a dedicated bronchoscope
Most Commonly Used for Sampling Mediastinal Lymph Nodes or Large Central Masses
Clinical Efficacy
Study of Minimally Invasive Endoscopic Staging Techniques for Suspected Lung Cancer (JAMA, 2008) [MEDLINE]
Endobronchial Ultrasound-Fine Needle Aspiration (EBUS-FNA) is More Sensitive than Transbronchial Needle Aspiration (TBNA)
Endobronchial Ultrasound (EBUS) + Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) May Allow Near-Complete Minimally Invasive Mediastinal Staging in Patients with Suspected Lung Cancer
Review of Diagnostic Methods for Lung Cancer (J Clin Med, 2018) [MEDLINE]
Linear Probe EBUS for Central Lesions: 82% sensitivity
Radial Probe EBUS for Peripheral Lesions: 73% sensitivity
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In a Patient Suspected of Having Lung Cancer Who Has a Central Lesion, Bronchoscopy is Recommended (Grade 1B Recommendation)
If Bronchoscopy is Negative/Non-Diagnostic and Suspicion of Lung Cancer Remains, Further Testing Should Be Performed
In a Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Radial Endobronchial Ultrasound (EBUS) is Recommended as an Adjunctive Modality (Grade 1C Recommendation)
Radial EBUS Can Confirm in Real-Time the Ideal Location for Bronchoscopic Sampling and Increase the Diagnostic Yeield Over Conventional Bronchoscopy for Peripheral Nodules
In a Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Electromagnetic Navigation is Recommended, if Expertise is Available (Grade 1C Recommendation)
Electromagnetic Navigation May Be Performed with/without Fluoroscopy and is Complementary to Radial EBUS
If Electromagnetic Navigation is Not Available, Transthoracic Needle Aspiration (TTNA) is Recommended
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Cryobiopsy
Rationale
Endobronchial Cryobiopsy May Provide Larger, Better Quality Histopathological Specimens
Cryobiopsy May Be Used with Navigation Techniques (Such as Radial Endobronchial Ultrasound, EBUS) Which Improve the Localization of Peripheral Lesions
Technique
Cryoprobe is Passed Through the Instrument Channel of the Bronchoscope
Once the Cryoprobe is in Position, Pressurized Gas is Passed Rapidly Through the End of the Cryoprobe to Produce an Extreme Drop in Temperature (to as Low as −89°C, Via the Joule-Thomson Effect)
The Tissue Adjacent to the Tip of the Probe is Frozen and Can Then Be Removed
Clinical Efficacy
Studies of the Efficacy of Cryobiopsy for the Diagnosis of Lung Cancer (Respiration, 2008) [MEDLINE] (Eur Respir J, 2012) [MEDLINE] (Eur Respir J, 2014) [MEDLINE] (J Clin Med, 2018) [MEDLINE]
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Transthoracic Needle Aspiration (TTNA) May Be Used for the Diagnosis of Peripheral Lung Lesions (Grade 1B Recommendation)
However, if TTNA Results are Non-Diagnostic and Suspicion for Lung Cancer Remains High, Further Testing Should Be Performed
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Surgical Procedure Which Requires General Anesthesia
Biopsy of Primary Lung Nodule/Mass
Biopsy of Mediastinal Lymph Nodes: allows access to almost all mediastinal nodal stations (4, 5, 6, 7, 8, 9, 10-14)
Access to the Right Side of the Mediastinum is Technically Easier Than Accessing the Left Side of the Mediastinum (Particularly the Left Paratracheal Nodes, 4L)
Typically, Only One Side Can Be Sampled: although bilateral VATS can be performed, it carries a higher morbidity/mortality rate
Allows Precise Localization of Areas of FDG Uptake to Normal Structures or to Abnormal Soft Tissue Masses
Clinical Efficacy
Study of PET-CT Staging in Non-Small Cell Lung Cancer (Ann Intern Med, 2009) [MEDLINE]
Preoperative PET-CT (with Cranial Imaging) Identifies More Patients with Mediastinal/Extrathoracic Disease than Conventional Staging: this spares more patients from stage-inappropriate surgery (but also incorrectly upstaged disease in more patients)
Randomized Trial of PET-CT vs Conventional Staging in Non-Small Cell Lung Cancer (NEJM, 2009) [MEDLINE]
Preoperative PET-CT Decreased the Total Number of Thoracotomies and the Number of Futile Thoracotomies, But Did Not Impact the Overall Mortality Rate
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer with Normal Clinical Evaluation and No Suspicious Extrathoracic Abnormalities on Chest CT Being Considered for Curative Treatment, PET Scan is Recommended to Evaluate for Metastases (Except in the Brain) (Grade 1B Recommendation) (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Presence of Ground-Glass Opacities Only on Chest CT Does Not Require PET Scan for Staging
Presence of Peripheral Stage cIA Tumor Does Not Require PET Scan for Staging
If PET Scan is Not Available, Bone Scan and Abdominal CT Scan are Reasonable Alternatives
With Abnormal PET Scan Suggestive of Metastasis, Tissue Sampling of Abnormality is Recommended Prior to Treatment (Grade 1B Recommendation)
Tissue Sampling is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Sites
Tissue Sampling of Mediastinal Lymph Nodes is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Distant Sites
Transbronchial Needle Aspiration (TBNA)
Clinical Efficacy
Study of Minimally Invasive Endoscopic Staging Techniques for Suspected Lung Cancer (JAMA, 2008) [MEDLINE]
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) is More Sensitive than Standard Transbronchial Needle Aspiration (TBNA)
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) + Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) May Allow Near-Complete Minimally Invasive Mediastinal Staging in Patients with Suspected Lung Cancer
Bronchoscopy with Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) (see Bronchoscopy)
Technique
Radial Endobronchial Ultrasound: uses a catheter deployed through the working channel of a standard bronchoscope
Most Commonly Used for Sampling Parenchymal Lung Lesions
Linear (Convex Probe) Endobronchial Ultrasound: incorporated into the distal tip of a dedicated bronchoscope
Most Commonly Used for Sampling Mediastinal Lymph Nodes or Large Central Masses
Lymph Node Accessibility
Lymph Nodes Which are Accessible Via EBUS-TBNA
Hilar Lymph Nodes (10R and 10L)
Retrotracheal Lymph Nodes (3p)
Subcarinal Lymph Nodes (7)
Upper/Lower Paratracheal Lymph Nodes (2R/2L and 4R/4L)
Lymph Nodes Which are Not Accessible Via EBUS-TBNA
Para-Aortic Lymph Nodes (6)
Paraesophageal Lymph Nodes (8)
Prevascular Lymph Nodes (3a)
Pulmonary Ligament Lymph Nodes (9)
Subaortic Lymph Nodes (5)
Clinical Efficacy
Study of Minimally Invasive Endoscopic Staging Techniques for Suspected Lung Cancer (JAMA, 2008) [MEDLINE]
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) is More Sensitive than Standard Transbronchial Needle Aspiration (TBNA)
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) + Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) May Allow Near-Complete Minimally Invasive Mediastinal Staging in Patients with Suspected Lung Cancer
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient Suspected of Having Lung Cancer Who Has a Central Lesion, Bronchoscopy is Recommended (Grade 1B Recommendation)
If Bronchoscopy is Negative/Non-Diagnostic and Suspicion of Lung Cancer Remains, Further Testing Should Be Performed
In Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Radial Endobronchial Ultrasound (EBUS) is Recommended as an Adjunctive Modality (Grade 1C Recommendation)
Radial EBUS Can Confirm in Real-Time the Ideal Location for Bronchoscopic Sampling and Increase the Diagnostic Yeield Over Conventional Bronchoscopy for Peripheral Nodules
In Patient Suspected of Having Lung Cancer Who Has a Peripheral Nodule, Electromagnetic Navigation is Recommended, if Expertise is Available (Grade 1C Recommendation)
Electromagnetic Navigation May Be Performed with/without Fluoroscopy and is Complementary to Radial EBUS
If Electromagnetic Navigation is Not Available, Transthoracic Needle Aspiration (TTNA) is Recommended
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Esophagoscopy with Ultrasound-Guided Mediastinal Nodal Sampling
Lymph Nodes Which are Accessible Via EUS-FNA
Paratracheal Lymph Nodes (2R)
Subcarinal Lymph Nodes (7)
Clinical Efficacy
Study of Minimally Invasive Endoscopic Staging Techniques for Suspected Lung Cancer (JAMA, 2008) [MEDLINE]
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) is More Sensitive than Standard Transbronchial Needle Aspiration (TBNA)
Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) + Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) May Allow Near-Complete Minimally Invasive Mediastinal Staging in Patients with Suspected Lung Cancer
PET-CT SUVmax and endobronchial ultrasound features for prediction of malignancy: A prospective study. Clin Lung Cancer. 2023 Aug 7;S1525-7304(23)00150-X. doi: 10.1016/j.cllc.2023.08.005 [MEDLINE]
Introduction: Accurate and early staging of lung cancer has a critical impact on its prognosis. EBUS-TBNA is often the procedure of choice for mediastinal staging. Comprehension of the likelihood of malignancy of each lymph node (LN) can assist puncture decision-making during EBUS and offer insight of the procedure expected diagnostic yield
Methods: Prospective analysis of mediastinal LN of patients undergoing EBUS-TBNA from April 2021 to May 2022. The relationship between PET-CT SUVmax levels, EBUS features, and malignancy on LN was investigated. For statistical analysis, patients were assigned to 3 groups: suspected malignancy (diagnosis and/or staging), confirmed malignancy (staging) or suspected benign disease
Results: A total of 363 LN from 132 patients (71% male, mean 62 years old) were analyzed. Among those with suspected benign disease, no LN puncture resulted in a diagnosis of malignancy. PET-CT SUVmax and short axis size were independent factors for malignancy in LN of patients who underwent EBUS for suspected (p < .001 and p = .047, respectively) or confirmed malignancy (p < .001 and p < .001, respectively). All malignant LN presented SUVmax≥1.85 (≥2.85 for staging EBUS cases) and/or short axis size ≥4.28mm. Vascularized LN were more often malignant in either those with suspected (p = .087) or confirmed (p = .095) malignancy, although not statistically significant. LN that were simultaneously vascularized and lacked central hilar structure were also more commonly malignant (p = .013)
Conclusion: LN that has higher SUVmax and are larger should be prioritized for puncture, followed by those vascularized and lacking central hilar structure. In staging EBUS cases, a systematic sampling (N3-N2-N1) is required and must precede any malignancy yield rationale
Needle Aspiration of Mediastinal Lymph Node (>1.5 cm) or Mass: however, other techniques are usually more useful to perform mediastinal lymph node biopsy
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Transthoracic Needle Aspiration (TTNA) May Be Used for the Diagnosis of Peripheral Lung Lesions (Grade 1B Recommendation): however, if TTNA results are non-diagnostic and suspicion for lung cancer remain high, further testing should be performed
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Surgical Procedure Which Requires General Anesthesia
Biopsy of Primary Lung Nodule/Mass
Biopsy of Mediastinal Lymph Nodes
VATS Allows Access to Almost All Mediastinal Nodal Stations (4, 5, 6, 7, 8, 9, 10-14)
VATS Access to the Right Side of the Mediastinum is Technically Easier Than Accessing the Left Side of the Mediastinum (Particularly the Left Paratracheal Nodes, 4L)
Typically, Only One Side Can Be Sampled with VATS: although bilateral VATS can be performed, it carries a higher morbidity/mortality rate
Other Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Extensive Mediastinal Infiltration and No Distant Metastases, Radiographic Assessment of the Mediastinal Stage is Adequate without Tissue Confirmation (Grade 2C Recommendation)
In Patient with Discrete Mediastinal Nodal Enlargement and No Distant Metastases (with or without PET Uptake in Mediastinal Nodes), Invasive Staging of Mediastinum is Recommended Over Staging by Imaging Alone (Grade 1C Recommendation)
In Patient with PET Activity in a Mediastinal Node, and Normal-Appearing Nodes by Chest CT and No Distant Metastases, Invasive Staging of Mediastinum is Recommended Over Staging by Imaging Alone (Grade 1C Recommendation)
In Patient with High Suspicion of N2/N3 Involvement (by Discrete Mediastinal Nodal Enlargement or PET Uptake) and No Distant Metastases, Needle Sampling (Via EBUS, EUS, or Combined EBUS/EUS) is Recommended Over Surgical Staging as the First Approach (Grade 1B Recommendation)
If Needle Technique is Negative, Surgical Staging (Via Mediastinoscopy or VATS) Should Be Performed
The Reliability of Mediastinal Staging May Be More Related to the Thoroughness with which the Procedure is Performed Than the Exact Procedure Which is Used
In Patient with Intermediate Suspicion of N2/N3 Involvement (by CT and PET-Negative Mediastinum, But Central Tumor and N1 Nodal Enlargement) and No Distant Metastases, Needle Sampling (Via EBUS, EUS, or Combined EBUS/EUS) is Recommended Over Surgical Staging as the First Approach (Grade 2B Recommendation)
If Needle Technique is Negative, Surgical Staging (Via Mediastinoscopy or VATS) Should Be Performed
In Patient with Intermediate Suspicion of N2/N3 Involvement (by CT and PET-Negative Mediastinum, But Central Tumor and N1 Nodal Enlargement) and No Distant Metastases, Invasive Surgical Staging is Recommended Over Staging by Imaging Alone (Grade 1C Recommendation)
In Patient with Peripheral Clinical Stage IA Tumor (CT and PET-Negative Mediastinum), Preoperative Invasive Mediastinal Staging is Not Required (Grade 2B Recommendation)
In Patient with a LUL Tumor in Whom Invasive Staging is Defined by the Above Recommendations, Invasive Mediastinal Staging of the Aortopulmonary Window Nodes Should Be Performed (Via Chamberlain Procedure, Extended Cervical Mediastinoscopy, or VATS) if Other Mediastinal Nodal Stations are Negative (Grade 2B Recommendation)
Integrated PET-CT (in a Single Gantry): allows precise localization of areas of FDG uptake to normal structures or to abnormal soft tissue masses
Clinical Efficacy
Study of PET-CT Staging in Non-Small Cell Lung Cancer (Ann Intern Med, 2009) [MEDLINE]
Preoperative PET-CT (with Cranial Imaging) Identifies More Patients with Mediastinal/Extrathoracic Disease than Conventional Staging: this spares more patients from stage-inappropriate surgery (but also incorrectly upstaged disease in more patients)
Randomized Trial of PET-CT vs Conventional Staging in Non-Small Cell Lung Cancer (NEJM, 2009) [MEDLINE]
Preoperative PET-CT Decreased the Total Number of Thoracotomies and the Number of Futile Thoracotomies, But Did Not Impact the Overall Mortality Rate
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer with Normal Clinical Evaluation and No Suspicious Extrathoracic Abnormalities on Chest CT Being Considered for Curative Treatment, PET Scan is Recommended to Evaluate for Metastases (Except in the Brain) (Grade 1B Recommendation) (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Presence of Ground-Glass Opacities Only on Chest CT Does Not Require PET Scan for Staging
Presence of Peripheral Stage cIA Tumor Does Not Require PET Scan for Staging
If PET Scan is Not Available, Bone Scan and Abdominal CT Scan are Reasonable Alternatives
With Abnormal PET Scan Suggestive of Metastasis, Tissue Sampling of Abnormality is Recommended Prior to Treatment (Grade 1B Recommendation)
Tissue Sampling is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Sites
Tissue Sampling of Mediastinal Lymph Nodes is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Distant Sites
Optimal Amount of Pleural Fluid to Collect When Malignant Pleural Effusion is Suspected is Unclear: although studies conflict, volumes of at least 50-60 mL should be evaluated
Clinical Efficacy
Meta-Analysis Studying the Sensitivity of Thoracentesis for the Diagnosis of Malignant Pleural Effusion (Chest, 2013) [MEDLINE]
Sensitivity (Mean): 72% (Range: 49-71%)
Study of Multiple Thoracenteses in the Diagnosis of Malignant Pleural Effusion (Mod Pathol, 1994) [MEDLINE]
Sensitivity of Thoracentesis for the Diagnosis of Malignant Pleural Effusion Increases (Anywhere from 5-30%) with Repeat Thoracenteses: study notes that examination of >3 samples had little additional diagnostic value
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer with Accessible Pleural Effusion, Thoracentesis is Recommended (Grade 1C Recommendation): ultrasound is recommended, as it improves the success rate of thoracentesis and decreases the rate of complicating pneumothorax
If Pleural Fluid Cytology is Negative by Thoracentesis, Repeat Thoracentesis May Be Considered, as it Increases the Diagnostic Yield of Pleural Fluid Cytology
In Patient with Suspected Lung Cancer with Cytology-Negative Pleural Effusion, Pleural Biopsy (Via Thoracoscopy) is Recommended Next (Grade 1C Recommendation)
If CT Demonstrates Pleural Thickening or Masses, Image-Guided Needle Biopsy May Be Considered as the First Step (Prior to Thoracoscopy)
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Sensitivity of Pleural Biopsy in the Diagnosis of Lung Cancer: 80-99%
Specificity of Pleural Biopsy in the Diagnosis of Lung Cancer: 93-100%
Clinical Efficacy
Meta-Analysis Studying the Sensitivity of VATS for the Diagnosis of Malignant Pleural Effusion (Chest, 2013) [MEDLINE]
Sensitivity: 95-97%
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer with Accessible Pleural Effusion, Thoracentesis is Recommended (Grade 1C Recommendation): ultrasound is recommended, as it improves the success rate of thoracentesis and decreases the rate of complicating pneumothorax
If Pleural Fluid Cytology is Negative by Thoracentesis, Repeat Thoracentesis May Be Considered, as it Increases the Diagnostic Yield of Pleural Fluid Cytology
In Patient with Suspected Lung Cancer with Cytology-Negative Pleural Effusion, Pleural Biopsy (Via Thoracoscopy) is Recommended Next (Grade 1C Recommendation)
If CT Demonstrates Pleural Thickening or Masses, Image-Guided Needle Biopsy May Be Considered as the First Step (Prior to Thoracoscopy)
Diagnosis of Lung Cancer by Sputum Cytology, TTNA, Bronchoscopy, or Pleural Fluid Should Provide Adequate Tissue to Determine Histologic Type and Allow Molecular Analysis (Grade 1B Recommendation)
Evaluation of Extrathoracic Sites for Potential Metastases
Allows Precise Localization of Areas of FDG Uptake to Normal Structures or to Abnormal Soft Tissue Masses
Clinical Efficacy
Study of PET-CT Staging in Non-Small Cell Lung Cancer (Ann Intern Med, 2009) [MEDLINE]
Preoperative PET-CT (with Cranial Imaging) Identifies More Patients with Mediastinal/Extrathoracic Disease than Conventional Staging: this spares more patients from stage-inappropriate surgery (but also incorrectly upstaged disease in more patients)
Randomized Trial of PET-CT vs Conventional Staging in Non-Small Cell Lung Cancer (NEJM, 2009) [MEDLINE]
Preoperative PET-CT Decreased the Total Number of Thoracotomies and the Number of Futile Thoracotomies, But Did Not Impact the Overall Mortality Rate
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient with Suspected Lung Cancer with Normal Clinical Evaluation and No Suspicious Extrathoracic Abnormalities on Chest CT Being Considered for Curative Treatment, PET Scan is Recommended to Evaluate for Metastases (Except in the Brain) (Grade 1B Recommendation) (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
Presence of Ground-Glass Opacities Only on Chest CT Does Not Require PET Scan for Staging
Presence of Peripheral Stage cIA Tumor Does Not Require PET Scan for Staging
If PET Scan is Not Available, Bone Scan and Abdominal CT Scan are Reasonable Alternatives
With Abnormal PET Scan Suggestive of Metastasis, Tissue Sampling of Abnormality is Recommended Prior to Treatment (Grade 1B Recommendation)
Tissue Sampling is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Sites
Tissue Sampling of Mediastinal Lymph Nodes is Not Required if There is Overwhelming Radiographic Evidence of Metastatic Disease at Multiple Distant Sites
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
If Brain MRI is Not Available, Head CT is Recommended for Patients with Non-Small Cell Stage III or IV Disease, Even with a Negative Clinical Evaluation (Grade 2C)
Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
In Patient Suspected of Having Lung Cancer Who Has a Solitary Extrathoracic Site Suspicious for Metastasis, Tissue Confirmation of the Metastatic Site Should Be Obtained by Fine Needle Aspiration or Biopsy (If Possible) (Grade 1C Recommendation)
In Patient Suspected of Having Lung Cancer Who Has Multiple Extrathoracic Sites Suspicious for Metastasis Which Would Be Technically Difficult to Access, Tissue Confirmation of the Lung Primary Lesion Should Be Obtained by the Least Invasive Method (Grade 1C Recommendation)
Tumor Testing for Targetable Oncogenic Driver Mutations
General Comments
Oncogenic Drivers Have Been Best Investigated in Lung Adenocarcinomas, But Drivers are Also Present in Squamous Cell Lung Cancer
In General, the Oncogenic Drivers are Usually Mutually Exclusive from One Another
Tumor Testing for Mutations Usually Requires More Tissue than is Available from Bronchoalveolar Lavage (BAL) Fluid
Biopsies are Often Required
Oncogenic Driver Mutations
Kirsten Rat Sarcoma Virus (KRAS) Gene Mutation
Prevalence
KRAS Mutation is the Most Frequently Mutated Oncogene in Non-Small Cell Lung Cancer (Expert Opin Investig Drugs, 2017) [MEDLINE]
KRAS Mutation is Present in 20% of Non-Small Cell Lung Cancers (Most Commonly in Adenocarcinomas)
Kirsten Rat Sarcoma (KRAS) Viral Oncogene Driver Mutations are Observed in Up to 86% of Invasive Mucinous Lung Adenocarcinoma Cases (Transl Lung Cancer Res, 2017) [MEDLINE]
KRAS Mutations are Associated with a History of Tobacco Smoke Exposure
Current/Former Smokers Most Commonly Demonstrate Transversion Mutations
Never Smokers are More Likely to Demonstrate Transition Mutations
KRAS Mutations are Most Commonly Seen in Caucasians
Presence of KRAS Mutation Usually Excludes the Presence of an EGFR Mutation (and Vice Versa)
Use of Multiplex Arrays to Detect Oncogenic Drivers in Lung Adenocarcinoma (JAMA, 2014) [MEDLINE]
Actionable Oncogenic Drivers were Detected in 64% of Lung Adenocarcinomas
KRAS: 25% of tumors
Sensitizing EGFR: 17% of tumors
ALK Rearrangement: 8% of tumors
Other EGFR: 4% of tumors
ERBB2 (Formerly HER2): 3% of tumors
BRAF: 2% of tumors
Median Survival in Patients with an Oncogenic Driver and Genotype-Directed Therapy: 3.5 yrs (as compared to 2.4 yrs in patients with an oncogenic driver who did not receive genotype-directed therapy)
In Patient with Clinically Limited-Stage Small Cell Lung Cancer, PET Scan is Suggested (Grade 2C Recommendation)
If PET Scan is Performed, Bone Scan is Not Required
In Patient with Small Cell Lung Cancer, Both the Veterans Administration Lung Study Group (VALSG) Staging System (Limited-Stage vs Extensive-Stage) and the American Joint Committee on Cancer/International Union Against Cancer Seventh Edition Staging System (TNM) Should Be Used to Stage the Tumor (Grade 1B Recommendation)
In Patient with Clinical Stage I Small Cell Lung Cancer Who are Being Considered for Curative Intent Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Brain MRI or Head CT; PET Scan or Abdominal CT with Bone Scan) are Recommended (Grade 1B Recommendation)
Staging
International Association for the Study of Lung Cancer (IASLC) Lymph Node Map
Supraclavicular Zone
1 = Low Cervical, Supraclavicular, and Sternal Notch Lymph Nodes
Superior Mediastinal Lymph Nodes (Upper Zone)
2R = Upper Paratracheal (Right) Lymph Nodes
2L = Upper Paratracheal (Left) Lymph Nodes
3a = Prevascular Lymph Nodes
3p = Retrotracheal Lymph Nodes
4R = Lower Paratracheal (Right) Lymph Nodes
4L = Lower Paratracheal (Left) Lymph Nodes
Aortic Lymph Nodes (AP Zone)
5 = Subaortic Lymph Nodes
6 = Para-Aortic (Ascending Aorta or Phrenic) Lymph Nodes
Inferior Mediastinal Lymph Nodes
Subcarinal Zone
7 = Subcarinal Lymph Nodes
Lower Zone
8 = Paraesophageal (Below Carina) Lymph Nodes
9 = Pulmonary Ligament Lymph Nodes
N1 Lymph Nodes
Hilar/Interlobar Zone
10 = Hilar Lymph Nodes
11 = Interlobar Lymph Nodes
Peripheral Zone
12 = Lobar Lymph Nodes
13 = Segmental Lymph Nodes
14 = Subsegmental Lymph Nodes
TNM Staging System for Non-Small Cell, Small Cell Lung Cancer, and Bronchial Carcinoid (IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer) (J Thorac Oncol, 2016) [MEDLINE]
Primary Tumor
Tx: primary tumor cannot be assessed (or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy)
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: tumor ≤3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)
Tia(mi): minimally invasive adenocarcinoma (solitary adenocarcinoma, ≤3 cm with a predominately lepidic pattern and ≤5 mm invasion in any one focus)
T1a: tumor ≤1 cm in diameter
The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a
T1b: tumor >1 cm but ≤2 cm in diameter
T1c: tumor >2 cm but ≤3 cm in diameter
T2: tumor >3 cm but ≤5 cm, or with any of the following (involvement of main bronchus regardless of distance from the carina, but without involvement of the carina, invasion of visceral pleural, or association with atelectasis or obstructive pneumonitis which extends to the hilar region involving part or all of the lung)
T2a: tumor >3 cm but ≤4 cm
T2 Tumors are Classified as T2a if ≤4 cm in Greatest Dimension or if Size Cannot Be Determined
T2b: tumor >4 cm but ≤5 cm
T2 Tumors are Classified as T2b if >4 cm But ≤5 cm in Greatest Dimension
T3: tumor >5 cm but ≤7 cm in greatest dimension or with associated with any of the following
Separate Tumor Nodule(s) in the Same Lobe as the Primary Tumor
For Diffuse Pneumonic-Type Lung Cancer, if There is Single Lobe Involvement, Designate Tumor as T3 (J Thorac Oncol, 2016) [MEDLINE]
Additionally, a Single N and M Category Should Be Used for All Pulmonary Areas of Involvement (J Thorac Oncol, 2016) [MEDLINE]
Directly Invades Any of the Following Structures
Chest Wall (Including the Parietal Pleura and Superior Sulcus Tumors)
Phrenic Nerve
Parietal Pericardium
T4: tumor >7 cm in greatest dimension or associated with any of the following
Separate Tumor Nodule(s) in a Different Ipsilateral Lobe than that of the Primary Tumor
For Diffuse Pneumonic-Type Lung Cancer: if there is ipsilateral different lobe involvement, designate as T4 (J Thorac Oncol, 2016) [MEDLINE]
Additionally, a Single N and M Category Should Be Used for All Pulmonary Areas of Involvement (J Thorac Oncol, 2016) [MEDLINE]
Directly Invades Any of the Following Structures
Carina
Diaphragm
Esophagus
Heart Great Vessels
Mediastinum
Recurrent Laryngeal Nerve
Trachea
Vertebral Body
Regional Lymph Nodes
Nx: regional lymph nodes cannot be assessed
N0: no regional lymph node metastases
N1: metastasis involving any of the following
Ipsilateral Peribronchial Lymph Nodes (Including Involvement by Direct Extension)
Ipsilateral Intrapulmonary Lymph Nodes (Including Involvement by Direct Extension)
Ipsilateral Hilar Lymph Nodes (Including Involvement by Direct Extension)
N2: metastasis involving any of the following
Ipsilateral Mediastinal Lymph Nodes
Subcarinal Lymph Nodes
N3: metastasis involving any of the following
Contralateral Mediastinal Lymph Nodes
Contralateral Hilar Lymph Nodes
Ipsilateral or Contralateral Scalene Lymph Nodes
Ipsilateral or Contralateral Supraclavicular Lymph Nodes
Distant Metastasis
M0: no distant metastases
M1: distant metastases
M1a
Separate Tumor Nodules in a Contralateral Lobe
Tumor with Pleural Nodule(s) or Malignant Pleural/Pericardial Effusion
While Most Pleural/Pericardial Effusions in Patients with Lung Cancer are Due to Tumor, in a Few Patients, However, Multiple Microscopic Examinations of Pleural/Pericardial Fluid are Negative for Tumor and the Fluid is Non-Bloody and Not Exudative (When These Elements and Clinical Judgment Dictate that the Effusion is Not Related to the Tumor, the Effusion Should Be Excluded as a Staging Descriptor)
For Diffuse Pneumonic-Type Lung Cancer: if there is contralateral involvement, designate as M1a (J Thorac Oncol, 2016) [MEDLINE]
When Both Lungs are involved, the T Classification is Based on the Most Advanced Tumor Size
Additionally, a Single N and M Category Should Be Used for All Pulmonary Areas of Involvement (J Thorac Oncol, 2016) [MEDLINE]
M1b
Single Extrathoracic Metastasis (This Includes Involvement of a Single Distant/Nonregional Lymph Node)
M1c
Multiple Extrathoracic Metastases in ≥1 Organs
Stage Groupings
Occult Carcinoma
Tx, N0, M0
Stage 0
Tis, N0, M0
Stage IA1
T1a(mi), N0, M0
T1a, N0, M0
Stage IA2
T1b, N0, M0
Stage IA3
T1c, N0, M0
Stage IB
T2a, N0, M0
Stage IIA
T2b, N0, M0
Stage IIB
T1a-c, N1, M0
T2a-b, N1, M0
T3 N0, M0
Stage IIIA
T1a-c, N2 M0
T2a-b, N2 M0
T3, N1, M0
T4, N0-1, M0
Stage IIIB
T1a-c, N3, M0
T2a-b, N3, M0
T3-4, N2, M0
Stage IIIC
T3, N3, M0
T4, N3, M0
Stage IVA
Any T, Any N, M1a-b
Stage IVB
Any T, Any N, M1c
Veterans Administration Lung Study Group (VALSG) Staging System for Small Cell Lung Cancer
Limited-Stage Small Cell Lung Cancer
Disease Confined to One Hemithorax (Although Local Extension May Be Present)
No Extrathoracic Metastases (Except for the Ipsilateral Supraclavicular Lymph Nodes)
Primary Tumor and Regional Nodes Which Can Be Encompassed Adequately in One Reasonably Safe Radiation Portal
Extensive-Stage Small Cell Lung Cancer
Disease Which Cannot Be Classified as Limited-Stage Disease
Contralateral Hilar or Supraclavicular Lymph Nodes
Hematogenous Metastases
Malignant Pericardial Effusion
Malignant Pleural Effusions
American Joint Committee on Cancer/International Union Against Cancer Seventh Edition Staging System for Small Cell Lung Cancer (TNM)
TNM Equivalent of Limited-Stage Small Cell Lung Cancer
T: any
N: any
M: M0 (Except T3-T4 Because of Multiple Lung Nodules)
TNM Equivalent of Extensive-Stage Small Cell Lung Cancer
T: any
N: any
M: M1a/b or T3-T4 Because of Multiple Lung Nodules
Lung Cancer Screening
Lung Cancer Prediction Models
Clinical Efficacy
Risk Model for the Prediction of Lung Cancer (J Natl Cancer Inst, 2007) [MEDLINE]
Risk Factors Used in Model: these are predictive of the risk of lung cancer
Environmental Tobacco Smoke
Family History of Lung Cancer
Prior Dust Exposure (Asbestos, etc)
Prior Respiratory Disease (Pneumonia, etc)
Smoking History Variables
Comparison of PLCO Model for Lung Cancer Risk to National Lung Cancer Screening Trial (NLST) Criteria (NEJM, 2013) [MEDLINE]
Prostate, Lung, Colorectal, and Ovarian Cancer M2012 Model (PLCO M2012) was More Sensitive than NLST Criteria for Lung Cancer Risk Stratification
NLST Risk Factors for Lung Cancer: ≥30 pack-years of smoking, <15 years since quitting smoking
PLCO M2012 Model Risk Factors
Age: odds ratio 1.081 for each 1 year increase
Race/Ethnic Group -> black increased risk relative to white, hispanic/asian decreased risk relative to white
Education (Per Increase of One Level) -> lower level increased risk
BMI (Per One Unit Increase) -> lower BMI increased risk
COPD (Yes or No) -> presence increased risk
Personal History of Cancer Yes or No) -> presence increased risk
Family History of Lung Cancer (Yes or No) -> presence increased risk
Smoking Status (Current vs Former)
Smoking Intensity
Duration of Smoking (Per One Year Increase)
Smoking Quit Time (Per One Year Increase)
Low-Dose Computed Tomography (CT) Lung Cancer Screening Trials
National Lung Screening Research Trial Team-Screening of High-Risk Patients with the Low-Dose CT Reduces Lung Cancer Mortality (NEJM, 2011) [MEDLINE]
Study: randomized, multi-center trial comparing low-dose CT with single-view PA CXR from 2002-2004 (n = 53,454 patients at high-risk for lung cancer -> at least 30 pack-yr smokers, within 15 yrs of quitting)
Results
Rate of Positive Screening Tests
Radiography: 6.9%
Low-Dose CT: 24.2%
Rate of False-Positive Screening Tests
Radiography: 94.5%
Low-Dose CT: 96.4%
Mortality Rate from Lung Cancer
Radiography: 309 deaths per 100,000 person-years (309 deaths per 26,732 participants)
Low-Dose CT: 247 deaths per 100,000 person-years (247 deaths per 26,722 participants)
All-Cause Mortality Rate: low-dose CT resulted in a 6.7% decrease in all-cause mortality (95% CI, 1.2 to 13.6; P=0.02), as compared to radiography
National Lung Screening Trial Research Team-Results of Initial Low-Dose CT Screening for Lung Cancer (NEJM, 2013) [MEDLINE]
Results
CXR and CT Detected Equal Numbers of Squamous Cell Lung Cancers, But CT Detected Many More Adenocarcinomas/Bronchioloalveolar Cell Carcinomas
CT Detected More Stage 1A Lung Cancers Than CXR, with No Difference in the Number of More Advanced Disease Cases (Stage IIB-IV)
Positive-Predictive Value
CXR: 5.7%
CT: 3.8%
Negative-Predictive Value
CXR: 99.9%
CT: 99.8%
Sensitivity/Specificity
CXR: 73.5% sensitivity/91.3% specificity
CT: 93.8% sensitivity/73.4% specificity
Benefits of Lung Cancer Screening are Proportional to the Risk of Lung Cancer Death in the Patient
Targeting of Lung Cancer Screening According to the Risk of Lung Cancer Death (NEJM, 2013) [MEDLINE]
The 60% of Participants Who are at the Highest Risk for Lung-Cancer Death (Quintiles 3-5): this group accounted for 88% of the screening-prevented lung cancer deaths
The 20% of Participants Who are at the Lowest Risk for Lung-Cancer Death (Quintile 1): accounted for only 1% of the screening-prevented lung cancer deaths
Conclusion: screening with low-dose CT prevented the greatest number of deaths from lung cancer among participants who were at the highest risk
Cost-Benefit Analysis of Low-Dose Chest CT Lung Cancer Screening
Unclear: requires further study (Cochrane Database Syst Rev, 2013) [MEDLINE]
In Addition, Health Insurers May Not Cover the Cost of the Screening Exam
Low-Dose Chest CT Screening Recommendations
American College of Chest Physicians/American Society of Clinical Oncology (2012)
Recommendation: annual low-dose CT screening for patients aged 55-74 y/o with 30 pack-yr smoking history and current smoker (or has quit within the last 15 yrs)
American Association of Thoracic Surgery (AATS) (2012)
Recommendation: annual low-dose CT screening for patients aged 55-74 y/o with 30 pack-yr smoking history and current smoker (or has quit within the last 15 yrs)
Additionally, Annual Screening is Recommended for Patients Age ≥50 with a 20 Pack-yr History and Cumulative Risk >5% (with Other Cancer Risk Factors: COPD, Family History, Environmental Exposure, Radiation Exposure) Over the Next 5 Years
American Cancer Society (2013)
Recommendation: annual low-dose CT screening for patients aged 55-74 y/o with 30 pack-yr smoking history and current smoker (or has quit within the last 15 yrs)
Informed Individual Decision-Making Prior to Testing
US Preventative Services Task Force (2014) [MEDLINE]
Recommendation: annual low-dose CT screening for patients aged 55-80 y/o with 30 pack-yr smoking history and current smoker (or has quit within the last 15 yrs)
Discontinue when Patient Has Not Smoked for ≥15 yrs or if Limited Life Expectancy
Other Types of Lung Cancer Screening
Lung Cancer Screening with Chest X-Ray and/or Sputum Cytology
No Clinical Benefit (Cochrane Database Syst Rev, 2013) [MEDLINE]
Lung cancer diagnosis and mortality beyond 15 years since quit in individuals with a 20+ pack-year history: A systematic review. CA Cancer J Clin. 2023 Nov 1. doi: 10.3322/caac.21808 [MEDLINE]
Current US lung cancer screening recommendations limit eligibility to adults with a pack-year (PY) history of ≥20 years and the first 15 years since quit (YSQ). The authors conducted a systematic review to better understand lung cancer incidence, risk and mortality among otherwise eligible individuals in this population beyond 15 YSQ. The PubMed and Scopus databases were searched through February 14, 2023, and relevant articles were searched by hand. Included studies examined the relationship between adults with both a ≥20-PY history and ≥15 YSQ and lung cancer diagnosis, mortality, and screening ineligibility. One investigator abstracted data and a second confirmed. Two investigators independently assessed study quality and certainty of evidence (COE) and resolved discordance through consensus. From 2636 titles, 22 studies in 26 articles were included. Three studies provided low COE of elevated lung cancer incidence beyond 15 YSQ, as compared with people who never smoked, and six studies provided moderate COE that the risk of a lung cancer diagnosis after 15 YSQ declines gradually, but with no clinically significant difference just before and after 15 YSQ. Studies examining lung cancer-related disparities suggest that outcomes after 15 YSQ were similar between African American/Black and White participants; increasing YSQ would expand eligibility for African American/Black individuals, but for a significantly larger proportion of White individuals. The authors observed that the risk of lung cancer not only persists beyond 15 YSQ but that, compared with individuals who never smoked, the risk may remain significantly elevated for 2 or 3 decades. Future research of nationally representative samples with consistent reporting across studies is needed, as are better data from which to examine the effects on health disparities across different populations.
Clinical Manifestations
General Comments
Presence of Clinical Symptoms
The Majority of Lung Cancer Patients Who Present with Symptoms/Signs Already Have Advanced Disease (Medicine-Baltimore, 1990) [MEDLINE]
Chest Pain is Present in 20% of Lung Cancer Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
Acute Pulmonary Embolism is Associated with Lung Cancer-Induced Hypercoagulability
Pulmonary Manifestations
Alveolar Infiltrate (Mimicking Pneumonia)
Epidemiology
Pneumonia-Like Infiltrate May Occur with Lepidic-Predominant Adenocarcinoma (Bronchioloalveolar Carcinoma) (Heart Lung, 2012) [MEDLINE]
Physiology
Lepidic-Predominant Adenocarcinoma (Bronchioloalveolar Carcinoma) is Characterized by Tumor Cells Which Proliferate Along the Surface of Intact Alveolar Walls without Pathologic Stromal or Vascular Invasion (J Thorac Dis. 2016) [MEDLINE]
Chest CT Findings Favoring the Diagnosis of Bronchioloalveolar Carcinoma (Over that of Infectious Pneumonia) Include an Air-Filled Bronchus within the Consolidation with Stretching, Squeezing (Diffuse Narrowing), Sweeping, or Widening of the Branching Angle within the Area of Consolidation (Br J Radiol, 2001) [MEDLINE]
Chest CT Findings Favoring the Diagnosis of Bronchioloalveolar Carcinoma (Over that of Infectious Pneumonia) Include Bulging of the Interlobar Fissure (Due to Mucin Production, Resulting in Swelling of the Lobe) (p<0.05) (Br J Radiol, 2001) [MEDLINE]
Present in 50-75% of Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
Cough is More Commonly Present in Squamous Cell and Small Cell Histologies
Due to the Propensity of These Tumor Subtypes to Involve the Central Airways
Physiology
Cough is Mediated by the Vagus Nerve Sensory Afferents Located at or Below the Level of the Larynx (Lancet Infect Dis, 2005) [MEDLINE]
However, Since the Vagus Nerve Also Supplies the External Ear, Esophagus, and Abdominal Organs, Cough Can Be Elicited from These Areas, as Well (Lancet Infect Dis, 2005) [MEDLINE]
Symmetrical, Painful Arthropathy of Ankles/Knees/Wrists/Elbows (and Occasionally Metacarpal/Metatarsal/Phalangeal Bones)
Neurologic Paraneoplastic Syndromes
Epidemiology
Lung Cancer is the Most Common Malignancy Associated with Neurologic Paraneoplastic Syndromes
Neurologic Paraneoplastic Syndromes are Associated Predominantly with Small Cell Lung Cancer
Physiology
Neurologic Paraneoplastic Syndromes are Immune-Mediated (Via Autoantibodies)
Clinical
Autonomic Neuropathy
Cerebellar Ataxia
Encephalomyelitis
Lambert-Eaton Myasthenic Syndrome (LEMS) (see Lambert-Eaton Myasthenic Syndrome): most common of the neurologic paraneoplastic syndromes associated with lung cancer (occurring in 3% of patients with small cell lung cancer)
Symptoms May Precede the Diagnosis of Small Cell Lung Cancer: often by months-years
Limbic Encephalitis
Opsomyoclonus
Retinopathy
Sensory Polyneuropathy
Treatment
Generally Unresponsive to Immunosuppression, But May Respond to Treatment of the Primary Lung Cancer
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The value of multiple fluid specimens in the cytological diagnosis of malignancy. Mod Pathol. 1994 Aug;7(6):665-8 [MEDLINE]
CT differentiation of pneumonic-type bronchioloalveolar cell carcinoma and infectious pneumonia. Br J Radiol. 2001;74(882):490-494 [MEDLINE]
Peripheral lung adenocarcinoma: Correlation of thin-section CT findings with histologic prognostic factors and survival. Radiology 220:803-809, 2001 [MEDLINE]
“Early” peripheral lung cancer: Prognostic significance of ground glass opacity on thin-section computed tomographic scan. Ann Thorac Surg 74:1635-1639, 2002 [MEDLINE]
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Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005 Nov;237(2):395-400 [MEDLINE]
Additional value of PET-CT in the staging of lung cancer: comparison with CT alone, PET alone and visual correlation of PET and CT. Eur Radiol. 2007;17(1):23 [MEDLINE]
Accuracy of PET/CT in characterization of solitary pulmonary lesions. J Nucl Med. 2007;48(2):214-220
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Solitary pulmonary nodules: meta-analytic comparison of cross-sectional imaging modalities for diagnosis of malignancy. Radiology. 2008;246(3):772-782 [MEDLINE]
Minimally invasive endoscopic staging of suspected lung cancer. JAMA. 2008 Feb 6;299(5):540-6. doi: 10.1001/jama.299.5.540 [MEDLINE]
Old meets modern: The use of traditional cryoprobes in the age of molecular biology. Respiration 2008, 76, 193–197 [MEDLINE]
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Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009 Jul 2;361(1):32-9. doi: 10.1056/NEJMoa0900043 [MEDLINE]
Incremental value of integrated FDG-PET/CT in evaluating indeterminate solitary pulmonary nodule for malignancy. Mol Imaging Biol. 2010;12(2):204-209
Volume-doubling time of pulmonary nodules with ground glass opacity at multidetector CT: assessment with computer-aided three-dimensional volumetry. Acad Radiol. 2011;18(1):63-69 [MEDLINE]
International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011 Feb;6(2):244-85. doi: 10.1097/JTO.0b013e318206a221 [MEDLINE]
Doubling times and CT screen–detected lung cancers in the Pittsburgh Lung Screening Study. Am J Respir Crit Care Med. 2012 Jan 1;185(1):85-9. doi: 10.1164/rccm.201107-1223OC [MEDLINE]
Cryobiopsy increases the diagnostic yield of endobronchial biopsy: A multicentre trial. Eur. Respir. J. 2012, 39, 685–690 [MEDLINE]
Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e93S-120S [MEDLINE]
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What causes false-negative PET findings for solid-type lung cancer?. Lung Cancer. 2013 Feb;79(2):132-6. doi: 10.1016/j.lungcan.2012.10.018 [MEDLINE]
Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e121S-41S [MEDLINE]
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Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology. 2013 Jan;266(1):304-17. doi: 10.1148/radiol.12120628. Epub 2012 Oct 15 [MEDLINE]
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Pure ground-glass opacity neoplastic lung nodules: Histopathology, imaging, and management. AJR Am J Roentgenol 202:W224-W233, 2014 [MEDLINE]
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Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014 May 21;311(19):1998-2006. doi: 10.1001/jama.2014.3741 [MEDLINE]
Lung adenocarcinomas: Correlation of computed tomography and pathology findings. Diagn Interv Imaging 97:955-963, 2016 [MEDLINE]
Software performance in segmenting ground-glass and solid components of subsolid nodules in pulmonary adenocarcinomas. Eur Radiol 26:4465-4474, 2016 [MEDLINE]
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Diagnosing Lung Cancer: The Complexities of Obtaining a Tissue Diagnosis in the Era of Minimally Invasive and Personalised Medicine. J Clin Med. 2018 Jun 29;7(7):163. doi: 10.3390/jcm7070163 [MEDLINE]
Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?. Ann Thorac Surg. 2020 Apr;109(4):1019-1025. doi: 10.1016/j.athoracsur.2019.10.061 [MEDLINE]
Staging
A clinical-severity staging system for patients with lung cancer. Medicine (Baltimore). 1990 Jan;69(1):1-33 [MEDLINE]
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007 Aug;2(8):706-14 [MEDLINE]
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The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016; 11:39 [MEDLINE]
The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016 May;11(5):666-680. doi: 10.1016/j.jtho.2015.12.113 [MEDLINE]
The Eighth Edition of TNM Staging of Lung Cancer: Reference Chart and Diagrams. Oncologist. 2018 Jul;23(7):844-848. doi: 10.1634/theoncologist.2017-0659 [MEDLINE]
The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg. 2018 Jan;155(1):356-359. doi: 10.1016/j.jtcvs.2017.08.138 [MEDLINE]
The new 8th TNM staging system of lung cancer and its potential imaging interpretation pitfalls and limitations with CT image demonstrations. Diagn Interv Radiol. 2019 Jul; 25(4): 270–279 [MEDLINE]
Clinical Manifestations
Presenting conditions of 1539 population-based lung cancer patients by cell type and stage in New Hampshire and Vermont. Cancer. 1985;56(8):2107 [MEDLINE]
A clinical-severity staging system for patients with lung cancer. Medicine (Baltimore). 1990 Jan;69(1):1-33 [MEDLINE]
Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital. Chest. 1997;112(2):440 [MEDLINE]
Non-small cell lung cancer in very young and very old patients. Chest. 2000;117(2):354 [MEDLINE]
Understanding the symptoms of the common cold and influenza. Lancet Infect Dis. 2005;5(11):718 [MEDLINE]
Superior vena cava syndrome in thoracic malignancies. Respir Care. 2011 May;56(5):653-66 [MEDLINE]
