Lung Cancer-Part 1

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
The Burden of Lung Cancer in Women Compared With Men in the US. JAMA Oncol. 2023 Oct 12:e234415. doi: 10.1001/jamaoncol.2023.4415 [MEDLINE]
- Research Letter: “We found that the higher lung cancer incidence in women than in men has not only continued in individuals younger than 50 years but also now extends to middle-aged adults as younger women with a high risk of the disease enter older age,” the authors write.”
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
United States Incidence and Relationship to Tobacco Exposure
- XXXXX
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- Rates of Lung Cancer Occurrence Lag Cigarette Smoking Rates by About 20 Years
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- All Histologies of Lung Cancer (Adenocarcinoma, Squamous Cell Carcinoma, Large Cell Carcinoma, and Small Cell Carcinoma) are Caused by Smoking
  - In the Last 50 Years, the Prevalence of Adenocarcinoma Histology (Which Tend to Be More Peripheral in Location) Has Increased, Coincident with a Decrease in Squamous Cell Histology (Which Tend to Be More Central in Location): this is probably related to the changing composition of cigarettes, allowing greater depth of inhalation
  - Changes in Cigarette Composition: increased use of filtered cigarettes (which allow air to be entrained during inhalation), lower levels of tar and nicotine, increased use of reconstituted tobacco, ammoniated cigarettes (US cigarettes are more ammoniated), etc
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- Menthol
  - Menthol is Commonly used as a flavoring agent and analgesic (with anti-irritant properties)
  - Menthol Cigarette Use is Higher in African-American Smokers
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- Lung Cancer Risk Decreases After Smoking Cessation
  - However, the increased risk from prior smoking appears to persist even out to 40 years later
Types of Tobacco Exposure
- Cigars
  - Risk of lung cancer is less than that of cigarette smoking (due to decreased frequency and depth of inhalation)
- Cigarettes
- Pipe Smoking
  - Risk of lung cancer is less than that of cigarette smoking (due to decreased frequency and depth of inhalation)

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
- General Data
  - Overall, Up to 25% of Lung Cancers Occur in Never Smokers (Particularly in Females Who Develop Lung Adenocarcinoma) (J Thorac Dis, 2017) [MEDLINE]
- 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]
- Physiology
  - Kirsten Rat Sarcoma (KRAS) Viral Oncogene Driver Mutations are Observed in Up to 86% of Invasive Mucinous Lung Adenocarcinoma Cases (Transl Lung Cancer Res, 2017) [MEDLINE]
  - Conversely, Epidermal Growth Factor Receptor (EGFR) Mutations are Very Rare in Invasive Mucinous Lung Adenocarcinoma Cases (Semin Ultrasound CT MR, 2019) [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]
  - May Demonstrate the Same Heterogeneous Mixture of Lepidic, Acinar, Papillary, Micropapillary, and Solid Growth as in Non-Mucinous Tumors (J Thorac Oncol, 2011) [MEDLINE] (Transl Lung Cancer Res, 2017) [MEDLINE]
  - Lepidic Growth Pattern with Microscopic Skip Lesions is a Characteristic of Invasive Mucinous Lung Adenocarcinoma (Semin Ultrasound CT MR, 2019) [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
- Diagnosis
  - Invasive Mucinous Lung Adenocarcinoma May Appear as a Solid Nodule, a Subsolid Nodule, or an Airspace Opacity (Mimicking Pneumonia) (Transl Lung Cancer Res, 2017) [MEDLINE] (Semin Ultrasound CT MR, 2019) [MEDLINE]
  - Biopsy May Be Nondiagnostic, as the Alveolar Spaces at the Tumor Periphery Can Be Entirely Filled with Mucin and Therefore, No Cells (Transl Lung Cancer Res, 2017) [MEDLINE]
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

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]
Lung adenocarcinoma: From molecular basis to genome-guided therapy and immunotherapy. J Thorac Dis 9:2142-2158, 2017 [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]

Physiology/Histology

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]
Biology of invasive mucinous adenocarcinoma of the lung. Transl Lung Cancer Res, 2017. 6:508-512 [MEDLINE]
Spectrum of Lung Adenocarcinoma. Semin Ultrasound CT MR. 2019 Jun;40(3):255-264. doi: 10.1053/j.sult.2018.11.009 [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]