Etiology and Background Processes
The vast majority of cases are associated with exogenous carcinogens. Genetic factors as an independent cause play a role only in isolated situations. Geographic factors also significantly impact incidence.
A particular role in the morphogenesis of peripheral cancer is played by pneumosclerosis of any etiology. The link between tumors and scars was first described by C. Friedrich (1939) using tuberculous pneumosclerosis as an example. Scar tissue acts as a pre-blastomatous (background) process.
Mechanisms of carcinogenesis in scars:
- Deposition: accumulation of exogenous and endogenous carcinogens.
- Genetic shifts: activation of proto-oncogenes (ras, fos, bcl-2) and loss of anti-oncogenes (p53).
- Microenvironmental changes: local hypoxia, immunosuppression, and uncoupling of intercellular contacts.
- Matrix remodeling: accumulation of type III collagen (typical of embryonic tissue and the regeneration phase) and decreased mature type I collagen in the scar zone. This disrupts the balance between epithelial proliferation and differentiation.
General Pathogenesis and Morphogenesis
Carcinogenesis in the lungs results from impaired cell division, maturation, and programmed cell death (apoptosis). The key event is always DNA damage in an epithelial cell (chromosomal aberrations and mutations).
Sequence of tissue changes: Hyperplasia foci $\rightarrow$ Metaplasia $\rightarrow$ Dysplasia (intraepithelial neoplasia) $\rightarrow$ Carcinoma.
Pathogenesis varies depending on localization:
- Central cancer (large bronchi): Carcinogens enter with inhaled air. They disrupt the mucociliary barrier and damage basal layer cells. This leads to squamous metaplasia, dysplasia, and subsequent malignant transformation.
- Peripheral cancer (small bronchi, alveoli): Toxins arrive not only aerogenically, but also via the bloodstream or lymphatics. However, concentrations brought exclusively by hematogenous or lymphatic routes are usually insufficient to induce a tumor—a combination of factors is required.
Role of Cellular Oncogenes
Four families of oncogenes (myc, ras, bcl, erb-B) are critical in lung cancer development. They determine the tumor profile, which is essential for diagnosis and targeted therapy selection.
- myc family (c-myc, L-myc, N-myc): These are immediate-early response genes encoding proteins that induce proliferation and suppress differentiation. c-myc amplification occurs in various cancers (10–25%), while L-myc and N-myc expression is characteristic only of neuroendocrine tumors. In small cell lung cancer, the activity of these genes significantly correlates with tumor size and metastasis.
- ras family: Responsible for growth signal transduction (p21 protein synthesis). K-ras mutations are inherent only to non-small cell lung cancer (up to 30% in adenocarcinoma). They are detected as early as the precancerous stage (atypical hyperplasia) and in surrounding tissue, forming a "field of carcinogenesis."
- bcl-2 family: Apoptosis regulators. Cell fate depends on balance. Pro-proliferative factors (bcl-2, bclXL) block apoptosis, whereas pro-apoptotic factors (bax, bclXS) trigger it. Equilibrium shifts determine tumor growth direction.
Tumor Suppressor Genes
Normally, tumor suppressor genes (such as p53 and Rb) block the proliferation of cells with damaged genomes and trigger apoptosis. A mutated suppressor gene is recessive, so tumor development requires damage to both alleles (e.g., mutation of one allele and deletion of the other). These changes occur at the earliest stages.
The p53 gene is the most frequently altered gene in tumor growth:
- Wild-type (normal): Functions as a transcription factor. Regulates the G1 to S-phase cell cycle transition, handles DNA repair, and initiates apoptosis. Interacts with p21, Mdm2, and bax proteins.
- Mutant type: Alters conformation, accumulates in nuclei (detected by immunohistochemistry), and acts as an oncogene, stimulating division. Induces specific antibody formation in the blood.
Accumulation of mutant p53 in precancerous lesions reliably predicts tumor development. However, about 50% of lung cancers develop without p53 mutations, indicating alternative molecular pathways of carcinogenesis.