L15 Lung Cancer (etiology and pathophysiology)

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

• -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

~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

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

• 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

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

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

-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

"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

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

• 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

• 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

• -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

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)

~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

-Preinvasive types: Adenocarcinoma in situ (AIS: Mucinous, nonmucinous).

• -Minimally invasive adenocarcinoma ("lepidic predominant")
• -Invasive adenocarcinoma (lepidic, acinar, papillary, micropapillary, solid predominant subtypes)

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