L15 Lung Cancer (etiology and pathophysiology)

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L15 Lung Cancer (etiology and pathophysiology)
2013-02-23 18:13:32
Pulmonary II

Lung cancer part 1
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  1. Cancer
    Cancer is always growing

    Cancer produces symptoms by occupying space, squashing normal structures, and producing substances

    • Cancer typically kills via a complications associated with the above process
    • • Carcinoma (Gk. Karkinos or "crab“+"growth")
    • – Most common type of cancer in man
    • – Epithelial cell origin
  2. Lung cancer
    • -Leading cause of cancer deaths in the US (~160K annually)
    • -Incidence to mortality ratio is extremely high relative to other cancers
    • -5 year survival: all stages combined is 15-17%

    • Cigarette smoke accounts for 80-85%
    • >>Asbestos, Radiation (Radon), Genetics, other industrial/combustion, diet
  3. Cigarette smoking
    ~20% of all American adults smoke

    • -Tobacco use is increasing in developing countries
    • -25% to 30% of all cancer deaths are from cigarette smoking
    • -Risk of lung cancer correlates with absolute exposure level
    • -10-15 cigarettes/day x 10 years = significant

    -Risk for lung cancer decreased progressively after cessation of smoking, but not to normal

    -Second hand smoke imparts a relatively small risk of lung cancer
  4. Smoking and lung cancer

    • Tobacco smoking changes bronchial epithelium
    • -loss of bronchial cilia, cellular hyperplasia, nuclear abnormalities

  5. Occupational risk factors for lung cancer
    • Asbestos - fibrous silicate formerly used widely as fire resistant insulation
    • -Shipbuilders, naval veterans, construction workers
    • -Carcinoma of the lung is the most likely malignancy associated with asbestos exposure (very rare mesothelioma is strongly associated with prior/remote asbestos exposure)
    • -cancer typically occurs >2 decades after exposure

    • Arsenic - pesticides, glass, pigments, and paints
    • Ionizing radiation - uranium miners
    • Halo ethers
    • Polycyclic aromatic hydrocarbon in petroleum, coal tar, foundry workers
  6. Genetic Factors in lung cancer
    Lung cancer only develops in some heavy smokers

    -increased risk in those with first-degree relatives

    • Candidate genetic factors:
    • -cytochrome P-450
    • -DNA repair mechanisms
    • ...possibly hormonal variation (slight female predominance among never-smokers)

    Theory: loss of heterozygosity of tumor suppressor gene (2nd hit model)

    • Oncogenes and Tumor Suppressors
    • -genes code for proteins controlling or regulating cell growth
    • -specific proto-oncogenes to lung cancer: ras, EGFR, EML4-ALK, BRAF, HER2, Bcl-2 families of dominant oncogenes
    • -Specific tumor suppressor genes include: retinoblastoma (rb) and p53 gene, deletion of genetic material from chromosome 3p
  7. Parenchymal scarring
    Scar carcinoma: lung cancer arising in an area of prior scar tissue

    -occurs in both focal (TB) or diffuse (pulmonary fibrosis) scars

    -most common form arising in this setting is adenocarcinoma

    • Subtype: adenocarcinoma in situ (AIS)
    • -tumor grows slowly, along alveolar wall
  8. Lung cancer in never-smokers
    -More targeted therapy: nearly 50% have treatable (or near-future) w/targeted therapies...vs. 10% of smokers

    -Frequency increasing (?) (at least the ratio of never:ever-smokers is increasing)

    -higher risk in Women, particularly Asian females

    -Adenocarcinoma:Squamous cell caricnoma is 3.4:1 (vs. ever-smokers adeno/squamous is ~1:1)

    • Risk factors:
    • 1. Occupational (asbestos, PAHs, silica, radon, heavy metals, diesel)
    • 2. Environmental Tobacco smoke (ETS) - especially women
  9. Lung cancer
    "old" paradigm: well-differentiated normal cells undergo 'dedifferentiation' and unrestricted growth when exposed to carcinogenic stimulus

    • "new" paradigm: Lung cancer arises from undifferentiated stem cells.
    • -malignant transformation causes cell to differentiate into heterogeneic histology seen in lung cancer
  10. Lung cancer pathology

    Tissue is the issue!

    -Classification is made by combining cellular morphology with IHC staining patterns

    Genetic analysis (EGFR-mutations) is important for therapy: Targeted therapies that apply to a number of adenocarcinomas almost never seen in squamous cell carcinomas
  11. Non-Small cell vs. Small cell
    • Small cell:
    • -highly metastatic
    • -aggressive, fast growing
    • -Surgery is not beneficial (sub clinical metastasis)

    • Non-small cells:
    • -depends on the specific type
    • - not as likely to metastasize
  12. Lung cancer classification
    by smoking
    • All types are associated with cigarette smoking
    • -Squamous and small cell uniformly in current or former smokers

    -Adenocarcinoma and large cell carcinoma may be seen in nonsmokers

    *Adenocarcinomas - common to find mutation (in EGFR tyrosine kinase inhibitor mutation) in Asian female non-smokers
  13. Squamous cell carcinoma
    • -25-30% of all lung cancers
    • -originate within epithelial layer of bronchial wall

    • Pathophys: chronic smoke exposure causes injury (98% occur in former or current smokers)
    • -Bronchial columnar epithelial cells undergo metaplasia; replaced by squamous epithelial
    • -Cells develop atypia - eventually carcinoma in situ and spread/invasion

    • Presentation:
    • -Tumors tend to be central (bronchial in origin) and cavitary (tendency for necrosis - outgrow their blood supply)

    • -hemoptysis
    • -central airway obstruction, pneumonia
    • -Significant central/intrathoracic spread prior to metastasis

    Prognosis: better overall than other cell-types

    • Histology:
    • -visible presence of keratin, "squamous pearls"
    • -intracellular desmosomes or bridges
    • -stain for cytokeratin
  14. Small cell carcinoma
    Small cell carcinoma ~15% of all lung cancers

    • Presentation:
    • -Originates in the proximal airways within the bronchial wall
    • -Nearly all occur in current or former smokers
    • -Commonly produce polypeptid hormones (paraneoplastic syndrome)
    • -Distant metatstasis early - brain, liver, bone (and marrow), adrenal glands
    • -Worst 5-year survival (of the 4 cell types)

    • Cell of origin is debated:
    • 1. Neurosecretory type of epithelial cells (K cell)
    • 2. Stem cell
    • -90% of small cell carcinomas have deletions on the short arm of chromosome 3 (3p)

    • Histology:
    • -Chromogranin A
    • -Neuron-Specific Enolase
    • -Synaptophysin

    • Radiographic findings:
    • -Proximal airways
    • -Tumor grows fast - submucosal invasion of lymphatics and blood vessels
    • -Hilar and mediastinal nodes involved early (often the dominant abnormality)
  15. Adenocarcinoma
    of the lung
    ~40% of all lung cancers

    • Presentation:
    • -Arise in periphery of lung, at bronchioles of the alveolar level
    • -Can arise at site of a prior parenchymal scar
    • -Most common lung cancer in Non-smokers (18% of lung adenocarcinomas occur in nonsmokers)
    • -5 year survival > small cell but still worse than squamous cell

    • Pathology:
    • -glandular structures that produce mucus
    • -IHC: stain for mucin 7 thyroid transcription factor-1 (TTF-1)

    • Spectrum of presentations:
    • -peripheral lung nodule or mass (>3cm)
    • -solitary pulmonary nodule (incidentally found on imaging)
    • -Advanced: bulky mediastinal spread with distinct metastasis. Liver, bone, CNS, adrenal glands (just like small cell)
    • -Months-years for adenocarcinoma
    • -(months for small cell)
    • -may spread locally and invade pleura or bronchus

    *Pleura involvement is equivalent to metastatic
  16. Adenocarcinoma
    new classification
    -Preinvasive types: Adenocarcinoma in situ (AIS: Mucinous, nonmucinous).

    • -Minimally invasive adenocarcinoma ("lepidic predominant")
    • -Invasive adenocarcinoma (lepidic, acinar, papillary, micropapillary, solid predominant subtypes)
  17. Large cell carcinoma
    15-20% of all lung cancers

    • -Tumors defined by the characteristic they lack
    • -Negative stains for cytokeratin and TTF-1
    • -Morphologically not Small cells
    • -Behave like adenocarcinomas

    • Distinguish from "large cell neuroendocrine carcinoma" (LCNEC)
    • -Neuroendocrine granule features (like Small Cell)
    • -May behave and be treated like small cell
    • -May be considered large-cell variant of small cell carcinoma