Epidemiology

General Comments (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]

• Lung Cancer is the Leading Etiology of Cancer Death in the World: lung cancer epidemic in the US began in the 1930’s
  • 2008 Data
    • Over 1.6 Million People Received a New Diagnosis of Lung Cancer
    • Lung Cancer Accounted for 13% of All New Cancer Diagnoses
    • Lung Cancer Accounted for 18% of All Cancer Deaths
• Sex-Related Differences
  • Cigarette Smoking Prevalence Peaked 2 Decades Earlier in Males Than in Females
  • Therefore, the Lung Cancer Epidemic Started Later in Females Than in Males
  • In Contrast to Males, Lung Cancer Rates in Females Have Not Yet Consistently Begun to Decrease
• Race-Related/Socioeconomic Differences
  • Lung Cancer Incidence is Higher Among African-American Males than Caucasian Males: African-American males also have higher mortality rates from lung cancer than do caucasian males
    • However, Lung Cancer Incidence is Similar Among African-American and Caucasian Females
  • Age-Adjusted Lung Cancer Incidence Rates per 100k by Race: lung cancer mortality rates are similar
    • African-American: 72.7
    • Caucasian: 63.3
    • American Indians/Alaskan Natives: 44.5
    • Asians/Pacific Islanders: 39.0
    • Hispanics: 32.5
  • Asian Ethnicity: lung cancer in Asians has better survival rate than in caucasians
    • Possibly Due to Different Tumor Characteristics: Asians have higher prevalence of EGFR mutations
  • Socioeconomic Status: lung cancer incidence is higher in poor and less educated populations
    • Low Socioeconomic Status is Associated with an Unfavorable Constellation of Interactive Lung Cancer Risk Factors (Smoking, Poor Diet, and Exposure to Inhaled Carcinogens in the Workplace and Local Environment)
• Geographic Differences
  • Geographic Risk of Lung Cancer Appears to Correlate to Cigarette Smoking Prevalence
  • Increased Risk of Lung Cancer in Females in China Appear to Be More Related to Indoor Air Pollution from Cooking Fumes
  • Increased Risk of Lung Cancer in Males in China is Related to a Significant Increase in Smoking Rates Since the 1950’s
• Lung Cancer in Never-Smokers
  • Approximately 300k Cases of Lung Cancer Occur Annually Worldwide in Never-Smokers

Risk Factors for Lung Cancer (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]

Smoking/Tobacco Abuse (see Tobacco)

• General Comments
  • Smoking is the Most Important Risk Factor for the Development of Lung Cancer
  • Smoking Cessation Decreases the Risk of Lung Cancer
• Association of Smoking with the Development of Lung Cancer
  • Smoking is Believed to Responsible for 90% of All Lung Cancers (Chest, 2003) [MEDLINE]
    • However, There are Major Geographic Differences in the Relationship Between Tobacco Exposure and the Development of Lung Cancer (CA Cancer J Clin, 2021) [MEDLINE]
      • Worldwide, 66% of Cases of Lung Cancer are Associated with Smoking
      • Worldwide, 33% of Lung Cancer Cases are Due to Other Risk Factors
      • The Disparity Between These Worldwide Data and the Representation that Smoking is Responsible for 90% of All Lung Cancers (as Noted Above) Likely Reflects the Observation that in Resource-Limited Environments (i.e. Countries Outside of the Developed World), Additional Risk Factors (Such as Smoke and Air Pollution) May Be Additional Important Risk Factors for the Development of Lung Cancer

Secondhand Tobacco Smoke Exposure

• Patients Exposed to Secondhand Smoke Via a Cohabiting Partner Have a 20-30% Increased Risk of Lung Cancer

Advancing Age

• Age is a Risk Factor for Many Cancers

Outdoor Air Pollution (see Air Pollution)

• Air Pollution Contains Multiple Substances (Polycyclic Aromatic Hydrocarbons, Arsenic, Nickel, and Chromium), Many of Which are Derived from the Combustion of Fossil Fuels)
• Fine Particulate Matter in Air Pollution Increases the Risk of Lung Cancer

Indoor Air Pollution

• Combustion Products from Heating and Cooking
  • Combustion of Biomass (Wood): association with lung cancer risk is weaker than that of fossil fuels
• Soil Gases: see radon below

β-Carotene Supplementation in Heavy Smokers (see β-Carotene) (NEJM, 1994) [MEDLINE]

• This Finding Conflicts with the Possible Protective Effect of Carotenoids Which are Present in Fruits and Vegetables

Chloromethyl Ethers

• Used in Chemical Manufacturing
• Epidemiology
  • Associated with Small Cell Lung Cancer

Family History of Lung Cancer

• Family History of Lung Cancer is Strongly Associated with an Increased Risk of Lung Cancer
  • History of lung cancer in two or more relatives is associated with an even higher risk of lung cancer

Infection

• Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
  • Lung Cancer is the 3rd Most Common Neoplasm in HIV (Most Common = Kaposi Sarcoma, Non-Hodgkin’s Lymphoma)
  • Lung Cancer Accounts for 16% of Deaths in Patients with HIV Infection
  • Patients with HIV and Lung Cancer are Almost Exclusively Smokers
• Tuberculosis (see Tuberculosis)
  • An Association Between Tuberculosis and Increased Risk of Lung Has Been Reported

Radiation Exposure

• Types of Radiation Exposure
  • Atomic Bomb Radiation Exposure
  • Radiation to Breast/Chest (see Radiation Therapy)
    • Radiation Therapy in Breast Cancer (see Breast Cancer)
    • Radiation Therapy in Hodgkin’s Disease (see Hodgkin’s Disease, [[Hodgkins Disease]])
  • Radiation from Medical Procedures and Imaging (CT Scans, etc)
  • Radiation Exposure in the Workplace
  • Radon Gas in Homes/Uranium Mines (see Radon Gas)
    • Radon is an Inert Gas Produced from the Decay of Radium in the Decay Series of Uranium
    • Radon is a Soil-Formed Gas, Which Enters Buildings
    • Radon and Cigarette Smoking Appear to Act Synergistically to Increase Lung Cancer Risk
    • Radon Exposure is Associated with Risk of Both Non-Small Cell and Small Cell Lung Cancer

Lung Disease

• Airflow Obstruction
  • Airflow Obstruction is Associated with an Increased Risk of Lung Cancer (Even After Controlling for Smoking)
    • COPD is associated with an Increased Risk of Lung Cancer
    • Studies Conflict with Regard with the Relationship Between Asthma and the Risk of Lung Cancer
• Pneumoconioses
  • Conflicting data with regard to risk of lung cancer (and probably confounded by variable causation due to different mineral fibers or environmental agents)
• Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis)
  • There is an association between IPF and risk of lung cancer (this risk is independent of smoking)
• Scleroderma (see Scleroderma)
  • Association Between Scleroderma and Risk of Lung Cancer

Toxin Exposure

• Arsenic (see Arsenic)
  • Arsenic is Present in Air Pollution
  • Lung Cancer Risk is Increased Even with Ingestion of Arsenic in Drinking Water
• Asbestos (see Asbestos)
  • Strong Association Between Asbestos Exposure and Risk of Lung Cancer
• Beryllium (see Beryllium)
• Chromium (see Chromium)
  • Chromium is Present in Air Pollution
• Diesel Exhaust: weak association with lung cancer risk
• Nickel (see Nickel)
  • Nickel is Present in Air Pollution
• Silica
  • Controversial association with lung cancer risk
• Tar and Soot (Contain Benzo[a]pyrene)
  • Tar and Soot Exposure Occurs in In Coke Workers

Other Factors Not Associated with an Increased Risk of Lung Cancer

• Alcohol Use (see Ethanol): studies conflict as to the association between alcohol use and the risk of lung cancer
  • Studies May Be Confounded Due to the Strong Association Between Alcohol Use and Smoking: therefore, studies need to control for smoking in the population studied
• Marijuana Smoking (see Tetrahydrocannabinol)
  • XXXXXXXXX

Protective Factors Against Lung Cancer

• Fruit Consumption
  • Appears to be inversely correlated with the risk of lung cancer
  • Fruits and Vegetables are the Major Dietary Sources of Antioxidants (Carotenoids(
• Vegetable Consumption
  • Appears to be inversely correlated with the risk of lung cancer, although the correlation is less strong than that of fruit consumption
  • Fruits and Vegetables are the Major Dietary Sources of Antioxidants (Carotenoids)
• Physical Activity
  • Moderate Levels of Physical Activity: 13% decrease in lung cancer risk
  • High Levels of Physical Activity: 30% decrease in lung cancer risk

Lung Cancer in Never Smokers

Definition

• Never Smoker is Defined as Someone Who Has Smoked <100 Cigarettes in Their Lifetime

Background

• Lung Cancer Data Collection Difficulties
  • Problematically, Most Population-Based Cancer Registries Do Not Collect Patient Smoking History
  • National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Database Collects Population-Based Tobacco Use Information, But the Data is Limited to Never Smoker Information Only in Broad Geographic Regions (J Natl Cancer Inst, 2008) [MEDLINE]

Incidence

• Worldwide, Approximately 66% of Cases of Lung Cancer are Associated with Smoking/Tobacco Use
• However, Since Approximately 33% of Lung Cancer Cases (Worldwide) are Due to Other Risk Factors, Lung Cancer in Never Smokers is an Important Entity (CA Cancer J Clin, 2021) [MEDLINE]
  • In Never Smoker Males Age 40-49 y/o, Age-Adjusted Incidence Ranges from 11.2-13.7 Lung Cancer Cases Per 100,000 Person-Years
  • In Never Smoker Females Age 40-49 y/o, Age-Adjusted Incidence Ranges from 15.2-20.8 Lung Cancer Cases Per 100,000 Person-Years
• Global Geographic Variations in the Incidence of Lung Cancer
  • United States Data
    • Approximately 19% of Lung Cancers in Females Occur in Never Smokers, as Compared to Only 9% of Lung Cancers in Males* (J Clin Oncol, 2007) [MEDLINE]
  • Asia Data
    • Approximately 60-80% of Female Lung Cancer Cases Occur in Never Smokers (Nat Rev Cancer, 2007) [MEDLINE]

Potential Risk Factors for Lung Cancer in Never Smokers

• Secondhand Smoke Exposure
  • Approximately 15-35% of Lung Cancer Cases in Never Smokers are Attributable to Secondhand Smoke Exposure (and Risk May Be Increased in Patients with Secondhand Smoke Exposure Prior to Age 25) (Environ Health, 2007) [MEDLINE] (Lung Cancer, 2010) [MEDLINE]
• Enviromental Exposures
  • Arsenic (see Arsenic)
  • Asbestos (see Asbestos)
  • Chromium (see Chromium)
  • Indoor Air Pollution (see Air Pollution)
  • Outdoor Air Pollution (see Air Pollution)
• Estrogens (see Estrogen)
• Genetic Factors
• Lung Disease
• Oncogenic Viruses
  • Human Papilloma Virus (HPV) (see Human Papilloma Virus)
• Radon (see Radon)

Pathologic Subtypes

• Adenocarcinoma
  • Adenocarcinoma Accounts for 50-60% of Lung Cancer Cases in Never Smokers
    • Adenocarcinoma is the Most Common Pathologic Subtype of Lung Cancer in Never Smokers (J Clin Oncol, 2006) [MEDLINE] (Nav Rev Cancer, 2007) [MEDLINE] (J Thorac Oncol, 2010) [MEDLINE]
  • Adenocarcinoma Accounts for Only 19% of Lung Cancer Cases in Smokers (Nav Rev Cancer, 2007) [MEDLINE]
• Squamous Cell Carcinoma
  • Squamous Cell Carcinoma Accounts for Only 10-20% of Lung Cancers in Never Smokers
• Small Cell Lung Cancer
  • Small Cell Lung Cancer is Rare in Never Smokers (Clin Lung Cancer, 2012) [MEDLINE]

Mutations in Lung Cancer

• There is a Higher Prevalence of Clinically-Actionable Driver Mutations in Lung Cancer Cases in Never Smokers, as Compared to Lung Cancer Cases in Ever Smokers
  • Clinically-Actionable Driver Mutations Occur in 78-92% of Never Smoker Lung Cancer Cases, as Compared to 50% of Ever Smoker Lung Cancer Cases (J Clin Oncol, 2021) [MEDLINE]
• Types of Driver Mutations
  • *Epidermal Growth Factor Receptor (EGFR) Pathway Abnormalities Occur with Increased Frequency in Lung Cancer in Never Smokers
    • These EGFR Pathway Abnormalities May be Responsive to EGFR Tyrosine Kinase Inhibitors (Such as Erlotinib, Gefitinib, Afatinib, or Osimertinib)
  • Anaplastic Lymphoma Kinase (ALK) Fusion Oncogene Occurs More Commonly in Lung Cancer in Never Smokers

Treatment/Prognostic Implications

• Whether or Not Never Smoker Patients with Non-Small Cell Lung Cancer Have a Better Response to Standard Lung Cancer Therapy and/or a Better Prognosis Than Ever Smoker Patients with Non-Small Cell Lung Cancer is Unclear

---

Physiology/Histology

General Comments

• The Distinction of Adenocarcinoma from Other Non-Small Cell Lung Cancer Pathologies Has Recently Become Critically Important with the Advent of Therapies Directed Against Target Driver Mutations
  • These Targeted Therapies Have Better Response Rates than Standard Chemotherapy

Incidence

• Non-Small Lung Cancer
  • General Comments
    • Non-Small Lung Cancer Accounts for 75-80% of All Lung Cancers
  • Adenocarcinoma
    • The Incidence of Adenocarcinoma Has Increased Significantly, with a Corresponding Decrease in Other Pathologic Subtypes
      • This May Be Due to the Changing Formulation of Cigarettes (as Noted Above)
  • Large Cell Carcinoma
  • Squamous Cell Carcinoma
• Small Cell Lung Cancer
  • Small Cell Lung Cancer Accounts for 15% of All Lung Cancers

Doubling Time

• 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-Bronchioloalveolar Carcinoma (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
  • Case Series Examining the Rate of Disease Progression in Patients with Non-Small Cell Lung Cancer (Int J Radiat Oncol Biol Phys, 2011) [MEDLINE]
    • Median Time Interval Between the First and Second CT Scans was 13.4 wks (and Median Time Interval Between the First and Second PET Scans was 9 wks)
      • Approximately 48% of the Patients Progressed Between the Scans
      • The Median Maximum Tumor Dimension Increased by 1.0 cm (Mean: 1.6 cm) Between the Scans: the median relative maximum tumor dimension increase was 35% (Mean: 59%)
      • Rate of Progression at 4 wks: 13%
      • Rate of Progression at 8 wks: 31%
      • Rate of Progression at 16 wks: 46%
    • Conclusions
      • Based on These Observations, if the Lung Cancer Evaluation Takes >8 wks to Complete, Repeat CT Scans are Probably Indicated
  • 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 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

Adenocarcinoma (WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

General Comments

• Over the Last 50 Years, the Prevalence of Adenocarcinoma Has Been Increasing, Relative to Other Lung Cancer Histopathologic Subtypes (Lung Cancer, 2001) [MEDLINE]
• Adenocarcinoma is Now the Most Common Histopathologic Subtype of Lung Cancer
  • Adenocarcinoma Accounts for Approximately 35-50% of All Non-Small Cell Lung Cancers in Modern Series (J Thorac Oncol, 2019) [MEDLINE]
    • It Has Been Speculated that the Increasing Incidence of Lung Adenocarcinoma is Related to the Introduction of Low-Tar Filter Cigarettes in the 1960’s, But This Theory is Unproven (Epidemiology, 2001) [MEDLINE]

Diagnosis

• Histologic Features
  • Gland Formation
• Immunohistochemical Stains
  • Thyroid Transcription Factor (TTF-1): positive
    • TTF-1 is Also Expressed in Thyroid Tissue and Rarely in Colorectal Tissue
    • When Both TTF-1 and Napsin A are Positive, it is Highly Suggestive of Adenocarcinoma of Lung Origin
  • Cytokeratin 7 (CK7): positive
  • Mucicarmine: positive (detects mucin)
  • Periodic Acid–Schiff–Diastase (PAS-D): positive (detects mucin)
  • Napsin-A: positive
    • Napsin-A is Also Expressed in Normal Kidney and in Some Renal Tumors
    • Napsin-A is a Protease Which is Regulated by TTF-1
    • When Both TTF-1 and Napsin-A are Positive, it Highly Suggests Lung Adenocarcinoma
  • Surf-A: positive
  • Surf-B: positive

Tumor Doubling Time

• Clinical Data
  • Study Using Volumetric Analysis of Lung Cancers (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 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

Classification of Lung Adenocarcinoma in Resection Specimens

Historical Perspective

• Bronchioloalveolar Carcinoma (Characterized by a Prominent Bronchioalveolar Pattern Associated with Variable Extension into the Surrounding Tissues) was First Clinically Described in 1876 by Malassez (Termed “Epithelioma”) and in 1903 by Musser (Termed “Primary Cancer of the Lung”) (Malassez L. 1876; Examen histologique d’un cas de cancer encephaloide du poumon – epithelioma. Arch Physiol Norm Pathol 1876;3:353-72) (Musser JH; 1903; Primary cancer of the lung. U Penn Med Bull 1903:16:289-96)
  • Subsequent Publications Termed This Entity as “Alveolar Cell Tumor of Lung”, “Pulmonary Adenomatosis”, and “Mucocellular Papillary Adenocarcinoma of the Lung”
• In 1960, Liebow First Identified Bronchioloalveolar Carcinoma as a Well-Differentiated Adenocarcinoma with Three Distinct Clinical Patterns (Single Nodule, Disseminated Nodules, or Diffuse) (Adv Intern Med, 1960) [MEDLINE]
  • Liebow’s “Diffuse” Pattern Mimicked the Alveolar Filling Process Typically Seen in Infectious Pneumonia (Adv Intern Med, 1960) [MEDLINE]
  • The Current Pathologic Classification System Below Does Not Recognize Bronchioloalveolar Carcinoma as a Separate Entity (Clin Adv Hematol Oncol, 2014) [MEDLINE]
  • In Terms of Clinical Behavior, Bronchioloalveolar Carcinoma Can Be Either Virulent or Indolent
    • In Indolent Cases, Lepidic-Predominant Adenocarcinoma Can Manifest Doubling Times Which are Measured in Periods as Long as Years (Radiology, 2007) [MEDLINE] (Acad Radiol, 2011) [MEDLINE] (Am J Respir Crit Care Med, 2012) [MEDLINE]

Preinvasive Glandular Lesions

• Atypical Adenomatous Hyperplasia (AAH)
• Adenocarcinoma In Situ (AIS) (≤3 cm) (Formerly Bronchioloalveolar Carcinoma)
  • Typical Chest CT Appearances
    • Ground Glass Nodule: most common
    • Part-Solid Lesion: common
    • Lesions with Bubble-Like Internal Lucencies
  • Subtypes
    • Non-Mucinous
    • Mucinous
    • Mixed Non-Mucinous/Mucinous

Minimally Invasive Lung Adenocarcinoma (≤3 cm Lepidic-Predominant Tumor and ≤5 mm of Stromal Invasion) (MIA)

• General Comments
  • Absence of Lymphatic/Vascular/Pleural Invasion and Tumor Necrosis
  • High Overall Survival Rate After Surgical Resection: 98% (Lung Cancer, 2013) [MEDLINE]
• Typical Chest Computed Tomography (Chest CT) Appearances
  • Ground Glass Nodule with a Small, Central Solid Component (≤5 mm)
    • Shape of a Ground Glass Nodule Does Not Appear to Be Useful in Differentiating Between Adenocarcinoma In Situ (AIS) and Minimally Invasive Lung Adenocarcinoma (MIA) (Insights Imaging, 2020) [MEDLINE]
• Subtypes
  • Minimally Invasive Non-Mucinous Adenocarcinoma
  • Mucinous Adenocarcinoma
  • Mixed Non-Mucinous/Mucinous Adenocarcinoma

Invasive Non-Mucinous Lung Adenocarcinoma

• Lepidic-Predominant (>5 mm Lymphatic/Vascular/Pleural Invasion with a Non-Mucinous Lepidic-Predominant Growth Pattern) (Formerly Termed as “Non-Mucinous Bronchioloalveolar Carcinoma”)
  • Epidemiology
    • Female-Predominance (72% of Cases Occur in Females) (J Thorac Oncol, 2011) [MEDLINE]
    • Weak Association with Smoking (Only 46% of Cases Occur in Smokers) (J Thorac Oncol, 2011) [MEDLINE]
  • Typical Chest Computed Tomography (Chest CT) Appearance
    • Typically Manifest Ground Glass Attenuation (J Thorac Oncol, 2011) [MEDLINE]
      • May Manifest Part-Solid Nodule or Mass (Insights Imaging, 2020) [MEDLINE]
      • Occasional Bubble-Like Lucencies (Insights Imaging, 2020) [MEDLINE]
  • Pathologic Appearance
    • The Word “Lepidic” Means Scaly (Referring to the Growth of Tumor Cells Along Intact Alveolar Septae)
  • High 5-Year Survival Rate After Surgical Resection: 90% (Insights Imaging, 2020) [MEDLINE]
• Acinar-Predominant
  • Invasive tumor composed of acini and tubules with columnar or cuboidal cells that resemble bronchial-lining epithelial cells
• Papillary-Predominant
  • Invasive tumor arranged as papillae structures with a fibrovascular core and complicated secondary and tertiary branches
• Micropapillary-Predominant
  • Small Papillary Tufts Containing Tumor Cells with Peripheral Nuclei But without a Fibrovascular Core
  • Lower 5-Year Survival Rate After Surgical Resection: 54% (Insights Imaging, 2020) [MEDLINE]
• Solid-Predominant with Mucin Production

Invasive Mucinous Lung Adenocarcinoma

• Invasive Mucinous Adenocarcinoma (Formerly Termed as “Mucinous Bronchioloalveolar Carcinoma”)
  • Epidemiology
    • Female-Predominance (58% of Cases Occur in Females) (J Thorac Oncol, 2011) [MEDLINE]
    • Weak Association with Smoking (Only 45% of Cases Occur in Smokers) (J Thorac Oncol, 2011) [MEDLINE]
  • Histologic Features
    • Distinctive Appearance with Tumor Cells Having a Goblet or Columnar Cell Morphology with Abundant Intracytoplasmic Mucin (J Thorac Oncol, 2011) [MEDLINE]
    • Alveolar Spaces Often Contain Mucin (J Thorac Oncol, 2011) [MEDLINE]
    • These Tumors May Demonstrate the Same Heterogeneous Mixture of Lepidic, Acinar, Papillary, Micropapillary, and Solid Growth as in Non-Mucinous Tumors (J Thorac Oncol, 2011) [MEDLINE]
  • Typical Chest Computed Tomography (Chest CT) Appearance
    • Typically Manifest as Consolidation (with Air Bronchograms) (J Thorac Oncol, 2011) [MEDLINE]
      • May Manifest Nodules/Masses, Solid, Part-Solid, or Ground Glass Density
    • Commonly Multifocal and Multilobar
    • Both Unifocal and Multifocal Forms of the Disease Demonstrate a Lower Lobe Predominance
• Mixed Invasive Mucinous and Non-Mucinous Adenocarcinoma

Other Lung Adenocarcinoma Subtypes

• Colloid Adenocarcinoma
  • These Manifest Extracellular Mucin in Abundant Pools, which Distend the Alveolar Spaces Associated with Destruction of their Walls (J Thorac Oncol, 2011) [MEDLINE]
• Fetal Adenocarcinoma (Low and High-Grade)
  • These Manifest Glandular Elements with Tubules Composed of Glycogen-Rich, Non-Ciliated Cells Which Resemble Fetal Lung Tubules (J Thorac Oncol, 2011) [MEDLINE]
• Enteric Adenocarcinoma
  • These are Termed “Enteric”, Since They Share Some Morphologic and Immunohistochemical Features with Colorectal Adenocarcinoma (J Thorac Oncol, 2011) [MEDLINE]
• Adenocarcinoma, Not Otherwise Specificed (NOS)

Squamous Cell Carcinoma

(WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

Diagnosis

• Histologic Features
  • Keratinization
  • Keratin Pearls
  • Intercellular Bridges
• Immunohistochemical Stains
  • p40: positive
  • p63: positive
  • Desmoglein: positive
  • Cytokeratin 5/6 (CK5/6): positive
  • Cytokeratin 7 (CK 7): usually negative

Tumor Doubling Time

• Clinical Data
  • Study Using Volumetric Analysis of Lung Cancers (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 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

Adenosquamous Carcinoma

(WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

Diagnosis

• Positive Immunohistochemical Stains
  • Adenosquamous Carcinomas Have a Combination of Immunohistochemical Staining Patterns from Both Adenocarcinoma and Squamous Cell Carcinoma
    • Adenosquamous Carcinoma is Defined as a Tumor Composed of >10% Malignant Glandular and Squamous Components

Large Cell Carcinoma

(WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

Diagnosis

• Positive Immunohistochemical Stains
  • May Have a Combination of Immunohistochemical Staining Patterns from Both Adenocarcinoma and Squamous Cell Carcinoma

Small Cell Lung Cancer

(WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

Epidemiology

• Incidence: 30,000 new small cell lung cancer cases are diagnosed each year in the US
  • Small Cell Lung Cancer is the 6th Most Common Cause of Cancer-Related Death in the US
  • Peak Incidence Occurred in the Late 1980’s
    • Declining incidence of small cell lung cancer since then (likely related to decreased smoking rates)
  • Male/Female Ratio Has Also Declined: currently 1:1
• Relationship to Smoking
  • >95% of small cell cases occur in smokers
• Origin
  • Small cell lung cancer originates from a neuroendocrine cell
• Diagnosis
  • Histologic Features
    • Small Cells: generally two to three times the size of small lymphocytes
    • Scant Cytoplasm
    • High Nuclear/Cytoplasmic Ratio
    • Nuclear Molding
    • Finely Granular Chromatin
    • Absent or Inconspicuous Nucleoli
    • Necrosis
    • Crush Artifact: common
    • Azzopardi Effect: perivascular basophilic condensation
• Clinical Presentation
  • Most Small Cell Cases Present with a Hilar Mass with Peribronchial Compression/Obstruction
  • Approximately 60-70% of Small Cell Cases Present with Extensive-Stage Disease (While Only 30-40% Present with Limited Stage Disease)

Diagnosis

• Histologic Features
  • Small, Round Fusiform Shape
  • Scant Cytoplasm
  • “Salt and Pepper” Chromatin
• Immunohistochemical Stains
  • Thyroid Transcription Factor (TTF-1): positive
    • TTF-1 is Also Expressed in Thyroid Tissue and Rarely in Colorectal Tissue
  • CD56: positive
  • Neuron-Specific Enolase (NSE): positive
  • High Proliferative Rate
    • Ki-67: positive
    • MIB-1: positive
  • Synaptophysin: variably positive (33% are positive)
  • Chromogranin: variably positive (33% are positive)

Other Tumors Which May Appear in Thorax and Have to Be Differentiated from Lung Cancer

(WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO Classification of Tumours, 5th ed, International Agency for Research on Cancer, Lyon, France 2021) [LINK]

Carcinoid

• Diagnosis
  • Histologic Features
    • Round-Oval Nuclei with Finely Dispersed Chromatin and Inconspicuous or Small Nucleoli
  • Positive Immunohistochemical Stains
    • CD56
    • Synaptophysin
    • Chromogranin

Malignant Mesothelioma

• Diagnosis
  • Histologic Features
    • XXXX
  • Positive Immunohistochemical Stains
    • Calretinin
    • WT1 (Wilms Tumor Gene Protein)
    • EMA (Epithelial Membrane Antigen)
    • Cytokeratin

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Diagnosis and Staging Procedures

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
  • Size >15 mm
  • Upper Lobe Location
  • Thick-Walled Cavitation (see Cystic-Cavitary Lung Lesions)

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

Chest X-Ray (CXR) (see Chest X-Ray)

• Chest X-Ray May Be Useful as Initial Diagnostic Test, But it Has a Low Sensitivity
• Clinical Efficacy
  • XXXX

Chest Computed Tomography (Chest CT) with Intravenous Contrast (see Chest Computed Tomography)

• Technique
  • Integrated PET-CT (in a Single Gantry)
    • 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

Dynamic Chest Computed Tomography (Chest CT) (see Chest Computed Tomography)

• Dynamic Chest Computed Tomography is Rarely Used in the Unites States
• Dynamic Chest Computed Tomography is Highly-Sensitive (But Non-Specific) for the Identification of Malignant Nodules

Positron Emission Tomography (PET) Scan (see Fluorodeoxyglucose-Positron Emission Tomography)

• 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 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
  • 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
• 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

Sputum Cytology (see Sputum Cytology)

• Technique
  • Obtain at Least Three Specimens
• 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 (see Bronchoscopy)

• Technique
  • 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)
      • Cytobrush: 52% sensitivity
      • Transbronchial Biopsy: 46% sensitivity
      • Bronchoalveolar Lavage (BAL)/Washing: 43% sensitivity
    • 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]
    • Central Endobronchial Lesions: 95% sensitivity
    • Peripheral Lesions: 74% sensitivity

Transthoracic Needle Aspiration (TTNA) (see Transthoracic Needle Aspiration)

• Technique
  • Needle Aspiration of Parenchymal Lung Nodule/Mass
  • Needle Aspiration of Mediastinal Lymph Node (>1.5 cm) or Mass
• Clinical Efficacy
  • Review of Performance Characteristics of Various Diagnostic Methods for Suspected Lung Cancer (Chest, 2003) [MEDLINE]
    • Peripheral Lesions of All Sizes
      • Transthoracic Needle Aspiration: 90% sensitivity (with a trend toward lower sensitivity with lesions <2 cm in diameter)
      • Cytobrush: 52% sensitivity
      • Transbronchial Biopsy: 46% sensitivity
      • Bronchoalveolar Lavage (BAL)/Washing: 43% sensitivity
• 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)

Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see Video-Assisted Thoracoscopic Surgery)

• Technique
  • 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

Evaluation of the Mediastinum

Chest CT with Intravenous Contrast (see Chest Computed Tomography)

• Sensitivity/Specificity of Chest CT vs PET for Staging the Mediastinum
  • CT Sensitivity/Specificity for Staging Mediastinum: 60%/81%
  • PET Sensitivity/Specificity for Staging Mediastinum: 85%/88%
• 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

Positron Emission Tomography (PET) Scan (see Fluorodeoxyglucose-Positron Emission Tomography)

• 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

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)

Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) (see Esophagogastroduodenoscopy)

• Technique
  • 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

Transthoracic Needle Aspiration (TTNA) (see Transthoracic Needle Aspiration)

• Technique
  • Needle Aspiration of Parenchymal Lung Nodule/Mass
  • 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)

Video-Assisted Thoracoscopic Surgery (VATS) with Mediastinal Lymph Node Biopsy (see Video-Assisted Thoracoscopic Surgery)

• Technique
  • 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

Mediastinoscopy (see Mediastinoscopy)

• Indications
  • Mediastinal Lymphadenopathy (see Mediastinal Mass)
    • Cervical Mediastinoscopy is Used Primarily as a Mediastinal Staging Modality
• Techniques
  • Standard Cervical Mediastinoscopy Allows Access to Pretracheal (1, 3), Paratracheal (2R, 2L, 4R, 4L), Anterior Subcarinal (7), and Occasionally Hilar (10) Lymph Nodes
  • Extended Cervical Mediastinoscopy Allows Access to Station 1, 2, 3, 4, 7, and 10 Lymph Nodes, as Well as Subaortic (5) and Para-Aortic (6) Lymph Nodes
    • Extended Cervical Mediastinoscopy is Limited to Centers with Local Expertise

Left Anterior Mediastinotomy (Chamberlain Procedure)

• Technique
  • Surgical Procedure Which Requires General Anesthesia
  • Allows Access to Aortopulmonary Window Lymph Nodes/Subaortic Lymph Nodes (5): cancers of the LUL preferentially drain to the subaortic (5) lymph nodes

Video-Assisted Mediastinal Lymphadenectomy (VAMLA)

• May Also Be Used in Some Centers

Transcervical Extended Mediastinal Lymphadenectomy (TEMLA)

• May Also Be Used in Some Centers

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)

Evaluation of Pleural Disease/Pleural Effusion

Chest CT with Intravenous Contrast (see Chest Computed Tomography)

• CT Features Which are Associated with Malignant Pleural Disease (in Patients with Diffuse Pleural Disease) (AJR Am J Roentgenol, 1990) [MEDLINE]
  • Circumferential Pleural Thickening: sensitivity = 41%/specificity = 100%
  • Nodular Pleural Thickening: sensitivity = 51%/specificity = 94%
  • Parietal Pleural Thickening >1 cm: sensitivity = 36%/specificity = 94%
  • Mediastinal Pleural Involvement: sensitivity = 56%/specificity = 88%
• 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

Positron Emission Tomography (PET) Scan (see Fluorodeoxyglucose-Positron Emission Tomography)

• 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

Thoracentesis (see Thoracentesis)

• Technique
  • 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)

Pleural Biopsy (see xxxx)

• xxx

Video-Assisted Thoracoscopic Surgery (VATS) with Pleural Biopsy (see Video-Assisted Thoracoscopic Surgery)

• Technique
  • 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

Positron Emission Tomography (PET) Scan (see Fluorodeoxyglucose-Positron Emission Tomography)

• 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

Bone Scan (see Bone Scan)

• Bone Scan May Be Useful to Diagnose Bone Metastases

Brain Magnetic Resonance Imaging (Brain MRI) (see Brain Magnetic Resonance Imaging)

• Recommendations (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]
  • Recommended for Patients with Non-Small Cell Stage III or IV Disease, Even with a Negative Clinical Evaluation (Grade 2C)

Head Computed Tomography (Head CT) (see Head Computed Tomography)

• 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)
    • 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)
  • Specific Therapy
    • Selumetinib (Koselugo) (see Selumetinib)
• Epidermal Growth Factor Receptor (EGFR) Mutation
  • Background
    • EGFR is a Transmembrane Signaling Receptor that Plays a Role in Cellular Proliferation, Migration, Adhesion, and Invasion
  • Prevalence
    • EGFR Mutations Occur in Multiple Epithelial Cancers and are Present in 10-15% of Non-Small Cell Lung Cancers
      • EGFR Mutations are Found More Commonly in Female, Non-Smokers with Lung Adenocarcinoma
      • EGFR Mutations are Found More Commonly in Lung Adenocarcinomas in Asian Patients (Present in 30-60% of These Cases)
  • Specific Therapy
    • Afatinib (Gilotrif) (see Afatinib)
    • Erlotinib (Tarceva) (see Erlotinib)
    • Gefitinib (Iressa) (see Gefitinib)
• Anaplastic Lymphoma Kinase (ALK)
  • Background
    • EML4-ALK Fusion Protein Has Potent Oncogenic Activity
  • Prevalence: present in 3-7% of non-small cell lung cancers
    • ALK Mutations are Most Commonly Seen in Younger Patients
  • Test with Fluorescence In Situ Hybridization (FISH) Using the FDA-Approved Vysis Probes Test
    • In Europe, Immunohistochemistry is Also Used
  • Specific Therapy
    • Crizotinib (Xalkori) (see Crizotinib)
    • Ceritinib (Zykadia) (see Ceritinib)
• BRAF Mutations: for example, the BRAF V600E mutation
  • Prevalence: present in 2-4% of non-small cell lung cancers
  • Specific Therapy
    • Dabrafenib (Tafinlar) (see Dabrafenib)
    • Dasatinib (Sprycel) (see Dasatinib)
    • Trametinib (Mekinist) (see Trametinib)
    • Vemurafenib (Zelboraf) (see Vemurafenib)
• HER2 Insertions
  • Prevalence: present in 2% of non-small cell lung cancers
  • Specific Therapy
    • Afatinib (Gilotrif) (see Afatinib)
    • Dacomitinib (see Dacomitinib)
    • Neratinib (see Neratinib)
• MET Amplification: for example, the Exon 14 skipping mutation
  • Prevalence: present in <1% of non-small cell lung cancers
  • Specific Therapy
    • Crizotinib (Xalkori) (see Crizotinib)
• RET Fusions
  • Prevalence: present in 1-2% of non-small cell lung cancers
  • Specific Therapy
    • Cabozantinib (Cometriq) (see Cabozantinib)
    • Sorafenib (Nexavar) (see Sorafenib)
    • Sunitinib (Sutent) (see Sunitinib)
    • Vandetanib (Caprelsa) (see Vandetanib)
• ROS1 Proto-Oncogene Receptor Tyrosine Kinase Mutation
  • Prevalence: found in approximately 1-2% of non-small cell lung cancers
  • Specific Therapy
    • Crizotinib (Xalkori) (see Crizotinib)

Clinical Efficacy

• 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)

Specific Staging of Small Cell Lung Cancer

• Recommendations (Chest, 2013) [MEDLINE]
  • In Patient with Suspected/Proven Small Cell Lung Cancer, Full Staging Evaluation is Recommended (Grade 1B Recommendation)
    • Complete Blood Count (CBC) (see Complete Blood Count)
    • Chemistry Panel with Hepatic/Renal Function Tests
    • Chest/Abdominal CT with Intravenous Contrast (see Chest Computed Tomography)
    • Brain MRI (or Head CT) (see Brain Magnetic Resonance Imaging and Head Computed Tomography)
    • Bone Scan (see Bone Scan)
  • 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)

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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

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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)
      • Relative Risk Reduction (as Compared to Radiography): (309-247)/309 = 20% relative risk reduction
      • Absolute Risk Reduction (as Compared to Radiography): 309/26,732 – 247/26,722 = 1.16% – 0.92% = 0.24% absolute risk reduction
  • 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]

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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]

Cardiovascular Manifestations

Chest Pain (see Chest Pain)

• Epidemiology
  • Present in 20% of Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
• Potential Physiologic Mechanisms
  • Direct Pleural Involvement
  • Post-Obstructive Pneumonia
  • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)
    • 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]
• Diagnosis
  • Chest Computed Tomography (Chest CT) (see Chest Computed Tomography)
    • 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]
• Clinical
  • May Present as an Unresolving Pneumonia

Bronchorrhea (see Bronchorrhea)

• Epidemiology
  • Associated with Mucinous Adenocarcinoma
• Clinical
  • Large Volume of Thin, Mucoid Secretions

Cough (see Cough)

• Epidemiology
  • Present in 50-75% of Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
  • More Commonly Present in Squamous Cell and Small Cell Histologies: due to propensity to involve the central airways
• Physiology
  • XXXXXXXXXXX

Dyspnea (see Dyspnea)

• Epidemiology
  • Present in 25% of Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
• Potential Physiologic Mechanisms
  • Endobronchial Obstruction with Atelectasis (see Atelectasis)
  • Extrinsic Airway Compression
  • Lung Consolidation or Infiltration/Mass Effect with Displacement
  • Lymphangitic Tumor Spread
  • Pericardial Effusion/Tamponade (see Tamponade)
  • Pleural Effusion (see Pleural Effusion-Exudate)
  • Pneumothorax (see Pneumothorax)
  • Post-Obstructive Pneumonia
  • Tracheal Obstruction
  • Tumor Embolism (see Tumor Embolism)
  • Unilateral Diaphragmatic Paralysis (see Unilateral Diaphragmatic Paralysis)

Endobronchial Lesion with Atelectasis (see Atelectasis)

• Physiology
  • Airway Obstruction
• Clinical
  • Localized Wheeze: may indicate an airway obstruction

Hemoptysis (see Hemoptysis)

• Epidemiology
  • Present in 20-50% of Cases (Cancer, 1985) [MEDLINE] (Chest, 1997) [MEDLINE] (Chest, 2000) [MEDLINE] (Respir Care, 2011) [MEDLINE]
• Physiology
  • Due to Endobronchial Tumor Necrosis or Tumor Erosion into Airway

Hoarseness (see Hoarseness)

• Epidemiology
  • Present in Some Cases
• Physiology
  • Due to Involvement of the Recurrent Laryngeal Nerve

Lung Nodule (see Lung Nodule or Mass)

• Clinical
  • Presentation with a Lung Nodule is a Common Presentation of Lung Cancer

Mediastinal Lymphadenopathy (see Mediastinal Mass)

• Epidemiology
  • XXXXXXXXX
• Clinical
  • Mass in or Adjacent to Hilum is Particularly Characteristic of Small Cell Lung Cancer: present in 78% of cases
  • Direct Mediastinal Invasion is Particularly Characteristic of Small Cell Lung Cancer: present in 78% of cases
  • Massive Mediastinal Lymphadenopathy is Particularly Characteristic of Small Cell Lung Cancer: present in 78% of cases

Pancoast Syndrome

• Epidemiology
  • Associated with Pancoast Tumor (Usually Non-Small Cell), Located in the Superior Sulcus
• Clinical
  • Atrophy of Hand Muscles
  • Bone Destruction
  • Horner’s Syndrome (see Horner’s Syndrome)
  • Pain: usually in the shoulder (or alternatively in the forearm, scapula, or fingers)

Pleural Effusion (see Pleural Effusion-Exudate)

• Epidemiology
  • XXXXXXXXX
• Clinical
  • Benign Pleural Effusion: may occur due to lymphatic obstruction, post-obstructive pneumonia, or atelectasis
  • Malignant Pleural Effusion: occurs in 10-5% of patients with lung cancer at some point in their disease course
    • May Be Serous, Serosanguineous, or Frankly Bloody
    • Exudative

Pleural Thickening (see Pleural Thickening)

• Epidemiology
  • Pleural Thickening May Occur without Pleural Effusion

Vascular Manifestations

Superior Vena Cava (SVC) Syndrome (see Superior Vena Cava Syndrome)

• Epidemiology
  • *Superior Vena Cava (SVC) Syndrome is More Common in Small Cell Lung Cancer, as Compared to Non-Small Cell Lung Cancer
• Physiology
  • Obstruction of the Superior Vena Cava (SVC)
• Diagnosis
  • Chest CT (see Chest Computed Tomography)
    • Right Hilar Mass
    • Widened Mediastinum
• Clinical
  • Dilated Neck Veins
  • Dyspnea (see Dyspnea)
  • Facial Edema
  • Facial Plethora
  • Headache (see Headache)

Constitutional Manifestations

• General Comments:
  • Constitutional Symptoms May Occur in Patients with Stage IV Disease
• Fatigue (see Fatigue)
• Weight Loss (see Weight Loss)
  • Epidemiology
    • Present in Many Patients

Metastases

General Comments

• The Following Sites are the Most Frequently Observed
  • Spread to Other Organs Can Occur Later in the Course of Disease

Adrenal Metastases

• Diagnosis
  • Adrenal Mass Lesions May Be Commonly Found During Lung Cancer Staging, But Usually are Due to an Etiology Other Than Lung Cancer
  • Negative Imaging Study Does Not Exclude the Presence of Adrenal Metastases
  • PET Scan is Useful to Detect Adrenal Metastases
• Clinical
  • Rarely Symptomatic

Bone Metastases

• Epidemiology
  • Approximately 20% of Non-Small Cell Lung Cancer Cases Have Bone Metastases on Presentation
  • Approximately 30-40% of Small Cell Lung Cancer Cases Have Bone Metastases on Presentation
• Diagnosis
  • Osteolytic Appearance is More common than Osteoblastic Appearance
  • Vertebral Bodies are the Most Common Site of Involvement
  • PET-CT is More Sensitive at Detecting Bone Metastases than CT Scan or Bone Scan
• Clinical: frequently symptomatic
  • Back/Chest/Extremity Pain
  • Elevated Serum Alkaline Phosphatase (see Serum Alkaline Phosphatase)
  • Hypercalcemia (see Hypercalcemia)

Brain Metastases

• Epidemiology
  • Brain Metastases are Present in 20-30% of Small Cell Lung Cancer Cases at Presentation
• Clinical
  • Symptoms are Typical of Other Mass-Occupying Brain Lesions

Hepatic Metastases

• Clinical
  • Detected by CT Scan
  • Detected by PET Scan
  • Elevated Liver Function Tests (LFT’s)

Paraneoplastic Syndromes

General Comments and Epidemiology

• Definition
  • Paraneoplastic Syndromes are Defined as Remote Effects of a Tumor that are Not Related to Direct Invasion, Obstruction, or Metastases
• Epidemiology
  • Paraneoplastic Syndromes are Most Associated with Small Cell Lung Cancer

Clinical Paraneoplastic Syndromes

• Cushing Syndrome (see Cushing Syndrome)
  • Epidemiology
    • Associated Predominantly with Small Cell Lung Cancer
  • Physiology
    • Ectopic Adrenocorticotropic Hormone Production
• Hematologic Paraneoplastic Syndromes
  • Clinical
    • Anemia (see Anemia)
    • Hypercoagulable State (see Hypercoagulable States)
      • Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
      • Non-Thrombotic Microangiopathy
      • Thrombotic Microangiopathy (see Thrombotic Microangiopathy)
      • Trousseau’s Syndrome (Migratory Superficial Thrombophlebitis) (see Trousseau’s Syndrome)
      • Venous Thromboembolism
    • Leukocytosis (see Leukocytosis)
    • Peripheral Eosinophilia (see Peripheral Eosinophilia): rarely reported in association with large cell lung cancer
    • Thrombocytosis (see Thrombocytosis)
• Hypercalcemia (see Hypercalcemia)
  • Epidemiology: most lung cancer patients with hypercalcemia have advanced stage III/IV malignancy (Lung Cancer, 2004) [MEDLINE]
    • Squamous Cell Histology: accounts for 51% of paraneoplastic hypercalcemia cases in lung cancer
    • Adenocarcinoma Histology: accounts for 22% of paraneoplastic hypercalcemia cases in lung cancer
    • Small Cell Histology: accounts for 15% of paraneoplastic hypercalcemia cases in lung cancer
  • Physiologic Mechanisms
    • Bone Metastases: as noted above
    • Tumor Production of PTH-Related Protein (PTHrP), Calcitriol, or Osteoclast-Activating Factors
• Hypertrophic Osteoarthropathy (see Hypertrophic Osteoarthropathy)
  • Physiology
    • Periosteal Proliferation of Tubular Bones
    • Clubbing and Hypertrophic Osteoarthropathy are Different Clinical Manifestations of the Same Disease Process
  • Clinical
    • Clubbing (see Clubbing)
    • 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: 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
• Polydermatomyositis (see Polydermatomyositis)
  • Clinical
    • Muscle Weakness
• Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
  • Epidemiology
    • SIADH is Associated Predominantly with Small Cell Histology
    • Approximately 10% of Small Cell Lung Cancer Cases Manifest SIADH
    • Small Cell Lung Cancer Accounts for Approximately 75% of All Malignancy-Associated SIADH Cases
  • Clinical
    • Hyponatremia (see Hyponatremia)

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Chemoprevention

• Recommendations (American College of Chest Physicians Evidence-Based Lung Cancer Guidelines, 3rd Edition) (Chest, 2013) [MEDLINE]
  • For Patient with >20 Pack-Year Smoking History or History of Lung Cancer, β-Carotene Supplementation is Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer (Grade 1A Recommendation)
    • β-Carotene Dose Used in Studies: 20-30 mg/day or 50 mg qOD
  • For Patient at Risk for Lung Cancer or History of Lung Cancer, Vitamin E, Retinoids, N-Acetylcysteine, Isotretinoin are Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer (Grade 1A Recommendation)
  • For Patient at Risk for Lung Cancer or History of Lung Cancer, Aspirin is Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer Outside of a Clinical Trial (Grade 1B Recommendation)
  • For Patient with a History of Early-Stage Lung Non-Small Cell Lung Cancer, Selenium is Not Recommended for the Tertiary Chemoprevention of Lung Cancer (Grade 1B Recommendation)
  • For Patient at Risk for Lung Cancer or History of Lung Cancer, Prostacyclin Analogs (Iloprost), Cyclooxygenase-2 Inhibitors (Celecoxib), and Anethole Dithiolethione are Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer Outside of a Clinical Trial (Grade 1B Recommendation)
  • For Patient at Risk for Lung Cancer or History of Lung Cancer, Inhaled Corticosteroids are Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer (Grade 1B Recommendation)
  • For Patient at Risk for Lung Cancer or History of Lung Cancer, Pioglitazone and Myoinositol are Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer Outside of a Clinical Trial (Grade 1B Recommendation)
  • For Patient at Risk for Lung Cancer, Tea Extract and Metformin are Not Recommended for the Primary/Secondary/Tertiary Chemoprevention of Lung Cancer Outside of a Clinical Trial (Grade 2C Recommendation)

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Treatment of Lung Cancer

Smoking Cessation (see Tobacco)

• Rationale
  • Patients Who Continue to Smoke After a Diagnosis of Lung Cancer Double Their Risk of Dying (Oncology, 2010) [MEDLINE]
• Recommendations for Current Smokers (American College of Chest Physicians Lung Cancer Practice Guidelines; Chest, 2013) [MEDLINE]
  • Current Smokers Undergoing Low-Dose Chest CT Screening Should Be Provided with Smoking Cessation Interventions (Including Counseling and Pharmacotherapy) (Grade 1B Recommendation)
  • Current Smokers with Smoking-Related Pulmonary Disease Should Receive Intensive Smoking Cessation Interventions (Grade 1B Recommendation)
• Recommendations for Patients with Lung Cancer (American College of Chest Physicians Lung Cancer Practice Guidelines; Chest, 2013) [MEDLINE]
  • In Lung Cancer Patients Undergoing Surgery, Perioperative Smoking Cessation Pharmacotherapy is Recommended to Improve the Abstinence Rate (Grade 1B Recommendation)
  • In Lung Cancer Patients Undergoing Surgery for Whom Smoking Cessation Pharmacotherapy is Contraindicated or Refused, Cessation Counseling Alone is Recommended During the Perioperative Period (Grade 2C Recommendation)
  • In Lung Cancer Patients Undergoing Surgery, the Timing of Cessation Does Not Appear to Increase the Risk of Postoperative Complications (Grade 2C Recommendation)
    • Cessation Interventions Should Begin in the Preoperative Period
  • In Lung Cancer Patients Attempting Cessation in Conjunction with Surgical Interventions Counseling and Pharmacotherapy are Recommended as the Outset of Surgical Intervention (Grade 1B Recommendation)
  • In Lung Cancer Patients Undergoing Chemotherapy, Smoking Cessation Interventions (Counseling and Pharmacotherapy) Improve Abstinence Rates (Grade 1B Recommendation)
  • In Lung Cancer Patients with Depressive Symptoms, Smoking Cessation with Bupropion is Recommended to Improve Abstinence Rate, Depressive Symptoms, and Quality of Life (Grade 2B Recommendation)
  • In Lung Cancer Patients for Whom Smoking Cessation Pharmacotherapy is Contraindicated or Refused, Cessation Counseling Alone is Recommended as a Method to Improve the Abstinence Rate (Grade 2B Recommendation)
  • In Lung Cancer Patients Undergoing Radiotherapy, Smoking Cessation Interventions (Counseling and Pharmacotherapy) are Recommended (Grade 1C Recommendation)

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Treatment of Non-Small Cell Lung Cancer

General Considerations

Patient Expectations Regarding Chemotherapy

• Cancer Care Outcomes Research and Surveillance (CanCORS) Study About Patient Expectations (NEJM, 2012) [MEDLINE]
  • Metastatic Lung Cancer: 69% of patients did not understand that chemotherapy was not at all likely to cure their cancer
  • Metastatic Colon Cancer: 81% of patients did not understand that chemotherapy was not at all likely to cure their cancer
  • Level of education, functional status, and the patient’s role in decision making were not associated with the inaccurate beliefs about chemotherapy

Stage I Non-Small Cell Lung Cancer

• Surgical Resection
  • Surgical Resection is First-Line Therapy for Stage I Non-Small Cell Lung Cancer
• Radiation Therapy
  • Radiation May Be Used For Patients Who are Not Surgical Candidates
  • Stereotactic Body Radiation Therapy (SBRT): single or very limited number of high-dose fractions to a radiographically discrete treatment volume by using multiple convergent beams -> preferred for tumors <5 cm
    • Preferred Radiotherapy Technique for the Definitive Management of Peripheral Stage I Lesions
  • Conventionally Fractionated Radiation Therapy: for patients who are not surgical candidates and whose tumor is too large for SBRT
  • Radiofrequency Ablation (RFA): unclear role at this time
  • Cryoablation: unclear role at this time
• Post-Operative Adjuvant Chemotherapy
  • Stage IB: adjuvant chemotherapy may have a role
  • Clinical Stage I/II with Mediastinal Lymph Node Involvement in Surgical Specimen (Pathologic Stage IIIA): adjuvant chemotherapy improves survival

Stage II Non-Small Cell Lung Cancer

• Surgical Resection
  • Surgical Resection is First-Line Therapy for Stage II Non-Small Cell Lung Cancer
• Radiation Therapy: for patients who are not surgical candidates
  • Stereotactic Body Radiation Therapy (SBRT): single or very limited number of high-dose fractions to a radiographically discrete treatment volume by using multiple convergent beams
    • Preferred radiotherapy technique for the definitive management of peripheral stage I lesions
  • Conventionally Fractionated Radiation Therapy: for patients who are not surgical candidates and whose tumor is too large for SBRT (>5 cm)
  • Radiofrequency Ablation (RFA): unclear role at this time
  • Cryoablation: unclear role at this time
  • Photodynamic Therapy: may be used as primary treatment in selected patients with superficial airway lesions
• Post-Operative Adjuvant Chemotherapy: improves survival in patients with pathologic stage II disease

Stage III Non-Small Cell Lung Cancer

• Surgical Resection
  • Stage III (N0-1): surgical resection is generally indicated
  • Stage IIIA (T3 N1): surgical resection, followed by adjuvant chemotherapy (for those with completely resected disease)
    • Have better prognosis than stage IIIA disease associated with mediastinal (N2) nodal involvement
    • Adjuvant chemotherapy (platinum-based doublet regimens) prolongs overall survival in patients with completely resected stage III disease
  • Superior Sulcus (Pancoast) Tumor with Hilar Lymph Node Involvement (T3-4 N1 M0) or without Hilar Lymph Node Involvement (T3-4 N0 M0): usually treated with chemoradiotherapy, followed by surgery
  • Stage IIIA (T4 N0-1): since resectable T4 N0-1 lesions are uncommon, most T4 lesions are best treated with definitive chemoradiotherapy
    • Patients with involvement of the carina/superior vena cava/vertebral body may benefit from surgery with a multimodal treatment approach
• Radiation Therapy: definitive radiation therapy is indicated for patients who are not surgical candidates
  • Stereotactic Body Radiation Therapy (SBRT): single or very limited number of high-dose fractions to a radiographically discrete treatment volume by using multiple convergent beams -> preferred for tumors <5 cm
  • Conventionally Fractionated Radiation Therapy: for patients who are not surgical candidates and whose tumor is too large for SBRT (>5 cm)
  • Radiofrequency Ablation (RFA): unclear role at this time
• Post-Operative Radiation Therapy: role is uncertain
  • Indications
    • Patients with Inadequate Lymph Node Sampling in Whom Mediastinal Node Involvement was Suspected But Not Confirmed: the use of post-operative radiation therapy in this case should not be prioritized over adjuvant chemotherapy
    • Patients with Involvement of Multiple Stations of Involved N2 Lymph Nodes
    • Patients with Positive Resection Margins
• Mediastinal (N2-3) Lymph Node Disease: concurrent chemoradiotherapy is recommended
  • For Patients with Potentially Resectable Disease: unclear if surgical resection offers a benefit over chemoradiotherapy alone
  • For Patients with Unresectable Disease: concurrent chemoradiotherapy alone
• Prophylactic Cranial Irradiation: not indicated (although patients with stage III disease are at high risk for brain metastases)

Stage IV Non-Small Cell Lung Cancer

Squamous Cell Lung Cancer

• Preferred Therapy
  • Platinum-Based (Usually Cisplatin) Combination Chemotherapy (see Cisplatin): 4-6 cycles
• Progression During or After Initial Therapy with a Platinum-Based Regimen
  • PD-1 Checkpoint Inhibitors (see Programmed Cell Death Protein 1 Checkpoint Inhibitors)
    • Nivolumab (Opdivo) (see Nivolumab)
      • Clinical Efficacy: durable overall radiologic response rates of 20%-25% in squamous lung cancer
    • Pembrolizumab (Keytruda) (see Pembrolizumab)
  • Alternative Agents
    • Docetaxel (Taxotere) (see Docetaxel)
    • Gemcitabine (Gemzar) (see Gemcitabine)
    • Ramucirumab (Cyramza) + Docetaxel (Taxotere) (see Ramucirumab and Docetaxel)
• Subsequent Maintenance Therapy: after initial 4-6 cycles (and in the absence of disease progression), maintenance therapy has been demonstrated to prolong progression-free survival and overall survival
  • Bevacizumab (Avastin) (see Bevacizumab)
  • Pemetrexed (Alimta) (see Pemetrexed)
• Clinical Efficacy
  • KEYNOTE-024 Trial of Pembrolizumab in Previously-Untreated Advanced PD-L1-Positive Non-Small Cell Lung Cancer Patients without EGFR/ALK Mutations (NEJM, 2016) [MEDLINE]
    • Pembrolizumab in PD-L1-Positive Non-Small Cell Lung Cancer (with PD-L1 Expression on ≥50% Cells) Improved Progression-Free and Overall Survival, with Fewer Adverse Effects than Platinum-Based Chemotherapy

Non-Squamous Cell Lung Cancer

• Preferred Therapy with Driver Mutations Absent
  • Platinum-Cased (Usually Cisplatin) Combination Chemotherapy: see Cisplatin): 4-6 cycles
    • May Supplement with Bevacizumab (Avastin) (see Bevacizumab)
• Preferred Therapy with Driver Mutations Present
  • Anaplastic Lymphoma Kinase (ALK) Mutation
    • Ceritinib (Zykadia) (see Ceritinib): inhibits ALK
    • Crizotinib (Xalkori) (see Crizotinib): small molecule tyrosine kinase inhibitor which inhibits ALK, ROS1, and MET
  • BRAF V600E Mutation
    • Dabrafenib (Tafinlar) (see Dabrafenib): inhibitor of B-Raf enzyme
  • Epidermal Growth Factor Receptor (EGFR) Mutation
    • Afatinib (Gilotrif) (see Afatinib): irreversible covalent inhibitor of receptor tyrosine kinases (EGFR and HER2)
    • Erlotinib (Tarceva) (see Erlotinib): reversible receptor tyrosine kinase inhibitor
    • Gefitinib (Iressa) (see Gefitinib): receptor tyrosine kinase inhibitor
  • MET Exon 14 Skipping Mutation
    • Crizotinib (Xalkori) (see crizotinib): small molecule tyrosine kinase inhibitor which inhibits ALK, ROS1, and MET
    • Cabozantinib (Cometriq) (see Cabozantinib): acts as a MET inhibitor
  • ROS1 Proto-Oncogene Receptor Tyrosine Kinase Mutation
    • Crizotinib (Xalkori) (see crizotinib) [MEDLINE]: small molecule tyrosine kinase inhibitor which inhibits ALK, ROS1, and MET
• Progression During or After Initial Therapy with a Platinum-Based Regimen
  • PD-1 Checkpoint Inhibitors (see Programmed Cell Death Protein 1 Checkpoint Inhibitors)
    • Nivolumab (Opdivo) (see Nivolumab)
    • Pembrolizumab (Keytruda) (see Pembrolizumab)
  • Alternative Agents
    • Docetaxel (Taxotere) (see Docetaxel)
    • Gemcitabine (Gemzar) (see Gemcitabine)
    • Pemetrexed (Alimta) (see Pemetrexed)
    • Ramucirumab (Cyramza) + Docetaxel (Taxotere) (see Ramucirumab and Docetaxel))
• Subsequent Maintenance Therapy: after initial 4-6 cycles (and in the absence of disease progression), maintenance therapy has been demonstrated to prolong progression-free survival and overall survival
  • Bevacizumab (Avastin) (see Bevacizumab))
  • Pemetrexed (Alimta) (see Pemetrexed)
  • Bevacizumab (Avastin) + Pemetrexed (Alimta) (see Bevacizumab and Pemetrexed)
  • Alternative Agents
    • Gemcitabine (Gemzar) (see Gemcitabine)
• Clinical Efficacy
  • KEYNOTE-024 Trial of Pembrolizumab in Previously-Untreated Advanced PD-L1-Positive Non-Small Cell Lung Cancer Patients without EGFR/ALK Mutations (NEJM, 2016) [MEDLINE]
    • Pembrolizumab in PD-L1-Positive Non-Small Cell Lung Cancer (with PD-L1 Expression on ≥50% Cells) Improved Progression-Free and Overall Survival, with Fewer Adverse Effects than Platinum-Based Chemotherapy

Other Special Clinical Circumstances in Stage IV Non-Small Cell Lung Cancer

• Stage IV Disease with an Isolated Metastasis (Brain, Adrenal)
  • May Benefit from Resection of Metastasis and Aggressive Therapy of the Primary Tumor
• Central Airway Involvement
  • May Benefit from Radiation Therapy, Rigid Bronchoscopy/Airway Stenting, or Brachytherapy
• Management of Bone Metastases
  • Zoledronate (Reclast) (see Zoledronate)
    • Zoledronate Significantly Decreases the Incidence of Skeletal Related Events in Patients with Bone Metastases from Non-Small Cell Lung Cancer and Other Solid Tumors
    • However, Zoledronate Does Not Improve Progression-Free Survival or Overall Survival in Stage III NSCLC

Specific Treatment of Lepidic Predominant Adenocarcinoma (Bronchioloalveolar Carcinoma)

General Approach

• Due to Variability in Clinical Behavior (Which Can Range from Subcentimeter Ground-Glass Opacities Which are Growing at a Barely Perceptible Rate Over Years in Both Lungs to Extensive Confluent Lobar Infiltrates Which Cause a Debilitating Productive Cough with Bronchorrhea and Rapid Progression to Respiratory Failure), Assessment of the Pace of Disease is Critical Prior to Treatment (Clin Adv Hematol Oncol, 2014) [MEDLINE]
  • In Indolent Cases, Lepidic-Predominant-Adenocarcinoma Can Manifest Doubling Times Which are Measured in Years (Radiology, 2007) [MEDLINE] (Acad Radiol, 2011) [MEDLINE] (Am J Respir Crit Care Med, 2012) [MEDLINE]
  • Bronchioloalveolar Carcinoma May Have Epidermal Growth Factor Receptor (EGFR) or May Have a a Translocation in the Gene for Anaplastic Lymphoma Kinase (ALK) or May Have No Actionable Gene Target (Clin Adv Hematol Oncol, 2014) [MEDLINE]

Surgical Resection

• In a Small Retrospective Series of Patients with Bronchioloalveolar Carcinoma, Early-Stage Non-Mucinous Bronchioloalveolar Carcinoma Had an Excellent Prognosis, While Mucinous Bronchioloalveolar Carcinoma Generally Had a Poor Prognosis (J Thorac Oncol, 2010) [MEDLINE]: n = 40
  • Early Stages (IA+IB) Non-Mucinous Bronchioloalveolar Carcinoma Had a 5-Year Overall Survival Rate of 91% (5-Year Overall Survival Rate was 100% for Stage IA Cases)
  • However, in Cases with Pneumonic-Like Bronchioloalveolar Carcinoma (All Mucinous), 71% of Cases Died of Recurrent/Progressive Disease
• Clinical Stage 1A Ground Glass Opacity-Predominant Adenocarcinomas Exhibited Low-Grade Malignancy and Had an Extremely Favorable Prognosis with Wedge Resection (for T1a Tumors) or Segmentectomy (for T1b Tumors) (Chest, 2014) [MEDLINE]
• Lepidic Adenocarcinoma Had a Good Prognosis and Could Be Amenable to Sublobar Resection Instead of Standard Lobectomy (J Thorac Dis, 2016) [MEDLINE]

Palliative Surgical Resection

• Some Patients with Pneumonic Bronchioloalveolar Carcinoma (Clinically Appearing Similar to Lobar Pneumonia) May Benefit from Palliative Surgical Resection to Relieve Symptoms of Dyspnea (Due to Bronchorrhea and/or Shunt) (Br J Radiol. 2001) [MEDLINE]

Lung Transplant (see Lung Transplant)

• Lung Transplant Has Been Used in Patients with Small Case Series of Patients with Multifocal Bronchioloalveolar Carcinoma or a Pneumonic Pattern of Diffuse Disease (Clin Adv Hematol Oncol, 2014) [MEDLINE]

Chemotherapy

• xxxxxx

Management of Bronchorrhea in Adenocarcinoma-Lepidic Type Lung Cancer (Bronchioloalveolar Carcinoma) (see Bronchorrhea)

• Nebulized Indomethacin (see Indomethacin): 25 mg in 2 ml NS (pH adjusted to 7.4 qith Na2CO3)
• Corticosteroids (see Corticosteroids): decrease mucous hypersecretion
• Nebulized Furosemide (Lasix) (see Furosemide): 20 mg in 2 ml NS TID
• Macrolides (see Macrolides): decrease bacteria (LPS is known to stimulate goblet cell secretion)

Special Clinical Treatment Issues and Recommendations (American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 3rd Edition) (Chest, 2013) [MEDLINE]

Pancoast Tumor

• Tissue Diagnosis Should Be Obtained Prior to Treatment of Pancoast Tumor (Grade 1C Recommendation)
• In Pancoast Tumor Being Considered for Curative-Intent Surgical Resection, MRI of the Thoracic Inlet and Brachial Plexus is Recommended to Characterize Possible Tumor Invasion of Vascular Structures or the Extradural Space (Grade 1C Recommendation)
• In Pancoast Tumor Being Considered for Curative-Intent Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Recommended (Grade 1C Recommendation)
  • Involvement of Mediastinal Nodes and/or Metastatic Disease is a Contraindication to Resection
• In Potentially-Resectable Pancoast Tumor and Good Performance Status, Preoperative Concurrent Chemoradiotherapy is Recommended (Grade 2B Recommendation)
• In Patient Undergoing Resection of a Pancoast Tumor, Every Effort Be Made to Achieve a Complete Resection (Grade 1B Recommendation)
• In Patient Undergoing Resection of a Pancoast Tumor, Resection Consisting of a Lobectomy (Instead of a Non-Anatomic Wedge Resection), as Well as the Involved Chest Wall Structures is Suggested (Grade 2C Recommendation)
• In Patient with an Unresectable, Non-Metastatic Pancoast Tumor Who Has Good Performance Status, Definitive Concurrent Chemotherapy and Radiotherapy are Suggested (Grade 2C Recommendation)
• In Patient with Pancoast Tumor Who is Not a Candidate for Curative-Intent Treatment, Palliative Radiotherapy is Suggested (Grade 2B Recommendation)

Tumor Invading the Chest Wall

• With NSC Lung Cancer Invading the Chest Wall Being Considered for Curative-Intent Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Suggested (Grade 2C Recommendation)
• With NSC Lung Cancer Invading the Chest Wall, Involvement of Mediastinal Nodes and/or Metastatic Disease Represent a Contraindication to Resection, and Definitive Chemoradiotherapy is Suggested (Grade 2C Recommendation)
• At the Time of Resection of a Tumor Invading the Chest Wall, Every Effort Should Be Made to Achieve a Complete Resection (Grade 1B Recommendation)

Central T4 N0-1 M0 Tumor

• With Clinical T4 N0-1 M0 NSC Lung Cancer Being Considered for Curative Resection, Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) is Recommended (Grade 1C Recommendation)
  • Metastatic Disease Represents a Contraindication to Resection
• With Clinical T4 N0-1 M0 NSC Lung Cancer without Distant Metastases Being Considered for Curative Resection, Invasive Mediastinal Staging Should Be Performed (Grade 2C Recommendation)
  • Mediastinal Nodal Involvement Represents a Contraindication to Primary Resection
  • Preoperative Chemotherapy and Resection has Resulted in Long-Term Survival in Experienced Centers in Patients with Mediastinal Nodal Involvement
• With Clinical T4 N0-1 M0 NSC Lung Cancer Being Considered for Curative Resection, Resection Should Only Be Performed at a Specialized Center (Grade 2C Recommendation)

Second Primary Lung Cancer

• With Two Foci Typical of a Primary Lung Cancer (Solid Spiculated Masses that are Either Proven or Suspected Lung Cancer), Identification of These as Second Primary Lung Cancers (Either Synchronous or Metachronous) Should be Based on the Judgment of a Multidisciplinary Team, Taking into Account Clinical, Radiologic, and Tumor Cytologic/Histologic Features (Grade 2C Recommendation)
• With Two Primary NSC Lung Cancers (Synchronous or Metachronous) Being Considered for Curative Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Recommended (Grade 1B Recommendation)
  • Mediastinal Nodal Involvement is a Contraindication and/or Metastatic Disease is a Contraindication to Resection
• In Patients Not Initially Suspected of Having a Second Focus of Lung Cancer Who is Found Intraoperatively to Have a Second Lung Cancer in a Different Lobe, Resection of Each Lesion is Suggested, Provided the Patient has Adequate Pulmonary Reserve and there is No N2 Nodal Involvement (Grade 2C Recommendation)

Additional Tumor Nodules in the Same Lobe (T3Satell)

• With Suspected or Proven Lung Cancer and an Additional (Suspected) Tumor Nodule within the Same Lobe, No Further Diagnostic Work-Up of the Additional Nodule is Recommended (Grade 1B)
• With an Additional (Suspected) Tumor Nodule within the Same Lobe as a Suspected or Proven Primary Lung Cancer, Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) Should Be Dictated by the Primary Lung Cancer Alone and Not Modified by the Presence of the Additional Lesion (Grade 1C)
• With NSC Lung Cancer and an Additional Focus of Lung Cancer within the Same Lobe (and No Mediastinal or Distant Metastases), Resection Via a Lobectomy is Recommended (Grade 1B)

Ipsilateral Different Lobe Tumor Nodules (T4Ipsi Nod)

• In Suspected or Proven NSC Lung Cancer with Ipsilateral Different Lobe Tumor Nodule(s), Multidisciplinary Team Should Reasonably Exclude the Possibility that this Represents a Benign Lesion or a Synchronous Primary Lung Cancer (Taking into Account Clinical, Radiologic, and Tumor Cytologic/Histologic Features) (Grade 1C Recommendation)
• With Ipsilateral Different Lobe Tumor Nodule(s), Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) is Recommended (Grade 2C Recommendation)
  • Presence of Distant Metastases Indicates that the Pulmonary Nodule Most Likely Represents Metastatic (M1b) Disease
• With Ipsilateral Different Lobe Tumor Nodule(s), Invasive Mediastinal Staging Should Be Performed (Grade 2C Recommendation)
  • Mediastinal Nodal Involvement is a Contraindication to Curative-Intent Treatment
• With Ipsilateral Different Lobe Tumor Nodule(s) (and No Mediastinal or Distant Metastases), Resection of Each Lesion is Suggested, Provided the Patient Has Adequate Pulmonary Reserve (Grade 1B Recommendation)

Contralateral Lobe Tumor Nodules (M1aContr Nod)

• With Contralateral Lobe Tumor Nodule(s), Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Recommended (Grade 2C Recommendation)
  • Involvement of Mediastinal Nodes and/or Metastatic Disease is a Contraindication to Curative-Intent Treatment
• With Contralateral Lobe Tumor Nodule(s) and No Mediastinal or Distant Mets, Resection of Each Lesion is Suggested, Provided the Patient Has Adequate Pulmonary Reserve (Grade 2C Recommendation)

Multifocal Lung Cancer

• With Multiple Lesions Which are at Least Partially Ground Glass and are Suspected to Be Malignant, These Should Be Classified as Multifocal Lung Cancer (MFLC) (Grade 2C Recommendation)
• In Suspected/Proven Multifocal Lung Cancer with a Negative Clinical Evaluation and Normal Mediastinum by CT, Distant and Mediastinal Staging are Not Considered Routinely Necessary (Grade 2C Recommendation)
• In Suspected/Proven Multifocal Lung Cancer, Curative-Intent Treatment Should Be Pursued (Grade 2C Recommendation)
• In Suspected/Proven Multifocal Lung Cancer, Sublobar Resection of All Lesions Suspected of Being Malignant Should Be Performed, if Feasible (Grade 2C Recommendation)

Isolated Brain Metastasis

• In Isolated Brain Metastasis from NSC Lung Cancer Being Considered for Curative-Intent Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Suggested (Grade 2C Recommendation)
  • Involvement of Mediastinal Nodes and/or Metastatic Disease is a Contraindication to Resection
• With No Other Sites of Metastases and a Synchronous Resectable N0-1 Primary NSC Lung Cancer, Resection or Radiosurgical Ablation of an Isolated Brain Metastasis is Recommended (as Well as Resection of the Primary Tumor) (Grade 1C Recommendation)
• With No Other Sites of Metastases and a Previously Completely Resected Primary NSC Lung Cancer (Metachronous Presentation), Resection or Radiosurgical Ablation of an Isolated Brain Metastasis is Recommended (Grade 1C Recommendation)
• Following Curative Resection of an Isolated Brain Metastasis, Adjuvant Whole-Brain Radiotherapy is Suggested (Grade 2B Recommendation)
  • Adjuvant Chemotherapy is Reasonable with a Good Performance Status with the Goal of Decreasing the Incidence of Brain Recurrences, Although No Studies Have Specifically Addressed This
• Following Curative Resection of an Isolated Brain Metastasis, Adjuvant Chemotherapy is Suggested (Grade 2B Recommendation)
  • Adjuvant Chemotherapy is Reasonable with a Good Performance Status, Although No Studies Have Specifically Addressed This

Isolated Adrenal Metastasis

• In Isolated Adrenal Metastasis from NSC Lung Cancer Being Considered for Curative-Intent Surgical Resection, Invasive Mediastinal Staging and Extrathoracic Imaging (Head CT/Brain MRI and Either Whole-Body PET or Abdominal CT with Bone Scan) are Suggested (Grade 2C Recommendation)
  • Involvement of Mediastinal Nodes and/or Distant Metastatic Disease is a Contraindication to Resection
• With a Synchronous Resectable N0-1 Primary NSC Lung Cancer and an Isolated Adrenal Metastasis with No Other Sites of Metastases, Resection of the Primary Tumor and the Adrenal Metastasis is Recommended (Grade 1C Recommendation)
• With No Other Sites of Metastases and a Previously Completely Resected Primary NSC Lung Cancer (Metachronous Presentation), Resection of an Isolated Adrenal Metastasis is Recommended (Grade 1C Recommendation)
• Following Curative Resection of an Isolated Adrenal Metastasis, Adjuvant Chemotherapy is Suggested (Grade 2B Recommendation)
  • Adjuvant Chemotherapy is Reasonable with a Good Performance Status, Although No Studies Have Specifically Addressed This

Surgical Considerations

• Clinical Efficacy
  • Systematic Review of Randomized and Non-Randomized Trials of Video-Assisted Thoracoscopic Surgery (VATS) Lobectomy for Early-Stage Non-Small-Cell Lung Cancer (J Clin Oncol, 2009) [MEDLINE]
    • No Differences in Post-Op Air Leak, Arrhythmias, Pneumonia, Mortality, or Local Recurrence as Compared to Open Lobectomy
    • VATS Had a Lower 5-Year Mortality Rate than Open Lobectomy
  • Comparison of VATS and Open Thoracotomy (Ann Thorac Surg, 2010) [MEDLINE]
    • VATS Had Higher Rate of Intraoperative Complications than Open Lobectomy
    • No Difference in Short-Term Mortality Rate, Length of Stay, and Hospitalization Cost
    • There was a Socioeconomic Disparity (in Terms of Annual Income) Between VATS and Open Thoracotomy Patients

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Treatment of Small Cell Lung Cancer

General Considerations

General Comments

• Small Cell Lung Cancer is Usually Very Responsive to Chemotherapy

Patient Expectations Regarding Chemotherapy

• Cancer Care Outcomes Research and Surveillance (CanCORS) Study About Patient Expectations (NEJM, 2012) [MEDLINE]
  • Metastatic Lung Cancer: 69% of patients did not understand that chemotherapy was not at all likely to cure their cancer
  • Metastatic Colon Cancer: 81% of patients did not understand that chemotherapy was not at all likely to cure their cancer
  • Level of Education, Functional Status, and the Patient’s Role in Decision-Making were not Associated with the Inaccurate Beliefs About Chemotherapy

General Treatment Recommendations

• Recommendations-Stage I Disease (Which is Amenable to Surgical Resection) (Chest, 2013) [MEDLINE]
  • In Patient with Clinical Stage I Small Cell Lung Cancer, Surgical Resection is Recommended Over Non-Surgical Treatment (Grade 2C Recommendation)
  • In Patient with Stage I Small Cell Lung Cancer Who Has Undergone Curative-Intent Surgical Resection, Platinum-Based Adjuvant Chemotherapy is Recommended (Grade 1C Recommendation)
• Recommendations-Role of Radiotherapy (Chest, 2013) [MEDLINE]
  • In Patient with Limited-Stage Small Cell Lung Cancer, Early Chemoradiotherapy with Accelerated Hyper-Fractionated Radiotherapy (Twice Daily) Concurrent with Platinum-Based Chemotherapy is Recommended (Grade 1B Recommendation)
  • In Patient with Either Limited or Extensive-Stage Small Cell Lung Cancer Who Achieve as Partial/Complete Response to Initial Therapy, Prophylactic Cranial Irradiation is Recommended (Grade 1B Recommendation): regimen of 25 Gy in 10 daily fractions has the largest amount of supporting safety and efficacy data
  • In Patient with Extensive-Stage Small Cell Lung Cancer Who Has Completed Chemotherapy and Achieved a Complete Response Outside the Chest and Partial/Complete Response in the Chest, Course of Consolidation Thoracic Radiotherapy is Suggested (Grade 2C Recommendation)
• Recommendations-Role of Chemotherapy (Chest, 2013) [MEDLINE]
  • In Patient with Either Limited or Extensive-Stage Small Cell Lung Cancer, 4-6 Cycles of Platinum-Based Chemotherapy (Cisplatin, Carboplatin) + Either Etoposide or Irinotecan is Recommended Over Other Regimens (Grade 1A Recommendation)
  • In Patient with Relapsed or Refractory Small Cell Lung Cancer, Administration of a Second-Line, Single Agent Chemotherapy is Recommended (Grade 1B Recommendation)
    • Reinitiation of the Previous First-Line Chemotherapy Regimen is Recommended in Patient Who Relapse >6 mo After Completion of Initial Chemotherapy
    • Enrollment in Clinical trial is Recommended
• Recommendations-Elderly Patient (Chest, 2013) [MEDLINE]
  • In Elderly Patient with Limited-Stage Small Cell Lung Cancer and Good Performance Status (ECOG 0-2), Combined Platinum-Based Chemotherapy and Thoracic Radiotherapy is Recommended (Grade 2B Recommendation): patient should be followed closely for toxicity
  • In Elderly Patient with Extensive-Stage Small Cell Lung Cancer and Good Performance Status (ECOG 0-2), Carboplatin-Based Chemotherapy is Recommended (Grade 2A Recommendation)
  • In Elderly Patient with Small Cell Lung Cancer and Poor Performance Status, Treatment with Chemotherapy is Suggested if the Poor Performance Status is Due to the Small Cell Lung Cancer (Grade 2C Recommendation)

Limited-Stage Small Cell Lung Cancer

T1/T2/Clinical Node (cN) Negative

• Mediastinum Pathologic Node (pN) Negative
  • Surgical Resection -> Pathologic Node (pN) Negative: adjuvant chemotherapy (usually cisplatin + etoposide) -> prophylactic cranial irradiation -> surveillance
  • Surgical Resection -> Pathologic Node (pN) Positive: adjuvant chemoradiotherapy (usually carboplatin + etoposide) -> prophylactic cranial irradiation -> surveillance
    • Addition of Radiation Therapy Has Been Demonstrated to Prolong Survival, as Compared to Chemotherapy Alone
• Mediastinum Pathologic Node (pN) Positive: concurrent chemoradiotherapy (usually carboplatin + etoposide)
  • Complete Response/Significant Tumor Regression: prophylactic cranial irradiation -> surveillance
  • Limited Response: surveillance
  • Limited Response/Disease Progression: second line therapy or clinical trial

Clinical T3/T4/N Positive

• Concurrent Chemoradiotherapy
  • Complete Response/Significant Tumor Regression: prophylactic cranial irradiation -> surveillance
  • Limited Response: surveillance
  • Limited Response/Disease Progression: second line therapy or clinical trial

Extensive-Stage Small Cell Lung Cancer

• Combination Chemotherapy (Platinum-Based x 4-6 Cycles): usually carboplatin + etoposide
  • Complete/Partial Response: prophylactic cranial irradiation + thoracic irradiation
  • Progressive Disease: second line chemotherapy or clinical trial
  • Stable Disease: observation
    • If Progression: second line chemotherapy or clinical trial

Recurrent Chemotherapy-Sensitive Small Cell Lung Cancer

• Topotecan (Hycamtin) (see Topotecan, [[Topotecan]])
  • Approved as Single-Agent for Recurrent Small Cell Lung Cancer: 20% response rate
  • Usually Used with Palliative Intent
  • Adverse Effects: myelosuppression

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Prognosis

Overall Survival Rates (American College of Chest Physicians Lung Cancer Guidelines; Chest, 2013) [MEDLINE]

• Overall 5-Year Survival Rate for Lung Cancer (2001-2007): 16.3%
  • Historically, 5-Year Survival Rate from Lung Cancer (1975-1977) was 12.3%
• Survival Rate Varies by Stage at the Time of Diagnosis
  • Local Disease: 52% survival
  • Regional Disease: 24% survival
  • Distant Disease: 4% survival
• Stage at Diagnosis Accounts for the Most Significant Variation in Prognosis
  • Factors Associated with Poorer Survival in Lung Cancer
    • African-American Race
    • Male Sex
    • Older Age

Non-Small Cell Lung Cancer

Prognostic Factors in Non-Small Cell Lung Cancer

• TNM Stage at Time of Diagnosis: best predictor of prognosis
• Performance Status
  • Factors Associated with Worse Survival
    • Anorexia
    • Poor Performance Status
    • Weight Loss
• Ethnicity
  • African-American Ethnicity: African-American race is not believed to be an independent predictor of poorer survival (when multivariate analysis accounted for performance status and weight loss)
  • Asian Ethnicity: Asians with lung cancer have better survival than caucasians (probably due to significantly higher prevalence of EGFR mutations, which is amenable to therapy)
• Histologic Subtype: there are conflicting results as to whether the distinction between adenocarcinoma and squamous cell carcinoma affects prognosis
• Degree of Differentiation: although some studies indicate that poorly differentiated tumors have a worse prognosis, studies regarding the impact of degree of differentiation are conflicting
• Degree of Lymphatic Vessel Invasion: associated with worse survival
• Degree of Microscopic Vascular Invasion: associated with worse survival
• Occult Lymph Node Metastases (Detected by Immunohistochemistry): negative impact on outcome in stage I disease
• Intense Lymphocytic Infiltration: associated with improved survival
• High PET Standardized Uptake Value: associated with worse survival (and possibly predict response to chemotherapy)
• EGFR Receptor Mutations: these patients are usually highly responsive to EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib) and have a far better prognosis than those without EGFR mutations
  • EGFR Receptor Mutations are Associated with Lung Adenocarcinoma (Which More Frequently Affects Never Smokers, Women, and/or of Patients of Asian Ethnicity)
• ROS1/ALK Mutations: these patients are highly responsive to crizotinib
  • ROS1/ALK Mutations are More Frequent in Non-Smokers or Former Smokers and Occur at a Younger Age
• Co-Morbidity: 3-year survival rates in stage I disease are worse with increasing co-morbidity
• Socioeconomic Status: lower socioeconomic status is associated with worse prognosis in lung cancer
  • Race-Related Differences in Lung Cancer Prognosis Tend to Diminish When Adjusted for Socioeconomic Status
• Hospital Case Volume: patients operated on for non-small cell lung cancer at hospitals which perform large numbers of procedures have lower peri-operative mortality rates than those operated on at lower volume institutions
  • Hospital Volume Also Affects 5-Year Survival

Survival Rate in Non-Small Cell Lung Cancer

• Survival with Adenocarcinoma In Situ (AIS) or Minimally Invasive Adenocarcinoma (MIA)
  • 5-Year Survival with Complete Resection: near 100% (J Thorac Oncol, 2011) [MEDLINE]
• 5-Year Survival Based on Clinical Stage (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]
  • Clinical Stage IA1 5-Year Survival: 92%
  • Clinical Stage IA2 5-Year Survival: 83%
  • Clinical Stage IA1 5-Year Survival: 77%
  • Clinical Stage IB 5-Year Survival: 68%
  • Clinical Stage IIA 5-Year Survival: 60%
  • Clinical Stage IIB 5-Year Survival: 53%
  • Clinical Stage IIIA 5-Year Survival: 36%
  • Clinical Stage IIIB 5-Year Survival: 26%
  • Clinical Stage IIIC 5-Year Survival: 13%
  • Clinical Stage IVA 5-Year Survival: 10%
  • Clinical Stage IVB 5-Year Survival: 0%
• 5-Year Survival Based on Pathologic Stage (Note that the Survival Based on Pathologic Stage is Higher Than That Based on the Clinical Stage) (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]
  • Pathologic Stage IA1 5-Year Survival: 90%
  • Pathologic Stage IA2 5-Year Survival: 85%
  • Pathologic Stage IA1 5-Year Survival: 80%
  • Pathologic Stage IB 5-Year Survival: 73%
  • Pathologic Stage IIA 5-Year Survival: 65%
  • Pathologic Stage IIB 5-Year Survival: 56%
  • Pathologic Stage IIIA 5-Year Survival: 41%
  • Pathologic Stage IIIB 5-Year Survival: 24%
  • Pathologic Stage IIIC 5-Year Survival: 12%

Small Cell Lung Cancer

Prognostic Factors in Small Cell Lung Cancer

• Extent of Disease at Presentation: most important prognostic factor

Survival Rate in Small Cell Lung Cancer

• Limited Stage Disease: median survival is 15-20 mo
  • 5-Year Survival: 10-13%
• Extensive Stage Disease: median survival is 8-13 mo
  • 5-Year Survival: 1-2%

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References

General

• Lung cancer. Cancer. 1995 Jan 1;75(1 Suppl):191-202 [MEDLINE]
• The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994 [MEDLINE]
• Is there a common etiology for the rising incidence of and decreasing survival with adenocarcinoma of the lung? Epidemiology. 2001;12(2):256 [MEDLINE]
• Epidemiology of 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):e1S-29S. doi: 10.1378/chest.12-2345 [MEDLINE]
• Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol. 2019 Oct;14(10):1732-1742. doi: 10.1016/j.jtho.2019.05.044 [MEDLINE]

Epidemiology

• Epidemiology of lung cancer. Chest. 2003;123(1 Suppl):21S [MEDLINE]
• Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol. 2006;24(15):2245 [MEDLINE]
• Lung cancer incidence in never smokers. J Clin Oncol. 2007;25(5):472 [MEDLINE]
• Lung cancer in never smokers–a different disease. Nat Rev Cancer. 2007;7(10):778 [MEDLINE]
• Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study. Environ Health. 2007;6:7 [MEDLINE]
• Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008;100(23):1672 [MEDLINE]
• Gender, histology, and time of diagnosis are important factors for prognosis: analysis of 1499 never-smokers with advanced non-small cell lung cancer in Japan. J Thorac Oncol. 2010;5(7):1011 [MEDLINE]
• Characteristics of never smoker lung cancer including environmental and occupational risk factors. Lung Cancer. 2010;67(2):144 [MEDLINE]
• Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke. Clin Lung Cancer. 2012;13(1):75 [MEDLINE]
• Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209 [MEDLINE]
• Genomic Profiling of Lung Adenocarcinoma in Never-Smokers. J Clin Oncol. 2021;39(33):3747 [MEDLINE]

Lung Cancer Screening

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• A risk model for prediction of lung cancer. J Natl Cancer Inst. 2007 May 2;99(9):715-26 [MEDLINE]
• The LLP risk model: an individual risk prediction model for lung cancer. Br J Cancer. 2008 Jan 29;98(2):270-6. Epub 2007 Dec 18 [MEDLINE]
• National Lung Screening Research Trial Team: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409 [MEDLINE]
• The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg 2012;144(1):33-38
• Estimating Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer. Ann Intern Med. 2012;157:776-784 [MEDLINE]
• Doubling Times and CT Screen–Detected Lung Cancers in the Pittsburgh Lung Screening Study. Am J Respir Crit Care Med Vol 185, Iss. 1, pp 85–89, Jan 1, 2012 [MEDLINE]
• A risk model for lung cancer incidence. Cancer Prev Res (Phila). 2012 Jun;5(6):834-46. doi: 10.1158/1940-6207.CAPR-11-0237. Epub 2012 Apr 11 [MEDLINE]
• Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143(5 Suppl):e78S-e92S
• The National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013 May 23;368(21):1980-91. doi: 10.1056/NEJMoa1209120 [MEDLINE]
• Screening for lung cancer. Cochrane Database Syst Rev. 2013 Jun 21;6:CD001991. doi: 10.1002/14651858.CD001991.pub3 [MEDLINE]
• Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013;369:245-254 [MEDLINE]
• Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2013 Feb 19;158(4):246-52. doi: 10.7326/0003-4819-158-4-201302190-00004 [MEDLINE]
• Selection criteria for lung-cancer screening. N Engl J Med. 2013 Feb 21;368(8):728-36. doi: 10.1056/NEJMoa1211776 [MEDLINE]
• Computed tomography screening for lung cancer. JAMA 2013;309:1163-1170 [MEDLINE]
• US Preventive Services Task Force. Screening for lung cancer: U.S. preventive services task force recommendation statement. Ann Intern Med 2014;160:330-338 [MEDLINE]
• An official American Thoracic Society/American College of Chest Physicians policy statement: the Choosing Wisely top five list in adult pulmonary medicine. Chest 2014;145(6):1383-1391
• The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy. 2016 Apr;8(4):479-88. doi: 10.2217/imt-2015-0002 [MEDLINE]
• NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. J Natl Compr Canc Netw. 2016 Mar;14(3):255-64 [MEDLINE]

Physiology/Pathology

• Bronchiolo-alveolar carcinoma. Adv Intern Med. 1960;10:329-358 [MEDLINE]
• Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer. 2001 Feb-Mar;31(2-3):139-48. doi: 10.1016/s0169-5002(00)00181-1 [MEDLINE]
• Rapid disease progression with delay in treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011 Feb;79(2):466-72 [MEDLINE]
• International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International multidisciplinary classification of lung adenocarcinoma: Executive summary. Proc Am Thorac Soc 8:381-385, 2011 [MEDLINE]
• Managing multifocal bronchioloalveolar carcinoma/lepidic predominant adenocarcinoma: changing rules for an evolving clinical entity. Clin Adv Hematol Oncol. 2014 Sep;12(9):593-600 [MEDLINE]
• Adenocarcinoma containing lepidic growth. J Thorac Dis. 2016 Sep;8(9):E1050-E1052. doi: 10.21037/jtd.2016.08.78 [MEDLINE]
• Adenocarcinoma of the lung: from BAC to the future. Insights Imaging. 2020 May 19;11(1):69. doi: 10.1186/s13244-020-00875-6 [MEDLINE]

Diagnosis

• CT in differential diagnosis of diffuse pleural disease. AJR Am J Roentgenol. 1990; 154(3):487-492 [MEDLINE]
• Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose: variations with body weight and a method for correction. Radiology. 1993 Dec;189(3):847-50. doi: 10.1148/radiology.189.3.8234714 [MEDLINE]
• 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]
• Performance characteristics of different modalities for diagnosis of suspected lung cancer: Summary of published evidence. Chest 2003, 123 (Suppl. 1), S115–S128 [MEDLINE]
• Hypercalcemia-leukocytosis syndrome associated with lung cancer. Lung Cancer. 2004 Mar;43(3):301-7 [MEDLINE]
• 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
• Five-year lung cancer screening experience: CT appearance, growth rate, location, and histologic features of 61 lung cancers. Radiology. 2007 Feb;242(2):555-62 [MEDLINE]
• Efficacy of PET/CT in the characterization of solid or partly solid solitary pulmonary nodules. Lung Cancer. 2008;61(2):186-194
• 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]
• Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med. 2009 Aug 18;151(4):221-8, W-48. Epub 2009 Jul 6 [MEDLINE]
• 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]
• Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):7S-37S. doi: 10.1378/chest.12-2377 [MEDLINE]
• 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]
• 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. doi: 10.1378/chest.12-2351 [MEDLINE]
• 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]
• Establishing the diagnosis of 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):e142S-65S. doi: 10.1378/chest.12-2353 [MEDLINE]
• Methods for staging non-small cell 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):e211S-50S. doi: 10.1378/chest.12-2355 [MEDLINE]
• Endobronchial Ultrasound-guided cryobiopsies in peripheral pulmonary lesions: A feasibility study. Eur Respir J. 2014, 43, 233–239 [MEDLINE]
• Pure ground-glass opacity neoplastic lung nodules: Histopathology, imaging, and management. AJR Am J Roentgenol 202:W224-W233, 2014 [MEDLINE]
• Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data. Eur Respir J. 2015;46(6):1751 [MEDLINE]
• 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]
• 18F-fluorodeoxyglucose positron emission tomographic scan in solid-type p-stage-I pulmonary adenocarcinomas: what can produce false-negative results?. Eur J Cardiothorac Surg. 2017 Apr 1;51(4):667-673. doi: 10.1093/ejcts/ezw394 [MEDLINE]
• 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]
• The stage classification of 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):e191S-210S. doi: 10.1378/chest.12-2354 [MEDLINE]
• 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

• 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]
• Superior vena cava syndrome in thoracic malignancies. Respir Care. 2011 May;56(5):653-66 [MEDLINE]
• Bronchoalveolar carcinoma (adenocarcinoma) mimicking recurrent bacterial community-acquired pneumonia (CAP). Heart Lung. Jan-Feb 2012;41(1):83-6. doi: 10.1016/j.hrtlng.2010.07.014 [MEDLINE]

Chemoprevention

• Chemoprevention of 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):e40S-60S. doi: 10.1378/chest.12-2348 [MEDLINE]

Treatment

General

• Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-3322 [MEDLINE]
• Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007 Sep;132(3 Suppl):266S-276S [MEDLINE]
• Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:42-47 [MEDLINE]
• Systematic review and meta-analysis of randomized and nonrandomized trials on safety and efficacy of video-assisted thoracic surgery lobectomy for early-stage non-small-cell lung cancer. J Clin Oncol 2009; 27: 2553–62 [MEDLINE]
• Video-assisted thoracoscopic versus open thoracotomy lobectomy in a cohort of 13,619 patients. Ann Thorac Surg 2010; 89: 1563–70 [MEDLINE]
• A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice. J Thorac Oncol. 2010;5(6):830-836 [MEDLINE]
• Non-small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1727-40. doi: 10.1016/S0140-6736(10)62101-0. Epub 2011 May 10 [MEDLINE]
• The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med. 2013 Oct 1;188(7):770-5. doi: 10.1164/rccm.201305-0843PP [MEDLINE]
• Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):7S-37S. doi: 10.1378/chest.12-2377 [MEDLINE]
• Special treatment issues in non-small cell 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):e369S-99S. doi: 10.1378/chest.12-2362 [MEDLINE]
• The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations. Lung Cancer, 2013. 81(3):371–376 [MEDLINE]
• Update on immune checkpoint inhibitors in lung cancer. Cancer Control 2014;21:80-89 [MEDLINE]
• Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. doi: 10.1056/NEJMoa1406766. Epub 2014 Sep 27 [MEDLINE]
• Appropriate sublobar resection choice for ground glass opacity- dominant clinical stage IA lung adenocarcinoma: wedge resection or segmentectomy. Chest 2014;145:66-71 [MEDLINE]
• Feasibility of segmental resection in non-small-cell lung cancer with ground-glass opacity. Eur J Cardiothorac Surg 2014;46:375-9; discussion 379 [MEDLINE]
• Anatomical thoracoscopic segmentectomy for lung cancer. en Thorac Cardiovasc Surg. 2014 Oct;62(10):586-93 [MEDLINE]
• Managing multifocal bronchioloalveolar carcinoma/lepidic predominant adenocarcinoma: changing rules for an evolving clinical entity. Clin Adv Hematol Oncol. 2014 Sep;12(9):593-600 [MEDLINE]
• 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]
• Personalized therapy for lung cancer. Chest. 2014 Dec;146(6):1649-57. doi: 10.1378/chest.14-0713 [MEDLINE]
• PDQ Adult Treatment Editorial Board. Non-Small Cell Lung Cancer Treatment (PDQ®): Health Professional Version. 2016 Jul 7. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65865/
• KEYNOTE-024 Trial. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016, Oct 8 [MEDLINE]
• Selumetinib for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs. 2017 Aug;26(8):973-984 [MEDLINE]

Prognosis

• Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol. 2019 Oct;14(10):1732-1742. doi: 10.1016/j.jtho.2019.05.044 [MEDLINE]

Psychosocial

• Talking with patients about dying. N Engl J Med 2012;367:1651-1652 [MEDLINE]
• Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012;367:1616-1625.2 [MEDLINE]

Smoking Cessation

• Smoking cessation: an integral part of lung cancer treatment. Oncology. 2010;78(5-6): 289-301 [MEDLINE]
• Treatment of tobacco use in 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):e61S-77S. doi: 10.1378/chest.12-2349 [MEDLINE]

Small Cell Lung Cancer

• Small cell lung cancer: past, present, and future. Curr Oncol Rep. 2010 Sep;12(5):327-34. doi: 10.1007/s11912-010-0120-5 [MEDLINE]
• Advances in the treatment of small-cell lung cancer. Semin Respir Crit Care Med. 2011 Feb;32(1):94-101. doi: 10.1055/s-0031-1272873. Epub 2011 Apr 15 [MEDLINE]
• Systemic therapy for small cell lung cancer. J Natl Compr Canc Netw 2013;11(7):780-787 [MEDLINE]
• Treatment of small cell 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):e400S-19S. doi: 10.1378/chest.12-2363 [MEDLINE]
• Advances in pharmacotherapy of small cell lung cancer. Expert Opin Pharmacother. 2014 Nov;15(16):2385-96. doi: 10.1517/14656566.2014.957180. Epub 2014 Sep 26 [MEDLINE]