Lung Cancer

Aka: Lung Cancer, Lung Carcinoma, Bronchogenic Carcinoma

1. See Also
   1. Non-Small Cell Lung Cancer
   2. Small Cell Lung Cancer
2. Epidemiology
   1. Lung Cancer is the top U.S. cause of cancer death
      1. Lung Cancer accounts for 27% of all U.S. cancer deaths
      2. Lung Cancer accounts for 33% of overall mortality in heavy smokers
      3. Humphrey (2013) Ann Intern Med 159(6): 411-20 [PubMed]
   2. Exceeds deaths from combination of 3 cancers
      1. Colon Cancer
      2. Breast Cancer
      3. Prostate Cancer
   3. Incidence: 200,000 in U.S. (2010)
   4. Mortality: 160,000 in U.S. (2010)
   5. Age at diagnosis: 68 to 70 years old on average
3. Pathophysiology
   1. Hematogenous seeding occurs at 1-2 mm
   2. Earliest detection of Tumor by CT Chest: 2 mm
   3. Tumor 1 cm size shed 3 to 6 million cells daily
4. Risk Factors
   1. Tobacco Abuse (Relative Risk 10-30)
      1. Women: Tobacco directly linked in 90% of cases
      2. Men: Tobacco directly linked in 79% of cases
      3. Passive Smoke Exposure (Relative Risk 1.3)
         1. Highest risk with younger age at time of exposure
   2. Asbestos Exposure
      1. Relative Risk in non-smokers: 3-6
      2. Relative Risk in smokers: 60
   3. Other associated environmental exposures
      1. Radon Gas (Relative Risk: 3)
         1. Major and emerging factor in pathophysiology of Lung Cancer
         2. Causes 21,000 cases of Lung Cancer per year in the United States
      2. Arsenic (drinking water contaminant)
      3. Beryllium
      4. Beta Carotene ingestion
      5. Chromium
      6. Nickel
      7. Vinyl chloride
      8. Soot
      9. Air Pollution
      10. History of Chemotherapy (Relative Risk: 4.2)
      11. Chest ionizing radiation exposure
          1. See Cancer Risk due to Diagnostic Radiology
          2. History of chest Radiotherapy (Relative Risk: 5.9)
   4. Comorbid conditions
      1. Chronic Obstructive Lung Disease (Relative Risk: 2-3.1)
      2. Idiopathic Pulmonary Fibrosis (Relative Risk: 7)
      3. Tuberculosis
      4. Human Immunodeficiency Virus or HIV (Relative Risk: 2-11)
   5. Genetic factors
      1. Family History of Lung Cancer (Relative Risk: 2)
      2. Epidermal Growth Factor Receptor (EGFR) gene mutations (20% of Lung Adenocarcinoma)
         1. Targeted agents for EGFR inhibition (erlotinab) and Monoclonal Antibody (cextuximab) are available
5. Types
   1. Non-Small Cell Lung Cancer or NSCLC (75-80% of Lung Cancers)
      1. Adenocarcinoma (40%)
         1. Peripheral Lung Cancers
      2. Squamous Cell Carcinoma (25%)
         1. Central Lung Cancers most often associated with Tobacco Smoking
      3. Large cell carcinoma (10%)
         1. Peripheral Lung Cancers
   2. Small Cell Lung Cancer or SCLC (15-20% of Lung Cancer)
      1. Central, large cancers with Lymphadenopathy
      2. Associated with paraneoplastic syndromes
   3. Other types (5%)
6. Symptoms
   1. Symptoms present in 90% of Lung Cancer patients at the time of diagnosis
   2. Constitutional symptoms
      1. Fatigue (LR+ 2.3, LR- 0.76)
      2. Anorexia or loss of appetite (LR+ 4.8, LR- 0.84)
      3. Weight loss (LR+ 6.2, LR- 0.76)
   3. Cardiopulmonary symptoms
      1. Persistent cough, especially with multiple evaluations (75%)
      2. Dyspnea (60%, LR+ 3.6, LR- 0.68)
      3. Chest Pain and rib pain (50% of cases, LR+ 3.3, LR- 0.52)
      4. Hemoptysis (35% of cases, LR+ 13.2, LR- 0.81)
      5. Digital Clubbing (LR+ 55, LR- 0.96)
7. Presentations: Intrathoracic spread (40% at diagnosis)
   1. Nerve injury
      1. Recurrent laryngeal nerve paralysis
         1. Hoarseness
         2. Weak cough
      2. Phrenic nerve lesion
         1. Left diaphragm elevated
         2. Dyspnea
      3. Brachial Plexus lesion
         1. Presents as Horner Syndrome (Ptosis, myosis, facial Anhidrosis)
         2. Associated with Pancoast's tumor (Shoulder Pain and Muscle wasting C8-T3)
   2. Chest wall invasion
      1. Pleuritic Chest Pain
   3. Malignant Pleural Effusion
      1. Decreased breath sounds
      2. Dyspnea
   4. Malignant Pericardial Effusion
      1. Decreased heart sounds
      2. Cardiomegaly on Chest XRay
   5. Esophageal invasion or obstruction
      1. Dysphagia
   6. Superior Vena Cava Obstruction
      1. Facial swelling
      2. Upper extremity edema
      3. Plethora
8. Presentations: Extrathoracic spread (33% at diagnosis)
   1. Long bone or Vertebral pathologic Fractures (up to 25% of cases)
      1. Bone Pain
      2. Includes spinal column
      3. Increased Alkaline Phosphatase
   2. Liver metastases (up to 60% of cases)
      1. Weakness
      2. Weight loss
      3. Anorexia
      4. Hepatomegaly
      5. Liver transaminases are paradoxically, rarely increased
   3. Brain metastases (up to 10% of cases)
      1. Headache
      2. Seizures
      3. Nausea or Vomiting
      4. Mental status change
   4. Lymph Nodes
      1. Supraclavicular Lymphadenopathy
   5. Adrenal Glands (rare)
      1. Adrenal Insufficiency
   6. Skin (rare)
      1. Subcutaneous Nodules
9. Presentation: Paraneoplastic Syndromes (10% at diagnosis, especially SCLC)
   1. Digital Clubbing (29% of cases, esp. NSCLC, LR+ 55, LR- 0.96)
   2. Hypercalcemia (10-20% of cases)
      1. Parathyroid Hormone-related peptide production
   3. Hyponatremia (1-5% of cases)
      1. Syndrome of Inappropriate Antidiuretic Hormone or
      2. Atrial natriuretic peptide ectopic production
   4. Other uncommon to rare syndromes
      1. Cushing's Syndrome
         1. Adrenocorticotropic Hormone (ACTH) ectopic production
      2. Hypertrophic pulmonary Osteoarthropathy (triad)
         1. Digital Clubbing
         2. Arthralgias
         3. Ossifying periostitis
      3. Lambert-Eaton myasthenia syndrome
         1. Muscle Weakness
      4. Paraneoplastic Encephalitis
         1. Mental status changes
10. Diagnosis
    1. Precautions
       1. Molecular testing requires a significant amount of tissue
          1. Targeted therapies (advanced disease)
          2. Patients without prior smoking
          3. Squamous Cell Lung Cancer
    2. Findings that most significantly increase Lung Cancer likelihood
       1. Hemoptysis or Digital Clubbing
       2. Two or more symptoms present in combination
       3. Age over 40 years old
       4. Risk factors as above
    3. Bronchoscopy based procedures
       1. Bronchoscopy with Bronchial samples and biopsy
          1. Indicated for central tumors
          2. Test Sensitivity for central lesions: 88%
          3. Test Sensitivity for peripheral lesions: 70%
       2. Transbronchial needle aspiration
          1. Indicated in central lesions
       3. Electromagnetic navigation bronchoscopy
          1. Allows for bronchoscopy of peripheral lesions
       4. Endobronchial Ultrasound-guided transbronchial aspiration
          1. Indicated in paratracheal, subcarinal or perihilar Lymph Nodes
    4. Other non-invasive and less invasive measures
       1. Sputum Cytology
          1. Test Sensitivity for central tumors: 71%
          2. Test Sensitivity for peripheral tumors: 50%
       2. Lymph Node or accessible metastasis biopsy or fine needle aspiration
          1. Indicated in palpable Lymph Node or metastasis
       3. CT-Guided Transthoracic needle aspiration
          1. Indicated in larger peripheral lesions seen on CT
          2. Test Sensitivity for peripheral lesions: 90%
       4. Pleural EffusionThoracentesis
          1. Send for Pleural Fluid cytology
          2. Pleural biposy may be considered when pleural cytology is non-diagnostic
    5. Surgery
       1. Video-assisted thoracic surgery
          1. Indicated in small, single, high-risk Nodules
       2. Thoracotomy
          1. Indicated for non-small cell carcinoma
          2. Lesion amenable to surgery
11. Staging
    1. Non-Small Cell Lung Cancer
       1. See Non-Small Cell Lung Cancer for staging
    2. Small Cell Lung Cancer
       1. Limited: Lesion confined to ipsilateral chest
       2. Extensive: Metastases beyond ipsilateral chest
12. Labs: Evaluation for metastases
    1. Complete Blood Count
    2. Basic metabolic panel
       1. Serum Electrolytes
       2. Serum Calcium
       3. Serum Creatinine
       4. Blood Urea Nitrogen (BUN)
    3. Liver Function Tests
       1. Alkaline Phosphatase
       2. Aspartate Aminotransferase (AST)
       3. Alanine Aminotransferase (ALT)
13. Imaging
    1. See Lung Nodule
    2. Chest XRay
       1. Does not exclude Lung Cancer if normal (False Negative in 20 to 25% of cases)
       2. Obtain chest CT with contrast if high level of suspicion
    3. Chest CT with contrast
       1. Preferred study for Lung Cancer diagnosis
       2. Ideal if imaging includes liver and Adrenal Glands for metastases
    4. Evaluation for metastases
       1. Chest CT and Abdominal CT with contrast
       2. PET Scan (enhances staging by Chest CT)
       3. MRI Brain
          1. Indicated in all cases except Stage IA NSCLC
14. Diagnostics: Functional Capacity
    1. Background
       1. Evaluation for lung resection
       2. Predictor of Chemotherapy tolerance
    2. Pulmonary Function Tests
       1. Initial Testing (FEV1, DLCO)
       2. Second-line testing (indicated for DLCO or FEV1 <80%)
          1. Cardiopulmonary Exercise testing
          2. Arterial Blood Gas sampling
    3. Eastern Cooperative Oncology Group Performance Status
       1. Grade 0
          1. Fully active and at predisease functional status without restriction
       2. Grade 1
          1. Ambulatory and able to perform light activity or sedentary work
          2. Restricted in physically strenuous activity
       3. Grade 2
          1. Ambulatory and able to perform self care
          2. Ambulatory >50% of working hours
          3. Unable to perform work activity of any kind
       4. Grade 3
          1. Able to perform self-care
          2. Confined to bed or chair >50% of waking hours
       5. Grade 4
          1. Completely disabled
          2. Unable to perform self-care
          3. Confined to bed or chair
15. Management
    1. See Non-Small Cell Lung Cancer
    2. See Small Cell Lung Cancer
16. Prevention
    1. Lung Cancer Prevention
       1. Consider Radon Gas testing in the home
       2. Tobacco Cessation
          1. Tobacco exposure is the predominant cause of Lung Cancer
          2. Never smoking is the best way to prevent Lung Cancer
          3. Quitting smoking reduces Lung Cancer 39% after 5 years (and all secondary cancers 3.5 fold)
          4. Tindle (2018) J Natl Cancer Inst 110(11): 1201-7 [PubMed]
    2. Lung Cancer Screening (2021 USPSTF screening guidelines)
       1. Indicated in age 50 to 80 years old with 20 py Tobacco use (ongoing or quit in last 15 years)
       2. Screen with annual low dose CT chest
       3. Indications to stop screening
          1. Patients who have quit smoking for >15 years
          2. Limited Life Expectancy <10 years
          3. Patient unwilling to undergo curative lung surgery
       4. Advantages
          1. Number Needed to Screen in 5 years to prevent one death: 312
          2. All cause mortality Relative Risk Reduction: 6.7%
       5. Disadvantages
          1. Cummulative radiation and cost ($12 billion/year) with annual screening will be substantial
          2. High False Positive Rate with screening (96%) will require significant resources to evaluate
       6. References
          1. Aberle (2011) N Engl J Med 365(5): 395-409 [PubMed]
          2. de Koning (2020) N Engl J Med 382(6): 503-13 [PubMed]
          3. Jonas (2021) JAMA 325(10): 971-87 [PubMed]
          4. Gates (2014) Am Fam Physician 90(9): 625-31 [PubMed]
          5. Kovalchik (2013) N Engl J Med 369(3): 245-54 [PubMed]
          6. Krist (2021) JAMA 325(10): 962-70 [PubMed]
    3. USPTF Lung Cancer screening guidelines
       1. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/lung-cancer-screening
17. Prognosis
    1. Five year survival >50% for localized Non-Small Cell Lung Cancer
    2. Five year survival survival <5% for distant metastases
    3. See staging and prognosis calculator link below
18. Resources
    1. Harvard Lung Cancer risk calculator
       1. http://www.diseaseriskindex.harvard.edu/update/
    2. Staging and Prognosis Calculator
       1. http://staginglungcancer.org/calculator
    3. NCI Adult Cancer Treatment
       1. http://www.cancer.gov/cancertopics/pdq/adulttreatment
19. References
    1. Beckles (2003) Chest 123(1 suppl): 97S-104S [PubMed]
    2. Kim (2022) Am Fam Physician 105(5): 487-94 [PubMed]
    3. Hamilton (2005) Thorax 60(12): 1059-65 [PubMed]
    4. Latimer (2015) Am Fam Physician 91(4): 250-6 [PubMed]