Clonal Theory and Tumor Progression
According to their origin, neoplasms are classified into monoclonal and polyclonal:
- Monoclonal tumors constitute the overwhelming majority. They are characterized by primary unicentric growth from a single cell precursor. However, in a mature tumor mass, monoclonality is frequently the result of clonal selection, where the most viable and aggressive clone gradually outgrows the others.
- Polyclonal tumors are significantly less common and manifest as multicentric growth. Classic examples include familial adenomatous polyposis of the colon, as well as multicentric variants of hepatic and breast cancer.
Willis's theory of the tumor field explains how several closely situated foci of transformation merge during growth into a single visually unified mass containing different clones. This is a key mechanism for the formation of recurrences following surgical removal.
During clonal evolution, malignant tumors continuously accumulate secondary mutations, increasing heterogeneity (polyclonality). In contrast, benign neoplasms maintain the dominance of a single clone throughout their existence.
Local and Systemic Effects on the Body
The impact of a neoplasm on the host comprises local alterations and systemic disorders.
Local Manifestations:
- Metabolic shifts in the microenvironment.
- Mechanical compression and direct destruction of adjacent tissues.
- Invasion into vascular walls leading to local venous congestion.
- Necrosis and ulceration of tumor tissue, resulting in hemorrhage and secondary infection.
Systemic Consequences:
- Development of anemic syndrome and cancer intoxication.
- Cancer cachexia — profound wasting of the body accompanied by brown atrophy of skeletal muscles, liver, and myocardium. Its pathogenesis includes a metabolic component (increased protein turnover, turning the tumor into a nutrient "trap") and a cytokine component (active production of TNF-α, known as cachectin, by macrophages).
Paraneoplastic Syndromes
Paraneoplasia refers to a complex of symptoms caused by a tumor remotely, rather than by its local growth or metastases.
Main variants of paraneoplastic reactions:
- Endocrinopathies: occur in hormonally active neoplasms. For instance, adenomas of the anterior pituitary or neuroendocrine lung carcinomas may provoke Cushing syndrome, while parathyroid adenomas and lung cancer can cause hypercalcemia with osteoporosis.
- Hemostatic disorders (thrombopathies): activation of coagulation processes by tumor factors leads to migrating thrombophlebitis, non-bacterial thrombotic endocarditis, and afibrinogenemia.
- Immunopathological processes: mediated by antibodies, cytotoxic reactions, or circulating immune complexes, manifesting as neuropathies, dermatopathies, and myopathies.
Anti-Tumor Immunity and Causes of Its Failure
Host defense is based on DNA repair, the balance of cellular oncogenes and tumor suppressor genes, and immune system responses.
Key effector cells play the following roles:
- Cytotoxic T lymphocytes (CTLs): recognize tumor antigens presented by MHC I molecules.
- Natural Killer (NK) cells: lyse neoplastic cells without prior sensitization — either directly or by binding to the Fc fragment of specific antibodies.
- Macrophages: exert direct damaging effects through the secretion of TNF-α, or participate in specific responses upon contact with antibody Fc fragments and under the influence of γ-IFN secreted by T lymphocytes.
The humoral response is realized through complement system activation with formation of the membrane attack complex or recruitment of NK cells and macrophages to the antibody Fc fragment.
Causes of Defense Ineffectiveness: immunosuppression developing in cancer patients, the phenomenon of "antigenic escape" (simplification and lability of tumor antigens), and paradoxical stimulation of neoplastic growth by anti-tumor antibodies.